Endocrine

, Volume 45, Issue 3, pp 462–468 | Cite as

The BRAF V600E mutation in papillary thyroid cancer with positive or suspected pre-surgical cytological finding is not associated with advanced stages or worse prognosis

  • Daniele Barbaro
  • Roberto Mario Incensati
  • Gabriele Materazzi
  • Giuseppe Boni
  • Mariano Grosso
  • Erica Panicucci
  • Paola Lapi
  • Cristina Pasquini
  • Paolo Miccoli
Original Article
First Online:
Received:
Accepted:

Abstract

The mutation BRAF V600E is thought to be a putative prognostic marker of the aggressiveness of several cancers among which is also papillary thyroid cancer. Our study aimed to evaluate whether this mutation is associated with advanced stages of disease or with a worse prognosis in a series of patients with cytological findings of Thyr 4 and Thyr 5 and who were undergoing total thyroidectomy and routine central compartment lymph-node dissection. 110 patients were consecutively enrolled over an 18-month period from September 2010 to March 2012. All patients had cytological findings that were either indicative of, or positive for papillary thyroid cancer, Thyr 4 or Thyr 5. Detection of BRAF mutation was made on fine-needle aspiration specimen by pyrosequencing after microdissection and DNA extraction of neoplastic cells. After surgical intervention, the patients underwent radioiodine ablation according to our protocol, and follow-up was performed after 8 months. The BRAF V600E mutation was found in 79 % of our cases: 85.7 % of these cases represented the classical variant, 57.8 % the follicular variant, 89.6 % the tall cell variant, and 33.3 % the solid variant. All patients had confirmation of papillary thyroid cancer after histology, with no differences being seen in pTNM presentation between patients with BRAF wild-type and patients with BRAF V600E mutation. Ninety-nine patients underwent radioiodine ablation. Results at follow-up 8 months after radioiodine ablation showed no differences in the rate of ablation between patients harboring BRAF V600E mutation and those having BRAF wild-type. The BRAF V600E mutation doesn’t appear to be a reliable risk factor for the aggressiveness of a tumor. BRAF analysis should neither be the only guide for pre-surgical decisions regarding the extent of surgery nor for post-surgical decisions regarding the aggressiveness of the treatment.

Keywords

BRAF V600E mutation Papillary thyroid cancer Thyr 4 Thyr 5 
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Notes

Conflict of interest

Nothing to declare.

