Late Recurrent Spitz Melanoma With a TMEM106B::BRAF Fusion

Melanoma is a clinically and genetically heterogeneous malignancy that can recur long after initial treatment. We report the case of a 70-year-old man who presented with metastatic cutaneous melanoma 36 years after the initial diagnosis. Initially diagnosed with nodular melanoma on the left heel at age 34 years, the patient experienced metastatic spread to the left groin lymph nodes by age 36 years, followed by various systemic therapies, including interferon and cytokine therapy, and subsequent observation, over 15 years. Two years before his current presentation, the patient noted a growing mass in his right thigh and an enlarged left inguinal lymph node. Fine-needle aspiration biopsy of the lymph node confirmed the recurrence of melanoma. He subsequently underwent inguinofemoral lymph node dissection and resection of the right thigh mass. Histopathological evaluation revealed melanoma characterized by tumorigenic proliferation of pleomorphic epithelioid and spindle cells with abundant eosinophilic cytoplasm, large nuclei with prominent nucleoli, sparse lymphocyte infiltration, and minimal necrosis, consistent with an initial diagnosis of Spitzoid melanoma. Genetic profiling using targeted next-generation sequencing identified a novel TMEM106B :: BRAF fusion, along with CHEK2 and MUTYH mutations. The BRAF fusion supports the diagnosis of Spitz melanoma, a genetically defined subset of Spitzoid melanoma. This case represents the first report of a TMEM106B :: BRAF fusion in melanoma, emphasizing the critical role of molecular profiling in diagnosing and managing this malignancy, and suggesting a potential avenue for future therapeutic exploration.