MAP2K1-mutated melanocytic tumors: correlation of histological features with their molecular functional class based on a study of 114 cases.

MAP2K1: mutated melanocytic tumors are relatively recently described and show diverse morphological features and complex genetic aberrations which require further characterization. In this study we describe the clinical, histomorphological, immunohistochemical and genetic characteristics of a cohort of 114 MAP2K1-mutated melanocytic neoplasms, including benign (n = 55), intermediate (n = 34) and malignant (n = 25) tumors, collected from different institutions, harboring Class I (RAF-dependent) (n = 16), Class II (RAF-regulated) (n = 59) and/or Class III (RAF-independent) (n = 44) MAP2K1 mutations. Five lesions exhibited dual MAP2K1 mutations, all involving 2 different functional classes. Benign melanocytic lesions with Class II/III MAP2K1 mutations show reproducible morphologic patterns, compatible with the assumption that the MAP2K1 variant is the molecular driver mutation in these lesions. These melanocytic lesions fall into a morphological spectrum which include either mainly dermal-based lesions with combined (nevoid to spitzoid) cytonuclear characteristics and associated desmoplastic stroma (22%), or mainly junctionally-located lesions with spitzoid Clark (SPARK) morphology (18%), as well as lesions with overlapping features (6%). A minority of lesions show a dysplastic nevus (4%) or desmoplastic Spitz nevus morphology (3%), that could represent the ends of this morphologic spectrum. Chromosome 15 amplifications and dual MAP2K1 mutations were demonstrated in a subset of lesions with the combined desmoplastic morphology. Furthermore, we describe MAP2K1-driven melanocytic lesions with secondary well-recognized pathogenic mutations, including WNT-activated melanocytomas (12%), but also a new, genetically and morphologically heterogenous group of melanocytomas, most often harboring Class II MAP2K1 mutations in conjunction with RAF-activating co-mutations (11%). In MAP2K1-driven melanoma, we demonstrate the presence of secondary mutations in classical progression genes, such as TERT promoter and CDKN2A, and a plexiform dermal, superficial spreading or desmoplastic melanoma morphology. Lastly, lesions harboring only Class I MAP2K1 mutations are mostly melanoma, commonly have RAF-activating co-mutations and show a heterogeneous morphological phenotype.