Different carcinogenic process in cholangiocarcinoma cases epidemically developing among workers of a printing company in Japan

Int J Clin Exp Pathol. 2014 Jul 15;7(8):4745-54. eCollection 2014.


Recently, cholangiocarcinoma has epidemically developed among young adult workers of a printing company in Japan. Exposure to organic solvents including 1,2-dichloropropane and/or dichloromethane is supposed to be associated with the carcinoma development. The metabolism of dichloromethane proceeds through a Theta-class glutathione S-transferase (GST) T1-1-catalyzed pathway, where its reactive intermediates have been implicated in genotoxicity and carcinogenicity. This study examined features of the carcinogenic process of the cholangiocarcinoma developed in the printing company. Surgically resected specimens of the cholangiocarcinoma cases were analyzed, where all cases were associated with precursor lesions such as biliary intraepithelial neoplasia (BilIN) and/or intraductal papillary neoplasm of the bile duct (IPNB). Immunohistochemical analysis confirmed constitutional expression of GST T1-1 in normal hepatobiliary tract. Immunostaining of γ-H2AX, a marker of DNA double strand break, showed that its expression was significantly increased in foci of BilIN, IPNB and invasive carcinoma as well as in non-neoplastic biliary epithelial cells of the printing company cases when compared to that of control groups. In the printing company cases, immunohistochemical expression of p53 was observed in non-neoplastic biliary epithelial cells and BilIN-1. Mutations of KRAS and GNAS were detected in foci of BilIN in one out of 3 cases of the printing company. These results revealed different carcinogenic process of the printing company cases, suggesting that the exposed organic solvents might act as a carcinogen for biliary epithelial cells by causing DNA damage, thereby contributing to the carcinoma development.

Keywords: DNA damage; Occupational cholangiocarcinoma; carcinogenesis; glutathione S-transferase; organic solvent.

MeSH terms

  • Adult
  • Aged
  • Animals
  • Bile Duct Neoplasms / genetics
  • Bile Duct Neoplasms / metabolism
  • Bile Duct Neoplasms / pathology*
  • Bile Ducts, Intrahepatic / pathology*
  • Carcinogenesis / chemically induced*
  • Carcinogenesis / genetics
  • Carcinogenesis / pathology
  • Carcinogens / toxicity
  • Cholangiocarcinoma / genetics
  • Cholangiocarcinoma / metabolism
  • Cholangiocarcinoma / pathology*
  • Chromogranins
  • DNA Mutational Analysis
  • Female
  • GTP-Binding Protein alpha Subunits, Gs / genetics
  • Humans
  • Immunohistochemistry
  • Japan
  • Male
  • Mice
  • Mice, Inbred ICR
  • Middle Aged
  • Occupational Diseases / genetics
  • Occupational Diseases / metabolism
  • Occupational Diseases / pathology
  • Occupational Exposure / adverse effects
  • Printing*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins p21(ras)
  • Rats
  • Rats, Inbred F344
  • Reverse Transcriptase Polymerase Chain Reaction
  • Solvents / adverse effects
  • Volatile Organic Compounds / adverse effects
  • ras Proteins / genetics


  • Carcinogens
  • Chromogranins
  • KRAS protein, human
  • Proto-Oncogene Proteins
  • Solvents
  • Volatile Organic Compounds
  • GNAS protein, human
  • GTP-Binding Protein alpha Subunits, Gs
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins