Well-Differentiated Papillary Thyroid Carcinoma

  • Lori A. Erickson
  • Ricardo V. Lloyd
Part of the Molecular Pathology Library book series (MPLB, volume 3)

Papillary thyroid carcinoma (PTC) is a malignant epithelial tumor showing follicular differentiation and distinctive nuclear features.1 Papillary thyroid carcinoma is the most common thyroid carcinoma, accounting for 80% of thyroid carcinomas.2 Numerous variants of PTC have been described, some of which behave more aggressively than conventional PTC. Three distinct molecular alterations are associated with PTC and are mutually exclusive.3 These include somatic BRAF point mutations, RET/PTC rearrangements, and somatic RAS point mutations. These molecular alterations are also associated with particular clinicopathologic features of PTC as well as particular subtypes of PTC.


Thyroid Carcinoma Papillary Thyroid Carcinoma Familial Adenomatous Polyposis BRAF Mutation Follicular Thyroid Carcinoma 


  1. 1.
    DeLellis RA, Lloyd RV, Heitz PU, Eng C. Pathology and Genetics of Tumours of Endocrine Organs. World Health Organization Classification of Tumours. Lyon: IARC; 2004:320.Google Scholar
  2. 2.
    Rosai J, Carcangiu ML, DeLellis RA. Tumors of the Thyroid Gland. Atlas of Tumor Pathology. Vol 5, 3rd Series edition. Washington, DC: Armed Forces Institute of Pathology; 1992:343.Google Scholar
  3. 3.
    Melillo RM, Castellone MD, Guarino V, et al. The RET/PTC-RAS-BRAF linear signaling cascade mediates the motile and mitogenic phenotype of thyroid cancer cells. J Clin Invest. 2005;115:1068–1081.PubMedGoogle Scholar
  4. 4.
    Calandra DB, Shah KH, Lawrence AM, Paloyan E. Total thyroidectomy in irradiated patients. A twenty-year experience in 206 patients. Ann Surg. 1985;202:356–360.PubMedCrossRefGoogle Scholar
  5. 5.
    Furmanchuk AW, Averkin JI, Egloff B, et al. Pathomorphological findings in thyroid cancers of children from the Republic of Belarus: a study of 86 cases occurring between 1986 (‘post-Chernobyl’) and 1991. Histopathology. 1992;21:401–408.PubMedCrossRefGoogle Scholar
  6. 6.
    Unger K, Zurnadzhy L, Walch A, et al. RET rearrangements in post-Chernobyl papillary thyroid carcinomas with a short latency analysed by interphase FISH. Br J Cancer. 2006;94:1472–1477.PubMedCrossRefGoogle Scholar
  7. 7.
    Williams ED, Abrosimov A, Bogdanova T, et al. Thyroid carcinoma after Chernobyl latent period, morphology and aggressiveness. Br J Cancer. 2004;90:2219–2224.PubMedGoogle Scholar
  8. 8.
    Nikiforova MN, Ciampi R, Salvatore G, et al. Low prevalence of BRAF mutations in radiation-induced thyroid tumors in contrast to sporadic papillary carcinomas. Cancer Lett. 2004;209:1–6.PubMedCrossRefGoogle Scholar
  9. 9.
    Akslen LA, LiVolsi VA. Prognostic significance of histologic grading compared with subclassification of papillary thyroid carcinoma. Cancer. 2000;88:1902–1908.PubMedCrossRefGoogle Scholar
  10. 10.
    Johnson TL, Lloyd RV, Thompson NW, Beierwaltes WH, Sisson JC. Prognostic implications of the tall cell variant of papillary thyroid carcinoma. Am J Surg Pathol. 1988;12:22–27.PubMedCrossRefGoogle Scholar
  11. 11.
    Michels JJ, Jacques M, Henry-Amar M, Bardet S. Prevalence and prognostic significance of tall cell variant of papillary thyroid carcinoma. Hum Pathol. 2007;38:212–219.PubMedCrossRefGoogle Scholar
  12. 12.
    Moreno Egea A, Rodriguez Gonzalez JM, Sola Perez J, Soria Cogollos T, Parrilla Paricio P. Prognostic value of the tall cell variety of papillary cancer of the thyroid. Eur J Surg Oncol. 1993;19:517–521.PubMedGoogle Scholar
  13. 13.
    Ferreiro JA, Hay ID, Lloyd RV. Columnar cell carcinoma of the thyroid: report of three additional cases. Hum Pathol. 1996;27:1156–1160.PubMedCrossRefGoogle Scholar
  14. 14.
    Besic N, Hocevar M, Zgajnar J, Petric R, Pilko G. Aggressiveness of therapy and prognosis of patients with Hurthle cell papillary thyroid carcinoma. Thyroid. 2006;16:67–72.PubMedCrossRefGoogle Scholar
  15. 15.
    Davies L, Welch HG. Increasing incidence of thyroid cancer in the United States, 1973-2002. JAMA. 2006;295:2164–2167.PubMedCrossRefGoogle Scholar
  16. 16.
