Endocrine Pathology

, Volume 16, Issue 4, pp 295–309 | Cite as

The role of immunohistochemical markers in the diagnosis of follicular-patterned lesions of the thyroid

  • Sylvia L. Asa
EPS Proceedings

Abstract

Thyroid nodules are extremely common in the general population. The differential diagnosis includes numerous entities, non-neoplastic and neoplastic, benign and malignant. However, the diagnosis of follicular-patterned lesions remains an area fraught with controversy and diagnostic criteria are highly variable. It is, therefore, a field in need of objective, scientific markers that better characterize these lesions than has been possible by classical morphology. A number of candidates have been proposed. No single marker can identify all malignant follicular-patterned lesions, however, various combinations have been proposed. They include HBME-1, high molecular weight cytokeratins and ret, galectin-3 and TPO, galectin-3, fibronectin-1, CITED-1, HBME-1, and CK19. Advances in our understanding of the molecular basis of thyroid cancer will allow the identification of new markers and more accurate characterization of specific subtypes of neoplasia and malignancy. As new markers are characterized and validated, directed by molecular profiling of thyroid lesions with characteristic morphology, behavior, and outcome, they will become available as routine immunohistochemical markers that will provide a more accurate, scientific, and clinically relevant consultation report from the pathologist for cytology and surgical pathology procedures. Application of these markers will enhance the diagnosis of thyroid nodules and better guide the management of patients with these lesions.

Key Words

Thyroid immunohistochemistry follicular lesions cytology 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Ezzat S, Sarti DA, Cain DR, Braunstein GD. Thyroid incidentalomas. Prevalence by palpation and ultrasonography. Arch Intern Med 154:1838–1840, 1994.PubMedGoogle Scholar
  2. 2.
    Hedinger C, Williams ED, Sobin LH. The WHO histological classification of thyroid tumors: A commentary on the second edition. Cancer 63:908–911, 1989.PubMedGoogle Scholar
  3. 3.
    LiVolsi VA. Surgical pathology of the thyroid. Philadelphia, PA: W.B. Saunders, 1990.Google Scholar
  4. 4.
    Murray D. The thyroid gland. In: Kovacs K and Asa SL, eds. Functional endocrine pathology, Boston: Blackwell Science, 1998, pp. 295–380.Google Scholar
  5. 5.
    Rosai J, Carcangiu ML, DeLellis RA. Tumors of the thyroid gland. Atlas of Tumor Pathology, Third Series, Fascicle 5. Washington, DC: Armed Forces Institute of Pathology, 1992.Google Scholar
  6. 6.
    Saxen E, Franssila K, Bjarnason O, Normann T, Ringertz N. Observer variation in histologic classification of thyroid cancer. Acta Pathol Microbiol Scand [A] 86A:483–486, 1978.Google Scholar
  7. 7.
    Hirokawa M, Carney JA, Goellner JR, et al. Observer variation of encapsulated follicular lesions of the thyroid gland. Am J Surg Pathol 26:1508–1514, 2002.PubMedGoogle Scholar
  8. 8.
    Fassina AS, Montesco MC, Ninfo V, Denti P, Masarotto G. Histological evaluation of thyroid carcinomas: reproducibility of the “WHO” classification. Tumori 79:314–320, 1993.PubMedGoogle Scholar
  9. 9.
    Franc B, de la Salmoniere P, Lange F, et al. Interobserver and intraobserver reproducibility in the histopathology of follicular thyroid carcinoma. Hum Pathol 34:1092–1100, 2003.PubMedGoogle Scholar
  10. 10.
    Lloyd RV, Erickson LA, Casey MB, et al. Observer variation in the diagnosis of follicular variant of papillary thyroid carcinoma. Am J Surg Pathol 28:1336–1340, 2004.PubMedGoogle Scholar
  11. 11.
    Studer H, Peter H-J, Gerber H. Natural heterogeneity of thyroid cells: the basis for understanding thyroid function and nodular goiter growth. Endocr Rev 10:125–135, 1989.PubMedGoogle Scholar
  12. 12.
    Aeschimann S, Kopp PA, Kimura ET, et al. Morphological and functional polymorphism within clonal thyroid nodules. J Clin Endocrinol Metab 77:846–851, 1993.PubMedGoogle Scholar
  13. 13.
