Re: Occupational cholangiocarcinoma

Known etiological factors for cholangiocarcinoma include hepatolithiasis, primary sclerosing cholangitis, pancreaticobiliary maljunction, and liver flukes such as Opisthorchis viverrini and Clonorchis sinensis. Recently, we have reported relatively young workers with cholangiocarcinoma who were exposed to extremely high concentrations of 1,2dichloropropane (DCP) and/or dichloromethane (DCM) for a long-term period [1–3]. These chlorinated organic solvents were used to clean ink residue in the offset proofprinting process. The cholangiocarcinoma in such workers was recognized as an occupational disease (occupational cholangiocarcinoma) by the Japanese Ministry of Health, Labour and Welfare on 1 October 2013 [4]. Humans are infected with liver flukes by ingesting the metacercariae in raw, fermented and/or partially cooked freshwater fish such as carp [5]. In northwest Thailand, there is a high incidence of cholangiocarcinoma due to Opisthorchis viverrini caused by infections from the consumption of raw freshwater fish such as genera Puntius, Cyclocheilichthys and Hampala. In Japan, Clonorchis sinensis were occasionally found in patients with biliary diseases many years ago in a limited area where people commonly ate raw freshwater fish. Usually, Japanese people eat raw fish from the sea, but not raw freshwater fish. The number of patients infected with Clonorchis sinensis has been dramatically decreased due to the improvements in health supervision and the decrease in the number of shellfish (Bithvnia sp) serving as a first intermediate host. So far, only 12 patients with cholangiocarcinoma associated with liver flukes have been reported in Japan. All of these patients were older than 50 years old (10 patients were older than 60 years old) and liver flukes were found in the bile or the resected specimens in all patients. The 17 patients in our previous first report [2] and the eight of nine patients in our second report [3] were younger than 50 years (one patient was 57 years old). Liver flukes were not detected in the bile, the resected specimen or the feces in any of the 26 patients. On diagnostic imaging, regional dilatation of the intrahepatic bile ducts without tumor-induced obstruction, like primary sclerosing cholangitis, was found to be a characteristic of patients with occupational cholangiocarcinoma [2, 3]. However, such findings have not been reported in cholangiocarcinoma patients with Clonorchis sinensis. As a result, the liver fluke infection could not be considered to have been the cause of the cholangiocarcinoma in the 26 previously reported patients [2, 3]. Recently, the International Agency for Research on Cancer assessed the carcinogenicity of DCP and DCM, and decided that DCP should be classified as carcinogenic to humans (group 1) on the basis of sufficient evidence in humans that exposure to DCP causes cholangiocarcinoma (biliary tract cancer), including our report [2]. DCM was classified as probably carcinogenic to humans (Group 2A) on the basis of limited evidence [6]. The epidemiologic relationship between chlorinated organic solvents and the development of cholangiocarcinoma has not been clarified. A large cohort set-up for four Nordic countries (Finland, Iceland, Norway, and Sweden) over a period of 45 years showed an increased risk of cholangiocarcinoma among individuals employed at the printing companies, although the study included various types of workers, such as typographers, printers, lithographers and bookbinders [7]. The results showed that the increased risk of cholangiocarcinoma among workers in the printing company in Osaka possibly extends beyond the specific company and country. It is therefore important to recognize that chlorinated organic solvents have possible carcinogenic effects, including the potential of development of cholangiocarcinoma.