Molecular characterization and patient outcome of melanoma nodal metastases and an unknown primary site

Ann Surg Oncol. 2014 Dec;21(13):4317-23. doi: 10.1245/s10434-014-3799-y. Epub 2014 May 28.

Abstract

Background: Melanoma of unknown primary site (MUP) is not a completely understood entity with nodal metastases as the most common first clinical manifestation. The aim of this multicentric study was to assess frequency and type of oncogenic BRAF/NRAS/KIT mutations in MUP with clinically detected nodal metastases in relation to clinicopathologic features and outcome.

Materials and methods: We analyzed series of 103 MUP patients (period: 1992-2010) after therapeutic lymphadenectomy (LND): 40 axillary, 47 groin, 16 cervical, none treated with BRAF inhibitors. We performed molecular characterization of BRAF/NRAS/KIT mutational status in nodal metastases using direct sequencing of respective coding sequences. Median follow-up time was 53 months.

Results: BRAF mutations were detected in 55 cases (53 %) (51 V600E, 93 %; 4 others, 7 %), and mutually exclusive NRAS mutations were found in 14 cases (14 %) (7 p.Q61R, 4 p.Q61K, 2 p.Q61H, 1 p.Q13R). We have not detected any mutations in KIT. The 5-year overall survival (OS) was 34 %; median was 24 months. We have not found significant correlation between mutational status (BRAF/NRAS) and OS; however, for BRAF or NRAS mutated melanomas we observed significantly shorter disease-free survival (DFS) when compared with wild-type melanoma patients (p = .04; 5-year DFS, 18 vs 19 vs 31 %, respectively). The most important factor influencing OS was number of metastatic lymph nodes >1 (p = .03).

Conclusions: Our large study on molecular characterization of MUP with nodal metastases showed that MUPs had molecular features similar to sporadic non-chronic-sun-damaged melanomas. BRAF/NRAS mutational status had negative impact on DFS in this group of patients. These observations might have potential implication for molecular-targeted therapy in MUPs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Biomarkers, Tumor / genetics*
  • Child
  • Child, Preschool
  • Female
  • Follow-Up Studies
  • GTP Phosphohydrolases / genetics*
  • Humans
  • Infant
  • Infant, Newborn
  • Lymph Node Excision
  • Lymphatic Metastasis
  • Male
  • Melanoma / genetics
  • Melanoma / mortality
  • Melanoma / secondary*
  • Membrane Proteins / genetics*
  • Middle Aged
  • Mutation / genetics*
  • Neoplasm Staging
  • Neoplasms, Unknown Primary / genetics
  • Neoplasms, Unknown Primary / mortality
  • Neoplasms, Unknown Primary / pathology*
  • Prognosis
  • Proto-Oncogene Proteins B-raf / genetics*
  • Proto-Oncogene Proteins c-kit / genetics*
  • Survival Rate
  • Young Adult

Substances

  • Biomarkers, Tumor
  • Membrane Proteins
  • Proto-Oncogene Proteins c-kit
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • GTP Phosphohydrolases
  • NRAS protein, human