Sclerosing melanocytic tumors with MAP2K1 in frame deletions and 15q gains: A distinctive pathway of nevogenesis with reproducible morphology.

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.