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Morphology predicts BRAF V600E mutation in papillary thyroid carcinoma: an interobserver reproducibility study

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Abstract

Papillary thyroid carcinomas (PTC) with BRAF V600E mutation are morphologically distinctive. They are typically classic or tall cell variants, show infiltrative borders, and are associated with desmoplasia/fibrosis, psammoma bodies, and well-developed nuclear features of papillary carcinoma. We hypothesize that morphologic features of PTC can help in the prediction of BRAF V600E mutation, and we evaluate the accuracy and the interobserver reproducibility of such prediction. Hematoxylin and eosin-stained sections from 50 PTCs comprising of 26 mutation-positive and 24 mutation-negative tumors were examined. BRAF V600E mutation was predicted correctly in 42/50 tumors (accuracy, 84 %) with 96 % sensitivity, 71 % specificity, and 78 % positive and 94 % negative predictive values (NPV). Subtle nuclear features of PTC (n = 10) had the highest (100 %) negative predictive value followed by well-circumscribed non-infiltrative tumor borders (17/22 mutation-negative tumors, 95 % NPV). The positive predictive value of infiltrative tumor borders (21/28 [75 %] mutation-positive), desmoplasia/fibrosis (23/31 [74 %] mutation-positive), and psammoma bodies (13/20 [65 %] mutation-positive) increased to 100 % when all three features were present (n = 8/8 mutation-positive). To assess interobserver reproducibility, two pathologists blinded to the mutational status evaluated 30 PTCs (15 mutation-positive and 15 mutation-negative) after self-training on 10 PTCs with known BRAF V600E mutational status (five mutation-positive and five mutation-negative). The prediction of the mutation was achieved with substantial agreement (κ value, 0.79) and accuracy (25/30, 83 %). This study demonstrates that BRAF V600E mutation in papillary thyroid carcinoma can be predicted on morphology with accuracy and with substantial interobserver agreement.

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References

  1. Baquero P, Sanchez-Hernandez I, Jimenez-Mora E, Orgaz JL, Jimenez B, Chiloeches A (2013) (V600E)BRAF promotes invasiveness of thyroid cancer cells by decreasing E-cadherin expression through a snail-dependent mechanism. Cancer Lett 335:232–241

    Article  PubMed  CAS  Google Scholar 

  2. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA (2002) Mutations of the BRAF gene in human cancer. Nature 417:949–954

    Article  PubMed  CAS  Google Scholar 

  3. Namba H, Nakashima M, Hayashi T, Hayashida N, Maeda S, Rogounovitch TI, Ohtsuru A, Saenko VA, Kanematsu T, Yamashita S (2003) Clinical implication of hot spot BRAF mutation, V599E, in papillary thyroid cancers. J Clin Endocrinol Metab 88:4393–4397

    Article  PubMed  CAS  Google Scholar 

  4. Rivera M, Ricarte-Filho J, Tuttle RM, Ganly I, Shaha A, Knauf J, Fagin J, Ghossein R (2010) Molecular, morphologic, and outcome analysis of thyroid carcinomas according to degree of extrathyroid extension. Thyroid 20:1085–1093

    Article  PubMed  Google Scholar 

  5. Finkelstein A, Levy GH, Hui P, Prasad A, Virk R, Chhieng DC, Carling T, Roman SA, Sosa JA, Udelsman R, Theoharis CG, Prasad ML (2012) Papillary thyroid carcinomas with and without BRAF V600E mutations are morphologically distinct. Histopathology 60:1052–1059

    Article  PubMed  Google Scholar 

  6. Soares P, Trovisco V, Rocha AS, Lima J, Castro P, Preto A, Maximo V, Botelho T, Seruca R, Sobrinho-Simoes M (2003) BRAF mutations and RET/PTC rearrangements are alternative events in the etiopathogenesis of PTC. Oncogene 22:4578–4580

    Article  PubMed  CAS  Google Scholar 

  7. Lupi C, Giannini R, Ugolini C, Proietti A, Berti P, Minuto M, Materazzi G, Elisei R, Santoro M, Miccoli P, Basolo F (2007) Association of BRAF V600E mutation with poor clinicopathological outcomes in 500 consecutive cases of papillary thyroid carcinoma. J Clin Endocrinol Metab 92:4085–4090

    Article  PubMed  CAS  Google Scholar 

  8. Durante C, Puxeddu E, Ferretti E, Morisi R, Moretti S, Bruno R, Barbi F, Avenia N, Scipioni A, Verrienti A, Tosi E, Cavaliere A, Gulino A, Filetti S, Russo D (2007) BRAF mutations in papillary thyroid carcinomas inhibit genes involved in iodine metabolism. J Clin Endocrinol Metab 92:2840–2843

    Article  PubMed  CAS  Google Scholar 

  9. Kim TH, Park YJ, Lim JA, Ahn HY, Lee EK, Lee YJ, Kim KW, Hahn SK, Youn YK, Kim KH, Cho BY, do Park J (2012) The association of the BRAF(V600E) mutation with prognostic factors and poor clinical outcome in papillary thyroid cancer: a meta-analysis. Cancer 118:1764–1773

    Article  PubMed  CAS  Google Scholar 

  10. Eloy C, Santos J, Soares P, Sobrinho-Simoes M (2011) 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 459:265–276

    Article  PubMed  CAS  Google Scholar 

  11. Yip L, Nikiforova MN, Carty SE, Yim JH, Stang MT, Tublin MJ, Lebeau SO, Hodak SP, Ogilvie JB, Nikiforov YE (2009) Optimizing surgical treatment of papillary thyroid carcinoma associated with BRAF mutation. Surgery 146:1215–1223

