Risk stratification of ThyroSeq results in indeterminate thyroid lesions: A single-institution experience of clinicopathologic correlation with cytologic findings

ThyroSeq offers the opportunity to stratify the risk of malignancy (ROM) in the characterization of indeterminate thyroid nodules, especially those categorized as atypia of undetermined significance (AUS). However, whether ThyroSeq interpretations correlate with cytologic features, management, and surgical outcome remains unclear. Thyroid fine-needle aspiration specimens categorized as AUS and follicular neoplasm (FN) from 2017 to 2021 were identified from a cytology database search. Patient clinical information and ThyroSeq results were collected and correlated with resection diagnosis if available. A total of 520 cases were classified as AUS and 111 cases were classified as FN. Within the AUS lesions, 190 cases (36.5%) were subcategorized as cytologic atypia (III-C), 109 cases (21.0%) as architectural atypia (III-A), 138 cases (26.5%) as both cytologic and architectural atypia (III-CA), and 69 cases (13.0%) as oncocytic cell aspirate (III-O). Category III-C showed the highest malignancy rate (16.7%; p = .29), and a higher ThyroSeq-defined probability of cancer or noninvasive follicular thyroid neoplasms with papillary-like nuclear features. Notably, within III-C, intermediate-risk mutations led to a significantly higher malignancy rate (46.7%; p = .0012). Conversely, III-A had the lowest malignancy rate (9.7%) but this was significantly increased by concurrent high-risk mutations (62.5%). BRAF -like mutations were frequently associated with III-C and classical papillary thyroid carcinoma in histology. RAS-like mutations were the most common alterations across all subcategories, and were frequently associated with follicular-patterned lesions. Atypia subcategories have differential ThyroSeq-defined ROMs and histologic outcomes. Combining atypia subcategory interpretation, ThyroSeq-defined ROMs and molecular results aids in optimal clinical management for indeterminate thyroid lesions.