Современный взгляд на проблему диагностики и лечения медуллярного рака щитовидной железы

За последние 4 года ведущие эндокринологические сообщества разных стран выпустили рекомендации, посвященные диагностике и лечению медуллярного рака щитовидной железы. Статья охватывает большинство аспектов ведения пациентов с данной патологией.

медуллярный рак щитовидной железы, синдром множественных эндокринных неоплазий 2 типа, кальцитонин, раково-эмбриональный антиген, RET- протоонкоген

1. Hundahl SA, Fleming ID, Fremgen AM, Menck HR. A National Cancer Data Base report on 53,856 cases of thyroid carcino ma treated in the U.S., 1985–1995. Cancer. 1998;83:2638-2648.

2. Leboulleux S, Baudin B, Travagli JP, Schlumberger M. Medullary thyroid carcinoma. Clin Endocrinol (Oxf). 2004;61:299-310.

3. Kebebew E, Ituarte PH, Siperstein AE et al. Medullary thyroid carcinoma: clinical characteristics, treatment, prognostic factors, and a comparison of staging systems. Cancer. 2000;88:1139-1148.

4. Xu L, Wang WB, Zhao YP et al. Medullary thyroid carcinoma with nodular goiter carries an excellent prognosis. J Surg Oncol. 2012;106:169-173.

5. PylayevaGupta Y, Grabocka E, BarSagi D. RAS oncogenes: weaving a tumorigenic web. Nat Rev Cancer. 2011;11:761-774.

6. Pelizzo MR, Boschin IM, Bernante P et al. Natural history, diagnosis, treatment and outcome of medullary thyroid can cer: 37 years experience on 157 patients. Eur J Surg Oncol. 2007;33:493-497.

7. Baloch ZW, LiVolsi VA. Prognostic factors in well-differentia ted follicular-derived carcinoma and medullary thyroid carci noma. Thyroid. 2001;11:637-645.

8. Paszko Z, Sromek M, Czetwertynska M et al. The occurrence and the type of germline mutations in the RET gene in patients with medullary thyroid carcinoma and their un affected kindreds from Central Poland. Cancer Invest. 2007;25:742749.

9. Bergant D, Hocevar M, Besic N et al. Hereditary medullary thyroid cancer in Slovenia – genotypephenotype correla tions. Wien Klin Wochenschr. 2006;118:411416.

10. Ильин АА, Румянцев ПО, Исаев ПА и др. Спорадический и семейный варианты медуллярного рака щитовидной железы. Проблемы эндокринологии. 2003;49(5):4547.

11. Ильин АА, Румянцева УВ, Васильев ЕВ и др. Результаты генетического скрининга наследственных форм медуллярного рака щитовидной железы. 15й Российский симпозиум по хирургической эндокринологии, г. Рязань. 2005;153154.

12. Бржезовский ВЖ. Современная стратегия диагностики и лечения медуллярного рака щитовидной железы: дис. … докт. мед. наук. ГУ Российский онкологический научный центр РАМН. М., 2004; 42-152.

13. Mulligan LM, Kwok JB, Healey CS et al. Germline mutations of the RET protooncogene in multiple endocrine neoplasia type 2A. Nature. 1993;363:458460.

14. DonisKeller H, Dou S, Chi D et al. Mutations in the RET protooncogene are associated with MEN 2A and FMTC. Hum Mol Genet. 1993;2:851-856.

15. Romei C, Pardi E, Cetani F, Elisei R. Genetic and clinical features of multiple endocrine neoplasia types 1 and 2. J Oncol. 2012:11-5.

16. Brandi ML, Gagel RF, Angeli A et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab. 2001;86:5658-5671.

17. Modigliani E, Cohen R, Campos JM et al. Prognostic factors for survival and for biochemical cure in medullary thyroid car cinoma: results in 899 patients. The GETC Study Group. Groupe d’etude des tumeurs a` calcitonine. Clin Endocrinol. 1998;48:265-273.

18. Iihara M, Yamashita T, Okamoto T et al. A nationwide clinical survey of patients with multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma in Japan. Jpn J Clin Oncol. 1997;27:128-134.

19. Юкина МЮ, Гончаров НП, Бельцевич ДГ, Трошина ЕА. Множественная эндокринная неоплазия 2го типа. Про блемы эндокринологии. 2011;6:21-26.

20. Farndon JR, Leight GS, Dilley WG et al. Familial medullary thyroid carcinoma without associated endocrinopathies: a distinct clinical entity. Br J Surg. 1986;73:278-281.

21. Eng C, Clayton D, Schuffenecker I et al. The relationship between specific RET protooncogene mutations and di sease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. JAMA. 1996;276:1575-1579.

