Predictive Value of a Genomic Classifier in Indeterminate Thyroid Nodules Based on Nodule Size

Abstract

IMPORTANCE Genomic classifiers were developed to better guide clinicians in the treatment of indeterminate thyroid nodules (ITNs). To our knowledge, whether there is variation in the diagnostic accuracy of these tests depending on ITN size has not been previously studied. OBJECTIVETo analyze the diagnostic performance of a genomic classifier in relation to ITN size. DESIGN, SETTING, AND PARTICIPANTSA case series study with medical records review was conducted including all patients with a cytologic diagnosis of ITN managed with genomic classifier testing and surgery from January 2015 to December 2018 at NYU Langone Health. Demographics, ITN characteristics, genomic profiles, treatment, and final pathologic findings were recorded. Data analysis was conducted from March to April 2021. MAIN OUTCOMES AND MEASURESThe primary aim was to assess the positive predictive value (PPV), negative predictive value (NPV), sensitivity, and specificity of a genomic classifier test (ThyroSeq) in relation to ITN size (<2, 2-4, and >4 cm). The secondary aim was to investigate the risk of cancer associated with genetic signatures. RESULTSOf the 212 patients with 218 ITNs, 158 (74.5%) were women; median (SD) age was 49 (15.6) years. Genomic classifier results were positive in 173 ITNs (79.4%) treated with surgery. In this group of 173 positive ITNs, 46 (26.6%) were malignant on final pathologic testing. Overall, the observed cancer prevalence in the population was 23.9% (52 ITNs). In 45 ITNs that underwent surgery despite a negative genomic classifier interpretation, 6 (13.3%) were malignant. The PPV of a positive test was 27% and the NPV was 87%. The PPV and NPV findings improved as the ITN size increased (<2 cm [n = 98]: PPV, 25%; NPV, 79% vs >4 cm [n = 33]: PPV, 50%; NPV, 89%). Test specificity was higher in larger ITNs (<2 cm: 15% vs >4 cm: 40%; P = .01). Isolated RAS sequence variations were the most common variant identified in malignant nodules (11 [21.1%] of all ITNs), followed by BRAF variants (7 [13.5%] of all ITNs). CONCLUSIONS AND RELEVANCEIn this case series, the performance of the ThyroSeq test improved for larger ITNs. The risk of cancer in large ITNs with negative test results was low. These data suggest that, in genomic classifier-negative ITNs larger than 4 cm, initial management of thyroid lobectomy may be sufficient.

Molecular Testing for Thyroid Nodules: The Experience at McGill University Teaching Hospitals in Canada

“…The data from the validation studies of the different molecular tests are showing that most of the ITNs after surgical resection are either benign, NIFTP or well-differentiated thyroid cancer with excellent prognoses [ 66 ]. There is a risk of having aggressive cancer in ITNs which is usually associated with the presence of aggressive mutations like BRAF-like mutations or high-risk mutations (e.g., TERT or TP53 ) [ 67 ]. Interestingly, a study by Turkodgan et al showed that in surgically resected ITNs, Bethesda III nodules are more likely to be aggressive than Bethesda IV nodules and molecular testing is strongly correlated with a higher risk of malignancy and aggressive features in these nodules [ 68 ].…”

Molecular Testing for Indeterminate Thyroid Nodules: Association of Negative Predictive Value With Nodule Size

“…Although both false negative results occurred in nodules classified as Bethesda IV, the false negative rate for Bethesda IV lesions was only 5.7% and not significantly different from the other categories (P = . 19).…”

“…Additionally, the missed malignancies in the current study were large suggesting that sampling error cannot account for the false negative results. Interestingly, Dublin and colleagues 19 recently published a review showing that the negative predictive value of ThyroSeq was actually higher in nodules over 4 cm (89%) compared with those less than 2 cm (79%). However, the overall rate of malignancy in their cohort of large nodules was substantially smaller than ours at less than 40% compared with our 64% which might account for the difference in negative predictive value between the 2 studies.…”

The prevalence of thyroid nodules and its factors among Chinese adult women: A cross-sectional study

“…It has been confirmed that it is closely related to age and gender and other factors ( 21 ). The incidence of TN(s) in women is significantly higher than that in men ( 22 – 24 ), but the specific mechanism is not completely clear. It may be associated with overweight or obesity, hypertension, hyperglycemia, metabolic syndrome, sleep quality, etc.…”