BRAFV600E Mutation, RET/PTC1 and PAX8-PPAR Gamma Rearrangements in Follicular Epithelium Derived Thyroid Lesions - Institutional Experience and Literature Review

Abstract

Background: Thyroid cancers are the most frequently occurring endocrine malignancy worldwide. In Turkey, thyroid cancers are ranked 2nd on the incidence list in women, with a rate of 16.2%, but they are not included among the top 10 cancer types in men. Aims: To identify the contribution of the BRAFV600E mutation, and the RET/PTC1 and PAX8-PPARγ rearrangements in the diagnosis and differential diagnosis of follicular epithelial-derived thyroid lesions. Study Design: Retrospective clinical and molecular genetic study. Methods: A total of 86 thyroid cases diagnosed between 2001 and 2012 at the Department of Pathology were included in the retrospective study group. Samples best representing the lesion and comprising capsules were chosen in the selection of paraffin blocks pertaining to the cases. The BRAFV600E mutation, and the RET/PTC1 and PAX8-PPARγ rearrangements were investigated in all cases. Results: The BRAFV600E mutation was observed in 12 out of 37 papillary carcinoma cases (32.4%), in 1 out of 15 follicular carcinoma cases (6.6%), and in 1 out of 7 undifferentiated carcinoma cases (14.3%). No mutation was detected in benign lesions. The RET/PTC1 rearrangement was detected in 2 out of 7 undifferentiated carcinoma cases (28.6%), and in 1 out of 15 follicular carcinoma cases (6.6%). No gene rearrangement was detected in benign lesions. The PAX8-PPARγ rearrangement was detected in 5 out of 15 follicular thyroid carcinoma cases (33.3%) and in 1 out of 15 follicular adenoma cases (6.6%). Conclusion: The BRAFV600E mutation and RET/PTC1 rearrangement were effective in distinguishing the follicular epithelium-derived benign and malignant lesions of the thyroid in the resection materials. The BRAFV600E mutation was rather specific to papillary carcinoma in the thyroid, and in cases where the BRAFV600E mutation was detected, multi-centricity, lymph node metastasis and capsular invasion findings were observed more frequently compared to cases in which no mutation was observed. The PAX8-PPARγ rearrangement was observed to be more effective in the differentiation of adenomas and carcinomas in follicular neoplasms of the thyroid, whereas the RET/PTC1 analysis contributed to the differential diagnosis of papillary carcinoma histogenesis at a frequency of 29% in undifferentiated thyroid carcinomas.

Keywords

• BRAFV600E, diagnosis, management, PAX8-PPARγ, RET/PTC1, thyroid gland

Kaynakça

1. 1. Public Healthy Institution of Turkey; Cancer Department; Turkish cancer incidence; 2009 http://kanser.gov.tr/daire-faaliyetleri/ kanser-istatistikleri/922-2009-kanser-insidansları.html.
2. 2. 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. [CrossRef]
3. 3. Kocjan G, Feichter G, Hagmar B, Kapila K, I.Kardum-Skelin, Kloboves-Prevodnik V, et al. Fine needle aspiration cytology: a survey of current European practice. Cytopathology 2006; 17:219-26. [CrossRef]
4. 4. Ali SZ. Thyroid cytopathology: Bethesda and beyond. Acta Cytol 2011;55:4-12. [CrossRef]
5. 5. Tubbs RR, Stoler MH. Molecular Endocrine Pathology in Goldblum JR (eds), Cell and tissue based molecular pathology. Elsevier 2009; 296-300.
6. 6. Zhu Z, Gandhi M, Nikiforova MN, Fischer AH, Nikiforov YE. 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 2003;120:71-7. [CrossRef]
7. 7. Nikiforov YE, Ohori NP, Hodak SP, Carty SE, LeBeau SO, Ferris RL, et al. Impact of mutational testing on the diagnosis and management of patients with cytologically indeterminate thyroid nodules: A prospective analysis of 1056 FNA samples. J Clin Endocrinol Metab 2011;96:3390-7. [CrossRef]
8. 8. Nikiforov YE, Steward DL, Robinson-Smith TM, Haugen BR, Klopper JP, Zhu Z, et al. Molecular testing for mutations in improving the fine-needle aspiration diagnosis of thyroid nodules. J Clin Endocrinol Metab 2009;94:2092-8. [CrossRef]