22. Carlson KM, Bracamontes J, Jackson CE et al. Parentofori gin effects in multiple endocrine neoplasia type 2B. Am J Hum Genet. 1994;55:1076-1082.

23. Kaufman FR, Roe TF, Isaacs H, Weitzman JJ. Metastatic medullary thyroid carcinoma in young children with mucosal neuroma syndrome. Pediatrics. 1982;70:263-267.

24. Machens A, Brauckhoff M, Holzhausen HJ et al. Codonspe cific development of pheochromocytoma in multiple endocrine neoplasia type 2. J Clin Endocrinol Metab. 2005;90:3999-4003.

25. Ciampi R, Mian C, Fugazzola L et al. Evidence of a low prevalence of RAS mutations in a large medullary thyroid cancer series. Thyroid. 2013;23(1):50-57.

26. Agrawal N, Jiao Y, Sausen M et al. Exomic sequencing of medullary thyroid cancer reveals dominant and mutually exclusive oncogenic mutations in RET and RAS. J Clin Endocrinol Metab. 2013;98(2):364-369.

27. Kloos RT, Eng Ch, Evans DB et al. Medullary Thyroid Cancer: Management Guidelines of the American Thyroid Asso ciation. Thyroid. 2009;19(6):565-512.

28. Cohen MS, Moley JF. Surgical treatment of medullary thyroid carcinoma. J Internal Med. 2003;253(6):616-626.

29. Cai S, Liu H, Li W et al. Ultrasonographic features of medullary thyroid carcinoma and their diagnostic values. Chin Med J. 2010;123(21):3074-3078.

30. Ильин АА, Втюрин БМ, Румянцев ПО. Ультразвуковая картина дифференцированного рака щитовидной железы у детей и подростков в загрязненных радионуклидами рай онах России. Ультразвуковая диагностика. 1997;4:68-74.

31. Kim SH, Kim BS, Jung SL et al. Ultrasonographic findings of medullary thyroid carcinoma: a comparison with papillary thy roid carcinoma. Korean J Radiol. 2009;10:101-105.

32. Lee S, Shin JH, Han BK, Ko EY. Medullary thyroid carcinoma: comparison with papillary thyroid carcinoma and application of current sonographic criteria. Am J Roentgenol. 2010;194:1090-1094.

33. Кондратьева ТТ. Возможности цитологического метода в диагностике нетипичных вариантов рака щитовидной железы. Рак щитовидной железы. Eso Red Square Seminar. Москва, 2004; 29-31.

34. Chang TC, Wu SL, Hsiao YL. Medullary thyroid carcinoma: pitfalls in diagnosis by fine needle aspiration cytology and relationship of cytomorphology to RET protooncogene mutations. Acta Cytolog. 2005;49:477-482.

35. Papaparaskeva K, Nagel H, Droese M. Cytologic diagnosis of medullary carcinoma of the thyroid gland. Diagn Cytopathol. 2000;22:351-358.

36. Bugalho MJ, Santos JR, Sobrinho L. Preoperative diagnosis of medullary thyroid carcinoma: fine needle aspiration cyto logy as compared with serum calcitonin measurement. J Surg Oncol. 2005;91:56-60.

37. Niccoli P, WionBarbot N, Caron P et al. Interest of routine measurement of serum calcitonin: study in a large series of thyroidectomized patients. The French Medullary Study Group. J Clin Endocrinol Metab. 1997;82:338-341.

38. Elisei R, Bottici V, Luchetti F et al. Impact of routine measure ment of serum calcitonin on the diagnosis and outcome of medullary thyroid cancer: experience in 10,864 patients with nodular thyroid disorders. J Clin Endocrinol Metab. 2004; 89:163-168.

39. Boi F, Maurelli I, Pinna G et al. Calcitonin measurement in washout fluid from fine needle aspiration of neck masses in patients with primary and metastatic medullary thyroid carci noma. J Clin Endocrinol Metab. 2007;92(6):2115-2118.

40. Исаев ПА. Медуллярный рак щитовидной железы (комплексная лучевая диагностика и лечение): дисс. … канд. мед. наук. ГУ Медицинский радиологический научный центр. Обнинск, 2004;9-15.

41. Massaro F, Dolcino M, Degrandi R et al. Calcitonin assay in washout fluid after fineneedle aspiration biopsy in patients with a thyroid nodule and borderline value of the hormone. J Endocrinol Invest. 2009;32(4):308-312.

42. Chambon G, Alovisetti C, IdouxLouche C et al. The use of preoperative routine measurement of basal serum thyrocalci tonin in candidates for thyroidectomy due to nodular thyroid disorders: results from 2733 consecutive patients. J Clin Endocrinol Metab. 2011;96(1):75-81.

