Objective: The BRAF V600E mutation has been associated with aggressive disease in papillary thyroid carcinoma (PTC). Molecular testing has been proposed as a useful adjunct to cytology in the diagnosis of malignancy and for tailoring clinical management. The aims of our study were to evaluate the BRAF mutational status using archived fine-needle aspiration biopsy (FNAB) material from patients with long-term follow-up and to correlate it with the original cytology diagnosis, clinicopathological stage at surgery, and prognosis. Study Design: FNAB material from 52 cases of PTC, with a mean follow-up of 8.4 years, was used in this study. DNA was extracted from archival cytology slides. Mutation analysis was performed by standard sequencing and locked nucleic acid-PCR/sequencing. Results: The BRAF V600E mutation was present in 46% of cases, but it was absent in all FNABs diagnosed originally as atypical and in 14 of 17 suspicious cases. Recurrence was significantly more frequent (p = 0.006) in cases with BRAF mutations and 54% of these cases presented with stage 2 or higher. Conclusion: The BRAF V600E mutation is associated with a higher pathological stage at surgery and a higher rate of recurrence. BRAF mutation analysis did not provide a significant increase in the accuracy of thyroid FNABs diagnosed as suspicious or atypical in our institution.

Keywords:
Thyroid, BRAF, Papillary carcinoma, Prognosis
1.
Nikiforova MN, Nikiforov YE: Molecular diagnostics and predictors in thyroid cancer. Thyroid 2009;19:1351–1361.
2.
Xing M: Prognostic utility of BRAF mutation in papillary thyroid cancer. Mol Cell Endocrinol 2010;321:86–93.
3.
Nucera C, Lawler J, Hodin R, Parangi S: The BRAF V600E mutation: what is it really orchestrating in thyroid cancer? Oncotarget 2010;1:751–756.
4.
Kebebew E, Weng J, Bauer J, Ranvier G, Clark OH, Duh QY, Shibru D, Bastian B, Griffin A: The prevalence and prognostic value of BRAF mutation in thyroid cancer. Ann Surg 2007;246:466–470, discussion 470–461.
5.
Yip L, Nikiforova MN, Carty SE, Yim JH, Stang MT, Tublin MJ, Lebeau SO, Hodak SP, Ogilvie JB, Nikiforov YE: Optimizing surgical treatment of papillary thyroid carcinoma associated with BRAF mutation. Surgery 2009;146:1215–1223.
6.
Marchetti I, Lessi F, Mazzanti CM, Bertacca G, Elisei R, Coscio GD, Pinchera A, Bevilacqua G: A morpho-molecular diagnosis of papillary thyroid carcinoma: BRAF V600E detection as an important tool in preoperative evaluation of fine-needle aspirates. Thyroid 2009;19:837–842.
7.
Adeniran AJ, Theoharis C, Hui P, Prasad ML, Hammers L, Carling T, Udelsman R, Chhieng DC: Reflex BRAF testing in thyroid fine-needle aspiration biopsy with equivocal and positive interpretation: a prospective study. Thyroid 2011;21:717–723.
8.
Arcila M, Lau C, Nafa K, Ladanyi M: Detection of KRAS and BRAS mutations in colorectal carcinoma roles for high-sensitivity locked nucleic acid-PCR sequencing and broad-spectrum mass spectrometry genotyping. J Mol Diagn 2011;13:64–73.
9.
Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, Mazzaferri EL, McIver B, Pacini F, Schlumberger M, Sherman SI, Steward DL, Tuttle RM: Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2009;19:1167–1214.
10.
Yang J, Schnadig V, Logrono R, Wasserman PG: Fine-needle aspiration of thyroid nodules: a study of 4,703 patients with histologic and clinical correlations. Cancer 2007;111:306–315.
11.
Cibas ES, Ali SZ: The Bethesda System for Reporting Thyroid Cytopathology. Am J Clin Pathol 2009;132:658–665.
12.
Kesmodel SB, Terhune KP, Canter RJ, Mandel SJ, LiVolsi VA, Baloch ZW, Fraker DL: The diagnostic dilemma of follicular variant of papillary thyroid carcinoma. Surgery 2003;134:1005–1012, discussion 1012.
13.
Brzezianska E, Pastuszak-Lewandoska D: A minireview: the role of MARK/ERK and PI3K/Akt pathways in thyroid follicular cell-derived neoplasm. Front Biosci 2011;16:422–439.
14.
Vriens MR, Schreinemakers JM, Suh I, Guerrero MA, Clark OH: Diagnostic markers and prognostic factors in thyroid cancer. Future Oncol 2009;5:1283–1293.
15.