    Studer H, Ramelli F. Simple goiter and its variants: euthyroid and hyperthyroid multinodular goiters. Endocr Rev 3:40–61, 1982.PubMedGoogle Scholar
  14. 14.
    Peter HJ, Gerber H, Studer H, Smeds S. Pathogenesis of heterogeneity in human multinodular goiter. A study on growth and function of thyroid tissue transplanted onto nude mice. J Clin Invest 76:1992–2002, 1985.PubMedGoogle Scholar
  15. 15.
    Apel RL, Ezzat S, Bapat B, Pan N, LiVolsi VA, Asa SL. Clonality of thyroid nodules in sporadic goiter. Diag Mol Pathol 4:113–121, 1995.Google Scholar
  16. 16.
    Parma J, Duprez L, Van Sandem H, et al. Diversity and prevalence of somatic mutations in the thyrotropin receptor and Gs alpha genes as a cause of toxic thyroid adenomas. J Clin Endocrinol Metab 82:2695–2701, 1997.PubMedGoogle Scholar
  17. 17.
    Krohn D, Fuhrer D, Holzapfel H, Paschke R. Clonal origin of toxic thyroid nodules with constitutively activating thyrotropin receptor mutations. J Clin Endocrinol Metab 83:180–184, 1998.Google Scholar
  18. 18.
    Ezzat S, Zheng L, Kholenda J, Safarian A, Freeman JL, Asa SL. Prevalence of activating ras mutations in morphologically characterized thyroid nodules. Thyroid 6:409–416, 1996.PubMedGoogle Scholar
  19. 19.
    Hicks DG, LiVolsi VA, Neidich JA, Puck JM, Kant JA. Clonal analysis of solitary follicular nodules in the thyroid. Am J Pathol 137:553–562, 1990.PubMedGoogle Scholar
  20. 20.
    Namba H, Matsuo K, Fagin JA. Clonal composition of benign and malignant human thyroid tumors. J Clin Invest 86:120–125, 1990.PubMedGoogle Scholar
  21. 21.
    Treseler PA, Clark OH. Prognostic factors in thyroid carcinoma. Surg Oncol Clin N Am 6:555–598, 1997.PubMedGoogle Scholar
  22. 22.
    Clark OH. Predictors of thyroid tumor aggressiveness. West J Med 165:131–138, 1996.PubMedGoogle Scholar
  23. 23.
    Yamashina M. Follicular neoplasms of the thyroid. Total circumferential evaluation of the fibrous capsule. Am J Surg Pathol 16:392–400, 1992.PubMedGoogle Scholar
  24. 24.
    Kahn NF, Perzin KH. Follicular carcinoma of the thyroid: an evaluation of the histologic criteria used for diagnosis. Pathol Annu 1:221–253, 1983.Google Scholar
  25. 25.
    Jorda M, Gonzalez-Campora R, Mora J, Herrero-Zapatero A, Otal C, Galera H. Prognostic factors in follicular carcinoma of the thyroid. Arch Pathol Lab Med 117:631–635, 1993.PubMedGoogle Scholar
  26. 26.
    van Heerden JA, Hay ID, Goellner JR, et al. Follicular thyroid carcinoma with capsular invasion alone: a nonthreatening malignancy. Surgery 112:1130–1138, 1992.PubMedGoogle Scholar
  27. 27.
    Harness JK, Thompson NW, McLeod MK, Eckhauser FE, Lloyd RV. Follicular carcinoma of the thyroid gland: trends and treatment. Surgery 96:972–980, 1984.PubMedGoogle Scholar
  28. 28.
    Samaan NA, Schultz PN, Haynie TP, Ordonez NG. Pulmonary metastasis of differentiated thyroid carcinoma: treatment results in 101 patients. J Clin Endocrinol Metab 65:376–380, 1985.Google Scholar
  29. 29.
    DeGroot LJ, Kaplan EL, Shukla MS, Salti G, Straus FH. Morbidity and mortality in follicular thyroid cancer. J Clin Endocrinol Metab 80:2946–2953, 1995.PubMedGoogle Scholar
  30. 30.
