Skip to main content
Log in

BRAFV600E Mutation Analysis in Papillary Thyroid Carcinoma: Is it Useful for all Patients?

  • Published:
World Journal of Surgery Aims and scope Submit manuscript

Abstract

Background

The BRAFV600E mutation has been adopted as a prognostic factor in papillary thyroid carcinoma (PTC). However, it remains unclear whether routine BRAF mutation analysis is useful in establishing a prognosis for PTC patients. In the present study we investigated BRAF mutation analysis in a large number of PTC patients with long-term follow-up.

Patients and methods

We enrolled 766 patients from our hospital who underwent initial surgery for PTC without distant metastasis at diagnosis between 1996 and 2001, and whose BRAF mutation of primary lesions could be analyzed. The average age and follow-up period were 51 years and 130 months, respectively.

Results

To date, 77 (10 %) and 37 (5 %) patients have developed lymph node and distant recurrence, respectively, and 10 (1 %) have died of PTC. The BRAF mutation was positive in 281 patients (37 %), and it had no prognostic impact on lymph node recurrence-free (LNRFS) (p = 0.700), distant recurrence-free (DRFS) (p = 0.696), and cause-specific (CSS) (p = 0.125) survival in our entire series. However, CSS of BRAF mutation-positive high-risk patients based on AMES (p = 0.030), MACIS (score >6) (p = 0.017), the UICC stage (IVa) (p = 0.021), CIH classification (Sugitani et al. Surgery 135:139–148, 2004) (p = 0.015), and our own classification system (Ito et al. World J Surg 34:2570–2580, 2010) (p = 0.010) were significantly poorer than CSS of mutation-negative high-risk patients. The BFAF mutation did not affect CSS of non-high-risk patients, although the incidence of the BRAF mutation did not significantly differ between high-risk and non-high-risk groups based on these classification systems. The BRAF mutation was not related to LNRFS and DRFS in the subsets of high-risk and non-high-risk patients.

Conclusions

BRAF mutation analysis is useful in estimating the CSS of high-risk PTC patients based on the representative classification systems. It was not related to the prognosis in non-high-risk patients, at least those living in Japan.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Ito Y, Tomoda C, Uruno T et al (2006) Prognostic significance of extrathyroid extension of papillary thyroid carcinoma: massive but not minimal extension affects the relapse-free survival. World J Surg 30:780–786. doi:10.1007/s00268-005-0270-z

    Article  PubMed  Google Scholar 

  2. Ito Y, Tomoda C, Uruno T et al (2005) Ultrasonographically and anatomopathologically detectable node metastases in the lateral compartment as indicators of worse relapse-free survival in patients with papillary thyroid carcinoma. World J Surg 29:917–920. doi:10.1007/s00268-005-7789-x

    Article  PubMed  Google Scholar 

  3. Ito Y, Kudo T, Kobayashi K et al (2012) Prognostic factors for recurrence of papillary thyroid carcinoma in the lymph nodes, lung, and bone: analysis of 5,768 patients with 10-year follow-up. World J Surg 36:1274–1278. doi:10.1007/s00268-012-1423-5

    Article  PubMed  Google Scholar 

  4. Marais R, Marshall CJ (1996) Control of the ERK MAP kinase cascade by Ras and Raf. In: Parker PJ, Pawson T (eds) Cell signaling. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, pp 101–125

    Google Scholar 

  5. Mercer KE, Pritchard CA (2003) Raf proteins and cancer: B-Raf is identified as a mutational target. Biochim Biophys Acta 1653:25–40

    CAS  PubMed  Google Scholar 

  6. Namba H, Nakashima M, Hayashi T et al (2003) Clinical implication of hot spot BRAF mutation, V599E, in papillary thyroid cancers. J Clin Endocrinol Metab 88:4393–4397