References

  1. 1.
    R. Siegler, D. Naishadham, A. Jemal, Cancer statistics 2012. CA Cancer J. Clin. 62(1), 10–29 (2012)CrossRefGoogle Scholar
  2. 2.
    M.J. Schlumberger, Papillary and follicular thyroid carcinoma. N. Engl. J. Med. 338(5), 297–306 (1998)PubMedCrossRefGoogle Scholar
  3. 3.
    V. Popovici, E. Budinska, S. Teipar, S. Weinrich, H. Estrella, G. Hodgson, E. Van Cutsem, T. Xie, F.T. Bosman, A.D. Roth, M. Delorenzi, Identification of a poor-prognosis BRAF-mutant-like population of patients with colon cancer. J. Clin. Oncol. 30(12), 1288–1295 (2012)PubMedCrossRefGoogle Scholar
  4. 4.
    J. Ziai, P. Hui, BRAF mutation testig in clinical practice. Expert Rev. Mol. Diagn. 12(2), 127–138 (2012)PubMedCrossRefGoogle Scholar
  5. 5.
    M.A. Zeiger, E.B. Schneider, BRAF V600E mutation independently predicts central compartment lymph node metastasis in patients with papillary thyroid cancer. Ann. Surg. Oncol. 20(1), 3–4 (2013)PubMedCrossRefGoogle Scholar
  6. 6.
    R.P. Tufano, J. Bishop, G. Wu, Reoperative central compartment dissection for patients with recurrent/persistent papillary thyroid cancer: efficacy, safety, and the association of the BRAF mutation. Laryngoscope 122(7), 1634–1640 (2012)PubMedCrossRefGoogle Scholar
  7. 7.
    G.M. Howell, S.E. Carty, M.J. Armstrong, S.O. Lebeau, S.P. Hodak, C. Coyne, M.T. Stang, K.L. McCoy, M.N. Nikiforova, Y.E. Nikiforov, L. Yip, Both BRAF V600E mutation and older age (≥65 years) are associated with recurrent papillary thyroid cancer. Ann. Surg. Oncol. 18(13), 3566–3571 (2011)PubMedCrossRefGoogle Scholar
  8. 8.
    G.M. Howell, M.N. Nikiforova, S.E. Carty, M.J. Armstrong, S.P. Hodak, M.T. Stang, K.L. McCoy, Y.E. Nikiforov, L. Yip, BRAF V600E mutation independently predicts central compartment lymph node metastasis in patients with papillary thyroid cancer. Ann. Surg. Oncol. 20(1), 47–52 (2012)PubMedCrossRefGoogle Scholar
  9. 9.
    S.J. Kim, K.E. Lee, J.P. Myong, J.H. Park, Y.K. Jeon, H.S. Min, S.Y. Park, K.C. Jung, H. Koo do, Y.K. Youn, BRAF V600E mutation is associated with tumor aggressiveness in papillary thyroid cancer. World J. Surg. 36(2), 310–317 (2012)PubMedCrossRefGoogle Scholar
  10. 10.
    W. Wang, W. Zhao, H. Wang, X. Teng, H. Wang, X. Chen, Z. Li, X. Yu, T.J. Fahey 3rd, L. Teng, Poorer prognosis and higher prevalence of BRAF (V600E) mutation in synchronous bilateral papillary thyroid carcinoma. Ann. Surg. Oncol. 19(1), 31–36 (2012)PubMedCrossRefGoogle Scholar
  11. 11.
    A. Chakraborty, A. Narkar, R. Mukhopadhyaya, S. Kane, A. D’Cruz, M.G. Rajan, BRAF V600E mutation in papillary thyroid carcinoma: significant association with node metastases and extra thyroidal invasion. Endocr. Pathol. 23(2), 83–93 (2012)PubMedCrossRefGoogle Scholar
  12. 12.
    N. Kurtulmus, M. Duren, U. Ince, M. Cengiz Yakicier, O. Peker, O. Aydın, E. Altiok, S. Giray, H. Azizlerli, BRAF(V600E) mutation in Turkish patients with papillary thyroid cancer: strong correlation with indicators of tumor aggressiveness. Endocrine 42(2), 404–410 (2012)PubMedCrossRefGoogle Scholar
  13. 13.
    Y.L. Zhou, W. Zhang, E.L. Gao, X.X. Dai, H. Yang, X.H. Zhang, O.C. Wang, Preoperative BRAF mutation is predictive of occult contralateral carcinoma in patients with unilateral papillary thyroid microcarcinoma. Asian Pac. J. Cancer Prev. 13(4), 1267–1272 (2012)PubMedCrossRefGoogle Scholar
