American College of Radiology–Developed Thyroid Imaging Reporting and Data System 3, 4, and 5 thyroid nodules are distinctive by cytology, genetic imprints, and histology

Thyroid nodules, found in up to 68% of adults, can be risk-stratified by high-resolution ultrasound. This study evaluates the concordance between "suspicious" Thyroid Imaging Reporting and Data System (TI-RADS) 3-5 nodules and cytologic and molecular findings from fine-needle aspiration. A total of 1199 suspicious thyroid nodules stratified as TI-RADS 3 (n = 384), TI-RADS 4 (n = 569), and TI-RADS 5 (n = 246) were studied. Cytopathologic and molecular results were correlated with clinical data from electronic medical records. Cytology, histology, and molecular testing revealed a lower risk of malignancy in TI-RADS 3 and 4 nodules compared to TI-RADS 5. Among TI-RADS 3 nodules, 75% (287 of 384) were cytologically benign, with only one case diagnosed as papillary thyroid carcinoma (PTC), and 8 of 48 resected nodules (17%) confirmed as carcinoma. In TI-RADS 4, 10% (56 of 569) were suspicious for or diagnosed as PTC by cytology, with 85 of 130 (65%) resected nodules confirmed as carcinoma. In TI-RADS 5, 44% (109 of 246) were cytologically suspicious for or diagnosed as PTC, and 129 of 154 (84%) resected nodules were malignant. High-risk mutations were more frequent in TI-RADS 5 than in TI-RADS 3 and 4. Overall malignancy rates were 2.0% (eight of 384) for TI-RADS 3, 14% (77 of 569) for TI-RADS 4, and 52% (129 of 246) for TI-RADS 5 nodules. TI-RADS 3, 4, and 5 nodules demonstrate distinct cytologic, molecular, and histologic features. TI-RADS 3 and 4 nodules are associated with lower malignancy risks, whereas TI-RADS 5 nodules exhibit a high risk of malignancy and are associated with higher mortality.