American Association of Endocrine Surgeon| Volume 148, ISSUE 6, P1170-1177, December 2010

A prospective study evaluating the accuracy of using combined clinical factors and candidate diagnostic markers to refine the accuracy of thyroid fine needle aspiration biopsy


      Approximately 30% of fine needle aspiration biopsies of the thyroid have inconclusive results. We conducted a prospective trial to determine whether clinical and molecular markers could be used in combination to improve the accuracy of thyroid fine needle aspiration biopsy.


      Clinical, tumor genotyping for common somatic mutations (BRAF V600E, NRAS, KRAS, RET/PTC1, RET/PTC3, and NTRK1), and the gene expression levels of 6 candidate diagnostic markers were analyzed by univariate and multivariate methods in 341 patients to determine whether they could distinguish reliably benign from malignant thyroid neoplasms, and a scoring model was derived.


      By a multivariate analysis, fine needle aspiration biopsy cytology classification, the presence of a NRAS mutation, and the tissue inhibitor of metalloproteinase 1 expression level were associated jointly with malignancy. The overall accuracy of the scoring model, including these 3 variables, to distinguish benign from malignant thyroid tumors was 91%, including 67% for the indeterminate and 77% for the suspicious FNA subgroups.


      Fine needle aspiration biopsy cytology classification, the presence of NRAS mutation, and tissue inhibitor of metalloproteinase 1 messenger RNA expression levels in combination provide a greater diagnostic accuracy than fine needle aspiration biopsy cytology alone to allow selection of more definitive initial operative treatment. The sensitivity of the scoring model, however, was too low to avoid the need for diagnostic thyroidectomies for indeterminate fine needle aspiration biopsy findings.
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      1. National Cancer Institute. SEER stat fact sheets: thyroid. Available from:

        • Vander J.B.
        • Gaston E.A.
        • Dawber T.R.
        The significance of nontoxic thyroid nodules. Final report of a 15-year study of the incidence of thyroid malignancy.
        Ann Intern Med. 1968; 69: 537-540
        • Castro M.R.
        • Gharib H.
        Thyroid fine needle aspiration biopsy: progress, practice, and pitfalls.
        Endocr Prac. 2003; 9: 128-136
        • Blansfield J.A.
        • Sack M.J.
        • Kukora J.S.
        Recent experience with preoperative fine-needle aspiration biopsy of thyroid nodules in a community hospital.
        Arch Surg. 2002; 137: 818-821
        • Renshaw A.A.
        Accuracy of thyroid fine-needle aspiration using receiver operator characteristic curves.
        Am J Clin Pathol. 2001; 116: 477-482
        • Raveto C.
        • Colombo L.
        • Dottorini M.E.
        Usefulness of fine-needle aspiration in thyroid carcinoma: a retrospective study in 37895 patients.
        Cancer. 2000; 90: 35-363
        • Layfield L.J.
        • Cibas E.S.
        • Gharib H.
        • Mandel S.J.
        Thyroid aspiration cytology: current status.
        CA Cancer J Clin. 2009; 59: 99-110
        • Layfield L.J.
        • Morton M.J.
        • Cramer H.M.
        • Hirschowitz S.
        Implications of the proposed fine-needle aspiration category of “follicular lesion of undetrmined significance.” A five year multi-institutional analysis.
        Diagn Cytopathol. 2009; 37: 710-714
        • Shibru D.
        • Chung K.
        • Kebebew E.
        Recent developments in the clinical application of thyroid cancer biomarkers.
        Curr Opin Oncol. 2008; 20: 13-18
        • Nikiforova M.N.
        • Nikiforov Y.E.
        Molecular diagnostics and predictors in thyroid cancer.
        Thyroid. 2009; 19: 1351-1361
        • Handkiewicz-Junak D.
        • Czarniecka A.
        • Jarzab B.
        Molecular prognostic markers in papillary and follicular thyroid cancer: current status and future directions.
        Mol Cell Endocrinol. 2010; 322: 8-28
        • Zeiger M.A.
        • Kourniavsky G.
        Thyroid tumorigenesis and molecular markers in thyroid cancer.
        Curr Opin Oncol. 2010; 22: 23-29
        • Xing M.
        • Clark D.
        • Guan H.
        • Ji M.
        • Dackiw A.
        • Carson K.A.
        • et al.
        BRAF mutation testing of thyroid fine-needle aspiration biopsy specimens for preoperative risk stratification in papillary thyroid cancer.
        J Clin Oncol. 2009; 27: 2977-2982
        • Oler G.
        • Cerutti J.M.
        High prevalence of BRAF mutation is a Brazilian cohort of patients with sporadic papillary thyroid carcinomas.
        Cancer. 2009; 115: 972-980
        • Freitas B.C.G.
        • Cerutti J.M.
        Genetic markers differentiating follicular thyroid carcinoma from benign lesions.
        Mol Cell Endocrinol. 2010; 321: 77-85
        • Kato M.A.
        • Fahey III, T.J.
        Molecular markers in thyroid cancer diagnostics.
        Surg Clin North Am. 2009; 89: 1139-1155
        • Kebebew E.
        • Peng M.
        • Reiff E.
        • McMillan A.
        Diagnostic and extent of disease multigene assay for malignant thyroid neoplasms.
        Cancer. 2006; 106: 2592-2597
        • Moses W.
        • Weng J.
        • Khanafshar E.
        • Duh Q.Y.
        • Clark O.H.
        • Kebebew E.
        Multiple genetic alterations in papillary thyroid cancer are associated with younger age at presentation.
        J Surg Res. 2010; 160: 179-183
        • Nikiforov Y.E.
        • Steward D.L.
        • Robinson-Smith T.M.
        • Haugen B.R.
        • Klopper J.P.
        • Zhu Z.
        • et al.
        Molecular testing for mutations in improving the fine-needle aspiration diagnosis of thyroid nodules.
        J Clin Endocrinol Metab. 2009; 6: 2092-2098
        • Sapio M.R.
        • Posca D.
        • Raggioli A.
        • Guerra A.
        • Marotta V.
        • Deandrea M.
        • et al.
        Detection of RET/PTC, TRK, and BRAF mutations in preoperative diagnosis of thyroid nodules with indeterminate cytological findings.
        Clin Endocrinol. 2007; 66: 678-683
        • Yip L.
        • Nikiforova M.N.
        • Carty S.E.
        • Yim J.H.
        • Stang M.T.
        • Tublin M.J.
        • et al.
        Optimizing surgical treatment of papillary thyroid carcinoma associated with BRAF mutation.
        Surgery. 2009; 146: 1215-1223

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        SurgeryVol. 151Issue 2
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          “A prospective study evaluating the accuracy of using combined clinical factors and candidate diagnostic markers to refine the accuracy of thyroid fine needle aspiration biopsy” by Aarti Mathur, Julie Weng, Willieford Moses, Seth M. Steinberg, Reza Rahabari, Mio Kitano, Elham Khanafshar, Britt-Marie Ljung, Quan-Yang Duh, Orlo H. Clark, and Electron Kebebew, which appeared in Surgery, Vol. 148, No. 6:1170-7, 2010 was published with an incorrect spelling of an author name. The correct spelling for Reza Rahabari should be Reza Rahbari.
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