Multidisciplinary Care for Melanoma of Unknown Primary: Experience in the Era of Molecular Profiling

Background Melanoma of unknown primary (MUP) accounts for approximately 3% of melanoma diagnoses. This study sought to evaluate treatment and outcomes for a modern MUP cohort. Methods A retrospective review of MUP was performed at a tertiary referral cancer center. Results Of 815 melanoma patients, 67 (8.2%) had MUP. Men were more likely to have MUP than women (67% vs. 55%; p = 0.04). The most common sites of MUP were lymph nodes (28%), visceral solid organs (25%), brain (16%), and skin/subcutaneous tissues (10%). Of the patients who underwent tumor genomic profiling, 52% harbored pathogenic BRAF mutations. Of the 24 patients who underwent multi-gene panel testing, all had pathogenic mutations and 21 (88%) had mutations in addition to or exclusive of BRAF, including 11 patients (46%) with telomerase reverse transcriptase promoter mutations. Checkpoint inhibitors (39%) and BRAF-MEK inhibitors (7%) were the most common first-line treatments. Upfront surgical resection was used for 25% of the MUP patients, and 12 of these resections were for curative intent. During a median follow-up period of 22.1 months, the median overall survival (OS) was not met for the patients with MUP isolated to lymph nodes. At 56.8 months, 75% of these patients were alive. The median OS was 37.4 months for skin/soft tissue MUP, 33.3 months for single solid organ viscera MUP, and 29.8 months for metastatic brain MUP. Conclusion Multigene panel testing identified pathogenic mutations in all tested MUP patients and frequently identified targets outside BRAF. Despite advanced stage, aggressive multimodal therapy for MUP can be associated with 5-year OS and should be pursued for appropriate candidates.