Dual-tracer [18F]F-FDG and [18F]F-FAPI-04 PET/CT for predicting tumor aggressiveness and prognosis in hepatocellular carcinoma

Noninvasive assessment of tumor aggressiveness and prognosis in hepatocellular carcinoma (HCC) prior to treatment remains challenging because histopathological evaluation is not routinely performed. Increased glucose metabolism and fibroblast activation protein (FAP) expression are associated with tumor progression. This study aimed to evaluate whether parameters derived from [ 18 F]F-FDG and [ 18 F]F-FAPI-04 PET/CT are associated with aggressive pathological features and prognosis in HCC. We prospectively analyzed treatment-naive patients with HCC who underwent both [ 18 F]F-FDG and [ 18 F]F-FAPI-04 PET/CT between August 2022 and March 2025. Tracer uptake was quantified using maximum standardized uptake value (SUV max ), tumor-to-background ratio (TBR), metabolic tumor volume (MTV), total lesion glycolysis (TLG), [ 18 F]F-FAPI-avid tumor volume (FTV), and total lesion fibroblast activation protein expression (TLF). Associations with pathological features were assessed using Spearman correlation. Kaplan–Meier analysis and Cox regression were performed for survival analysis. A total of 48 patients with HCC (46 males and 2 females; median age, 56.5 years) were analyzed. Patients with CK19-positive tumors showed higher [ 18 F]F-FDG SUV max than those with CK19-negative tumors (5.4 vs. 4.1, P = 0.04). [ 18 F]F-FAPI-04 SUV max was higher in GPC3-positive than in GPC3-negative tumors (10.2 vs. 5.9, P = 0.008). High Ki-67 expression was associated with higher [ 18 F]F-FAPI-04 SUV max , TBR, and [ 18 F]F-FDG SUV max (10.4 vs. 6.1, P = 0.006; 7.4 vs. 3.9, P = 0.04; 7.7 vs. 4.7, P = 0.03). Poorly differentiated HCC tended to have higher [ 18 F]F-FDG SUV max , MTV, TLG, [ 18 F]F-FAPI-04 SUV max , TBR, FTV, and TLF compared with moderately or well-differentiated tumors (all P < 0.05). On multivariable analysis, MTV and TLF were independent predictors of progression-free survival, whereas treatment modality, MTV, and TLF were associated with overall survival. This exploratory study suggests that PET parameters from baseline [ 18 F]F-FDG and [ 18 F]F-FAPI-04 PET/CT may be associated with aggressive tumor features and survival in HCC. These findings warrant validation in larger cohorts. ClinicalTrials.gov NCT05485792. Registered 3 August 2022.