  14. 14.
    X. Lee, M. Gao, Y. Ji, Y. Yu, Y. Feng, Y. Li, Y. Zhang, W. Cheng, W. Zhao, Analysis of differential BRAF V600E mutational status in high aggressive papillary thyroid microcarcinoma. Ann. Surg. Oncol. 16(2), 240–245 (2009)PubMedCrossRefGoogle Scholar
  15. 15.
    R. Elisei, D. Viola, L. Torregrossa, R. Giannini, C. Romei, C. Ugolini, E. Molinaro, L. Agate, A. Biagini, C. Lupi, L. Valerio, G. Materazzi, P. Miccoli, P. Piaggi, A. Pinchera, P. Vitti, F. Basolo, The BRAF V600 E mutation is an indipendent, poor prognostic factor fort the out come of patients with low-risk intrathyroid papillary thyroid carcinoma: single-institution results from a large cohort study. J. Clin. Endocrin. Metab. 97(12), 4390–4398 (2012)CrossRefGoogle Scholar
  16. 16.
    J.Y. Joo, J.Y. Park, Y.H. Yoon, B. Choi, J.M. Kim, Y.S. Jo, M. Shong, B.S. Koo, Prediction of occult central lymph node metastasis in papillary thyroid carcinoma by preoperative BRAF analysis using fine-needle aspiration biopsy: a prospective study. J. Clin. Endocrinol. Metab. 97(11), 3996–4003 (2012)PubMedCrossRefGoogle Scholar
  17. 17.
    C. Nucera, A. Pontecorvi, Clinical outcome, role of BRAF(V600E), and molecular pathways in papillary thyroid microcarcinoma: is it an indolent cancer or an early stage of papillary thyroid cancer? Front Endocrinol. (Lausanne) 3, 33 (2012)Google Scholar
  18. 18.
    R.P. Tufano, G.V. Teixeira, J. Bishop, K.A. Carson, M. Xing, BRAF mutation in papillary thyroid cancer and its value in tailoring initial treatment: a systematic review and meta-analysis. Medicine (Baltimore) 91(5), 274–286 (2012)CrossRefGoogle Scholar
  19. 19.
    C. Nucera, J. Lawler, R. Hodin, S. Parangi, The BRAF V600E mutation: what is really orchestrating in thyroid cancer? Oncotarget 1(8), 751–756 (2010)PubMedCentralPubMedGoogle Scholar
  20. 20.
    Dutenhefner SE, Marui S, Santos AB, Lima EU, Inoue M, Neto JD, Shiang C, Fukushima J, Cernea CR, Friguglietti C 2012 BRAF, a tool in the decision to perform elective neck dissection? Thyroid Nov 27 (2012)Google Scholar
  21. 21.
    X. Li, A.B. Abdel-Mageed, E. Kandil, BRAF mutation in papillary thyroid carcinoma. Int. J. Clin. Exp. Med. 5(4), 310–315 (2012)PubMedCentralPubMedGoogle Scholar
  22. 22.
    H. Pelttari, C. Schalin-Jäntti, J. Arola, E. Löyttyniemi, S. Knuutila, M.J. Välimäki, BRAF V600E mutation does not predict recurrence after long-term follow-up in TNM stage I or II papillary thyroid carcinoma patients. APMIS 120(5), 380–386 (2012)PubMedCrossRefGoogle Scholar
  23. 23.
    C. Eloy, J. Santos, P. Soares, M. Sobrinho-Simoes, The preeminence of growth pattern and invasiveness and the limited influence of BRAF and RAS mutations in the occurrence of papillary thyroid carcinoma lymph node metastases. Virchows Arch. 459(3), 265–276 (2011)PubMedCrossRefGoogle Scholar
  24. 24.
    J.K. Nam, C.K. Jung, B.J. Song, D.J. Lim, B.J. Chae, N.S. Lee, W.C. Park, J.S. Kim, S.S. Jung, J.S. Bae, Is the BRAF (V600E) mutation useful as a predictor of preoperative risk in papillary thyroid cancer? Am. J. Surg. 203(4), 436–441 (2012)PubMedCrossRefGoogle Scholar
  25. 25.