    Baloch ZW, LiVolsi VA. Microcarcinoma of the thyroid. Adv Anat Pathol. 2006;13:69–75.PubMedCrossRefGoogle Scholar
  17. 17.
    de Matos PS, Ferreira AP, Ward LS. Prevalence of papillary microcarcinoma of the thyroid in Brazilian autopsy and surgical series. Endocr Pathol. 2006;17:165–173.PubMedCrossRefGoogle Scholar
  18. 18.
    Harach HR, Franssila KO, Wasenius VM. Occult papillary carcinoma of the thyroid. A “normal” finding in Finland. A systematic autopsy study. Cancer. 1985;56:531–538.PubMedCrossRefGoogle Scholar
  19. 19.
    Haas SN. Management of papillary microcarcinoma of the thyroid. S D Med. 2006;59:425–427.PubMedGoogle Scholar
  20. 20.
    Lo CY, Chan WF, Lang BH, Lam KY, Wan KY. Papillary microcarcinoma: is there any difference between clinically overt and occult tumors? World J Surg. 2006;30:759–766.PubMedCrossRefGoogle Scholar
  21. 21.
    Lupoli G, Vitale G, Caraglia M, et al. Familial papillary thyroid microcarcinoma: a new clinical entity. Lancet. 1999;353:637–639.PubMedCrossRefGoogle Scholar
  22. 22.
    Crile G Jr, Hazard JB. Relationship of the age of the patient to the natural history and prognosis of carcinoma of the thyroid. Ann Surg. 1953;138:33–38.PubMedCrossRefGoogle Scholar
  23. 23.
    Hazard JB, Crile G Jr, Dinsmore RS, Hawk WA, Kenyon R. Neoplasms of the thyroid: classification, morphology, and treatment. AMA Arch Pathol. 1955;59:502–513.PubMedGoogle Scholar
  24. 24.
    Lindsay S. Natural history of thyroid carcinoma. Ariz Med. 1960;17:623–627.PubMedGoogle Scholar
  25. 25.
    Chem KT, Rosai J. Follicular variant of thyroid papillary carcinoma: a clinicopathologic study of six cases. Am J Surg Pathol. 1977;1:123–130.PubMedCrossRefGoogle Scholar
  26. 26.
    Lloyd RV, Erickson LA, Casey MB, et al. Observer variation in the diagnosis of follicular variant of papillary thyroid carcinoma. Am J Surg Pathol. 2004;28:1336–1340.PubMedCrossRefGoogle Scholar
  27. 27.
    Vestfrid MA. Papillary carcinoma of the thyroid gland with lipomatous stroma: report of a peculiar histological type of thyroid tumour. Histopathology. 1986;10:97–100.PubMedCrossRefGoogle Scholar
  28. 28.
    Hawk WA, Hazard JB. The many appearances of papillary carcinoma of the thyroid. Cleve Clin Q. 1976;43:207–215.PubMedGoogle Scholar
  29. 29.
    Nardone HC, Ziober AF, LiVolsi VA, et al. c-Met expression in tall cell variant papillary carcinoma of the thyroid. Cancer. 2003;98:1386–1393.PubMedCrossRefGoogle Scholar
  30. 30.
    Evans HL. Columnar-cell carcinoma of the thyroid. A report of two cases of an aggressive variant of thyroid carcinoma. Am J Clin Pathol. 1986;85:77–80.PubMedGoogle Scholar
  31. 31.
    Nikiforov YE, Erickson LA, Nikiforova MN, Caudill CM, Lloyd RV. Solid variant of papillary thyroid carcinoma: incidence, clinical-pathologic characteristics, molecular analysis, and biologic behavior. Am J Surg Pathol. 2001;25:1478–1484.PubMedCrossRefGoogle Scholar
  32. 32.
    Keelawat S, Poumsuk U. Association between different variants of papillary thyroid carcinoma and risk-group according to AMES (age, metastasis, extent and size) classification system. J Med Assoc Thai. 2006;89:484–489.PubMedGoogle Scholar
  33. 33.
    Nikiforov Y, Gnepp DR. Pediatric thyroid cancer after the Chernobyl disaster. Pathomorphologic study of 84 cases (1991-1992) from the Republic of Belarus. Cancer. 1994;74:748–766.PubMedCrossRefGoogle Scholar
  34. 34.
    Mai KT, Thomas J, Yazdi HM, Commons AS, Lamba M, Stinson AW. Pathologic study and clinical significance of Hurthle cell papillary thyroid carcinoma. Appl Immunohistochem Mol Morphol. 2004;12:329–337.PubMedGoogle Scholar
  35. 35.
    Herrera MF, Hay ID, Wu PS, et al. Hurthle cell (oxyphilic) papillary thyroid carcinoma: a variant with more aggressive biologic behavior. World J Surg. 1992;16:669-674. discussion 774–775.PubMedCrossRefGoogle Scholar
  36. 36.
    Apel RL, Asa SL, LiVolsi VA. Papillary Hurthle cell carcinoma with lymphocytic stroma. “Warthin-like tumor” of the thyroid. Am J Surg Pathol. 1995;19:810–814.PubMedCrossRefGoogle Scholar
  37. 37.
