Adrenal Cortex

  • Hironobu Sasano
  • Yasuhiro Nakamura
  • Takuya Moriya
  • Takashi Suzuki
Chapter

Abstract

Histopathological abnormalities of the adrenal cortex include a wide variety of lesions. These range from cortical nodules to adrenal cortical adenomas and carcinomas. Many adrenal cortical nodules and tumors are functional and are associated with Cushing’s syndrome or hyperaldosteronism. The Weiss criteria are most commonly used to distinguish adenomas from carcinomas.

Recent cellular and molecular studies have provided new insights into the development and diagnoses of adenomas and carcinomas. These range from studies on proliferation with Ki67 to a variety of cytogenetic studies.

Keywords

Adrenal cortex Adenoma Carcinoma Ki67 Primary pigmented adrenocortical disease 

References

  1. 1.
    Sasano H, Mason JI, Sasano N, Nagura H (1990) Immunolocalization of 3 beta-hydroxysteroid dehydrogenase in human adrenal cortex and in its disorders. Endocr Pathol 1:94–101Google Scholar
  2. 2.
    Sasano H, Sasano N, Okamoto M (1989) Immunohistochemical demonstration of cholesterol side-chain cleavage cytochrome P-450 in bovine and human adrenal. Pathol Res Pract 184:337–342PubMedGoogle Scholar
  3. 3.
    Sasano H, White PC, New MI, Sasano N (1988) Immunohistochemical localization of cytochrome P-450c21 in human adrenal cortex and its relation to endocrine function. Hum Pathol 19:181–185PubMedGoogle Scholar
  4. 4.
    Sasano H, White PC, New MI, Sasano N (1988) Immunohistochemistry of cytochrome P450 21-hydroxylase: microscopic examination of the enzyme in bovine adrenal cortex and kidney. Endocrinology 122:291–295PubMedGoogle Scholar
  5. 5.
    Sasano H, Mason JI, Sasano N (1989) Immunohistochemical analysis of cytochrome P-450 17α-hydroxylase in pig adrenal cortex, testis and ovary. Mol Cell Endocrinol 62:197–202PubMedGoogle Scholar
  6. 6.
    Sasano H, Mason JI, Sasano N (1989) Immunohistochemical study of cytochrome P45017αin human adrenal disorders. Hum Pathol 20:113–117PubMedGoogle Scholar
  7. 7.
    Sasano H, Okamoto M, Sasano N (1988) Immunohistochemical study of human adrenal cortex with mineralo- and glucocorticoid excess. Virchows Arch A Pathol Anat Histopathol 413:313–318PubMedGoogle Scholar
  8. 8.
    Sasano H (1994) Localization of steroidogenic enzymes in adrenal cortex and its disorders. Endocr J 41:471–482PubMedGoogle Scholar
  9. 9.
    Sasano H (1992) New approaches in human adrenocortical pathology: assessment of adrenocortical function in surgical specimen of human adrenal glands. Endocr Pathol 3:4–13Google Scholar
  10. 10.
    Sasano N (1975) Functional pathology of adrenocortical endocrine disorders. Trans Soc Pathol Jpn 64:31–54Google Scholar
  11. 11.
    Neville AM, O’Hare MJ (1982) The human adrenal cortex. Springer, Berlin, GermanyGoogle Scholar
  12. 12.
    Lack EE (1990) Pathology of the adrenal glands. Churchill Livingstone, New YorkGoogle Scholar
  13. 13.
    Sasano N, Sasano H (1993) The adrenal cortex. In: Kovacs K, Asa SL (eds) Functional endocrine pathology. Oxford, Blackwell, pp 546–584Google Scholar
  14. 14.
    Mcleod MK, Thompson NW, Gross MD, Bondeson AG, Bondeson L (1990) Subclinical Cushing’s syndrome in patients with adrenal gland incidentalomas. Pitfalls in diagnosis and management. Am Surg 56:398–403PubMedGoogle Scholar
