The Role of Ultrasound as a Predictor of Malignancy in Indeterminate Thyroid Nodules—A Multicenter Study

Background and Objectives: Indeterminate thyroid nodules (Bethesda III and IV) are a common clinical entity that present a diagnostic challenge due to their intermediate risk of malignancy. This study aimed to evaluate the role of ultrasound in risk stratification and malignancy prediction to support clinical decision-making and reduce unnecessary surgical interventions. Materials and Methods: This retrospective multicenter cohort study included patients aged ≥18 years who underwent thyroid surgery between 2016 and 2022 at four centers in the Eastern Province of Saudi Arabia. Only nodules with indeterminate cytology (Bethesda III or IV) were included. Data collected included demographic characteristics, thyroid function, ultrasound features, cytology results, and histopathological findings. Results: A total of 679 patients with 733 nodules were reviewed. Of these, 206 patients with 223 indeterminate nodules were included (median age: 42 years; 88.3% female). The overall malignancy rate was 46.6%. Independent predictors of malignancy included solid hypoechoic composition (OR = 2.26, p = 0.012), microcalcifications (OR = 3.07, p = 0.002), lymph node involvement (OR = 2.43, p = 0.021), American Thyroid Association (ATA) intermediate to high suspicion category (OR = 1.9, p = 0.018), and Thyroid Imaging Reporting and Data Systems (TI-RADS) categories 4–5 (OR = 2.3, p = 0.003). Solid hypoechoic nodules showed 82.3% specificity and 63.0% positive predictive value (PPV); microcalcifications demonstrated 84.1% specificity and 68.4% PPV; lymph node involvement had 87.6% specificity and 68.9% PPV. The ATA and TI-RADS classifications showed higher sensitivity (63.5% and 68.0%, respectively), but lower specificity (53.1% and 52.8%, respectively). Conclusions: Ultrasound features, particularly solid hypoechoic composition, microcalcifications, and lymph node involvement, as well as ATA and TI-RADS classifications, were independent predictors of malignancy in indeterminate thyroid nodules. Although ATA and TI-RADS offered higher sensitivity, individual features demonstrated greater specificity and PPV. These findings support the use of ultrasound risk stratification to guide surgical decisions in high-risk cases and suggest that additional diagnostic evaluation may be appropriate for low-risk nodules.