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Observation |

α-Melanocyte-Stimulating Hormone–Induced Eruptive Nevi FREE

Adela R. Cardones, MD; James M. Grichnik, MD, PhD
[+] Author Affiliations

Author Affiliations: Department of Medicine, Duke University Medical Center, Durham, North Carolina (Dr Cardones); and Department of Dermatology, University of Miami Health System, Miami, Florida (Dr Grichnik).


Arch Dermatol. 2009;145(4):441-444. doi:10.1001/archdermatol.2008.623.
Text Size: A A A
Published online

ABSTRACT

Background  Synthetic peptides that target proopiomelanocortin receptors are being investigated as a novel and safe way to tan. It has been postulated that synthetic α-melanocyte-stimulating hormone (α-MSH) peptides may have protective effects against the development of melanoma because of their melanogenic activity. Their ultimate biological effect, however, especially in patients with dysplastic nevi or previous melanoma, has yet to be determined.

Observations  A 40-year-old white man with a history of melanoma and multiple dysplastic nevi self-administered synthetic α-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 α-MSH use was discontinued, the nevi progressively lightened and lost their growth features.

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

Figures in this Article

A known physiologic regulator of pigmentation, α-melanocyte-stimulating hormone (α-MSH),1 is mitogenic for melanocytes, induces dispersion of melanosomes, increases tyrosinase activity and melanin synthesis, and, consequently, protects against UV-mediated DNA damage. Mutations in the melanocortin 1 receptor MC1R, and the resultant inability to respond to α-MSH, are associated with enhanced cytotoxic effects of UV-B2 and predisposition for melanoma formation. Superpotent, long-acting, synthetic analogues of α-MSH are being developed as a strategy for melanoma prevention.3 Although not approved by the US Food and Drug Administration, synthetic α-MSH analogues have gained popularity for enhancing tanning.

REPORT OF A CASE

A 40-year-old white man visited the Pigmented Lesion Clinic at Duke University Medical Center for rapidly growing new moles, several of which were irregularly shaped. He was being followed up regularly because of atypical nevi and his history of melanoma (Clark level II and Breslow depth of 0.25 mm, completely excised, approximately 9 years earlier). There was no family history of melanoma or eruptive nevi. Six weeks before the present clinic visit, the patient had started injecting himself with an α-MSH analogue (Melanotan II; Melanocorp Inc, Hendersonville, Tennessee; http://www.melanocorp.com) subcutaneously twice weekly, according to the manufacturer's recommendations, as a tanning agent. He had learned about α-MSH and its effects from fellow bodybuilders and had purchased the peptide online. It was important for him to be tan for the bodybuilding competition, but he was aware of the negative consequences of UV light tanning and thought that α-MSH would be a good option.

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.

Place holder to copy figure label and caption
Figure 1.

Photographs taken 1 year before using α-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.

Graphic Jump Location
Place holder to copy figure label and caption
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.

Graphic Jump Location
Place holder to copy figure label and caption
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.

Graphic Jump Location

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

α-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 melanogenesis and enhances DNA repair in melanocytes,4 and is important in the regulation of pigmentation. Pituitary extracts of an α-MSH induce darkening of integument of different vertebrates in vivo.5 It is therefore an attractive target for inducing protective tanning without the deleterious effects of UV exposure.6

Melanotan I and melanotan II are synthetic peptide analogues that are up to 1000 times more potent than endogenous α-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 α-MSH may induce eruptive nevi in susceptible patients owing to its direct stimulatory activity on the melanocyte and through immunoregulatory effects. The α-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, α-MSH is thought to exert a profound immunosuppressive effect, inhibiting nuclear factor–κB activation and tumor necrosis factor–induced intracellular adhesion molecule expression in melanocytes and melanoma cells.18,19 The α-MSH decreases T-cell–melanoma interaction in vitro,20 possibly allowing escape from immune detection and enhancing survival. Decreased levels of α-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 α-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 α-MSH stimulation to continue to drive growth and prevent regression.

The development of synthetic α-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.

ARTICLE INFORMATION

Correspondence: James M. Grichnik, MD, PhD, Department of Dermatology, University of Miami Health System, University of Miami Hospital and Clinics/Sylvester Comprehensive Cancer Center, Melanoma Program, 1475 NW 12th Ave, Location D-1, Miami, FL 33136 (grichnik@miami.edu).

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.

