Cutaneous melanocytic tumors with concomitant NRAS Q61R and IDH1 R132C mutations: a report of six cases

We report a series of six melanocytic proliferations harboring both NRAS and IDH1 hotspot mutations. Clinically, there was no specific sex-ratio, ages ranged from 18 to 85 years, and the trunk and limbs were the most affected localizations. In half of the cases, progressive modification of a pre-existing nevus was reported. Morphologically, all tumors were predominantly based in the dermis and the most striking pathological finding was the presence of a background architecture of congenital-type nevi with a superimposed biphasic pattern formed by dendritic pigmented melanocytes surrounding areas of nevoid melanocytes. This finding was further underscored by HMB45 staining, which was positive in the dendritic cells and negative in the nevoid melanocytes. Four cases displayed increased cellularity and one case showed increased dermal mitotic activity. DNA and RNA sequencing revealed NRAS Q61R and IDH1 R132C co-mutations in all six cases, with homogeneous expression data according to unsupervised clustering analysis. Array-CGH revealed no copy number alteration for the two most cellular and mitogenic cases. All were surgically excised, available follow-up for two patients showed no relapse nor metastases. We hypothesize that the IDH1 mutation is a secondary event in a pre-existing NRAS-mutated nevus and could be in part responsible for the emergence of a pigmented dendritic dermal component. So far, such co-mutations have been reported in one benign melanocytic nevus and several melanomas. This combination could represent a new subgroup of intermediate prognosis (melanocytoma) with a distinctive morphology. Further acquisition of genomic anomalies could progressively lead to malignant transformation.