Our objective was to compare the diagnostic performance of ⁶⁸Ga-labeled fibroblast activation protein (FAP) inhibitor (FAPI) and ¹⁸F-labeled FDG PET/CT in diagnosing lymphomas and to characterize the influence of FAP and glycolytic markers on tracer uptake by involved lesions. Methods: Participants with different lymphoma subtypes who were prospectively recruited from May 2020 to December 2021 underwent ⁶⁸Ga-FAPI and ¹⁸F-FDG PET/CT. Immunohistochemistry was performed to evaluate FAP, hexokinase 2, and glucose transporter 1 (GLUT1) expression, and the paired-samples t test and Wilcoxon signed-rank test were used to compare parameters. The correlation between the immunochemistry results and tracer uptake was determined by the Spearman rank correlation coefficient. Results: In total, 186 participants (median age, 52 y [interquartile range, 41–64 y]; 95 women) were included. Dual-tracer imaging produced 3 types of imaging profiles. ¹⁸F-FDG PET possessed a higher staging accuracy (98.4%) than ⁶⁸Ga‐FAPI PET (86.0%). In 5,980 lymphoma lesions, ¹⁸F-FDG PET/CT detected more nodal (4,624 vs. 2,196) and extranodal (1,304 vs. 845) lesions than ⁶⁸Ga-FAPI PET/CT. Additionally, 52 ⁶⁸Ga-FAPI–positive/¹⁸F-FDG–negative lesions and 2,939 ⁶⁸Ga-FAPI–negative/¹⁸F-FDG–positive lesions were observed. In many lymphoma subtypes, semiquantitative evaluation revealed no significant differences in SUV_max or target-to-liver ratios between ⁶⁸Ga-FAPI and ¹⁸F-FDG PET/CT (P > 0.05). Interestingly, GLUT1 and hexokinase 2 were overexpressed both in lymphoma cells and in the tumor microenvironment, whereas FAP was expressed only in stromal cells. FAP and GLUT1 expression correlated positively with ⁶⁸Ga-FAPI SUV_max (r = 0.622, P = 0.001) and ¹⁸F-FDG SUV_max (r = 0.835, P < 0.001), respectively. Conclusion:⁶⁸Ga-FAPI PET/CT was inferior to ¹⁸F-FDG PET/CT in diagnosing lymphomas with low FAP expression. However, the former may supplement the latter and help reveal the molecular profile of lymphomas. Visual Abstract

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