Clinical Manifestations of Multiple Endocrine Neoplasia Type 2

Part of the Medical Intelligence Unit book series (MIU.LANDES)


Though uncommon in the general population, the multiple endocrine Neoplasia type 2 (MEN 2) syndromes are noteworthy for their distinctive genetic, developmental and biochemical features, and their unique clinical associations. Elucidation of the genetic basis of the MEN 2 syndromes has spawned substantial improvements in diagnosis which in turn have led to more prompt and appropriate treatment of the associated endocrine tumors. In the foreseeable future, greater understanding of the molecular pathogenesis of these tumors is likely to allow a more rational targeting of anti-tumor therapy. This introductory chapter reviews the natural history and summarizes current approaches to diagnosis and management of patients with the MEN 2 syndromes.


Medullary Thyroid Carcinoma Multiple Endocrine Neoplasia Type Cutaneous Lichen Amyloidosis Familial Pheochromocytoma Apparent Family History 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Hazard JB, Hawk WA, Crile G Jr. Medullary (solid) carcinoma of the thyroid: a clinicopathologic entity. J Clin Endocrinol Metab 1959; 19: 152–61.PubMedCrossRefGoogle Scholar
  2. 2.
    Sipple JH. The association of pheochromocytoma with carcinoma of the thyroid gland. Am J Med 1961; 31: 163–6.CrossRefGoogle Scholar
  3. 3.
    Cushman P Jr. Familial endocrine tumors. Report of two unrelated kindreds affected with pheochromocytoma, one also with multiple thyroid carcinomas. Am J Med 1962; 32: 352–60.PubMedCrossRefGoogle Scholar
  4. 4.
    Manning PC Jr, Molnar GD, Black BM et al. Pheochromocytoma, hyperparathyroidism, and thyroid carcinoma occurring coincidentally. N Engl J Med 1963; 268: 68–72.CrossRefGoogle Scholar
  5. 5.
    Nourok DS. Familial pheochromocytoma and thyroid carcinoma. Ann Intern Med 1964; 60: 1028.CrossRefGoogle Scholar
  6. 6.
    Schimke RN, Hartmann WH, Prout TE et al. Syndrome of bilateral pheochromocytoma, medullary thyroid carcinoma, and mul-tiple neuromas. N Engl J Med 1968; 279: 1–17.PubMedCrossRefGoogle Scholar
  7. 7.
    Copp DH, Cameron EC, Cheney BA et al. Evidence for calcitonin: a new hormone from the parathyroid that lowers blood calcium. Endocrinology 1962; 70: 638–49.PubMedCrossRefGoogle Scholar
  8. 8.
    Foster GV, Maclntyre I, Pearse AGE. Calcitonin production and the mitochondrion-rich cells of the dog thyroid. Nature 1964; 203: 1029–30.PubMedCrossRefGoogle Scholar
  9. 9.
    Williams ED. Histogenesis of medullary carcinoma of the thyroid. J Clin Pathol 1966; 19: 114–8.PubMedCrossRefGoogle Scholar
  10. 10.
    LeDouarin N, Le Lievre C. Demonstration de l’origine neurale des cellules a calcitonine du corps ultimobranchial chez l’embryon de poulet. Comptes Rendues Seances Acad Sci D Paris 1970; 270: 2857–60.Google Scholar
  11. 11.
    Weston, JA. The regulation of normal and abnormal neural crest development. Adv Neurol 1981; 29: 77–95.PubMedGoogle Scholar
  12. 12.
    Melvin KEW, Tashjian AH Jr. The syndrome of excessive thyrocalcitonin produced by medullary carcinoma of the thyroid. Proc Natl Acad Sci USA 1968; 59: 1261–2.CrossRefGoogle Scholar
  13. 13.
    Mathew CGP, Chin KS Easton DF et al. A linked genetic marker for multiple endocrine neoplasia type 2A on chromosome 10. Nature 1987; 328: 527–8.PubMedCrossRefGoogle Scholar
  14. 14.
