Mac-2 Binding Protein Glycosylation Isomer (M2BPGi)-Based Risk Stratification Refined by Tumor Metabolic Activity in Hepatocellular Carcinoma.

AIM: To evaluate the prognostic significance of preoperative Mac-2 binding protein glycosylation isomer (M2BPGi) and determine whether tumor metabolic activity provides additional risk stratification after hepatic resection for hepatocellular carcinoma (HCC). METHODS: We retrospectively analyzed 291 patients with HCC who underwent hepatic resection at a single Japanese institution between 2015 and 2023 and had available preoperative M2BPGi and 18F-fluorodeoxyglucose positron emission tomography/computed tomography data. Associations with clinicopathological features, recurrence-free survival (RFS), and overall survival (OS) were evaluated. RESULTS: High M2BPGi was associated with impaired liver function and F3-F4 fibrosis but not with tumor-related features or tumor metabolic activity. In contrast, high tumor metabolic activity was associated with higher des-γ-carboxy prothrombin (DCP) levels, larger tumors, poor differentiation, microscopic vascular invasion, and intrahepatic metastasis. High M2BPGi and high tumor metabolic activity independently predicted worse RFS (hazard ratio [HR], 1.61; p = 0.0105 and HR, 1.94; p = 0.0023, respectively) and OS (HR, 2.03; p = 0.0042 and HR, 1.93; p = 0.0199, respectively). The dual-high group had the poorest RFS and OS (both p < 0.0001). In public data analysis, M2BPGi-related fibrosis and glycolysis-related signatures were positively correlated with a mechanistic target of rapamycin complex 1 (mTORC1)-related anabolic signature (R = 0.439 and R = 0.670, respectively; p < 0.0001), and a high mTORC1-related signature was associated with worse OS (p = 0.0074). CONCLUSIONS: Preoperative M2BPGi identifies fibrosis-related risk after HCC resection, whereas tumor metabolic activity further distinguishes patients with particularly poor outcomes.