Fatal Melanoma With MAP4::RAF1 Fusion: Expanding the Clinicopathologic and Prognostic Spectrum of RAF1-Fused Melanomas

Cutaneous melanomas are most commonly driven by somatic mutations in genes such as BRAF , NRAS , KIT , or NF1 , with kinase fusions being rare in conventional melanomas of non-Spitz lineage. RAF1 , a key upstream regulator of the mitogen-activated protein kinase pathway, is infrequently rearranged in non-Spitz melanomas (ie, bona fide melanomas without Spitz-nevus-like cytomorphology), with a reported frequency of less than 1%. As a result, the clinicopathologic features and prognostic implications of RAF1 -rearranged melanomas remain poorly defined. We report a case of melanoma harboring a MAP4::RAF1 fusion in a 24-year-old man who presented with a 1-cm papule on the left ankle. Histopathologically, the tumor was an ulcerated nodular melanoma with a Breslow thickness of 4.1 mm. The tumor cells were predominantly epithelioid and amelanotic, arranged in large and small nests, without definitive spitzoid cytomorphologic features. Sentinel lymph node biopsy revealed metastatic melanoma, resulting in a final stage of pT4bN1a. Molecular profiling demonstrated a triple wild-type melanoma harboring a MAP4::RAF1 fusion, a TERT promoter mutation, and several additional previously undescribed somatic mutations, with a panel-derived tumor mutational burden of 7 mutations/Mb, as estimated using a targeted next-generation sequencing assay with an approximately 2.1 Mb capture region. The disease was refractory to multiple lines of treatment, including dual immunotherapy and chemotherapy, and the patient died 18 months after diagnosis. This case represents a rare and fatal example of a triple wild-type cutaneous melanoma with a MAP4::RAF1 fusion in a young adult, thereby expanding the clinicopathologic and prognostic spectrum of RAF1 -fused melanomas of non-Spitz lineage.