Dermatology: Practical and Conceptual Review | Dermatol Pract Concept 2018;8(3):9 191 DERMATOLOGY PRACTICAL & CONCEPTUAL www.derm101.com Obligate and facultative paraneoplastic dermatoses: an overview Stefano Caccavale1, Gabriella Brancaccio1, Marina Agozzino1, Paola Vitiello1, Roberto Alfano2, Giuseppe Argenziano1 1 Dermatology Unit, University of Campania Luigi Vanvitelli, Naples, Italy 2 Department of Anesthesiology, Surgery and Emergency, University of Campania Luigi Vanvitelli, Naples, Italy Key words: dermatological paraneoplastic syndromes, obligate paraneoplastic dermatoses, facultative paraneoplastic dermatoses, malignancy, oncological dermatology Citation: Caccavale S, Brancaccio G, Agozzino M, Vitiello P, Alfano R, Argenziano G. Obligate and facultative paraneoplastic dermatoses: an overview. Dermatol Pract Concept. 2018;8(3):191-197. DOI: https://doi.org/10.5826/dpc.0803a09 Received: January 15, 2018; Accepted: March 9, 2018; Published: July 31, 2018 Copyright: ©2018 Caccavale et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: None. Competing interests: The authors have no conflicts of interest to disclose. All authors have contributed significantly to this publication. Corresponding author: Stefano Caccavale, MD, Dermatology Unit, University of Campania Luigi Vanvitelli, Via Sergio Pansini, 5, 80131 Naples, Italy. Email: stefano85med@gmail.com Introduction The skin is the most accessible organ of the body and can be easily examined using noninvasive techniques, provid- ing the doctor with clues that can be suggestive of systemic disturbances, thus contributing to the diagnosis of many dis- eases, including malignancies [1,2]. The skin may be directly or indirectly involved in malignancies. Direct involvement is due to the presence of tumor cells in the skin caused by direct tumor extension or metastasis. Indirect involvement of the skin can be determined by a variety of polypeptides, hormones, cytokines, antibodies, or growth factors related to the neoplasia. These inflammatory, proliferative, or metabolic factors act as mediators, interfering with cell communication and, consequently, with its activity. In this case, there is no presence of neoplastic cells in the skin, and this involvement is considered a dermatological paraneoplastic syndrome [1]. Thus, paraneoplastic syndromes are a group of diseases associated with a malignancy, but not directly related to the primary tumor itself or to its metastases. It is not always easy to determine the correlation between a dermatologic finding and an internal neoplasm. The follow- ing criteria, defined by McLean in 1986 [3], should be veri- fied to assess the causal relationship between the dermatosis and the potential underlying malignancy: (1) development of a dermatosis only after the development of a malignant Dermatological paraneoplastic syndromes are a group of cutaneous diseases associated with malig- nancy, but not directly related to the primary tumor itself or to its metastases. It is of utmost impor- tance for the dermatologist to recognize the major cutaneous paraneoplastic syndromes to diagnose the underlying tumors that trigger them as early as possible. In this overview, skin conditions that are highly correlated with malignancy, whose recognition implies a mandatory investigation of internal cancer, are described. ABSTRACT 192 Review | Dermatol Pract Concept 2018;8(3):9 showing a genetic pattern (genodermatoses)—are described [1]. Acanthosis Nigricans Maligna Acanthosis nigricans (AN) can be classified as benign or malignant [1]. Benign AN is relatively common; it may be familial or occur in association with drug use, obesity, and/or endocrinopathy, thus being regarded as a sign of hyperinsulin- ism and insulin resistance. It is characterized by the