Utility of genomic sequencing classifier in managing cytologically indeterminate oncocytic thyroid nodules

CONTEXT: Oncocytic cells can occur in benign and malignant thyroid nodules, posing a diagnostic challenge. This has reduced the diagnostic performance of molecular testing for indeterminate oncocytic thyroid nodules. OBJECTIVE: To evaluate the performance of Afirma genomic sequencing classifier (GSC) in thyroid nodules with Bethesda III or IV cytology and oncocytic predominance. DESIGN, SETTING, PATIENTS, AND INTERVENTION: A multicenter retrospective study was conducted in adults with Bethesda III and IV thyroid nodules showing oncocytic predominance who underwent a fine-needle aspiration biopsy and Afirma GSC testing between July 2017 and December 2023. Variables included presence of Hashimoto's thyroiditis and Thyroid Imaging Reporting and Data System (TIRADS) classification. MAIN OUTCOME MEASURES: Outcomes included benign call rate (BCR), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of Afirma GSC testing. RESULTS: Of 359 nodules (57% Bethesda III, 43% Bethesda IV) tested with Afirma GSC, the mean nodule size was 2.0 cm. BCR was 81% and 74% for Bethesda III and IV nodules, respectively. GSC sensitivity, specificity, PPV, and NPV were 89%, 86%, 24%, and 99% for Bethesda III nodules and 94%, 87%, 50%, and 99% for Bethesda IV nodules, respectively. A concurrent diagnosis of Hashimoto's thyroiditis significantly reduced the specificity and PPV in Bethesda III nodules. TIRADS classification did not affect the BCR or PPV in Bethesda III or IV nodules. CONCLUSION: Afirma GSC has a high BCR and improved performance over earlier generation molecular tests in oncocytic thyroid nodules, particularly for Bethesda IV. However, the PPV in Bethesda III nodules remains low, especially in the presence of Hashimoto's thyroiditis.