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Brief Report
October 2017

Association of Incident Amelanotic Melanoma With Phenotypic Characteristics, MC1R Status, and Prior Amelanotic Melanoma

Author Affiliations
  • 1Department of Dermatology, University of North Carolina, Chapel Hill
  • 2Department of Medicine, University of Virginia, Charlottesville
  • 3Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
  • 4Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York
  • 5Department of Internal Medicine, University of New Mexico Cancer Center, University of New Mexico, Albuquerque
  • 6Sydney School of Public Health, University of Sydney, Sydney, New South Wales, Australia
  • 7Department of Epidemiology, University of California, Irvine
  • 8USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles
  • 9Cancer Control Research, British Columbia Cancer Agency, Vancouver, British Columbia, Canada
  • 10Piedmont Cancer Registry, Centre for Epidemiology and Prevention in Oncology in Piedmont, Turin, Italy
  • 11Politecnico di Torino, Turin, Italy
  • 12Universitá degli Studi di Torino, Turin, Italy
  • 13George Institute for Global Health, Nuffield Department of Obstetrics and Gynecology, University of Oxford, England
  • 14Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill
  • 15Department of Surgery, University of North Carolina, Chapel Hill
JAMA Dermatol. 2017;153(10):1026-1031. doi:10.1001/jamadermatol.2017.2444
Key Points

Question  Are phenotypic characteristics, MC1R variants, and prior amelanotic melanoma associated with amelanotic melanoma?

Findings  In this analysis of population-based and cancer-based registries, absence of back nevi, presence of many freckles, a sun-sensitive phenotype, and prior amelanotic melanoma were associated with development of amelanotic melanoma. MC1R was associated with amelanotic melanoma, but this association lost significance in a model with phenotype.

Meaning  Prior amelanotic melanoma and the phenotypes associated with it should raise clinician index of suspicion for amelanotic melanoma when examining a suspicious but nonpigmented skin lesion, and clinicians might also use these characteristics to prompt periodic, meticulous screening of nonpigmented as well as pigmented skin lesions.


Importance  We previously reported that survival is poorer from histopathologically amelanotic than pigmented melanoma because of more advanced stage at diagnosis. Identifying patients at risk of amelanotic melanoma might enable earlier diagnosis and improved survival; however, the phenotypic characteristics and underlying genetics associated with amelanotic melanoma are unknown.

Objective  To determine whether phenotypic characteristics, carriage of MC1R variants, and history of amelanotic melanoma are associated with histopathologically amelanotic melanoma.

Design, Setting, and Participants  The Genes, Environment, and Melanoma (GEM) study is an international cohort study that enrolled patients with incident primary cutaneous melanomas from population-based and hospital-based cancer registries (1998 to 2003). The GEM participants included here were 2387 patients with data for phenotypes, MC1R genotype, and primary melanomas scored for histopathologic pigmentation. Of these 2387 patients with incident melanomas scored for pigmentation, 527 had prior primary melanomas also scored for pigmentation.

Main Outcomes and Measures  Associations of phenotypic characteristics (freckles, nevi, phenotypic index) and MC1R status with incident amelanotic melanomas were evaluated using logistic regression models adjusted for age, sex, study center, and primary status (single or multiple primary melanoma); odds ratios (ORs) and 95% CIs are reported. Association of histopathologic pigmentation between incident and prior melanomas was analyzed using an exact logistic regression model.

Results  This study included 2387 patients (1065 women, 1322 men; mean [SD] age at diagnosis, 58.3 [16.1] years) and 2917 primary melanomas. In a multivariable model including phenotypic characteristics, absence of back nevi, presence of many freckles, and a sun-sensitive phenotypic index were independently associated with amelanotic melanoma. Carriage of MC1R variants was associated with amelanotic melanoma but lost statistical significance in a model with phenotype. Further, patients with incident primary amelanotic melanomas were more likely to have had a prior primary amelanotic melanoma (OR, 4.62; 95% CI, 1.25-14.13) than those with incident primary pigmented melanomas.

Conclusions and Relevance  Absence of back nevi, presence of many freckles, a sun-sensitive phenotypic index, and prior amelanotic melanoma increase odds for development of amelanotic melanoma. An increased index of suspicion for melanoma in presenting nonpigmented lesions and more careful examination for signs of amelanotic melanoma during periodic skin examination in patients at increased odds of amelanotic melanoma might lead to earlier diagnosis and improved survival.

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