MULTIPLE ENDOCRINE NEOPLASIA, TYPE 2

MEN-2 is subclassified into three distinct syndromes: MEN-2A, MEN-2B, and familial medullary thyroid cancer.

• MEN-2A, or Sipple syndrome, is characterized by pheochromocytoma, medullary carcinoma, and parathyroid hyperplasia. Medullary carcinomas of the thyroid occur in

almost 100% of patients. They are usually multifocal and are virtually always associated with foci of C-cell hyperplasia in the adjacent thyroid. The medullary carcinomas may

elaborate calcitonin and other active products and are usually clinically aggressive. Forty per cent to 50% of patients with MEN-2A have pheochromocytomas, which are often

bilateral and may arise in extra-adrenal sites. As in the case of pheochromocytomas in general, they may be benign or malignant. Ten per cent to 20% of patients have

parathyroid hyperplasia and evidence of hypercalcemia or renal stones. MEN-2A is clinically and genetically distinct from MEN-1 and has been linked to germ-line mutations in

the RET (rearranged during transfection) protooncogene on chromosome 10q11.2. As was noted earlier, the RET protooncogene is a receptor tyrosine kinase that binds

glialderived neurotrophic factor (GDNF) and other ligands in the GDNF family and transmits growth and differentiation signals ( Chapter 7 ). Loss of function mutations in RET

result in intestinal aganglionosis and Hirschsprung disease ( Chapter 17 ). In contrast, in MEN-2A (as well as in MEN-2B), germ-line mutations constitutively activate the RET

receptor, resulting in gain of function.[133] This scenario is different from most other inherited predispositions to neoplasia, which are due to heritable loss of function mutations

that inactivate tumor-suppressor proteins ( Chapter 7 ).

• MEN-2B has significant clinical overlap with MEN-2A. Patients develop medullary thyroid carcinomas, which are usually multifocal and more aggressive than in MEN-2A,

and pheochromocytomas. However, unlike in MEN-2A, primary hyperparathyroidism is not present. In addition, MEN-2B is accompanied by neuromas or ganglioneuromas

involving the skin, oral mucosa, eyes, respiratory tract, and gastrointestinal tract, and a marfanoid habitus, with long axial skeletal features and hyperextensible joints. A single

amino acid change in RET (RETMet918Thr ), distinct from the

mutational spectra that are seen in MEN-2A, appears to be responsible for virtually all cases of MEN-2B and affects a critical region of the tyrosine kinase catalytic domain of the

protein.[134]

• Familial medullary thyroid cancer is a variant of MEN-2A, in which there is a strong predisposition to medullary thyroid cancer but not the other clinical manifestations of

MEN-2A or MEN-2B. A substantial majority of cases of medullary thyroid cancer are sporadic, but as many as 20% may be familial. Familial medullary thyroid cancers

develop at an older age than those occurring in the full-blown MEN-2 syndrome and follow a more indolent course.

In contrast to MEN-1, in which the long-term benefit of early diagnosis via genetic screening is not well established, diagnosis via screening of at-risk family members in MEN-2A

kindred is important because medullary thyroid carcinoma is a life-threatening disease that can be prevented by early thyroidectomy. Prior to the advent of genetic testing, family

members of patients with the MEN-2 syndrome were screened with annual biochemical tests, which often lacked sensitivity. Now, routine genetic testing identifies RET mutation

carriers earlier and more reliably in MEN-2 kindred; all individuals carrying germ-line RET mutations are advised to undergo prophylactic thyroidectomy to prevent the inevitable

development of medullary carcinomas.

Pineal Gland

Normal

The rarity of clinically significant lesions (virtually only tumors) justifies brevity in the consideration of the pineal gland. It is a minute, pinecone-shaped organ (hence its name),

weighing 100 to 180 mg and lying between the superior colliculi at the base of the brain. It is composed of a loose, neuroglial stroma enclosing nests of epithelial-appearing pineocytes,

cells with photosensory and neuroendocrine functions (hence the designation of the pineal gland as the "third eye"). Silver impregnation stains reveal that these cells have long, slender

processes reminiscent of primitive neuronal precursors intermixed with the processes of astrocytic cells.

