Passive reporting of TACO grossly underestimates its actual prevalence. Educational efforts are needed to enhance physician recognition of TACO reactions.

Background: Approximately 25% of thyroid nodule fine-needle aspirates (FNAs) have cytology that is indeterminate for malignant disease. Accurate risk stratification of these FNAs with ancillary testing would reduce unnecessary thyroid surgery. Methods: We evaluated the performance of an ancillary multiplatform test (MPTX) that has three diagnostic categories (negative, moderate, and positive). MPTX includes the combination of a mutation panel (ThyGeNEXT ®) and a microRNA risk classifier (ThyraMIR ®). A blinded, multicenter study was performed using consensus histopathology diagnosis among three pathologists to validate test performance. Results: Unanimous consensus diagnosis was reached in 197 subjects with indeterminate thyroid nodules; 36% had disease. MPTX had 95% sensitivity (95% CI,86%-99%) and 90% specificity (95% CI,84%-95%) for disease in prevalence adjusted nodules with Bethesda III and IV cytology. Negative MPTX results ruledout disease with 97% negative predictive value (NPV; 95% CI,91%-99%) at a 30% disease prevalence, while positive MPTX results ruledin high risk disease with 75% positive predictive value (PPV; 95% CI,60%-86%). Such results are expected in four out of five Bethesda III and IV nodules tested, including RAS positive nodules in which the microRNA classifier was useful in rulingin disease. 90% of mutation panel false positives were due to analytically verified RAS mutations detected in benign adenomas. Moderate MPTX results had a moderate rate of disease (39%, 95% CI,23%-54%), primarily due to RAS mutations, wherein the possibility of disease could not be excluded. Conclusions: Our results emphasize that decisions for surgery should not solely be based on RAS or RAS-like mutations. MPTX informs management decisions while accounting for these challenges.

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INTRODUCTION: Focused and expanded mutation panels were assessed for the incremental utility of using an expanded panel in combination with microRNA risk classification. METHODS: Molecular results were reviewed for patients who underwent either a focused mutation panel (ThyGenX ® ) or an expanded mutation panel (ThyGeNEXT ® ) for strong and weak oncogenic driver mutations and fusions. microRNA results (ThyraMIR ® ) predictive of malignancy, including strong positive results highly specific for malignancy, were examined. RESULTS: Results of 12 993 consecutive patients were reviewed (focused panel = 8619, expanded panel = 4374). The expanded panel increased detection of strong drivers by 8% (P < .001), with BRAFV600E and TERT promoters being the most common. Strong drivers were highly correlated with positive microRNA results of which 90% were strongly positive. The expanded panel increased detection of coexisting drivers by 4% (P < .001), with TERT being the most common partner often paired with RAS. It increased the detection of weak drivers, with RAS and GNAS being the most common. 49% of nodules with weak drivers had positive microRNA results of which 33% were strongly positive. The expanded panel also decreased the number of nodules lacking mutations and fusions by 15% (P < .001), with 8% of nodules having positive microRNA results of which 22% were strongly positive.CONCLUSIONS: Using expanded mutation panels that include less common mutations and fusions can offer increased utility when used in combination with microRNA classification, which helps to identify high risk of malignancy in the cases where risk is otherwise uncertain due to the presence of only weak drivers or the absence of all drivers.

BACKGROUND: Medullary thyroid carcinoma (MTC) is an aggressive malignancy originating from the parafollicular C cells. Preoperatively, thyroid nodule fine-needle aspiration cytology (FNAC) and pathogenic gene mutations are definitive in approximately one-half of cases. MicroRNAs (miRNAs) are endogenous, noncoding, single-stranded RNAs that regulate gene expression, a characteristic that confers the potential for identifying malignancy. In the current study, the authors hypothesized that differential pairwise (diff-pair) analysis of miRNA expression levels would reliably identify MTC in FNA samples. METHODS: The relative abundance of 10 different miRNAs in total nucleic acids was obtained from ThyraMIR test results. Diff-pair analysis was performed by subtracting the critical threshold value of one miRNA from the critical threshold values of other miRNAs. Next-generation sequencing with the ThyGeNEXT panel identified oncogenic gene alterations. The discovery cohort consisted of 30 formalin-fixed, paraffin-embedded benign and malignant thyroid neoplasms, including 4 cases of MTC. After analytical validation, clinical validation was performed using 3 distinct cohorts (total of 7557 specimens). RESULTS: In the discovery cohort, 9 diff-pairs were identified as having significant power using the Kruskal-Wallis test (P < .0001) to distinguish MTC samples from non-MTC samples. The assay correctly classified all MTC and non-MTC samples in the analytical validation study and in the 3 clinical validation cohorts. The overall test accuracy was 100% (95% confidence interval, 99%-100%). In indeterminate FNAC samples, the sensitivity of the diff-pair analysis was greater than that of the MTC-specific mutation analysis (100% vs 25%; P = .03). CONCLUSIONS: Pairwise miRNA expression analysis of ThyraMIR results were found to accurately predict MTC in thyroid FNA samples, including those with indeterminate FNAC findings.

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Background Molecular testing of thyroid fine‐needle aspirates has demonstrated value in cases of indeterminate cytology (Bethesda categories III, IV, and V) enabling optimized individual patient management leading to better outcomes with health economic benefits. For most molecular testing modalities, including mutational panels and classifier analyses, part or all of a dedicated needle aspiration pass is required to obtain an adequate sample for testing. Our analysis, which is based on a combination approach (mutation detection and microRNA classifier status), has documented clinical validity and utility when performed on thyroid fine‐needle aspirates placed directly into RNA preservative fluid. Here we show that the combination approach can be extended to microdissected stained cytology slides provides the physician greater opportunity to resolve cytological indeterminacy. Methods Extracted nucleic acid from needle aspirate and corresponding cytology preparations of 47 thyroid nodules were analyzed using identical methodology and results were compared. Results Of 94 molecular analyses (47 mutational analyses, 47 microRNA classifier assessments based on a validated 10 marker panel) only 5 samples showed discordant results. Conclusion These findings, together with supplementary work using archival specimens shows that the combination approach can be effectively applied to both direct aspirated thyroid nodule aspirates or to nucleic acid extracted from macrodissected and microdissected cytology slide smears, with the expectation of equivalent results. The advantages of both specimen sources, direct aspirate, and cytology slide smears are discussed.

Myoepitheliomas are rare neoplasms that are typically found in the major and minor salivary glands and represent approximately 1.5% of all salivary gland neoplasms. We present a patient with an exophytic anterior midline neck mass, which was initially believed to be a thyroid isthmus nodule that underwent fine needle aspiration (FNA) biopsy. FNA cytologic evaluation reveals numerous plump spindle cells and a myxoid background, thus raising the possibility of rare benign mixed tumor of the thyroid. However, the resected specimen consists of predominately spindle cells with a minor component of chondromyxoid matrix, and no ductal epithelial cells, favoring a diagnosis of myoepithelioma. Although this lesion clinically and radiologically appeared to arise from the thyroid gland, at the time of resection, it was found to be adjacent to the thyroid isthmus and was ultimately diagnosed as a soft tissue myoepithelioma of the midneck.