Pathology of Hepatocellular Carcinoma and Tumor-Bearing Liver Tissue in Association with Promoter Mutation.

BACKGROUND

The promoter mutation represents a common and early event in hepatocarcinogenesis, but its linkage to the morphological status of the underlying liver tissue is poorly understood. We analyzed the connection between the histopathological changes in tumor-bearing liver tissue and the occurrence of the promoter mutation in hepatocellular carcinoma (HCC), correlated with clinical data.

METHODS

The study cohort comprised 160 histologically confirmed HCC in patients with or without cirrhosis that were investigated for the promoter mutation. We evaluated the frequency of the promoter mutation in patients with HCC with or without cirrhosis and correlated it with potential clinical and histopathological drivers. In particular, we examined tumor-bearing noncirrhotic liver tissue regarding inflammation; the modified histological activity index (mHAI), fibrosis, and steatosis; and its correlation with the frequency of the promoter mutation in HCC. We evaluated overall survival with multivariate Cox regression. Furthermore, we compared hTERT antibody immunohistochemistry and molecular promoter mutation analysis of both HCC and background liver tissue.

RESULTS

The promoter mutation was especially related to HCC in cirrhotic compared with noncirrhotic liver ( < 0.001) and independently of cirrhosis in patients ≥ 60 years ( = 0.005). Furthermore, the promoter mutation was associated with cirrhosis caused by alcohol toxicity and hepatitis C virus infection. In noncirrhotic liver tissue, the frequency of -promoter-mutated HCC increased with the degree of inflammation and fibrosis. Nevertheless, 25% of the -promoter-mutated HCC developed in normal liver tissue without HCC risk factors. Multivariate Cox regression analysis did not reveal an influence of the promoter mutation in HCC on overall survival at 3, 5, and 16 years. Immunohistochemical analysis with the hTERT antibodies LS-B95 and 2D8 in -promoter-mutated HCC and -wildtype HCC showed a mildly stronger immunoreaction compared with the tumor-bearing liver tissue (LS-B95: < 0.01, 2D8: < 0.01).

CONCLUSIONS

Our study reveals a connection between pathological changes in tumor-bearing liver tissue and the promoter mutation in most HCC, even in noncirrhotic liver tissue. Immunohistochemical hTERT antibodies do not discriminate between -promoter-mutated and wildtype HCC.