Pathology

All tumors involving the pineal are rare; most (50% to 70%) arise from sequestered embryonic germ cells. They most commonly take the form of so-called germinomas, resembling

testicular seminoma ( Chapter 21 ) or ovarian dysgerminoma ( Chapter 22 ). Other lines of germ cell differentiation include embryonal carcinomas; choriocarcinomas; mixtures of

germinoma, embryonal carcinoma, and choriocarcinoma; and, uncommonly, typical teratomas (usually benign). Whether to characterize these germ cell neoplasms as pinealomas is still

a subject of debate, but most "pinealophiles" favor restricting the term pinealoma to neoplasma arising from the pineocytes.

PINEALOMAS

These neoplasms are divided into two categories, pineoblastomas and pineocytomas, based on their level of differentiation, which, in turn, correlates with their neoplastic aggressiveness.

[135]

Morphology.

Pineoblastomasare encountered mostly in the first two decades of life and appear as soft, friable, gray masses punctuated with areas of hemorrhage and necrosis. They typically invade

surrounding structures, such as the hypothalamus, midbrain, and lumen of the third ventricle. Histologically, they are composed of masses of pleomorphic cells two to four times the

diameter of an erythrocyte. Large hyperchromatic nuclei appear to occupy almost the entire cell, and mitoses are frequent. The cytology is that of primitive embryonal tumor("small

blue cell neoplasm") similar to medulloblastoma ( Chapter 28 ) or retinoblastoma ( Chapter 29 ).

Pineoblastomas, like medulloblastomas, tend to spread via the cerebrospinal fluid. As might be expected, the enlarging mass may compress the aqueduct of Sylvius, giving rise to

internal hydrocephalus and all its consequences. Survival beyond 1 or 2 years is rare.

In contrast, pineocytomasoccur mostly in adults and are much slower-growing than pineoblastomas. They tend to be well-circumscribed, gray, or hemorrhagic masses that compress but

do not infiltrate surrounding structures. Histologically, the tumors may be pure pineocytomas or exhibit divergent glial, neuronal, and retinal differentiation.The tumors are

composed largely of pineocytes having darkly staining, round-to-oval, fairly regular nuclei. Necrosis is unusual, and mitoses are virtually absent. The neoplastic cells resemble normal

pineocytes in their strong immunoreactivity for neuro-specific enolase and synaptophysin. Particularly distinctive are the pineocytomatous pseudorosettesrimmed by rows of

pineocytes. The centers of these rosettes are filled with eosinophilic cytoplasmic material representing tumor cell processes. These cells are set against a background of thin,

fibrovascular, anastomosing septa, which confer a lobular growth pattern to the tumor. Glial and retinal differentiation is detectable by immunoreactivity for glial fibrillary acidic protein

and retinal S-antigen, respectively.

The clinical course of patients with pineocytomas is prolonged, averaging 7 years. The manifestations are the consequence of their pressure effects and consist of visual disturbances,

headache, mental deterioration, and sometimes dementia-like behavior. The lesions being located where they are, it is understandable that successful excision is at best difficult.

References

1. Elster AD: Modern imaging of the pituitary. Radiology 187(1):1–14, 1993.

2. Asa SL, Ezzat S: The pathogenesis of pituitary tumours. Nat Rev Cancer 2(11):836–849, 2002.

3. Suhardja A, Kovacs K, and Rutka J: Genetic basis of pituitary adenoma invasiveness: a review. J Neurooncol 52(3):195–204, 2001.

4. Yamada S, et al: Growth hormone-producing pituitary adenomas: correlations between clinical characteristics and morphology. Neurosurgery 33(1):20–27, 1993.

5. Asa SL, Ezzat S: The cytogenesis and pathogenesis of pituitary adenomas. Endocr Rev 19(6):798–827, 1998.

6. Sheehan HL: The recognition of chronic hypopituitarism resulting from postpartum pituitary necrosis. Am J Obstet Gynecol, 111(6):852–854, 1971.

7. Rodriguez R, Andersen B: Cellular determination in the anterior pituitary gland: PIT-1 and PROP-1 mutations as causes of human combined pituitary hormone deficiency. Minerva

Endocrinol 28(2):123–133, 2003.

