Spitz Nevi With Novel BRAF Fusions: A Report of Two Cases With Striking Morphologic Features

Abstract: Spitz neoplasms comprise a spectrum of melanocytic lesions with overlapping clinical and histologic features. BRAF fusions account for only 5%–6% of Spitz neoplasms with a limited number of fusion partners being characterized. We report 2 Spitz nevi with novel BRAF fusions and reproducible morphologic findings. The first case, a 35-year-old man with a finger mass, morphologically demonstrated intraepidermal and dermal proliferation of enlarged epithelioid melanocytes without maturation, and a striking pattern of neurotropism and angiotropism. Immunohistochemistry revealed <30% PRAME expression and retained p16, while next-generation sequencing identified a novel in-frame AHNAK::BRAF fusion. The second case, a 47-year-old man with an atypical skin lesion on the back of his neck, exhibited a circumscribed intradermal proliferation of epithelioid and spindle melanocytes with Spitzoid cytomorphology, again characterized by the striking pattern of neurotropism and entrapment of epithelioid cells within a fibrous stroma. This lesion was PRAME-negative with retained p16, and molecular studies identified a novel PDE4DIP::BRAF fusion. Both fusions preserved the BRAF kinase domain while eliminating its N-terminal regulatory regions. These cases expand the molecular spectrum of Spitz neoplasms and underscore neurotropism as a potential morphologic clue for BRAF fusion-driven Spitz nevi.