MAP2K1-mutated melanocytic tumors have reproducible histopathologic features and share similarities with melanocytic tumors with BRAF V600E mutations.

BACKGROUND: Melanocytic tumors driven by MAP2K1 in-frame deletions are among the most recently described class of melanocytic neoplasms. The reported range of diagnoses and associated genomic aberrations in these neoplasms is wide and includes melanomas, deep penetrating melanocytomas, and pigmented epithelioid melanocytoma. However, little is known about the characteristics of these tumors, especially in the absence of well-known second molecular "hits." Moreover, despite their frequent spitzoid cytomorphology, their potential categorization among the Spitz tumors is debatable.

MATERIALS AND METHODS: We conducted a retrospective search through our molecular archives to identify sequenced melanocytic tumors with MAP2K1 in-frame deletions. We reviewed the clinical and histomorphological features of these tumors and compared them to similar neoplasms reported to date. In addition, we performed single-nucleotide polymorphism (SNP) array testing to identify structural chromosomal aberrations.

RESULTS: Of 27 sequenced tumors, 6 (22%) showed a pathogenic MAP2K1 in-frame deletion (with or without insertion) and were included in this series. Five (83%) were females with lesions involving the upper limb. Histopathologically, all neoplasms were compounded with plaque-like or wedge-shaped silhouettes, spitzoid cytomorphology, and impaired cytologic maturation. All cases showed background actinic damage with sclerotic stroma replacing solar elastosis, variable pagetoid scatter, and occasional dermal mitotic figures (range 1-2/mm2 ). Five cases (83%) had a small component of nevic-looking melanocytes. Biologically, these tumors likely fall within the spectrum of unusual nevi. Five cases (83%) had a relatively high mutational burden and four (67%) showed an ultraviolet radiation signature. Four cases (67%) showed in-frame deletion involving the p.I103_K104del locus while two cases (33%) showed in-frame deletion involving the p.Q58_E62del locus. SNP array testing showed structural abnormalities ranging from 1 to 5 per case. Five of these cases showed a gain of chromosome 15 spanning the MAP2K1 gene locus.

DISCUSSION AND CONCLUSION: Melanocytic tumors with MAP2K1 in-frame deletion could represent another spectrum of melanocytic tumors with close genotypic-phenotypic correlation. They are largely characterized by a spectrum that encompasses desmoplastic Spitz nevus as shown in our series and Spitz and Clark nevus as shown by others. Evolutionary, they share many similarities with tumors with BRAF V600E mutations, suggesting they are better classified along the conventional pathway rather than the Spitz pathway despite the frequent spitzoid morphology.