Dermatology: Practical and Conceptual Observation | Dermatol Pract Concept 2016;6(1):4 9 DERMATOLOGY PRACTICAL & CONCEPTUAL www.derm101.com Introduction The neutrophilic dermatoses are a group of disorders char- acterized by skin lesions for which histological examination reveals intense epidermal and/or dermal inflammatory infil- trates composed primarily of neutrophils without evidence of infection [1]. Cutaneous findings of neutrophilic dermatoses vary; lesions can present as nodules, plaques, ulcerations, or vesiculopustules and can be localized or widespread. In some cases, extracutaneous involvement may occur [2,3]. While the exact pathogenesis of neutrophilic dermatoses is unknown, these disorders may represent a state of immunologic reac- tivity [4]. In patients who have an underlying malignancy, neutrophilic dermatoses may occur as an anti-neoplastic therapy-related disorder, a paraneoplastic syndrome, or, less commonly, as an idiopathic condition [5]. The group of disor- ders that comprise neutrophilic dermatoses includes Behçet’s disease, bowel (intestinal) bypass syndrome, erythema eleva- Histiocytoid Sweet’s syndrome in a patient with myelodsyplastic syndrome: report and review of the literature Michael M. Shalaby1, Ryan R. Riahi2, Les B. Rosen3, Erik J. Soine2,4 1 Medical School, Louisiana State University Health Sciences Center, New Orleans, LA, USA 2 Department of Dermatology, Louisiana State University, New Orleans, LA, USA 3 Dermpath Diagnostics, Pompano Beach, FL, USA 4 Soine Dermatology & Aesthetics, New Orleans, LA, USA Key words: histiocytoid Sweet’s, myelodysplasia, myelodysplastic, sweet, sweet’s, syndrome Citation: Shalaby MM, Riahi RR, Rosen LB, Soine EJ. Histiocytoid Sweet’s syndrome in a patient with myelodysplastic syndrome: report and review of the literature. Dermatol Pract Concept 2016;6(1):4. doi: 10.5826/dpc.0601a04 Received: September 10, 2015; Accepted: October 6, 2015; Published: January 31, 2016 Copyright: ©2016 Shalaby 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: Michael Shalaby BA, Department of Dermatology, Louisiana State University, New Orleans, LA, USA. Tel. 504- 417-0249 . Email: mshal3@lsuhsc.edu The neutrophilic dermatoses are a group of disorders characterized by skin lesions for which his- tological examination reveals intense epidermal and/or dermal inflammatory infiltrates composed primarily of neutrophils without evidence of infection. The myelodysplastic syndromes consist of a heterogeneous group of malignant hematopoietic stem cell disorders characterized by dysplastic and inadequate blood cell production with a variable risk of transformation to acute leukemia. Rarely, his- tiocytoid Sweet’s syndrome occurring in patients with myelodysplastic syndrome has been described. We present a case of a 66-year-old woman with a history of myelodysplastic syndrome who developed histiocytoid Sweet’s syndrome. We also review the literature and characterize patients with myelodys- plastic syndrome who have developed histiocytoid Sweet’s syndrome. ABSTRACT 10 Observation | Dermatol Pract Concept 2016;6(1):4 tender. The patient reported she had not started any new medications. Complete blood count at time of diagnosis demonstrated: white blood cell count 1.5, hemoglobin 8.2, hematocrit 24.1, and platelets 26. tum diutinum, neutrophilic dermatosis of the dorsal hand, neutrophilic eccrine hidradenitis [6], pyoderma gangrenosum, and Sweet’s syndrome (SS) [1]. The myelodysplastic syndromes (MDS) consist of a het- erogeneous group of malignant hematopoietic stem cell disorders characterized by dysplastic and inadequate blood cell production and a variable risk of transformation to acute leukemia. MDS may occur de novo or may arise years after exposure to potentially mutagenic therapy (i.e., chemother- apy, radiation exposure). The patients’ inability to properly produce normal erythrocytes, mature granulocytes, and plate- lets, often results in an array of systemic consequences such as anemia, bleeding, and an increased risk of infection [7]. Evidence from cancer databases suggests that there are approximately 10,000 new cases of MDS diagnosed annu- ally in the United States [8]. MDS occurs most commonly in older adults with a median age at diagnosis of 65 years and a male predominance. Review of the literature reveals six cases of histiocytoid Sweet’s syndrome with MDS [9-14]. When Sweet’s syndrome is present, it portends a poor prognosis in patients with MDS [12]. Histiocytoid Sweet’s syndrome is a rare variant of SS. Histologically, histiocytoid Sweet’s syndrome can