presence of hyperpigmented, velvety plaques most often seen on the sides and nape of the neck (“dirty neck” appearance) and other flexural (antecubital, popliteal fossae) or intertriginous areas (inguinal, axillae, inframammary folds). Acrochordons frequently arise on the plaques of AN [11]. By contrast, acanthosis nigricans maligna (ANM) can be distinguished by its severity and its rapid and extensive spread. Sudden-onset AN is often associated with malig- nancy, especially in adult (average age 40 years) nonobese patients [1]. ANM may be more widespread or generalized and involve atypical areas (interdigital, knuckles, soles, pal- mar, eyelids, perioral) and even mucosal surfaces, including neoplasm and (2) both the dermatosis and the malignant neoplasm follow a parallel clinical course, so the cutaneous symptoms disappear when the tumor is treated and reappear in cases of recurrence or metastasis [3]. Paraneoplastic syndromes occur in about 7% to 15% of patients with cancer and may be the presenting sign of an unknown neoplasm, precede the diagnosis of malignancy, occur late in the course of illness, or be the first sign of recur- rence. Their recognition may result in earlier diagnosis and better prognosis for the patient, prolonging life expectancy [4-8]. A few rare paraneoplastic dermatoses are consistently associated with malignancies in almost 100% of the cases (obligate paraneoplastic dermatoses) [1-29]; others are more common skin disorders, associated with tumors in only 3% to 30% of the cases, so the coexistence of these dermatoses and neoplasms may be coincidental and the causal link is more controversial (facultative paraneoplastic dermatoses) [9,10,30] (Table 1). In this overview, dermatoses that highly correlate with malignancy and that, when recognized, require mandatory investigation of internal cancer—excluding those disorders TABLE 1. Association of Main Facultative Paraneoplastic Dermatoses with Systemic Neoplasms Main Facultative Paraneoplastic Dermatoses Main Associated Neoplasms [1,4,30] Leser-Trélat sign Gastrointestinal (GI), lymphoma, breast, lung Dermatomyositis Bronchogenic adenocarcinoma, ovary, genital, breast, cervix carcinoma, GI Palmoplantar keratoderma Esophageal carcinoma Pyoderma gangrenosum Myelodysplastic syndrome, myeloma, leukemia, lymphoma Sweet syndrome Acute myelogenous leukemia, myelodysplastic syndrome, myeloproliferative disorders, lymphoproliferative disorders Trousseau’s syndrome Pancreas, lung, stomach Vasculitis Leukemia, lymphoma, lung, multiple myeloma Pruritus Hodgkin and non-Hodgkin lymphoma Extramammary Paget’s disease GI, genitourinary (GU) Digital clubbing Lung, mesothelioma Raynaud’s phenomenon Testicle, GU, GI Multicentric reticulohistiocytosis Hematologic malignancies, breast, stomach Amyloidosis Multiple myeloma, Hodgkin lymphoma, kidney Flushing Carcinoid, medullary carcinoma of thyroid, leukemia, kidney Linear IgA dermatosis Lymphoproliferative malignancies, esophagus, renal cell, thyroid, bladder Mucous membrane pemphigoid Chronic lymphocytic leukemia, non-Hodgkin lymphoma, acute myeloid leukemia, pancreas, lung, ovary, cervix, liver, GI, thymoma Bullous pemphigoid Breast, prostate, lung, thyroid, larynx, GI, cervix, uterus, bladder, lymphoreticular system, kidney, melanoma, and squamous cell carcinomas Review | Dermatol Pract Concept 2018;8(3):9 193 other areas may be affected such as the elbows, knees, legs, arms, cheeks, and scalp, with centripetal distribution of the lesions. Nails may also be involved with subungual hyper- keratosis, onycholysis, and dystrophy. Bullous lesions, mainly in the hands and feet, have been described [1]. Biopsies are nonspecific. Histologically, some psoriasi- form features are present including hyperkeratosis, parakera- tosis, and a