Skip to main content
SpringerLink
Log in

Follicular Histotypes of Oncocytic Thyroid Carcinomas Do Not Carry Mutations of the BRAF Hot-spot

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

Abstract

Background

The BRAF V600E mutation is the most prevalent genetic aberration in papillary thyroid carcinomas (PTCs), and it is found exclusively in RET/PTC-negative tumors. In oncocytic (Hürthle cell, oxyphilic) thyroid tumors, the presence of RET/PTC rearrangements is associated with either the conventional papillary histotype or the “solid” Hürthle cell tumors, whereas all predominantly follicular oncocytic carcinomas do not harbor RET/PTC chimeras. Although 12% of tumors of the follicular variant of PTC carry BRAF mutations, none of the few oncocytic follicular thyroid adenomas (oncoAd) or carcinomas (oncoFTC) published worldwide tested positive. An aspired molecular-based classification of oncocytic thyroid tumors is in need of additional evidence on BRAF mutations in the follicular histotype.

Methods

A series of 44 oncocytic thyroid tumors with well-documented clinicopathological data was subjected to BRAF mutation analysis (complete exon 15) by automated sequencing.

Results

The series of oncocytic thyroid tumors consisted of 21 adenomas (oncoAds: 17 females, 4 males; mean age, 54.5 years; range, 27–80 years), 20 follicular carcinomas (oncoFTCs: 14 females, 6 males; mean age, 61.4 years; range, 39–80 years), and 3 “classic” papillary carcinomas (oncoPTCs: 3 females; mean age, 58.1 years; range, 46–70 years; 3x T2 tumors). The follicular variants of oncocytic cancers are divided into 11x T2, 5x T3, and 4x T4 tumor stages (International Union Against Cancer [UICC] TNM 5th edition). None of the 44 neoplasms of the presented series demonstrated genetic alterations in the BRAF hot-spot region (exon 15, codons 599–601). Congruently, 0/10 oncoAd and 0/20 oncoFTC described in the literature so far carried BRAF V600E mutations.

Conclusions

Our results add to the evidence that, in contrast to follicular variants of oncoPTCs, predominantly follicular oncocytic thyroid tumors harbor neither RET/PTC rearrangements nor BRAF mutations. Furthermore, the findings support the concept that oncocytic neoplasms of the thyroid gland are oncocytic counterparts of the respective histotype (adenoma, FTC, PTC, or poorly differentiated thyroid carcinoma) rather than a separate tumor entity. Molecular characterization of oncocytic thyroid malignancies for RET/PTC or BRAF genetic alterations may help with (preoperative) classification and prognostic evaluation of these tumors.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Sobrinho-Simoes M, Maximo V, Castro IV et al. (2005) Hürthle (oncocytic) cell tumors of thyroid: etiopathogenesis, diagnosis and clinical significance. Int J Surg Pathol 13:29–35

    Article  PubMed  Google Scholar 

  2. Cheung CC, Ezzat S, Ramyar L et al. (2000) Molecular basis of Hürthle cell papillary thyroid carcinoma. J Clin Endocrinol Metab 85:878–882

    Article  PubMed  CAS  Google Scholar 

  3. Chiappetta G, Toti P, Cetta F et al. (2002) The RET/PTC oncogene is frequently activated in oncocytic thyroid tumors (Hürthle cell adenomas and carcinomas), but not in oncocytic hyperplastic lesions. J Clin Endocrinol Metab 87:364–369

    Article  PubMed  CAS  Google Scholar 

  4. Musholt PB, Imkamp F, von Wasielewski R et al. (2003) RET rearrangements in archival oxyphilic thyroid tumors: new insights in tumorigenesis and classification of Hürthle cell carcinomas? Surgery 134:881–889; discussion 889

    Article  PubMed  Google Scholar 

  5. Schmid KW, Farid NR (2006) How to define follicular thyroid carcinoma? Virchows Arch 448:385–393

    Article  PubMed  Google Scholar 

  6. WHO (2004) Histological classification of thyroid and parathyroid tumours. In DeLellis RA, Lloyd RV, Heitz PU, Eng C (eds.), World Health Organization Classification of Tumours. Pathology & Genetics. Tumours of Endocrine Organs, Lyon, France, IARC Press, pp. 49–123

  7. Mitsutake N, Miyagishi M, Mitsutake S et al. (2006) BRAF mediates RET/PTC-induced mitogen-activated protein kinase activation in thyroid cells: functional support for requirement of the RET/PTC-RAS-BRAF pathway in papillary thyroid carcinogenesis. Endocrinology 147:1014–1019

    Article  PubMed  CAS  Google Scholar 

  8. Kimura ET, Nikiforova MN, Zhu Z et al. (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 63:1454–1457

    PubMed  CAS  Google Scholar 

  9. Xu X, Quiros RM, Gattuso P et al. (2003) High prevalence of BRAF gene mutation in papillary thyroid carcinomas and thyroid tumor cell lines. Cancer Res 63:4561–4567

    PubMed  CAS  Google Scholar 

  10. Xing M (2005) BRAF mutation in thyroid cancer. Endocr Relat Cancer 12:245–262

    Article  PubMed  CAS  Google Scholar 

  11. Fugazzola L, Puxeddu 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  PubMed  CAS  Google Scholar 

  12. Lee JH, Lee ES, Kim YS (2007) Clinicopathologic significance of BRAF V600E mutation in papillary carcinomas of the thyroid: a meta-analysis. Cancer 110:38–46

