Abstract:

Activating gene mutations and chromosomal copy number gains represent two fundamental mechanisms of oncogenesis. Activating mutations in the NRAS gene initiate the majority of congenital melanocytic nevi and a subset of acquired melanocytic nevi. We describe the distinct clinicopathologic features of melanocytic tumors with mutation and secondary amplification of mutant NRAS. In our cohort (n=7), the tumors generally occurred in younger patients (median age 20 years, range 6 to 56) and presented as pink to brown papules on the helix (n=4) and extremities (n=3). Histopathologically, the tumors were compound proliferations of epithelioid, polygonal, and fusiform melanocytes with abundant amphophilic cytoplasm, enlarged and irregularly shaped nuclei, and conspicuous nucleoli. Melanocytes were arrayed as nests and short fascicles within the dermis with limited maturation and occasional extension into the subcutis. Occasional dermal mitoses were present, including rare atypical mitotic figures. Genetic analysis by comparative genomic hybridization, targeted next generation sequencing, and/or Sanger sequencing revealed missense point mutations in NRAS at codon 61 (Q61R in 3, Q61H in 2, Q61L in 2) and concurrent copy number amplification of the mutant NRAS locus. Limited additional copy number alterations were present in all cases, including loss of chromosome 1p distal to NRAS and loss of portions of chromosome 9. In conclusion, melanocytic tumors with amplification of mutant NRAS show distinct clinicopathologic features, with a predilection for younger patients, frequent occurrence on the helix, atypical spitzoid cytomorphology, and nested and fascicular growth. The apparent intermediate morphologic and genetic features suggests that these tumors may represent an intermediate stage of melanocytic neoplasia. While they show histopathologic overlap with tumors of the Spitz lineage, they are genetically distinct.

Financial Disclosure: No current or relevant financial relationships exist.

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Jeffrey Cloutier, MD, PhD