superficial lymphohistiocytic infiltrate, but other non-psoriasiform changes also exist (vacuolar degeneration with melanin-containing macrophages in the dermis and dyskeratotic keratinocytes) [11]. Almost all the cases cited in the literature were associated with malignancy. This syndrome typically precedes the diag- nosis of malignancy by approximately 2 to 6 months in 65% to 70% of patients. About 80% of cases are associated with tumors of the upper aerodigestive tract (oral cavity, larynx, pharynx, trachea, esophagus, and lung), commonly squamous cell carcinomas (SCC) or metastasis to cervical lymph nodes. In a retrospective study, 49% of cancers involved the orophar- ynx and larynx, followed by the lung (17%) and esophagus (10.6%) [1]. Additional isolated cases associated with breast cancer, cholangiocarcinoma, colon adenocarcinoma, and Hodgkin lymphoma have been reported [1]. Case reports also describe SCCs of the thymus, vulva, and skin [13,14]. Its underlying mechanism is not well understood. Immu- nological factors with antibodies directed against the tumor in a cross-reaction with the epidermis or basement membrane have been considered. Possibly, a tumor production of a kera- tinocyte growth factor such as TGF-α may be involved [1]. Paraneoplastic acrokeratosis generally responds to successful treatment of the underlying tumor, and fails to improve when the neoplasm persists. Topical corticosteroids and systemic retinoids may be helpful. The physician should inquire regarding risk factors for malignancy (smoking habits, alcohol consumption, weight loss, family history) and perform a complete physical exami- nation, including head and neck and endoscopic and pelvic examination in women [13,14]. the palate. Palmar and plantar keratoderma with prominent fingerprint markings known as pachydermatoglyphy or tripe palms may be seen [10,11] (Figure 1). Skin biopsy is rarely necessary. Common histopathologic findings are hyperkera- tosis, papillomatosis, acanthosis alongside epidermal atrophy, and absence of an inflammatory infiltrate. Nearly all malignancies associated with ANM are adeno- carcinomas (most commonly gastrointestinal adenocarcino- mas). Many others have been reported, including adrenal, bile duct, bladder, breast, cervical, endometrium, liver, larynx, lung, lymphoid hematological malignancies, ovary, pituitary, prostate, kidney, testicle, thyroid, and sarcomas [11]. ANM can precede or occur simultaneously or after the diagnosis of cancer [1]. In a review study, this dermatological finding was observed in 58% of patients before tumor diagnosis [1,12]. The pathogenesis for the development of ANM is debated (insulin-like growth factors or transforming growth factor alpha (TGF-α) may be responsible for the epidermal prolif- eration) [10]. Depending on the clinical scenario, an extensive search for visceral malignancy may be warranted (fecal occult blood testing, endoscopy, imaging, etc.). In the case of ANM, as for all paraneoplastic dermatoses, skin lesions may regress after systemic chemotherapy or radical surgery. Acrokeratosis Paraneoplastica (Bazex Syndrome) Patients affected by acrokeratosis paraneoplastica are typi- cally men older than 40 years [11]. Cutaneous lesions are psoriasiform and manifest as asymptomatic, symmetrical erythematous-violaceous scaly patches. However, their dis- tribution is not typical of psoriasis: in initial stages, the der- matosis involves the bridge of the nose, auricular helices, and distal ends of the extremities. As the disease progresses, des- quamation may affect the dorsal and palmoplantar regions, producing a violaceous keratoderma. In advanced stages, Figure 1. Acanthosis nigricans maligna: clinical and dermatoscopical pictures. [Copyright: ©2018 Caccavale et al.] 194 Review | Dermatol Pract Concept 2018;8(3):9 In patients with EGR who did not have an underlying internal cancer, nonneoplastic conditions including tubercu- losis, pregnancy, calcinosis, esophageal dysmotility, sclero- dactyly, Sjögren’s syndrome, and CREST syndrome may be rarely associated [1,17,18]. Histopathology is nonspecific, showing mild hyperkeratosis, parakeratosis, acanthosis, and spongiosis with a perivascular mononuclear inflammatory infiltrate in the dermis [1]. Its pathophysiology remains unknown. Immune mechanisms are probably involved since immunosuppression accompanies the resolution of EGR [1]. In paraneoplastic cases, therapy is aimed at treating the underlying malignancy. Systemic corticosteroids have been tried with only partial success. Necrolytic Migratory Erythema or Glucagonoma Syndrome Necrolytic migratory erythema (NME) is more common in women more than 45 years of age, with an average age of onset of 52 years [1]. NME presents as a pruritic and sometimes painful mucocutaneous eruption with a pinkish, maculopapular erythema with irregular edges and annular or arciform lesions that tend to coalesce and adopt a polycyclic pattern. Lesions are prominent in areas of pressure or trauma, commonly in intertriginous areas, groin, perineum, buttocks, distal extremities, and the central face. Sometimes there is formation of flaccid blisters that rupture easily, forming ero- sions and crusts, while new vesicles continue to develop along the edges. Residual hyperpigmentation at sites previously affected is common [1,19]. The disease has a waxing and waning course. The eruption may resemble such dermatoses as pemphigus foliaceus, acrodermatitis enteropathica, chronic mucocutaneous candidiasis, psoriasis, and severe seborrheic dermatitis [11]. Erythema Gyratum Repens Erythema gyratum repens (gyrate from the Greek, meaning “a circle”; repens from the Latin, meaning “to creep”) (EGR) is a rare paraneoplastic dermatosis, usually occurring in patients older than 40 years, with a mean age of about 60 years; the male-to-female ratio is 2:1 [1,11,15]. The primary lesion is a pruriginous, macular erythema. Numerous serpiginous bands are arranged in a parallel con- figuration of red swirls over most of the body, producing con- centric figures that resemble a wood surface (“wood-grained” appearance) (Figure 2). The edges of the lesions migrate at a rapid rate, about 1 cm/day. A slight scale can be found along the trailing edge of erythema. The hands, feet, and face are often spared [1,15]. Peripheral eosinophilia is frequent. The presentation of EGR is so typical that a differential diagnosis is difficult to generate. Another gyrate erythema, erythema annulare centrifugum (EAC), demonstrates poly- cyclic erythematous rings with a trailing edge of scale. Similarly, this eruption can be pruritic. Unlike EGR, EAC migrates slowly and is usually localized to smaller areas on the trunk and extremities [11,16] (Figure 2). Other figurate erythemas are erythema chronicum migrans and erythema marginatum. Patients with EGR should be mandatorily evaluated for the presence of malignancy because the disease is virtually always associated with an internal cancer [1]. Malignant neoplasms are found in 82% of patients with EGR. Lung cancer is the most common (32%), followed by cancer of the esophagus (8%) and breast (6%). Other malignan- cies have been associated, such as colon, stomach, bladder, prostate, uterine, rectal, and pancreatic cancer and multiple myeloma. The diagnosis of EGR precedes the diagnosis of the neoplasia in approximately 80% of patients, on average from 4 to 9 months [13]. Figure 2. Erythema gyratum repens (left) and erythema annulare centrifugum (right). [Copyright: ©2018 Caccavale et al.] Review | Dermatol Pract Concept 2018;8(3):9 