    Article  CAS  PubMed  Google Scholar 

  7. Kim TY, Kim WB, Rhee YS et al (2006) The BRAF mutation is useful for prediction of clinical recurrence in low-risk patients with conventional papillary thyroid carcinoma. Clin Endocrinol 65:364–368

    Article  CAS  Google Scholar 

  8. Ademiran AJ, Zhu Z, Gandhi M et al (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  Google Scholar 

  9. Fugazzola L, Peuxeddu E, Avenia N et al (2006) Correlation between B-RAFV600E mutation and clinico-pathologic parameters in papillary thyroid carcinoma: data from a multicentric Italian study and review of the literature. Endocr Relat Cancer 13:455–464

    Article  CAS  PubMed  Google Scholar 

  10. Kebebew E, Weng J, Bauer J et al (2007) The prevalence and prognostic value of BRAF mutation in thyroid cancer. Ann Surg 246:466–471

    Article  PubMed  Google Scholar 

  11. Lupi C, Glannini R, Ugolini C et al (2007) Association of BRAF V600E mutation with poor clinicopathologic outcomes in 500 consecutive cases of papillary thyroid carcinoma. J Clin Endocrinol Metab 92:4085–4090

    Article  CAS  PubMed  Google Scholar 

  12. Nikiforova MN, Kimura ET, Gandhi M et al (2003) BRAF mutations in thyroid tumors are restricted to papillary carcinomas and anaplastic or poorly differentiated carcinomas arising from papillary carcinomas. J Clin Endocrinol Metab 88:5399–5404

    Article  CAS  PubMed  Google Scholar 

  13. Riesco-Eizaguirre G, Gutierrez-Martinez P, Garcia-Cabezas MA et al (2006) The oncogene BRAFV600E 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 13:257–269

    Article  CAS  PubMed  Google Scholar 

  14. Xing M, Westra WH, Tufano RP et al (2005) BRAF mutation predicts poorer clinical prognosis for papillary thyroid cancer. J Clin Endocrinol Metab 90:6373–6379

    Article  CAS  PubMed  Google Scholar 

  15. Frasca F, Nucera C, Pelligreti G et al (2008) BRAF(V600E) mutation and the biology of papillary thyroid cancer. Endocr Relat Cancer 15:191–205

    Article  CAS  PubMed  Google Scholar 

  16. Ellisei R, Ugolini C, Viola D et al (2008) BRAF(V600E) mutation and outcome of patients with papillary thyroid carcinoma: 15-year median follow-up study. J Clin Endocrinol Metab 93:3943–3949

    Article  Google Scholar 

  17. Kwak JY, Ekim EK, Chung WY et al (2009) Association of BTAFV600E mutation with poor clinical prognostic factors and US features in Korean patients with papillary thyroid microcarcinoma. Radiology 253:854–860

    Article  PubMed  Google Scholar 

  18. O’Neill CJ, Bullock M, Chou A et al (2010) BRAF(V600E) mutation is associated with an increased risk of nodal recurrence requiring reoperative surgery in patients with papillary thyroid cancer. Surgery 148:1139–1145

    Article  PubMed  Google Scholar 

  19. Kim TH, Park YJ, Lim JA et al (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  CAS  PubMed  Google Scholar 

  20. Tufano RP, Telxeira FB, Bishop J et al (2012) BRAF mutation in papillary tyroid cancer and its value in tailoring initial treatment: a systematic review and meta-analysis. Medicine 91:274–286

    Article  CAS  PubMed  Google Scholar 

  21. Lee CLK, Schneider EB, Zeiger MA (2012) BRAFV600E mutation and its association with clinicopathological features of papillary thyroid cancer: a meta-analysis. J Clin Endocrinol Metab 97:4559–4570

    Article  PubMed  Google Scholar 

  22. Ellisei R, Viola D, Torregrossa L et al (2012) The BRAFV600E mutation is an independent, poor prognostic factor for the outcome of patients with low-risk intrathyroid papillary thyroid carcinoma: single-institution results form a large cohort study. J Clin Endocrinol Metab 97:4390–4398

