Disease kinetics but not disease burden is relevant for survival in melanoma of unknown primary tumor.

Melanoma of unknown primary (MUP) is a type of metastatic melanoma with no evidence of a primary tumor. Recent evidence suggested better survival in MUP as compared to melanoma with a known primary site (MKP). However, prognostic markers that reliably predict overall survival in MUP are lacking. The primary objective of this study was to analyze the mutational status of the BRAF, NRAS, and KIT oncogenes and to investigate if the genotype or other clinical parameters were associated with overall survival. We retrospectively analyzed the genotype and the clinical course of 40 patients with MUP. Mutations of BRAF and NRAS were determined with pyrosequencing. Mutations of KIT were investigated with a nested PCR approach followed by Sanger sequencing. Survival fractions were calculated applying the Kaplan-Meier model. Mutations in the BRAF (50.0%), NRAS (17.5%), and KIT genes (5.0%) were found frequently, but had no major impact on overall survival (p=0.62). The AJCC stage was a strong prognostic factor with a hazard ratio for death of 0.17 (stage III vs. IV; p=0.04). All patients diagnosed with stage III disease survived the median follow-up period of 23 months (p=0.03). The survival rates of patients with stage IV were significantly associated with rapid disease progression but not with metastatic tumor load at primary diagnosis (p=0.01). Altogether, AJCC stage and time to disease progression were important prognostic parameters. We propose that the kinetics of the disease but not the initial metastatic burden nor the mutational status is relevant for survival in advanced MUP.