Preferential Localization of MET Expression at the Invasion Front and in Spreading Cells Through Air Spaces in Non-Small Cell Lung Carcinomas

Am J Surg Pathol. 2017 Mar;41(3):414-422. doi: 10.1097/PAS.0000000000000810.


The involvement of the HGF/MET pathway in acquisition of an invasive phenotype in non-small cell lung carcinomas (NSCLCs) suggests that MET inhibitors might prove effective against these cancers, but clinical trials have yielded conflicting results. The aim of our study was to evaluate how intratumoral heterogeneity (ITH) of MET staining affects the determination of MET status for therapeutic purposes. We analyzed 64 NSCLC samples, including 33 adenocarcinomas (ADCs) and 31 squamous cell carcinomas (SCCs). We used immunohistochemistry to detect MET and phospho-MET on whole slides and determined the MET SP44 immunoscore and the H-score. A high METMab score (2+/3+) was observed in 34% of NSCLCs and was more prevalent in ADCs (52%) than in SCCs (16%). We found ITH in 73% of ADCs and 77% of SCCs, with higher levels of MET and phospho-MET at the invasion front (in 52% of ADCs and 22% of SCCs) and in tumor cells spreading through air spaces in ADCs. Within-sample ITH was high in 40% of the ADCs and 29% of the SCCs. When different samples from the same tumor were compared, discordant assessments (high MET vs. low MET) were made for 12% of the ADCs and 10% of the SCCs. C-MET and phospho-MET overexpression occurred preferentially in ADCs and in areas involved in tumor progression, in support of the view that MET activation plays a role in the development of an invasive phenotype in NSCLC. To use MET status adequately as a biomarker, one must take the resulting high level of ITH into account.

MeSH terms

  • Adenocarcinoma / diagnosis
  • Adenocarcinoma / genetics*
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology
  • Aged
  • Aged, 80 and over
  • Biomarkers, Tumor / genetics*
  • Biomarkers, Tumor / metabolism
  • Carcinoma, Non-Small-Cell Lung / diagnosis
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Carcinoma, Squamous Cell / diagnosis
  • Carcinoma, Squamous Cell / genetics*
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / pathology
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Immunohistochemistry
  • In Situ Hybridization
  • Lung Neoplasms / diagnosis
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Male
  • Middle Aged
  • Neoplasm Invasiveness
  • Prognosis
  • Proto-Oncogene Proteins c-met / genetics*
  • Proto-Oncogene Proteins c-met / metabolism
  • Retrospective Studies


  • Biomarkers, Tumor
  • MET protein, human
  • Proto-Oncogene Proteins c-met