Annals of Surgical Oncology

, Volume 16, Issue 2, pp 240–245 | Cite as

Analysis of Differential BRAFV600E Mutational Status in High Aggressive Papillary Thyroid Microcarcinoma

  • Xiaolong Lee
  • Ming Gao
  • Yifeng Ji
  • Yang Yu
  • Ying Feng
  • Yigong Li
  • Yan Zhang
  • Wenyuan Cheng
  • Wenchuan Zhao
Head and Neck Oncology

Abstract

Papillary thyroid cancers often occur as microcarcinoma. Some papillary thyroid microcarcinoma (PTMC) have been considered to be high aggressive according to advanced disease stages, extrathyroidal extension, and severe cervical lymph node metastasis. Although several factors are thought to predict the occurrence of aggressiveness from PTMCs, the origin of aggressiveness has been rarely studied. To answer this question, the correlation between BRAFV600E mutation and high aggressive PTMCs was investigated. The clinicopathological characteristic of totally 64 cases of PTMCs was investigated and the BRAFV600E mutational status of them was identified. BRAFV600E mutation was exclusively detected in PTMCs (37.5%). The data provided no correlation between the occurrence of BRAFV600E mutations and clinicopathological parameters, such as sex, age, and tumor-like lesions combination. The prevalence of BRAFV600E mutation of PTMCs with high aggressiveness (advanced disease stages, extrathyroidal extension, and nodal metastasis) was significantly higher (< 0.05) than that of PTMCs without aggressive behavior. The BRAFV600E mutated PTMCs exhibited signs of higher aggressiveness than PTMCs without the mutation. BRAFV600E mutation may be a marker of high aggressiveness in PTMCs.

Notes

Acknowledgements

The authors thank Drs. Baocun Sun for providing material, and Lili Yang and Feng Fei for grant support to Xiaolong Lee, Ming Gao, Yifeng Ji, Yang Yu, Ying Feng, Yigong Li, Yan Zhang, Wenyuan Cheng, and Wenchuan Zhao.