8. LiVolsi VA, Perzin KH, Savetsky L: Carcinoma arising in median ectopic thyroid (including thyroglossal duct tissue). Cancer 34(4):1303–1315, 1974.

9. Cheng SY: Multiple mechanisms for regulation of the transcriptional activity of thyroid hormone receptors. Rev Endocr Metab Disord 1(1–2):9–18, 2000.

10. Helfand M, Redfern CC: Clinical guideline. Part 2: screening for thyroid disease: an update. American College of Physicians. Ann Intern Med 129(2):144–158, 1998.

11. Refetoff S: Resistance to thyroid hormone with and without receptor gene mutations. Ann Endocrinol (Paris) 64(1):23–25, 2003.

12. Yen PM: Thyrotropin receptor mutations in thyroid diseases. Rev Endocr Metab Disord 1(1–2):123–129, 2000.

13. Clifton-Bligh RJ, et al: Mutation of the gene encoding human TTF-2 associated with thyroid agenesis, cleft palate and choanal atresia. Nat Genet 19(4):399–401, 1998.

14. Macchia PE, et al: PAX8 mutations associated with congenital hypothyroidism caused by thyroid dysgenesis. Nat Genet 19(1):83–86, 1998.

15. Barbesino G, Chiovato L: The genetics of Hashimoto's disease. Endocrinol Metab Clin North Am 29(2):357–374, 2000.

16. Tomer Y, et al: Common and unique susceptibility loci in Graves and Hashimoto diseases: results of whole-genome screening in a data set of 102 multiplex families. Am J Hum

Genet 73(4):736–747, 2003.

17. Stassi G, De Maria R: Autoimmune thyroid disease: new models of cell death in autoimmunity. Nat Rev Immunol 2(3):195–204, 2002.

18. Pearce EN, Farwell AP, Braverman LE: Thyroiditis. N Engl J Med 348:2646, 2003.

19. Muller AF, Drexhage HA, Berghout A: Postpartum thyroiditis and autoimmune thyroiditis in women of childbearing age: recent insights and consequences for antenatal and

postnatal care. Endocr Rev 22(5):605–630, 2001.

20. Kouki T, et al: Relation of three polymorphisms of the CTLA-4 gene in patients with Graves' disease. J Endocrinol Invest 25(3):208–213, 2002.

21. Ueda H, et al: Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423(6939):506–511, 2003.

22. Weetman AP: Grave's disease 1835–2002. Horm Res 59 (suppl 1):114–118, 2003.

23. Heufelder AE: Pathogenesis of ophthalmopathy in autoimmune thyroid disease. Rev Endocr Metab Disord 1(1–2):87–95, 2000.

24. Apel RL, et al: Clonality of thyroid nodules in sporadic goiter. Diagn Mol Pathol 4(2):113–121, 1995.

25. Siegel RD, Lee SL: Toxic nodular goiter: toxic adenoma and toxic multinodular goiter. Endocrinol Metab Clin North Am 27(1)151–168, 1998.

26. Rodien P, et al: Activating mutations of TSH receptor. Ann Endocrinol (Paris) 64(1):12–16, 2003.

27. Lang W, et al: The differentiation of atypical adenomas and encapsulated follicular carcinomas in the thyroid gland. Virchows Arch 385(2):125–141, 1980.

28. Kroll TG, et al: PAX8-PPARgammal fusion oncogene in human thyroid carcinoma [corrected]. Science 289(5483):1357–1360, 2000.

29. Nikiforova MN, et al: RAS point mutations and PAX8-PPAR gamma rearrangement in thyroid tumors: evidence for distinct molecular pathways in thyroid follicular carcinoma. J

Clin Endocrinol Metab 88(5):2318–2326, 2003.

30. Nikiforova MN, et al: PAX8-PPARgamma rearrangement in thyroid tumors: RT-PCR and immunohistochemical analyses. Am J Surg Pathol 26(8):1016–1023, 2002.

31. Nikiforov YE: RET/PTC rearrangement in thyroid tumors. Endocr Pathol 13(1):3–16, 2002.

32. Pierotti MA, Vigneri P, Bongarzone I: Rearrangements of RET and NTRK1 tyrosine kinase receptors in papillary thyroid carcinomas. Recent Results Cancer Res, 154:237-247,

1998.

