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.

Steatotic hepatocellular carcinoma: a variant associated with metabolic factors and late tumour relapse

“…employed a Food and Drug Administration (FDA)‐approved diagnostic platform (Elements assay; NanoString Technologies, Seattle, WA, USA) to correlate clinicopathological features and molecular subclasses of HCC, and showed that 57.9% of steatohepatitic HCC harboured molecular signatures of the subclass S1 . HCC of the molecular subclass S1 is characterized by Wnt and TGF‐β activation, larger tumour, poorer differentiation and early tumour relapse, all of which oppose to features of steatotic and steatohepatitic HCC documented by us and others: rare β‐catenin activation, smaller tumour, better differentiation and late tumour relapse. The pathogenesis of steatotic HCC and steatohepatitic HCC remains inconclusive, and warrants additional studies.…”

Clinicopathological investigation of steatohepatitic hepatocellular carcinoma: A multicenter study using immunohistochemical analysis of adenoma‐related markers

“…They hypothesized that deregulation of the Wnt/β‐catenin pathway had a minor role in the development of this type of HCC . Ando and colleagues are also found that β‐catenin alteration is rare in SH‐HCC . Given that obesity is associated with chronic low‐grade systemic inflammation, these results are quite acceptable.…”

Precision pathology analysis of the development and progression of hepatocellular carcinoma: Implication for precision diagnosis of hepatocellular carcinoma

“…92 Moreover, SH-HCC patients reportedly have a relatively good prognosis. 100 These characteristics are similar to steatotic sHCC, but SH-HCC and steatotic sHCC are not the same, because fibrous stroma is not a necessary criterion for SH-HCC. 97,98 Because there is some overlap in steatotic sHCC and SH-HCC, further investigation is required to clarify the differences between these two subtypes.…”

“…Low nuclear accumulation of β‐catenin and low expression levels of GS, SALL4 and EpCAM have been reported in SH‐HCC, and a recent study revealed that SH‐HCC was associated with the G4 subclasss . Moreover, SH‐HCC patients reportedly have a relatively good prognosis . These characteristics are similar to steatotic sHCC, but SH‐HCC and steatotic sHCC are not the same, because fibrous stroma is not a necessary criterion for SH‐HCC .…”