Rates and Predictors of Malignancy in Bethesda III and IV Thyroid Nodules: A Prospective Study

Thyroid nodules, based on high-resolution ultrasonography (HRUS), are among the most common endocrine abnormalities that affect the general population because of their high estimated prevalence rates. Fine needle aspiration cytology (FNAC) is a safe, cost-effective modality to differentiate between benign and malignant thyroid nodules based on the Bethesda System for Reporting Thyroid Cytopathology (BSRTC), thus avoiding unnecessary surgery. However, categories III and IV of BSRTC remain a controversial issue in clinical practice, encompassing a wide range of risks of malignancy. Hence, our study aimed to assess the malignancy rates of thyroid nodules classified as Bethesda III and IV categories as evidenced by post-thyroidectomy histopathology; study the association between the American College of Radiologists Thyroid Image Reporting and Data System (ACR-TIRADS) score of these two categories and the postoperative histopathological analysis; and study the predictors of malignancy in these two categories. A prospective study was conducted on 242 patients who underwent FNAC throughout the study from December 2022 to August 2023. All patients who performed FNAC were primarily subjected to history taking, clinical examination, thyroid-stimulating hormone (TSH), thyroid autoantibodies (antithyroglobulin (anti-TG) and thyroid peroxidase antibodies (TPO Abs)), and HRUS with a further categorization of thyroid nodules according to the ACR-TIRADS scoring system. The cytological aspirates were categorized according to the BSRTC. Patients with Bethesda III and IV categories were resorted to surgery according to clinical factors, sonographic features, and patients' preferences. A total of 17 cases with Bethesda III and 65 patients with Bethesda IV were included. Seventy-one out of 82 patients (86.6%) underwent surgical intervention. The proportions of malignant nodules classified as TIRADS-2, TIRADS-3, TIRADS-4, and TIRADS-5 scores were 0.0, 4.5 (n=1/22), 22.7 (n=5/22), and 72.7% (n=16/22), respectively. The rate of malignancy was 18.2% (n=2/11) among class III and 33.3% (n=20/60) among class IV-categorized Bethesda thyroid nodules. In univariate logistic regression analysis, age ≥ 40 years, body mass index ≥ 30 kg/m², higher TSH, positive anti-TG antibodies, radiation exposure, irregular borders, marked hypoechogenicity, ill-defined margins, microcalcifications, solid consistency, taller than wide growth, solitary nodule, and nodule size > 2 cm, and suspicious lymph nodes were associated with higher malignancy risk. In multivariate regression analysis, positive anti-TG Abs, radiation exposure, irregular borders, taller-than-wide growth, hypoechogenicity, calcifications, and solid consistency remain to be independent predictors of malignancy. The malignancy rates of Bethesda class III and IV nodules in this study met the estimated malignancy risk proposed by BSRTC. TIRADS scores 4 and 5 confer a higher risk of malignancy in Bethesda III and IV thyroid nodules. Positive thyroglobulin antibodies and radiation exposure are independent factors of malignancy in Bethesda III and IV nodules. Moreover, ultrasound features, including irregular borders, taller-than-wider growth, hypoechogenicity, calcifications, and solid consistency, are associated with increased malignancy risk and should be considered in the surgical selection of patients.