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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  2017;125:313–322.  © 2017 The Authors.  Cancer Cytopathology  published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

cancer cytopathology

Qualifiers of atypia in the cytologic diagnosis of thyroid nodules are associated with different Afirma gene expression classifier results and clinical outcomes