195 interferon, minoxidil, phenytoin, spironolactone, and cetux- imab) [1,20]. An extensive clinical history and physical examination are necessary, in conjunction with blood tests, laboratory screening, and imaging (chest radiography, CT, colonoscopy, and, in women, mammography) [1]. Pathogen- esis of AHL is unclear. Prolongation of the anagen phase of vellus hairs by a tumor-induced serum growth factor has been hypothesized [1,10]. Ichthyosis Acquisita Ichthyosis acquisita is a cutaneous keratinization disorder, characterized by small white or brownish rhomboidal scales that rise above the skin surface, particularly localized sym- metrically on the extensor surfaces of the extremities and on the trunk and scalp. The dry scales may be also thickened and widespread [13]. Flexures, palms, and soles are spared [21]. Ichthyosis may be due to systemic diseases (eg, leprosy, hypothyroidism, lymphoma, and AIDS) or to drug intake (eg, nicotinic acid, triparanol, and butyrophenones) [13]. New onset of ichthyosis in adult life is often related to an underlying malignancy [13,21]. Ichthyosis acquisita is mostly seen in association with Hodgkin lymphoma, non-Hodgkin lymphoma (including mycosis fungoides), other lymphop- roliferative diseases (eg, reticulolymphosarcoma, multiple myeloma), and nonlymphoproliferative diseases (Kaposi sar- coma, leiomyosarcoma, breast, ovarian, lung, liver, and cervi- cal carcinomas) [21,22]. Acquired ichthyosis usually appears several weeks or months after detection of the cancer [2]. It has been suggested that TGF-α secreted from the tumor cells, may be implicated in the pathogenesis [22]. Treatment of ichthyosis includes removal of exacerbating factors and of related systemic diseases, as well as applying moisturizers and keratolytics [13]. Pityriasis Rotunda P a t i e n t s o f t e n m a n i f e s t p i t y r i a s i s r o t u n d a ( P R ) between 20 and 45 years of age (range of 2 to 89) [23], except among the Sardinian cohort, in which patients pre- sented during childhood [24]. Incidence is equal among men and women. The disease lasts from several months to more than 20 years, with reports of exacerbation during winter months [25]. PR is a rare disease characterized by round or oval, well-defined, scaly, hypo- or hyperpigmented patches or thin plaques typically found on the trunk, back, buttocks, or arms, but that can occur in every area of the body. Lesions number ranges in number from 1 to over 100, and the diam- eter from 1-10 cm. The hands, feet, and face are usually spared. Lesions are asymptomatic but may be associated with minimal pruritus [13]. NME is typically associated with glucagonoma syndrome. Glucagonoma is a rare endocrine, usually slow-growing, tumor of pancreatic alpha cells. Glucagon-secreting tumors of the pancreas are responsible of the triad hyperglucago- nemia, whose levels are greater than 1000 pg/mL, diabetes or glucose intolerance and NME [1,19]. Other common manifestations are glossitis, angular cheilitis, weight loss, diarrhea, steatorrhea, abdominal pain, normocytic anemia, hypoaminoacidemia, thromboembolic disease, and psychi- atric disturbances [1,19]. NME can be associated also with non-glucagon-secreting tumors (small-cell lung cancer, liver cancer, insulin-secreting tumors, and duodenal neoplasms), and in malabsorption syndromes, liver failure, inflammatory bowel disease, and celiac disease, leading to pseudogluca- gonoma syndrome [1]. A CT scan may be useful in the diagnosis. About 95% of glucagonomas are positive in somatostatin receptor scintig- raphy. Somatostatin positivity may be useful in the treatment of the symptoms and signs of glucagonoma (octreotide, a somatostatin analogue, inhibits glucagon production) [1]. Celiac arteriography is considered most sensitive