    Article  PubMed  Google Scholar 

  12. Xing M, Clark D, Guan H, Ji M, Dackiw A, Carson KA, Kim M, Tufaro A, Ladenson P, Zeiger M, Tufano R (2009) BRAF mutation testing of thyroid fine-needle aspiration biopsy specimens for preoperative risk stratification in papillary thyroid cancer. J Clin Oncol 27:2977–2982

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  13. Sarne DH (2012) A piece of the puzzle: what does BRAF status mean in the management of patients with papillary thyroid carcinoma? J Clin Endocrinol Metab 97:3094–3096

    Article  PubMed  CAS  Google Scholar 

  14. Salvatore G, De Falco V, Salerno P, Nappi TC, Pepe S, Troncone G, Carlomagno F, Melillo RM, Wilhelm SM, Santoro M (2006) BRAF is a therapeutic target in aggressive thyroid carcinoma. Clin Cancer Res 12:1623–1629

    Article  PubMed  CAS  Google Scholar 

  15. Kloos RT, Ringel MD, Knopp MV, Hall NC, King M, Stevens R, Liang J, Wakely PE Jr, Vasko VV, Saji M, Rittenberry J, Wei L, Arbogast D, Collamore M, Wright JJ, Grever M, Shah MH (2009) Phase II trial of sorafenib in metastatic thyroid cancer. J Clin Oncol 27:1675–1684

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  16. Gupta-Abramson V, Troxel AB, Nellore A, Puttaswamy K, Redlinger M, Ransone K, Mandel SJ, Flaherty KT, Loevner LA, O’Dwyer PJ, Brose MS (2008) Phase II trial of sorafenib in advanced thyroid cancer. J Clin Oncol 26:4714–4719

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  17. Trovisco V, Vieira de Castro I, Soares P, Maximo V, Silva P, Magalhaes J, Abrosimov A, Guiu XM, Sobrinho-Simoes M (2004) BRAF mutations are associated with some histological types of papillary thyroid carcinoma. J Pathol 202:247–251

    Article  PubMed  CAS  Google Scholar 

  18. Adeniran AJ, Zhu Z, Gandhi M, Steward DL, Fidler JP, Giordano TJ, Biddinger PW, Nikiforov YE (2006) Correlation between genetic alterations and microscopic features, clinical manifestations, and prognostic characteristics of thyroid papillary carcinomas. Am J Surg Pathol 30:216–222

    Article  PubMed  Google Scholar 

  19. Virk RK, Van Dyke AL, Finkelstein A, Prasad A, Gibson J, Hui P, Theoharis CG, Carling T, Roman SA, Sosa JA, Udelsman R, Prasad ML (2013) BRAFV600E mutation in papillary thyroid microcarcinoma: a genotype-phenotype correlation. Mod Pathol 26:62–70

    Article  PubMed  CAS  Google Scholar 

  20. DeLellis RA, Lloyd R, Heitz PU, Eng C (eds) (2004) World Health Organization classification of tumours. Pathology and genetics of tumours of endocrine organs. IARC Press, Lyon

    Google Scholar 

  21. Carpenter CR (2005) Kappa statistic. CMAJ 173:15–16, author reply 17

    Article  PubMed Central  PubMed  Google Scholar 

  22. Basolo F, Torregrossa L, Giannini R, Miccoli M, Lupi C, Sensi E, Berti P, Elisei R, Vitti P, Baggiani A, Miccoli P (2010) Correlation between the BRAF V600E mutation and tumor invasiveness in papillary thyroid carcinomas smaller than 20 millimeters: analysis of 1,060 cases. J Clin Endocrinol Metab 95:4197–4205

    Article  PubMed  CAS  Google Scholar 

  23. Eloy C, Santos J, Cameselle-Teijeiro J, Soares P, Sobrinho-Simoes M (2012) TGF-beta/SMAD pathway and BRAF mutation play different roles in circumscribed and infiltrative papillary thyroid carcinoma. Virchows Arch 460:587–600

    Article  PubMed  CAS  Google Scholar 

  24. Capper D, Preusser M, Habel A, Sahm F, Ackermann U, Schindler G, Pusch S, Mechtersheimer G, Zentgraf H, von Deimling A (2011) Assessment of BRAF V600E mutation status by immunohistochemistry with a mutation-specific monoclonal antibody. Acta Neuropathol 122:11–19

    Article  PubMed  CAS  Google Scholar 

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Disclosure

A part of this study was presented as an abstract (poster) at the annual meeting of the United States and Canadian Academy of Pathology, Vancouver, 2012.

Conflict of interest

The authors have no conflict of interest to report.

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Authors and Affiliations

  1. Department of Pathology, Yale School of Medicine, 310 Cedar Street, LH-108, New Haven, CT, 06520, USA

    Renu K. Virk, Constantine G. A. Theoharis, David Chhieng & Manju L. Prasad

  2. Department of Neurology, Hartford Hospital, 80 Seymour St, Hartford, CT, 06102, USA

    Avinash Prasad

Authors
  1. Renu K. Virk
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  2. Constantine G. A. Theoharis
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  3. Avinash Prasad
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  4. David Chhieng
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  5. Manju L. Prasad
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Correspondence to Manju L. Prasad.

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Virk, R.K., Theoharis, C.G.A., Prasad, A. et al. Morphology predicts BRAF V600E mutation in papillary thyroid carcinoma: an interobserver reproducibility study. Virchows Arch 464, 435–442 (2014). https://doi.org/10.1007/s00428-014-1552-3

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  • DOI: https://doi.org/10.1007/s00428-014-1552-3

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