Track

Case Reports

Abstract

Cutaneous melanomas are typically driven by somatic mutations in BRAF, NRAS, KIT, or NF1, with kinase fusions being rare in non-Spitz melanomas. RAF1, a key MAPK pathway regulator, is infrequently rearranged with a reported incidence below 1%. Consequently, the clinicopathologic and prognostic features of RAF1-rearranged melanomas remain poorly characterized. We present a case of a fatal melanoma in a 24-year-old male, arising as a 1 cm papule on the left ankle. Histologically, the tumor was an ulcerated nodular melanoma (Breslow depth 4.1 mm), composed of predominantly epithelioid, amelanotic cells in nested architecture, lacking definitive spitzoid features. Sentinel lymph node biopsy confirmed metastasis (final stage: pT4bN1a). Molecular profiling revealed a triple wild-type melanoma harboring a MAP4::RAF1 fusion, a TERT promoter mutation, and several novel somatic alterations, with a tumor mutational burden of 7 mutations/Mb. Despite multiple lines of therapy—including dual immunotherapy and chemotherapy—the disease was refractory, and the patient died 18 months post-diagnosis. This case highlights a rare and aggressive example of MAP4::RAF1-fused, triple wild-type melanoma in a young adult, expanding the clinicopathologic and prognostic spectrum of RAF1-rearranged melanomas outside the Spitz lineage.