to locate the tumor because of its vascularity [10]. Histological findings of NME are nonspecific (edema and epidermal acanthosis with basal cell hyperplasia, spongiosis, parakeratosis with vacuolated epidermal cells associated with necrosis of the upper epidermis, cleft-like detachment from the deeper epidermis and loss of the granular cell layer, mild to moderate perivascular inflammatory infiltrate) [1,10]. The pathogenesis is poorly understood. Various metabolic abnor- malities and nutritional deficiencies have been implicated, including hypoaminoacidemia, zinc, and essential fatty acid deficiencies [10]. Acquired Hypertrichosis Lanuginosa Acquired hypertrichosis lanuginosa (AHL) is a rare paraneo- plastic condition characterized by the sudden appearance of long, thin, soft, unpigmented, lanugo-like hair initially on the face and ears and then on the trunk, axillae, and extremities, with sparing of the palms, soles, and genital area [2]. It is more common in women than in men. Other symptoms are painful glossitis, angular cheilitis, and papillary hypertrophy of the tongue [2, 20]. In men, AHL is most commonly associated with lung can- cer, followed by colorectal cancer. In women, the most com- mon neoplasms are, in order of frequency, colorectal cancer, lung cancer, and breast cancer. However, AHL has also been described in association with other cancers (ovary, uterus, bladder, pancreas, kidney, lymphomas, and leukemia) [2,20]. AHL must be differentiated from hypertrichosis associ- ated with endocrine or metabolic alterations and use of medication (cyclosporine, penicillamine, glucocorticoids, 196 Review | Dermatol Pract Concept 2018;8(3):9 ing [1]. The diagnostic criteria for PNP can be distinguished into major criteria and minor criteria (Table 2) [29]: 3 major criteria or 2 major and 2 minor are needed [1,11]. Contrary to pemphigus vulgaris, in which direct immunofluorescence shows only intercellular deposition in epithelial cells, both basement membrane and epidermis are affected in PNP [1]. Two-thirds of patients have a recognized neoplasia at the onset of PNP. Approximately, 80% of associated malignancies are of hematological origin (non-Hodgkin B-cell lymphoma, chronic lymphocytic leukemia, Hodgkin lymphoma, T-cell lymphoma, Castleman disease, thymoma, Waldenström’s macroglobulinemia). In children and adolescents, associa- tion with Castleman disease is the most frequent [1]. Other neoplasms associated with PNP include Kaposi’s sarcoma and carcinomas of the breast, skin, mucous membranes, lung, uterus, ovary, stomach, liver, and gastrointestinal tract [13]. PNP is characterized by production of autoantibodies directed against proteins of the plakin and cadherin families involved in cell architecture maintenance and tissue cohesion. Autoantibodies immunoprecipitate keratinocyte antigens at 250 kD (desmoplakin I), 230 kD [bullous pemphigoid antigen I (BPAG1)], 210 kD (desmoplakin II and envoplakin), and 190 kD (periplakin) in all samples and at 170 kD in some samples. The production of autoantibodies that bind epider- mal proteins is responsible of skin and mucosal displacement [13,27,28]. Conclusions Skin, being the most visible and external organ of the body, may be considered as a mirror for many systemic diseases [7]. It is of utmost importance for the dermatologist to recognize the major cutaneous paraneoplastic syndromes to diagnose the underlying tumors that trigger them as early as possible. References 1. Silva JA, Mesquita KC, Igreja AC, et al. Paraneoplastic cutane- ous manifestations: concepts and updates. An Bras Dermatol. 