REFERENCES

Abdel-Malek  ZSwope  VBSuzuki  I  et al.  Mitogenic and melanogenic stimulation of normal human melanocytes by melanotropic peptides. Proc Natl Acad Sci U S A 1995;92 (5) 1789- 1793
PubMed Link to Article
Kadekaro  ALKanto  HKavanagh  RAbdel-Malek  ZA Significance of the melanocortin 1 receptor in regulating human melanocyte pigmentation, proliferation, and survival. Ann N Y Acad Sci 2003;994359- 365
PubMed Link to Article
Hadley  MEDorr  RT Melanocortin peptide therapeutics: historical milestones, clinical studies and commercialization. Peptides 2006;27 (4) 921- 930
PubMed Link to Article
Virador  VMMuller  JWu  X  et al.  Influence of α-melanocyte-stimulating hormone and ultraviolet radiation on the transfer of melanosomes to keratinocytes. FASEB J 2002;16 (1) 105- 107
PubMed
Lande  SLerner  AB The biochemistry of melanotropic agents. Pharmacol Rev 1967;19 (1) 1- 20
PubMed
Abdel-Malek  ZAKadekaro  ALKavanagh  RJ  et al.  Melanoma prevention strategy based on using tetrapeptide α-MSH analogs that protect human melanocytes from UV-induced DNA damage and cytotoxicity. FASEB J 2006;20 (9) 1561- 1563
PubMed Link to Article
Dorr  RTLines  RLevine  N  et al.  Evaluation of melanotan-II, a superpotent cyclic melanotropic peptide in a pilot phase-I clinical study. Life Sci 1996;58 (20) 1777- 1784
PubMed Link to Article
Dorr  RTDvorakova  KBrooks  C  et al.  Increased eumelanin expression and tanning is induced by a superpotent melanotropin [Nle4-D-Phe7]-α-MSH in humans. Photochem Photobiol 2000;72 (4) 526- 532
PubMed Link to Article
Fitzgerald  LMFryer  JLDwyer  THumphrey  SM Effect of MELANOTAN, [Nle4, D-Phe7]-α-MSH, on melanin synthesis in humans with MC1R variant alleles. Peptides 2006;27 (2) 388- 394
PubMed Link to Article
Soltani  KBernstein  JELorincz  AL Eruptive nevocytic nevi following erythema multiforme. J Am Acad Dermatol 1979;1 (6) 503- 505
PubMed Link to Article
Kopf  AWGrupper  CBaer  RLMitchell  JC Eruptive nevocytic nevi after severe bullous disease. Arch Dermatol 1977;113 (8) 1080- 1084
PubMed Link to Article
Onsun  NSaracoglu  SDemirkesen  CKural  YBAtilganoglu  U Eruptive widespread Spitz nevi: can pregnancy be a stimulating factor? J Am Acad Dermatol 1999;40 (5, pt 2) 866- 867
PubMed
Reutter  JCLong  EMMorrell  DSThomas  NEGroben  PA Eruptive post-chemotherapy in situ melanomas and dysplastic nevi. Pediatr Dermatol 2007;24 (2) 135- 137
PubMed Link to Article
Piaserico  SAlaibac  MFortina  ABPeserico  A Clinical and dermatoscopic fading of post-transplant eruptive melanocytic nevi after suspension of immunosuppressive therapy. J Am Acad Dermatol 2006;54 (2) 338- 340
PubMed Link to Article
Alaibac  MPiaserico  SRossi  CR  et al.  Eruptive melanocytic nevi in patients with renal allografts: report of 10 cases with dermoscopic findings. J Am Acad Dermatol 2003;49 (6) 1020- 1022
PubMed Link to Article
Scott  GCassidy  LAbdel-Malek  Z α-Melanocyte-stimulating hormone and endothelin-1 have opposing effects on melanocyte adhesion, migration, and pp125FAK phosphorylation. Exp Cell Res 1997;237 (1) 19- 28
PubMed Link to Article
Thody  AJ α-MSH and the regulation of melanocyte function. Ann N Y Acad Sci 1999;885217- 229
PubMed Link to Article
Haycock  JWWagner  MMorandini  RGhanem  GRennie  IGMac Neil  S α-Melanocyte-stimulating hormone inhibits NF-κB activation in human melanocytes and melanoma cells. J Invest Dermatol 1999;113 (4) 560- 566
PubMed Link to Article
Haycock  JWRowe  SJCartledge  S  et al.  α-Melanocyte-stimulating hormone reduces impact of proinflammatory cytokine and peroxide-generated oxidative stress on keratinocyte and melanoma cell lines. J Biol Chem 2000;275 (21) 15629- 15636
PubMed Link to Article
Hedley  SJMurray  ASisley  K  et al.  α-Melanocyte stimulating hormone can reduce T-cell interaction with melanoma cells in vitro. Melanoma Res 2000;10 (4) 323- 330
PubMed Link to Article
Quereux  GPandolfino  MCKnol  AC  et al.  Tissue prognostic markers for adoptive immunotherapy in melanoma. Eur J Dermatol 2007;17 (4) 295- 301
PubMed
Grichnik  JMBurch  JASchulteis  RD  et al.  Melanoma, a tumor based on a mutant stem cell? J Invest Dermatol 2006;126 (1) 142- 153
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Photographs taken 1 year before using α-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.

Graphic Jump Location
Place holder to copy figure label and caption
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.

Graphic Jump Location
Place holder to copy figure label and caption
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.