References

  1. 1.
    Namba H, Nakashima M, Hayashi T, Hayashida N, Maeda S, Rogounovitch TI, et al. Clinical implication of hot spot BRAF mutation, V599E, in papillary thyroid cancers. J Clin Endocrinol Metab. 2003;88:4393–7.PubMedCrossRefGoogle Scholar
  2. 2.
    Nikiforova MN, Kimura ET, Gandhi M, Biddinger PW, Knauf JA, Basolo F, et al. BRAF mutations in thyroid tumors are restricted to papillary carcinomas and anaplastic or poorly differentiated carcinomas arising from papillary carcinomas. J Clin Endocrinol Metab. 2003;88:5399–404.PubMedCrossRefGoogle Scholar
  3. 3.
    Xu X, Quiros RM, Gattuso P, Ain KB, Prinz RA. High prevalence of BRAF gene mutation in papillary thyroid carcinomas and thyroid tumor cell lines. Cancer Res. 2003;63:4561–7.PubMedGoogle Scholar
  4. 4.
    Kim KH, Kang DW, Kim SH, Seong IO, Kang DY. Mutations of the BRAF gene in papillary thyroid carcinoma in a Korean population. Yonsei Med J. 2004;45:818–21.PubMedGoogle Scholar
  5. 5.
    Puxeddu E, Moretti S, Elisei R, Romei C, Pascucci R, Martinelli M, et al. BRAF (V599E) mutation is the leading genetic event in adult sporadic papillary thyroid carcinomas. J Clin Endocrinol Metab. 2004;89:2414–20.PubMedCrossRefGoogle Scholar
  6. 6.
    Leenhardt L, Grosclaude P, Chérié-Challine L for the Members of the Thyroid Cancer Committee. Increased incidence of thyroid carcinoma in France: a true epidemic or thyroid nodule management effects? Report from the French thyroid cancer committee. Thyroid. 2004;14:1056–60.Google Scholar
  7. 7.
    Chow SM, Law SCK, Chan JKC, Au SK, Yau S, Lau WH. Papillary microcarcinoma of the thyroid-prognostic significance of lymph node metastasis and multifocality. Cancer. 2003;98:31–40.PubMedCrossRefGoogle Scholar
  8. 8.
    Yamashita H, Noguchi S, Murakami N, Toda M, Uchino S, Watanabe S, et al. Extracapsular invasion of lymph node metastasis. A good indicator of disease recurrence and poor prognosis in patients with thyroid microcarcinoma. Cancer. 1999;86:842–84.PubMedCrossRefGoogle Scholar
  9. 9.
    Roti E, Rossi R, Trasforini G, Bertelli F, Ambrosio MR, Busutti L, et al. Clinical and histological characteristics of papillary thyroid microcarcinoma: results of a retrospective study in 243 patients. J Clin Endocrinol Metab. 2006;91:2171–8.PubMedCrossRefGoogle Scholar
  10. 10.
    Wada N, Duh QY, Sugino K, Iwasaki H, Kameyama K, Mimura T, et al. Lymph node metastasis from 259 papillary thyroid microcarcinomas: frequency, pattern of occurrence, and optimal strategy for neck dissection. Ann Surg. 2003;237:399–407.PubMedCrossRefGoogle Scholar
  11. 11.
    Pelizzo MR, Boschin IM, Toniato A, Pagetta C, Piotto A, Bernante P, et al. Natural history, diagnosis, treatment and outcome of papillary thyroid microcarcinoma (PTMC): a mono-institutional 12-year experience. Nucl Med Commun. 2004;25:547–52.PubMedCrossRefGoogle Scholar
  12. 12.
    Pellegriti G, Scollo C, Lumera G, Regalbuto C, Vigneri R, Belfiore A 2004 Clinical behavior and outcome of papillary thyroid cancers smaller than 1.5 cm in diameter: study of 299 cases. J Clin Endocrinol Metab. 89:3713–20.PubMedCrossRefGoogle Scholar
  13. 13.
    Fukushima T, Suzuki S, Mashiko M, Ohtake T, Endo Y, Takebayashi Y, et al. BRAF mutations in papillary carcinomas of the thyroid. Oncogene. 2003;22:6455–7.PubMedCrossRefGoogle Scholar
  14. 14.
    Cohen Y, Xing M, Mambo E, Guo Z, Wu G, Trink B, et al. BRAF mutation in papillary thyroid carcinoma. J Natl Cancer Inst. 2003;95:625–7.PubMedCrossRefGoogle Scholar
  15. 15.
    Kimura ET, Nikiforova MN, Zhu Z, Knauf JA, Nikiforov YE, Fagin JA. High prevalence of BRAF mutations in thyroid cancer: genetic evidence for constitutive activation of the RET/PTC–RAS–BRAF signaling pathway in papillary thyroid carcinoma. Cancer Res. 2003;63:1454–7.PubMedGoogle Scholar
  16. 16.
    Salvatore G, Giannini R, Faviana P, Caleo A, Migliaccio I, Fagin JA, et al. Analysis of BRAF point mutation and RET/PTC rearrangement refines the fine-needle aspiration diagnosis of papillary thyroid carcinoma. J Clin Endocrinol Metab. 2004;89:5175–80.PubMedCrossRefGoogle Scholar
  17. 17.
