Are Bethesda III Thyroid Nodules More Aggressive than Bethesda IV Thyroid Nodules When Found to Be Malignant?

SIMPLE SUMMARY: The Bethesda classification system is a widespread tool used in the initial screening test for thyroid nodules. The system classifies the biopsy of the nodule into 6 categories, each with its associated malignancy risk and recommendations for management. Nodules classified as Bethesda III and IV are considered intermediate risk, and although Bethesda III nodules are more likely to be benign than Bethesda IV, our hypothesis is that out of those that are malignant, a subset may be more aggressive given their diverse cellular features. In this study we looked at 628 individuals who underwent surgery with a Bethesda III or IV nodule and compared the number of aggressive features found in those with confirmed malignancy. We discovered that Bethesda III nodules that were found to be malignant were more likely to have aggressive features, such as aggressive sub-types of thyroid cancer, spread of cancer beyond the thyroid capsule, and spread of cancer to the lymph nodes. Our results suggest that Bethesda III thyroid nodules may not as indolent as they seem, and these findings may affect management decisions in individuals with indeterminate thyroid nodules. ABSTRACT: The Bethesda classification system for thyroid fine needle aspirate (FNA) is used to predict the risk of malignancy and to guide the management of thyroid nodules. We postulated that thyroid malignancies characterized as Bethesda III on FNA have more aggressive features than those classified as Bethesda IV. A retrospective chart review was performed to identify those who underwent thyroid surgery at a single tertiary hospital setting between 2015 and 2020. Associations between Bethesda category, molecular genetic test results, and histopathologic findings were examined. Out of 628 surgeries that were performed, 199 (54.2%) Bethesda III nodules and 216 (82.8%) Bethesda IV nodules were malignant. Of those that were malignant, 37 (18.6%) and 22 (10.2%) Bethesda III and Bethesda IV nodules showed aggressive features, respectively (p value = 0.014). There was a proportionally increased number of aggressive features in extra-thyroidal extension, lymph nodes metastasis, and all aggressive subtypes of papillary thyroid cancer in the Bethesda III category. Although Bethesda IV nodules are much more likely to be malignant (p value = 0.002), our study suggests that Bethesda III nodules that are resected are more likely to have aggressive features than Bethesda IV nodules, with a statistically significant increase in the solid variant of papillary thyroid cancer and lymph node metastasis.