Graphic Jump Location

Tables

References

Abdel-Malek  ZSwope  VBSuzuki  I  et al.  Mitogenic and melanogenic stimulation of normal human melanocytes by melanotropic peptides. Proc Natl Acad Sci U S A 1995;92 (5) 1789- 1793
PubMed Link to Article
Kadekaro  ALKanto  HKavanagh  RAbdel-Malek  ZA Significance of the melanocortin 1 receptor in regulating human melanocyte pigmentation, proliferation, and survival. Ann N Y Acad Sci 2003;994359- 365
PubMed Link to Article
Hadley  MEDorr  RT Melanocortin peptide therapeutics: historical milestones, clinical studies and commercialization. Peptides 2006;27 (4) 921- 930
PubMed Link to Article
Virador  VMMuller  JWu  X  et al.  Influence of α-melanocyte-stimulating hormone and ultraviolet radiation on the transfer of melanosomes to keratinocytes. FASEB J 2002;16 (1) 105- 107
PubMed
Lande  SLerner  AB The biochemistry of melanotropic agents. Pharmacol Rev 1967;19 (1) 1- 20
PubMed
Abdel-Malek  ZAKadekaro  ALKavanagh  RJ  et al.  Melanoma prevention strategy based on using tetrapeptide α-MSH analogs that protect human melanocytes from UV-induced DNA damage and cytotoxicity. FASEB J 2006;20 (9) 1561- 1563
PubMed Link to Article
Dorr  RTLines  RLevine  N  et al.  Evaluation of melanotan-II, a superpotent cyclic melanotropic peptide in a pilot phase-I clinical study. Life Sci 1996;58 (20) 1777- 1784
PubMed Link to Article
Dorr  RTDvorakova  KBrooks  C  et al.  Increased eumelanin expression and tanning is induced by a superpotent melanotropin [Nle4-D-Phe7]-α-MSH in humans. Photochem Photobiol 2000;72 (4) 526- 532
PubMed Link to Article
Fitzgerald  LMFryer  JLDwyer  THumphrey  SM Effect of MELANOTAN, [Nle4, D-Phe7]-α-MSH, on melanin synthesis in humans with MC1R variant alleles. Peptides 2006;27 (2) 388- 394
PubMed Link to Article
Soltani  KBernstein  JELorincz  AL Eruptive nevocytic nevi following erythema multiforme. J Am Acad Dermatol 1979;1 (6) 503- 505
PubMed Link to Article
Kopf  AWGrupper  CBaer  RLMitchell  JC Eruptive nevocytic nevi after severe bullous disease. Arch Dermatol 1977;113 (8) 1080- 1084
PubMed Link to Article
Onsun  NSaracoglu  SDemirkesen  CKural  YBAtilganoglu  U Eruptive widespread Spitz nevi: can pregnancy be a stimulating factor? J Am Acad Dermatol 1999;40 (5, pt 2) 866- 867
PubMed
Reutter  JCLong  EMMorrell  DSThomas  NEGroben  PA Eruptive post-chemotherapy in situ melanomas and dysplastic nevi. Pediatr Dermatol 2007;24 (2) 135- 137
PubMed Link to Article
Piaserico  SAlaibac  MFortina  ABPeserico  A Clinical and dermatoscopic fading of post-transplant eruptive melanocytic nevi after suspension of immunosuppressive therapy. J Am Acad Dermatol 2006;54 (2) 338- 340
PubMed Link to Article
Alaibac  MPiaserico  SRossi  CR  et al.  Eruptive melanocytic nevi in patients with renal allografts: report of 10 cases with dermoscopic findings. J Am Acad Dermatol 2003;49 (6) 1020- 1022
PubMed Link to Article
Scott  GCassidy  LAbdel-Malek  Z α-Melanocyte-stimulating hormone and endothelin-1 have opposing effects on melanocyte adhesion, migration, and pp125FAK phosphorylation. Exp Cell Res 1997;237 (1) 19- 28
PubMed Link to Article
Thody  AJ α-MSH and the regulation of melanocyte function. Ann N Y Acad Sci 1999;885217- 229
PubMed Link to Article
Haycock  JWWagner  MMorandini  RGhanem  GRennie  IGMac Neil  S α-Melanocyte-stimulating hormone inhibits NF-κB activation in human melanocytes and melanoma cells. J Invest Dermatol 1999;113 (4) 560- 566
PubMed Link to Article
Haycock  JWRowe  SJCartledge  S  et al.  α-Melanocyte-stimulating hormone reduces impact of proinflammatory cytokine and peroxide-generated oxidative stress on keratinocyte and melanoma cell lines. J Biol Chem 2000;275 (21) 15629- 15636
PubMed Link to Article
Hedley  SJMurray  ASisley  K  et al.  α-Melanocyte stimulating hormone can reduce T-cell interaction with melanoma cells in vitro. Melanoma Res 2000;10 (4) 323- 330
PubMed Link to Article
Quereux  GPandolfino  MCKnol  AC  et al.  Tissue prognostic markers for adoptive immunotherapy in melanoma. Eur J Dermatol 2007;17 (4) 295- 301
PubMed
Grichnik  JMBurch  JASchulteis  RD  et al.  Melanoma, a tumor based on a mutant stem cell? J Invest Dermatol 2006;126 (1) 142- 153
PubMed Link to Article

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