Abstract

Melanocytomas” are low-grade borderline melanocytic neoplasm with a driver mutation (typically canonical BRAF, NRAS, GNAQ, or GNA11) and a secondary morphology-modifying genetic event. We hypothesized that most nevi previously diagnosed as “combined nevus”, represent WHO-defined melanocytomas. To investigate this, we retrieved 187 cases previously diagnosed as combined nevi, from our institutional archives and consultation files, all of which had material available for histologic review. We studied morphologic features on H&E-stained sections and IHC. Of 187 cases, 63 (34%) were confirmed as DPN by IHC and 47 cases (25%) were non-DPN lesions that showed IHC support for classification as another type of melanocytoma, nevus variant, or combined nevus. Among these 47 cases, 30 were identified as lesions such as PKC-fused neoplasms, NRAS/ IDH1-mutated neoplasms, BAP1-inactivated lesions, and pigmented epithelioid melanocytomas. The remaining 17 cases were categorized as other specific nevus types, including special site nevi (with or without congenital features), dysplastic nevi with focal epithelioid or spindled change, blue nevi with cellular features, and variants such as Reed, Spitz, perineuriomatous, or desmoplastic nevi. In 77 of the 187 cases (41%), IHC could not be performed or yielded inconclusive results; a subset of these currently pending next-generation sequencing. Our findings show that a substantial proportion of combined nevi morphologically and/or immunohistochemically represent recognized melanocytomas. These nevi with more than one cytomorphologic appearance (typically more or less epithelioid or spindled) cause diagnostic difficulty and can lead to consultation with immunohistochemical and/or molecular work-up. A large percentage of these lesions represent WNT-activated melanocytomas. PKC-fused neoplasms may be relatively common amongst combined nevi. NRAS driven melanocytic neoplasms commonly show both epithelioid and spindled features. BRAF nevi can less commonly show desmoplastic and perineuriomatous spindle cell features. Recollection of the differential diagnosis of “combined” nevi, with utilization of select IHC markers, should help avoid over diagnosis as melanoma arising in nevi.