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BACKGROUND Thyroid nodules with atypia of undetermined significance (AUS) on fine-needle aspiration (FNA) have a low risk of malignancy that appears to vary based on specific features described in the AUS diagnosis. The Afirma gene expression classifier (GEC) is a molecular test designed to improve preoperative risk stratification of thyroid nodules, but its performance for different patterns of AUS has not been defined. The objective of this study was to assess GEC results and clinical outcomes in AUS nodules with architectural atypia (AUS-A), cytologic atypia (AUS-C) or both (AUS-C/A). METHODS This was a retrospective review of all thyroid nodules with AUS cytopathology that underwent GEC testing at the authors' institution over a period of >4 years. RESULTS In 227 nodules that had AUS cytology results and Afirma GEC testing, the rate of benign GEC results was higher in AUS-A nodules (70 of 107; 65%) than in AUS-C/A nodules (25 of 65; 38%; P = .0008), and AUS-C nodules exhibited an intermediate rate of benign results (27 of 55 nodules; 59%). The risk of cancer among patients who had GEC-suspicious nodules, 86% of whom underwent resection, was 19% (6 of 25) for AUS-A nodules compared with 57% (21 of 37) for AUS-C/A nodules (P = .003) and 45% (10 of 22) for AUS-C nodules (P = .07). In nodules that had an indeterminate repeat cytology result, no difference was observed in the rate of benign GEC results or in the malignancy rate compared with nodules that had a single cytology result. CONCLUSIONS The performance characteristics of Afirma GEC testing vary, depending on qualifiers of cytologic atypia. Recognition of these differences may enable clinicians to provide improved counseling and treatment recommendations to patients. Cancer Cytopathol 2016. © 2017 The Authors. Cancer Cytopathology published by Wiley Periodicals, Inc. on behalf of American Cancer Society.

BACKGROUND Thyroid nodules with atypia of undetermined significance (AUS) on fine‐needle aspiration (FNA) have a low risk of malignancy that appears to vary based on specific features described in the AUS diagnosis. The Afirma gene expression classifier (GEC) is a molecular test designed to improve preoperative risk stratification of thyroid nodules, but its performance for different patterns of AUS has not been defined. The objective of this study was to assess GEC results and clinical outcomes in AUS nodules with architectural atypia (AUS‐A), cytologic atypia (AUS‐C) or both (AUS‐C/A). METHODS This was a retrospective review of all thyroid nodules with AUS cytopathology that underwent GEC testing at the authors' institution over a period of >4 years. RESULTS In 227 nodules that had AUS cytology results and Afirma GEC testing, the rate of benign GEC results was higher in AUS‐A nodules (70 of 107; 65%) than in AUS‐C/A nodules (25 of 65; 38%; P = .0008), and AUS‐C nodules exhibited an intermediate rate of benign results (27 of 55 nodules; 59%). The risk of cancer among patients who had GEC‐suspicious nodules, 86% of whom underwent resection, was 19% (6 of 25) for AUS‐A nodules compared with 57% (21 of 37) for AUS‐C/A nodules (P = .003) and 45% (10 of 22) for AUS‐C nodules (P = .07). In nodules that had an indeterminate repeat cytology result, no difference was observed in the rate of benign GEC results or in the malignancy rate compared with nodules that had a single cytology result. CONCLUSIONS The performance characteristics of Afirma GEC testing vary, depending on qualifiers of cytologic atypia. Recognition of these differences may enable clinicians to provide improved counseling and treatment recommendations to patients. Cancer Cytopathol 2017;125:313–322. © 2017 American Cancer Society., Thyroid nodules with atypia of undetermined significance cytology and Afirma gene expression classifier (GEC) testing are analyzed based on the presence of architectural, cytologic, or both cytologic and architectural atypia. Nodules with architectural atypia are the most likely to have a benign GEC result and least likely to be malignant, suggesting that clinicians should be aware of these cytologic qualifiers when advising patients regarding GEC testing and the risk of malignancy.

BACKGROUND: Most malignancies identified by thyroid fine-needle aspiration (FNA) are papillary thyroid carcinoma (PTC). This study sought to determine if clinically adverse features of PTC correlate with the preceding cytologic diagnosis. METHODS: Thyroid FNA diagnoses were correlated with subsequent histopathologic findings. RESULTS: From 6175 thyroid FNAs, histologic follow-up confirmed PTC in 52 of 184 (28%) FNAs with atypia of undetermined significance (AUS), 52 of 190 (27%) FNAs suspicious for follicular neoplasm, 182 of 229 (79%) FNAs that were suspicious for malignancy, and 188 of 198 (95%) FNAs that were malignant (M). Sex, age, and disease multifocality did not differ among FNA diagnosis groups. However, PTCs following an M FNA were more likely to have a higher American Joint Committee on Cancer T and N stage, and have lymphovascular invasion and/or extrathyroidal extension. Two patients had distant metastasis at initial surgery, whereas 16 developed subsequent recurrence and/or metastasis; all had a preceding M FNA. High-risk histologic subtypes of PTC also stratify to the M category, accounting at least partly for the association of cytologic diagnosis with adverse pathological parameters. Conversely, follicular variants of PTC predominate in non-M categories. CONCLUSIONS: The Bethesda System for Reporting Thyroid Cytopathology conveys malignancy risk, but also predicts the presence of pathological risk factors and disease progression when the malignancy is PTC. M diagnoses identify higher risk PTCs, whereas AUS diagnoses identify low-risk PTCs, mostly follicular variants. These findings support the concept of conservative clinical management for some patients with AUS, while suggesting that a central neck dissection may be routinely justified in some patients with a M FNA. Cancer (Cancer Cytopathol) 2012;. © 2012 American Cancer Society.