ThyroSeq v3 for Bethesda III and IV: An institutional experience

Abstract

Background The ThyroSeq v3 genomic classifier is a commercial molecular test that examines a wide spectrum of genomic alterations in a thyroid fine‐needle aspiration (FNA) sample and reports test results as either negative or positive. The authors report their institutional experience with ThyroSeq v3. Methods Thyroid FNA specimens diagnosed as either atypia of undetermined significance or follicular lesion of undetermined significance (AUS/FLUS) (Bethesda category III [Bethesda III] according to The Bethesda System for Reporting Thyroid Cytopathology) or follicular neoplasm/suspicious for follicular neoplasm (FN/SFN) (Bethesda IV) that had ThyroSeq v3 results available from December 2017 through October 2019 were retrieved for analysis. FNA diagnoses were correlated with ThyroSeq v3 results and follow‐up histopathology. Results In total, 415 cases (AUS/FLUS, n = 251; FN/SFN, n = 164) were retrieved: 294 (71%) were reported as ThyroSeq v3‐negative, and 121 (29%) were reported as ThyroSeq v3‐positive. The benign call rate (BCR) of ThyroSeq v3 for AUS/FLUS (82%; 206 of 251 cases) was significantly higher (P < .001) than that for FN/SFN (BCR, 54%; 88 of 164 cases). Histopathologic follow‐up was available for 127 cases (ThyroSeq v3‐positive, 96; ThyroSeq v3‐negative, 31), of which 57 were benign and 70 were malignant (including noninvasive follicular thyroid neoplasm with papillary‐like nuclear features). The negative predictive value of ThyroSeq v3 was significantly higher for AUS/FLUS (99.5%) than for FN/SFN (95.4%; P < .0294), given malignancy rates of 10% for AUS/FLUS and 30% for FN/SFN. Forty‐five unique combinations of genetic alterations were detected in the operated ThyroSeq‐positive cases, and there were only 5 false‐negative cases, comprised of 4 low‐risk neoplasms. Conclusions The high BCR of ThyroSeq v3 for AUS/FLUS prevents surgery in a majority of patients. The ThyroSeq v3 genomic classifier reveals the complexity of the genetic signature of indeterminate nodules.

Atypia of undetermined significance in thyroid cytology: Nuclear atypia and architectural atypia are associated with different molecular alterations and risks of malignancy

“…28 Accordingly, THADA fusion cases were present in both 3A and 3C, with one eventually diagnosed as NIFTP and the other diagnosed as follicular variant of PTC. Although few such cases were present in our cohort, Desai et al 23 noted that 10 of 11 patients with THADA fusions, 1 of 4 with PTEN mutations, and 1 of 1 with a TERT mutation had a malignant diagnosis. In the literature review conducted by Goldner et al, 12 malignancy was present in 13 of 14 patients with THADA fusions, in 7 of 8 with TERT mutations, and in 0 of 2 with PTEN mutations.…”

“…These were associated with follicular adenoma, follicular carcinoma, and, less likely, PTC. Similarly, Desai et al 23 noted that RAS mutations were the most common alterations in their cohort as well, and they were also associated with a lower risk of malignancy. As in our study, Bellevicine et al 22 found RAS mutations with all types of atypia.…”

Combining molecular testing and the Bethesda category III:VI ratio for thyroid fine‐needle aspirates: A quality‐assurance metric for evaluating diagnostic performance in a cytopathology laboratory

“…21,[38][39][40] Furthermore, the likelihood that a specimen will fall into an indeterminate TBS category differs, depending on its morphologic features, particularly architectural pattern and nuclear atypia. [41][42][43][44][45][46][47][48][49] In other words, although they successfully account for differences in the overall malignancy rate, QA metrics such as the NGA rate and the III:VI ratio, which are limited to the characteristics of a single TBS category, fail to account for differences in the distribution of types of malignancy (ie, follicular carcinoma, follicular variant of PTCA, classical variant of PTCA, etc) across different populations. To account for those differences, the calculation of additional, potentially onerous QA metrics across all TBS categories would be required.…”

“…Conversely, research has also shown that certain morphologic subtypes correlate strongly with the presence of specific genetic alterations 21,38‐40 . Furthermore, the likelihood that a specimen will fall into an indeterminate TBS category differs, depending on its morphologic features, particularly architectural pattern and nuclear atypia 41‐49 . In other words, although they successfully account for differences in the overall malignancy rate, QA metrics such as the NGA rate and the III:VI ratio, which are limited to the characteristics of a single TBS category, fail to account for differences in the distribution of types of malignancy (ie, follicular carcinoma, follicular variant of PTCA, classical variant of PTCA, etc) across different populations.…”

Blurred lines for management of thyroid nodules in the era of atypia of undetermined significance/ follicular lesion of undetermined significance: novel subdivisions of categories IIIA and IIIB in a possible forthcoming The Bethesda System for Reporting Thyroid Cytopathology, 3rd edition; amending versus unnecessary?

“…Finally, the recommended usual management for AUS/FLUS is repeat FNA, molecular testing, or lobectomy in the 2nd ed. TBSRTC, compatible with both TIR3A and TIR3B, in spite of propounding ROM of Category III, TBSRTC, 2nd ed., is consonant with TIR3B, ICCRTC 5,6 . We recently emphasized whether it is essential to maintain Category III, TBSRTC as a unique and indivisible category, per se, among indeterminate cytology of thyroid nodules or not, published in Volume 67, Revista da Associação Médica Brasileira 7 .…”