AACE/ACE disease state commentary: molecular diagnostic testing of thyroid nodules with indeterminate cytopathology

• Approximately 10 to 25% of fine-needle aspiration (FNA) biopsies yield an indeterminate result often labeled as atypia of undetermined significance or follicular lesion of undetermined significance (AUS/FLUS) or follicular neoplasm/suspicious for follicular neoplasm (FN/SFN). The risk of malignancy typically varies between 15 and 30% for these categories. • Although many markers are in development and have been studied in a research setting, 2 principal tests are currently marketed for use to improve the malignancy risk assessment of "indeterminate" thyroid nodules. "Rule In" and "Rule Out" tests attempt to confirm or exclude the presence of cancer within a thyroid nodule by means of robust positive (PPV) or negative predictive values (NPV), respectively. • The Rule In tests determine the presence of single gene point mutations (BRAFV600E or RAS) or gene rearrangements (RET/PTC, PAX8/PPARγ) that have been shown to increase the ability to predict cancer, while the Rule Out test (Afirma® gene expression classifier, GEC) utilizes a proprietary gene expression classifier (RNA expression) specifically designed to maximize the ability to define a process as benign. • Among the presently available tests, only the BRAFV600E and RET/PTC rearrangement are associated with a PPV that approaches 100%. • The category of cytologically "indeterminate" nodule (AUS/FLUS, FN/SFN), cytopathology practice patterns, and the prevalence of malignancy within the population being tested all impact the NPVs and PPVs for the tests in question. • At present, molecular testing is meant to complement and not replace clinical judgment, sonographic assessment, and visual cytopathology interpretation. • As molecular testing is new and advances in the field are regularly occurring, clinicians need to stay informed, as recommendations for use within practice are expected to evolve.