    Simpson NE, Kidd KK, Goodfellow PJ et al. Assignment of multiple endocrine neoplasia type 2A to chromosome 10 by linkage. Nature 1987; 328: 528–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Mulligan LM, Kwok JBJ, Healey CS et al. Germline mutations of the ret proto-oncogene in multiple endocrine neoplasia type 2A. 1993; 363: 458–60.Google Scholar
  16. 16.
    Donis-Keller H, Dou S, Chi D et al. Mutations in the ret proto-oncogene are associated with MEN 2A and FMTC. Hum Mol Genet 1993; 2: 851–6.PubMedCrossRefGoogle Scholar
  17. 17.
    Hofstra RMW, Landsvater RM, Ceccherini I et al. A mutation in the ret proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature 1994; 367: 375–6.PubMedCrossRefGoogle Scholar
  18. 18.
    Franssila K. Value of histologic classification of thyroid cancer. Acta Pathol Microbiol Scand 1971; Supp1. 225: 5–76.Google Scholar
  19. 19.
    Hill CS, Ibanez ML, Samaan NA et al. Medullary (solid) carcinoma of the thyroid gland: an analysis of the M.D. Anderson Hospital Experience with patients with the tumor, its special features and its histogenesis. Medicine 1973; 52: 141–71.PubMedCrossRefGoogle Scholar
  20. 20.
    Steiner AL, Goodman AD, Powers SR. Study of a kindred with pheochromocytoma, medullary thyroid carcinoma, hyperparathyroidism, and Cushing’s disease: MEN, type II. Medicine 1968; 47: 371–409.PubMedCrossRefGoogle Scholar
  21. 21.
    Gagel RF, Jackson CE, Ponder BAJ et al. Multiple Endocrine Neoplasia Type 2 Syndromes: Nomenclature Recommendations from the Workshop Organizing Committee. Henry Ford Hosp Med J 1989; 37: 99.Google Scholar
  22. 22.
    Farndon JR, Leight GS, Dilley WG et al. Familial medullary thyroid carcinoma without associated endocrinopathies: a distinct clinical entity. Br J Surg 1986; 73: 278–81.PubMedCrossRefGoogle Scholar
  23. 23.
    Nunziata V, Giannattasio R, di Giovanni G et al. Hereditary localized pruritis in affected members of a kindred with multiple endocrine neoplasia type 2A (Sipple’s Syndrome). Clin Endocrinol 1989; 30: 57.CrossRefGoogle Scholar
  24. 24.
    Gagel RF, Levy ML, Donovan DT et al. Multiple endocrine neoplasia type 2a associated with cutaneous lichen amyloidosis. Ann Intern Med 1989; 111: 802.PubMedCrossRefGoogle Scholar
  25. 25.
    Mulligan LM, Eng C, Attie T et al. Diverse phenotypes associated with exon 10 mutations of the ret proto-oncogene. Hum Mol Gen 1994; 3: 2163–67.PubMedCrossRefGoogle Scholar
  26. 26.
    Ponder BAJ, Ponder MA, Coffey R et al. Risk estimation and screening in families of patients with medullary thyroid carcinoma. Lancet 1988; 1: 397–400.PubMedCrossRefGoogle Scholar
  27. 27.
    Wells SA Jr, Chi DD, Toshima K et al. Predictive DNA testing and prophylactic thyroidectomy in patients at risk for multiple endocrine neoplasia type 2A. Ann Surg 1994; 220: 237–50.PubMedCrossRefGoogle Scholar
  28. 28.
    Lips CJM, Landsvater RM, Hoppener JWM et al. Clinical screening as compared with DNA analysis in families with multiple endocrine neoplasia type 2A. N Engl J Med 1994; 331: 828–35.PubMedCrossRefGoogle Scholar
  29. 29.
    Baylin SB, Hsu SH, Gann DS. Inherited medullary thyroid carcinoma: a final monoclonal mutation in one of multiple clones of susceptible cells. Science 1978; 199: 429–31.PubMedCrossRefGoogle Scholar
  30. 30.
    Telander RL, Zimmerman D, van Heerden JA et al. Results of early thyroidectomy for medullary thyroid carcinoma in children with multiple endocrine neoplasia type 2. J Ped Surg 1986; 21: 1190–9.CrossRefGoogle Scholar
  31. 31.