present with an infiltrate containing predominantly mononuclear cells with large, slightly eccentric kidney-shaped or elongated nuclei with single indistinct nucleoli and slightly eosinophilic cytoplasm accompanied by numerous mature neutrophils and some mature lymphocytes; these cells may be misinter- preted as histiocytes. We present the case of a 66-year-old woman with a history of myelodysplasia who developed violaceous papules, some with central ulceration, on her face, bilateral upper extremities, and bilateral lower extremities, which later spread to include her right cheek and center of her chest. Subsequent biopsy of the left posterior forearm confirmed the diagnosis of histiocytoid Sweet’s syndrome. Herein we describe patients with myelodysplastic syndromes who developed histiocytoid Sweet’s syndrome and discuss the therapeutic options for the treatment of SS. Case report A 66-year-old woman presented to the dermatology clinic with a one-month history of a rash. The patient reported she was diagnosed with MDS via bone marrow biopsy one year prior; she was started on azacitidine and continued this therapy with minimal improvement. The patient was receiv- ing blood transfusions for anemia and thrombocytopenia. She had not received granulocyte colony-stimulating-factor (G-CSF) at any point during her treatment. Physical exam revealed violaceous papules and plaques involving the face (Figure 1), upper extremities (Figure 2), and lower extremities (Figure 3). The lesions were slightly Figure 1. Frontal view of the patient’s face demonstrating deeply er- ythematous to violaceous, edematous plaques on the bilateral cheeks and right upper eyelid. [Copyright: ©2016 Shalaby et al.] Figure 2. Multiple erythematous, edematous papules and plaques involving the left upper extremity. [Copyright: ©2016 Shalaby et al.] Figure 3. Lower extremities demonstrating ecchymosis and viola- ceous plaques bilaterally. [Copyright: ©2016 Shalaby et al.] Observation | Dermatol Pract Concept 2016;6(1):4 11 is precipitated by the patient having received a dermatosis- associated medication, most notoriously G-CSF [4]. SS may also result from a hypersensitivity reaction to a bacterial or viral antigen [16]. It has been postulated that photosensitivity may also play a role in the pathogenesis of SS, although the mechanism is unknown [17]. Furthermore, an alteration in the gene encoding protein tyrosine phosphatase nonreceptor 6 appears to be involved in the pathogenesis of SS and other subsets of neutrophilic dermatoses [18]. While the pathogenesis of MDS remains poorly under- stood, studies suggest that the cell of origin has acquired multiple mutations resulting in dysplasia and ineffective hematopoiesis [19]. MDS genomes are characterized by global DNA hypomethylation with concomitant hypermeth- ylation of gene-promoter regions relative to normal controls [20]. The underlying mechanism of altered DNA methylation in MDS genomes is unclear; however, studies have implicated mutations in genes that encode enzymes, such as TET2 (10,11 translocation), IDH1 (isocitrate dehydrogenase-1), and IDH2 (isocitrate dehydrogenase-2), that influence DNA methylation directly or indirectly [21]. Histiocytoid Sweet’s syndrome is a histopathologic vari- ant of SS characterized by an infiltrate of mononuclear cells that have a histiocytic appearance and represent immature granulocytes [22-25]. Rarely, histiocytoid Sweet’s syndrome has been associated with MDS. A PubMed search was performed using the keywords: histiocytoid Sweet’s, myelodysplasia, myelodysplastic, sweet, syndrome, which yielded six patients with histiocytoid Sweet’s syndrome and MDS. To the best of our knowledge, our patient is the seventh patient with MDS to develop his- tiocytoid Sweet’s syndrome [9-14]. These patients have been characterized in [Table 1] [9-14]. Four of the seven patients A 3 mm punch biopsy was performed on the left posterior forearm which showed papillary dermal edema in association with a diffuse dermal infiltrate consisting of lymphocytes, his- tiocytes, few neutrophils with leukocytoclasis, and occasional eosinophils (Figures 4 and 5). The biopsy was consistent with histiocytoid Sweet’s syndrome. Our patient was initially treated with 90 mg of oral prednisone daily and dapsone 5% gel. The patient experienced resolution of many of her lesions. After four weeks of this regimen, prednisone was tapered and finally stopped. Discussion SS was first described in 1964 by Robert Sweet as a constel- lation of clinical and laboratory findings he had observed in eight women