key: cord-0889750-mmy9tplt authors: Labourier, Emmanuel; Fahey, Thomas J. title: Preoperative molecular testing in thyroid nodules with Bethesda VI cytology: Clinical experience and review of the literature date: 2020-10-14 journal: Diagn Cytopathol DOI: 10.1002/dc.24637 sha: dd5c2f0a39c96c4f04433f6151af3b24405a2713 doc_id: 889750 cord_uid: mmy9tplt Risk assessment is critical to determine the timing of elective surgeries and preserve valuable resources in time of pandemic. This study was undertaken to better understand the potential value of molecular testing to risk‐stratify thyroid nodules with malignant cytology (Bethesda VI). Systematic review of the literature contributed 21 studies representing 2036 preoperative specimens. The BRAF p.V600E substitution was detected in 46% to 90% of cases with a pooled positivity rate of 70% (95% confidence intervals: 64%‐76%). None of the studies used comprehensive oncogene panels. Retrospective analysis of 531 clinical specimens evaluated with the next‐generation sequencing ThyGeNEXT Thyroid Oncogene Panel identified a total of 436 gene alterations. BRAF mutation rate was 64% in specimens tested as part of standard clinical care and 75% in specimens from cross‐sectional research studies (P = .022). Testing for additional actionable gene alterations such as TERT promoter mutations or RET and NTRK gene rearrangements further increased the diagnostic yield to 78%‐85% and up to 95% when including the ThyraMIR Thyroid miRNA Classifier. These data support the role of molecular cytopathology in surgical and therapeutic decision‐making and warrant additional studies. Multiple surgical societies have issued recommendations for a safe and responsible return to practice amid the COVID-19 pandemic. [1] [2] [3] As elective surgeries resume, surgeons face a major backlog of cases and must prioritize patients based on individual's risk, local and state requirements and available resources. Preoperative risk stratification of thyroid nodules typically involves a combination of blood work, imaging and fine needle aspiration biopsy (FNAB), as well as molecular testing for nodules with indeterminate cytology. [4] [5] [6] These testing modalities are also offered clinically to aid surgical and therapeutic decisions for advanced or metastatic thyroid cancers and for nodules with high-risk cytopathologic features. Yet, little information is available on the type and distribution of gene alterations present in FNAB positive for malignancy (Bethesda category VI). To address this point, we conducted a systematic review of the literature and analyzed molecular data generated in two distinct sets of preoperative FNAB: (1) Representative clinical cases submitted to a CLIA-certified laboratory for evaluation with the next-generation sequencing ThyGeNEXT Thyroid Oncogene Panel; and (2) Cross-sectional cohort of cases previously collected and tested during the development and validation of the ThyraMIR Thyroid miRNA Classifier. The data underscore the value of comprehensive, actionable molecular results to further the risk assessment of thyroid nodules with malignant cytology and inform clinical decision-making. In summary, our systematic review of the literature indicates that 70% to 75% of FNAB with malignant/Bethesda VI cytology are expected to be positive for the oncogenic BRAF p.V600E substitution. The majority of these studies (71%) assessed only BRAF mutational status. Our 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. Additional work is required to fully assess the role of molecular testing for the preoperative risk stratification of malignant FNAB, clinical decision-making, timing of surgery and optimal utilization of valuable healthcare resources. The authors would like to thank Gyanendra Kumar, Venkata A. Timmaraju, Keith Haugh and the CLIA Laboratory team from Interpace Biosciences for providing the deidentified molecular data used in the clinical experience analysis. E.L. is a consultant for Interpace Biosciences Inc. The data that support the findings of this study are available from the corresponding author upon reasonable request. 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Preoperative molecular testing in thyroid nodules with Bethesda VI cytology: Clinical experience and review of the literature