    Carney JA, Sizemore GW, Hayles AB. Multiple endocrine neoplasia, type 2B. Pathobiol Ann 1978; 8: 105–53.Google Scholar
  32. 32.
    LiVolsi VA. Surgical Pathology of the Thyroid. Philadelphia: WB Saunders, 1990.Google Scholar
  33. 33.
    Russell CF, Van Heerden JA, Sizemore GW et al. The surgical management of medullary thyroid carcinoma. Ann Surg 1983; 197: 42–8.PubMedGoogle Scholar
  34. 34.
    Ellenhorn JDI, Shah JP, Brennan MF. Impact of therapeutic regional lymph node dissection for medullary carcinoma of the thyroid gland. Surgery 1993; 114: 1078–81.PubMedGoogle Scholar
  35. 35.
    Dralle H, Scheumann GFW, Proye C et al. The value of lymph node dissection in hereditary medullary thyroid carcinoma: a retrospective, European multicentre study. J Int Med 1995; 238: 357–61.CrossRefGoogle Scholar
  36. 36.
    Melvin KEW, Tashjian AH Jr., Cassidy CE et al. Cushing’s syndrome caused by ACTH- and calcitonin-secreting medullary carcinoma of the thyroid. Metabolism 1970; 19: 831–8.PubMedCrossRefGoogle Scholar
  37. 37.
    Chen H, Doppman JL, Chrousos GP et al. Adrenocorticotropic hormone-secreting pheochromocytomas: the exception to the rule. Surgery 1995; 118: 988–94.PubMedCrossRefGoogle Scholar
  38. 38.
    Becker KL Nash D, Silva OL et al. Increased serum and urinary calcitonin levels in patients with pulmonary disease. Chest 1981; 79: 211–6.PubMedCrossRefGoogle Scholar
  39. 39.
    Simmons RE, Hjelle JT, Mahoney C et al. Renal metabolism of calcitonin. Am J Physiol 1988; 254: F593–600.PubMedGoogle Scholar
  40. 40.
    Wells SA, Dilley WG, Farndon JA et al. Early diagnosis and treatment of medullary thyroid carcinoma. Arch Intern Med 1985; 145: 1248–52.PubMedCrossRefGoogle Scholar
  41. 41.
    Amara SG, Jonas V, Rosenfeld MG et al. Alternative RNA processing in calcitonin gene expression generates mRNAs encoding different polypeptide products. Nature 1982; 298: 240–4PubMedCrossRefGoogle Scholar
  42. 42.
    Tache Y, Holzer P, Rosenfeld MG, eds. Calcitonin gene-related peptide: the first decade of a novel pleiotropic neuropeptide. Annals of the New York Academy of Sciences 1992; 657: 561.Google Scholar
  43. 43.
    Mason RT, Shulkes A, Zajac JD et al. Basal and stimulated release of calcitonin gene-related peptide (CGRP) in patients with medullary thyroid carcinoma. Clin Endocrinol (Oxf) 1986; 25: 675–85.CrossRefGoogle Scholar
  44. 44.
    Schifter S. Calcitonin gene related peptide and calcitonin as tumour markers in MEN 2 family screening. Clin Endocrinol (Oxf) 1989; 30: 263–70.CrossRefGoogle Scholar
  45. 45.
    Roos BA, Huber B, Birnbaum RS et al. Medullary thyroid carcinomas secrete a non calcitonin peptide corresponding to the carboxyl-terminal region of pre-procalcitonin. J Clin Endocrinol Metab 1983; 56: 802–7.PubMedCrossRefGoogle Scholar
  46. 46.
    Modigliani E, Vasen HM, Raue K et al. Pheochromocytoma in multiple endocrine neoplasia type 2: European study. J Intern Med 1995; 238: 363–7.PubMedCrossRefGoogle Scholar
  47. 47.
    Lairmore TC, Ball DW, Baylin SB et al. The management of pheochromocytoma in patients with multiple endocrine neoplasia type 2 syndromes. Ann Surg. 1993; 217: 595–601.PubMedCrossRefGoogle Scholar
  48. 48.
