Original ArticlesCutaneous Melanocytic Tumors With Concomitant NRASQ61R and IDH1R132C Mutations A Report of 6 CasesMacagno, Nicolas MD, PhD*,†; Pissaloux, Daniel PhD‡,§; Etchevers, Heather PhD†; Haddad, Véronique PhD‡; Vergier, Beatrice MD, PhD∥; Sierra-Fortuny, Sandrine MD¶; Tirode, Franck PhD‡,§; de la Fouchardière, Arnaud MD, PhD‡,§Author Information *APHM, Timone, Department of Pathology †INSERM, MMG, Aix Marseille University, Marseille ‡Department of Biopathology, Centre Léon Bérard §INSERM 1052, CNRS 5286, Centre Léon Bérard, Cancer Research Center of Lyon, Equipe Labellisée Ligue contre le Cancer, Université de Lyon, Université Claude Bernard Lyon 1, Lyon ∥Pathology Department, Hôpital Haut-Lévêque, University Hospital of Bordeaux, Bordeaux ¶Cabinet de dermatologie, Le Mans, France A.F. conceived the study and provided the cases. N.M. and A.F. collected and analyzed the clinical and histopathologic data, and wrote, edited, and reviewed the manuscript. D.P., F.T., and V.H., performed the molecular analysis of the samples. B.V. contributed one case and reviewed the manuscript. H.E. reviewed the manuscript. S.S.F. and B.V. contributed one case and reviewed the manuscript. The study was conducted according to the Declaration of Helsinki and has been approved by the research ethics committee of the Centre Léon Bérard, Lyon, France (Ref: L20-08). Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: Nicolas Macagno, MD, PhD, APHM, CHU Timone, Department of Pathology, Marseille 13385, France (e-mail: [email protected]). The American Journal of Surgical Pathology: October 2020 - Volume 44 - Issue 10 - p 1398-1405 doi: 10.1097/PAS.0000000000001500 Buy Metrics Abstract We report a series of 6 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 pathologic 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 1 case showed increased dermal mitotic activity. DNA and RNA sequencing revealed NRASQ61R and IDH1R132C comutations in all 6 cases, with homogenous expression data according to unsupervised clustering analysis. Array-comparative genomic hybridization revealed no copy number alteration for the 2 most cellular and mitogenic cases. All were surgically excised, available follow-up for 2 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 comutations 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. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.