BACKGROUND : Most cytologically indeterminate thyroid nodules (ITN) with benign molecular testing do not undergo surgery. The data on clinical outcomes of these nodules are limited.

METHODS : We retrospectively analyzed all ITN that underwent molecular testing with either Afirma Gene Expression Classifier (GEC) or Afirma Gene Sequencing Classifier (GSC) between 2011 and 2018 at a single institution.

RESULTS : Thirty-eight out of 289 molecularly benign ITN were ultimately resected. The most common reason for surgery was compressive symptoms (39%). In multivariable modeling, patients <40 years old, nodules > 3 cm, presence of Afirma suspicious nodule other than the index nodule and compressive symptoms were associated with higher surgery rates with hazard ratios (HR) for surgery of 3.5 (p<0.001), 3.2 (p<0.001), 16.8 (p<0.001) and 7.31 (p<0.001), respectively. Of resected nodules, 5 were malignant. False-negative rate (FNR) was 1.7% presuming all unresected nodules were truly benign and 13.2% restricting analysis to resected cases. FNR was significantly higher in nodules with a high-risk sonographic appearance for cancer (American Thyroid Association (ATA) high risk classification and American College of Radiology Thyroid Imaging Reporting And Data Systems (ACR-TIRADS) score of 5) compared to nodules with all other sonographic categories (11.8% vs 1.1%, p=0.03 and 11.1% vs. 1.1%, p=0.02, respectively).

CONCLUSIONS : Younger age, larger nodule size, presence of Afirma suspicious nodule other than the index nodule and compressive symptoms were associated with a higher rate of surgery. False-negative rate of benign Afirma was significantly higher in nodules with high-risk sonographic features.