  15. 15.
    Hensen J, Buhl M, Bähr V, Oelkers W (1990) Endocrine activity of the “silent” adrenocortical adenoma is uncovered by response to corticotropin-releasing hormone. Klin Wochenschr 68:608–614PubMedGoogle Scholar
  16. 16.
    Reincke M, Nieke J, Krestin GP, Saeger W, Allolio B, Winkelmann W (1992) Preclinical Cushing’s syndrome in adrenal “incidentalomas”: comparison with adrenal Cushing’s syndrome. J Clin Endocrinol Metab 75:826–832PubMedGoogle Scholar
  17. 17.
    Huiras CM, Pehling GB, Caplan RH (1989) Adrenal insufficiency after operative removal of apparently nonfunctioning adrenal adenomas. JAMA 261:894–898PubMedGoogle Scholar
  18. 18.
    Sasano H, Sato F, Shizawa S, Nagura H, Coughtrie MWH (1995) Immunolocalization of dehydroepiandrosterone sulfotransferase in normal and pathologic human adrenal gland. Mod Pathol 8:891–896PubMedGoogle Scholar
  19. 19.
    Chute AL, Robinson GC, Donohue WL (1949) Cushing’s syndrome in children. J Pediatr 34:20–28PubMedGoogle Scholar
  20. 20.
    Carney JA, Gordon H, Carpenter PC, Shenoy BV, Gro VLW (1985) The complex of myxomas, spotty pigmentation and endocrine overactivity. Medicine (Baltimore) 64:270–283Google Scholar
  21. 21.
    Carney JA, Hruska LS, Beauchamp GD, Gordon H (1986) Dominant inheritance of myxomas, spotty pigmentation and endocrine overactivity. Mayo Clin Proc 61:165–172PubMedGoogle Scholar
  22. 22.
    Sasano H, Miyazaki S, Sawai T, Sasano N, Nagura H, Funahashi H, Aiba M, Demura H (1992) Primary pigmented nodular adrenocortical disease (PPNAD): immunohistochemical and in situ hybridization analysis of steroidogenic enzymes in eight cases. Mod Pathol 5:23–29PubMedGoogle Scholar
  23. 23.
    Libé R, Bertherat J (2005) Molecular genetics of adrenocortical tumours, from familial to sporadic diseases. Eur J Endocrinol 153:477–487PubMedGoogle Scholar
  24. 24.
    Bertherat J (2001) Protein kinase A in Carney complex: a new example of cAMP pathway alteration in endocrine tumors. Eur J Endocrinol 144:209–211PubMedGoogle Scholar
  25. 25.
    Bossis I, Stratakis CA (2004) Minireview: Prkar1a: normal and abnormal functions. Endocrinology 145:5452–5458PubMedGoogle Scholar
  26. 26.
    Kirschner LS, Carney JA, Pack SD, Taymans SE, Giatzakis C, Cho YS, Cho-Chung YS, Stratakis CA (2000) Mutations of the gene encoding the protein kinase a type I-alpha regulatory subunit in patients with the Carney complex. Nat Genet 26:89–92PubMedGoogle Scholar
  27. 27.
    Kirschner LS, Sandrini F, Monbo J, Lin JP, Carney JA, Stratakis CA (2000) Genetic heterogeneity and spectrum of mutations of the PRKAR1a gene in patients with the Carney complex. Hum Mol Genet 9:3037–3046PubMedGoogle Scholar
  28. 28.
    Veugelers M, Wilkes D, Burton K, McDermott DA, Song Y, Goldstein MM, La Perle K, Vaughan CJ, O’Hagan A, Bennett KR, Meyer BJ, Legius E, Karttunen M, Norio R, Kaariainen H, Lavyne M, Neau JP, Richter G, Kirali K, Farnsworth A, Stapleton K, Morelli P, Takanashi Y, Barnforth JS, Eitelberger F, Noszian I, Manfroi W, Powers J, Mochizuki Y, Imai T, Ko GT, Driscoll DA, Goldmuntz E, Edelberg JM, Collins A, Eccles D, Irvine AD, McKnight GS, Basson CT (2004) Comparative PRKAR1A genotype-phenotype analyses in humans with Carney complex and PRKAR1a haploinsufficient mice. Proc Natl Acad Sci U S A 101:14222–14227PubMedGoogle Scholar
