Α-Melanocyte-Stimulating Hormone–Induced Eruptive Nevi

OBSERVATION ␣-Melanocyte-Stimulating Hormone–Induced Eruptive Nevi

Adela R. Cardones, MD; James M. Grichnik, MD, PhD

Background: Synthetic peptides that target proopi- new pigmented nevi, many of which had atypical clini- omelanocortin receptors are being investigated as a novel cal and histopathologic features. The preexisting nevi be- and safe way to tan. It has been postulated that syn- came darker and acquired growth features. After ␣- thetic ␣-melanocyte-stimulating hormone (␣-MSH) pep- MSH use was discontinued, the nevi progressively tides may have protective effects against the develop- lightened and lost their growth features. ment of melanoma because of their melanogenic activity. Their ultimate biological effect, however, especially in Conclusions: Synthetic ␣-MSH peptides can drive pro- patients with dysplastic nevi or previous melanoma, has liferation of neoplastic melanocytic cells in predisposed yet to be determined. patients. This could present an increased risk for melanoma development. Observations: A 40-year-old white man with a history of melanoma and multiple dysplastic nevi self- administered synthetic ␣-MSH. He developed crops of Arch Dermatol. 2009;145(4):441-444

KNOWN PHYSIOLOGIC REGU- larly because of atypical nevi and his his- lator of pigmentation, ␣- tory of melanoma (Clark level II and Bres- melanocyte-stimulating low depth of 0.25 mm, completely excised, hormone (␣-MSH),1 is mi- approximately 9 years earlier). There was togenic for melanocytes, no family history of melanoma or erup- inducesA dispersion of melanosomes, in- tive nevi. Six weeks before the present clinic creases tyrosinase activity and melanin syn- visit, the patient had started injecting him- thesis, and, consequently, protects against self with an ␣-MSH analogue (Melanotan UV-mediated DNA damage. Mutations in II; Melanocorp Inc, Hendersonville, Ten- the melanocortin 1 receptor MC1R, and nessee; http://www.melanocorp.com) sub- the resultant inability to respond to ␣- cutaneously twice weekly, according to the MSH, are associated with enhanced cyto- manufacturer’s recommendations, as a tan- toxic effects of UV-B2 and predisposition ning agent. He had learned about ␣-MSH for melanoma formation. Superpotent, and its effects from fellow bodybuilders and long-acting, synthetic analogues of ␣- had purchased the peptide online. It was MSH are being developed as a strategy for important for him to be tan for the body- melanoma prevention.3 Although not ap- building competition, but he was aware of proved by the US Food and Drug Admin- the negative consequences of UV light tan- istration, synthetic ␣-MSH analogues have ning and thought that ␣-MSH would be a gained popularity for enhancing tanning. good option. Three weeks after starting treatment, he noticed new moles on his trunk, neck, and Author Affiliations: REPORT OF A CASE arms. These, and the old nevi, began to Department of Medicine, Duke darken, to grow rapidly, and to appear University Medical Center, Durham, North Carolina A 40-year-old white man visited the Pig- more irregular, prompting him to discon- (Dr Cardones); and Department mented Lesion Clinic at Duke University tinue treatment. He did not report any of Dermatology, University of Medical Center for rapidly growing new other adverse effects. Miami Health System, Miami, moles, several of which were irregularly On physical examination, the patient Florida (Dr Grichnik). shaped. He was being followed up regu- had scattered new pigmented nevi on

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©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 One lesion on his left upper middle back just medial A of the midline had clinical and dermoscopic features wor- risome for melanoma (Figure 2). Histopathologic findings were interpreted by the Department of Pathology, Duke University Medical Center, to reveal a compound nevus with moderate to severe architectural and cytologic atypia extending to the margins (Figure 2). There was a marked presence of pigment-laden keratinocytes and occasional pagetoid melanocytes in the epidermis. The nevocytes in the superficial dermis exhibited melanin pigmentation. The area was excised again, and no re- sidual nevus was noted. A second biopsy of a lesion on his left abdomen revealed a moderately dysplastic compound nevus. During the next 9 months, there was progressive light- ening of the nevi. Growth features disappeared as well. B He continues to have regular follow-up without further complications.

