Hepatitis Viruses Cause Cholangiocarcinomas

Both HBV and HCV are implicated as causes of intrahepatic cholangiocarcinomas. Hepaitis B surface antigen (HBsAg) alone fails to identify many cases of HBV infection. Core antigen (HBcAg) and HBV DNA in tissue samples should also be tested. And HCV DNA by reverse transcriptase PCR as well as antibodies to HCV.

[Expression of five different antigens of HBV in human intrahepatic cholangiocarcinoma and cholangiohepatocarcinoma]. WL Wang. Zhonghua Zhong Liu Za Zhi 1993 Jul;15(4):252-255. 12 intrahepatic cholangiocarcinomas, 8 cholangiohepatocarcinomas, and neighboring liver tissues with chronic hepatitis or cirrhosis surrounding the tumor. By IHC, "15 were positive for HBxAg (75%), 8 positive for pre-S1 and pre-S2 (40%), respectively and 2 for HBsAg (10%). Sixteen of 19 liver tissues surrounding the tumor were also positive for HBxAg (84.2%), 9 for pre-S1 and pre-S2 each (47.4%), 6 for HBsAg and HBcAg each (31.6%)."

[Expression and significance of hepatitis B virus genes in human primary intrahepatic cholangiocarcinoma and its surrounding tissue]. W Wang, G Gu, M Hu. Zhonghua Zhong Liu Za Zhi 1996 Mar;18(2):127-130. By ISH, "33 cases (82.5%) were positive for HBV DNA, while 31 (77.5%), 26 (65.0%), 24 (60.0%) and 27 (67.5%) cases were positive for X gene, pre-S gene, S gene and C gene, respectively. The results of this study suggest that there exists a close relationship between human primary intrahepatic cholangiocarcinoma and HBV chronic persistent infection. The expression of X gene might play an important role in the pathogenesis of the primary intrahepatic cholangiocarcinoma."

Intrahepatic cholangiocarcinoma and hepatitis C and B virus infection, alcohol intake, and hepatolithiasis: a case-control study in Italy. F Donato, U Gelatti, A Tagger, M Favret, ML Ribero, F Callea, C Martelli, A Savio, P Trevisi, G Nardi. Cancer Causes Control 2001 Dec;12(10):959-964. 26 ICC cases from a liver cancer group, 824 controls. "Seropositivity for anti-HCV, HBsAg, alcohol intake >80 g/day and history of hepatolithiasis were found in 25%, 13%, 23.1%, and 26.9% of ICC cases and in 5.8%, 6.7%, 32.9%, and 10.6% of controls, respectively. The odds ratios adjusted for demographic factors by logistic regression (95% confidence interval; 95% CI) were 9.7 (1.6-58.9) for anti-HCV, 2.7 (0.4-18.4) for HBsAg, and 6.7 (1.3-33.4) for hepatolithiasis, whereas no association was found with alcohol drinking."

Hepatitis C virus infection as a likely etiology of intrahepatic cholangiocarcinoma. S Yamamoto, S Kubo, S Hai, T Uenishi, T Yamamoto, T Shuto, S Takemura, H Tanaka, O Yamazaki, K Hirohashi, T Tanaka. Cancer Sci 2004 Jul;95(7):592-595. A "hospital-based case-control study including 50 ICC patients and 205 other surgical patients without primary liver cancer. HCV seropositivity was detected in 36% of ICC patients and 3% of controls. By univariate analysis, the odds ratio (OR) for association of anti-HCV antibodies with development was 16.87 (95% confidence interval (CI), 5.69 to 50.00)." Tests for HCV not specified in the abstract.

Clinicopathologic characteristics of hepatitis C virus-associated intrahepatic cholangiocarcinoma. S Hai, S Kubo, S Yamamoto, T Uenishi, H Tanaka, T Shuto, S Takemura, O Yamazaki, K Hirohashi. Dig Surg 2005;22(6):432-439. In Osaka, Japan, 19 of 50 patients who underwent surgical treatment were positive for HCV. "In 15 patients in the HCV-positive group, ICC was detected during follow-up for chronic hepatitis C." Tests for HCV not specified in the abstract.

