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The aim of this study was to examine whether the type of bilioenterostomy enhances biliary carcinogenesis in the hamster model. Syrian hamsters were divided into the following groups; simple laparotomy (control group), cholecystoduodenostomy with dissection of the extrahepatic bile duct on the distal end of the common duct (CDDB group) and cholecystoileostomy with dissection of the extrahepatic bile duct on the distal end of the common duct (CIDB group). Following these procedures, all hamsters received N-nitrosobis(2-oxopropyl)amine. The diameter of the extrahepatic bile duct and plasma levels of cholecystokinin (CCK) were measured and the number of neoplastic lesions was counted microscopically. Proliferative effect of the procedures on the biliary epithelium was examined by proliferative cell nuclear antigen. In the CDDB group the extrahepatic bile duct was significantly dilated and carcinogenesis of the gall-bladder and extrahepatic bile ducts was enhanced. In the CIDB group the CCK bioactivity was stimulated and intrahepatic biliary duct, but not gall bladder and extrahepatic bile duct, carcinogenesis was promoted more than that observed in the CDDB group. Proliferation of the biliary duct epithelium was enhanced in both the CDDB and CIDB groups. Cholecystoduodenostomy enhanced intra- and extrahepatic bile duct carcinoma, whereas cholecystoileostomy promoted only intrahepatic bile duct carcinoma. Some factors in the intestinal juice seem to play a role in the promotion of biliary tract carcinoma.

Background and Objectives In our laboratory, we have developed a new model of carcinoma of the bile duct in Syrian golden hamsters, using N‐nitrosobis(2‐oxopropyl)amine (BOP). Morphologic and biologic characteristics of the carcinoma induced in this model are similar to those seen in humans. In order to examine the gene‐related carcinogenesis of intrahepatic bile duct carcinoma, we investigated mutations in the K‐ras gene in various early hyperplastic and neoplastic lesions of these hamsters, according to the original sites of the lesions. Methods Inbred female hamsters were given a subcutaneous injection of N‐nitrosobis(2‐oxopropyl)amine (BOP) following dissection of the extrahepatic bile duct on the distal end of the common duct and preparation of a cholecystoduodenostomy (CDDB) or simple laparotomy (SL). Neoplastic lesions arising from the intrahepatic bile duct were histologically examined, and K‐ras mutations were investigated. Results Mutations of K‐ras codon 12 were evident in 12% of tubular hyperplasias, 19% of tubular adenocarcinomas, 15% of papillary hyperplasias and 36% of papillary adenocarcinomas. In papillary adenocarcinoma arising from a large bile duct, K‐ras mutations occurred more frequently than in tubular adenocarcinoma arising from ductule or ductular proliferation. K‐ras mutations were present even in a hyperplasia; the positive rates of the mutations increased in the presence of a carcinoma. Genetic changes in carcinoma of the intrahepatic bile duct varied based on sites of the duct and the histological type. Conclusions A part of the hyperplastic lesions of the intrahepatic bile duct presented K‐ras gene mutation. This suggests that K‐ras gene mutation is an early event in the carcinogenic process. In carcinoma of the intrahepatic bile duct, the lesion arising from a large bile duct of the hepatic hilum tended to exhibit a higher frequency of K‐ras gene mutation than did a tubular lesion arising from ductule or ductal proliferation. This hamster model is useful to examine the carcinogenesis of human intrahepatic bile duct carcinoma. J. Surg. Oncol. 1997;66:97–103. © 1997 Wiley‐Liss, Inc.

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