Combined molecular and histologic end points inform cancer risk estimates for thyroid nodules classified as atypia of undetermined significance

Abstract

BACKGROUND: Thyroid nodules classified as atypia of uncertain significance (AUS) on fine-needle aspiration cytology are heterogeneous. Prior studies reported a higher risk of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP)/cancer among AUS nodules that had cytologic (AUS-C) versus architectural (AUS-A) atypia; however, such studies were generally confined to resected cohorts, introducing bias into risk calculations. The authors hypothesized that combined histologic and molecular end points would permit clinically meaningful calculations of NIFTP/malignancy risk among AUS nodules. METHODS: The study consisted of 279 thyroid nodules classified as AUS on initial fine-needle aspiration and tested by the Afirma Gene Expression Classifier (GEC) between June 2013 and October 2017. Results of GEC testing and histopathologic diagnoses were stratified by AUS classifiers. The AUS-A category was further subclassified as 1) hypocellular microfollicular or 2) cellular with mixed but predominantly microfollicular architecture. NIFTP/cancer risk was calculated for each subgroup, with the inclusion of unresected nodules that had benign GEC results as low-risk end points comparable to histologically benign nodules. RESULTS: When only histologic end points were considered, there was no difference in NIFTP/cancer risk (25% vs 23%; P = .82). By using molecular and histologic end points, AUS cases with cytologic atypia trended toward higher NIFTP/cancer risk than AUS-A cases (14% vs 6%; P = .06). Furthermore, AUS-A cases showed a trend toward lower NIFTP/cancer risk for hypocellular microfollicular aspirates (3%) compared with cellular samples that had mixed/predominantly microfollicular architecture (13%; P = .18). CONCLUSIONS: The inclusion of unresected benign GEC nodules in risk-of-malignancy calculations provides more accurate results, which may be helpful for informing patient management as well as quality improvement in the cytopathology laboratory.

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

“…Indeed, Veracyte now offers an MT that it markets for thyroid aspirates in TBS category V. 56,65,66 Laboratories have also reported widely variable AUS rates, including some that are significantly higher than those suggested by TBS, as well as widely variable rates of thyroid aspirates falling into TBS category I (nondiagnostic), which has implications for the analytic sensitivity of currently available molecular tests. [67][68][69] The advantage of the approach presented in the current study is its plasticity. Even when working with a heterogenous data set like that used here, as long as genetic information is collected consistently across specimens, the current approach is tolerant of differences in practice settings and imaging characteristics.…”

“…Indeed, Veracyte now offers an MT that it markets for thyroid aspirates in TBS category V 56,65,66 . Laboratories have also reported widely variable AUS rates, including some that are significantly higher than those suggested by TBS, as well as widely variable rates of thyroid aspirates falling into TBS category I (nondiagnostic), which has implications for the analytic sensitivity of currently available molecular tests 67‐69 …”

Quality Metrics to Assess Cytopathology Practice Patterns: Focus on Thyroid Fine-Needle Aspiration Cytology

“…Although as discussed previously surgical outcome data represent the gold standard for thyroid nodule characterization, not all indeterminate nodules are resected. As such, reliance on the high negative predictive value these molecular test offer for benign nodules can help provide an acceptable surrogate end point for nodules that are not surgically resected, thereby providing better ROM estimates than relying solely on resected nodules 10 . Incorporating this concept to a quality assurance program, leveraging these surrogate end points can help provide more robust and timely data on those thyroid FNAs assigned an indeterminate diagnosis when ancillary molecular testing is performed.…”

“…As such, reliance on the high negative predictive value these molecular test offer for benign nodules can help provide an acceptable surrogate end point for nodules that are not surgically resected, thereby providing better ROM estimates than relying solely on resected nodules. 10 Incorporating this concept to a quality assurance program, leveraging these surrogate end points can help provide more robust and timely data on those thyroid FNAs assigned an indeterminate diagnosis when ancillary molecular testing is performed. In these 2 studies, the paradigm of combining base metrics such as AUS rate or the AUS:M ratio with surrogate outcome data in the form of abnormal/suspicious molecular testing results provides a multivariate framework for explaining cytopathologist practice patterns.…”

Molecular Characterization of Thyroid Follicular Lesions in the Era of “Next-Generation” Techniques

“…Hence, a negative GEC result reduces the ROM from 24% to 5%, supporting a simple follow-up for those patients ( 57 ). Furthermore, different papers found that patients with GEC suspicious nodules had higher ROM in cases with both architectural and nuclear atypia (57%) than in cases with architectural or nuclear atypia alone (19% and 45%, respectively) ( 58 – 61 ). Furthermore, an AUS/FLUS lesion with a Hürthle cell pattern endows with a low rate of GEC benign results and a very low ROM ( 62 ).…”