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Molecular Testing for Mutations in Improving the Fine-Needle Aspiration Diagnosis of Thyroid Nodules

Department of Pathology (Y.E.N., T.M.R.-S., Z.Z., M.N.N.), University of Cincinnati College of Medicine, Cincinnati, Ohio 45267; Department of Pathology (Y.E.N., M.N.N.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261; Department of Otolaryngology—Head and Neck Surgery (D.L.S.), University of Cincinnati College of Medicine, Cincinnati, Ohio 45267; Department of Medicine (B.R.H., J.P.K., K.W.), University of Colorado Cancer Center, Division of Endocrinology, Metabolism and Diabetes, University of Colorado at Denver School of Medicine, Aurora, Colorado 80045; and Division of Endocrinology and Metabolism (J.A.F., M.F.), University of Cincinnati College of Medicine, Cincinnati, Ohio 45267

Address all correspondence and requests for reprints to: Dr. Yuri E. Nikiforov, Department of Pathology, University of Pittsburgh Medical Canter, Presbyterian Hospital, 200 Lothrop Street, C-606, Pittsburgh, Pennsylvania 15213. E-mail: nikiforovye{at}upmc.edu.

Context: Thyroid nodules are common in adults, but only a small fraction of them are malignant. Fine-needle aspiration (FNA) with cytological evaluation is the most reliable tool for cancer diagnosis in thyroid nodules. However, 10–40% of nodules are diagnosed as indeterminate by cytology, making it difficult to optimally manage these patients.

Objective: The aim of this study was to establish the feasibility and role of testing for tumor-specific mutations in improving the FNA diagnosis of thyroid nodules.

Design: The prospective study included 470 FNA samples of thyroid nodules from 328 patients. At the time of aspiration, a small portion of the material was collected and tested for BRAF, RAS, RET/PTC, and PAX8/PPAR mutations. The mutational status was correlated with cytology and either surgical pathology diagnosis or follow-up (mean, 34 months).

Results: A sufficient amount of nucleic acids were isolated in 98% of samples. Thirty-two mutations were found, including 18 BRAF, eight RAS, five RET/PTC, and one PAX8/PPAR. The presence of any mutation was a strong indicator of cancer because 31 (97%) of mutation-positive nodules had a malignant diagnosis after surgery. A combination of cytology and molecular testing showed significant improvement in the diagnostic accuracy and allowed better prediction of malignancy in the nodules with indeterminate cytology.

Conclusions: These results indicate that molecular testing of thyroid nodules for a panel of mutations can be effectively performed in a clinical setting. It enhances the accuracy of FNA cytology and is of particular value for thyroid nodules with indeterminate cytology.

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