COMMENT

␣-MSH is a melanotropic cytokine produced by several types of cells, including neural cells, endothelial cells, macrophages, and keratinocytes. It acts by activation of the melanocortin 1 receptor, which increases mela- nogenesis and enhances DNA repair in melanocytes,4 and is important in the regulation of pigmentation. Pituitary extracts of an ␣-MSH induce darkening of integument of different vertebrates in vivo.5 It is there- fore an attractive target for inducing protective tanning without the deleterious effects of UV exposure.6 C Melanotan I and melanotan II are synthetic peptide analogues that are up to 1000 times more potent than endogenous ␣-MSH, with melanotan II being the more potent of the two.3 Early phase 1 and phase 2 trials confirmed that subcutaneous delivery of these peptides exaggerates the tanning response to UV-B and increases the eumelanin level and tanning without additional UV exposure.7,8 This response may be enhanced in persons with melanocortin 1 receptor variants.2,9 Because of its ability to bind to other melanocortin receptors and its effects on other cells, melanotan II is also being developed as a treatment for erectile dysfunction, obesity, and insulin resistance. No tumorigenesis has been documented in previous 3 Figure 1. Photographs taken 1 year before using ␣-melanocyte-stimulating studies. Neither has the effect of these potent mela- hormone (A) and at consultation showing new atypical melanocytic nevi and nocortins on patients with atypical nevi or a history of increased pigmentation and growth of preexisting nevi (B). C, At 6-month melanoma been addressed. To our knowledge, this is follow-up, the nevi were markedly lighter. The photographs were taken under different conditions, not allowing for an assessment of skin color changes. the first documented case of eruptive atypical nevi sec- ondary to exogenous melanocortin administration. The phenomenon of eruptive nevi is well described his neck, trunk, and extremities, confirmed by com- in the literature and may be caused by stimulatory parison with photographs taken 1 year earlier cytokines or by immunosuppression. Severe bullous (Figure 1). Peripheral dots and “pseudopod-like” diseases, such as toxic epidermal necrolysis and ery- structures were found at the edges of many of the thema multiforme, have preceded the appearance of lesions, suggesting active growth (Figure 2 and eruptive nevi, presumably resulting from melanocytic Figure 3). There was no recurrence of pigmentation hyperplasia during the healing process of denuded at the melanoma site or at the sites of previously areas of skin.10,11 A case of eruptive Spitz nevi during excised melanocytic nevi. No mucosal pigmented pregnancy has also been reported.12 Eruptive nevi have lesions were noted. There was no evidence of lymph- been described in patients who develop AIDS and in adenopathy. He felt well. patients with cancer receiving chemotherapy. In some

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C D

Figure 2. Clinical (A) and dermoscopic (B) photographs of a melanocytic lesion on the patient’s upper back that was a concern for melanoma. Histopathologic review of the entire lesion revealed a compound nevus with moderate to severe architectural and cytologic atypia of the melanocytic cells. C and D, Histopathologic analyses also revealed marked pigment accumulation in the keratinocytes and an occasional pagetoid melanocyte. Bars denote 100 µm.

cases, the eruptive nevi were followed by the develop- factor ␤, were good prognostic factors for response to ment of melanoma.13 Decreased immunosurveillance immunotherapy of melanoma.21 is thought to play a role because eruptive nevi have Although the biological mechanisms of acquired ne- been observed to fade after interruption of chemo- vus development are still being elucidated, it is reason- therapy.14 Immunosuppressed patients with renal allo- able to assume that melanocytes, nevi, and melanomas grafts have been documented to have eruptive nevi are derived from a melanocytic precursor (stem) cell.22 with peripheral rims of globules on dermoscopy, simi- The existence and location of these cells in the dermis lar to what we had documented in our patient.15 (or epidermis) have yet to be fully determined. We pro- The ␣-MSH may induce eruptive nevi in susceptible pose that administration of a superpotent ␣-MSH ana- patients owing to its direct stimulatory activity on the logue in our patient, who had a background of mela- melanocyte and through immunoregulatory effects. noma and atypical nevi, may have driven his already The ␣-MSH and its analogues are mitogenic for human genetically mutated melanocytic stem cells to produce melanocytes.16 It has been shown to induce changes in several new, atypical nevi. Because withdrawal of the cyto- cell shape and to increase the dendricity of melano- kine resulted in fading and loss of growth features in our cytes and melanoma cells.17 In addition, ␣-MSH is patient’s atypical nevi, we suggest that the precursor cells thought to exert a profound immunosuppressive stimulated to generate the nevi depended on the exces- effect, inhibiting nuclear factor–␬B activation and sive ␣-MSH stimulation to continue to drive growth and tumor necrosis factor–induced intracellular adhesion prevent regression. molecule expression in melanocytes and melanoma The development of synthetic ␣-MSH analogues cells.18,19 The ␣-MSH decreases T-cell–melanoma inter- has been valuable in studying melanocyte biological action in vitro,20 possibly allowing escape from mechanisms, and they hold potential therapeutic immune detection and enhancing survival. Decreased applications.3 However, caution must be exercised in levels of ␣-MSH and other immunosuppressive cyto- pursuing the use of these potent melanocortins in kines, such as interleukin 10 and transforming growth patients because their biological effect on the develop-

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©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 vision of the manuscript for important intellectual content: A B Cardones and Grichnik. Administrative, technical, and ma- terial support: Grichnik. Study supervision: Grichnik. Financial Disclosure: Dr Grichnik is a founder and ma- jor shareholder of Digital Derm Inc, MoleMapCD (total- body photography) and a member of the editorial board of Archives of Dermatology. He has received consulting fees and grants from Electro-Optical Sciences Inc, Melafind (melanoma detection device), and Spectral Image Inc, Der- matologic Diagnostics. Funding/Support: This study was funded by the Division C D of Dermatology at Duke University Medical Center.

REFERENCES

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