Virchows Archiv

, Volume 446, Issue 6, pp 589–595 | Cite as

Type and prevalence of BRAF mutations are closely associated with papillary thyroid carcinoma histotype and patients’ age but not with tumour aggressiveness

  • Vítor Trovisco
  • Paula Soares
  • Ana Preto
  • Inês Vieira de Castro
  • Jorge Lima
  • Patrícia Castro
  • Valdemar Máximo
  • Tiago Botelho
  • Severina Moreira
  • Ana Margarida Meireles
  • João Magalhães
  • Alexander Abrosimov
  • José Cameselle-Teijeiro
  • Manuel Sobrinho-Simões
Original Article

Abstract

A high prevalence of the BRAFV600E somatic mutation was recently reported in several series of papillary thyroid carcinomas (PTC). This mutation appears to be particularly prevalent in PTC with a predominantly papillary architecture. Another BRAF mutation (K601E) was detected in a follicular adenoma and in some cases of the follicular variant of PTC. The few studies on record provided controversial data on the relationship between the occurrence of BRAF mutations and clinicopathologic parameters such as gender, age and tumour staging. In an attempt to clarify such controversies we decided to enlarge our previous series to 315 tumours or tumour-like lesions diagnosed in 280 patients, including a thorough analysis of several clinicopathologic features. The BRAFV600E mutation was exclusively detected in PTC with a papillary or mixed follicular/papillary architecture both of the conventional type (46%) and of other histotypes, such as microcarcinoma (43%), Warthin-like PTC (75%) and oncocytic variant of PTC (55%). The BRAFK601E mutation was detected in four of the 54 cases of the follicular variant of PTC (7%). The mean age of patients with conventional PTC harbouring BRAFV600E (46.7 years) was significantly higher (P<0.0001) than that of patients with conventional PTC without BRAFV600E (29.5 years). The BRAF (BRAFV600E) mutated PTC did not exhibit signs of higher aggressiveness (size, vascular invasion, extra-thyroid extension and nodal metastasis) and were in fact less often multicentric than PTC without the mutation.

Keywords

Thyroid Papillary carcinoma Follicular variant of PTC Oncocytic variant BRAF Oncogene 