as an “acute febrile neutrophilic dermatosis” [4,15]. SS skin lesions are typically tender, red to violaceous papules or nodules. Sites frequently involved include the face, neck, and upper extremities [16]. Salient features of SS include: pyrexia, elevated neutrophil count, painful erythema- tous cutaneous lesions characterized by an infiltrate of mature neutrophils typically located in the upper dermis, and prompt clinical improvement following the initiation of corticosteroid therapy [4]. Arthralgias, malaise, headache, and myalgia are other symptoms associated with SS. Subtypes of SS have been described and include: (i) the “classic” presentation, which may be associated with upper respiratory tract or gastrointestinal infection, inflammatory bowel disease, and pregnancy; (ii) the “malignancy-asso- ciated” presentation, in which the dermatosis is either the presenting manifestation of a previously undiagnosed cancer or the recurrence of malignancy in an oncology patient; and (iii) the “drug-induced” presentation, when the condition Figure 4. 10x view demonstrating focal compact parakeratosis with marked edema of the papillary dermis bordering on vesiculation. A superficial and deep perivascular, interstitial and periadnexal infil- trate consisting of lymphocytes, red blood cells and histiocytoid cells is present. [Copyright: ©2016 Shalaby et al.] Figure 5. 63x view demonstrating showing a perivascular and inter- stitial infiltrate consisting of lymphocytes, red blood cells and histio- cytoid cells. [Copyright: ©2016 Shalaby et al.] 12 Observation | Dermatol Pract Concept 2016;6(1):4 known as neutrophilic dermatoses, which are characterized by skin lesions, which histologically consist of intense epider- mal and/or dermal inflammatory infiltrates composed pri- marily of neutrophils without evidence of infection [1]. The myelodysplastic syndromes consist of a group of malignant hematopoietic stem cell disorders which result in impaired blood cell production and which pose a risk of transforma- tion to acute leukemia. SS has been shown to be associated with gastrointestinal or upper respiratory tract infection, hematopoietic malignancy, and various drugs, notably G-CSF [25]. First-line treatment for SS is systemic corticosteroids. Herein we have presented the case of a 66-year-old woman with a history of myelodysplastic syndrome who developed histiocytoid Sweet’s syndrome. References 1. Callen JP. Neutrophilic dermatoses. Dermatol Clin. 2002;20(3): 409-19. PMID: 12170875 2. Jorizzo JL, Solomon AR, Zanolli MD, Leshin B. Neutrophilic vascular reactions. J Am Acad Dermatol. 1988;19(6):983-1005. PMID: 3060489 3. Moschella SL. Review of so-called aseptic neutrophilic derma- toses. Australas J Dermatol. 1983;24(2):55-62. PMID: 6362643 described were women; the average age of patients with MDS who developed histiocytoid Sweet’s syndrome was 65 years (range 44-75 years of age). Systemic corticosteroids are the mainstay of therapy for SS. Prednisone, at a dosage of 1 mg/kg/day, may be given as a single morning dose. Intravenous pulse administration of methylprednisone sodium succinate (up to 1000 mg/day) over 1 or more hours, daily for three to five days, may be utilized for patients whose condition is refractory to other therapies [4]. Other therapies include: clofazimine, colchicine, cyclosporine, dapsone, high-potency corticosteroids (such as clobetasol propionate 0.05%), indometacin, intralesional cor- ticosteroids, Lugol’s solution, and potassium iodide [4]. Met- ronidazole has been effective in patients whose dermatosis is related to inflammatory bowel disease [4]. Tumor necrosis factor (TNF) antagonists such as etanercept, infliximab, and thalidomide have been shown to be effective [4,23]. Conclusion Histiocytoid Sweet’s syndrome is a rare variant of SS, which was originally described by Robert Sweet and is sometimes associated with MDS. SS belongs to a group of conditions TABLE 1. Cases of concomitant Sweet’s syndrome and myelodsyplastic syndrome in the same patient [9-14] Case Age/ Sex Clinical Appearance Time Period to Progression of Leukemia after Diagnosis of Sweet’s Syndrome MDS Present at Time of Diagnosis of Sweet’s Syndrome Ref 1 44W Multiple papules, plaques, and nodules on the face and extremities N/A Yes [14] 2 66W Violaceous papules and plaques involving the face, upper extremities, and lower extremities 16 months Yes [CR] 3 68W 20 scattered 0.5-2 cm, pink to pink- purple firm, non-tender nodules on the legs and left arm No progression Yes [9] 4 73W Multiple red tender plaques on trunk and upper