BACKGROUND Recommendations regarding how many nodules to biopsy with thyroid fine‐needle aspiration vary. METHODS The authors reviewed fine‐needle aspiration specimens of 12,763 nodules from 10,506 patients and correlated them with the number of nodules biopsied. RESULTS Compared with patients in whom only a single nodule was biopsied, patients in whom multiple nodules were biopsied were found to be significantly younger, more likely female, and to have larger tumors, and those tumors were more often papillary (all P<.001). On fine‐needle aspiration, patients who had multiple nodules biopsied were more often diagnosed with benign findings (P<.001), but usually had no significant difference in the risk of malignancy associated with any cytologic diagnosis. Performing biopsy in 3 nodules detected all carcinomas in the current series. Combining all cases in the literature demonstrated that performing only 3 biopsies in a patient with at least 4 suspicious nodules had a risk of malignancy of 1.2%. CONCLUSIONS Biopsy of 3 different nodules in patients with multiple nodules appears to lower the risk of malignancy to that of a benign fine‐needle aspiration specimen. Although exceptions can occur, cytologists may be able to improve the accuracy of their diagnoses by focusing predominantly on identifying papillary carcinoma after the first 2 nodules have been biopsied. Cancer Cytopathol 2017;125:848–53. © 2017 American Cancer Society.
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