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The Bethesda System for Reporting Thyroid Cytopathology (TBS) provides limited guidance for the appropriate use of category III (<jats:italic>atypia of undetermined significance<\/jats:italic> [AUS]). The authors combined MT with cytomorphology to monitor AUS diagnoses in a cytopathology laboratory.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Neoplasia\u2010associated genetic alterations (NGAs) were determined by MT of preoperative FNA biopsies or resected malignancies and were categorized as <jats:italic>BRAF<\/jats:italic> V600E mutations, <jats:italic>RAS<\/jats:italic>\u2010like mutations (<jats:italic>HRAS<\/jats:italic>, <jats:italic>NRAS<\/jats:italic>, or <jats:italic>KRAS<\/jats:italic> mutations or non\u2010V600E <jats:italic>BRAF<\/jats:italic> mutations), or <jats:italic>other<\/jats:italic> mutations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Among 7382 thyroid FNA biopsies, the AUS rate was 9.3% overall and ranged from 4.3% to 24.2% among 6 cytopathologists (CPs) who evaluated &gt;150 cases. The ratio of specimens falling into TBS category III to specimens falling into category VI (<jats:italic>malignant<\/jats:italic>) (the III:VI ratio) was 2.4 overall (range, 1.1\u20108.1), and the ratio of specimens falling into TBS categories III and IV (<jats:italic>follicular neoplasm<\/jats:italic> or <jats:italic>suspicious for follicular neoplasm<\/jats:italic>) combined (III+IV) to specimens falling into category VI (the <jats:italic>[III+IV]:VI ratio<\/jats:italic>) was 2.9 overall (range, 1.4\u20109.5). MT was performed on 588 cases from 560 patients (79% women) with a median age of 56 years (range, 8\u201089 years). <jats:italic>BRAF<\/jats:italic> V600E mutation was the most common (76% of cases) in TBS category VI and was rare (3%) in category III. <jats:italic>RAS<\/jats:italic>\u2010like mutations were most common in TBS categories III (13%), IV (25%), and V (<jats:italic>suspicious for malignancy<\/jats:italic>) (17.5%). The NGA rate in AUS cases fell between 5% and 20% for 5 of 6 CPs and did not correlate with the III:VI ratio or the (III+IV):VI ratio.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Lack of correlation between the NGA rate and easily calculable diagnostic ratios enables the calibration of diagnostic thresholds, even for CPs who have <jats:italic>normal<\/jats:italic> metrics. Specifically, calculation of the NGA rate and the III:VI ratio may allow individual CPs to determine whether they are <jats:italic>overcalling<\/jats:italic> or <jats:italic>undercalling<\/jats:italic> cases that other CPs might otherwise recategorize.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cncy.22542","type":"journal-article","created":{"date-parts":[[2021,12,28]],"date-time":"2021-12-28T11:39:01Z","timestamp":1640691541000},"page":"259-274","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Combining molecular testing and the Bethesda category III:VI ratio for thyroid fine\u2010needle aspirates: A quality\u2010assurance metric for evaluating diagnostic performance in a cytopathology laboratory"],"prefix":"10.1002","volume":"130","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8782-9908","authenticated-orcid":false,"given":"Hamza N.","family":"Gokozan","sequence":"first","affiliation":[{"name":"Division of 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