    Mulligan LM, Marsh DJ, Robinson BG et al. Genotype-phenotype correlation in multiple endocrine neoplasia type 2: report of the international ret mutation consortium. J Intern Med 1995; 238: 343–6.PubMedCrossRefGoogle Scholar
  49. 49.
    Thomas JE, Rooke ED, Kvale WF. The neurologist’s expereince with pheochromocytoma: a review of 46 cases. J Urol 1974; 111: 715–21.Google Scholar
  50. 50.
    Hermann H, Mornex R. Human tumors secreting catecholamines. New York: Macmillan, 1964: 1–14.Google Scholar
  51. 51.
    Neumann HP, Berger DP, Sigmund G et al. Pheochromocytomas, multiple endocrine neoplasia type 2, and von Hippel-Lindau disease New Engl Med 1993; 329: 1531–8.Google Scholar
  52. 52.
    Keiser HR. Pheochromocytoma and other diseases of the sympathetic nervous system. In: Becker KL, ed. Principles and Practice of Endocrinology and Metabolism. 1st ed. Philadelphia: JB Lippincott, 1990: 676–682.Google Scholar
  53. 53.
    Glowniack JV, Shapiro B, Sisson, JC et al. Familial extra-adrenal pheochromocytoma: a new syndrome. Arch Intern Med 1985; 145: 257–61.CrossRefGoogle Scholar
  54. 54.
    Crossey PA, Richards FM, Foster K et al. Identification of intragenic mutations in the Von Hippel-Lindau disease tumour suppressor gene and correlation with disease phenotype. Hum Mol Genet 1994; 3: 1303–8.PubMedCrossRefGoogle Scholar
  55. 55.
    Evans DB, Lee JE, Merrell RC et al. Adrenal medullary disease in multiple endocrine neoplasia type 2. Endocrinol Metab Clin N Am 1994; 23: 167–76.Google Scholar
  56. 56.
    Hamilton BP, Landsberg L, Levine RJ. Measurement of urinary epinephrine inscreening for pheochromocytoma in multiple endocrine neoplasia 2. Am J Med 1978; 65: 1027–32.PubMedCrossRefGoogle Scholar
  57. 57.
    Feldman JM. Phenylethanloamine-N-methyltransferase activity determines the epinephrine concentration of pheochromocytomas. Res Commun Chem Pathol Pharmacol 1981; 34: 389–98.PubMedGoogle Scholar
  58. 58.
    Kimura N, Miura Y, Nagatsu I et al. Catecholamine synthesizing enzymes in 70 cases of functioning and nonfunctioning pheochromocytoma and extra-adrenal paraganglioma. Virchows Arch A Pathol Anat Histopathol 1992; 421: 25–32.PubMedCrossRefGoogle Scholar
  59. 59.
    DeLellis RA, Wofe HJ, Gagel RF et al. Adrenal medullary hyperplasia. A morphometric analysis in patients with familial medullary thyroid carcinoma. Am J Pathol 1976; 83: 177–96.PubMedGoogle Scholar
  60. 60.
    Melvin KEW, Tashjian AH Jr, Miller HH. Studies in familial (medullary) thyroid carcinoma. Rec Prog Horm Res 1972; 28: 399–470.PubMedGoogle Scholar
  61. 61.
    Mulligan LM, Eng C, Healey CS et al. Specific mutations of the ret proto-oncogene are related to disease phenotype in MEN 2A and FMTC. Nat Genet 1994; 6: 70–4.PubMedCrossRefGoogle Scholar
  62. 62.
    Carney JA, Roth SI, Heath H III et al. The parathyroid glands in multiple endocrine neoplasia type 2B. Am J Pathol 1980; 99: 387–98.PubMedGoogle Scholar
  63. 63.
    Gagel RF, Tashjian AH Jr., Cummings T et al. The clinical outcome of prospective screening for multiple endocrine neoplasia type 2a. An 18 year experience. N Engl J Med 1988; 318: 478–84.PubMedCrossRefGoogle Scholar
  64. 64.
    Eng C, Smith DP, Mulligan LM et al. A novel point mutation in the tyrosine kinase domain of the ret proto-oncogene in sporadic medullary thyroid carcinoma and in a family with FMTC. Oncogene 1995; 10: 509–13.PubMedGoogle Scholar
  65. 65.
