Journal
VIRCHOWS ARCHIV
Volume 467, Issue 5, Pages 535-542Publisher
SPRINGER
DOI: 10.1007/s00428-015-1836-2
Keywords
Hepatocellular carcinoma; Steatohepatitis; Non-alcoholic fatty liver disease; beta-catenin; Glutamine synthetase; Sonic hedgehog
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Funding
- Grants-in-Aid for Scientific Research [26893045] Funding Source: KAKEN
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Hepatocellular carcinoma (HCC) with steatohepatitic features (steatohepatitic HCC, SH-HCC) is a histological subset of HCC, highly associated with metabolic disease and underlying steatohepatitis. Although it has distinct clinicopathologic characteristics, little is known about the immunophenotype or genetic characteristics of SH-HCC. We conducted an immunohistochemical analysis on a tissue microarray containing 197 HCCs (70 SH-HCCs and 127 conventional HCCs (C-HCCs)), focusing on proteins associated with genetic subtypes of HCC and those associated with non-alcoholic fatty liver disease (NAFLD) or NAFLD-associated HCC. We also investigated CTNNB1 mutations in 84 HCCs (31 SH-HCCs and 53 C-HCCs) to better characterize the SH-HCC. When compared to C-HCC, SH-HCC was characterized by a significantly lower incidence of nuclear accumulation of beta-catenin (5.7 vs. 25.2 %, p < 0.001) and by a lower incidence of overexpression (H-score = 300) of glutamine synthetase (4.3 vs. 26.0 %, p < 0.001). Multivariate logistic regression analysis revealed that the low rate of nuclear beta-catenin accumulation in SH-HCC was independent of background etiology, including underlying steatohepatitis (p < 0.001). In accordance with the immunohistochemical results, CTNNB1 mutations were less frequent in SH-HCC than C-HCC (3.1 vs. 20.8 %, p < 0.048). Other notable findings included the ubiquitous expression of sonic hedgehog ligand in typical SH-HCC (100 %) and the less frequent expression of progenitor markers, such as SALL4 and EpCAM, in SH-HCC. These results indicate that SH-HCC as a subtype is not only characterized by morphology but also by distinct phenotypic and genetic traits.
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