Features of Cytologically Indeterminate Molecularly Benign Nodules Treated With Surgery

Most cytologically indeterminate thyroid nodules (ITNs) with benign molecular testing are not surgically removed. The data on clinical outcomes of these nodules are limited.

We retrospectively analyzed all ITNs where molecular testing was performed either with the Afirma gene expression classifier or Afirma gene sequencing classifier between 2011 and 2018 at a single institution.

Thirty-eight out of 289 molecularly benign ITNs were ultimately resected. The most common reason for surgery was compressive symptoms (39%). In multivariable modeling, patients aged <40 years, nodules ≥3 cm, presence of an Afirma suspicious nodule other than the index nodule, and compressive symptoms were associated with higher surgery rates with hazard ratios 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. The FNR was significantly higher in nodules with a high-risk sonographic appearance for cancer (American Thyroid Association high-risk classification and American College of Radiology Thyroid Imaging Reporting and Data Systems score of 5) compared with nodules with all other sonographic categories (11.8% vs 1.1%; P = 0.03 and 11.1% vs 1.1%; P = 0.02, respectively).

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