References

  1. 1.
    Baloch ZW, LiVolsi VA (2002) Etiology and significance of the optically clear nucleus. Endocr Pathol 13:289–299CrossRefPubMedGoogle Scholar
  2. 2.
    Belchetz G, Cheung CC, Freeman J, Rosen IB, Witterick IJ, Asa SL (2002) Hurthle cell tumors: using molecular techniques to define a novel classification system. Arch Otolaryngol Head Neck Surg 128:237–240PubMedGoogle Scholar
  3. 3.
    Brose MS, Volpe P, Feldman M, Kumar M, Rishi I, Gerrero R, Einhorn E, Herlyn M, Minna J, Nicholson A, Roth JA, Albelda SM, Davies H, Cox C, Brignell G, Stephens P, Futreal PA, Wooster R, Stratton MR, Weber BL (2002) BRAF and RAS mutations in human lung cancer and melanoma. Cancer Res 62:6997–7000PubMedGoogle Scholar
  4. 4.
    Castro P, Fonseca E, Magalhaes J, Sobrinho-Simoes M (2002) Follicular, papillary, and “hybrid” carcinomas of the thyroid. Endocr Pathol 13:313–320CrossRefPubMedGoogle Scholar
  5. 5.
    Cheung CC, Ezzat S, Ramyar L, Freeman JL, Asa SL (2000) Molecular basis off hurthle cell papillary thyroid carcinoma. J Clin Endocrinol Metab 85:878–882CrossRefPubMedGoogle Scholar
  6. 6.
    Cohen Y, Xing M, Mambo E, Guo Z, Wu G, Trink B, Beller U, Westra WH, Ladenson PW, Sidransky D (2003) BRAF mutation in papillary thyroid carcinoma. J Natl Cancer Inst 95:625–627PubMedGoogle Scholar
  7. 7.
    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 417:949–954CrossRefPubMedGoogle Scholar
  8. 8.
    Kim KH, Kang DW, Kim SH, Seong IO, Kang DY (2004) Mutations of the BRAF gene in papillary thyroid carcinoma in a Korean population. Yonsei Med J 45:818–821PubMedGoogle Scholar
  9. 9.
    Kimura ET, Nikiforova MN, Zhu Z, Knauf JA, Nikiforov YE, Fagin JA (2003) 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 63:1454–1457PubMedGoogle Scholar
  10. 10.
    Kumar R, Angelini S, Snellman E, Hemminki K (2004) BRAF mutations are common somatic events in melanocytic nevi. J Invest Dermatol 122:342–348CrossRefPubMedGoogle Scholar
  11. 11.
    Lima J, Trovisco V, Soares P, Maximo V, Magalhaes J, Salvatore G, Santoro M, Bogdanova T, Tronko M, Abrosimov A, Jeremiah S, Thomas G, Williams D, Sobrinho-Simoes M (2004) BRAF mutations are not a major event in post-chernobyl childhood thyroid carcinomas. J Clin Endocrinol Metab 89:4267–4271CrossRefPubMedGoogle Scholar
  12. 12.
    LiVolsi V (1990) Surgical pathology of the thyroid. Saunders, PhiladelphiaGoogle Scholar
  13. 13.
    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 88:4393–4397CrossRefPubMedGoogle Scholar
  14. 14.
    Nikiforova MN, Ciampi R, Salvatore G, Santoro M, Gandhi M, Knauf JA, Thomas GA, Jeremiah S, Bogdanova TI, Tronko MD (2004) Low prevalence of BRAF mutations in radiation-induced thyroid tumors in contrast to sporadic papillary carcinomas. Cancer Lett 209:1–6CrossRefPubMedGoogle Scholar
  15. 15.
    Nikiforova MN, Kimura ET, Gandhi M, Biddinger PW, Knauf JA, Basolo F, Zhu Z, Giannini R, Salvatore G, Fusco A, Santoro M, Fagin JA, Nikiforov YE (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 88:5399–5404CrossRefPubMedGoogle Scholar
  16. 16.
    Peyssonnaux C, Eychene A (2001) The Raf/MEK/ERK pathway: new concepts of activation. Biol Cell 93:53–62CrossRefPubMedGoogle Scholar
  17. 17.
    Puxeddu E, Moretti S, Elisei R, Romei C, Pascucci R, Martinelli M, Marino C, Avenia N, Rossi ED, Fadda G, Cavaliere A, Ribacchi R, Falorni A, Pontecorvi A, Pacini F, Pinchera A, Santeusanio F (2004) BRAFV599E mutation is the leading genetic event in adult sporadic papillary thyroid carcinomas. J Clin Endocrinol Metab 89:2414–2420CrossRefPubMedGoogle Scholar
  18. 18.
    Rajagopalan H, Bardelli A, Lengauer C, Kinzler KW, Vogelstein B, Velculescu VE (2002) Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature 418:934CrossRefPubMedGoogle Scholar
  19. 19.
    Rosai J, Carcangiu ML, DeLellis RA (1992) Tumours of the thyroid gland. Armed Forces Institute of Pathology, WashingtonGoogle Scholar
  20. 20.
    Soares P, Fonseca E, Wynford-Thomas D, Sobrinho-Simoes M (1998) Sporadic ret-rearranged papillary carcinoma of the thyroid: a subset of slow growing, less aggressive thyroid neoplasms? J Pathol 185:71–78CrossRefPubMedGoogle Scholar
  21. 21.
    Soares P, Trovisco V, Rocha AS, Feijao T, Rebocho AP, Fonseca E, Vieira de Castro, I, Cameselle-Teijeiro J, Cardoso-Oliveira M, Sobrinho-Simoes M (2004) BRAF mutations typical of papillary thyroid carcinoma are more frequently detected in undifferentiated than in insular and insular-like poorly differentiated carcinomas. Virchows Arch 444:572–576CrossRefPubMedGoogle Scholar
  22. 22.
    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 22:4578–4580CrossRefPubMedGoogle Scholar
  23. 23.
    Tallini G, Santoro M, Helie M, Carlomagno F, Salvatore G, Chiappetta G, Carcangiu ML, Fusco A (1998) RET/PTC oncogene activation defines a subset of papillary thyroid carcinomas lacking evidence of progression to poorly differentiated or undifferentiated tumor phenotypes. Clin Cancer Res 4:287–294PubMedGoogle Scholar
  24. 24.
    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 202:247–251CrossRefPubMedGoogle Scholar
  25. 25.
    Vickery AL Jr, Carcangiu ML, Johannessen JV, Sobrinho-Simoes M (1985) Papillary carcinoma. Semin Diagn Pathol 2:90–100PubMedGoogle Scholar
  26. 26.
    Xu X, Quiros RM, Gattuso P, Ain KB, Prinz RA (2003) High prevalence of BRAF gene mutation in papillary thyroid carcinomas and thyroid tumor cell lines. Cancer Res 63:4561–4567PubMedGoogle Scholar
  27. 27.
    Zhu Z, Gandhi M, Nikiforova MN, Fischer AH, Nikiforov YE (2003) Molecular profile and clinical-pathologic features of the follicular variant of papillary thyroid carcinoma. An unusually high prevalence of ras mutations. Am J Clin Pathol 120:71–77CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Vítor Trovisco
    • 1
  • Paula Soares
    • 1
    • 2
  • Ana Preto
    • 1
  • Inês Vieira de Castro
    • 3
  • Jorge Lima
    • 1
  • Patrícia Castro
    • 1
  • Valdemar Máximo
    • 1
  • Tiago Botelho
    • 1
  • Severina Moreira
    • 1
  • Ana Margarida Meireles
    • 1
  • João Magalhães
    • 4
  • Alexander Abrosimov
    • 5
  • José Cameselle-Teijeiro
    • 6
  • Manuel Sobrinho-Simões
    • 1
    • 2
    • 4
  1. 1.IPATIMUP (Institute of Molecular Pathology and Immunology of the University of Porto)PortoPortugal
  2. 2.Department of PathologyMedical Faculty of the University of PortoPortoPortugal
  3. 3.Department of PathologyMedical Faculty of the University of São PauloSão PauloBrazil
  4. 4.Department of PathologyHospital São JoãoPortoPortugal
  5. 5.Pathology Department, Medical Radiology Research CentreRussian Academy of Medical SciencesObninskRussia
  6. 6.Department of Pathology, Hospital Clínico UniversitarioUniversity of Santiago de CompostelaSantiago de CompostelaSpain

Personalised recommendations