Risk factors of intrahepatic cholangiocarcinoma in the United States: a case-control study. YH Shaib, HB El-Serag, JA Davila, R Morgan, KA McGlynn. Gastroenterology 2005 Mar;128(3):620-626. 625 cases and 90,834 controls, from the SEER-Medicare database [which was reported elsewhere to have a viral hepatitis prevalence of only 30% -cast]. "Several risk factors were significantly more prevalent among cases. These included nonspecific cirrhosis (adjusted odds ratio, 27.2; P <.0001), alcoholic liver disease (adjusted odds ratio, 7.4; P <.0001), hepatitis C virus infection (adjusted odds ratio, 6.1; P <.0001), human immunodeficiency virus infection (adjusted odds ratio, 5.9; P=.003), diabetes (adjusted odds ratio, 2.0; P <.0001), and inflammatory bowel diseases (adjusted odds ratio, 2.3; P=.002)." Viral tests not specified in the abstract.

Risk factors for intrahepatic and extrahepatic cholangiocarcinoma: a hospital-based case-control study. YH Shaib, HB El-Serag, AK Nooka, M Thomas, TD Brown, YZ Patt, MM Hassan. Am J Gastroenterol 2007 May;102(5):1016-1021. 246 cases (83 ICC and 163 ECC) and 236 controls, at M.D. Anderson Cancer Center. "ICC patients had a higher prevalence of anti-HCV antibodies (6.0%vs 0.8%, P=0.01), anti-HBc (9.6%vs 0%, P<0.0001), and heavy alcohol consumption (21.7%vs 3.8%, P<0.0001). The adjusted odds ratio and 95% confidence interval (CI) were 7.9 (95% CI 1.3-84.5), 28.6 (95% CI 3.9-1,268.1), and 5.9 (95% CI 2.1-17.4), respectively. Only heavy alcohol consumption was higher in patients with ECC than in controls (17.8%vs 3.8%, P=0.003). The prevalence of diabetes and smoking were not significantly different between cases (ICC or ECC) and controls."

Clinicopathologic characteristics of intrahepatic cholangiocarcinoma in patients with positive serum a-fetoprotein. YM Zhou, JM Yang, B Li, ZF Yin, F Xu, B Wang, P Liu, ZM Li. World J Gastroenterol 2008 Apr 14;14(14):2251-2254. "Positive serum hepatitis B surface antigen (HBsAg) and hepatitis C antibody were biomarkers of chronic viral hepatitis." "The positive rate of HBsAg (78.1%) and transaminase of the positive AFP group was higher than that of the negative AFP group (P = 0.000 and P = 0.036 respectively)..."

Hepatitis B virus infection and intrahepatic cholangiocarcinoma in Korea: a case-control study. TY Lee, SS Lee, SW Jung, SH Jeon, SC Yun, HC Oh, S Kwon, SK Lee, DW Seo, MH Kim, DJ Suh. Am J Gastroenterol 2008 Jul;103(7):1716-1720. 622 patients and 2,488 healthy controls. "HBV infection (odds ratio [OR] 2.3, 95% confidence interval [CI] 1.6-3.3), but not HCV infection, was significantly related to ICC." Tests for viruses not specified in abstract.

Risk of hepatobiliary and pancreatic cancers after hepatitis C virus infection: A population-based study of U.S. veterans. HB El-Serag, EA Engels, O Landgren, E Chiao, L Henderson, HC Amaratunge, TP Giordano. Hepatology 2009 Jan;49(1):116-123. 75 cases of ECC, 37 cases of ICC, 617 cases of pancreatic cancer, and 1679 cases of HCC, among a cohort of 146,394 HCV-infected U.S. veterans. "Risk for ICC was elevated with HCV infection 2.55; 1.31, 4.95), but risk for ECC was not significantly increased (1.50; 0.60, 1.85)."