33. Xu X, et al: High prevalence of BRAF gene mutation in papillary thyroid carcinomas and thyroid tumor cell lines. Cancer Res 63(15):4561–4567, 2003.

34. Cohen Y, et al: BRAF mutation in papillary thyroid carcinoma. J Natl Cancer Inst 95(8):625–627, 2003.

35. Kimura ET, et al: 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(7):1454–1457, 2003.

36. Eng C, et al: The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2: International RET Mutation

Consortium analysis. JAMA 276(19):1575–1579, 1996.

37. Marsh DJ, et al: Somatic mutations in the RET proto-oncogene in sporadic medullary thyroid carcinoma. Clin Endocrinol (Oxf) 44(3):249–257, 1996.

38. Ito T, et al: Unique association of p53 mutations with undifferentiated but not with differentiated carcinomas of the thyroid gland. Cancer Res 52(5):1369–1371, 1992.

39. Rybakov SJ, et al: Thyroid cancer in children Ukraine after the Chernobyl accident. World J Surg 24(11):1446–1449, 2000.

40. LiVolsi VA: Surgical Pathology of the Thyroid: Major Problems in Pathology. Philadelphia, WB Saunders, 1990.

41. Baloch ZW, Livolsi VA: Follicular-patterned lesions of the thyroid: the bane of the pathologist. Am J Clin Pathol 117(1):143–150, 2002.

42. Ruter A, Nishiyama R, Lennquist S: Tall-cell variant of papillary thyroid cancer: disregarded entity? World J Surg 21(1):15–20; discussion: 20–21, 1997.

43. Basolo F, et al: Potent mitogenicity of the RET/PTC3 oncogene correlates with its prevalence in tall-cell variant of papillary thyroid carcinoma. Am J Pathol 160(1):247-254, 2002.

44. Cheung CC, et al: Hyalinizing trabecular tumor of the thyroid: a variant of papillary carcinoma proved by molecular genetics. Am J Surg Pathol 24(12):1622-1626, 2000.

45. WellsˆSA Jr, Franz C: Medullary carcinoma of the thyroid gland. World J Surg 24(8):952–956, 2000.

46. Perry A, Molberg K, Albores-Saavedra J: Physiologic versus neoplastic C-cell hyperplasia of the thyroid: separation of distinct histologic and biologic entities. Cancer 77(4):750–

756, 1996.

47. Krueger JE, Maitra A, Albores-Saavedra J: Inherited medullary micro-carcinoma of the thyroid: a study of 11 cases. Am J Surg Pathol 24(6):853–858, 2000.

48. Machens A, et al: Early malignant progression of hereditary medullary thyroid cancer. N Engl J Med 349:1517, 2003.

49. Yip L, et al: Multiple endocrine neoplasia type 2: evaluation of the genotype-phenotype relationship. Arch Surg 138:409, 2003.

50. Boyle WJ, Simonet WS, Lacey DL: Osteoclast differentiation and activation. Nature 423:337, 2003.

51. Fiaschi-Taesch NM, Stewart AF: Minireview: parathyroid hormone-related protein as an intracrine factor: trafficking mechanisms and functional consequences. Endocrinology 144

(2):407–411, 2003.

52. Bilezikian JP, Silverberg SJ: Clinical spectrum of primary hyperparathyroidism. Rev Endocr Metab Disord 1(4):237–245, 2000.

53. Fuleihan Gel H: Familial benign hypocalciuric hypercalcemia. J Bone Miner Res 17 (suppl 2):N51–N56, 2002.

54. Arnold A., et al: Molecular pathogenesis of primary hyperparathyroidism. J Bone Miner Res 17 (suppl 2):N30–N36, 2002.

55. Silver J, Kilav R, Naveh-Many T: Mechanisms of secondary hyperparathyroidism. Am J Physiol Renal Physiol 283(3):F367–F376, 2002.

56. Anderson MS, et al: Projection of an immunological self shadow within the thymus by the aire protein. Science 298(5597):1395–1401, 2002.

57. Li Y, et al: Autoantibodies to the extracellular domain of the calcium sensing receptor in patients with acquired hypoparathyroidism. J Clin Invest 97(4):910–914, 1996.