2013;88(1):9-22. doi: 10.1590/S0365-05962013000100001. One-third of patients have an underlying disease, includ- ing tuberculosis, leprosy, and liver, kidney, heart, and lung diseases. Associated neoplasms include hepatocellular, gastric and esophageal carcinoma, prostate cancer, chronic lympho- cytic leukemia, and multiple myeloma [1]. PR has been classified into  2  distinct subtypes. Type 1 occurs predominantly in elderly patients of Asian and African descent and is frequently associated with systemic illness, infections, or malignancy. Lesions are often hyper- pigmented and generally fewer than 40. Type 1 PR often improves with treatment of underlying systemic illness [26]. Type 2 occurs in younger patients of Northern European descent. It has a strong hereditary predisposition and it is believed to belong to the spectrum of congenital ichthyoses. Lesions are typically hypopigmented and more numerous. Type 2 PR is often self-limiting and improves through adult- hood [26]. PR can be treated with retinoids, salicylates, or lactate emollients. Paraneoplastic Pemphigus Paraneoplastic pemphigus (PNP) is a severe acantholytic mucocutaneous syndrome characterized by painful mucosal erosions, ulcerations, and polymorphous skin lesions that progress to blistering eruptions on the trunk and extremities [27,28]. Oral involvement with persistent, painful stomatitis is seen in almost all cases and can often be the first symptom. Oral lesions may be severe, and affect the entire mouth, with diffuse areas of shallow ulceration, and lips, with hemor- rhagic crusting, and also the hypopharynx and esophagus; they may also involve other mucosa (conjunctival and ano- rectal) with ulcers and erosions. Contrary to pemphigus vulgaris, acral and paronychial involvement is common in PNP. Cutaneous manifestations can be classified in several groups: (1) pemphigus-like, (2) bullous pemphigoid-like, (3) erythema multiforme-like, (4) graft-versus-host disease, and (5) lichen planus-like [27,28]. The prognosis of PNP is severe. Some patients have respi- ratory complications, such as bronchiolitis obliterans, respon- sible for dyspnea and respiratory failure. The high mortality rate of PNP (75%-80%) is also secondary to sepsis and bleed- TABLE 2. Diagnostic Criteria for Paraneoplastic Pemphigus (proposed by Camisa and Helm) [29] Major Criteria Minor Criteria Polymorphous skin eruption Histological evidence of intraepithelial acantholysis Concurrent internal neoplasia Positive direct immunofluorescence (DIF) with deposits both intercellularly and at the basement membrane zone with IgG and C3 deposition Antibodies with an immunoprecipitation specific pattern Positive indirect immunofluorescence (IIF) on rat bladder epithelium Review | Dermatol Pract Concept 2018;8(3):9 197 18. Rongioletti F, Fausti V, Parodi A. Erythema gyratum repens is not an obligate paraneoplastic disease: a systematic review of the literature and personal experience. J Eur Acad Dermatol Venereol. 2014;28(1):112-115. doi: 10.1111/j.1468-3083.2012.04663.x 19. John AM, Schwartz RA. Glucagonoma syndrome: a review and update on treatment. J Eur Acad Dermatol Venereol. 2016;30(12):2016-2022. doi: 10.1111/jdv.13752 20. Slee PH, van der Waal RI, Schagen van Leeuwen JH, et  al. Paraneoplastic hypertrichosis lanuginosa acquisita: uncommon or overlooked? Br J Dermatol. 2007;157(6):1087-1092. doi: 10.1111/j.1365-2133.2007.08253.x 21. Patel N, Spencer LA, English JC III, Zirwas MJ. Acquired ichthyo- sis. J Am Acad Dermatol. 2006;55(4):647-656. doi: 10.1016/j. jaad.2006.04.047 22. Kleyn CE, Lai-Cheong JE, Bell HK. Cutaneous manifestations of internal malignancy: diagnosis and management. Am J Clin Dermatol. 2006;7(2):71-84. doi: 10.2165/00128071-200607020- 00001 23. Friedmann AC, Ameen M, Swale VJ. Familial pityriasis ro- tunda in black-skinned patients; a first report. Br J Derma- tol. 2007;156(6):1365-1367. doi: 10.1111/j.1365-2133.2007. 