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Early diagnosis improves melanoma survival, yet the histopathological diagnosis of cutaneous primary melanoma can be challenging even for expert dermatopathologists. Analysis of epigenetic alterations, such as DNA methylation, that occur in melanoma can aid in its early diagnosis. Using a genome-wide methylation screen, we assessed CpG methylation in a diverse set of 89 primary invasive melanomas, 73 nevi, and 41 melanocytic proliferations of uncertain malignant potential, classified based on interobserver review by dermatopathologists. Melanomas and nevi were split into training and validation sets. Predictive modeling in the training set using ElasticNet identified a 40-CpG classifier distinguishing 60 melanomas from 48 nevi. High diagnostic accuracy (area under the receiver operator characteristics (ROC) curve (AUC)=0.996, sensitivity=96.6%, and specificity=100.0%) was independently confirmed in the validation set (29 melanomas, 25 nevi) and other published sample sets. The 40-CpG melanoma classifier included homeobox transcription factors and genes with roles in stem cell pluripotency or the nervous system. Application of the 40-CpG melanoma classifier to the diagnostically uncertain samples assigned melanoma or nevus status, potentially offering a diagnostic tool to assist dermatopathologists. In summary, the robust, accurate 40-CpG melanoma classifier offers a promising assay for improving primary melanoma diagnosis.

Telomerase reverse transcriptase (TERT) promoter mutations are commonly found in malignant melanomas but rare in melanocytic nevi. To assess its potential diagnostic utility for the distinction of melanoma from nevus, we determined the TERT promoter mutation status of 86 primary melanomas, 72 melanocytic nevi, and 40 diagnostically problematic melanocytic proliferations. Of the 86 melanomas, 67 (77.9%) were TERT-positive, defined as harboring a hotspot TERT promoter mutation at positions -124C>T, -124_125CC>TT, -138_139CC>TT, or -146C>T. Of the 72 nevi, only 1 (1.4%) was TERT-positive. Of the 40 diagnostically uncertain melanocytic proliferations, 2 (5.0%) were TERT-positive. TERT positivity as a test for melanoma versus nevus had an accuracy of 87.3% [95% confidence interval (CI), 81.1-92.1], a sensitivity of 77.9% (95% CI, 68.9-85.4), a specificity of 98.6% (95% CI, 95.8-100), a positive predictive value of 98.5% (95% CI, 95.6-100), and a negative predictive value of 78.9% (95% CI, 72.6-85.4). Our results indicate that hotspot TERT promoter mutation status may be a useful ancillary parameter for the diagnosis of melanoma. In particular, the high specificity of these mutations for melanoma indicates the presence of a TERT promoter mutation in a melanocytic neoplasm associated with diagnostic controversy, or uncertainty should increase concern for a melanoma.

Burn injuries are known to compromise host immune defenses through disruption of mucocutaneous barriers and suppression of cell-mediated immune responses, which may render patients with burn injuries susceptible to viral infections in the days to years after an initial insult. We report a case of verrucae planae developing as a secondary condition confined to former xenograft sites in a child, appearing more than 3.5 years after initial second-degree burn injuries. Only a few reports have previously described the development of verrucae in former burn sites, with most reporting latency to onset of verrucae appearance of months rather than years. Current hypotheses suggest that the postburn immune response shifts from an early proinflammatory to a late antiinflammatory response characterized by altered cytokine profiles and diminished cellular cytotoxicity mediated by cytotoxic T-lymphocytes, natural killer cells, and epidermal antigen-presenting cells, which together likely contribute to an enduring postburn regional immunosuppression that allows for the seeding and proliferation of viral agents.