    Mizukami Y, Michigishi T, Nonomura A, et al. Distant metastases in differentiated thyroid carcinomas: a clinical and pathologic study. Hum Pathol 21:283–290, 1990.PubMedGoogle Scholar
  31. 31.
    LiVolsi VA, Asa SL. The demise of follicular carcinoma of the thyroid gland. Thyroid 4:233–235, 1994.PubMedGoogle Scholar
  32. 32.
    Shah JP, Loree TR, Dharker D, Strong EW. Lobectomy versus total thyroidectomy for differentiated carcinoma of the thyroid: a matched-pair analysis. Am J Surg 166:331–335, 1993.PubMedGoogle Scholar
  33. 33.
    Singer PA, Cooper DS, Daniels GH, et al. Treatment guidelines for patients with thyroid nodules and well-differentiated thyroid cancer. American Thyroid Association. Arch Intern Med 156:2165–2172, 1996.PubMedGoogle Scholar
  34. 34.
    Pasieka JL, Thompson NW, McLeod MK, Burney RE, Macha M. The incidence of bilateral well-differentiated thyroid cancer found at completion thyroidectomy. World J Surg 16:711–717, 1992.PubMedGoogle Scholar
  35. 35.
    Mazzaferri EL, Jhiang SM. Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med 97:418–428, 1994.PubMedGoogle Scholar
  36. 36.
    Benker G, Olbricht Th, Reinwein D, et al. Survival rates in patients with differentiated thyroid carcinoma. Influence of postoperative external radiotherapy. Cancer 65:1517–1520, 1990.PubMedGoogle Scholar
  37. 37.
    Tsang RW, Brierley JD, Simpson WJ, Panzarella T, Gospodarowicz MK, Sutcliffe SB. The effects of surgery, radioiodine, and external radiation therapy on the clinical outcome of patients with differentiated thyroid carcinoma. Cancer 82:375–388, 1998.PubMedGoogle Scholar
  38. 38.
    LiVolsi VA, Merino MJ. Worrisome histologic alterations following fine needle aspiration of the thyroid. Pathol Annu 29:99–120, 1994.PubMedGoogle Scholar
  39. 39.
    Vickery AL. Thyroid papillary carcinoma. Pathological and philosophical controversies. Am J Surg Pathol 7:797–807, 1983.PubMedGoogle Scholar
  40. 40.
    Vickery AL, Carcangiu ML, Johannessen JV, et al. Papillary carcinoma. Semin Diagn Pathol 2:90–100, 1985.PubMedGoogle Scholar
  41. 41.
    Rosai J, Zampi G, Carcangiu ML, et al. Papillary carcinoma of the thyroid. Am J Surg Pathol 7:809–817, 1983.PubMedGoogle Scholar
  42. 42.
    Carcangiu ML, Zampi G, Pupi A, Castagnoli A, Rosai J. Papillary carcinoma of the thyroid. A clinicopathologic study of cases treated at the University of Florence Italy. Cancer 805:822, 1985.Google Scholar
  43. 43.
    LiVolsi VA. Papillary neoplasms of the thyroid. Pathologic and prognostic features. Am J Clin Pathol 97:426–434, 1992.PubMedGoogle Scholar
  44. 44.
    Carcangiu ML, Zampi G, Rosai J. Papillary thyroid carcinoma: a study of its many morphologic expressions and clinical correlates. Pathol Annu 20:1–44, 1985.PubMedGoogle Scholar
  45. 45.
    Bocker W, Schroder S, Dralle H. Minimal thyroid neoplasia. Rec Results Cancer Res 106:131–138, 1988.Google Scholar
  46. 46.
    Carcangiu ML, Zampi G, Rosai J. Papillary thyroid carcinoma: a study of its many morphologic expressions and clinical correlates. Pathol Annu 20 (Part 1):1–44, 1985.PubMedGoogle Scholar
  47. 47.
    Hay ID. Papillary thyroid carcinoma. Endocrinol Metab Clin North Am 19:545–576, 1990.PubMedGoogle Scholar
  48. 48.
    Mazzaferri E, Jhiang S. Long-term follow-up impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med 97:418–428, 1994.PubMedGoogle Scholar
  49. 49.
