Several Helicobacter species have recently been isolated from the bile and hepatobiliary systems of murine species, and are well recognized as a pathogen of the hepatobiliary disorder. This study was planned to investigate whether Helicobacter species possess a causative potential for human hepatobiliary disease, especially for hepatobiliary carcinogenesis. Bile and hepatobiliary tissue samples from 19 patients with hepatobiliary cancer and 19 patients with benign biliary diseases were subjected to polymerase chain reaction analyses for the detection of Helicobacter DNAs. Using a proliferating cell nuclear antigen (PCNA) staining technique, we also investigated the biliary epithelial cell kinetics with special reference to the presence of Helicobacter DNAs in the hepatobiliary system. We found that Helicobacter DNAs were positive in 10 (52.6%) of the 19 patients with hepatobiliary cancer. The incidence was significantly higher than that (15.7%) in the benign cases (P = 0.03). The PCNA labeling index in the biliary epithelium in Helicobacter DNA-positive patients was statistically higher than that in Helicobacter DNA-negative ones, regardless of whether the patient was suffering from hepatobiliary cancer and/or biliary inflammation. A close correlation between the presence of Helicobacter DNAs and an elevation of the PCNA labeling index in the biliary epithelium was demonstrated by multiple regression analysis. Our findings suggest that Helicobacter species may play a role in the pathogenesis of hepatobiliary cancer through an acceleration of biliary cell kinetics.

Biliary carcinomas can occur as a delayed complication of bilioenterostomy. The aim of this study was to determine whether bilioenterostomy influences biliary carcinogenesis in hamsters. Syrian hamsters were subjected to three different surgical procedures: simple laparotomy (SL), choledochoduodenostomy (CD) and choledochojejunostomy (CJ). They were given no carcinogens, and five to six hamsters from each group were killed every 20 weeks up to 120 weeks after surgery. Thirty-seven, 32 and 38 hamsters were sampled from the SL, CD and CJ groups, respectively. Cholangiocarcinomas developed in 5.4, 15.6 and 23.7% of hamsters in the SL, CD and CJ groups, respectively. The incidence of biliary carcinoma was significantly higher in the bilioenterostomy groups, especially CJ (P < 0.05), than in SL. The tumor latency period after surgery was 20-40 weeks shorter in the bilioenterostomy groups than in SL. Persistent cholangitis and bile stasis were frequent in the bilioenterostomy groups, and a significant correlation between cholangitis and biliary carcinogenesis was noted in the CD group. The proliferative cell nuclear antigen (PCNA) labeling index was higher in the biliary epithelium of the bilioenterostomy groups. In conclusion, persistent cholangitis after bilioenterostomy accelerates biliary carcinogenesis through activation of biliary epithelial cell kinetics.

The present study was designed to evaluate whether etodolac, a cyclooxgenase-2 (COX-2)-specific inhibitor, could prevent chemically induced biliary carcinogenesis in bilioenterostomized hamsters. Syrian golden hamsters were subjected to choledochojejunostomy and then received subcutaneous injections of N-nitrosobis(2-oxopropyl)amine (BOP) every 2 weeks at a dose of 10 mg/kg body wt. BOP administration was started 4 weeks after surgery, and continued for 18 weeks. The animals were simultaneously orally administered etodolac three times per week at a dose of 10 mg/kg body wt in 0.5% methylcellose solution (etodolac group). The control hamsters were administered methylcellose solution alone. The hamsters were killed 22 weeks after surgery, and the biliary carcinomas were evaluated histologically. The presence and degree of cholangitis and the cell kinetic status of the biliary epithelium were also evaluated with special reference to biliary carcinogenesis. Intrahepatic bile duct carcinomas developed in 15 of 17 (88%) hamsters in the control group, and in only six of 18 (33%) hamsters in the etodolac group (P < 0.01). The incidence and number of developing biliary carcinomas were well correlated with the degree of cholangitis, and severe cholangitis was evident in the controls. The cell kinetic study demonstrated that the proliferating cell nuclear antigen-labeling index of the biliary epithelium was 9.67 and 5.14% in the control and etodolac groups, respectively (P < 0.05). The mean levels of prostaglandin E(2) (PGE(2)) products in the liver tissue were 14.14 +/- 3.31 pg/total protein (TP) mg in the control group, and 7.46 +/- 2.34 pg/TP mg in the etodolac group (P < 0.05). These findings indicated that etodolac reduced both the occurrence of severe cholangitis and the acceleration of biliary epithelial cell kinetics after bilioenterostomy, resulting in the prevention of BOP-induced biliary carcinogenesis in hamsters. In conclusion, COX-2-specific inhibitor (etodolac) may be a possible agent against not only reflux cholangitis, but also biliary carcinoma after bilioenterostomy.

Background: This study was performed to investigate the oncologic role of lymph node (LN) management and to propose a surgical strategy for treating intrahepatic cholangiocarcinoma (IHCC). Methods: The medical records of patients with resected IHCC were retrospectively reviewed from multiple institutions in Korea and Japan. Short-term and long-term oncologic outcomes were analyzed according to lymph node metastasis (LNM). A nomogram to predict LNM in treating IHCC was established to propose a surgical strategy for managing IHCC. Results: A total of 1138 patients were enrolled. Of these, 413 patients underwent LN management and 725 did not. A total of 293 patients were found to have LNM. The No. 12 lymph node (36%) was the most frequent metastatic node, and the No. 8 lymph node (21%) was the second most common. LNM showed adverse long-term oncologic impact in patients with resected IHCC (14 months, 95% CI (11.4–16.6) vs. 74 months, 95% CI (57.2–90.8), p < 0.001), and the number of LNM (0, 1–3, 4≤) was also significantly related to negative oncologic impacts in patients with resected IHCC (74 months, 95% CI (57.2–90.8) vs. 19 months, 95% CI (14.4–23.6) vs. 11 months, 95% CI (8.1–13.8)), p < 0.001). Surgical retrieval of more than four (≥4) LNs could improve the survival outcome in resected IHCC with LNM (13 months, 95% CI (10.4–15.6)) vs. 30 months, 95% CI (13.1–46.9), p = 0.045). Based on preoperatively detectable parameters, a nomogram was established to predict LNM according to the tumor location. The AUC was 0.748 (95% CI: 0.706–0.788), and the Hosmer and Lemeshow goodness of fit test showed p = 0.4904. Conclusion: Case-specific surgical retrieval of more than four LNs is required in patients highly suspected to have LNM, based on a preoperative detectable parameter-based nomogram. Further prospective research is needed to validate the present surgical strategy in resected IHCC.

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