Immunohistochemical study of HBV antigens in 338 liver cell carcinomas

Tumor tissue (n = 338) and liver parenchyma (n = 276) from patients of Asian (n = 31) and European descent (n = 307) with hepatocellular carcinoma (HCC, n = 299), cholangiocellular carcinoma (CCC, n = 16) and combined HCC/CCC (n = 23) were screened with immunohistochemical methods for HBV antigens (HBs, preS1, preS2, HBc, HBe and HBx). Of the HCC cases nine were of the fibrolamellar type (FLC). All cases of HCC/CCC and CCC were from Western European patients. HBV antigens could be demonstrated more frequently in HCC cases of Asian descent (59.09% in liver parenchyma and 66.67% in tumor tissue) compared to Western European HCC cases (23.11% and 30.77%; chi-square test, p = 0.0003 and p = 0.0001, respectively), HCC/CCC (26.32% and 30.43%), CCC (7.14% and 20%) and FLC (0% and 25%). Results for HBx were not considered here due to questionnable HBV specificity of the antibodies employed. Immunohistochemical detection mainly HBs, whereas HBc, HBe and preS antigens played only a minor part. Comparing the results obtained with a rabbit and a goat polyclonal HBs antibody and a cocktail of seven monoclonal HBs antibodies showed statistically significant superior sensitivity for the goat antibody. Reactivity of tumor tissue for HBc and/or HBe as observed in twelve cases is suggestive of virus replication within tumor tissue. These data plus the demonstration of HBV antigens within so-called proliferated bile ducts, which represent metaplastic hepatocytes, underscore the nature of CCC as malignant counterpart of proliferated bile ducts. Consequently, it is proposed to divide the entity liver cell carcinoma (LCC) into the subcategories HCC and CCC in contrast to adenocarcinomas arising from bile ducts or peribiliary glands. In conclusion, HBV seems to play a part in the pathogenesis of LCC in Asian and in Western European patients. Further factors like HCV and other chronic inflammatory processes may be employed here.