Intrahepatic cholangiocarcinoma frequently shows loss of BAP1 and PBRM1 expression, and demonstrates specific clinicopathological and genetic characteristics with BAP1 loss

Histopathology. 2017 Apr;70(5):766-774. doi: 10.1111/his.13127. Epub 2017 Jan 18.

Abstract

Aims: BAP1 and PBRM1 expression loss has been observed in multiple cancers, including intrahepatic cholangiocarcinoma (ICC). We investigated BAP1 and PBRM1 expression in ICC using immunohistochemistry, and analysed its association with clinicopathological and genetic features, including two histological subtypes.

Methods and results: Whole-section slides of 108 consecutive primary ICC cases were immunostained against BAP1 and PBRM1. Complete loss of BAP1 and PBRM1 was observed in 21 (19.4%) and 25 (23.1%) cases, respectively, and partial loss was identified in four (3.7%) and nine (8.4%) cases. In all cases, normal bile ducts were strongly and diffusely positive for both BAP1 and PBRM1. ICC with BAP1 loss showed lower serum CA19-9 levels, less perineural invasion, rare mucin production, weaker immunoreactivity against S-100P and stronger immunoreactivity against N-cadherin and NCAM. IDH mutations were identified more frequently in ICCs with BAP1 loss. All ICC with BAP1 loss corresponded to small-duct type ICC. Multivariate Cox regression analysis showed that BAP1 loss was an independent prognostic factor for both overall and recurrence-free survival (P < 0.05). Conversely, PBRM1 loss was found in both small-duct type and large-duct type ICC, and was not associated significantly with any specific characteristics, including prognosis.

Conclusion: BAP1 and PBRM1 loss is seen frequently in ICC. ICC with BAP1 loss shares features of small-duct type ICC.

Keywords: BAP1; Immunohistochemistry; PBRM1; intrahepatic cholangiocarcinoma.

MeSH terms

  • Adult
  • Aged
  • Bile Duct Neoplasms / metabolism
  • Bile Duct Neoplasms / mortality
  • Bile Duct Neoplasms / pathology*
  • Biomarkers, Tumor / analysis
  • Cholangiocarcinoma / metabolism
  • Cholangiocarcinoma / mortality
  • Cholangiocarcinoma / pathology*
  • DNA-Binding Proteins
  • Female
  • Humans
  • Immunohistochemistry
  • Kaplan-Meier Estimate
  • Male
  • Middle Aged
  • Nuclear Proteins / analysis
  • Nuclear Proteins / biosynthesis*
  • Prognosis
  • Proportional Hazards Models
  • Transcription Factors / analysis
  • Transcription Factors / biosynthesis*
  • Tumor Suppressor Proteins / analysis
  • Tumor Suppressor Proteins / biosynthesis*
  • Ubiquitin Thiolesterase / analysis
  • Ubiquitin Thiolesterase / biosynthesis*

Substances

  • BAP1 protein, human
  • Biomarkers, Tumor
  • DNA-Binding Proteins
  • Nuclear Proteins
  • PBRM1 protein, human
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Ubiquitin Thiolesterase