extremities varying in size from 0.5 to 5 cm No progression Yes [10] 5 57M Multiple tender, raised, annular erythematous lesions on ankles and trunk. No progression Yes [12] 6 71 M Multiple, slightly tender, erythematous nodules and plaques scattered over the neck, thighs, and trunk, and confluent erythematous indurated plaques on the forearms No progression Yes [11] 7 75M Burning, maculopapular, erythematous, sharp-edged lesions, affecting abdomen, arms, back, and face Leukemia at time of diagnosis Yes [13] Legend: CR = Current Report; M = male; MDS—myelodysplastic syndrome; N/A—not available; W = woman; Observation | Dermatol Pract Concept 2016;6(1):4 13 tentially related to decitabine in a patient with myelodysplastic syndrome; Eur J Dermatol. 2012;22(6):811-2. PMID: 23178879 15. Sweet RD. An acute febrile neutrophilic dermatosis. Br J Derma- tol. 1964 ;76:349-56. PMID: 14201182 16. Anzalone CL, Cohen PR. Acute febrile neutrophilic dermatosis (Sweet’s syndrome). Curr Opin Hematol. 2013;20(1):26-35. PMID: 23207661 17. Meyer V, Schneider SW, Bonsmann G, Beissert S. Experimentally confirmed induction of Sweet’s syndrome by phototestin. Acta Derm Venereol 2011;91(6):720-1. PMID: 21681361 18. Nesterovitch AB, Gyorfy Z, Hoffman MD, et al. Alteration in the gene encoding protein tyrosine phosphatase nonreceptor 6 (PTPN6/SHP1) may contribute to neutrophilic dermatoses. Am J Pathol. 2011;178(4):1434-41. PMID: 21406173 19. Pang WW, Pluvinage JV, Price EA, et al. Hematopoietic stem cell and progenitor cell mechanisms in myelodysplastic syndromes. Proc Natl Acad Sci USA. 2013;110(8):3011-6. PMID: 23388639 20. Xu W, Yang H, Liu Y, et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. Cancer Cell. 2011;19(1):17-30. PMID: 21251613 21. Cazzola M. IDH1 and IDH2 mutations in myeloid neoplasms— novel paradigms and clinical implications. Haematologica. 2010;95;(10):1623-7. PMID: 20884716 22. Wilson TC, Stone MS, Swick BL. Histiocytoid Sweet’s syndrome with haloed myeloid cells masquerading as a cryptococcal infec- tion. Am J Dermatopathol. 2014;36(3):264-9. PMID: 23739245 23. Maalouf D, Battistella M, Bouaziz JD. Neutrophilic derma- tosis: disease mechanism and treatment. Curr Opin Hematol. 2015;22(1):23-9. PMID: 25394310 24. Peroni A, Colato C, Schena D, Rongioletti F, Girolomoni G. Histiocytoid Sweet syndrome is infiltrated predominantly by M2-like macrophages. J Am Acad Dermatol. 2015;72(1):131-9. PMID: 25440433 25. So JK, Carlos CA, Frucht CS, Cohen PR. Histiocytoid giant cellulitis-like Sweet’s syndrome: Case report and review of the literature. Dermatology Online Journal. 2015: in press. 4. Cohen PR. Neutrophilic dermatoses: a review of current treat- ment options. Am J Clin Dermatol. 2009;10(5):301-12. PMID: 19658442 5. Cohen PR. Neutrophilic dermatoses occurring in oncology patients. Int J Dermatol. 2007;46(1):106-11. PMID: 17214733 6. Harrist TJ, Fine JD, Berman RS, Murphy GF, Mihm MC Jr. Neu- trophilic eccrine hidradenitis. A distinctive type of neutrophilic dermatosis associated with myelogenous leukemia and chemo- therapy. Arch Dermatol. 1982;118(4):263-66. PMID: 6950689 7. Steensma DP, Bennet JM. The myelodysplastic syndromes: diag- nosis and treatment. Mayo Clin Proc. 2006;81(1):104-30. PMID: 16438486 8. Ma X, Does M, Raza A, Mayne ST. Myelodysplastic syndromes: incidence and survival in the United States. Cancer. 2007;109(8): 1536-42. PMID: 17345612 9. Lin J, Zhang Q, Chen M. Subcutaneous histiocytoid Sweet’s syndrome in a patient associated with myelodysplastic syn- drome-refractory anemia. J Dermatol. 2012;39(1):99-101. PMID: 22007966 10. Ten Oever J, Kuijper PH,, Kuijpers AL, Dercksen MW, Vreudgen- hil G. Complete remission of MDS RAEB following immunosup- pressive treatment in a patient with Sweet’s syndrome. Neth J Med. 2009;67(8):347-50. PMID: 19767665 11. Pinal-Fernandez I, Ferrer Fabrega B, Ramentol Sintas M, Solans Laque R. Histiocytoid Sweet syndrome and cutaneous polyarteri- tis nodosa secondary to myelodysplastic syndrome. Int J Rheum Dis. 2013;16(6):777-9. PMID: 24382288 12. Kaiser R, Connolly K, Linker C, Maldonado J, Fye K. Stem cell transplant for myelodysplastic syndrome-associated histiocytoid Sweet’s syndrome in a patient with arthritis and myalgias. Arthri- tis Rheum. 2008 ;59(12):1832-4. PMID: 19035416 13. Srisuttiyakorn C, Reeve J, Reddy S, Imaeda S, Lazova R. Subcu- taneous histiocytoid Sweet’s syndrome in a patient with myelo- dysplastic syndrome and acute myeloblastic leukemia. J Cutan Pathol. 2014;41(5):475-9. PMID: 24877196 14. Park JY, Park JS, Kim YC. Histiocytoid Sweet’s syndrome po-