Clinical, Morphologic, and Molecular Features of Benign and Intermediate-grade Melanocytic Tumors With Activating Mutations in MAP2K1.

Abstract

Activating mutations in MAP2K1 can be seen in benign and intermediate-grade melanocytic neoplasms with spitzoid morphology. We analyzed the clinical, histopathologic, and genetic features for 16 cases of benign and intermediate-grade melanocytic tumors harboring activating MAP2K1 mutations. We compared them to Spitz neoplasms with characteristic Spitz fusions or HRAS mutation. We also compared the mutational pattern of benign and intermediate-grade MAP2K1 -mutated neoplasms and melanomas with activating MAP2K1 mutations. Among the 16 cases, the favored morphologic diagnosis was Spitz nevus (8/16), atypical Spitz tumors (6/16), and deep penetrating nevus (2/16). The 2 most common architectural patterns seen included a plaque-like silhouette with fibroplasia around the rete reminiscent of a dysplastic nevus (n=7) or a wedge-shaped or nodular pattern with the plexiform arrangement of the nests aggregating around the adnexa or neurovascular bundle (n=8). The cases with dysplastic architecture and spitzoid cytology resembled dysplastic Spitz nevi. Compared with true Spitz neoplasms, MAP2K1 -mutated neoplasms occurred in older age groups and had more frequent pagetosis and a lower average mitotic count. The most common type of mutation in the benign and intermediate-grade cases in the literature involves an in-frame deletion, while, in melanomas, missense mutations are predominant. Benign and intermediate-grade melanocytic neoplasms with activating mutations in MAP2K1 can have morphologic overlap with Spitz neoplasms. A significant proportion of melanomas also have activating MAP2K1 mutations. In-frame deletions are predominantly seen in the benign and intermediate-grade cases, and missense mutations are predominantly seen in melanomas.