Dual-Tracer PET/CT Imaging Linked to Tumor Aggressiveness in Liver Cancer

A prospective study of patients with hepatocellular carcinoma reports that imaging parameters from two PET tracers, [18F]F-FDG and [18F]F-FAPI-04, are associated with aggressive pathological features and with survival outcomes in this hard-to-treat liver cancer.

Histopathological evaluation, the current reference standard, requires biopsy or surgical specimens and is not routinely performed in these patients. The researchers set out to test whether quantitative measurements from combined PET/CT imaging could fill that gap by capturing two biological hallmarks of tumor progression: elevated glucose metabolism, traced by fluorodeoxyglucose, and high expression of fibroblast activation protein, traced by the FAPI-04 ligand.

The study prospectively enrolled treatment-naive patients with hepatocellular carcinoma who underwent both [18F]F-FDG PET/CT and [18F]F-FAPI-04 PET/CT between August 2022 and March 2025. The trial was registered on ClinicalTrials.gov as NCT05485792. In total, 48 patients were analyzed, 46 of them male and 2 female, with a median age of 56.5 years. For each tumor, the team quantified uptake using several standard parameters: maximum standardized uptake value (SUVmax), tumor-to-background ratio (TBR), metabolic tumor volume (MTV), total lesion glycolysis (TLG), FAPI-avid tumor volume (FTV), and total lesion fibroblast activation protein expression (TLF).

The imaging measurements were then compared against pathological features of the tumors. Patients whose tumors expressed cytokeratin 19, a marker associated with more aggressive behavior, showed higher [18F]F-FDG SUVmax than patients with CK19-negative tumors, with values of 5.4 versus 4.1 and a P value of 0.04. Glypican-3 positivity, another immunohistochemical marker, was linked to the FAPI tracer: [18F]F-FAPI-04 SUVmax reached 10.2 in GPC3-positive tumors compared with 5.9 in GPC3-negative tumors, a difference that was statistically significant at P = 0.008.

Proliferative activity also left an imaging signature. Tumors with high Ki-67 expression, indicating a larger fraction of dividing cells, showed higher [18F]F-FAPI-04 SUVmax (10.4 versus 6.1, P = 0.006), higher [18F]F-FAPI-04 TBR (7.4 versus 3.9, P = 0.04), and higher [18F]F-FDG SUVmax (7.7 versus 4.7, P = 0.03) than tumors with lower Ki-67 levels. Tumor grade showed a similar pattern: poorly differentiated hepatocellular carcinoma tended to have higher values across the board, including [18F]F-FDG SUVmax, MTV, TLG, [18F]F-FAPI-04 SUVmax, TBR, FTV, and TLF, with all comparisons reaching P < 0.05 relative to moderately or well-differentiated tumors.

The prognostic analysis used Kaplan–Meier curves and Cox regression models. On multivariable analysis, two volumetric parameters emerged as independent predictors of progression-free survival: metabolic tumor volume from the FDG scan and total lesion FAP expression from the FAPI scan. For overall survival, three factors were associated with outcome: the treatment modality the patient received, MTV, and TLF.

The biological rationale for the dual-tracer approach rests on complementary mechanisms.

The authors are careful to frame the work as exploratory. With 48 patients, the study is small, and the conclusions explicitly call for validation in larger cohorts before any clinical adoption. The article was shared early as a peer-reviewed accepted manuscript carrying a permanent DOI, a version that remains subject to further editorial edits before the final Version of Record.

Subject of Research: Dual-tracer FDG and FAPI-04 PET/CT imaging as a noninvasive marker of tumor aggressiveness and prognosis in hepatocellular carcinoma

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

Article References: Yan, S., Liang, J., Song, J., Li, S., Jiang, S., Li, W., Peng, H., Hao, Y., Liu, Z., Zhou, M., Zhang, R., & Zhang, L. (2026). Dual-tracer [18F]F-FDG and [18F]F-FAPI-04 PET/CT for predicting tumor aggressiveness and prognosis in hepatocellular carcinoma. Cancer Imaging. https://doi.org/10.1186/s40644-026-01131-8

Image Credits: AI Generated

DOI: 10.1186/s40644-026-01131-8

Keywords: hepatocellular carcinoma, PET/CT, [18F]F-FDG, [18F]F-FAPI-04, tumor aggressiveness, Ki-67, glypican-3, cytokeratin 19, progression-free survival, overall survival, fibroblast activation protein, molecular imaging