What question did this study set out to answer?

The study aims to analyze the oncogenic patterns of melanoma of unknown primary and compare its clinical course with melanoma of known primary origins.

February 22, 2026

Melanoma of unknown primary shows oncogenic pattern and clinical course of sun-exposed melanoma

Key Points

The study aims to analyze the oncogenic patterns of melanoma of unknown primary and compare its clinical course with melanoma of known primary origins.
Included MUP patients diagnosed between 1999 and 2022 from the DeCOG registry ADOREG.
Compared with MKP patients from the skin cancer center Essen diagnosed in the same period.
Conducted genetic analyses using next-generation sequencing on available tumour samples.
Survival outcomes compared using Kaplan-Meier, adjusted for age, sex, and tumour stage.
Identified 727 MUP and 587 MKP patients; median age at diagnosis was 62 for MUP and 63 for MKP.
46% of MUP patients had stage III disease at first diagnosis.
Overall survival at 48 months was 65% for MUP and 68% for MKP patients.
Common mutations included BRAF V600E in 39.1% and TERT promoter mutations in 66.4% of MUP samples.

Abstract

Abstract Background Melanoma of unknown primary accounts for up to 10% of all metastatic melanoma patients. The origin of melanoma of unknown primary is unclear, and previous studies on the clinical course in comparison to cutaneous melanoma have reported different results. Objective The study was conducted to assess the oncogenic pattern of melanoma of unknown primaries (MUP) and compare clinical course with melanoma of known cutaneous primary (MKP). Methods MUP patients diagnosed between 1999 and 2022 were included in this cohort study from the prospective multicentre real-word DeCOG registry ADOREG and from the tumour database of the University Hospital Essen. For comparison, consecutive MKP patients with stage III or IV disease from the skin cancer centre Essen between 1999 and 2022 were used. The median follow-up was 3.5 years. Available tumour samples were genetically analysed using next-generation sequencing. Survival outcome was compared to MKP patients adjusted for age, sex and tumour stage with Kaplan-Meier. Results In total, n=727 MUP and n=587 MKP patients were identified. Median age of MUP and MKP patients at first diagnosis was 62 and 63 years, respectively. More patients were male (MUP 62%, n=448, MKP 56%, n=330). At first diagnosis, 46% of MUP (n=337) patients had stage III disease. Overall survival (OS) at 48 months was 65% (95% CI 61-69) for all MUP and 68% (95%CI 64-72) for all MKP patients. Survival analyses adjusted for age, sex and tumour stage showed comparable OS rates for MUP and MKP patients. The genetic analyses among 110 MUP patients detected CT and CCTT as most common nucleotide variations. Median tumour mutational burden was 5 per million bases (95% CI 4-5). Activating BRAF V600E (c.620T A) mutations were detected in 39.1% (n=43), activating NRAS mutations in 33.6% (n=37), RAC1 P29S mutations in 6.3% (n=7) and TERT promoter mutations in 66.4% (n=73) of the analysed tumour samples. No activating KIT mutations were detected. Conclusions The oncogenic pattern of MUP showed a UV signature suggesting an origin in sun-exposed localisations. OS of MUP is comparable to melanoma of known cutaneous primary.

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