9. 9. Giordano TJ, Kuick R, Thomas DG, Misek DE, Vinco M, Sanders D, et al. Molecular classification of papillary thyroid carcinoma: distinct BRAF, RAS, and RET/PTC mutation-specific gene expression profiles discovered by DNA microarray analysis. Oncogene 2005;24:6646-56. [CrossRef]
10. 10. Pizzolanti G, Russo L, Richiusa P, Bronte V, Nuara RB, Rodolico V, et al. Fine-needle aspiration molecular analysis for the diagnosis of papillary thyroid carcinoma through BRAF V600E mutation and RET/PTC rearrangement. Thyroid 2007;17:1109-15. [CrossRef]
11. 11. Cheung CC, Ezzat S, Ramyar L, Freeman JL, Asa SL. Molecular basis of hurtle cell papillary thyroid. J Clin Endocrinol Metab 2000;85:878-82. [CrossRef]
12. 12. Ciampi R, Nikiforov YE. RET/PTC Rearrangements and BRAF mutations in thyroid tumorigenesis. Endocrinology 2007;148:936-41. [CrossRef]
13. 13. Tang KT, Lee CH. BRAF Mutation in Papillary thyroid carcinoma: pathogenic role and clinical implications. J Chin Med Assoc 2010;73:113-28. [CrossRef]
14. 14. Greco A, Borrello MG, Miranda C, Degl’Innocenti D, Pierotti MA. Molecular pathology of differentiated thyroid cancer. Q J Nucl Med Mol Imaging 2009;53:440-53.
15. 15. Kakudo K, Bai Y, Liu Z, Li Y, Ito Y, Ozaki T. Classification of thyroid follicular cell tumors: with special reference to borderline lesions. Endocr J 2012;59:1-12. [CrossRef]
16. 16. Hunt L J. Molecular testing in solid tumors. Arch Pathol Lab Med 2008;132:164-7.
17. 17. Sheu SY, Schwertheim S, Worm K, Grabellus F, Schmid KW. Diffuse sclerosing variant of papillary thyroid carcinoma: lack of BRAF mutation but occurrence of RET/PTC rearrangements. Mod Pathol 2007;20:779-87. [CrossRef]
18. 18. Fagin JA, Mitsiades N. Molecular pathology of thyroid cancer: diagnostic and clinical implications. Best Pract Res Clin Endocrinol Metab 2008;22:955-69. [CrossRef]
19. 19. Sadow PM, Heinrich MC, Corless CL, Fletcher JA, Nosé V. Absence of BRAF, NRAS, KRAS, HRAS mutations, and RET/ PTC gene rearrangements distinguishes dominant nodules in Hashimoto thyroiditis from papillary thyroid carcinomas. Endocr Pathol 2010;21:73-9. [CrossRef]
20. 20. Yip L, Kebebew E, Milas M, Carty SE, Fahey TJ, Parangi S, et al. Summary statement: utility of molecular marker testing in thyroid cancer. Surgery 2010;148:1313-5. [CrossRef]
21. 21. Trovisco V, Soares P, Preto A, de Castro IV, 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 tumor aggressiveness. Virchows Arch 2005;446:589-95. [CrossRef]
22. 22. Lee HJ, Choi J, Hwang TS, Shong YK, Hong SJ, Gong G. Detection of BRAF mutations in thyroid nodules by allele-specific PCR using a dual priming oligonucleotide system. Am J Clin Pathol 2010;133:802-8. [CrossRef]
23. 23. Xing M. BRAF mutation in thyroid cancer. Endocr Relat Cancer 2005;12:245-62. [CrossRef]
24. 24. Kumagai A, Namba H, Akanov Z, Saenko VA, Meirmanov S, Ohtsuru A, et al. Clinical implications of pre-operative rapid BRAF analysis for papillary thyroid cancer. Endocr J 2007;54:399-405. [CrossRef]
25. 25. Kim SW, Lee JI, Kim JW, Ki CS, Oh YL, Choi YL, et al. BRAFV600E mutation analysis in fine-needle aspiration cytology specimens for evaluation of thyroid nodule: A large series in a BRAFV600E-prevalent population. J Clin Endocrinol Metab 2010;95:3693-700. [CrossRef]
26. 26. Marotta V, Guerra A, Sapio MR, Vitale M. RET/PTC rearrangement in benign and malignant thyroid diseases: a clinical standpoint. Eur J Endocrinol 2011;165:499-507. [CrossRef]
27. 27. Brzezianska E, Pastuszak-Lewandoska D, Lewinski A. Rearrangements of NTRK1 oncogene in papillary thyroid carcinoma. Neuro Endocrinol Lett 2007;28:221-9.
28. 28. Cheung CC, Carydis B, Ezzat S, Bedard YC, Asa SL. Analysis of RET/PTC gene rearrangements refines the fine needle aspiration diagnosis of thyroid cancer. J Clin Endocrinol Metab 2001;86:2187-90. [CrossRef]
29. 29. Marotta V, Guerra A, Sapio MR, Campanile E, Motta M, Fenzi G, et al. Growing thyroid nodules with benign histology and RET rearrangement. Endocr J 2010;57:1081-7. [CrossRef]
30. 30. Chiappetta G, Toti P, Cetta F, Giuliano A, Pentimalli F, Amendola I, et al. The RET/PTC oncogene is frequently activated in oncocytic thyroid tumors (Hurtle cell adenomas and carcinomas), but not in oncocytic hyperplastic lesions. J Clin Endocrinol Metab 2002;87:364-9. [CrossRef]