    Brierley JD, Panzarella T, Tsang RW, Gospodarowicz MK, O’Sullivan B. A comparison of different staging systems predictability of patient outcome. Thyroid carcinoma as an example. Cancer 79:2414–2423, 1997.PubMedGoogle Scholar
  50. 50.
    Noguchi M, Tanaka S, Akiyama T, et al. Clinicopathological studies of minimal thyroid and ordinary thyroid cancers. Jpn J Surg 13:110–117, 1984.Google Scholar
  51. 51.
    Fink A, Tomlinson G, Freeman JL, Rosen IB, Asa SL. Occult micropapillary carcinoma associated with benign follicular thyroid disease and unrelated thyroid neoplasms. Mod Pathol 9:816–820, 1996.PubMedGoogle Scholar
  52. 52.
    Harach HR, Franssila KO, Wasenius V-M. Occult papillary carcinoma of the thyroid. A “normal” finding in Finland. A systematic autopsy study. Cancer 56:531–538, 1985.PubMedGoogle Scholar
  53. 53.
    Yamashita H, Noguchi S, Murkama N, et al. Prognosis of minute carcinoma of the thyroid. Follow-up study of 48 patients. Acta Pathol Jpn 36:1469–1475, 1986.PubMedGoogle Scholar
  54. 54.
    Yamashita H, Nakayama I, Noguchi S, et al. Thyroid carcinoma in benign thyroid diseases. An analysis from minute carcinoma. Acta Pathol Jpn 35:781–788, 1985.PubMedGoogle Scholar
  55. 55.
    Chen KTK, Rosai J. Follicular variant of thyroid papillary carcinoma: a clinicopathologic study of six cases. Am J Surg Pathol 1:123–130, 1977.Google Scholar
  56. 56.
    Tielens ET, Sherman SI, Hruban RH, et al. Follicular variant of papillary thyroid carcinoma; a clinicopathologic study. Cancer 73:424–431, 1994.PubMedGoogle Scholar
  57. 57.
    Hedinger C, Williams ED, Sobin LH. Histological typing of thyroid tumours. In: World Health Organization international histological classification of tumours. Berlin: Springer-Verlag, 1988.Google Scholar
  58. 58.
    Sugg SL, Ezzat S, Rosen IB, Freeman J, Asa SL. Distinct multiple ret/PTC gene rearrangements in multifocal papillary thyroid neoplasia. J Clin Endocrinol Metab 83:4116–4122, 1998.PubMedGoogle Scholar
  59. 59.
    Miettinen M, Karkkainen P. Differential reactivity of HBME-1 and CD15 antibodics in benign and malignant thyroid tumours. Preferential reactivity with malignant tumours. Virchows Arch 429:213–219, 1996.PubMedGoogle Scholar
  60. 60.
    Sack MJ, Astengo-Osuna C, Lin BT, Battifora H, LiVolsi VA. HBME-1 immunostaining in thyroid fine-needle aspirations: a useful marker in the diagnosis of carcinoma. Mod Pathol 10:668–674, 1997.PubMedGoogle Scholar
  61. 61.
    van Hoeven KH, Kovatich AJ, Miettinen M. Immunocytochemical evaluation of HBME-1, CA 19-9, and CD-15 (Leu-M1) in fine-needle aspirates of thyroid nodules. Diagn Cytopathol 18:93–97, 1997.Google Scholar
  62. 62.
    Fernandez PL, Merino MJ, Gomez M, et al. Galectin-3 and laminin expression in neoplastic and non-neoplastic thyroid tissue. J Pathol 181:80–86, 1997.PubMedGoogle Scholar
  63. 63.
    Orlandi F, Saggiorato E, Pivano G, et al. Galectin-3 is a presurgical marker of human thyroid carcinoma. Cancer Res 58:3015–3020, 1998.PubMedGoogle Scholar
  64. 64.
    Cvejic D, Savin S, Paunovic I, Tatic S, Havelka M, Sindinovic J. Immunohistochemical localization of galectin-3 in malignant and benign human thyroid tissue. Anticancer Res 18:2637–2642, 1998.PubMedGoogle Scholar
  65. 65.
    Mehrotra P, Okpokam A, Bouhaidar R, et al. Galectin-3 does not reliably distinguish benign from malignant thyroid neoplasms. Histopathology 45:493–500, 2004.PubMedGoogle Scholar
  66. 66.
