Value of Multitracer Imaging in Hepatocellular Carcinomas with Different Metastatic Potential

Background: Hepatocellular carcinoma (HCC) shows marked heterogeneity and varying metastatic potential, challenging prognosis and treatment. This study evaluated multitracer PET imaging with [^18F]FDG, [^18F]FLT, and [^18F]FAC to differentiate HCCs by metastatic behavior and explored its prognostic relevance. Methods: Four human HCC cell lines with varying metastatic potential (HepG2, QGY7701, MHCC97-H, MHCC97-L) were assessed for in vitro tracer uptake, proliferation, and invasion. Subcutaneous and spontaneous metastasis models were established in nude mice. Tumor uptake of tracers was quantified via microPET/CT. mRNA expression of MMP9 and VEGFR-2 and survival were analyzed. Fisher’s classifier was applied to compare single-, dual-, and triple-tracer datasets with cross-validation. Results: Tracer uptake significantly differed among cell lines (P < 0.001). The triple-tracer model ([^18F]FDG+[ ^18F]FLT+[ ^18F]FAC) yielded the lowest classification error rate (0.074) compared with dual tracers (0.085–0.362). In vivo, [^18F]FDG uptake correlated with metastatic potential, MMP9 and VEGFR-2 expression (r = 0.770–0.911, P < 0.05), and inversely with survival (r = − 0.726, P = 0.005). [^18F]FLT uptake showed moderate correlation with biomarkers but not with survival, while [^18F]FAC had no significant discriminative value. Conclusions: Multitracer PET imaging, particularly combining [^18F]FDG and [^18F]FLT, improves differentiation of HCCs with distinct metastatic behaviors. [^18F]FDG uptake is a robust noninvasive prognostic marker, reflecting tumor heterogeneity and correlating with survival and metastasis-related biomarkers. This approach may aid in clinical stratification and personalized management of HCC.