Immunophenotypes and Tumor Immune Microenvironment in Hepatocellular Carcinoma With Macrotrabecular Massive and Vessels Encapsulating Tumor Clusters.

BACKGROUND/AIM: Recently, vessels encapsulating tumor clusters (VETC) pattern and macrotrabecular massive (MTM) pattern of hepatocellular carcinoma (HCC) have been reported as aggressive histological types. These histological patterns showed an immunosuppressive tumor immune microenvironment (TIME). Since there have been no reports on the differences of these two subtypes simultaneously, this study examined the immunophenotypes and TIME of MTM-HCC and VETC-HCC immunohistochemically. PATIENTS AND METHODS: Seventy-four cases of previously diagnosed HCC, including 32 MTM-HCCs, 21 VETC-HCCs, and 21 conventional HCCs, were enrolled in immunohistochemical analysis. We conducted immunohistochemical analysis. RESULTS: We found that MTM-HCC showed less frequent expression of HepPar-1, which is one of the most common hepatocytic markers. In MTM-HCC, the frequency of high expression levels of Keratin19, carbonic anhydrase (CA) IX, and PD-L1 was higher compared to VETC-HCC and conventional HCC. PD-L1 expression was found in 34.4% of MTM-HCC, 0% of VETC-HCC, and 19.0% of conventional HCC. The rate of PD-L1 expression in MTM-HCC was significantly higher than the others (p=0.0015). PD-L1 expression was significantly associated with epithelial cell adhesion molecules and CA IX expression, which are representative markers of tumor stemness and hypoxic conditions, respectively. The CD8 infiltration in VETC-HCC was significantly lower than that in conventional HCC. CONCLUSION: MTM-HCC had different immunophenotypes and TIMEs compared to HCC with the VETC pattern. Although both had immunosuppressive TIME, the elements forming TIME were quite different. To enhance the immune checkpoint inhibitor efficacy, changing TIME from a suppressive to an active form is essential.

Sonic hedgehog expression in steatohepatitic hepatocellular carcinoma and its clinicopathological significance.

Hedgehog (Hh) signaling pathway dysregulation is involved in the pathogenesis of metabolic dysfunction-associated steatohepatitis, and the sonic Hh (SHh) protein, a pivotal molecule in the Hh pathway, is expressed in ballooned hepatocytes. The present study aimed to investigate the clinicopathological significance of SHh expression in steatohepatitic hepatocellular carcinoma (SH-HCC). Reverse transcription-quantitative polymerase chain reaction and immunohistochemistry were performed to examine SHh gene and SHh protein expression in SH-HCC. Additionally, patients with conventional HCC (C-HCC) were included in the control group. Comparisons of patient and tumor characteristics were also performed. The prevalence of SH-HCC was 3% in the whole cohort, and it was significantly associated with a high prevalence of diabetes mellitus. SHh mRNA was detected in all patients with SH-HCC, but not in 23% of patients with C-HCC. Notably, SHh mRNA expression was not significantly different between patients with SH-HCC and those with C-HCC; however, high SHh protein expression was significantly more frequent in SH-HCC patients than in those with C-HCC. Although the prognosis was not significantly different between the SH-HCC and C-HCC groups, high SHh protein expression was an independent poor prognostic factor for HCC. In conclusion, SHh could potentially serve as a therapeutic target for patients with HCC.