Molecular Characterization of Sclerosing Nevi With Pseudomelanomatous Features

ABSTRACT Introduction Sclerosing nevi with pseudomelanomatous features (SNPF) are rare melanocytic lesions characterized by a distinctive trizonal architecture, created by lateral shouldering of the junctional component and nests of melanocytes within the dermis that can histologically mimic melanoma, posing a diagnostic dilemma. Although prior clinicopathologic studies suggest benign behavior, their molecular features have not been characterized. Methods We retrospectively identified nine SNPFs (2004–2024) and performed detailed histopathologic and immunohistochemical evaluation. Targeted next‐generation sequencing (NGS) with a 498‐gene hybrid capture‐based panel was performed on microdissected, melanocyte‐enriched tissue, with macrodissection used as salvage in low nucleic acid yield cases that initially failed. SNPF results were compared to a comparator group of BRAF ‐mutated melanomas tested on the same assay. Results Patients ranged from 25 to 65 years (median: 41), with lesions most commonly on the trunk. All cases demonstrated classic trizonal morphology with epidermal flattening, superficial dermal fibroplasia, and deeper dermal nevus nests. Immunohistochemistry showed uniform PRAME negativity and retained mosaic p16 expression. Molecular testing was successful in eight of the nine cases, all of which harbored a BRAF V600E mutation (VAF: 1.3%–27%). No additional pathogenic mutations or copy number alterations were identified. Comparator BRAF ‐mutated melanomas had additional, detectable co‐occurring pathogenic mutations and/or copy number variations in 19 of the 20 cases. Conclusions SNPFs consistently demonstrate a molecular profile indistinguishable from conventional benign nevi and lack genomic features of melanoma. These findings provide molecular support for the benign nature of SNPF.