SKIN January 2021 Volume 5 Issue 1 Copyright 2021 The National Society for Cutaneous Medicine 75 SHORT COMMUNICATIONS Imatinib-Induced Acquired Dermal Melanocytosis Anna Eversman, BS1, Sakeena Fatima, MD2, Kord S. Honda, MD1,2, Mara G. Beveridge, MD1,2 1Case Western Reserve University School of Medicine, Cleveland, OH 2University Hospitals Cleveland Medical Center, Department of Dermatology, Cleveland, OH Imatinib, a tyrosine kinase inhibitor, is commonly used to treat gastrointestinal stromal tumors and hematologic malignancies.1 Cutaneous reactions occur in up to 69% of patients, most commonly manifesting as superficial edema and an exanthem-like rash.2 Recent literature documents changes in pigmentation, with higher rates of hypopigmentation (40.9%) as compared to hyperpigmentation (3.6%).3 While the histologic appearance of imatinib- induced hyperpigmentation varies, intradermal hemosiderosis is the most common finding.4 We report a rare case of hyperpigmented patches secondary to dermal melanocytosis following imatinib treatment in an African American patient with acute lymphoblastic leukemia (ALL). An 81-year-old African American woman with a history of ALL presented to dermatology clinic with diffuse hyperpigmented patches of her face, upper back, and shoulders in February of 2020. She was initially diagnosed with ALL in August of 2014, and complete remission was achieved shortly thereafter with 2 cycles of hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) and initiation of imatinib therapy. At the time of presentation, imatinib use had been continuous for more than 5 years. Physical examination revealed diffuse, ill-defined, slate-grey hyperpigmented patches distributed symmetrically on the bilateral temples, forehead, upper back, and shoulders. Hyperpigmented patches of her face were first observed in September of 2015, with ABSTRACT Background: Imatinib, a tyrosine kinase inhibitor, is commonly used to treat gastrointestinal stromal tumors and hematologic malignancies. Hyperpigmentation is a known side-effect of imatinib, with intradermal hemosiderosis being the most common histologic finding. Case Presentation: We report a rare case of hyperpigmentation secondary to dermal melanocytosis following imatinib treatment in an African American patient with acute lymphoblastic leukemia. Conclusion: The efficacy of imatinib and the benign nature of the pigment abnormalities should be emphasized to prevent unnecessary treatment cessation in patients presenting with imatinib-induced dermal melanocytosis. INTRODUCTION CASE PRESENTATION SKIN January 2021 Volume 5 Issue 1 Copyright 2021 The National Society for Cutaneous Medicine 76 Figure 1. Clinical examination showed ill-defined, slate-grey hyperp igmentation of (A) forehead, (B) temples, (C) and upper back. later expansion to her shoulders and neck. A punch biopsy of the right shoulder was obtained, revealing occasional pigmented spindled cells in the superficial and deep reticular dermis. An iron stain was negative. The pigment stained positive with Fontana- Masson and the cells stained with antibodies against Melan-A. A final diagnosis of dermal melanocytosis was made. Given the patient’s positive response to imatinib, the favorable side effect profile of imatinib compared to other tyrosine kinase inhibitors, and the benign nature of the pigmentation abnormalities, she remains on imatinib. Imatinib has been known to induce dyspigmentation. 