Risk factors for intrahepatic and extrahepatic cholangiocarcinoma: a case-control study in China. LY Tao, XD He, Q Qu, L Cai, W Liu, L Zhou, SM Zhang. Liver Int 2010 Feb;30(2):215-221. 190 patients (61 ICC; 129 ECC) and 380 age- and sex-matched controls. "HBsAg (P<0.001) and anti-HBc without HBsAg (P=0.001) were significantly related to ICC. The adjusted odds ratios (OR) and 95% confidence intervals (CI) were 18.1 (95% CI: 7.5-44.0) and 3.6 (95% CI: 1.7-7.6) respectively. Diabetes mellitus (P=0.007), cholecystolithiasis (P=0.004) and previous cholecystectomy (P<0.001) were significantly associated with ECC. The prevalence of cirrhosis was higher in ICC than that in ECC (P<0.001). Furthermore, on excluding the ICC patients with cirrhosis, ICC patients showed significant independent associations with HBsAg (OR: 7.3; 95% CI: 3.1-17.2) and anti-HBc without HBsAg (OR: 2.4; 95% CI: 1.1-5.2)."

Etiological and clinicopathologic characteristics of intrahepatic cholangiocarcinoma in young patients. HB Zhou, H Wang, DX Zhou, H Wang, Q Wang, SS Zou, HP Hu. World J Gastroenterol 2010 Feb 21;16(7):881-885. 317 consecutive ICC patients in Shanghai, China. 34 (85.0%) of patients less than or at 40 years of age were seropositive for HBsAg. Only one case of ICC had HCV.

Impact of hepatitis B virus infection on outcome following resection for intrahepatic cholangiocarcinoma. L Zhang, JQ Cai, JJ Zhao, XY Bi, XG Tan, T Yan, C Li, P Zhao. J Surg Oncol 2010 Mar 1;101(3):233-238. 29 of 40 (74.4%) consecutive ICC patients were positive for HBsAg or anti-HBc.

Hepatitis B virus-associated intrahepatic cholangiocarcinoma and hepatocellular carcinoma may hold common disease process for carcinogenesis. H Zhou, H Wang, D Zhou, H Wang, Q Wang, S Zou, Q Tu, M Wu, H Hu. Eur J Cancer 2010 Apr;46(6):1056-1061. 317 ICC patients and 634 healthy controls in China. 154 patients (48.6%) were seropositive for HBsAg. "The age and sex distribution profiles were nearly identical between seropositive-HBsAg ICC patients and HBV-associated HCC patients."

Risk factors for intrahepatic cholangiocarcinoma: a possible role of hepatitis B virus. M Tanaka, H Tanaka, H Tsukuma, A Ioka, A Oshima, T Nakahara. J Viral Hepat 2010 Oct;17(10):742-748. 11 cases of ICC among 154,814 blood donors in Japan during an average of 7.6 years. "Compared with those who tested negative for both HBsAg and anti-HCV, those who tested HBsAg-positive had a significantly higher risk for ICC (HR: 8.56; 95%CI: 1.33-55.20)." "The hazard ratio for anti-HCV positivity was 2.63, although it was not significant." "The mechanism of carcinogenesis by HBV in intrahepatic bile ducts has not yet been elucidated, but HBV infection is an established risk factor for hepatocellular carcinoma. Because both hepatocytes and cholangiocytes differentiate from the same progenitor cells, HBV might induce carcinogenesis in both cell types through the same mechanism. The HBV gene has been detected in cholangiocarcinoma tissue in some studies, and its presence has been associated with the potential of carcinogenesis in human cholangiocytes. Alternatively, hepatitis-associated ICC may arise from hepatic progenitor cells, as suggested by Lee et al."

Intrahepatic cholangiocarcinoma: new insights in pathology. C Sempoux, G Jibara, SC Ward, C Fan, L Qin, S Roayaie, MI Fiel, M Schwartz, SN Thung. Semin Liver Dis 2011 Feb;31(1):49-60. 73 ICCs from The Mount Sinai Medical Center in New York City. "Cholangiocarcinomas are malignant tumors that derive from cholangiocytes of small intrahepatic bile ducts or bile ductules (intrahepatic cholangiocarcinoma; ICC), or of large hilar or extrahepatic bile ducts (extrahepatic cholangiocarcinoma; ECC). ICC and ECC differ in morphology, pathogenesis, risk factors, treatment, and prognosis... Classical ICCs (54.8%) were characterized by a tubular, glandular, or nested pattern of growth, were significantly associated with tumor size of more than 5 cm and the absence of underlying liver disease and/or advanced fibrosis. Nonclassical ICCs (45.2%) consisted of tumors with trabecular architecture, tumors that exhibited features of extrahepatic carcinomas, and carcinomas considered to be derived from hepatic progenitor cells, i.e., combined hepatocellular/cholangiocarcinomas and cholangiolocellular carcinomas (ductular type of ICC). They were smaller and often arose in chronic liver disease, mostly HCV infection, and/or with significant fibrosis."