58. Weinstein LS, et al: Endocrine manifestations of stimulatory G protein alpha-subunit mutations and the role of genomic imprinting. Endocr Rev 22(5):675–705, 2001.

59. GuG, Brown JR, Melton DA: Direct lineage tracing reveals the ontogeny of pancreatic cell fates during mouse embryogenesis. Mech Dev 120(1):35–43, 2003.

60. Narayan KM, et al: Lifetime risk for diabetes mellitus in the United States. JAMA 290(14):1884–1890, 2003.

61. Zimmet P, Alberti KG, Shaw J: Global and societal implications of the diabetes epidemic. Nature 414(6865):782–787, 2001.

62. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 25 (suppl 1):S5–S20, 2002.

63. Thorens B: GLUT2 in pancreatic and extra-pancreatic gluco-detection (review). Mol Membr Biol 18(4):265–273, 2001.

64. Reis AF, Velho G: Sulfonylurea receptor-1 (SUR1): genetic and metabolic evidences for a role in the susceptibility to type 2 diabetes mellitus. Diabetes Metab 28(1):14–19, 2002.

65. Saltiel AR, Kahn CR: Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414(6865):799–806, 2001.

66. Avruch J, et al: Ras activation of the Raf kinase: tyrosine kinase recruitment of the MAP kinase cascade. Recent Prog Horm Res 56:127–155, 2001.

67. Shepherd PR, Kahn BB: Glucose transporters and insulin action: implications for insulin resistance and diabetes mellitus. N Engl J Med 341(4):248–257, 1999.

68. Kozma SC, Thomas G: Regulation of cell size in growth, development and human disease: PI3K, PKB and S6K. Bioessays 24(1):65–71, 2002.

69. Mathis D, Vence L, Benoist C: Beta-cell death during progression to diabetes. Nature 414(6865):792–798, 2001.

70. Bach JF, Chatenoud L: Tolerance to islet autoantigens in type 1 diabetes. Annu Rev Immunol 19:131–161, 2001.

71. Pietropaolo M, Eisenbarth GS: Autoantibodies in human diabetes. Curr Dir Autoimmun 4:252–282, 2001.

72. Todd JA, Wicker LS: Genetic protection from the inflammatory disease type 1 diabetes in humans and animal models. Immunity 15(3):387–395, 2001.

73. McDevitt H: The role of MHC class II molecules in the pathogenesis and prevention of Type I diabetes. Adv Exp Med Biol 490:59–66, 2001.

74. Pugliese A, et al: HLA-DQB1 0602 is associated with dominant protection from diabetes even among islet cell antibody-positive first-degree relatives of patients with IDDM.

Diabetes 44(6):608–613, 1995.

75. Jaeckel E, Manns M, Von Herrath M: Viruses and diabetes. Ann N Y Acad Sci 958:7–25, 2002.

76. Horwitz MS, Sarvetnick N: Viruses, host responses, and autoimmunity. Immunol Rev 169:241, 1999.

77. Benoist C, Mathis D: Autoimmunity provoked by infection: how good is the case for T cell epitope mimicry? Nat Immunol 2(9):797–801, 2001.

78. Saltiel AR: Series introduction: the molecular and physiological basis of insulin resistance: emerging implications for metabolic and cardiovascular diseases. J Clin Invest 106

(2):163–164, 2000.

79. Shulman GI: Cellular mechanisms of insulin resistance. J Clin Invest 106(2):171–176, 2000.

80. Kadowaki T: Insights into insulin resistance and type 2 diabetes from knockout mouse models. J Clin Invest 106(4):459–465, 2000.

81. Elbein SC: Perspective: the search for genes for type 2 diabetes in the post-genome era. Endocrinology 143(6):2012–2018, 2002.