    Soares P, Trovisco V, Rocha AS, Lima J, Castro P, Preto A, et al. BRAF mutations and RET/PTC rearrangements are alternative events in the etiopathogenesis of PTC. Oncogene. 2003;22:4578–80.PubMedCrossRefGoogle Scholar
  18. 18.
    Mitsutake N, Knauf JA, Mitsutake S, Mesa C Jr, Zhang L, Fagin JA. Conditional BRAFV600E expression induces DNA synthesis, apoptosis, dedifferentiation, and chromosomal instability in thyroid PCCL3 cells. Cancer Res. 2005;65:2465–73.PubMedCrossRefGoogle Scholar
  19. 19.
    Fugazzola L, Mannavola D, Cirello V, Vannucchi G, Muzza M, Vicentini L, et al. BRAF mutations in an Italian cohort of thyroid cancers. Clin Endocrinol. 2004;61:239–43.CrossRefGoogle Scholar
  20. 20.
    Sedliarou I, Saenko V, Lantsov D, Rogounovitch T, Namba H, Abrosimov A, et al. The BRAFT1796A transversion is a prevalent mutational event in human thyroid microcarcinoma. Int J Oncol. 2004;25:1729–35.PubMedGoogle Scholar
  21. 21.
    Vasko V, Hu S, Wu G, Xing JC, Larin A, Savchenko V, et al. High prevalence and possible de novo formation of BRAF mutation in metastasized papillary thyroid cancer in lymph nodes. J Clin Endocrinol Metab. 2005;90:5265–9.PubMedCrossRefGoogle Scholar
  22. 22.
    Reinhoff WF Jr. Lymphatic vessels of thyroid gland in dog and man. Arch Surg. 1931;23:783–804.Google Scholar
  23. 23.
    Park SY, Park YJ, Lee YJ, Lee HS, Choi SH, Choe G, et al. Analysis of differential BRAFV600E mutational status in multifocal papillary thyroid carcinoma. Cancer. 2006;107:1831–8.PubMedCrossRefGoogle Scholar
  24. 24.
    Xing M. BRAF mutation in thyroid cancer. Endocr Relat Cancer. 2005;12:245–62.PubMedCrossRefGoogle Scholar
  25. 25.
    Hay ID, Grant CS, van Heerden JA, Goellner JR, Ebersold JR, Bergstralh EJ. Papillary thyroid microcarcinoma: a study of 535 cases observed in a 50-year period. Surgery. 1992;112:1139–47.PubMedGoogle Scholar
  26. 26.
    Roh JL, Kim JM, Park CI. Central cervical nodal metastasis from papillary thyroid microcarcinoma: pattern and factors predictive of nodal metastasis. Ann Surg Oncol. 2008;15:2482–6.PubMedCrossRefGoogle Scholar
  27. 27.
    Lin JD, Kuo SF, Chao TC, Hsueh C. Incidental and nonincidental papillary thyroid microcarcinoma. Ann Surg Oncol. 2008;15:2287–92.PubMedCrossRefGoogle Scholar
  28. 28.
    Leboulleux S, Rubino C, Baudin E, Caillou B, Hartl DM, Bidart JM, et al. Prognostic factors for persistent or recurrent disease of papillary thyroid carcinoma with neck lymph node metastases and/or tumor extension beyond the thyroid capsule at initial diagnosis. J Clin Endocrinol Metab. 2005;90:5723–9.PubMedCrossRefGoogle Scholar
  29. 29.
    Mazzaferri EL, Young RL. Papillary thyroid carcinoma: a 10 year follow-up. Report of the impact of therapy in 576 patients. Am J Med. 1981;70:511–8.PubMedCrossRefGoogle Scholar
  30. 30.
    Jukkola A, Bloigu R, Ebeling T, Salmela P, Blanco G. Prognostic factors in differentiated thyroid carcinomas and their implications for current staging classifications. Endocr Relat Cancer. 2004;11:571–9.PubMedCrossRefGoogle Scholar
  31. 31.
    Trovisco V, Vieira de Castro I, Soares P, Máximo V, Silva P, Magalhães J, et al. BRAF mutations are associated with histologic types of papillary thyroid carcinoma. J Pathol. 2004;202:247–51.PubMedCrossRefGoogle Scholar
  32. 32.
    Trovisco V, Soares P, Preto A, Vieira de Castro I, Lima J, Castro P, et al. 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;446:589–95.PubMedCrossRefGoogle Scholar
  33. 33.
    Knauf JA, Ma X, Smith EP, et al. Targeted expression of BRAFV600E in thyroid cells of transgenic mice results in papillary thyroid cancers that undergo dedifferentiation. Cancer Res. 2005;65:4238–45.PubMedCrossRefGoogle Scholar

Copyright information

© Society of Surgical Oncology 2008

Authors and Affiliations

  • Xiaolong Lee
    • 1
  • Ming Gao
    • 1
  • Yifeng Ji
    • 1
  • Yang Yu
    • 1
  • Ying Feng
    • 1
  • Yigong Li
    • 1
  • Yan Zhang
    • 1
  • Wenyuan Cheng
    • 1
  • Wenchuan Zhao
    • 1
  1. 1.Department of Thyroid & NeckTianjin Medical University Cancer HospitalTianjinChina

Personalised recommendations