To examine the origin, current progress, and future directions of molecular testing in indeterminate Bethesda III and Bethesda IV thyroid nodules.

The diagnostic performance of current genomic tests shows improved benign call rates, specificity and positive-predictive values over prior test versions. The choice of test platform for clinical use should consider test performance, institutional rate of malignancy, nodule cytology and the potential for prognostication to help guide decision-making. Current challenges include test reliability, defining the optimal duration of surveillance, and improving test performance in challenging cytology, such as oncocytic nodules and NIFTP. Opportunities also remain to optimize cost-effectiveness across multiple clinical and practice settings and to refine the use of molecular testing for dynamic risk stratification, such as with BRAF V600E mutation testing.

Molecular testing of indeterminate thyroid nodules has helped to reduce the burden of diagnostic surgery, associated healthcare costs, and potential complications. Current-generation tests have demonstrated improvement in diagnostic performance, but challenges remain in improving test performance and refining the scope of testing in care. Decision-making for the management of indeterminate thyroid nodules should consider cytology, clinical and sonographic features, patient values and preferences and molecular testing results, whenever available.