82. Kahn BB, Flier, JS: Obesity and insulin resistance. J Clin Invest 106(4):473–481, 2000.

83. Saltiel AR: You are what you secrete. Nat Med 7(8):887–888, 2001.

84. Flier, JS: Diabetes. The missing link with obesity? Nature 409(6818):292–293, 2001.

85. Yamauchi T, et al: The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 7(8):941–946, 2001.

86. Steppan CM, et al: The hormone resistin links obesity to diabetes. Nature 409(6818):307–312, 2001.

87. Shimomura I, et al: Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature 401(6748):73–76, 1999.

88. Celi FS, Shuldiner AR: The role of peroxisome proliferator-activated receptor gamma in diabetes and obesity. Curr Diab Rep 2(2):179–185, 2002.

89. Fajans SS, Bell GI, Polonsky KS: Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young. N Engl J Med 345(13):971–980, 2001.

90. Ellard S, et al: A high prevalence of glucokinase mutations in gestational diabetic subjects selected by clinical criteria. Diabetologia 43(2):250–253, 2000.

91. Maechler P, Wollheim CB: Mitochondrial function in normal and diabetic beta-cells. Nature 414(6865):807–812, 2001.

92. Saltiel AR: New perspectives into the molecular pathogenesis and treatment of type 2 diabetes. Cell 104(4):517–529, 2001.

93. The Diabetes Control and Complications Trial Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in

insulin-dependent diabetes mellitus. N Engl J Med 329(14):977–986, 1993.

94. UK Prospective Diabetes Study (UKPDS) Group: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in

patients with type 2 diabetes (UKPDS 33). Lancet 352(9131):837–853, 1998.

95. Sheetz MJ, King GL: Molecular understanding of hyperglycemia's adverse effects for diabetic complications. JAMA 288(20):2579–2588, 2002.

96. Stitt AW, Jenkins AJ, Cooper ME: Advanced glycation end products and diabetic complications. Expert Opin Investig Drugs 11(9):1205–1223, 2002.

97. Brownlee M: Biochemistry and molecular cell biology of diabetic complications. Nature 414(6865):813–820, 2001.

98. Frank RN: Potential new medical therapies for diabetic retinopathy: protein kinase C inhibitors. Am J Ophthalmol 133(5):693–698, 2002.

99. Lee AY, Chung SS: Contributions of polyol pathway to oxidative stress in diabetic cataract. FASEB J 13(1):23–30, 1999.

100. Haffner SM, et al: Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 339

(4):229–234, 1998.

101. Wendt T, et al: Receptor for advanced glycation endproducts (RAGE) and vascular inflammation: insights into the pathogenesis of macrovascular complications in diabetes. Curr

Atheroscler Rep 4(3):228–237, 2002.

102. Eckel RH, et al: Prevention Conference VI: Diabetes and Cardiovascular Disease: Writing Group II: pathogenesis of atherosclerosis in diabetes. Circulation 105(18):E138–E143,

2002.

103. Diabetic nephropathy. Diabetes Care 25 (suppl 1):S85–S89, 2002.

104. Frank RN: Diabetic retinopathy. N Engl J Med 350:48, 2004.

105. Astrup A, Finer N: Redefining type 2 diabetes: "diabesity" or "obesity dependent diabetes mellitus"? Obesity Rev 1:57–59, 2000.

106. Rindi G, Capella C, Solcia E: Cell biology, clinicopathological profile, and classification of gastro-enteropancreatic endocrine tumors. J Mol Med 76(6):413–420, 1998.

107. Solcia E, Capella C, Kloppel G: Tumors of the endocrine pancreas. In Rosai J (ed): Atlas of Tumor Pathology: Tumors of the Pancreas. Washington, DC, AFIP, 1997.

108. Goossens A, Heitz P, Kloppel G: Pancreatic endocrine cells and their non-neoplastic proliferations. In Dayal Y (ed): Endocrine Pathology of the Gut and Pancreas. Boca Raton, FL,

CRC Press, 1991, pp 69–104.

109. Komminoth P, Heitz PU, Kloppel G: Pathology of MEN-1: morphology, clinicopathologic correlations and tumour development. J Intern Med 243(6):455–464, 1998.

110. Zollinger RM, Ellison EH: Primary peptic ulcerations of the jejunum associated with islet cell tumors of the pancreas: 1955. CA Cancer J Clin 39(4):231–247, 1989.

111. Newell-Price J, et al: The diagnosis and differential diagnosis of Cushing's syndrome and pseudo-Cushing's states. Endocr Rev 19(5):647–672, 1998.

