Occupational cholangiocarcinoma caused by exposure to 1,2-dichloropropane and/or dichloromethane

Abstract

A cluster of cholangiocarcinoma among printing company workers who were exposed to 1,2-dichloropropane and/or dichloromethane was classified by the Ministry of Health, Labour and Welfare of Japan on 1 October 2013 as "occupational cholangiocarcinoma". At the time of the diagnosis of cholangiocarcinoma, levels of γ-glutamyl transferase, and aspartate and alanine aminotransferases were elevated, and had been elevated in some patients several years prior to the diagnosis. Regional dilatation of intrahepatic bile ducts without tumor-induced obstruction was characteristic in diagnostic imaging. Pathological examination found chronic bile duct injury with DNA damage, precancerous/preinvasive lesions such as biliary intraepithelial neoplasia and intraductal papillary neoplasm of the bile duct in various sites of the large bile ducts, and invasive cholangiocarcinoma such as mass-forming type and intraductal growth-type intrahepatic cholangiocarcinoma and mainly papillary-type extrahepatic cholangiocarcinoma. Whole-exome analysis of the cancerous tissues showed hypermutation, substantial strand bias, and unique trinucleotide mutational changes. Patients seemed to suffer high incidence of postoperative complications including intra-abdominal, which might be related to chronic bile duct injury. Postoperative recurrence from multicentric origins occurred in some patients, as DNA-injured bile ducts have high carcinogenic potential. Aggressive treatment, including second resections for such multicentric recurrences, appeared to be effective. In 2014, the International Agency for Research on Cancer classified 1,2-dichloropropane as Group 1 (carcinogenic to humans) and dichloromethane as Group 2A (probably carcinogenic to humans) carcinogens.

Keywords: 1,2‐dichloropropane; biliary intraepithelial neoplasia; cholangiocarcinoma; dichloromethane; intraductal papillary neoplasm of the bile duct.

Figure 1

Diagnostic imaging of patients with occupational cholangiocarcinoma.2 (A) Mass‐forming type of intrahepatic cholangiocarcinoma (arrow). (B) Intraductal growth type of intrahepatic cholangiocarcinoma (arrow). (C) Intrahepatic bile ducts dilated with cholangiocarcinoma‐induced obstruction of the bile ducts (arrow). (D) Intrahepatic bile ducts, dilated but without tumor‐induced obstruction (arrows)

Figure 2

Screening and surveillance of cholangiocarcinoma in workers exposed to chlorinated organic solvents.12 CEA, carcinoembryonic antigen; CT, computed tomography; ERCP, endoscopic retrograde cholangiopancreatography; FDG‐PET, fluorodeoxyglucose–positron emission tomography; MRCP, magnetic resonance cholangiopancreatography; MRI, magnetic resonance imaging

Figure 3

Surgical specimens. (A) Mass‐forming type of intrahepatic cholangiocarcinoma (arrow).2 (B) Intraductal growth type of intrahepatic cholangiocarcinoma (arrow).2 (C) Extrahepatic cholangiocarcinoma of the papillary type (arrow)

Figure 4

Pathological features of surgical specimens in patients with occupational cholangiocarcinoma. (A) Mass‐forming type of intrahepatic cholangiocarcinoma with tubular adenocarcinoma (H‐E staining, ×400).2 (B) Intraductal growth type of intrahepatic cholangiocarcinoma with focal invasion (arrow, ×150).2 (C) Biliary intraepithelial neoplasia‐3 (×300).2 (D) Sclerotic lesion in intrahepatic bile duct (×300). (E) Biliary epithelial hyperplasia (arrow). (F) Hyperplasia of the peribiliary glands (×300)

Figure 5

Pathological findings corresponding to bile duct imaging: mapping chart of atypical epithelium (H‐E staining).16 (A) (×40), (B) (×100) The main lesion in segment 4 (B4) is a papillary adenocarcinoma growing in the bile duct. The tumor cells have eosinophil granules, and the tumor was diagnosed as an oncocytic intraductal papillary neoplasm of the bile duct (IPNB), with invasion. (C,D) (×40) IPNB with a different form to that of the main tumor in the B4 periphery (C) and proximal side of segment 3 (D). (E) (×40), (F) (×200) The main tumor invaded the proximal side of segment 2. (G,H) (×200) Biliary intraepithelial neoplasia‐2/3 lesion is visible throughout the entire excised specimen

Figure 6

Immunohistochemical analysis for neoplastic changes and DNA injury.16 (A,E) Immunohistochemical expression of S100P and γ‐H2AX in invasive carcinoma. (B,F) Biliary intraepithelial neoplasia (BilIN)‐2/3. (C,G) Intraductal papillary neoplasm of the bile duct (IPNB) (×200). (D,H) In non‐neoplastic bile duct, although S100P expression is relatively weak or absent (H), γH2AX expression is observed (D)