Diagnostic utility of FAPI PET/CT in radioiodine-refractory thyroid cancer and TENIS syndrome: a systematic review

Background Fibroblast activation protein inhibitor (FAPI) positron emission tomography/computed tomography (PET/CT) has emerged as a promising molecular imaging modality with favorable lesion-to-background contrast across several malignancies. In radioiodine-refractory thyroid carcinoma (RAIR-TC) and thyroglobulin-elevated negative iodine scintigraphy (TENIS) syndrome, conventional radioiodine imaging and fluorodeoxyglucose (FDG) PET/CT may be limited in selected clinical scenarios. This systematic review evaluated the diagnostic utility, comparative performance, and potential clinical impact of FAPI PET/CT in this patient population. Methods PubMed, Embase, and Scopus were searched from inception to 6 August 2025 according to PRISMA 2020 guidelines. Eligible studies included original clinical studies and case reports evaluating FAPI PET/CT in RAIR-TC or TENIS syndrome. Non-original, non-human, in vitro , conference abstract, and non-English publications were excluded. Two reviewers independently performed study selection, data extraction, and quality assessment. QUADAS-2 was applied to eligible cohort studies. Results Eight studies comprising 167 patients were included: three prospective studies, one retrospective study, and four case reports. FAPI PET/CT showed promising complementary diagnostic value in selected clinical scenarios, particularly for lesions with low FDG conspicuity or high physiologic FDG background. In one prospective cohort of 24 patients, [ 68 Ga]Ga-DOTA-FAPI-04 PET/CT detected disease in 87.5% of patients. In the largest retrospective cohort (n = 117), [ 68 Ga]Ga-DOTA.SA.FAPi showed higher detection than FDG PET/CT for selected metastatic sites, including lymph nodes, liver, and brain. However, comparative performance varied across tracers, lesion sites, and study designs; one prospective [ 18 F]FAPI-74 study reported lower lesion detection than FDG PET/CT. Conclusion FAPI PET/CT demonstrates promising but preliminary diagnostic utility in RAIR-TC and TENIS syndrome. Current evidence supports a complementary role in selected patients, but remains insufficient to establish routine diagnostic superiority over FDG PET/CT. Larger prospective multicenter studies with standardized protocols and robust reference validation are required. Systematic Review Registration https://www.crd.york.ac.uk/PROSPERO/view/CRD420251123809 .