Probability of malignancy and molecular alterations as determined by ThyroSeq v3 genomic classifier in Bethesda Category IV.

BACKGROUND: ThyroSeq molecular testing assesses the probability of malignancy (POM) in thyroid fine-needle aspiration cytology (FNAC) with indeterminate cytology. The aim was to investigate whether Bethesda category IV (BIV) subcategories are associated with specific molecular alterations, molecular-derived risk of malignancy (MDROM), and risk of malignancy (ROM). METHODS: FNAC slides, associated ThyroSeq, version 3, Genomic Classifier results, and surgical follow-up were retrieved for BIV nodules. Nodules were subcategorized as follicular neoplasm (FN) with or without cytologic atypia or oncocytic follicular neoplasm (OFN). The MDROM, ROM, and frequency of molecular alterations in FN and OFN were analyzed. p < .05 was considered significant. RESULTS: A total of 92 FNAC were identified and subcategorized into 46 FN (15 with and 31 without cytologic atypia) and 46 OFN. The benign call rate and the positive call rate were 49% and 51%, respectively. The MDROM in BIV was 34.3%, trending lower in OFN than in FN. RAS mutations were significantly more frequent in FN when compared to OFN (p = .02). Chromosomal copy number alterations were more often present in OFN than in FN (p < .01). On histologic follow-up, ROM in OFN was trending lower than in FN (p = .1). The most common diagnosis in OFN was oncocytic adenoma, whereas follicular variant papillary thyroid carcinoma was most common in FN. CONCLUSIONS: The MDROM and ROM were trending lower in OFN compared with FN, and the molecular alterations differed between OFN and FN subcategories.

Probability of malignancy as determined by ThyroSeq v3 genomic classifier varies according to the subtype of atypia.

BACKGROUND: ThyroSeq assesses the probability of malignancy (POM) in thyroid fine-needle aspiration cytology specimens diagnosed as atypia of undetermined significance (AUS). The authors investigated whether defined AUS subcategories are associated with specific molecular alterations, the molecular-derived risk of malignancy (MDROM), and the risk of malignancy (ROM). METHODS: Fine-needle aspiration cytology reports of AUS and corresponding results from the ThyroSeq version 3 genomic classifier results were retrieved and subcategorized as follicular cells with either cytologic atypia (FC-C), architectural atypia (FC-A), both cytologic and architectural atypia (FC-CA), or a predominance of Hurthle cells (PHC). The MDROM, ROM, and frequency of molecular alterations by subcategory were computed and analyzed, and p < .05 was considered significant. RESULTS: The final analysis included 541 cases subdivided into 233 with FC-A, 104 with FC-C, 116 with FC-CA, and 88 with PHC. The benign call rate and positive call rate for the AUS category were 72% and 28%, respectively, which varied between AUS subcategories. The MDROM by subcategory was 15.9% FC-A, 20.5% FC-C, 33.8% FC-CA, and 14.4% PHC. Histologic follow-up was available for 155 (28%) AUS cases with a follow-up period ≥12 months. The 95% confidence intervals of the MDROMs overlapped with the ROMs. The highest MDROM and ROM were in the FC-CA subcategory. RAS mutations were present in all subcategories. BRAF V600E mutations and papillary thyroid carcinoma were most frequent in the FC-CA subcategory. Noninvasive follicular thyroid neoplasm with papillary-like nuclear features was significantly more frequent in the FC-C subcategory. CONCLUSIONS: The current results demonstrated that AUS subcategories are associated with specific genetic alterations, the MDROM, and the ROM. Molecular results and an awareness of various cancer probabilities within AUS subcategories can allow for a more tailored management.