Abstract
Previous work identified a subset of melanocytic nevi with distinctive histomorphologic features associated with gains of chromosome 15q. Subsequently, two additional cases with similar morphology demonstrated in-frame MAP2K1 deletions together with 15q gains, suggesting a potential unifying genetic pathway. This study aimed to further characterize the molecular and clinicopathologic features of such lesions through retrospective and prospective analysis. A total of eleven melanocytic tumors were analyzed. This cohort included four cases from a previously published series as well as five newly identified, prospectively collected cases. For completeness, two additional tumors with known MAP2K1 mutations and chromosome 15q gains—previously reported by some of our co-authors—were reanalyzed and incorporated into the overall analysis. All tumors underwent comprehensive histopathologic evaluation, assessment of 15q copy number status by SNP microarray, FISH, or whole exome sequencing, and next-generation sequencing to detect MAP2K1 alterations and other relevant oncogenic events. All eleven tumors displayed reproducible histopathologic features: a dome-shaped silhouette, Clark’s/dysplastic nevus-like epidermal changes, and a prominent dermal component with sclerotic stroma. Each case harbored a copy number gain of chromosome 15q and an in-frame MAP2K1 deletion. No lesion showed additional high-risk oncogenic mutations, aside from isolated findings in TP53, NF1, FBXW7, and ROS1. All MAP2K1 variants were classified as Class 2 or Class 3, capable of activating the MAPK pathway independently of BRAF or NRAS. Follow-up data revealed indolent behavior, including one local recurrence without histologic progression. We describe a novel subset of melanocytic tumors defined by distinctive morphologic features, 15q copy number gains, and Class 2/3 MAP2K1 in-frame deletions. These findings suggest a unique, pathway of nevogenesis. While biologically indolent, the presence of atypical features in select cases supports cautious clinical management, including complete excision and molecular correlation when appropriate.

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