    Article  PubMed  Google Scholar 

  13. 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  PubMed  CAS  Google Scholar 

  14. Sheu SY, Schwertheim S, Worm K et al. (2007) Diffuse sclerosing variant of papillary thyroid carcinoma: lack of BRAF mutation but occurrence of RET/PTC rearrangements. Mod Pathol 20:779–787

    Article  PubMed  CAS  Google Scholar 

  15. Musholt TJ, Musholt PB, Khaladj N et al. (2000) Prognostic significance of RET and NTRK1 rearrangements in sporadic papillary thyroid carcinoma. Surgery 128:984–993

    Article  PubMed  CAS  Google Scholar 

  16. Tallini G, Asa SL (2001) RET oncogene activation in papillary thyroid carcinoma. Adv Anat Pathol 8:345–354

    Article  PubMed  CAS  Google Scholar 

  17. Santoro M, Melillo RM, Carlomagno F et al. (2004) Minireview: RET: normal and abnormal functions. Endocrinology 145:5448–5451

    Article  PubMed  CAS  Google Scholar 

  18. Soares P, Trovisco V, Rocha AS et al. (2003) BRAF mutations and RET/PTC rearrangements are alternative events in the etiopathogenesis of PTC. Oncogene 22:4578–4580

    Article  PubMed  CAS  Google Scholar 

  19. Adeniran 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  PubMed  Google Scholar 

  20. 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  PubMed  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  22. Trovisco V, Soares P, Preto A et al. (2005) Type and prevalence of BRAF mutations are closely associated with papillary thyroid carcinoma histotype and patients’ age but not with tumour aggressiveness. Virchows Arch 446:589–595

    Article  PubMed  CAS  Google Scholar 

  23. Di Cristofaro J, Silvy M, Lanteaume A et al. (2006) Expression of tpo mRNA in thyroid tumors: quantitative PCR analysis and correlation with alterations of ret, Braf, ras and pax8 genes. Endocr Relat Cancer 13:485–495

    Article  PubMed  CAS  Google Scholar 

  24. Imkamp F, von Wasielewski R, Musholt TJ et al. (2007) Rearrangement analysis in archival thyroid tissues: punching microdissection and artificial RET/PTC 1–12 transcripts. J Surg Res 143(2):350–363

    Google Scholar 

  25. Davies H, Bignell GR, Cox C et al. (2002) Mutations of the BRAF gene in human cancer. Nature 417:949–954

    Article  PubMed  CAS  Google Scholar 

  26. Trovisco V, Soares P, Soares R et al. (2005) A new BRAF gene mutation detected in a case of a solid variant of papillary thyroid carcinoma. Hum Pathol 36:694–697

    Article  PubMed  CAS  Google Scholar 

  27. Carta C, Moretti S, Passeri L et al. (2006) Genotyping of an Italian papillary thyroid carcinoma cohort revealed high prevalence of BRAF mutations, absence of RAS mutations and allowed the detection of a new mutation of BRAF oncoprotein (BRAF(V599lns)). Clin Endocrinol (Oxf) 64:105–109

    Article  CAS  Google Scholar 

  28. Ciampi R, Zhu Z, Nikiforov YE (2005) BRAF copy number gains in thyroid tumors detected by fluorescence in situ hybridization. Endocr Pathol 16:99–105

    Article  PubMed  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  30. Salvatore G, Chiappetta G, Nikiforov YE et al. (2005) Molecular profile of hyalinizing trabecular tumours of the thyroid: high prevalence of RET/PTC rearrangements and absence of B-raf and N-ras point mutations. Eur J Cancer 41:816–821

    Article  PubMed  CAS  Google Scholar 

  31. Kumagai A, Namba H, Akanov Z et al. (2007) Clinical implications of preoperative rapid BRAF analysis for papillary thyroid cancer. Endocr J 54:399–405

    Article  PubMed  CAS  Google Scholar 

  32. Sapio 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 (Oxf) 66:678–683

    Article  CAS  Google Scholar 

  33. Ciampi R, Giordano TJ, Wikenheiser-Brokamp K, Koenig RJ, Nikiforov YE (2007) HOOK3-RET: a novel type of RET/PTC rearrangement in papillary thyroid carcinoma. Endocr Relat Cancer 14(2):445–452

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors thank numerous colleagues in Germany and Austria who contributed follow-up data on the patients. We are grateful to Kathrin Dymek for methodical hints and to Caroline Stang and Anja Voege for expert technical support.

Author information

Authors and Affiliations

  1. Department of Endocrine Surgery, Gutenberg University Medical School, Johannes Gutenberg University, Langenbeckstr. 1, 55101, Mainz, Germany

    Petra B. Musholt, Thomas J. Musholt & Saskia C. Morgenstern

  2. Department of Pathology, University Hospital Essen, Hufelandstr. 55, 45122, Essen, Germany

    Karl Worm, Sien-Yi Sheu & Kurt W. Schmid

Authors
  1. Petra B. Musholt
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Thomas J. Musholt
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Saskia C. Morgenstern
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Karl Worm
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sien-Yi Sheu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kurt W. Schmid
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Petra B. Musholt.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Musholt, P.B., Musholt, T.J., Morgenstern, S.C. et al. Follicular Histotypes of Oncocytic Thyroid Carcinomas Do Not Carry Mutations of the BRAF Hot-spot. World J Surg 32, 722–728 (2008). https://doi.org/10.1007/s00268-007-9431-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00268-007-9431-6

Keywords

Search

Navigation