Molecular Testing of Atypical Thyroid Nodules with Corresponding Surgical Correlation: Five-Year Retrospective Review...

Objective We report the results of a retrospective five-year study within a veteran population aimed at correlating abnormal thyroid fine-needle aspiration (FNA) diagnosis with associated molecular testing to the histology of the surgical resection. Methods A retrospective analysis of abnormal thyroid FNAs with associated molecular testing and surgical outcome was conducted from January 1, 2015 to December 31, 2020. Aspirates were classified using the Bethesda system for reporting thyroid cytopathology, including atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS), follicular neoplasm/suspicious for follicular neoplasm (FN/SFN), suspicious for malignancy (SM), and malignant. Pertinent data, including patient demographics, imaging, and ancillary testing were reviewed. A thyroid cancer mutation panel assessing the most common mutations and rearrangements associated with neoplasia was utilized. The results of molecular testing were directly compared and correlated with final cytological and histological diagnosis. Results A total of 1850 thyroid aspirates were performed, 200 of which were given an abnormal cytologic diagnosis. Thirty-six samples were submitted for molecular testing and subsequent surgical follow-up. Four were called malignant on cytology. 32 were placed in an indeterminate category (89%). Within indeterminate cases: 53% exhibited positive molecular mutations (n=17), 34% no mutation detected (n=11), and 13% insufficient quantity for testing (n=4). Upon surgical resection in the mutation-positive group: 18% had no malignancy (n=3), and the remaining 82% were positive for malignancy (n=14). Mutations in the histologically malignant group included: 57% BRAF (n=8), 21% NRAS (n=3), 7% HRAS (n=1), 7% KRAS (n=1), and 7% PAX8/PPAR gamma (n=1). In indeterminate cases with no mutation detected, 10 cases were found to be benign, and one case of malignancy was diagnosed. The probability of indeterminate diagnosis in combination with no mutation yielded a 91% chance of benign entity and 9% chance of malignancy. We demonstrated 93% sensitivity and 91% negative predictive value (NPV) for the risk of malignancy in indeterminate cytology specimens with ancillary molecular testing. There was 77% specificity and 82% positive predictive value (PPV) for our data set. Conclusions In indeterminate samples, the detection of a mutation was highly predictive of malignancy and a strong indicating factor for surgery with a high sensitivity and NPV. Molecular testing refined or established the diagnosis in 89% of the cases. Our results indicate that molecular testing of thyroid nodules enhances the accuracy of FNA cytology and the subsequent surgical outcome.