Glutamine Synthetase Immunostaining Correlates with Pathologic Features of Hepatocellular Carcinoma and Better Survival after Radiofrequency Thermal Ablation

Abstract

Purpose: Activation of the wnt pathway identifies a subgroup of hepatocellular carcinomas (HCC) with specific epidemiologic and genetic profiles. Wnt activation is predicted by mutation and/or nuclear translocation of β-catenin and by glutamine synthetase (GS) immunoreactivity. We investigated whether GS staining associates with specific pathologic features of HCC and with survival after radiofrequency thermal ablation.Experimental Design: Monoistitutional retrospective-prospective study in a tertiary hospital setting. Two hundred and seven cirrhotics (mean age, 70 years; 63% males, 82.1% hepatitis C virus positive) with early HCC were consecutively treated with radiofrequency thermal ablation (RFTA). Mean tumor size was 2.7 cm; 20.3% of patients had multiple nodules; and median follow-up was 36 months with 54.6% overall mortality. Tumor samples were mainly obtained by biopsy (92,5%) and examined by H&E and immunostaining for β-catenin and GS. Main outcome measures were overall and tumor-specific mortality by Kaplan-Meier analysis and Cox proportional hazard models corrected for competing risks.Results: Ninety-one patients (43.9%) had GS-positive HCCs by immunostaining. These tumors had larger size (P = 0.012) and characteristic histology (low grade, pseudoacini, hydropic changes, bile staining, lack of steatosis, and fibrosis). Other clinical or treatment variables were similar between groups. Variables correlating with tumor-specific and overall mortality by univariate analysis were tumor recurrence, advanced disease, posttreatment α-fetoprotein levels, and GS staining. Yearly, overall mortality rate was lower in GS-positive patients (12.4 versus 20% yearly; P = 0.006). By multivariate analysis, GS immunostaining correlated with reduced specific (hazard ratio, 0.58; 95% confidence interval, 0.34-0.97) and overall mortality (hazard ratio, 0.62; 95% confidence interval, 0.40-0.96).Conclusions: Standard histology and GS status identify a HCC subset with distinct clinical and pathologic features. Clin Cancer Res; 16(7); 2157-66. ©2010 AACR.

Repeated radiofrequency ablation for management of patients with cirrhosis with small hepatocellular carcinomas: A long-term cohort study

“…21,22 Differences in the clinical outcome of HCCs diagnosed at the same stage in patients with preserved liver function may reflect biological differences of the tumor and cirrhotic liver tissue. 37,38 This study also shows that mortality unrelated to cancer progression has an important impact on the survival of HCC patients, who in Western countries are generally elderly. 3,4,32 In conclusion, our ability to select optimal treatment strategies for patients with cirrhosis with HCCs is currently limited by three factors: (1) unpredictability of tumor progression and de novo carcinogenesis 37,38 ; (2) tumor understaging 14 ; and (3) substantial risk of HCCunrelated death.…”

Glutamine fuels a vicious cycle of autophagy in the tumor stroma and oxidative mitochondrial metabolism in epithelial cancer cells

“…35 Some studies have also shown that the downregulation of GLUL, a key enzyme in glutamine synthesis, correlates with a worse prognosis in some tumors. 36,37 Accordingly, our data indicate that when cocultured with fibroblasts under conditions that better mimic the tumor microenvironment, cancer cells display the downregulation of GLUL, suggesting a decreased need for glutamine neogenesis, and increase GLS and GLUD1, two key enzymes in glutamine catabolism. It will be important to evaluate the prognostic value of GLS and GLUL in the different tumor compartments (stromal vs. epithelial), especially as this relates to tumor progression.…”

The Role of Cancer-Associated Fibroblasts and Fibrosis in Liver Cancer

“…Interestingly, mechanotransduction-induced YAP signals promote the generation of CAFs, suggesting a complex interplay between tumor mechanics and stromal fibroblasts that contributes to the evolution of key components of the TME (77). In addition, specific genomic profiles of HCC appear to influence the activation of the stromal compartment as demonstrated by lower fibrosis in patients with beta-catenin-mutated HCCs (78, 79). There is increasing evidence from clinical studies that the presence of liver fibrosis, α-SMA-positive myofibroblasts, or activated HSC signatures is associated with a poor prognosis after curative HCC resection, suggesting a key role of the fibrotic TME in promoting HCC progression: In patients with curative HCC resection, a high degree of peritumoral myofibroblast infiltration was associated with a 2.6-fold hazard ratio for overall survival and a 3.3-fold hazard ratio for recurrence-free survival (52).…”