    Article  Google Scholar 

  23. Guerra A, Fugazzola L, Marotta V et al (2012) A high percentage of BRAFV600E alleles in papillary thyroid carcinoma predicts a poorer outcome. J Clin Endocrinol Metab 97:2333–2340

    Article  CAS  PubMed  Google Scholar 

  24. Ricarte-Filho J, Ganly I, Rivera M et al (2012) Papillary thyroid carcinomas with cervical lymph node metastases can be stratified into clinically relevant prognostic categories using oncogenic BRAF, the number of nodal metastases, and extra-nodal extension. Thyroid 22:575–584

    Article  CAS  PubMed  Google Scholar 

  25. Kim SJ, Lee KE, Myong JP et al (2012) BRAFV600E mutation is associated with tumor aggressiveness in papillary thyroid cancer. World J Surg 36:310–317. doi:10.1007/s00268-011-1383-1

    Article  PubMed  Google Scholar 

  26. Prescott JD, Sadow PM, Hodin RA et al (2012) BRAFV600E status adds incremental value to current risk classification systems in predicting papillary thyroid carcinoma recurrence. Surgery 152:984–990

    Article  PubMed Central  PubMed  Google Scholar 

  27. Abrosimov A, Saenko V, Rogounovitch T et al (2007) Different structural components of conventional papillary thyroid carcinoma display mostly identical BRAF status. Int J Cancer 120:196–200

    Article  CAS  PubMed  Google Scholar 

  28. Fugazzola L, Mannavola D, Cirello V et al (2004) BRAF mutations in an Italian cohort of thyroid cancers. Clin Endocrinol 61:239–243

    Article  CAS  Google Scholar 

  29. Sapino MR, Posca D, Raggioli A et al (2007) Detection of RET/PTC, TRK, and BRAF mutations in preoperative diagnosis of thyroid nodules with indeterminate cytological findings. Clin Endocrinol 66:678–683

    Article  Google Scholar 

  30. Brzezianska E, Pastuszak-Lewandoska D, Wojciechowska K et al (2007) Investigation of V600E BRAF mutation in papillary thyroid carcinoma in the Polish population. Neuro Endocrinol Lett 28:351–359

    CAS  PubMed  Google Scholar 

  31. Kim TY, Kim WB, Song JY et al (2005) The BRAFV600E mutation is not associated with poor prognostic factors in Korean patients with conventional papillary thyroid microcarcinoma. Clin Endocrinoil 63:588–593

    Article  CAS  Google Scholar 

  32. Liu RT, Chen YJ, Chou FF et al (2005) No correlation between BRAFV600E mutation and clinicopathological features of papillary thyroid carcinomas in Taiwan. Clin Endocrinol 63:461–466

    Article  Google Scholar 

  33. Stanojevic B, Dzodic R, Saenko V et al (2011) Mutational and clinico-pathological analysis of papillary thyroid carcinoma in Serbia. Endocr J 58:381–393

    Article  CAS  PubMed  Google Scholar 

  34. Sancisi V, Nicoli D, Ragazzi M et al (2012) BRAFV600E mutation does not mean distant metastasis in thyroid papillary carcnomas. J Clin Endocrinol Metab 97:1745–1749

    Article  Google Scholar 

  35. Kurt B, Yalcun S, Alagoz E et al (2012) The relationship of the BRAF(V600E) mutation and the established prognostic factors in papillary thyroid carcinomas. Endocr Pathol 23:135–140

    Article  CAS  PubMed  Google Scholar 

  36. Ulisse S, Baldini E, Sorrenti S et al (2012) In papillary thyroid carcinoma BRAFV600E is associated with increased expression of the urokinase plasminogen activator and its cognate receptor, but not with disease-free interval. Clin Endocrinol 77:780–786