    Inohara H, Honjo Y, Yoishii T, et al. Expression of galectin-3 in fine-needle aspirates as a diagnostic marker differentiating benign from malignant thyroid neoplasms. Cancer 85:2475–2484, 1999.PubMedGoogle Scholar
  67. 67.
    Sahoo S, Hoda SA, Rosai J, DeLellis RA. Cytokeratin 19 immunoreactivity in the diagnosis of papillary thyroid carcinoma: a note of caution. Am J Clin Pathol 116:696–702, 2001.PubMedGoogle Scholar
  68. 68.
    Asa SL, Cheung CC. The mind’s eye. Am J Clin Pathol 116:635–636, 2001.PubMedGoogle Scholar
  69. 69.
    Raphael SJ, Apel RL, Asa SL. Detection of high-molecular-weight cytokeratins in neoplastic and non-neoplastic thyroid tumors using microwave antigen retrieval. Mod Pathol 8:870–872, 1995.PubMedGoogle Scholar
  70. 70.
    Santoro M, Carlomagno F, Hay ID, et al. Ret oncogene activation in human thyroid neoplasms is restricted to the papillary cancer subtype. J Clin Invest 89:1517–1522, 1992.PubMedGoogle Scholar
  71. 71.
    Tallini G, Asa SL. RET oncogene activation in papillary thyroid carcinoma. Adv Anat Pathol 8:345–354, 2001.PubMedGoogle Scholar
  72. 72.
    Fusco A, Grieco M, Santoro M, et al. A new oncogene in human thyroid papillary carcinomas and their lymph-nodal metastases. Nature 328:170–172, 1987.PubMedGoogle Scholar
  73. 73.
    Pierotti MA, Santoro M, Jenkins RB, et al. Characterization of an inversion on the long arm of chromosome 10 juxtaposing D10S170 and RET and creating the oncogenic sequence RET/PTC. Proc Natl Acad Sci USA 89:1616–1620, 1992.PubMedGoogle Scholar
  74. 74.
    Minoletti F, Butti MG, Coronelli S, et al. The two genes generating RET/PTC3 are localized in chromosomal band 10q11.2. Genes, Chromosomes Cancer 11:51–57, 1994.PubMedGoogle Scholar
  75. 75.
    Sozzi G, Bongarzone I, Miozzo M, et al. A t(10;17) translocation creates the RET/PTC2 chimeric transforming sequence in papillary thyroid carcinoma. Genes, Chromosomes Cancer 9:244–250, 1994.PubMedGoogle Scholar
  76. 76.
    Jhiang SM, Mazzaferri EL. The ret/PTC oncogene in papillary thyroid carcinoma [Review]. J Lab Clin Med 123:331–337, 1994.PubMedGoogle Scholar
  77. 77.
    Ishizaka Y, Shima H, Sugimura T, Nagao M. Detection of phosphorylated ret/TPC oncogene product in cytoplasm. Oncogene 7:1441–1444, 1992.PubMedGoogle Scholar
  78. 78.
    Jhiang SM, Sagartz JE, Tong Q, et al. Targeted expression of the ret/PTC1 oncogene induces papillary thyroid carcinomas. Endocrinology 137:375–378, 1996.PubMedGoogle Scholar
  79. 79.
    Santoro M, Chiappetta G, Cerrato A, et al. Development of thyroid papillary carcinomas secondary to tissue-specific expression of the RET/PTC1 oncogene in transgenic mice. Oncogene 12:1821–1826, 1996.PubMedGoogle Scholar
  80. 80.
    Klugbauer S, Lengfelder E, Demidchik EP, Rabes HM. High prevalence of RET rearrangement in thyroid tumors of children from Belarus after the Chernobyl reactor accident. Oncogene 11:2459–2467, 1995.PubMedGoogle Scholar
  81. 81.
    Nishisho I, 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 carcinoma in children. Cancer Res 57:1690–1694, 1997.Google Scholar
  82. 82.
    Klugbauer S, Lengfelder E, Demidchik EP, Rabes HM. A new form of RET rearrangement in thyroid carcinomas of children after the Chernobyl reactor accident. Oncogene 13:1099–1102, 1996.PubMedGoogle Scholar
  83. 83.
    Fugazzola L, Pierotti MA, Vigano E, Pacini F, Vorontsova TV, Bongarzone I. Molecular and biochemical analysis of RET/PTC4, a novel oncogenic rearrangement between RET and ELE1 genes, in a post-Chernobyl papillary thyroid cancer. Oncogene 13:1093–1097, 1996.PubMedGoogle Scholar
  84. 84.
    Klugbauer S, Demidchik EP, Lengfelder E, Rabes HM. Detection of a novel type of RET rearrangement (PTC5) in thyroid carcinomas after Chernobyl and analysis of the involved RET-fused gene RFG5. Cancer Res 58:198–203, 1998.PubMedGoogle Scholar
  85. 85.
    Williams GH, Rooney S, Thomas GA, Cummins G, Williams ED. RET activation in adult and childhood papillary thyroid carcinoma using a reverse transcriptase-poly-merase chain reaction approach on archivalnested material. Br J Cancer 74:585–589, 1996.PubMedGoogle Scholar
  86. 86.
    Jhiang SM, Caruso DR, Gilmore E, et al. Detection of the PTC/retTPC oncogene in human thyroid cancers. Oncogene 7:1331–1337, 1992.PubMedGoogle Scholar
  87. 87.
    Sugg SL, Zheng L, Rosen IB, Freeman JL, Ezzat S, Asa SL. ret/PTC-1,-2 and -3 oncogene rearrangements in human thyroid carcinomas: implications for metastatic potential? J Clin Endocrinol Metab 81:3360–3365, 1996.PubMedGoogle Scholar
  88. 88.
    Mayr B, Brabant G, Goretzki P, Ruschoff J, Dietmaier W, Dralle H. ret/Ptc-1, -2, and -3 oncogene rearrangements in human thyroid carcinomas: implications for metastatic potential? [letter; comment]. J Clin Endocrinol Metab 82:1306–1307, 1997.PubMedGoogle Scholar
  89. 89.
    Viglietto G, Chiappetta G, Martinez-Tello FJ, et al. RET/PTC oncogene activation is an early event in thyroid carcinogenesis. Oncogene 11:1207–1210, 1995.PubMedGoogle Scholar
  90. 90.
    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 86:2187–2190, 2001.PubMedGoogle Scholar
  91. 91.
    Thompson NW, Dunn EL, Batsakis JG, Nishiyama RH. Hürthle cell lesions of the thyroid gland. Surg Gynecol Obstet 139:555–560, 1974.PubMedGoogle Scholar
  92. 92.
    Grant CS, Barr D, Goellner JR, Hay ID. Benign Hürthle cell tumors of the thyroid: a diagnosis to be trusted? World J Surg 12:488–495, 1988.PubMedGoogle Scholar
  93. 93.
    Cheung CC, Ezzat S, Ramyar L, Freeman JL, Asa SL. Molecular basis of Hurthle cell papillary thyroid carcinoma. J Clin Endocrinol Metab 85:878–882, 2000.PubMedGoogle Scholar
  94. 94.
    Chiappetta G, Toti P, Cetta F, et al. The RET/PTC oncogene is frequently activated in oncocytic thyroid tumors (Hurthle cell adenomas and carcinomas), but not in oncocytic hyperplastic lesions. J Clin Endocrinol Metab 87:364–369, 2002.PubMedGoogle Scholar
  95. 95.
    Belchetz G, Cheung CC, Freeman J, Rosen IB, Witterick IJ, Asa SL. Hurthle cell tumors: using molecular techniques to define a novel classification system. Arch Otolaryngol Head Neck Surg 128:237–240, 2002.PubMedGoogle Scholar
  96. 96.
    Asa SL. My approach to oncocytic tumours of the thyroid. J Clin Pathol 57:225–232, 2004.PubMedGoogle Scholar
  97. 97.
    Volante M, Bozzalla-Cassione F, DePompa R, et al. Galectin-3 and HBME-1 expression in oncocytic cell tumors of the thyroid. Virchows Arch 445:183–188, 2004.PubMedGoogle Scholar
  98. 98.
    Cohen Y, Xing M, Mambo E, et al. BRAF mutation in papillary thyroid carcinoma. J Natl Cancer Inst 95:625–627, 2003.PubMedGoogle Scholar
  99. 99.
    Fukushima T, Suzuki S, Mashiko M, et al. BRAF mutations in papillary carcinomas of the thyroid. Oncogene 22:6455–6457, 2003.PubMedGoogle Scholar
  100. 100.
    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 63:1454–1457, 2003.PubMedGoogle Scholar
  101. 101.
    Namba H, Nakashima M, Hayashi T, et al. Clinical implication of hot spot BRAF mutation, V599E, in papillary thyroid cancers. J Clin Endocrinol Metab 88:4393–4397, 2003.PubMedGoogle Scholar
  102. 102.
    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 88:5399–5404, 2003.PubMedGoogle Scholar
  103. 103.
    Soares P, Trovisco V, Rocha AS, et al. BRAF mutations and RET/PTC rearrangements are alternative events in the etiopathogenesis of PTC. Oncogene 22:4578–4580, 2003.PubMedGoogle Scholar
  104. 104.
    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 63:4561–4567, 2003.PubMedGoogle Scholar
  105. 105.
    Trovisco V, Vieira DC, I, Soares P, et al. BRAF mutations are associated with some histological types of papillary thyroid carcinoma. J Pathol 202:247–251, 2004.PubMedGoogle Scholar
  106. 106.
    Xing M, Vasko V, Tallini G, et al. BRAF T1796A transversion mutation in various thyroid neoplasms. J Clin Endocrinol Metab 89:1365–1368, 2004.PubMedGoogle Scholar
  107. 107.
    Umbricht CB, Saji M, Westra WH, Udelsman R, Zeiger MA, Sukumar S. Telomerase activity: a marker to distinguish follicular thyroid adenoma from carcinoma. Cancer Res 57:2144–2147, 1997.PubMedGoogle Scholar
  108. 108.
    Haugen BR, Nawaz S, Markham N, et al. Telomerase activity in benign and malignant thyroid tumors. Thyroid 7:337–342, 1997.PubMedGoogle Scholar
  109. 109.
    Khoo ML, Ezzat S, Freeman JL, Asa SL. Cyclin D1 protein expression predicts metastatic behavior in thyroid papillary microcarcinomas but is not associated with gene amplification. J Clin Endocrinol Metab 87:1810–1813, 2002.PubMedGoogle Scholar
  110. 110.
    Khoo ML, Beasley NJ, Ezzat S, Freeman JL, Asa SL. Overexpression of cyclin D1 and underexpression of p27 predict lymph node metastases in papillary thyroid carcinoma. J Clin Endocrinol Metab 87:1814–1818, 2002.PubMedGoogle Scholar
  111. 111.
    Khoo ML, Freeman JL, Witterick IJ, et al. Underexpression of p27/Kip in thyroid papillary microcarcinomas with gross metastatic disease. Arch Otolaryngol Head Neck Surg 128:253–257, 2002.PubMedGoogle Scholar
  112. 112.
    Mitselou A, Peschos D, Dallas P, Charalabopoulos K, Agnantis NJ, Vougiouklakis T. Immunohistochemical analysis of expression of bcl-2 protein in papillary carcinomas and papillary microcarcinomas of the thyroid gland. Exp Oncol 26:282–286, 2004.PubMedGoogle Scholar
  113. 113.
    Kroll TG, Sarraf P, Pecciarini L, et al. PAX8-PPARgammal fusion oncogene in human thyroid carcinoma. Science 289:1357–1360, 2000.PubMedGoogle Scholar
  114. 114.
    Nikiforova MN, Biddinger PW, Caudill CM, Kroll TG, Nikiforov YE. PAX8-PPARgamma rearrangement in thyroid tumors: RT-PCR and immunohistochemical analyses. Am J Surg Pathol 26:1016–1023, 2002.PubMedGoogle Scholar
  115. 115.
    Lacroix L, Mian C, Barrier T, et al. PAX8 and peroxisome proliferator-activated receptor gamma 1 gene expression status in benign and malignant thyroid tissues. Eur J Endocrinol 151:367–374, 2004.PubMedGoogle Scholar
  116. 116.
    Gustafson KS, LiVolsi VA, Furth EE, Pasha TL, Putt ME, Baloch ZW. Peroxisome proliferator-activated receptor gamma expression in follicular-patterned thyroid lesions. Caveats for the use of immunohistochemical studies. Am J Clin Pathol 120:175–181, 2003.PubMedGoogle Scholar
  117. 117.
    Sahin M, Allard BL, Yates M, et al. PPAR {gamma} staining as a surrogate for PAX8/PPAR{gamma} fusion oncogene expression in follicular neoplasms: clinico-pathologic correlation and histopathological diagnostic value. J Clin Endocrinol Metab 90:463–468, 2004.PubMedGoogle Scholar
  118. 118.
    Mineo R, Costantino A, Frasca F, et al. Activation of the hepatocyte growth factor (HGF)-Met system in papillary thyroid cancer: biological effects of HGF in thyroid cancer cells depend on Met expression levels. Endocrinology 145:4355–4365, 2004.PubMedGoogle Scholar
  119. 119.
    Weber KB, Shroyer KR, Heinz DE, Nawaz S, Said MS, Haugen BR. The use of a combination of galectin-3 and thyroid peroxidase for the diagnosis and prognosis of thyroid cancer. Am J Clin Pathol 122:524–531, 2004.PubMedGoogle Scholar
  120. 120.
    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 14:169–175, 2004.PubMedGoogle Scholar
  121. 121.
    Casey MB, Zhang S, Jin L, Kajita S, Lloyd RV. Expression of cyclooxygenase-2 and thromboxane synthase in non-neoplastic and neoplastic thyroid lesions. Endocr Pathol 15:107–116, 2004.PubMedGoogle Scholar
  122. 122.
    Nasir A, Catalano E, Calafati S, Cantor A, Kaiser HE, Coppola D. Role of p53, CD44V6 and CD57 in differentiating between benign and malignant follicular neoplasms of the thyroid. In Vivo 18:189–195, 2004.PubMedGoogle Scholar
  123. 123.
    Chen Z, Mustafa T, Trojanowicz B, et al. CD82, and CD63 in thyroid cancer. Int J Mol Med 14:517–527, 2004.PubMedGoogle Scholar
  124. 124.
    Czyz W, Balcerczak E, Jakubiak M, Pasieka Z, Kuzdak K, Mirowski M. HMGI(Y) gene expression as a potential marker of thyroid follicular carcinoma. Langenbecks Arch Surg 389:193–197, 2004.PubMedGoogle Scholar
  125. 125.
    Wreesmann VB, Sieczka EM, Socci ND, et al. Genome-wide profiling of papillary thyroid cancer identifies MUC1 as an independent prognostic marker. Cancer Res 64:3780–3789, 2004.PubMedGoogle Scholar
  126. 126.
    Torres-Cabala C, Panizo-Santos A, Krutzsch HC, et al. Differential expression of S100C in thyroid lesions. Int J Surg Pathol 12:107–115, 2004.PubMedGoogle Scholar
  127. 127.
    Cheung CC, Ezzat S, Freeman JL, Rosen IB, Asa SL. Immunohistochemical diagnosis of papillary thyroid carcinoma. Mod Pathol 14:338–342, 2001.PubMedGoogle Scholar
  128. 128.
    Prasad ML, Pellegata NS, Huang Y, Nagaraja HN, Chapelle AA, Kloos RT. Galectin-3, fibronectin-1, CITED-1, HBME1 and cytokeratin-19 immunohistochemistry is useful for the differential diagnosis of thyroid tumors. Mod Pathol 8:48–57, 2005.Google Scholar
  129. 129.
    Huang Y, Prasad M, Lemon WJ, et al. Gene expression in papillary thyroid carcinoma reveals highly consistent profiles. Proc Natl Acad Sci U S A 98:15044–15049, 2001.PubMedGoogle Scholar

Copyright information

© Humana Press Inc 2005

Authors and Affiliations

  • Sylvia L. Asa
    • 1
    • 2
  1. 1.Department of Laboratory Medicine and PathobiologyUniversity of TorontoTorontoCanada
  2. 2.University Health Network, Toronto General Hospital Toronto Western Hospital—Princess Margaret HospitalTorontoCanada

Personalised recommendations