Trovisco V, Soares P, Preto A, de Castro IV, Lima J, Castro P, Maximo V, Botelho T, Moreira S, Meireles AM, Magalhaes J, Abrosimov A, Cameselle-Teijeiro J, Sobrinho-Simoes M: Type and prevalence of BRAF mutations are closely associated with papillary thyroid carcinoma histotype and patients’ age but not with tumour aggressiveness. Virchows Arch 2005;446:589–595.
16.
Shibru D, Chung KW, Kebebew E: Recent developments in the clinical application of thyroid cancer biomarkers. Curr Opin Oncol 2008;20:13–18.
17.
Melck AL, Yip L, Carty SE: The utility of BRAF testing in the management of papillary thyroid cancer. Oncologist 2010;15:1285–1293.
18.
Nikiforov YE, Steward DL, Robinson-Smith TM, Haugen BR, Klopper JP, Zhu Z, Fagin JA, Falciglia M, Weber K, Nikiforova MN: Molecular testing for mutations in improving the fine-needle aspiration diagnosis of thyroid nodules. J Clin Endocrinol Metab 2009;94:2092–2098.
19.
Ohori NP, Nikiforova MN, Schoedel KE, LeBeau SO, Hodak SP, Seethala RR, Carty SE, Ogilvie JB, Yip L, Nikiforov YE: Contribution of molecular testing to thyroid fine-needle aspiration cytology of ‘follicular lesion of undetermined significance/atypia of undetermined significance’. Cancer Cytopathol 2010;118:17–23.
20.
Rivera M, Ricarte-Filho J, Knauf J, Shaha A, Tuttle M, Fagin JA, Ghossein RA: Molecular genotyping of papillary thyroid carcinoma follicular variant according to its histological subtypes (encapsulated vs. infiltrative) reveals distinct BRAF and RAS mutation patterns. Mod Pathol 2010;23:1191–1200.
21.
Riesco-Eizaguirre G, Gutierrez-Martinez P, Garcia-Cabezas MA, Nistal M, Santisteban P: The oncogene BRAF V600E is associated with a high risk of recurrence and less differentiated papillary thyroid carcinoma due to the impairment of Na+/I- targeting to the membrane. Endocr Relat Cancer 2006;13:257–269.
22.
Lin KL, Wang OC, Zhang XH, Dai XX, Hu XQ, Qu JM: The BRAF mutation is predictive of aggressive clinicopathological characteristics in papillary thyroid microcarcinoma. Ann Surg Oncol 2010;17:3294–3300.
23.
Smith RA, Salajegheh A, Weinstein S, Nassiri M, Lam AK: Correlation between BRAF mutation and the clinicopathological parameters in papillary thyroid carcinoma with particular reference to follicular variant. Hum Pathol 2011;42:500–506.
24.
Zatelli MC, Trasforini G, Leoni S, Frigato G, Buratto M, Tagliati F, Rossi R, Cavazzini L, Roti E, degli Uberti EC: BRAF V600E mutation analysis increases diagnostic accuracy for papillary thyroid carcinoma in fine-needle aspiration biopsies. Eur J Endocrinol 2009;161:467–473.
25.
Salvatore G, Giannini R, Faviana P, Caleo A, Migliaccio I, Fagin JA, Nikiforov YE, Troncone G, Palombini L, Basolo F, Santoro M: Analysis of BRAF point mutation and RET/PTC rearrangement refines the fine-needle aspiration diagnosis of papillary thyroid carcinoma. J Clin Endocrinol Metab 2004;89:5175–5180.
26.
Kim SK, Kim DL, Han HS, Kim WS, Kim SJ, Moon WJ, Oh SY, Hwang TS: Pyrosequencing analysis for detection of a BRAFV600E mutation in an FNAB specimen of thyroid nodules. Diagn Mol Pathol 2008;17:118–125.
27.
Kwak JY, Kim EK, Kim JK, Han JH, Hong SW, Park TS, Choi JR: Dual priming oligonucleotide-based multiplex PCR analysis for detection of BRAFV600E mutation in FNAB samples of thyroid nodules in BRAFV600E mutation-prevalent area. Head Neck 2010;32:490–498.
28.
Kim SK, Hwang TS, Yoo YB, Han HS, Kim DL, Song KH, Lim SD, Kim WS, Paik NS: Surgical results of thyroid nodules according to a management guideline based on the BRAF(V600E) mutation status. J Clin Endocrinol Metab 2011;96:658–664.
29.
Bentz BG, Miller BT, Holden JA, Rowe LR, Bentz JS: B-RAF V600E mutational analysis of fine needle aspirates correlates with diagnosis of thyroid nodules. Otolaryngol Head Neck Surg 2009;140:709–714.
© 2011 S. Karger AG, Basel
2011
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.