    Bugalho MJM, Cote GJ, Khoran S et al. Identification of a polymorphism in exon 11 of the ret proto-oncogene. Hum Mol Genet 1994; 3: 2263.Google Scholar
  66. 66.
    Wohlik N, Cote GJ, Bughalho D et al. Relevance of ret proto-oncogene analysis in sporadic MTC. (Abstract) 77th Endocrine Society Meeting, 1995: 464.Google Scholar
  67. 67.
    Zedenius J, Wallin G, Hamberger B et al. Somatic and MEN 2A de novo mutations identified in the ret proto-oncogene by screening of sporadic MTC’s. Hum Mol Genet 1994; 3: 1259–62.PubMedCrossRefGoogle Scholar
  68. 68.
    Blaugrund JE, Johns MM, Ebyl YJ et al. ret proto-oncogene mutations in inherited and sporadic medullary thyroid cancer. Hum Mol Genet 1994; 3: 1895–7.PubMedCrossRefGoogle Scholar
  69. 69.
    van Heerden JA, Grant CS, Gharib H et al. Long term course of patients with persistent hypercalcitoninemia after apparent curative primary surgery for medullary thyroid carcinoma. Ann Surg 1990; 212: 395–401.PubMedCrossRefGoogle Scholar
  70. 70.
    Tisell LE, Hansson G, Jansson S et al. Reoperation in the treatment of asymptomatic metastasizing medullary thyroid carcinoma. Surgery 1986; 99: 60–6.PubMedGoogle Scholar
  71. 71.
    Moley JF, Wells SA, Dilley WG et al. Reoperation for recurrent or persistent medullary thyroid cancer. Surgery 1993; 114: 1090–5.PubMedGoogle Scholar
  72. 72.
    Saad MF, Ordonez NA, Rashid RK et al. Medullary carcinoma of the thyroid: a study of the clinical features and prognostic factors in 161 patients. Medicine 1984; 63: 319–42.PubMedCrossRefGoogle Scholar
  73. 73.
    Samaan NA, Schultz PN, Hickey RC. Medullary thyroid carcinoma: prognosis of familial versus sporadic disease and the role of radiotherapy. J Clin Endocrinol Metab 1988; 67: 801–5.PubMedCrossRefGoogle Scholar
  74. 74.
    Wu LT, Averbuch SD. Chemotherapy of Advanced Thyroid Cancer. In: Cobin RH, Srota DK, eds. Malignant Tumors of the Thyroid. New York: Springer-Verlag, 1992: 204.CrossRefGoogle Scholar
  75. 75.
    Wu L-T, Averbuch SD, Ball DW et al. Treatment of advanced medullary thyroid carcinoma with a combination of cyclophosphamide, vincristine and dacarbazine. Cancer 1994; 73: 432–6.PubMedCrossRefGoogle Scholar
  76. 76.
    Gagner M, Lacroix A, Prinz RA et al. Early experience with laparoscopic approach for adrenalectomy. Surgery 1993; 114: 1120–4.PubMedGoogle Scholar
  77. 77.
    Bergholm U, Adami H-O, Auer G et al. Histopathologic characteristics and nuclear DNA content as prognostic factors in medullary thyroid carcinoma. Cancer 1989; 64: 135–42.PubMedCrossRefGoogle Scholar
  78. 78.
    Saad MF, Fritsche HA, Samaan NA. Diagnostic and prognostic values of carcinoembryonic antigen in medullary carcinoma of the thyroid. J Clin Endocrinol Metab 1984; 58: 889–94.PubMedCrossRefGoogle Scholar
  79. 79.
    Mendelsohn G, Wells SA, Baylin, SB. Relationship of tissue carcinoembryonic antigen and calcitonin to tumor virulence in medullary thyroid carcinoma. Cancer 1984; 54: 657–62.PubMedCrossRefGoogle Scholar
  80. 80.
    Ball DW, de Bustros A, Baylin SB. Medullary Thyroid Carcinoma. In: Braverman LE, Utiger RD, eds. The Thyroid. Philadelphia: Lippincott 1995: 946–960.Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1996

Authors and Affiliations

There are no affiliations available

Personalised recommendations