Details of human epidermal growth factor receptor 2 status in 454 cases of biliary tract cancer

Hum Pathol. 2020 Nov:105:9-19. doi: 10.1016/j.humpath.2020.08.006. Epub 2020 Sep 3.


Human epidermal growth factor receptor 2 (HER2)-targeted therapy has improved clinical outcomes in patients with HER2-positive breast and gastric cancers, although ineffective or recurrent cases are present. One reason for this is the heterogeneity of HER2 expression in cancer cells. The aim of this study was to investigate the clinicopathological characteristics and HER2 status of patients with biliary tract cancers (BTCs). We examined HER2 protein expression by immunohistochemistry, HER2 gene amplification by fluorescence in situ hybridization, and both HER2 protein and gene levels simultaneously by gene-protein assay. Samples were collected from 454 patients who underwent surgical resection for BTCs (110 intrahepatic cholangiocarcinomas [ICC], 67 perihilar extrahepatic cholangiocarcinomas [ECC-Bp], 119 distal extrahepatic cholangiocarcinomas [ECC-Bd], 80 gallbladder carcinomas [GBC], and 79 ampullary carcinomas [AVC]). HER2 status was assessed according to the guidelines for HER2 testing in gastroesophageal adenocarcinoma. HER2-positive status was detected in 14.5% of BTCs (3.7% of ICC, 3.0% of ECC-Bp, 18.5% of ECC-Bd, 31.3% of GBC, and 16.4% of AVC). Furthermore, HER2-positivity tended to correlate with low histological grade, tumor histology, and macroscopic features in certain tumors. HER2 heterogeneity was common and highly frequent (83%) in BTC cases. Reduced HER2 protein expression in the deeper invasive areas with simultaneous dedifferentiation was frequently observed in HER2-positive cancer cells. The findings of this study suggest that a large subgroup of HER2-positive BTC cases can be considered for HER2-targeted therapy. Moreover, the HER2 status in BTCs should be determined carefully using a sensitive approach toward larger cancer tissues.

Keywords: Biliary tract cancer; HER2; Heterogeneity; Papillary adenocarcinoma; Targeted therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Biliary Tract Neoplasms / enzymology*
  • Biliary Tract Neoplasms / genetics
  • Biliary Tract Neoplasms / pathology
  • Biliary Tract Neoplasms / surgery
  • Biomarkers, Tumor / analysis*
  • Biomarkers, Tumor / genetics
  • Female
  • Gene Amplification
  • Genetic Predisposition to Disease
  • Humans
  • Immunohistochemistry
  • In Situ Hybridization, Fluorescence
  • Male
  • Phenotype
  • Receptor, ErbB-2 / analysis*
  • Receptor, ErbB-2 / genetics


  • Biomarkers, Tumor
  • ERBB2 protein, human
  • Receptor, ErbB-2