    Lam KY, Lo CY, Wei WI. Warthin tumor-like variant of papillary thyroid carcinoma: a case with dedifferentiation (anaplastic changes) and aggressive biological behavior. Endocr Pathol. 2005;16:83–89.PubMedCrossRefGoogle Scholar
  38. 38.
    Vickery AL Jr, Carcangiu ML, Johannessen JV, Sobrinho-Simoes M. Papillary carcinoma. Semin Diagn Pathol. 1985;2:90–100.PubMedGoogle Scholar
  39. 39.
    Carcangiu ML, Bianchi S. Diffuse sclerosing variant of papillary thyroid carcinoma. Clinicopathologic study of 15 cases. Am J Surg Pathol. 1989;13:1041–1049.PubMedCrossRefGoogle Scholar
  40. 40.
    Soares J, Limbert E, Sobrinho-Simoes M. Diffuse sclerosing variant of papillary thyroid carcinoma. A clinicopathologic study of 10 cases. Pathol Res Pract. 1989;185:200–206.PubMedGoogle Scholar
  41. 41.
    Falvo L, Giacomelli L, D’Andrea V, Marzullo A, Guerriero G, de Antoni E. Prognostic importance of sclerosing variant in papillary thyroid carcinoma. Am Surg. 2006;72:438–444.PubMedGoogle Scholar
  42. 42.
    Thompson LD, Wieneke JA, Heffess CS. Diffuse sclerosing variant of papillary thyroid carcinoma: a clinicopathologic and immunophenotypic analysis of 22 cases. Endocr Pathol. 2005;16:331–348.PubMedCrossRefGoogle Scholar
  43. 43.
    Erickson LA, Yousef OM, Jin L, Lohse CM, Pankratz VS, Lloyd RV. p27kip1 expression distinguishes papillary hyperplasia in Graves’ disease from papillary thyroid carcinoma. Mod Pathol. 2000;13:1014–1019.PubMedCrossRefGoogle Scholar
  44. 44.
    Ivanova R, Soares P, Castro P, Sobrinho-Simoes M. Diffuse (or multinodular) follicular variant of papillary thyroid carcinoma: a clinicopathologic and immunohistochemical analysis of ten cases of an aggressive form of differentiated thyroid carcinoma. Virchows Arch. 2002;440:418–424.PubMedCrossRefGoogle Scholar
  45. 45.
    Mizukami Y, Nonomura A, Michigishi T, Ohmura K, Noguchi M, Ishizaki T. Diffuse follicular variant of papillary carcinoma of the thyroid. Histopathology. 1995;27:575–577.PubMedCrossRefGoogle Scholar
  46. 46.
    Akslen LA, Varhaug JE. Thyroid carcinoma with mixed tall-cell and columnar-cell features. Am J Clin Pathol. 1990;94:442–445.PubMedGoogle Scholar
  47. 47.
    Gaertner EM, Davidson M, Wenig BM. The columnar cell variant of thyroid papillary carcinoma. Case report and discussion of an unusually aggressive thyroid papillary carcinoma. Am J Surg Pathol. 1995;19:940–947.PubMedCrossRefGoogle Scholar
  48. 48.
    Evans HL. Encapsulated columnar-cell neoplasms of the thyroid. A report of four cases suggesting a favorable prognosis. Am J Surg Pathol. 1996;20:1205–1211.PubMedCrossRefGoogle Scholar
  49. 49.
    Baloch ZW, LiVolsi VA. Warthin-like papillary carcinoma of the thyroid. Arch Pathol Lab Med. 2000;124:1192–1195.PubMedGoogle Scholar
  50. 50.
    Chan JK, Carcangiu ML, Rosai J. Papillary carcinoma of thyroid with exuberant nodular fasciitis-like stroma. Report of three cases. Am J Clin Pathol. 1991;95:309–314.PubMedGoogle Scholar
  51. 51.
    Carcangiu ML, Sibley RK, Rosai J. Clear cell change in primary thyroid tumors. A study of 38 cases. Am J Surg Pathol. 1985;9:705–722.PubMedCrossRefGoogle Scholar
  52. 52.
    Variakojis D, Getz ML, Paloyan E, Straus FH. Papillary clear cell carcinoma of the thyroid gland. Hum Pathol. 1975;6:384–390.PubMedCrossRefGoogle Scholar
  53. 53.
    Casey MB, Lohse CM, Lloyd RV. Distinction between papillary thyroid hyperplasia and papillary thyroid carcinoma by immunohistochemical staining for cytokeratin 19, galectin-3, and HBME-1. Endocr Pathol. 2003;14:55–60.PubMedCrossRefGoogle Scholar
  54. 54.
    Prasad ML, Pellegata NS, Huang Y, Nagaraja HN, de la Chapelle A, Kloos RT. Galectin-3, fibronectin-1, CITED-1, HBME1 and cytokeratin-19 immunohistochemistry is useful for the differential diagnosis of thyroid tumors. Mod Pathol. 2005;18:48–57.PubMedCrossRefGoogle Scholar
  55. 55.
    Scognamiglio T, Hyjek E, Kao J, Chen YT. Diagnostic usefulness of HBME1, galectin-3, CK19, and CITED1 and evaluation of their expression in encapsulated lesions with questionable features of papillary thyroid carcinoma. Am J Clin Pathol. 2006;126:700–708.PubMedCrossRefGoogle Scholar
  56. 56.
    de Matos PS, Ferreira AP, de Oliveira Facuri F, Assumpcao LV, Metze K, Ward LS. Usefulness of HBME-1, cytokeratin 19 and galectin-3 immunostaining in the diagnosis of thyroid malignancy. Histopathology. 2005;47:391–401.PubMedCrossRefGoogle Scholar
  57. 57.
    Barroeta JE, Baloch ZW, Lal P, Pasha TL, Zhang PJ, LiVolsi VA. Diagnostic value of differential expression of CK19, Galectin-3, HBME-1, ERK, RET, and p16 in benign and malignant follicular-derived lesions of the thyroid: an immunohistochemical tissue microarray analysis. Endocr Pathol. 2006;17:225–234.PubMedCrossRefGoogle Scholar
  58. 58.
    Nakamura N, Erickson LA, Jin L, et al. Immunohistochemical separation of follicular variant of papillary thyroid carcinoma from follicular adenoma. Endocr Pathol. 2006;17:213–223.PubMedCrossRefGoogle Scholar
  59. 59.
    Nasr MR, Mukhopadhyay S, Zhang S, Katzenstein AL. Immunohistochemical markers in diagnosis of papillary thyroid carcinoma: utility of HBME1 combined with CK19 immunostaining. Mod Pathol. 2006;19:1631–1637.PubMedCrossRefGoogle Scholar
  60. 60.
    Gaffney RL, Carney JA, Sebo TJ, et al. Galectin-3 expression in hyalinizing trabecular tumors of the thyroid gland. Am J Surg Pathol. 2003;27:494–498.PubMedCrossRefGoogle Scholar
  61. 61.
    Prasad ML, Pellegata NS, Kloos RT, Barbacioru C, Huang Y, de la Chapelle A. CITED1 protein expression suggests Papillary Thyroid Carcinoma in high throughput tissue microarray-based study. Thyroid. 2004;14:169–175.PubMedCrossRefGoogle Scholar
  62. 62.
    Huang Y, Prasad M, Lemon WJ, et al. Gene expression in papillary thyroid carcinoma reveals highly consistent profiles. Proc Natl Acad Sci USA. 2001;98:15044–15049.PubMedCrossRefGoogle Scholar
  63. 63.
    Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949–954.PubMedCrossRefGoogle Scholar
  64. 64.
    Nakamura N, Carney JA, Jin L, et al. RASSF1A and NORE1A methylation and BRAFV600E mutations in thyroid tumors. Lab Invest. 2005;85:1065–1075.PubMedCrossRefGoogle Scholar
  65. 65.
    Cohen Y, Xing M, Mambo E, et al. BRAF mutation in papillary thyroid carcinoma. J Natl Cancer Inst. 2003;95:625–627.PubMedCrossRefGoogle Scholar
  66. 66.
    Fukushima T, Suzuki S, Mashiko M, et al. BRAF mutations in papillary carcinomas of the thyroid. Oncogene. 2003;22:6455–6457.PubMedCrossRefGoogle Scholar
  67. 67.
    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;63:1454–1457.PubMedGoogle Scholar
  68. 68.
    Soares P, Trovisco V, Rocha AS, et al. BRAF mutations and RET/PTC rearrangements are alternative events in the etiopathogenesis of PTC. Oncogene. 2003;22:4578–4580.PubMedCrossRefGoogle Scholar
  69. 69.
    Trovisco V, Vieira de Castro I, Soares P, et al. BRAF mutations are associated with some histological types of papillary thyroid carcinoma. J Pathol. 2004;202:247–251.PubMedCrossRefGoogle Scholar
  70. 70.
    Trovisco V, Soares P, Soares R, Magalhaes J, Sa-Couto P, Sobrinho-Simoes M. A new BRAF gene mutation detected in a case of a solid variant of papillary thyroid carcinoma. Hum Pathol. 2005;36:694–697.PubMedCrossRefGoogle Scholar
  71. 71.
    Moretti S, Macchiarulo A, De Falco V, et al. Biochemical and molecular characterization of the novel BRAF(V599Ins) mutation detected in a classic papillary thyroid carcinoma. Oncogene. 2006;25:4235–4240.PubMedCrossRefGoogle Scholar
  72. 72.
    Xing M. BRAF mutation in papillary thyroid cancer: pathogenic role, molecular bases, and clinical implications. Endocr Rev. 2007;28:742–762.PubMedCrossRefGoogle Scholar
  73. 73.
    Liu D, Hu S, Hou P, Jiang D, Condouris S, Xing M. Suppression of BRAF/MEK/MAP kinase pathway restores expression of iodide-metabolizing genes in thyroid cells expressing the V600E BRAF mutant. Clin Cancer Res. 2007;13:1341–1349.PubMedCrossRefGoogle Scholar
  74. 74.
    Ball DW, Jin N, Rosen DM, et al. Selective growth inhibition in BRAF mutant thyroid cancer by the mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244. J Clin Endocrinol Metab. 2007;92:4712–4718.PubMedCrossRefGoogle Scholar
  75. 75.
    Powell N, Jeremiah S, Morishita M, et al. Frequency of BRAF T1796A mutation in papillary thyroid carcinoma relates to age of patient at diagnosis and not to radiation exposure. J Pathol. 2005;205:558–564.PubMedCrossRefGoogle Scholar
  76. 76.
    Trovisco V, Soares P, Preto A, 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;446:589–595.PubMedCrossRefGoogle Scholar
  77. 77.
    Adeniran AJ, Zhu Z, Gandhi M, et al. Correlation between genetic alterations and microscopic features, clinical manifestations, and prognostic characteristics of thyroid papillary carcinomas. Am J Surg Pathol. 2006;30:216–222.PubMedCrossRefGoogle Scholar
  78. 78.
    Collins BJ, Schneider AB, Prinz RA, Xu X. Low frequency of BRAF mutations in adult patients with papillary thyroid cancers following childhood radiation exposure. Thyroid. 2006;16:61–66.PubMedCrossRefGoogle Scholar
  79. 79.
    Ciampi R, Knauf JA, Kerler R, et al. Oncogenic AKAP9-BRAF fusion is a novel mechanism of MAPK pathway activation in thyroid cancer. J Clin Invest. 2005;115:94–101.PubMedGoogle Scholar
  80. 80.
    Xing M, Westra WH, Tufano RP, et al. BRAF mutation predicts a poorer clinical prognosis for papillary thyroid cancer. J Clin Endocrinol Metab. 2005;90:6373–6379.PubMedCrossRefGoogle Scholar
  81. 81.
    Kim TY, Kim WB, Rhee YS, et al. The BRAF mutation is useful for prediction of clinical recurrence in low-risk patients with conventional papillary thyroid carcinoma. Clin Endocrinol (Oxf). 2006;65:364–368.CrossRefGoogle Scholar
  82. 82.
    Riesco-Eizaguirre G, Gutierrez-Martinez P, Garcia-Cabezas MA, Nistal M, Santisteban P. The oncogene BRAF V600E 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. 2006;13:257–269.PubMedCrossRefGoogle Scholar
  83. 83.
    Di Cristofaro J, Marcy M, Vasko V, et al. Molecular genetic study comparing follicular variant versus classic papillary thyroid carcinomas: association of N-ras mutation in codon 61 with follicular variant. Hum Pathol. 2006;37:824–830.PubMedCrossRefGoogle Scholar
  84. 84.
    Jin L, Sebo TJ, Nakamura N, et al. BRAF mutation analysis in fine needle aspiration (FNA) cytology of the thyroid. Diagn Mol Pathol. 2006;15:136–143.PubMedCrossRefGoogle Scholar
  85. 85.
    Lupi C, Giannini R, Ugolini C, et al. Association of BRAF V600E mutation with poor clinicopathological outcomes in 500 consecutive cases of papillary thyroid carcinoma. J Clin Endocrinol Metab. 2007;92:4085–4090.PubMedCrossRefGoogle Scholar
  86. 86.
    Kim TY, Kim WB, Song JY, et al. The BRAF mutation is not associated with poor prognostic factors in Korean patients with conventional papillary thyroid microcarcinoma. Clin Endocrinol (Oxf). 2005;63:588–593.CrossRefGoogle Scholar
  87. 87.
    Liu RT, Chen YJ, Chou FF, et al. No correlation between BRAFV600E mutation and clinicopathological features of papillary thyroid carcinomas in Taiwan. Clin Endocrinol (Oxf). 2005;63:461–466.CrossRefGoogle Scholar
  88. 88.
    Nikiforova MN, Kimura ET, Gandhi M, 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;88:5399–5404.PubMedCrossRefGoogle Scholar
  89. 89.
    Abrosimov A, Saenko V, Rogounovitch T, et al. Different structural components of conventional papillary thyroid carcinoma display mostly identical BRAF status. Int J Cancer. 2007;120:196–200.PubMedCrossRefGoogle Scholar
  90. 90.
    Frattini M, Ferrario C, Bressan P, et al. Alternative mutations of BRAF, RET and NTRK1 are associated with similar but distinct gene expression patterns in papillary thyroid cancer. Oncogene. 2004;23:7436–7440.PubMedCrossRefGoogle Scholar
  91. 91.
    Lee JH, Lee ES, Kim YS, Won NH, Chae YS. BRAF mutation and AKAP9 expression in sporadic papillary thyroid carcinomas. Pathology. 2006;38:201–204.PubMedCrossRefGoogle Scholar
  92. 92.
    Sedliarou I, Saenko V, Lantsov D, et al. The BRAFT1796A transversion is a prevalent mutational event in human thyroid microcarcinoma. Int J Oncol. 2004;25:1729–1735.PubMedGoogle Scholar
  93. 93.
    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;120:71–77.PubMedCrossRefGoogle Scholar
  94. 94.
    Pasini B, Hofstra RM, Yin L, et al. The physical map of the human RET proto-oncogene. Oncogene. 1995;11:1737–1743.PubMedGoogle Scholar
  95. 95.
    Nikiforov YE. RET/PTC rearrangement in thyroid tumors. Endocr Pathol. 2002;13:3–16.PubMedCrossRefGoogle Scholar
  96. 96.
    Nikiforov YE, Rowland JM, Bove KE, Monforte-Munoz H, Fagin JA. Distinct pattern of ret oncogene rearrangements in morphological variants of radiation-induced and sporadic thyroid papillary carcinomas in children. Cancer Res. 1997;57:1690–1694.PubMedGoogle Scholar
  97. 97.
    Nakazawa T, Kondo T, Kobayashi Y, et al. RET gene rearrangements (RET/PTC1 and RET/PTC3) in papillary thyroid carcinomas from an iodine-rich country (Japan). Cancer. 2005;104:943–951.PubMedCrossRefGoogle Scholar
  98. 98.
    Sugg SL, Ezzat S, Rosen IB, Freeman JL, Asa SL. Distinct multiple RET/PTC gene rearrangements in multifocal papillary thyroid neoplasia. J Clin Endocrinol Metab. 1998;83:4116–4122.PubMedCrossRefGoogle Scholar
  99. 99.
    de Groot JW, Links TP, Plukker JT, Lips CJ, Hofstra RM. RET as a diagnostic and therapeutic target in sporadic and hereditary endocrine tumors. Endocr Rev. 2006;27:535–560.PubMedCrossRefGoogle Scholar
  100. 100.
    Collins BJ, Chiappetta G, Schneider AB, et al. RET expression in papillary thyroid cancer from patients irradiated in childhood for benign conditions. J Clin Endocrinol Metab. 2002;87:3941–3946.PubMedCrossRefGoogle Scholar
  101. 101.
    Bounacer A, Wicker R, Caillou B, et al. High prevalence of activating ret proto-oncogene rearrangements, in thyroid tumors from patients who had received external radiation. Oncogene. 1997;15:1263–1273.PubMedCrossRefGoogle Scholar
  102. 102.
    Rabes HM, Klugbauer S. Molecular genetics of childhood papillary thyroid carcinomas after irradiation: high prevalence of RET rearrangement. Recent Results Cancer Res. 1998;154:248–264.PubMedGoogle Scholar
  103. 103.
    Rabes HM, Demidchik EP, Sidorow JD, et al. Pattern of radiation-induced RET and NTRK1 rearrangements in 191 post-chernobyl papillary thyroid carcinomas: biological, phenotypic, and clinical implications. Clin Cancer Res. 2000;6:1093–1103.PubMedGoogle Scholar
  104. 104.
    Rabes HM. Gene rearrangements in radiation-induced thyroid carcinogenesis. Med Pediatr Oncol. 2001;36:574–582.PubMedCrossRefGoogle Scholar
  105. 105.
    Thomas GA, Bunnell H, Cook HA, et al. High prevalence of RET/PTC rearrangements in Ukrainian and Belarussian post-Chernobyl thyroid papillary carcinomas: a strong correlation between RET/PTC3 and the solid-follicular variant. J Clin Endocrinol Metab. 1999;84:4232–4238.PubMedCrossRefGoogle Scholar
  106. 106.
    Fenton CL, Lukes Y, Nicholson D, Dinauer CA, Francis GL, Tuttle RM. The ret/PTC mutations are common in sporadic papillary thyroid carcinoma of children and young adults. J Clin Endocrinol Metab. 2000;85:1170–1175.PubMedCrossRefGoogle Scholar
  107. 107.
    Corvi R, Martinez-Alfaro M, Harach HR, Zini M, Papotti M, Romeo G. Frequent RET rearrangements in thyroid papillary microcarcinoma detected by interphase fluorescence in situ hybridization. Lab Invest. 2001;81:1639–1645.PubMedGoogle Scholar
  108. 108.
    Tallini G, Santoro M, Helie M, et al. 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. 1998;4:287–294.PubMedGoogle Scholar
  109. 109.
    Basolo F, Giannini R, Monaco C, 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;160:247–254.PubMedGoogle Scholar
  110. 110.
    Ruter A, Dreifus J, Jones M, Nishiyama R, Lennquist S. Overexpression of p53 in tall cell variants of papillary thyroid carcinoma. Surgery. 1996;120:1046–1050.PubMedCrossRefGoogle Scholar
  111. 111.
    Santoro M, Thomas GA, Vecchio G, et al. Gene rearrangement and Chernobyl related thyroid cancers. Br J Cancer. 2000;82:315–322.PubMedCrossRefGoogle Scholar
  112. 112.
    Wirtschafter A, Schmidt R, Rosen D, et al. Expression of the RET/PTC fusion gene as a marker for papillary carcinoma in Hashimoto’s thyroiditis. Laryngoscope. 1997;107:95–100.PubMedCrossRefGoogle Scholar
  113. 113.
    Arif S, Blanes A, Diaz-Cano SJ. Hashimoto’s thyroiditis shares features with early papillary thyroid carcinoma. Histopathology. 2002;41:357–362.PubMedCrossRefGoogle Scholar
  114. 114.
    Nikiforova MN, Caudill CM, Biddinger P, Nikiforov YE. Prevalence of RET/PTC rearrangements in Hashimoto’s thyroiditis and papillary thyroid carcinomas. Int J Surg Pathol. 2002;10:15–22.PubMedCrossRefGoogle Scholar
  115. 115.
    Rhoden KJ, Johnson C, Brandao G, Howe JG, Smith BR, Tallini G. Real-time quantitative RT-PCR identifies distinct c-RET, RET/PTC1 and RET/PTC3 expression patterns in papillary thyroid carcinoma. Lab Invest. 2004;84:1557–1570.PubMedCrossRefGoogle Scholar
  116. 116.
    Vasko V, Ferrand M, Di Cristofaro J, Carayon P, Henry JF, de Micco C. Specific pattern of RAS oncogene mutations in follicular thyroid tumors. J Clin Endocrinol Metab. 2003;88:2745–2752.PubMedCrossRefGoogle Scholar
  117. 117.
    Hara H, Fulton N, Yashiro T, Ito K, DeGroot LJ, Kaplan EL. N-ras mutation: an independent prognostic factor for aggressiveness of papillary thyroid carcinoma. Surgery. 1994;116:1010–1016.PubMedGoogle Scholar
  118. 118.
    Capella G, Matias-Guiu X, Ampudia X, de Leiva A, Perucho M, Prat J. Ras oncogene mutations in thyroid tumors: polymerase chain reaction-restriction-fragment-length polymorphism analysis from paraffin-embedded tissues. Diagn Mol Pathol. 1996;5:45–52.PubMedCrossRefGoogle Scholar
  119. 119.
    Motoi N, Sakamoto A, Yamochi T, Horiuchi H, Motoi T, Machinami R. Role of ras mutation in the progression of thyroid carcinoma of follicular epithelial origin. Pathol Res Pract. 2000;196:1–7.PubMedGoogle Scholar
  120. 120.
    Namba H, Rubin SA, Fagin JA. Point mutations of ras oncogenes are an early event in thyroid tumorigenesis. Mol Endocrinol. 1990;4:1474–1479.PubMedCrossRefGoogle Scholar
  121. 121.
    Xing M. Gene methylation in thyroid tumorigenesis. Endocrinology. 2007;148:948–953.PubMedCrossRefGoogle Scholar
  122. 122.
    Hu S, Liu D, Tufano RP, et al. Association of aberrant methylation of tumor suppressor genes with tumor aggressiveness and BRAF mutation in papillary thyroid cancer. Int J Cancer. 2006;119:2322–2329.PubMedCrossRefGoogle Scholar
  123. 123.
    Qi JH, Ebrahem Q, Moore N, et al. A novel function for tissue inhibitor of metalloproteinases-3 (TIMP3): inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2. Nat Med. 2003;9:407–415.PubMedCrossRefGoogle Scholar
  124. 124.
    Porra V, Ferraro-Peyret C, Durand C, et al. Silencing of the tumor suppressor gene SLC5A8 is associated with BRAF mutations in classical papillary thyroid carcinomas. J Clin Endocrinol Metab. 2005;90:3028–3035.PubMedCrossRefGoogle Scholar
  125. 125.
    Hoque MO, Rosenbaum E, Westra WH, et al. Quantitative assessment of promoter methylation profiles in thyroid neoplasms. J Clin Endocrinol Metab. 2005;90:4011–4018.PubMedCrossRefGoogle Scholar
  126. 126.
    Xing M, Usadel H, Cohen Y, et al. Methylation of the thyroid-stimulating hormone receptor gene in epithelial thyroid tumors: a marker of malignancy and a cause of gene silencing. Cancer Res. 2003;63:2316–2321.PubMedGoogle Scholar
  127. 127.
    Aldred MA, Huang Y, Liyanarachchi S, et al. Papillary and follicular thyroid carcinomas show distinctly different microarray expression profiles and can be distinguished by a minimum of five genes. J Clin Oncol. 2004;22:3531–3539.PubMedCrossRefGoogle Scholar
  128. 128.
    Eszlinger M, Krohn K, Kukulska A, Jarzab B, Paschke R. Perspectives and limitations of microarray based gene expression profiling of thyroid tumors. Endocr Rev. 2007;28(3):322–338.PubMedCrossRefGoogle Scholar
  129. 129.
    Ruvkun G. Molecular biology. Glimpses of a tiny RNA world. Science. 2001;294:797–799.PubMedCrossRefGoogle Scholar
  130. 130.
    Cahill S, Smyth P, Denning K, et al. Effect of BRAFV600E mutation on transcription and post-transcriptional regulation in a papillary thyroid carcinoma model. Mol Cancer. 2007;6:21.PubMedCrossRefGoogle Scholar
  131. 131.
    Cahill S, Smyth P, Finn SP, et al. Effect of ret/PTC 1 rearrangement on transcription and post-transcriptional regulation in a papillary thyroid carcinoma model. Mol Cancer. 2006;5:70.PubMedCrossRefGoogle Scholar
  132. 132.
    Tetzlaff MT, Liu A, Xu X, et al. Differential expression of miRNAs in papillary thyroid carcinoma compared to multinodular goiter using formalin fixed paraffin embedded tissues. Endocr Pathol. 2007;18:163–173.PubMedCrossRefGoogle Scholar
  133. 133.
    Hunt JL, Fowler M, Lomago D, et al. Tumor suppressor gene allelic loss profiles of the variants of papillary thyroid carcinoma. Diagn Mol Pathol. 2004;13:41–46.PubMedCrossRefGoogle Scholar
  134. 134.
    Roque L, Nunes VM, Ribeiro C, Martins C, Soares J. Karyotypic characterization of papillary thyroid carcinomas. Cancer. 2001;92:2529–2538.PubMedCrossRefGoogle Scholar
  135. 135.
    Alsanea O, Clark OH. Familial thyroid cancer. Curr Opin Oncol. 2001;13:44–51.PubMedCrossRefGoogle Scholar
  136. 136.
    Corvi R, Lesueur F, Martinez-Alfaro M, et al. RET rearrangements in familial papillary thyroid carcinomas. Cancer Lett. 2001;170:191–198.PubMedCrossRefGoogle Scholar
  137. 137.
    Eng C. Familial papillary thyroid cancer - many syndromes, too many genes? J Clin Endocrinol Metab. 2000;85:1755–1757.PubMedCrossRefGoogle Scholar
  138. 138.
    Frich L, Glattre E, Akslen LA. Familial occurrence of nonmedullary thyroid cancer: a population-based study of 5673 first-degree relatives of thyroid cancer patients from Norway. Cancer Epidemiol Biomarkers Prev. 2001;10:113–117.PubMedGoogle Scholar
  139. 139.
    Gorson D. Familial papillary carcinoma of the thyroid. Thyroid. 1992;2:131–132.PubMedCrossRefGoogle Scholar
  140. 140.
    Malchoff CD, Sarfarazi M, Tendler B, Forouhar F, Whalen G, Malchoff DM. Familial papillary thyroid carcinoma is genetically distinct from familial adenomatous polyposis coli. Thyroid. 1999;9:247–252.PubMedCrossRefGoogle Scholar
  141. 141.
    Malchoff CD, Malchoff DM. Familial papillary thyroid carcinoma. Cancer Treat Res. 2004;122:381–387.PubMedCrossRefGoogle Scholar
  142. 142.
    McKay JD, Williamson J, Lesueur F, et al. At least three genes account for familial papillary thyroid carcinoma: TCO and MNG1 excluded as susceptibility loci from a large Tasmanian family. Eur J Endocrinol. 1999;141:122–125.PubMedCrossRefGoogle Scholar
  143. 143.
    Narita T, Takagi K. Ataxia-telangiectasia with dysgerminoma of right ovary, papillary carcinoma of thyroid, and adenocarcinoma of pancreas. Cancer. 1984;54:1113–1116.PubMedCrossRefGoogle Scholar
  144. 144.
    Cameselle-Teijeiro J, Chan JK. Cribriform-morular variant of papillary carcinoma: a distinctive variant representing the sporadic counterpart of familial adenomatous polyposis-associated thyroid carcinoma? Mod Pathol. 1999;12:400–411.PubMedGoogle Scholar
  145. 145.
    Chan JK, Loo KT. Cribriform variant of papillary thyroid carcinoma. Arch Pathol Lab Med. 1990;114:622–624.PubMedGoogle Scholar
  146. 146.
    Harach HR, Williams GT, Williams ED. Familial adenomatous polyposis associated thyroid carcinoma: a distinct type of follicular cell neoplasm. Histopathology. 1994;25:549–561.PubMedCrossRefGoogle Scholar
  147. 147.
    Soravia C, Sugg SL, Berk T, et al. Familial adenomatous polyposis-associated thyroid cancer: a clinical, pathological, and molecular genetics study. Am J Pathol. 1999;154:127–135.PubMedGoogle Scholar
  148. 148.
    Xu B, Yoshimoto K, Miyauchi A, et al. Cribriform-morular variant of papillary thyroid carcinoma: a pathological and molecular genetic study with evidence of frequent somatic mutations in exon 3 of the beta-catenin gene. J Pathol. 2003;199:58–67.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Lori A. Erickson
    • 1
  • Ricardo V. Lloyd
    • 2
  1. 1.Department of Laboratory Medicine and PathologyMayo ClinicRochesterUSA
  2. 2.Department of PathologyMayo ClinicRochesterUSA

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