Beyond metastases: a mechanism-based guide to misleading ¹³¹I uptake on whole-body scintigraphy

¹³¹I whole-body scintigraphy (WBS) remains a cornerstone in the follow-up of differentiated thyroid carcinoma (DTC). However, radioiodine uptake is not specific, and many benign conditions can result in focal or diffuse radioiodine activity that mimics metastatic disease. A narrative literature review spanning more than five decades was conducted to identify and categorise reported sites of misleading radioiodine uptake on WBS in patients with DTC. Case reports, case series, original studies, and reviews were analysed with particular emphasis on the underlying mechanisms of uptake. The majority of false-positive findings were attributable to non-tumorous conditions, followed by benign neoplasms and, less frequently, non-thyroidal malignancies. Ectopic thyroid tissue was documented at numerous sites beyond classical thyroglossal duct remnants. Although pathological NIS expression was demonstrated in several non-thyroidal tumors, its presence did not consistently correlate with functional iodide transport. No single imaging feature reliably differentiates non-tumorous radioiodine uptake from true metastatic disease. Accurate interpretation, therefore, requires integration of clinical history, biochemical findings, and complementary imaging, particularly single-photon emission computed tomography/computed tomography (SPECT/CT). A mechanism-based approach to unexpected radioiodine uptake offers a practical strategy to reduce false-positive interpretations and avoid unnecessary diagnostic procedures.