    D. Ahn, J.S. Park, J.H. Sohn, J.H. Kim, S.K. Park, A.N. Seo, J.Y. Park, BRAF (V600E) mutation does not serve as a prognostic factor in Korean patients with papillary thyroid carcinoma. Auris Nasus Larynx 39(2), 198–203 (2012)PubMedCrossRefGoogle Scholar
  26. 26.
    T.Y. Kim, W.B. Kim, J.Y. Song, Y.S. Rhee, G. Gong, Y.M. Cho, S.Y. Kim, S.C. Kim, S.J. Hong, Y.K. Shong, The BRAF mutation is not associated with poor prognostic factors in Korean patients with conventional papillary thyroid microcarcinoma. Clin. Endocrinol. (Oxf) 63(5), 588–593 (2005)CrossRefGoogle Scholar
  27. 27.
    T.H. Kim, Y.J. Park, J.A. Lim, H.Y. Ahn, E.K. Lee, Y.J. Lee, K.W. Kim, S.K. Hahn, Y.K. Youn, K.H. Kim, B.Y. Cho, J. do Park, The association of the BRAF(V600E) mutation with prognostic factors and poor clinical outcome in papillary thyroid cancer: a meta-analysis. Cancer 118(7), 1764–1773 (2012)PubMedCrossRefGoogle Scholar
  28. 28.
    C. Li, K.C. Lee, B. Schneider, M.A. Zeiger, BRAF V600E mutation and its association with clinicopathological features of papillary thyroid cancer: a meta-analysis. J. Clin. Endocrinol. Metab. 97(12), 4559–4570 (2012)PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    K.C. Lee, C. Li, E.B. Schneider, Y. Wang, H. Somervell, M. Krafft, C.B. Umbricht, M.A. Zeiger, Is BRAF Imutation associated with lymph node metastasis in patients with papillary thyroid cancer? Surgery 152(6), 977–983 (2012)PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Y.K. So, Y.I. Son, J.Y. Park, C.H. Baek, H.S. Jeong, M.K. Chung, Preoperative BRAF Mutation has different predictive values for lymph node metastasis according to tumor size. Otolaryngol. Head Neck Surg. 145(3), 422–427 (2011)PubMedCrossRefGoogle Scholar
  31. 31.
    A. Proietti, R. Giannini, C. Ugolini, M. Miccoli, G. Fontanini, G. Di Coscio, R. Romani, P. Berti, P. Miccoli, F. Basolo, BRAF status of follicular variant of papillary thyroid carcinoma and its relationship to its clinical and cytological features. Thyroid 20(11), 1263–1270 (2010)PubMedCrossRefGoogle Scholar
  32. 32.
    C. Romei, L. Fugazzola, E. Puxeddu, F. Frasca, D. Viola, M. Muzza, S. Moretti, L.M. Nicolosi, C. Giani, V. Cirello, N. Avenia, S. Rossi, P. Vitti, A. Pinchera, R. Elisei, Modifications in the papillary thyroid cancer gene profile over the last 15 years. J. Clin. Endocrinol. Metab. 97(9), E1758–E1765 (2012)PubMedCrossRefGoogle Scholar
  33. 33.
    J.D. Prescott, P.M. Sadow, R.A. Hodin, L.P. Le, R.D. Gaz, G.W. Randolph, A.E. Stephen, S. Parangi, G.H. Daniels, C.C. Lubitz, BRAF (V600E) status adds incremental value to current risk classification systems in predicting papillary thyroid carcinoma recurrence. Surgery 152(6), 984–990 (2012)PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    D.S. Cooper, G.M. Doherty, B.R. Haugen, R.T. Kloos, S.L. Lee, S.J. Mandel, E.L. Mazzaferri, B. McIver, F. Pacini, M. Schlumberger, S.I. Sherman, D.L. Steward, R.M. Tuttle, American Thyroid Association (ATA) guidelines taskforce on thyroid nodules and differentiated thyroid cancer. Thyroid 19(11), 1167–1214 (2009)PubMedCrossRefGoogle Scholar
  35. 35.