Hepatitis B virus infection: a favorable prognostic factor for intrahepatic cholangiocarcinoma after resection. HB Zhou, H Wang, YQ Li, SX Li, H Wang, DX Zhou, QQ Tu, Q Wang SS Zou, MC Wu, HP Hu. World J Gastroenterol 2011 Mar 14;17(10):1292-1303. 87 of 155 ICC patients in China were positive for HBsAg in serum or liver tissue.

Hepatitis B virus infection and risk of intrahepatic cholangiocarcinoma and non-Hodgkin lymphoma: a cohort study of parous women in Taiwan. CW Fwu, YC Chien, SL You, KE Nelson, GD Kirk, HS Kuo, M Feinleib, CJ Chen. Hepatology 2011 Apr;53(4):1217-1225. Cohort study from Taiwan, with "18 cases of ICC and 192 cases of NHL, including 99 cases of diffuse large B-cell lymphoma (DLBCL). Incidence rates of ICC were 0.09 and 0.43 per 100,000 person-years, respectively, among women who were hepatitis B surface antigen (HBsAg)-seronegative and HBsAg-seropositive, showing an age-adjusted hazard ratio (HR(adj) ) (95% confidence interval [CI]) of 4.80 (1.88-12.20)... Among NHL subtypes, HBsAg-seropositive women had an increased risk of DLBCL compared with those who were HBsAg-seronegative (incidence rates: 1.81 and 0.60 per 100,000 person-years, respectively; HR(adj) [95% CI]: 3.09 [2.06-4.64])."

Evaluation of risk factors and clinicopathologic features for intrahepatic cholangiocarcinoma in Southern China: a possible role of hepatitis B virus. NF Peng, LQ Li, X Qin, Y Guo, T Peng, KY Xiao, XG Chen, YF Yang, ZX Su, B Chen, M Su, LN Qi. Ann Surg Oncol 2011 May;18(5):1258-1266. 98 patients with pathologically confirmed ICC and 196 healthy control subjects. Viral tests not specified. "There was an association between ICC and each of HBV infection, liver cirrhosis, hepatolithiasis, and liver fluke infestation with the odds ratios (95% confidence intervals) of 2.75 (1.27-5.95), 8.42 (2.50-28.37), 22.81 (7.16-72.68), and 3.55 (1.60-7.89), respectively, with a marked synergism of cirrhosis and HBV infection (20.67; 5.40-79.06)."

Viral hepatitis is associated with intrahepatic cholangiocarcinoma with cholangiolar differentiation and N-cadherin expression. TH Yu, RH Yuan, YL Chen, WC Yang, HC Hsu, YM Jeng. Mod Pathol 2011 Jun;24(6):810-819. 69 of 170 patients (41%) were positive for hepatitis B and/or C virus, tests not specified in abstract. N-cadherin was strongly associated with hepatitis virus infection.

Detection of hepatitis B virus DNA in paraffin-embedded intrahepatic and extrahepatic cholangiocarcinoma tissue in the northern Chinese population. Y Wu, T Wang, S Ye, R Zhao, X Bai, Y Wu, K Abe, X Jin. Hum Pathol 2011 Jul 19 [Epub ahead of print]. 23 patients with intrahepatic cholangiocarcinoma and 43 with extrahepatic cholangiocarcinoma. "Hepatitis B surface antigen seropositivity was found in 52.2% (12/23) of intrahepatic cholangiocarcinoma cases and 13.9% (6/43) of extrahepatic cholangiocarcinoma cases. Hepatitis B virus DNA (X region) was detectable in 34.8% (8/23) of intrahepatic cholangiocarcinoma cases. Hepatitis B surface antigen and/or hepatitis B core antigen was detectable in 30.4% (7/23) of intrahepatic cholangiocarcinoma cases. All cases with detected viral protein were also positive for hepatitis B virus DNA. In contrast, no hepatitis B virus antigens or hepatitis B virus gene was detected in any of the 43 extrahepatic cholangiocarcinoma cases."

See Also:

cast 07-31-11