Abstract

Genetic profiling of biphasic melanocytic proliferations with “combined blue nevus” morphology has recently revealed at least two separate genetic signatures involved in their pathogenesis, including protein kinase C fusions and NRAS/IDH1 co-mutations. To our knowledge, only 6 cases in this latter group have been documented in the literature. We report the clinicopathologic findings of four melanocytic neoplasms with morphology resembling combined blue nevus and possessing both an activating NRAS mutation and additional pathogenic co-mutation. All cases occurred in young-to-middle-aged females, ranging in size from 5-8 mm. Histologically, each shared a biphasic morphology, including a largely subtle junctional proliferation with conventional nevic nests in the superficial dermis and a deeper, hypercellular proliferation of spindled-to-ovoid melanocytes lacking overt maturation. Cytologic atypia was mild/focal moderate at most, while one case showed rare superficial mitoses. Other recurrent features included pigmented melanocytes and collagen trapping. By IHC, all tested cases showed negative PRAME, retained p16, and low Ki-67 (≤1%). Next-generation sequencing revealed activating NRAS mutations (p.Q61R/K) in all cases along with pathogenic IDH1 p.R132C (n=3) or ARAF p.S214F (n=1, with additional WT1 copy loss). Transcriptomic profiling of NRAS/IDH1-mutated cases revealed significant clustering separate from GNAQ/GNA11-mutated blue nevi. Three cases underwent complete excision without recurrence on clinical follow-up. Given their reported rarity and increased genetic complexity, prediction of clinical behavior is difficult and further confounded by the existence of melanomas with NRAS/IDH1 co-mutations. In theory, those with multi-hit pathogenic mutations could be more likely to progress and thus may warrant management similar to other well-defined melanocytomas.