5 Although Imatinib- induced hypopigmentation has been attributed to inhibition of the c-Kit/SCF pathway which is responsible for the differentiation, survival, and proliferation of melanocytes, the mechanism of paradoxical imatinib-induced hyperpigmentation is unclear and the histologic findings are diverse.1 Among patients with imatinib- induced hyperpigmentation, intradermal hemosiderosis is the most common finding on biopsy.4 The pathophysiology involves damage to the dermal vessels and subsequent deposition of iron in the skin. As later development of hepatic hemosiderosis has been reported, these patients should be closely monitored for signs of liver disease.6 Rarely, imatinib-induced hyperpigmentation has been attributed to dermal melanocytosis. Kok et al reported 3 cases of generalized hypopigmentation and progression of existing dermal melanocytosis.7 Although dermal melanocytosis appears bluish-grey and the pigmentation of intradermal hemosiderosis is classically dark brown, color changes vary and can be difficult to distinguish clinically. Biopsy is therefore essential to ensure appropriate diagnosis and subsequent management. Although dermal melanocytosis is evidence of melanocyte activation, there are only 5 reported cases of primary cutaneous DISCUSSION A. B. C. SKIN January 2021 Volume 5 Issue 1 Copyright 2021 The National Society for Cutaneous Medicine 77 Figure 2. Histopathologic examination revealed (A) heavily-pigmented superficial spindled cells in the dermis (H&E, 40x). (B) Fontana-Masson staining showed spindled melanocytes in the dermis (40x). melanoma arising in the context of acquired dermal melanocytosis.8,9 The precursor lesion was a nevus of Ota in all 5 of these cases, in contrast to our patient.9 Furthermore, imatinib may offer a protective benefit as it inhibits the c-Kit/SCF pathway and has been used in the treatment of melanoma with KIT mutations.10,11 For these reasons, we are doubtful our patient’s dermal melanocytosis confers an increased risk of melanoma, although there is a lack of literature regarding this topic. The efficacy of imatinib and the benign nature of the pigment abnormalities should be emphasized to prevent unnecessary treatment cessation in patients presenting with imatinib-induced dermal melanocytosis. Conflict of Interest Disclosures: None Funding: None Corresponding Author: Mara Beveridge, MD 2109 Adelbert Road Cleveland, OH 44016 Phone: 216-514-8630 Email: Mara.Beveridge@uhhospitals.org References: 1. Verma D, Kantarjian H, Strom SS, Rios MB, Jabbour E, Quintas-Cardama A, et al. Malignancies occurring during therapy with tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia (CML) and other hematologic malignancies. Blood. 2011;118:4353–4358. 2. Scheinfeld N. Imatinib mesylate and dermatology part 2: a review of the cutaneous side effects of imatinib mesylate. J Drugs Dermatol 2006;5:228–231. 3. Arora B, Kumar L, Sharma A, Wadhwa J, Kochupillai V. Pigmentary changes in chronic myeloid leukemia patients treated with imatinib mesylate. Ann Oncol 2004;15:358-9. 4. Pureesrisak P, Tienthavorn T. Imatinib mesylate induced acquired dermal melanocytosis: a rare case report. Thai Journal of Dermatology. 2017; 33(4): 297-305. 5. Grichnik JM, Burch JA, Burchette J, Shea CR. The SCF/KIT pathway plays a critical role in the control of normal human melanocyte homeostasis. J Invest Dermatol 1998;111:233-8. 6. Maiti B, Setrakian S, Daw HA. Hepatic iron overload, a possible consequence of treatment with imatinib mesylate: a case report. Cases J. 2009; 2:7526. 7. Kok WL, Chen Q, Lee SSJ, Chua SH, Ng SK. A case series of imatinib-induced generalized hypopigmentation and progression of existing acquired dermal melanocytosis. J Dermatolog Treat. 2017;28(8):762–3. 8. Baykal C, Yılmaz Z, Sun GP, Büyükbabani N. The spectrum of benign dermal dendritic melanocytic proliferations. J Eur Acad Dermatol Venereol. 2019;33(6):1029-1041. 9. Tse JY, Walls BE, Pomerantz H, Yoon CH, et al. Melanoma arising in a nevus of Ito: novel genetic mutations and a review of the literature on cutaneous malignant transformation of dermal melanocytosis. J Cutan Pathol. 2016;43(1):57-63. 10. Curtin JA, Busam K, Pinkel D, Bastian BC. Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol. 2006;24(26):4340-6. 11. Hodi FS, Corless CL, Giobbie-Hurder A, et al. Imatinib for melanomas harboring mutationally activated or amplified KIT arising on mucosal, acral, and chronically sun- damaged skin. J Clin Oncol. 2013;31(26):3182-90. A. B.