    Article  CAS  Google Scholar 

  37. Ahn D, Park JS, Sohn JH et al (2012) BRAFV600E mutation does not serve as a prognostic factor in Korean patients with papillary thyroid carcinoma. Auris Nesus Larynx 39:198–203

    Article  Google Scholar 

  38. Nam JK, Jung CK, Song BJ et al (2012) Is the BRAF(V600E) mutation useful as a predictor of preoperative risk in papillary thyroid cancer? Am J Surg 203:436–441

    Article  CAS  PubMed  Google Scholar 

  39. Ito Y, Yoshida H, Maruo R et al (2008) BRAF mutation in papillary thyroid carcinoma in a Japanese population: its lack of correlation with high-risk clinicopathological features and disease-free survival of patients. Endocr J 56:89–97

    Article  PubMed  Google Scholar 

  40. Cady B, Rosai R (1988) An expanded view of risk group definition in differentiated thyroid carcinoma. Surgery 104:947–953

    CAS  PubMed  Google Scholar 

  41. Hay ID, Bergstrahl EJ, Goellner JR et al (1993) Predicting outcome in papillary thyroid carcinoma: development of a reliable prognostic scoring system in a cohort of 1779 patients surgically treated at one institution during 1940 through 1989. Surgery 114:1050–1058

    CAS  PubMed  Google Scholar 

  42. Sobin LH, Wittekind CH (eds) (2011) UICC: TNM classification of malignant tumors, 7th edn. Wiley, New York

    Google Scholar 

  43. Sugitani I, Kasai N, Fujimoto Y et al (2004) A novel classification system for patients with PTC: addition of the new variable of large (3 cm or greater) nodal metastases and reclassification during the follow-up period. Surgery 135:139–148

    Article  PubMed  Google Scholar 

  44. Ito Y, Ichihara K, Masuoka H et al (2010) Establishment of an intraoperative staging system (iStage) by improving UICC TNM classification system for papillary thyroid carcinoma. World J Surg 34:2570–2580. doi:10.1007/s00268-010-0710-2

    Article  PubMed  Google Scholar 

  45. Durante C, Puxeddu E, Feretti E et al (2007) BRAF mutations in papillary thyroid carcinomas inhibit genes involved in iodine metabolism. J Clin Endocrinol Metab 92:2840–2943

    Article  CAS  PubMed  Google Scholar 

  46. Barollo S, Pennelli G, Vianello F et al (2010) BRAF in primary and recurrent papillary thyroid cancers: the relationship with 131I and 2-[18F] fluoro-2-deoxy-d-glucose uptake ability. Eur J Endocrinol 163:659–663

    Article  CAS  PubMed  Google Scholar 

  47. Gao WL, Wie LL, Chao YG et al (2012) Prognostic prediction of BRAF(V600E) and its relationship with sodium iodide symporter in classic variant of papillary thyroid carcinomas. Clin Lab 58:919–926

    CAS  PubMed  Google Scholar 

  48. Guerra A, Sapio MR, Marotta V et al (2012) The primary occurrence of BRAFV600E is a rare clonal event in papillary thyroid carcinoma. J Clin Endocrinol Metab 97:517–524

    Article  CAS  PubMed  Google Scholar 

  49. Brose MS, Nutting C, Jarzab B, et al (2013) Sorafenib in locally advanced or metastatic patients with radioactive iodine-refractory differentiated thyroid cancer. The phase III DECISION trial. The 49th annual meeting of the American Society of Clinical Oncology (ASCO) Plenary session Abstract #4

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Yasuhiro Ito.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ito, Y., Yoshida, H., Kihara, M. et al. BRAFV600E Mutation Analysis in Papillary Thyroid Carcinoma: Is it Useful for all Patients?. World J Surg 38, 679–687 (2014). https://doi.org/10.1007/s00268-013-2223-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00268-013-2223-2

Keywords

Navigation