    M. Xing, A.S. Alzahrani, K.A. Carson, D. Viola, R. Elisei, B. Bendlova, L. Yip, C. Mian, F. Vianello, R.M. Tuttle, E. Robenshtok, J.A. Fagin, E. Puxeddu, L. Fugazzola, A. Czarniecka, B. Jarzab, C.J. O’Neill, Sywak, A.K. Lam, G. Riesco-Eizaguirre, P. Santisteban, H. Nakayama, R.P. Tufano, S.I. Pai, M.A. Zeiger, W.H. Westra, D.P. Clark, R. Clifton-Bligh, D. Sidransky, P.W. Ladenson, V. Sykorova, Association between BRAF V600E mutation and mortality in patients with papillary thyroid cancer. JAMA 309(14), 1493–1501 (2013)PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    J.C. Watkinson, The Brithish Thyroid Association guidelines for the management of thyroid cancer in adults. Nucl. Med. Commun. 25(9), 897–900 (2004)PubMedCrossRefGoogle Scholar
  37. 37.
    A. Guerra, V. Marotta, M. Deandrea, M. Motta, P.P. Limone, A. Caleo, P. Zeppa, S. Esposito, F. Fulciniti, M. Vitale, BRAF (V600E) associates with cytoplasmatic localization of p27kip1 and higher cytokeratin 19 expression in papillary thyroid carcinoma. Endocrine (2012). doi: 10.1007/s12020-012-9843-4 PubMedGoogle Scholar
  38. 38.
    C. Durante, E. Puxeddu, E. Ferretti, R. Morisi, S. Moretti, R. Bruno, F. Barbi, N. Avenia, A. Scipioni, A. Verrienti, E. Tosi, A. Cavaliere, A. Gulino, S. Filetti, D. Russo, BRAF mutations in papillary thyroid carcinomas inhibit genes involved in iodine metabolism. J. Clin. Endocrinol. Metab. 92(7), 2840–2843 (2007)PubMedCrossRefGoogle Scholar
  39. 39.
    Pupilli C, Pinzani P, Salvianti F, Fibbi B, Rossi M, Petrone L, Perigli G, De Feo M, Vezzosi V, Pazzagli M, Orlando C, Forti G Circulating BRAFV600E in the diagnosis and follow up of differentiated papillary thyroid carcinoma. J. Clin. Endocrinol. Metab. Jun 20 (2013)Google Scholar
  40. 40.
    Lim JY, Hong SW, Lee YS, Kim BW, Park CS, Chang HS, Cho JY Clinicopathologic implications of the BRAFV600E mutation in papillary thyroid cancer; a subgroup analysis of 3130 cases in a single center. Thyroid Mar 17 (2013)Google Scholar
  41. 41.
    E. Puxeddu, C. Durante, N. Avenia, S. Filetti, D. Russo, Clinical implications of BRAF muttion in thyroid carcinoma. Trends Endocrinol. Metab. 19(4), 138–145 (2008)PubMedCrossRefGoogle Scholar
  42. 42.
    M. Xing, Prognostic utility of BRAF mutation in papillary thyroid cancer. Mol. Cell. Endocrinol. 32(1), 86–93 (2010)CrossRefGoogle Scholar
  43. 43.
    Wartofsky L Should patients with papillary microcarcinoma undergo radioiodine ablation? Endocrine Jul 2 (2013)Google Scholar
  44. 44.
    Kunavisarut T Diagnostic biomarkers of differentiated thyroid cancer. Endocrine May 4 (2013)Google Scholar
  45. 45.
    Guerra A, Di Stasi V, Zeppa P, Faggiano A, Marotta V, Vitale M BRAF V600E assessment by pyrosequencing in fine needle aspirates of thyroid nodules with concurrent Hashimoto’s thyroiditis is a reliable assay. Endocrine Dec 1 (2013)Google Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Daniele Barbaro
    • 1
  • Roberto Mario Incensati
    • 2
  • Gabriele Materazzi
    • 3
  • Giuseppe Boni
    • 1
  • Mariano Grosso
    • 5
  • Erica Panicucci
    • 4
  • Paola Lapi
    • 1
  • Cristina Pasquini
    • 1
  • Paolo Miccoli
    • 3
  1. 1.Section of EndocrinologyASL 6 LivornoLeghornItaly
  2. 2.U.O. of PathologyASL 6 LivornoLeghornItaly
  3. 3.Department of SurgeryUniversity of PisaPisaItaly
  4. 4.Department of PathologyUniversity of PisaPisaItaly
  5. 5.U.O. of Nuclear MedicineUniversity of PisaPisaItaly

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