Malignancy Risk Within Hyperfunctioning Thyroid Nodules: Clinicopathologic Features and Diagnostic Implications

Background/Objectives: Hyperfunctioning thyroid nodules are generally considered to have a low malignancy risk, but data on genuine hyperfunctioning thyroid neoplasms remain limited. This study aimed to characterize the clinicopathologic features and diagnostic implications of true hyperfunctioning thyroid neoplasms through lesion-level imaging-pathologic correlation and to estimate their observed frequency within a surgically treated cohort. Methods: We retrospectively reviewed 82 hyperthyroid patients at our institution with thyroid scintigraphy suggestive of solitary or multiple toxic nodules between 2014 and 2024; 25 underwent thyroidectomy. True hyperfunctioning thyroid neoplasms were defined by lesion-level imaging-pathologic correlation. Results: Among the 25 surgically treated patients, seven had confirmed hyperfunctioning carcinoma or tumors of uncertain malignant potential (UMP) (28.0%; 95% CI, 14.1-47.8%). When referenced against the full scintigraphic cohort of 82 patients, of whom only 30.5% underwent surgery, the observed rate was 8.5% (95% CI, 4.2-16.6%); however, this figure should be interpreted with caution given the inherent surgical selection bias. Four patients had overt carcinomas. The remaining three patients had UMPs. In nodule-based analysis, hyperfunctioning neoplasms were significantly larger than coexisting tumors (5.0 ± 2.8 vs. 0.8 ± 0.7 cm, p = 0.007) and more often follicular-patterned (85.7% vs. 27.3%; RR, 3.14; 95% CI, 1.14 to 8.64; p = 0.0498). Conclusions: These findings indicate that hyperfunctioning status does not definitively exclude malignancy, while also emphasizing that the absolute malignancy frequency in unselected hyperthyroid populations remains uncertain.