title: β-catenin alteration is rare in hepatocellular carcinoma with steatohepatitic features: immunohistochemical and mutational study.
abstract: 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 β-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 β-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.
authors: Department of Pathology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
authors: Sumiyo
authors: S
authors: Ando
authors: Department of Pathology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
authors: Junji
authors: J
authors: Shibahara
authors: Department of Pathology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
authors: Akimasa
authors: A
authors: Hayashi
authors: Department of Pathology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan. mfukayama-tky@umin.org.
authors: Masashi
authors: M
authors: Fukayama
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005974:Glutamate-Ammonia Ligase / Q000378:metabolism; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology*; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism*
chemical_list: C495270:CTNNB1 protein, human; D053823:Hedgehog Proteins; C509239:SHH protein, human; D051176:beta Catenin; D005974:Glutamate-Ammonia Ligase
keywords: Glutamine synthetase; Hepatocellular carcinoma; Non-alcoholic fatty liver disease; Sonic hedgehog; Steatohepatitis; β-catenin