07874.x 24. Aste N, Pau M, Aste N, Biggio P. Pityriasis rotunda: a sur- vey of  42  cases observed in Sardinia, Italy. Dermatology. 1997;194(1):32-35. doi: 10.1159/000246053 25. Batra P, Cheung W, Meehan SA, Pomeranz M. Pityriasis rotunda. Dermatol Online J. 2009;15(8):14. 26. Grimalt R, Gelmetti C, Brusasco A, Tadini G, Caputo R. Pity- riasis rotunda: report of a familial occurrence and review of the literature. J Am Acad Dermatol. 1994;31(5 Pt 2):866-871. doi: 10.1016/S0190-9622(94)70248-9 27. Kartan S, Shi VY, Clark AK, Chan LS. Paraneoplastic pemphigus and autoimmune blistering diseases associated with neoplasm: characteristics, diagnosis, associated neoplasms, proposed patho- genesis, treatment. Am J Clin Dermatol. 2017;18(1):105-126. doi: 10.1007/s40257-016-0235-z 28. Wieczorek M, Czernik A. Paraneoplastic pemphigus: a short review. Clin Cosmet Investig Dermatol. 2016;9:291-295. doi: 10.2147/CCID.S100802 29. Camisa C, Helm TN. Paraneoplastic pemphigus is a dis- tinct neoplasia-induced autoimmune disease. Arch Der- matol. 1993;129(7):883-886. doi: 10.1001/archderm.1993. 01680280071014 30. Caccavale S. The association of bullous pemphigoid and ma- lignancy: a case control study. G Ital Dermatol Venereol. 2015;150(6):764-765. 2. Yuste Chaves M, Unamuno Pérez P. Cutaneous manifesta- tions of systemic malignancies: part 2. Actas Dermosifiliogr. 2013;104(7):543-553. doi: 10.1016/j.adengl.2012.05.026. 3. McLean DI. Cutaneous paraneoplastic syndromes. Arch Der- matol. 1986;122(7):765-767. doi: 10.1001/archderm.1986. 01660190043013. 4. Brenner S, Tamir E, Maharshak N, Shapira J. Cutaneous manifes- tations of internal malignancies. Clin Dermatol. 2001;19(3):290- 297. doi: 10.1016/S0738-081X(01)00174-2. 5. Moore RL, Devere TS. Epidermal manifestations of internal ma- lignancy. Dermatol Clin. 2008;26(1):17-29, vii. doi: 10.1016/j. det.2007.08.008. 6. Pipkin CA, Lio PA. Cutaneous manifestations of internal malig- nancies: an overview. Dermatol Clin. 2008;26(1):1-15, vii. doi: 10.1016/j.det.2007.08.002. 7. Vora RV, Kota RS, Diwan NG, Jivani NB, Gandhi SS. Skin: A mirror of internal malignancy. Indian J Med Paediatr Oncol. 2016;37(4):214-222. doi: 10.4103/0971-5851.195730. 8. Miyashiro D, Sanches JA. Paraneoplastic skin disorders: a review. G Ital Dermatol Venereol. 2016;151(1):55-76. 9. Károlyi Z. [Paraneoplastic dermatoses]. Orv Hetil. 2002;143(31): 1827-1833. 10. Thomas I, Schwartz RA. Cutaneous paraneoplastic syndromes: uncommon presentations. Clin Dermatol. 2005;23(6):593-600. doi: 10.1016/j.clindermatol.2005.01.006. 11. Stone SP, Buescher LS. Life-threatening paraneoplastic cutaneous syndromes. Clin Dermatol. 2005;23(3):301-306. doi: 10.1016/j. clindermatol.2004.06.011. 12. Ehst BD, Minzer-Conzetti K, Swerdlin A, Devere TS. Cutane- ous manifestations of internal malignancy. Curr Probl Surg. 2010;47(5):384-445. doi: 10.1067/j.cpsurg.2010.01.003. 13. Abreu Velez AM, Howard MS. Diagnosis and treatment of cuta- neous paraneoplastic disorders. Dermatol Ther. 2010;23(6):662- 675. doi: 10.1111/j.1529-8019.2010.01371.x. 14. Räßler F, Goetze S, Elsner P. Acrokeratosis paraneoplastica (Ba- zex syndrome) - a systematic review on risk factors, diagnosis, prognosis and management. J Eur Acad Dermatol Venereol. 2017;31(7):1119-1136. doi: 10.1111/jdv.14199. 15. Boyd AS, Neldner KH, Menter A. Erythema gyratum repens: a para- neoplastic eruption. J Am Acad Dermatol. 1992;26(5 Pt 1):757- 762. doi: 10.1016/0190-9622(92)70107-Q. 16. Tyring SK. Reactive erythemas: erythema annulare centrifugum and erythema gyratum repens. Clin Dermatol. 1993;11(1):135- 139. doi: 10.1016/0738-081X(93)90110-X. 17. Lo Schiavo A, Caccavale S, Orlando I, Tirri R. Erythema gyra- tum repens and rheumatoid arthritis: an unrecognized associa- tion? Indian J Dermatol Venereol Leprol. 2012;78(1):122. doi: 10.4103/0378-6323.90974.