Observations  A 40-year-old white man with a history of melanoma and multiple dysplastic nevi self-administered synthetic -MSH. He developed crops of new pigmented nevi, many of which had atypical clinical and histopathologic features. The preexisting nevi became darker and acquired growth features. After -MSH use was discontinued, the nevi progressively lightened and lost their growth features.

Conclusions  Synthetic -MSH peptides can drive proliferation of neoplastic melanocytic cells in predisposed patients. This could present an increased risk for melanoma development.

REPORT OF A CASE

Three weeks after starting treatment, he noticed new moles on his trunk, neck, and arms. These, and the old nevi, began to darken, to grow rapidly, and to appear more irregular, prompting him to discontinue treatment. He did not report any other adverse effects.

On physical examination, the patient had scattered new pigmented nevi on his neck, trunk, and extremities, confirmed by comparison with photographs taken 1 year earlier (Figure 1). Peripheral dots and "pseudopod-like" structures were found at the edges of many of the lesions, suggesting active growth (Figure 2 and Figure 3). There was no recurrence of pigmentation at the melanoma site or at the sites of previously excised melanocytic nevi. No mucosal pigmented lesions were noted. There was no evidence of lymphadenopathy. He felt well.

View larger version (262K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 1. Photographs taken 1 year before using -melanocyte-stimulating hormone (A) and at consultation showing new atypical melanocytic nevi and increased pigmentation and growth of preexisting nevi (B). C, At 6-month follow-up, the nevi were markedly lighter. The photographs were taken under different conditions, not allowing for an assessment of skin color changes.

View larger version (172K): [in this window] [in a new window] [as a PowerPoint slide]   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.

View larger version (188K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 3. Dermoscopic features of the patient's nevi. A, C, E, and G, Features at consultation including dark brown pigmentation with peripheral pigment extensions (pseudopods) and peripheral dots; B, D, F, and H, fading of these features 6 months later.

One lesion on his left upper middle back just medial of the midline had clinical and dermoscopic features worrisome 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 residual 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 lightening of the nevi. Growth features disappeared as well. He continues to have regular follow-up without further complications.

COMMENT

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 studies.³ Neither has the effect of these potent melanocortins on patients with atypical nevi or a history of melanoma been addressed. To our knowledge, this is the first documented case of eruptive atypical nevi secondary to exogenous melanocortin administration.

The phenomenon of eruptive nevi is well described in the literature and may be caused by stimulatory cytokines or by immunosuppression. Severe bullous diseases, such as toxic epidermal necrolysis and erythema multiforme, have preceded the appearance of eruptive nevi, presumably resulting from melanocytic hyperplasia during the healing process of denuded areas of skin.^10-11 A case of eruptive Spitz nevi during pregnancy has also been reported.¹² Eruptive nevi have been described in patients who develop AIDS and in patients with cancer receiving chemotherapy. In some cases, the eruptive nevi were followed by the development of melanoma.¹³ Decreased immunosurveillance is thought to play a role because eruptive nevi have been observed to fade after interruption of chemotherapy.¹⁴ Immunosuppressed patients with renal allografts have been documented to have eruptive nevi with peripheral rims of globules on dermoscopy, similar to what we had documented in our patient.¹⁵

The -MSH may induce eruptive nevi in susceptible patients owing to its direct stimulatory activity on the melanocyte and through immunoregulatory effects. The -MSH and its analogues are mitogenic for human melanocytes.¹⁶ It has been shown to induce changes in cell shape and to increase the dendricity of melanocytes and melanoma cells.¹⁷ In addition, -MSH is thought to exert a profound immunosuppressive effect, inhibiting nuclear factor–B activation and tumor necrosis factor–induced intracellular adhesion molecule expression in melanocytes and melanoma cells.^18-19 The -MSH decreases T-cell–melanoma interaction in vitro,²⁰ possibly allowing escape from immune detection and enhancing survival. Decreased levels of -MSH and other immunosuppressive cytokines, such as interleukin 10 and transforming growth factor β, were good prognostic factors for response to immunotherapy of melanoma.²¹

Although the biological mechanisms of acquired nevus development are still being elucidated, it is reasonable to assume that melanocytes, nevi, and melanomas are derived from a melanocytic precursor (stem) cell.²² The existence and location of these cells in the dermis (or epidermis) have yet to be fully determined. We propose that administration of a superpotent -MSH analogue in our patient, who had a background of melanoma and atypical nevi, may have driven his already genetically mutated melanocytic stem cells to produce several new, atypical nevi. Because withdrawal of the cytokine resulted in fading and loss of growth features in our patient's atypical nevi, we suggest that the precursor cells stimulated to generate the nevi depended on the excessive -MSH stimulation to continue to drive growth and prevent regression.

The development of synthetic -MSH analogues has been valuable in studying melanocyte biological mechanisms, and they hold potential therapeutic applications.³ However, caution must be exercised in pursuing the use of these potent melanocortins in patients because their biological effect on the development of atypical and even malignant pigmented neoplasms is not yet well understood.

AUTHOR INFORMATION

Accepted for Publication: November 21, 2008.

Author Contributions: Both authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Acquisition of data: Cardones and Grichnik. Analysis and interpretation of data: Cardones and Grichnik. Drafting of the manuscript: Cardones and Grichnik. Critical revision of the manuscript for important intellectual content: Cardones and Grichnik. Administrative, technical, and material support: Grichnik. Study supervision: Grichnik.

Financial Disclosure: Dr Grichnik is a founder and major 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, Dermatologic Diagnostics.

Funding/Support: This study was funded by the Division of Dermatology at Duke University Medical Center.