Comprehensive Genomic Characterization of Primary Dermal Melanoma: Delineating it from Metastatic Melanoma with...

Primary dermal melanoma (PDM) is a rare type of melanoma that originates in the dermis or subcutis without epidermal involvement. PDM poses significant diagnostic challenges for accurate staging, because it may be confused with cutaneous metastatic melanoma (CMM). To assess potential misclassification of PDM, we retrospectively reviewed referred cases of metastatic melanoma with unknown primary (MUP) that underwent concurrent molecular profiling using the MSK-IMPACT platform. Nineteen cases meeting criteria for PDM were identified and exhibited a lower overall burden of genomic alterations, and a superior overall survival compared with CMM, supporting their reclassification as primary neoplasms rather than metastatic lesions. In PDM, the most frequently altered genes were TERT (79%), TP53 (37%), NRAS (37%), and APC (32%). Exclusive mutations identified in PDM included ZFHX3, FGFR3, NTRK3, and SMARCA4. Compared with CMM, PDM demonstrated a distinct mutational profile, characterized by a higher frequency of NRAS and TP53 mutations, and a lower prevalence of BRAF alterations. Clinically, PDM exhibited a more favorable overall survival (follow-up: 8.9 years) relative to conventional primary melanoma, further supporting the distinction from metastatic disease. Patients harboring isolated NRAS or concurrent NRAS/TP53 mutations exhibited superior survival compared with their respective NRAS wild-type or NRAS/TP53 wild-type counterparts. Taken together, these findings highlight the genomic and clinical distinctiveness of PDM relative to CMM, refine its molecular characterization, and support its recognition as a separate entity with implications for accurate staging and therapeutic decision-making.