43. Valle LA, Kloos RT. The prevalence of occult medullary thyroid carcinoma at autopsy. J Clin Endocrinol Metab. 2011;96(1): 109-113.

44. Ahmed SR, Ball DW. Incidentally discovered medullary thyroid cancer: diagnostic strategies and treatment. J Clin Endocrinol Metab. 2011;96:1237-1245.

45. Beressi N, Campos JM, Beressi JP. Sporadic medullary microcarcinoma of the thyroid: a retrospective analysis of eighty cases. Thyroid. 1998;8:1039-1044.

46. Kaserer K, Scheuba C, Neuhold N. Sporadic versus familial medullary thyroid microcarcinoma: a histopathologic study of 50 consecutive patients. Am J Surg Pathol. 2001;25: 1245-1251.

47. Peix JL, Braun P, Saadat M. et al. Occult micro medullary thy roid carcinoma: therapeutic strategy and followup. Wld J Surg. 2000;24:1373-1376.

48. Hamy A, Pessaux P, Mirallie E. Central neck dissection in the management of sporadic medullary thyroid microcarcinoma. Eur J Surg Oncol. 2005;31:774-777.

49. Henry JF, Denizot A, Puccini M. Latent subclinical medullary thyroid carcinoma: diagnosis and treatment. World J Surg. 1998;22:752-757.

50. Pillarisetty VG, Katz SC, Ghossein RA et al. Micromedullary thyroid cancer: how micro is truly micro? Ann Surg Oncol. 2009;16:2875-2881.

51. Costante G, Meringolo D, Durante C et al. Predictive value of serum calcitonin levels for preoperative diagnosis of medullary thyroid carcinoma in a cohort of 5817 consecutive patients with thyroid nodules. J Clin Endocrinol Metab. 2007; 92:450-455.

52. Pacini F, Fontanelli M, Fugazzola L et al. Routine measurement of serum calcitonin in nodular thyroid diseases allows the pre operative diagnosis of unsuspected sporadic medullary thyroid carcinoma. J. Clin. Endocrinol. Metab. 1994;78: 826-829.

53. Rieu M, Lame MC, Richard A et al. Prevalence of sporadic medullary thyroid carcinoma: the importance of routine measurement of serum calcitonin in the diagnostic evaluation of thyroid nodules. Clin Endocrinol (Oxf). 1995;42:453-460.

54. Vierhapper H, Raber W, Bieglmayer C et al. Routine mea surement of plasma calcitonin in nodular thyroid diseases. J Clin Endocrinol Metab. 1997;82:1589-1593.

55. Kaserer K, Scheuba C, Neuhold N et al. Ccell hyperplasia and medullary thyroid carcinoma in patients routinely screened for serum calcitonin. Am J Surg Pathol. 1998;22: 722-728.

56. Ozgen AG, Hamulu F, Bayraktar F et al. Evaluation of routine basal serum calcitonin measurement for early diagnosis of medullary thyroid carcinoma in seven hundred seventy three patients with nodular goiter. Thyroid. 1999;9:579-582.

57. Привалов ВА, Кулеев ИА, Сергийко СВ и др. Клинико-анатомические особенности рака щитовидной железы. 35летний опыт хирургического лечения. Современные аспекты хирургической эндокринологии. Рязань, 2005; 274-280.

58. Hahm JR, Lee MS, Min YK et al. Routine measurement of serum calcitonin is useful for early detection of medullary thyroid carcinoma in patients with nodular thyroid diseases. Thyroid. 2001;11:73-80.

59. D’Herbomez M, Caron P, Bauters C. French Group GTE (Groupe des Tumeurs Endocrines). Reference range of serum calcitonin levels in humans: influence of calcitonin assays, sex, age, and cigarette smoking. Eur J Endocrinol. 2007;157:749-755.

60. Kotzmann H, Schmidt A, Scheuba C. Basal calcitonin levels and the response to pentagastrin stimulation in patients after kidney transplantation or on chronic hemodialysis as indicators of medullary carcinoma. Thyroid. 1999;9:943-947.

61. Erdogan MF, Gullu S, Baskal N et al. Omeprazole: calcitonin stimulation test for the diagnosis followup and family screen ing in medullary thyroid carcinoma. J Clin Endocrinol Metab. 1997;82:897-899.

62. LiVolsi VA. Ccell hyperplasia = neoplasia. J Clin Endocrinol Metab. 1997;82:3941.

63. Machens A, Hoffmann F, Sekulla C, Dralle H. Importance of gender-specific calcitonin thresholds in screening for occult sporadic medullary thyroid cancer. Endocr Relat Cancer. 2009;16:1291-1298.

64. Wells Jr SA, Baylin SB, Linehan WM et al. Provocative agents and the diagnosis of medullary carcinoma of the thyroid gland. Ann Surg. 1978;188:139-141.

65. Gharib H, Kao PC. Determination of silicapurified plasma calcitonin for the detection and management of medullary thyroid carcinoma: comparison of two provocative tests. Mayo Clin Proc. 1987;62:373-378.

66. Doyle P, Duren C, Nerlich K et al. Potency and tolerance of calcitonin stimulation with highdose calcium versus pentagastrin in normal adults. J Clin Endocrinol Metab. 2009; 94:2970-2974.

67. Colombo C, Verga U, Perrino M et al. Highdose calcium and pentagastrin tests in patients with cured or persistent medullary thyroid cancer and in controls: comparison of the efficacy and the tolerance. Abstract 14th Annual International Thyroid Congress. Paris, 2010;09-23.

68. Cheung K, Roman SA, Wang TS et al. Calcitonin measurement in the evaluation of thyroid nodules in the United States: a costeffectiveness and decision analysis. J Clin Endocrinol Metab. 2008;93:2173-2180.

69. Iacobone M, NiccoliSire P, Sebag F et al. Can sporadic medullary thyroid carcinoma be biochemically predicted? Prospective analysis of 66 operated patients with elevated serum calcitonin levels. Wld J Surg. 2002;26:886-890.

70. Vierhapper H, Niederle B, Bieglmayer C et al. Early diagnosis and curative therapy of medullary thyroid carcinoma by routine measurement of serum calcitonin in patients with thyroid disorders. Thyroid. 2005;15:1267-1272.

71. Ванушко ВЭ, Бельцевич ДГ, Кузнецов НС и др. Кальцитонин – маркер адекватности хирургического лечения медуллярного рака щитовидной железы. Клиническая тиреоидология. 2003;1(2):24-27.

72. Ванушко ВЭ, Кузнецов НС, Бельцевич ДГ, и др. Прицельная тонкоигольная пункционная биопсия в диагностике рака щитовидной железы. Хирургия. 2003;10:67-72.

73. Cooper DS, Doherty GM, Haugen BR et al. Management Guidelines for Patients with Thyroid Nodules and Differen tiated Thyroid Cancer. Thyroid. 2009;19(11):14-8.

74. Elisei R, Romei C. Calcitonin estimation in patients with nodu lar goiter and its significance for early detection of MTC: european comments to the guidelines of the American Thyroid Association. Thyroid Research. 2013;6(Suppl 1):S2.

75. Румянцев ПО, Ильин АА, Румянцева УВ, Газизова ДО. Факторы клинического прогноза медуллярного рака щитовидной железы. Опухоли головы и шеи. 2011;4:48-54.

76. Исаев ПА, Медведев ВС, Ильин АА и др. Динамика уровня кальцитонина в периферической крови у больных медуллярным раком щитовидной железы. Российский онкологический журнал. 2002;6:31-33.

77. Redding AH, Levine SN, Fowler MR. Normal preoperative calcitonin levels do not always exclude medullary thyroid carcinoma in patients with large palpable thyroid masses. Thyroid. 2000;10:919-922.

78. Pacini F, Basolo F, Elisei R et al. Medullary thyroid cancer. An immunohistochemical and humoral study using six separate antigens. Am J Clin Pathol. 1991;95:300-308.

79. Elisei R, Lorusso L, Romei C et al. Medullary thyroid cancer secreting carbohydrate antigen 199 (Ca 199): a fatal case report. J Clin Endocrinol Metab. 2013;98(9):3550-3554.

80. Locker GY, Hamilton S, Harris J et al. Update of recommen dations for the use of tumor markers in gastrointestinal cancer. J Clin Oncol. 2006;24(9):5313-5327.

81. Larena A, Vierbuchen M, Fischer R. Blood group antigen expression in malignant tumors of the thyroid: a parallel between medullary and nonmedullary carcinomas. Langen becks Arch Chir. 1995;380:269272.

82. Milman S, Whitney KD, Fleischer N. Metastatic medullary thyroid cancer presenting with elevated levels of CA 199 and CA 125. Thyroid. 2011;21:913-916.

83. Wiench M, Wygoda Z, Gubala E et al. Estimation of risk of inherited medullary thyroid carcinoma in apparent sporadic patients. J Clin Oncol. 2001;19:13741380.

84. Erdogan M, Gursoy A, Gullu S et al. Clinical and genetic experience in Turkish multiple endocrine neoplasia type 2 families. Endocrinologist. 2007;17:273-277.

85. Hyer SL, Vini L, A’Hern R, Harmer C. Medullary thyroid cancer: multivariate analysis of prognostic factors influencing survival. Eur J Surg Oncol. 2000;26:686-690.

86. Дедов ИИ, Трошина ЕА, Мазурина НВ и др. Молекулярно-генетические аспекты новообразований щитовидной железы. Проблемы эндокринологии. 2000;46(2):22-30.

87. Васильев ЕВ, Румянцев ПО, Полякова ЕЮ и др. Молекулярная диагностика мутаций протоонкогена RET при различных формах медуллярного рака щитовидной железы. Молекулярная медицина. 2004;4:54-60.

88. Elisei R, Romei C, Cosci B et al. Brief report: RET genetic screening in patients with medullary thyroid cancer and their relatives: experience with 807 individuals at one center. J Clin Endocrinol Metab. 2007;92(12):4725-4729.

89. Hansford JR, Mulligan LM. Multiple endocrine neoplasia type 2 and RET: from neoplasia to neurogenesis. J Med Genetics. 2000;37(11):817-827.

90. Zbuk KM, Eng C. Cancer phenomics: RET and PTEN as illustrative models. Nat Rev Cancer. 2007;7(1):35-45.

91. Амосенко ФА, Калинин ВН, Козлова ВМ и др. Мутации в протоонкогене RET у больных с медуллярным раком щитовидной железы и возможности доклинической диагностики и профилактического лечения носителей этого заболевания. Вестник РОНЦ имени Н.Н. Блохина РАМН. 2000;11(1):20-26.

92. Heshmati HM, Gharib H, Khosla S et al. Genetic testing in medullary thyroid carcinoma syndromes: mutation types and clinical significance. Mayo Clin Proc. 1997;72:430-436.

93. Marsh DJ, Mulligan LM, Eng C. RET protooncogene muta tions in multiple endocrine neoplasia type 2 and medullary thyroid carcinoma. Horm Res. 1997;47:168-178.

94. Romei C, Mariotti S, Fugazzola L et al. ItaMEN network, Multiple endocrine neoplasia type 2 syndromes (MEN 2): results from the ItaMEN network analysis on the prevalence of different genotypes and phenotypes. Eur J Endocrinol. 2010;163(2):301-308.

95. Mulligan LM, Eng C, Healey CS et al. Specific mutations of the RET protooncogene are related to disease phenotype in MEN 2A and FMTC. Nat Genet. 1994;6:70-74.

96. FrankRaue K, Hoppner W, Frilling A et al. Mutations of the ret protooncogene in German multiple endocrine neoplasia fa milies: relation between genotype and phenotype. J Clin Endocrinol Metab. 1996;81(5):1780-1783.

97. Machens A, NiccoliSire P, Hoegel J et al. Early malignant progression of hereditary medullary thyroid cancer. N Engl J Med. 2003;349(16):1517-1525.

98. Romei C, Cosci B, Renzini G et al. RET genetic screening of sporadic medullary thyroid cancer (MTC) allows the preclini cal diagnosis of unsuspected gene carriers and the identification of a relevant percentage of hidden familial MTC (FMTC). Clin Endocrinol. 2011;74(2):241-247.

99. Miyauchi A, Futami H, Hai N et al. Two germline missense mutations at codons 804 and 806 of the RET protooncogene in the same allele in a patient with multiple endocrine neopla sia type 2B without codon 918 mutation. Jpn J Cancer Res. 1999;90(1):1-5.

100. Menko FH, van der Luijt RB, DeValketal IAJ. Atypical MEN type 2B associated with two germline RET mutations on the same allele not involving codon 918. J Clin Endocrinol Metab. 2002;87(1):393-397.

101. NiccoliSire P, Murat A, Rohmer V et al. Familial medullary thyroid carcinoma with noncysteine RET mutations: pheno typegenotype relationship in a large series of patients. J Clin Endocrinol Metab. 2001;86(8):3746-3753.

102. Erdogan MF, Gürsoy A, Özgen G et al. Ret protooncogene mutations in apparently sporadic Turkish medullary thyroid carcinoma patients: Turkmen study. J Endocrinol Invest. 2005;28(9):806-809.

103. Eng C, Mulligan LM, Smith DP et al. Low frequency of germline mutations in the RET protooncogene in patients with apparently sporadic medullary thyroid carcinoma. Clin Endocrinol. 1995;43(1):123-127.

104. Orgiana G, Pinna G, Camedda A et al. A new germline RET mutation apparently devoid of transforming activity serendip itously discovered in a patient with atrophic autoimmune thy roiditis and primary ovarian failure. J Clin Endocrinol Metab. 2004;89(10):4810-4816.

105. Cosci B, Vivaldi A, Romei C et al. In silico and in vitro analysis of rare germline allelic variants of RET oncogene associa ted with medullary thyroid cancer. Endocrine-Related Cancer. 2011;18(5):603-612.

106. Figlioli G, Landi S, Romei C et al. Medullary thyroid carcino ma (MTC) and RET protooncogene: Mutation spectrum in the familial cases and a metaanalysis of studies on the sporadic form. Mutation Research. 2013;752:36-44.

107. FrankRaue K, Rondot S, Raue F. Molecular genetics and phenomics of RET mutations: impact on prognosis of MTC. Molecular and Cellular Endocrinol. 2010;322(12):2-7.

108. Поляков ВГ, Шишков РВ, Павловская АИ, Козлова ВМ. 30-летний опыт лечения медуллярного рака щитовидной железы у детей и подростков в НИИ детской онкологии и гематологии ГУ РОНЦ им. Н.Н. Блохина. 15й Российский симпозиум по хирургической эндокринологии, г. Рязань. 2005; 254-356.

109. Румянцев ПО, Ильин АА, Румянцева УВ и др. Клинические рекомендации по диагностике и лечению рака щито видной железы у детей и подростков. Диагностика и лечение узлового зоба. Материалы третьего Всероссийского тиреоидологического конгресса. М., 2004;49–60.

110. Elisei R, Romei C, Renzini G et al. The timing of total thy roidectomy in RET gene mutation carriers could be persona lized and safely planned on the basis of serum calcitonin: 18 years experience at one single center. J Clin Endocrinol Metab. 2012;97(2):426-435.

111. Lau GSK, Lang BHH, Lo CY et al. Prophylactic thyroidecto my in ethnic Chinese patients with multiple endocrine neopla sia type 2A syndrome after the introduction of genetic testing. Hong Kong Med J. 2009;15(5):326-331.

112. Rohmer V, VidalTrecan G, Bourdelot A. Prognostic factors of disease-free survival after thyroidectomy in 170 young patients with a RET germline mutation: a multicenter study of the Groupe Fran ,

113. cais d’Etude des Tumeurs Endocrines. J Clin Endocrinol Metab. 2011;96(3):E509-E518.

114. Eng Ch, Mulligan LM, Healey CS. Heterogeneous mutation of the RET protooncogene in subpopulations of medullary thyroid carcinoma. Cancer Res. 1996;56:2167-2170.

115. Schilling T, Burck J, Sinn HP et al. Prognostic value of codon 918 (ATG3ACG) RET protooncogene mutations in sporadic medullary thyroid carcinoma. Int J Cancer (Pred Oncol). 2001;95:62-66.

116. Elisei R, Barbara Cosci B, Romei C et al. Prognostic signifi cance of somatic RET oncogene mutations in sporadic medullary thyroid cancer: A 10year follow-up study. J Clin Endocrinol Metab. 2008;93:682-687.

117. Moura MM, Cavaco BM, Pinto AE et al. Correlation of RET somatic mutations with clinicopathological features in sporadic medullary thyroid carcinomas. Br J Cancer. 2009; 100(11):1777-1783.

118. Zedenius J, Dwight T, Robinson BG et al. A rapid method for DNA extraction from fine-needle aspiration biopsies of thyroid tumors, and subsequent RET mutation analysis. Cancer Detect Prev. 1998;22(6):544-548.

119. Uchino S, Noguchi S, Yamashita H et al. Somatic mutations in RET exons 12 and 15 in sporadic medullary thyroid carcinomas: different spectrum of mutations in sporadic type from hereditary type. Jpn J Cancer Res. 1999;90:1231-1237.

120. Uchino S, Noguchi S, Adachi M et al. Novel point mutations and allele loss at the RET locus in sporadic medullary thyroid carcinomas. Jpn J Cancer Res. 1998;89:411-418.

121. Marsh DJ, Learoyd DL, Andrew SD et al. Somatic mutations in the RET protooncogene in sporadic medullary thyroid car cinoma. Clin Endocrinol (Oxf). 1996;44:249-257.

122. Shan L, Nakamura M, Nakamura Y et al. Somatic mutations in the RET protooncogene in Japanese and Chinese sporadic medullary thyroid carcinomas. Jpn J Cancer Res. 1998;89: 883886.

123. Rapa I, Saggiorato E, Giachino D et al. Mammalian target of rapamycin pathway activation is associated to RET mutation status in medullary thyroid carcinoma. J Clin Endocrinol Metab. 2011;96:2146-2153.

124. Basolo F, Pisaturo F, Pollina LE et al. Nras mutation in poor ly differentiated thyroid carcinomas: correlation with bone metastases and inverse correlation to thyroglobulin expres sion. Thyroid. 2000;10:19-23.

125. Yoshimoto K, Iwahana H, Fukuda A et al. Ras mutations in endocrine tumors: mutation detection by polymerase chain reactionsingle strand conformation polymorphism. Jpn J Cancer Res. 1992;83:1057-1062.

126. Horie H, Yokogoshi Y, Tsuyuguchi M, Saito S. Point muta tions of ras and Gs alpha subunit genes in thyroid tumors. Jpn J Cancer Res. 1995;86:737-742.

127. Fenton C, Anderson J, Lukes Y et al. Ras mutations are uncommon in sporadic thyroid cancer in children and young adults. J Endocrinol Invest. 1999;22:781-789.

128. Bockhorn M, Frilling A, Kalinin V et al. Absence of H- and K-ras oncogene mutations in sporadic medullary thyroid carci noma. Exp Clin Endocrinol Diabetes. 2000;108:49-53.

129. Moley JF, Brother MB, Wells SA et al. Low frequency of ras-gene mutations in neuroblastomas, pheochromocytomas, and medullary thyroid cancers. Cancer Res. 1991;51:1596-1599.

130. Dockhorn-Dworniczak B, Caspari S, Schroder S et al. Demonstration of activated oncogenes of the ras family in human thyroid tumors using the polymerase chain reaction. Verh Dtsch Gas Pathol. 1990;74:415-418.

131. Schulten HJ, AlMaghrabi J, AlGhamdi K et al. Mutational screening of RET, HRAS, KRAS, NRAS, BRAF, AKT1, and CTNNB1 in medullary thyroid carcinoma. Anticancer Res. 2011;31:4179-4183.

132. Schlumberger MJ, Elisei R, Bastholt L et al. Phase II study of safety and efficacy of motesanib in patients with progressive or symptomatic, advanced or metastatic medullary thyroid cancer. J Clin Oncol. 2009;27:3794-3801.

133. Okazaki M, Miya A, Tanaka N et al. Allele loss on chromo some 10 and point mutation of ras oncogenes are infrequent in tumors of MEN 2A. Henry Ford Hosp Med J 1989;37: 112-115.

134. Goutas N, Vlachodimitropoulos D, Bouka M et al. MBRAF and KRAS mutation in a Greek papillary and medullary thy roid carcinoma cohort. Anticancer Res. 2008;28:305-308.

135. Franc S, NiccoliSire P, Cohen R et al. Complete surgical lymph node resection does not prevent authentic recurrences of medullary thyroid carcinoma. Clin Endocrinol. 2001;55: 403-409.

136. Machens A, Schneyer U, Holzhausen HJ, Dralle H. Prospects of remission in medullary thyroid carcinoma according to basal calcitonin level. J Clin Endocrinol Metab. 2005;90:2029-2034.

137. Skinner MA, Moley JA, Dilley WG et al. Prophylactic thyroidectomy in multiple endocrine neoplasia type 2A. N Engl J Med. 2005;1105-1113.

138. Tamagnini P, Bernante P, Piotto A et al. Reoperation of medullary thyroid carcinoma: longterm results. Ann Chir. 2001;126:762-767.

139. Tisell LE, Jansson S. Recent results of reoperative surgery in medullary carcinoma of the thyroid. Wien Klin Wochenschr. 1988;100:347-348.

140. Kebebew E, Kikuchi S, Duh QY, Clark OH. Longterm results of reoperation and localizing studies in patients with persis tent or recurrent medullary thyroid cancer. Arch Surg 2000;135:895-901.

141. Fialkowski E, Debenedetti M, Moley J. Longterm outcome of reoperations for medullary thyroid carcinoma. Wld J Surg. 2008;32:754-765.

142. Shoback D, Strewler G. Disorders of the parathyroids and calcium metabolism. In: McPhee S., Lingappa V.R., Ganong W., Lange J. Pathophysiology of disease: an introduction to clinical medicine. 2nd ed. Stamford, CT: Appleton and Lange. 1995. P. 416–417.

143. Leboulleux S, Baudin E, Travagli JP, Schlumberger M. Medullary thyroid carcinoma. Clin Endocrinol (Oxf). 2004;61:299-310.

144. Engelbach M, Gorges R, Forst T et al. Improved diagnostic methods in the followup of medullary thyroid carcinoma by highly specific calcitonin measurements. J Clin Endocrinol Metab. 2000;85:1890-1894.

145. Tisell LE, Dilley WG, Wells SA. Progression of postoperative residual medullary thyroid carcinoma as monitored by plasma calcitonin levels. Surgery. 1996;119:34-39.

146. Stepanas AV, Samaan NA, Hill CS, Hickey RC. Medullary thyroid carcinoma: importance of serial serum calcitonin measurement. Cancer. 1979;43:825-837.

147. Fugazzola L, Pinchera A, Luchetti F et al. Disappearance rate of serum calcitonin after total thyroidectomy for medullary thyroid carcinoma. Int J Biol Markers. 1994;9: 21-24.

148. Girelli ME, Dotto S, Nacamulli D et al. Prognostic value of early postoperative calcitonin level in medullary thyroid carci noma. Tumori. 1994;8(2): 113-117.

149. Miyauchi A, Onishi T, Morimoto S et al. Relation of doubling time of plasma calcitonin levels to prognosis and recurrence of medullary thyroid carcinoma. Ann Surg. 1984;199: 461-466.

150. Barbet J, Campion L, KraeberBodere F, Chatal JF. Prog nostic impact of serum calcitonin and carcinoembryonic anti gen doublingtimes in patients with medullary thyroid carcinoma. J Clin Endocrinol Metab. 2005;90:6077-6084.

151. Giraudet AL, Al Ghulzan A, Auperin A et al. Progression of medullary thyroid carcinoma: assessment with calcitonin and carcino-embryonic antigen doubling times. Eur J Endocrinol. 2008;158:239-246.

152. Wells SA, Baylin SB, Gann DS et al. Medullary thyroid carci noma: relationship of method of diagnosis to pathologic stag ing. Ann Surg. 1978;188:377-383.

153. Schlumberger M, Bastholt L, Dralle H et al. European Thyroid Association Guidelines for Metastatic Medullary Thyroid Cancer. Eur Thyroid J. 2012;1:5-14.

154. Wu LT, Averbuch SD, Ball DW et al. Treatment of advanced medullary thyroid carcinoma with a combination of cyclophosphamide, vincristine, and dacarbazine. Cancer. 1994;73:432-436.

155. Schlumberger M, Abdelmoumene N, Delisle MJ, Couette JE. Treatment of advanced medullary thyroid cancer with an alternating combination of 5 FUstreptozocin and 5 FU dacarbazine. The Groupe d’Etude des Tumeurs a Calcitonine (GETC). Br J Cancer. 1995;71:363-365.

156. Bajetta E, Rimassa L, Carnaghi C et al. 5Fluorouracil, dacarbazine, and epirubicin in the treatment of patients with neuroendocrine tumors. Cancer. 1998;83:372-378.

157. Бржезовский ВЖ, Любаев ВЛ. Диагностика и лечение медуллярного рака щитовидной железы. Практическая онкология. 2007;8(1):29-34.

158. Papewalis C, Wuttke M, Seissler J et al. Dendritic cell vacci nation with xenogenic polypeptide hormone induces tumor rejection in neuroendocrine cancer. Clin Cancer Res. 2008;14:4298-4305.

159. Schott M, Seissler J, Lettmann M et al. Immunotherapy for medullary thyroid carcinoma by dendritic cell vaccination. J Clin Endocrinol Metab. 2001;86(10):4965-4969.

160. Chatal JF, Campion L, KraeberBodere F et al. Survival improvement in patients with medullary thyroid carcinoma who undergo pretargeted anticarcino-embryonic antigen radioimmunotherapy: a collaborative study with the French Endocrine Tumor Group. J Clin Oncol. 2006;24:1705-1711.

161. Wells SA, Gosnell JE, Gagel RF et al. Vandetanib in metastatic hereditary medullary thyroid cancer: followup results of an open-label phase II trial. ASCO Annual Meeting Procee dings Part I. 2007;25:60-16.

162. Lam ET, Ringel MD, Kloos RT et al. Antitumor activity of Sorafenib in patients with metastatic medullary thyroid carci noma. Proceedings of the American Association for Cancer Research. 2009. Abstract 4513.

163. Salgia R, Sherman S, Hong DS et al. A phase I study of XL184, a RET, VEGFR2, and MET kinase inhibitor, in patients (pts) with advanced malignancies, including pts with medullary thyroid cancer (MTC). J Clin Oncol. 2008;26: Abstract 3522.

164. Wells S, Gosnell J, Gagel R et al. Vandetanib for the treat ment of patients with locally advanced or metastatic hereditary medullary thyroid cancer. J Clin Oncol. 2010;28:767-772.

165. Robinson BG, PazAres L, Krebs A et al. Vandetanib (100 mg) in patients with locally advanced or metastatic hereditary medullary thyroid cancer. J Clin Endocrinol Metab. 2010;95:2664-2671.

166. Wells SA, Robinson BG, Gagel RF et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, doubleblind phase III trial (ZETA). J Clin Oncol. 2012;30:134-141.