A systematic review of the literature was conducted in addition to an analysis of molecular data generated from fine needle aspiration biopsies (FNAB).

Twenty-one studies from 12 countries involving 2036 preoperative thyroid specimens with malignant/Bethesda VI cytology were identified from the National Center for Biotechnology Information biomedical literature database. Studies limited to RNA biomarkers were not included in the analysis.

A review of FNAB cases submitted for molecular testing as part of standard clinical care between April 2015 and June 2020 yielded 381 unique Bethesda VI specimens with molecular data. Cases collected and tested as part of clinical research studies yielded an additional 150 Bethesda VI specimens with molecular data. A total of 531 representative clinical specimens were analyzed.

Overall, 75% (287/381) of the specimens were positive by molecular testing, 270 for mutations in the BRAF, PIK3CA, RAS and/or TERT genes (94% of positive cases), and 17 for PAX8, NTRK or RET gene rearrangements (6% of positive cases).

The majority of studies reviewed (71%) assessed only BRAF mutational status with 70% to 75% of FNABs with malignant/Bethesda VI cytology expected to be positive for the oncogenic BRAF p.V600E substitution.

The diagnostic yield was increased from 78%-85% to up to 95% when including the ThyraMIR^® Thyroid miRNA Classifier.

This analysis of 531 representative clinical specimens is the first to report the potential value of a comprehensive oncogene panel combined with a miRNA expression classifier. Combination testing with a miRNA expression classifier may further raise the risk profile of nodules positive for weaker driver mutations, such as RAS.

These data support the role of molecular cytopathology in surgical and therapeutic decision-making and warrant additional studies.