Elena G. Hughes

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.

Background: Patients residing in rural and frontier areas experience worse thyroid cancer outcomes than those in urban areas. This novel qualitative study sought the perspectives of rural surgeons to identify practical measures that could mitigate the disparities in thyroid cancer care between rural and urban contexts. Methods: We contacted general and head and neck surgeons at all of California’s Critical Access Hospitals (n = 35), which are remote, rural hospitals, and requested self-referral to our study through the American College of Surgeons. We performed semi-structured qualitative interviews with surgeons at rural hospitals to understand the assets and vulnerabilities of rural hospitals in providing the highest quality care to patients with thyroid cancer. Responses were coded and analyzed using mixed-methods qualitative analysis methodology. Results: Rural surgeons (n = 13) from a geographically diverse sample of states and regions (AK, AR, CA, NE, NC, NM, TX, UT, WY, and Newfoundland) participated. All initially trained in general surgery; 46% had fellowship training (15% in endocrine surgery) and performed a median of 8.5 thyroidectomies annually. Rural surgeons from all training backgrounds felt adequately trained to treat thyroid cancer and reported a strong desire to provide comprehensive thyroid cancer care. Most reported patients’ strong preference to be treated near home. Key challenges to local, comprehensive thyroid cancer care included limited or no access to medical endocrinology, lack of continuing education on thyroid cancer management, and professional isolation in decision-making. Interviewed rural surgeons identified connections with university health systems, expert colleagues, and telemedicine consultations as valuable assets in treating thyroid cancer in geographically isolated hospitals. Discussion: This study identified key challenges and clear avenues for interventions in treating rural thyroid cancer patients. Interviewed rural surgeons specifically suggest improving access to endocrinology specialists, developing educational initiatives on thyroid cancer management, and fostering connections and collaborations with urban colleagues to reduce professional isolation.

Context: Molecular testing can refine the risk of malignancy in thyroid nodules with indeterminate cytology to decrease unnecessary diagnostic surgery. Objective: This study was performed to evaluate the outcomes of cytologically indeterminate thyroid nodules managed with Afirma genomic sequencing classifier (GSC) testing. Methods: Adult patients who underwent a biopsy at 3 major academic centers between July 2017 and June 2021 with Bethesda III or IV cytology were included. All patients had surgery or minimum follow-up of 1 year ultrasound surveillance. The primary outcomes were the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of GSC in Bethesda III and IV nodules. Results: The median nodule size of the 834 indeterminate nodules was 2.1 cm and the median follow-up was 23 months. GSC sensitivity, specificity, PPV, and NPV across all institutions were 95%, 81%, 50%, and 99% for Bethesda III nodules and 94%, 82%, 65%, and 98% for Bethesda IV nodules, respectively. The overall false-negative rate was 2%. The NPV of GSC in thyroid nodules with oncocytic predominance was 100% in Bethesda III nodules and 98% in Bethesda IV nodules. However, the PPV of oncocytic nodules was low (17% in Bethesda III nodules and 45% in Bethesda IV nodules). Only 22% of thyroid nodules with benign GSC results grew during surveillance. Conclusion: GSC is a key tool for managing patients with indeterminate cytology, including the higher-risk Bethesda IV category. GSC-benign thyroid nodules can be observed similarly to thyroid nodules with benign cytology.

Context: Molecular testing has improved risk stratification and increased nonoperative management for patients with indeterminate thyroid nodules, but data on the long-term outcomes of current molecular tests Afirma Gene Sequencing Classifier (GSC) and Thyroseq v3 are limited. Objective: To determine the rate of delayed operation and the false negative rate of the Afirma GSC and Thyroseq v3 in Bethesda III and IV thyroid nodules. Methods: Prospective follow-up of a single center, randomized, clinical trial comparing the performance of Afirma GSC and Thyroseq v3 in the diagnosis of indeterminate thyroid nodules at the University of California, Los Angeles (UCLA). Consecutive participants who underwent thyroid biopsy in the UCLA health system with Bethesda III and IV cytology from August 2017 to November 2019. The main outcome measure was false negative rate of molecular testing. Results: Of 176 indeterminate nodules with negative or benign molecular test results, 14 (8%) nodules underwent immediate resection, with no malignancies found on surgical pathology. Nonoperative management with active surveillance was pursued for 162 (92%) nodules with benign or negative test results. The median surveillance was 34 months (range 12-60 months), and 44 patients were lost to follow-up. Of 15 nodules resected during surveillance, 1 malignancy was found (overall false negative rate of 0.6%). This was a 2.7 cm minimally invasive Hurthle cell carcinoma that initially tested negative with Thyroseq v3 and underwent delayed resection due to sonographic growth during surveillance. Conclusions: The majority of Bethesda III/IV thyroid nodules with negative or benign molecular test results are stable over 3 years of follow-up. These findings support the high sensitivity of current molecular tests and their role in ruling out malignancy in indeterminate thyroid nodules.