Intrapatient homogeneity of BRAFV600E expression in melanoma

Am J Surg Pathol. 2014 Mar;38(3):377-82. doi: 10.1097/PAS.0000000000000136.


Concern regarding the presence of intertumoral heterogeneity of BRAF mutation status in patients with metastatic melanoma has led to uncertainty surrounding which specimens should preferentially undergo BRAF testing. We sought to examine the extent of intrapatient heterogeneity of BRAF(V600E) protein expression in patients with multiple tumors. Sixty-four patients with 171 tumors at various stages of disease progression had tumor BRAF(V600E) protein expression immunohistochemically (IHC) assessed using the BRAF(V600E) mutant-specific antibody VE1. Melanoma sections were examined for staining intensity (score 0 to 3), the presence of intratumoral heterogeneity, and concordance with molecular BRAF genotype. Intrapatient, intertumoral heterogeneity of BRAF(V600E) expression was also assessed by comparing VE1 staining on different tumors within the same patient. All specimens from 64 patients displayed complete intertumoral homogeneity of BRAF(V600E) expression status, and all tumors had concordant molecular and IHC BRAF status. Only 1 patient demonstrated >1 level of staining intensity heterogeneity between specimens. Intratumoral heterogeneity of staining intensity was not observed in any specimen. IHC-measured BRAF(V600E) protein expression displays complete intertumoral homogeneity, minimal intertumoral intensity heterogeneity, and no intratumoral heterogeneity in metastatic melanoma patients in various stages of disease progression. Our results suggest that, provided there is adequate quantity of viable tumor cells and minimal admixture of nontumor cells, testing any melanoma sample from a patient with metastatic disease will accurately determine BRAF status for treatment planning.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers, Tumor / analysis
  • Biomarkers, Tumor / genetics*
  • Genetic Predisposition to Disease
  • Humans
  • Immunohistochemistry
  • Melanoma / enzymology
  • Melanoma / genetics*
  • Melanoma / pathology
  • Mutation*
  • Phenotype
  • Predictive Value of Tests
  • Proto-Oncogene Proteins B-raf / analysis
  • Proto-Oncogene Proteins B-raf / genetics*
  • Reproducibility of Results
  • Skin Neoplasms / enzymology
  • Skin Neoplasms / genetics*
  • Skin Neoplasms / pathology


  • Biomarkers, Tumor
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf