An Introduction to Managing Medullary Thyroid Cancer

Hereditary Cancer in Clinical Practice

John TM Plukker²  Robert MW Hofstra³  Thera P Links⁴  Jan Willem de Groot¹ 

[1] Department of Internal Medicine, Isala Klinieken Zwolle, the Netherlands;Department of Surgical Oncology, University Medical Center Groningen, University of Groningen, the Netherlands;Department of Genetics, University Medical Center Groningen, University of Groningen, the Netherlands;Department of Endocrinology, University Medical Center Groningen, University of Groningen, the Netherlands

关键词: RET mutation;    MEN 2;    medullary thyroid cancer;   

Others  :  811954
DOI  :  10.1186/1897-4287-4-3-115

 received in 2006-07-24, accepted in 2006-07-27,  发布年份 2006

【 摘 要 】

MTC is a rare neuroendocrine thyroid tumour accounting for 3% to 10% of all thyroid malignancies. It can occur in a sporadic and a hereditary clinical setting. Hereditary MTC may either occur alone (familial MTC, FMTC) or as part of multiple endocrine neoplasia (MEN) type 2A, or MEN 2B. These disorders are due to germline mutations in the RET (REarranged during Transfection) gene. In carriers of MEN 2B-associated RET mutations, prophylactic thyroidectomy is indicated before the first year of life. In the case of MEN 2A-associated germline RET mutations with a high-risk profile, total thyroidectomy is warranted before the age of 2 years and certainly before the age of 4 years. At that age the risk of invasive MTC and metastases is acceptably low. Depending on the type of RET mutation, thyroidectomy can take place at an older age in patients with a lower risk profile. In case of elevated basal or stimulated serum calcitonin, preventive surgery including total thyroidectomy and central compartment dissection should be performed regardless of age. When MTC presents as a palpable tumour, total thyroidectomy should be combined with extensive lymph node dissection of levels II-V on both sides and level VI to prevent locoregional recurrences.

   

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【 参考文献 】

• [1]Hazard JB, Hawk WA, Crile G Jr: Medullary (solid) carcinoma of the thyroid; a clinicopathologic entity. J Clin Endocrinol Metab 1959, 19:152-161.
• [2]Hundahl SA, Fleming ID, Fremgen AM, Menck HR: A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the U.S., 1985-1995 [see comments]. Cancer 1998, 83:2638-2648.
• [3]Kebebew E, Ituarte PH, Siperstein AE, Duh QY, Clark OH: Medullary thyroid carcinoma: clinical characteristics, treatment, prognostic factors, and a comparison of staging systems. Cancer 2000, 88:1139-1148.
• [4]Leboulleux S, Baudin E, Travagli JP, Schlumberger M: Medullary thyroid carcinoma. Clin Endocrinol (Oxf) 2004, 61:299-310.
• [5]Mulligan LM, Kwok JB, Healey CS, Elsdon MJ, Eng C, Gardner E, Love DR, Mole SE, Moore JK, Papi L, et al.: Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature 1993, 363:458-460.
• [6]Donis-Keller H, Dou S, Chi D, Carlson KM, Toshima K, Lairmore TC, Howe JR, Moley JF, Goodfellow P, Wells SA Jr: Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. Hum Mol Genet 1993, 2:851-856.
• [7]Hofstra RM, Landsvater RM, Ceccherini I, Stulp RP, Stelwagen T, Luo Y, Pasini B, Hoppener JW, van Amstel HK, Romeo G, et al.: A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature 1994, 367:375-376.
• [8]Khurana R, Agarwal A, Bajpai VK, Verma N, Sharma AK, Gupta RP, Madhusudan KP: Unraveling the amyloid associated with human medullary thyroid carcinoma. Endocrinology 2004, 145:5465-5470.
• [9]Livolsi VA: C cell hyperplasia/neoplasia. J Clin Endocrinol Metab 1997, 82:39-41.
• [10]Wolfe HJ, Melvin KE, Cervi-Skinner SJ, Saadi AA, Juliar JF, Jackson CE, Tashjian AH Jr: C-cell hyperplasia preceding medullary thyroid carcinoma. N Engl J Med 1973, 289:437-441.
• [11]Guyetant S, Josselin N, Savagner F, Rohmer V, Michalak S, Saint-Andre JP: C-cell hyperplasia and medullary thyroid carcinoma: clinicopathological and genetic correlations in 66 consecutive patients. Mod Pathol 2003, 16:756-763.
• [12]Guyetant S, Rousselet MC, Durigon M, Chappard D, Franc B, Guerin O, Saint-Andre JP: Sex-related C cell hyperplasia in the normal human thyroid: a quantitative autopsy study. J Clin Endocrinol Metab 1997, 82:42-47.
• [13]Quayle FJ, Moley JF: Medullary thyroid carcinoma: including MEN 2A and MEN 2B syndromes. J Surg Oncol 2005, 89:122-129.
• [14]Saad MF, Ordonez NG, Rashid RK, Guido JJ, Hill CS Jr, Hickey RC, Samaan NA: Medullary carcinoma of the thyroid. A study of the clinical features and prognostic factors in 161 patients. Medicine (Baltimore) 1984, 63:319-342.
• [15]Orlandi F, Caraci P, Mussa A, Saggiorato E, Pancani G, Angeli A: Treatment of medullary thyroid carcinoma: an update. Endocr Relat Cancer 2001, 8:135-147.
• [16]Tashjian AH Jr, Melvin EW: Medullary carcinoma of the thyroid gland. Studies of thyrocalcitonin in plasma and tumour extracts. N Engl J Med 1968, 279:279-283.
• [17]Goltzman D, Potts JT Jr, Ridgway RC, Maloof F: Calcitonin as a tumour marker. Use of the radioimmunoassay for calcitonin in the postoperative evaluation of patients with medullary thyroid carcinoma. N Engl J Med 1974, 290:1035-1039.
• [18]Karanikas G, Moameni A, Poetzi C, Zettinig G, Kaserer K, Bieglmayer C, Niederle B, Dudczak R, Pirich C: Frequency and relevance of elevated calcitonin levels in patients with neoplastic and nonneoplastic thyroid disease and in healthy subjects. J Clin Endocrinol Metab 2004, 89:515-519.
• [19]Gharib H, Kao PC, Heath H III: Determination of silica-purified plasma calcitonin for the detection and management of medullary thyroid carcinoma: comparison of two provocative tests. Mayo Clin Proc 1987, 62:373-378.
• [20]Vitale G, Ciccarelli A, Caraglia M, Galderisi M, Rossi R, Del Prete S, Abbruzzese A, Lupoli G: Comparison of two provocative tests for calcitonin in medullary thyroid carcinoma: omeprazole vs pentagastrin. Clin Chem 2002, 48:1505-1510.
• [21]Busnardo B, Girelli ME, Simioni N, Nacamulli D, Busetto E: Nonparallel patterns of calcitonin and carcinoembryonic antigen levels in the follow-up of medullary thyroid carcinoma. Cancer 1984, 53:278-285.
• [22]Mendelsohn G, Wells SA Jr, Baylin SB: Relationship of tissue carcinoembryonic antigen and calcitonin to tumour virulence in medullary thyroid carcinoma. An immunohistochemical study in early, localized, and virulent disseminated stages of disease. Cancer 1984, 54:657-662.
• [23]Sobol RE, Memoli V, Deftos LJ: Hormone-negative, chromogranin A-positive endocrine tumours. N Engl J Med 1989, 320:444-447.
• [24]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.
• [25]Bockhorn M, Frilling A, Rewerk S, Liedke M, Dirsch O, Schmid KW, Broelsch CE: Lack of elevated serum carcinoembryonic antigen and calcitonin in medullary thyroid carcinoma. Thyroid 2004, 14:468-470.
• [26]Bugalho MJ, Santos JR, Sobrinho L: Preoperative diagnosis of medullary thyroid carcinoma: fine needle aspiration cytology as compared with serum calcitonin measurement. J Surg Oncol 2005, 91:56-60.
• [27]Sipple JH: The association of pheochromocytoma with carcinoma of the thyroid gland. Am J Med 1961, 31:163-166.
• [28]Williams ED, Pollock DJ: Multiple mucosal neuromata with endocrine tumours: a syndrome allied to von Recklinghausen's disease. J Pathol Bacteriol 1966, 91:71-80.
• [29]Steiner AL, Goodman AD, Powers SR: Study of a kindred with pheochromocytoma, medullary thyroid carcinoma, hyperparathyroidism and Cushing's disease: multiple endocrine neoplasia, type 2. Medicine (Baltimore) 1968, 47:371-409.
• [30]Carney JA: Familial multiple endocrine neoplasia: the first 100 years. Am J Surg Pathol 2005, 29:254-274.
• [31]Chong GC, Beahrs OH, Sizemore GW, Woolner LH: Medullary carcinoma of the thyroid gland. Cancer 1975, 35:695-704.
• [32]Vitale G, Caraglia M, Ciccarelli A, Lupoli G, Abbruzzese A, Tagliaferri P, Lupoli G: Current approaches and perspectives in the therapy of medullary thyroid carcinoma. Cancer 2001, 91:1797-1808.
• [33]Telander RL, Zimmerman D, van Heerden JA, Sizemore GW: Results of early thyroidectomy for medullary thyroid carcinoma in children with multiple endocrine neoplasia type 2. J Pediatr Surg 1986, 21:1190-1194.
• [34]Lips CJ, Landsvater RM, Hoppener JW, Geerdink RA, Blijham G, van Veen JM, van Gils AP, de Wit MJ, Zewald RA, Berends MJ, et al.: Clinical screening as compared with DNA analysis in families with multiple endocrine neoplasia type 2A. N Engl J Med 1994, 331:828-835.
• [35]de Groot JW, Links TP, Plukker JT, Lips CJ, Hofstra RM: RET as a diagnostic and therapeutic target in sporadic and hereditary endocrine tumours. Endocr Rev 2006, 27:535-560.
• [36]Machens A, Ukkat J, Brauckhoff M, Gimm O, Dralle H: Advances in the management of hereditary medullary thyroid cancer. J Intern Med 2005, 257:50-59.
• [37]Machens A, Niccoli-Sire P, Hoegel J, Frank-Raue K, van Vroonhoven TJ, Roeher HD, Wahl RA, Lamesch P, Raue F, Conte-Devolx B, Dralle H, European Multiple Endocrine Neoplasia (EUROMEN) Study Group: Early malignant progression of hereditary medullary thyroid cancer. N Engl J Med 2003, 349:1517-1525.
• [38]Brandi ML, Gagel RF, Angeli A, Bilezikian JP, Beck-Peccoz P, Bordi C, Conte-Devolx B, Falchetti A, Gheri RG, Libroia A, Lips CJ, Lombardi G, Mannelli M, Pacini F, Ponder BA, Raue F, Skogseid B, Tamburrano G, Thakker RV, Thompson NW, Tomassetti P, Tonelli F, Wells SA Jr, Marx SJ: Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 2001, 86:5658-5671.
• [39]van Santen HM, Aronson DC, van Trotsenburg AS, ten Kate FJ, Wetering MD, Wiersinga WM, de Vijlder JJ, Vulsma T: Disseminated Medullary Thyroid Carcinoma Despite Early Thyroid Surgery in the Multiple Endocrine Neoplasia-2A Syndrome. Thyroid 2005, 15:485-488.
• [40]Decker RA, Geiger JD, Cox CE, Mackovjak M, Sarkar M, Peacock ML: Prophylactic surgery for multiple endocrine neoplasia type IIa after genetic diagnosis: is parathyroid transplantation indicated? World J Surg 1996, 20:814-820.
• [41]Skinner MA, Norton JA, Moley JF, DeBenedetti MK, Wells SA Jr: Heterotopic autotransplantation of parathyroid tissue in children undergoing total thyroidectomy. J Pediatr Surg 1997, 32:510-513.
• [42]Frank-Raue K, Hoppner W, Buhr H, Herfarth C, Raue F: Results and follow-up in eleven MEN 2A gene carriers after prophylactic thyroidectomy. Exp Clin Endocrinol Diabetes 1997, 105(Suppl 4):76-78.
• [43]Hotz HG, Runkel NS, Frank-Raue K, Raue F, Buhr HJ: Prophylactic thyroidectomy in MEN IIA: does the calcitonin level correlate with tumour spread? Langenbecks Arch Surg 1998, 383:170-173.
• [44]Dralle H, Gimm O, Simon D, Frank-Raue K, Gortz G, Niederle B, Wahl RA, Koch B, Walgenbach S, Hampel R, Ritter MM, Spelsberg F, Heiss A, Hinze R, Hoppner W: Prophylactic thyroidectomy in 75 children and adolescents with hereditary medullary thyroid carcinoma: German and Austrian experience. World J Surg 1998, 22:744-750.
• [45]Wells SA Jr, Skinner MA: Prophylactic thyroidectomy, based on direct genetic testing, in patients at risk for the multiple endocrine neoplasia type 2 syndromes. Exp Clin Endocrinol Diabetes 1998, 106:29-34.
• [46]Lallier M, St-Vil D, Giroux M, Huot C, Gaboury L, Oligny L, Desjardins JG: Prophylactic thyroidectomy for medullary thyroid carcinoma in gene carriers of MEN2 syndrome. J Pediatr Surg 1998, 33:846-848.
• [47]Arts CH, Bax NM, Jansen M, Lips CJ, Vroom TM, van Vroonhoven TJ: Prophylactic total thyroidectomy in childhood for multiple endocrine neoplasia type 2A: preliminary results. Ned Tijdschr Geneeskd 1999, 143:98-104.
• [48]van Heurn LW, Schaap C, Sie G, Haagen AA, Gerver WJ, Freling G, van Amstel HK, Heineman E: Predictive DNA testing for multiple endocrine neoplasia 2: a therapeutic challenge of prophylactic thyroidectomy in very young children. J Pediatr Surg 1999, 34:568-571.
• [49]Iler MA, King DR, Ginn-Pease ME, O'Dorisio TM, Sotos JF: Multiple endocrine neoplasia type 2A: a 25-year review. J Pediatr Surg 1999, 34:92-96.
• [50]Niccoli-Sire P, Murat A, Baudin E, Henry JF, Proye C, Bigorgne JC, Bstandig B, Modigliani E, Morange S, Schlumberger M, Conte-Devolx B: Early or prophylactic thyroidectomy in MEN 2/FMTC gene carriers: results in 71 thyroidectomized patients. The French Calcitonin Tumours Study Group (GETC). Eur J Endocrinol 1999, 141:468-474.
• [51]Ukkat J, Lorenz K, Hinze R, Thomusch O, Dralle H: Importance of early screening and prophylactic thyroidectomy in asymptomatic nonindex RET germline carriers. World J Surg 2001, 25:713-717.
• [52]Sanso GE, Domene HM, Garcia R, Pusiol E, de M, Roque M, Ring A, Perinetti H, Elsner B, Iorcansky S, Barontini M: Very early detection of RET proto-oncogene mutation is crucial for preventive thyroidectomy in multiple endocrine neoplasia type 2 children: presence of C-cell malignant disease in asymptomatic carriers. Cancer 2002, 94:323-330.
• [53]Rodriguez GJ, Balsalobre MD, Pomares F, Torregrosa NM, Rios A, Carbonell P, Glower G, Sola J, Tebar J, Parrilla P: Prophylactic thyroidectomy in MEN 2A syndrome: experience in a single center. J Am Coll Surg 2002, 195:159-166.
• [54]Brauckhoff M, Gimm O, Weiss CL, Ukkat J, Sekulla C, Brauckhoff K, Thanh PN, Dralle H: Multiple endocrine neoplasia 2B syndrome due to codon 918 mutation: clinical manifestation and course in early and late onset disease. World J Surg 2004, 28:1305-1311.
• [55]Kahraman T, de Groot JW, Rouwe C, Hofstra RM, Links TP, Sijmons RH, Plukker JT: Acceptable age for prophylactic surgery in children with multiple endocrine neoplasia type 2a. Eur J Surg Oncol 2003, 29:331-335.
• [56]de Groot JW, Links TP, Rouwe CW, Wal JE, Hofstra RM, Plukker JT: Prophylactic thyroidectomy in children who are carriers of a multiple endocrine neoplasia type 2 mutation: description of 20 cases and recommendations based on the literature. Ned Tijdschr Geneeskd 2006, 150:311-318.
• [57]Sosa JA, Bowman HM, Tielsch JM, Powe NR, Gordon TA, Udelsman R: The importance of surgeon experience for clinical and economic outcomes from thyroidectomy. Ann Surg 1998, 228:320-330.
• [58]Modigliani E, Cohen R, Campos JM, Conte-Devolx B, Maes B, Boneu A, Schlumberger M, Bigorgne JC, Dumontier P, Leclerc L, Corcuff B, Guilhem I: Prognostic factors for survival and for biochemical cure in medullary thyroid carcinoma: results in 899 patients. The GETC Study Group. Groupe d'etude des tumeurs a calcitonine. Clin Endocrinol (Oxf) 1998, 48:265-273.
• [59]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.
• [60]de Groot JW, Plukker JT, Wolffenbuttel BH, Wiggers T, Sluiter WJ, Links TP: Determinants of life expectancy in medullary thyroid cancer: Age does not matter. Clin Endocrinol (Oxf) 2006, in press.
• [61]de Groot JW, Links TP, Jager PL, Kahraman T, Plukker JT: Impact of 18F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) in patients with biochemical evidence of recurrent or residual medullary thyroid cancer. Ann Surg Oncol 2004, 11:786-794.