Clinical, Morphologic, and Genomic Differences in Deep-Penetrating Nevi and Deep-Penetrating Nevus-like Melanomas

Deep-penetrating nevi (DPNs) are characterized by activating mutations in the MAP kinase and Wnt/β-catenin pathways that result in large melanocytes with increased nuclear atypia, cytoplasmic pigmentation, and often mitotic activity. Together with a lack of maturation, this constellation of findings creates challenges for pathologists to distinguish DPN from DPN-like melanoma. To assess the utility of next-generation sequencing (NGS) in resolving this diagnostic dilemma, we performed NGS studies on 35 lesions including 24 DPNs and 11 DPN-like melanomas to characterize the specific genomic differences between the 2 groups and elucidate the genetic events involved in malignant transformation of DPNs. Compared with DPNs, DPN-like melanomas were clinically larger in size (1.1 vs 0.6 cm, P = .02) and on histopathologic examination more frequently showed high-grade nuclear atypia (11/11 vs 9/24; P = .00052), increased mitotic activity (mean 3.9 vs 1.3 per mm²; P = .0004), sheet-like growth pattern (5/11 vs 2/24; P = .01), and involvement of the subcutis (4/5 vs 3/13; P = .026). From a genomic standpoint, DPN-like melanomas had a higher tumor mutation burden (mean 37.1 vs 7.8 mutations/megabase; P = .002) than DPNs and more frequently harbored NRAS mutation (3/11 vs 1/24; P = .046), whereas MAP2K1 in-frame deletions were only identified in DPNs (0/11 vs 5/24). There was no statistically significant difference in the frequency or type of CTNNB1 or APC mutations between the 2 groups. Within progression genes, DPN-like melanomas were more frequently found to have pathogenic variants in TERT promoter (7/11 vs 0/24; P < .00001), CDKN2A (4/11 vs 0/24; P = .0008), and protein subunits of the SWI/SNF complex (7/11 vs 3/24; P = .02) compared with DPNs. Our findings provide a framework for employing NGS in the evaluation of deep-penetrating melanocytic tumors.