Whole-Body PET/CT Radioligand Imaging for Metastatic Disease Across Solid Tumors: Current Diagnostic Accuracy, Comparative Modalities, and Future Horizons

Whole-body positron emission tomography/computed tomography (PET/CT) is a cornerstone for detecting metastatic disease in solid tumors, integrating metabolic and anatomic data to guide therapeutic decisions. This narrative review synthesizes contemporary literature (2013–2025) to evaluate PET/CT’s diagnostic accuracy, compare it with stand-alone CT, MRI, and PET/MRI, and explore emerging radioligands and future directions. In multi-cancer cohorts, 18F-FDG PET/CT achieves patient-level sensitivity of 75–90% and specificity above 90%, with organ-specific limitations in the liver and brain due to physiologic uptake. PET/MRI offers superior sensitivity for hepatic and intracranial metastases but at higher cost and longer scan times, limiting its role to problem-solving scenarios. Non-FDG radioligands, such as 68Ga-PSMA for prostate cancer and 68Ga-DOTATATE for neuroendocrine tumors, target molecular pathways, enhancing detection in low-FDG-avidity organs, though multi-cancer accuracy data remain sparse. Methodological challenges, including partial verification bias and heterogeneous reference standards, complicate cross-study comparisons. Economic analyses suggest PET/MRI’s incremental cost-effectiveness is modest, with management changes in <5% of cases. Proposed algorithms advocate FDG PET/CT as the first-line modality, with biology-matched tracers (e.g., PSMA, FAPI) for specific histologies or equivocal findings, and PET/MRI for liver or CNS concerns. Future priorities include AI-driven quantitative PET, multicenter basket trials aligning tracers with molecular pathways, and cost-utility studies to justify novel ligands. This review equips clinicians with an integrated perspective on PET/CT’s current role, comparative performance, and the evidence needed to advance precision imaging for metastatic staging.