Diagnostic Value of Molecular Testing in Sonographically Suspicious Thyroid Nodules

Abstract

Objective: Molecular testing can refine the diagnosis for the 20% of thyroid fine-needle aspiration biopsies that have indeterminate cytology. We assessed the diagnostic accuracy of molecular testing based on ultrasound risk classification.

Methods: This retrospective cohort study analyzed all thyroid nodules with indeterminate cytology at an academic US medical center (2012-2016). All indeterminate nodules underwent reflexive molecular testing with the Afirma Gene Expression Classifier (GEC). Radiologists performed blinded reviews to categorize each nodule according to the American Thyroid Association (ATA) ultrasound classification and the American College of Radiology Thyroid Imaging, Reporting and Data System. GEC results and diagnostic performance were compared across ultrasound risk categories.

Results: Of 297 nodules, histopathology confirmed malignancy in 65 (22%). Nodules by ATA classification were 8% high suspicion, 44% intermediate, and 48% low/very low suspicion. A suspicious GEC result was more likely in ATA high-suspicion nodules (81%) than in nodules of all other ATA categories (57%; P = .04). The positive predictive value (PPV) of GEC remained consistent across ultrasound categories (ATA high suspicion, 64% vs all other ATA categories, 48%; P = .39). The ATA high-suspicion category had higher specificity than a suspicious GEC result (93% vs 51%; P < .01). A suspicious GEC result did not increase specificity for the ATA high-suspicion category.

Conclusion: The PPV of molecular testing remained consistent across ultrasound risk categories. However, a suspicious GEC result was very likely in ATA high-suspicion nodules and did not improve specificity in this sonographic category.

Keywords: molecular testing; ACR TI-RADS; ATA; nodule; thyroid; ultrasound.

Figure 1.

Representative thyroid nodule images from the study cohort exhibiting ultrasound features that are more suspicious vs less suspicious for malignancy. More suspicious features include A, irregular margins; B, microcalcifications presenting as punctate echogenic foci; C, taller-than-wide shape on transverse view; and D, extrathyroidal extension. Less suspicious features include E, cystic-appearing composition; F, spongiform composition; G, hyperechogenicity; and H, smooth margins.

Figure 2.

Flow diagram illustrating the pathway to the final study cohort (297 nodules).

Figure 3.

Nodule sizes (in centimeters), by Bethesda cytopathologic classification. Each dot represents one nodule. Box and whisker plots indicate median and quartiles.

Figure 4.

Intersection of nodule ultrasound classifications and Afirma GEC result. Bold numbers represent the total number of nodules in each cell. A total of 237 nodules were included in this analysis (excludes the 60 nodules lacking a concordant ATA and/ or ACR-TIRADS classification). ACR TI-RADS, American College of Radiology Thyroid Imaging, Reporting and Data System; ATA, American Thyroid Association ultrasound classification system; GEC, Afirma Gene Expression Classifier.

Figure 5.

Intersection of ultrasound and GEC. Left: Overlap in ultrasound and GEC results, reflected as the proportion of nodules in each ultrasound group that also had a suspicious GEC result. Right: GEC’s PPV stratified by ultrasound classification. ACR TI-RADS, American College of Radiology Thyroid Imaging, Reporting and Data System; ATA, American Thyroid Association ultrasound classification system; GEC, Afirma Gene Expression Classifier; NS, nonsignificant (P > .05); PPV, positive predictive value.

Figure 6.

Likelihood of an Afirma Gene Expression Classifier (GEC) suspicious result for nodules with suspicious sonographic features. “Presence” indicates that one or more of the radiologists evaluating the nodule noted the presence of the feature. Although there are positive trends between the presence of these suspicious features and increased likelihood of a suspicious result on GEC, these associations were not statistically significant using the Fisher exact test.