31. 31. Elisei R, Romei C, Vorontsova T, Cosci B, Veremeychik V, Kuchinskaya E, et al. RET/PTC rearrangements in thyroid nodules: studies in irradiated and not irradiated, malignant and benign thyroid lesions in children and adults. J Clin Endocrinol Metab 2001;86:3211-6. [CrossRef]
32. 32. Santoro M, Melillo RM, Fusco A. RET/PTC activation in papillary thyroid carcinoma. Eur J Endocrinol 2006;155:645-53. [CrossRef]
33. 33. Cyniak-Magierska A, Wojciechowska-Durczyńska K, Krawczyk-Rusiecka K, Zygmunt A, Lewiński A. Assessment of RET/ PTC1 and RET/PTC3 rearrangements in fine-needle aspiration biopsy specimens collected from patients with Hashimoto’s thyroiditis. Thyroid Res 2011;4:5. [CrossRef]
34. 34. Basolo F, Giannini R, Monaco C, Melillo RM, Carlomagno F, Pancrazi M, et al. Potent mitogenicity of the RET/PTC3 oncogene correlates with Its prevalence in tall-cell variant of papillary thyroid carcinoma. Am J Pathol 2002;160:247-54. [CrossRef]
35. 35. Nikiforova MN, Lynch RA, Biddinger PW, Alexander EK, Dorn GW, Tallini G, et al. RAS point mutations and PAX8-PPAR gamma rearrangement in thyroid tumors: evidence for distinct molecular pathways in thyroid follicular carcinoma. J Clin Endocrinol Metab 2003;88:2318-26. [CrossRef]
36. 36. Foukakis T, Au AYM, Wallin G, Geli J, Forsberg L, CliftonBligh R, et al. The ras effector NORE1A is suppressed in follicular thyroid carcinomas with a PAX8-PPARγ fusion. J Clin Endocrinol Metab 2006;91:1143-9. [CrossRef]
37. 37. Marques AR, Espadinha C, Catarino AL, Moniz SN, Pereira T, Sobrinho LG, et al. Expression of PAX8-PPAR rearrangements in both follicular thyroid carcinomas and adenomas; J Clin Endocrinol Metab 2002;87:3947-52. [CrossRef]
38. 38. Nikiforova MN, Kimura ET, Gandhi M, Bindinger 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. [CrossRef]
39. 39. 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.
40. 40. Cheung L, Messina M, Gill A, Clarkson A, Learoyd D, Delbridge L, et al. Detection of the PAX8-PPAR fusion oncogene in both follicular thyroid carcinomas and adenomas. J Clin Endocrinol Metab 2003;88:354-57. [CrossRef]
41. 41. Trovisco V, Castro V, Soares P, Maximo V, Silva P, Magalhaes J, et al. BRAF mutations are associated with some histological types of papillary thyroid carcinoma. J Pathol 2004;202:247-51. [CrossRef]
42. 42. Begum S, Rosenbaum E, Henrique R, Cohen Y, Sidransky D, Westra WH. BRAF mutations in anaplastic thyroidcarcinoma: implications for tumor origin, diagnosis and treatment. Mod Pathol 2004;17:1359-63. [CrossRef]
43. 43. Sahin M, Allard BL, Yates M, Powell JG, Wang X, Hay ID et al. PPARγ staining as a surrogate for PAX8/PPARγ fusion oncogene expression in follicular neoplasms: clinico pathological correlation and histopathological diagnostic value. J Clin Endocrinol Metab 2005;90:463-8. [CrossRef]
44. 44. Castro P, Rebocho AP, Soares RJ, Magalhaes J, Roque L, Trovisco V, et al. PAX8-PPAR {gamma} rearrangement is frequently detected in the follicular variant of papillary thyroid carcinoma. J Clin Endocrinol Metab 2006;91:213-20. [CrossRef]
45. 45. Lupi C, Giannini R, Ugolini C, Proietti A, Berti P, Minuto M, et al. Association of BRAF V600E mutation with poor clinicopathological outcomes in 500 consecutive cases of papillary thyroid carcinoma. J Clin Endocrinol Metab 2007;92:4085-90. [CrossRef]
46. 46. Sapio MR, Guerra A, Posca D, Limone PP, Deandrea M, Motta M, et al. Combined analysis of galectin-3 and BRAFV600E improves the accuracy of fine-needle aspiration biopsy with cytological findings suspicious for papillary thyroid carcinoma. Endocr Relat Cancer 2007;14:1089-97. [CrossRef]
47. 47. Kebebew E, Weng J, Bauer J, Ranvier G, Clark OH, Duh QY, et al. The prevalence and prognostic value of BRAF mutation in thyroid cancer. Ann Surg 2007;246:466-70. [CrossRef]
48. 48. Mochizuki K, Kondo T, Nakazawa T, Iwashina M, Kawasaki T, Nakamura N, et al. RET rearrangements and BRAF mutation in undifferentiated thyroid carcinomas having papillary carcinoma components. Histopathology 2010;57:444-50. [CrossRef]