Abstract
Background/Objectives: Disease recurrence and resistance to radioiodine (RAI) therapy are major challenges in the management of differentiated thyroid cancer (DTC). In particular, the TENIS (Thyroglobulin Elevated Negative Iodine Scintigraphy) syndrome, characterised by elevated thyroglobulin (Tg) serum levels in addition to a negative radioiodine whole body scan (WBS), complicates disease monitoring and treatment decisions. Conventional imaging techniques often fail to detect disease in WBS-negative patients with rising Tg levels, leading to limitations in therapeutic intervention. This systematic review and meta-analysis aims to evaluate the diagnostic accuracy of nuclear imaging modalities in detecting disease recurrence in patients with the TENIS syndrome and to provide insights to guide therapeutic approaches in this complex clinical scenario. Methods: A comprehensive search of PubMed/MEDLINE and EMBASE databases up to March 2024 was performed according to PRISMA guidelines. Eligible studies were selected, and quality assessment was performed with the QUADAS-2 tool. For each study, relevant data were extracted and synthesised. A meta-analysis of the diagnostic accuracy of [(18)F]FDG PET/CT was performed, and patient-based pooled sensitivity and specificity were calculated using a random-effects model. Statistical heterogeneity between studies was assessed using the I2 statistic. Results: Of the 538 studies initially identified, 22 were included in the systematic review, of which 18 were eligible for meta-analysis. The eligible studies, mainly focused on [(18)F]FDG PET/CT, showed variable sensitivity and specificity for the detection of RAI-refractory thyroid cancer lesions. For [(18)F]FDG PET/CT, pooled estimates displayed a sensitivity of 0.87 (95% CI: 0.82-0.90) and a specificity of 0.76 (95% CI: 0.61-0.86), with moderate heterogeneity between studies. Conclusions: [(18)F]FDG PET/CT remains central in the detection of disease recurrence in patients with the TENIS syndrome. The emergence of novel radiopharmaceuticals with specific molecular targets is a promising way to overcome the limitations of [(18)F]FDG in these patients and to open new theranostics perspectives. This review highlights the great potential of nuclear medicine in guiding therapeutic strategies for RAI-refractory thyroid cancer.