112. Cushing HW: The basophil adenomas of the pituitary body and their clinical manifestations (pituitary basophilism). Bull Johns Hopkins Hosp 50:137–195, 1932.

113. Stratakis CA, Kirschner LS: Clinical and genetic analysis of primary bilateral adrenal diseases (micro- and macronodular disease) leading to Cushing syndrome. Horm Metab Res 30

(6–7):456–463, 1998.

114. Groussin L, et al: Mutations of the PRKAR1A gene in Cushing's syndrome due to sporadic primary pigmented nodular adrenocortical disease. J Clin Endocrinol Metab 87(9):4324–

4329, 2002.

115. Fardella CE, Mosso L: Primary aldosteronism. Clin Lab 48(3–4):181–190, 2002.

116. Takeda Y: Genetic alterations in patients with primary aldosteronism. Hypertens Res 24(5):469–474, 2001.

117. Dluhy RG, Lifton RP: Glucocorticoid-remediable aldosteronism. J Clin Endocrinol Metab 84(12):4341–4344, 1999.

118. Speiser PW, White PC: Congenital adrenal hyperplasia. N Engl J Med 349:776, 2003.

119. Merke DP, et al: NIH conference. Future directions in the study and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Ann Intern Med 136(4):320–

334, 2002.

120. Merke DP, et al: Adrenomedullary dysplasia and hypofunction in patients with classic 21-hydroxylase deficiency. N Engl J Med 343(19):1362–1368, 2000.

121. Peterson P, Uibo R, Krohn KJ: Adrenal autoimmunity: results and developments. Trends Endocrinol Metab 11(7):285–290, 2000.

122. Pitkanen J, Peterson P: Autoimmune regulator: from loss of function to autoimmunity. Genes Immun 4(1):12–21, 2003.

123. Vaidya B, Pearce S, Kendall-Taylor P: Recent advances in the molecular genetics of congenital and acquired primary adrenocortical failure. Clin Endocrinol (Oxf) 53(4):403–418,

2000.

124. Meeks JJ, Weiss J, Jameson JL: Dax1 is required for testis determination. Nat Genet 34(1):32–33, 2003.

125. Burke BA, et al: Congenital adrenal hypoplasia and selective absence of pituitary luteinizing hormone: a new autosomal recessive syndrome. Am J Med Genet 31(1):75–97, 1988.

126. Wenig BM, Heffess CS, Adair CF: Neoplasms of the adrenal gland. In Wenig BM, et al (ed): Atlas of Endocrine Pathology. Philadelphia, WB Saunders, 1997, pp 288–329.

127. Brunt LM, Moley JF: Adrenal incidentaloma. World J Surg 25(7):905–913, 2001.

128. Thompson LD: Pheochromocytoma of the adrenal gland scaled score (PASS) to separate benign from malignant neoplasms: a clinicopathologic and immunophenotypic study of

100 cases. Am J Surg Pathol 26(5):551–566, 2002.

129. Brandi ML: Multiple endocrine neoplasia type 1. Rev Endocr Metab Disord 1(4):275–282, 2000.

130. Mignon M, Cadiot G: Diagnostic and therapeutic criteria in patients with Zollinger-Ellison syndrome and multiple endocrine neoplasia type 1. J Intern Med 243(6):489–494, 1998.

131. Chandrasekharappa SC, et al: Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science 276(5311):404–407, 1997.

132. Poisson A, Zablewska B, Gaudray P: Menin interacting proteins as clues toward the understanding of multiple endocrine neoplasia type 1. Cancer Lett 189(1):1–10, 2003.

133. Santoro M, et al: Different mutations of the RET gene cause different human tumoral diseases. Biochimie 81(4):397–402, 1999.

134. Salvatore D, et al: Increased in vivo phosphorylation of ret tyrosine 1062 is a potential pathogenetic mechanism of multiple endocrine neoplasia type 2B. Cancer Res 61(4):1426–

1431, 2001.

135. Mena H, et al: Pineal parenchymal tumors. In Cavanee WK (ed): World Health Organization Classification of Tumors: Pathology and Genetics of Tumors of the Nervous System.

Lyon, France, IARC Press, 2000, pp 115–121.

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