  29. 29.
    Groussin L, Kirschner LS, Vincent-Dejean C, Perlemoine K, Jullian E, Delemer B, Zacharieva S, Pignatelli D, Carney JA, Luton JP, Bertagna X, Stratakis CA, Bertherat J (2002) Molecular analysis of the cyclic AMP-dependent protein kinase a (PKA) regulatory subunit 1a (PRKAR1a) gene in patients with Carney complex and primary pigmented nodular adrenocortical disease (PPNAD) reveals novel mutations and clues for pathophysiology: Augmented PKA signaling is associated with adrenal tumorigenesis in PPNAD. Am J Hum Genet 71:1433–1442PubMedGoogle Scholar
  30. 30.
    Cheitlin RA, Westphal M, Cabrera CM, Fujii DK, Snydre J, Fitzerald PA (1988) Cushing’s syndrome due to bilateral adrenal macronodular hyperplasia with undetectable ACTH: cell culture of adenoma cells on extracellular matrix. Horm Res 29:162–167PubMedGoogle Scholar
  31. 31.
    Hashimoto K, Kawada Y, Murakami K, Hattori T, Suematsu S, Kageyama J, Ota Z, Hatayama S, Ohashi H (1983) Cortisol responsiveness to insulin-induced hypoglycemia in Cushing’s syndrome with huge nodular adrenocortical hyperplasia. Endocrinology 33:479–487Google Scholar
  32. 32.
    Takemura T, Eishi Y, Hatakeyama S, Takahashi Y (1983) Cushing’s syndrome with bilateral multinodular adrenal hyperplasia. Ultrastructural, histochemical and immunohistochemical study. Acta Pathol Jpn 33:159–167PubMedGoogle Scholar
  33. 33.
    Aiba M, Hirayama A, Iri H, Ito Y, Fujimoto Y, Mabuchi G, Murai M, Tazaki H, Maruyama H, Saruta T, Suda T, Demura H (1991) Adrenocorticotropic hormone-independent bilateral adrenocortical macronodular hyperplasia as a distinct subtype of Cushing’s syndrome. Am J Clin Pathol 96:334–340PubMedGoogle Scholar
  34. 34.
    Sasano H, Suzuki T, Nagura H (1994) ACTH-independent macronodular adrenocortical hyperplasia: immunohistochemical and in situ hybridization studies of steroidogenic enzymes. Mod Pathol 7:215–219PubMedGoogle Scholar
  35. 35.
    Swords FM, Baig A, Malchoff DM, Malchoff CD, Thorner MO, King PJ, Hunyady L, Clark AJ (2002) Impaired desensitization of a mutant adrenocorticotropin receptor associated with apparent constitutive activity. Mol Endocrinol 16:2746–2753PubMedGoogle Scholar
  36. 36.
    Swords FM, Noon LA, King PJ, Clark AJ (2004) Constitutive activation of the human ACTH receptor resulting from a synergistic interaction between two naturally occurring missence mutations in the MC2R gene. Mol Cell Endocrinol 213:149–154PubMedGoogle Scholar
  37. 37.
    Suzuki T, Sasano H, Sawai T, Tsunoda K, Nishikawa T, Abe K, Yoshinaga K, Nagura H (1992) Small adrenocortical tumors without apparent clinical endocrine abnormalities. Immunolocalization of steroidogenic enzymes. Pathol Res Pract 188:883–889PubMedGoogle Scholar
  38. 38.
    Sasano H (1994) Localization of steroidogenic enzymes in adrenal cortex and its disorders. Endocrine J 41:471–482Google Scholar
  39. 39.
    Sasano H, Suzuki T, Sano T, Kameya T, Sasano N, Nagura H (1991) Adrenocortical oncocytoma. A true nonfunctioning adrenocortical tumor. Am J Surg Pathol 15:949–956PubMedGoogle Scholar
  40. 40.
    Osella G, Terzolo M, Borretta G, Magro G, Ali A, Piovesan A, Paccotti P, Angeli A (1994) Endocrine evaluation of incidentally discovered adrenal masses (Incidentalomas). J Clin Endocrinol Metab 79:1532–1539PubMedGoogle Scholar
  41. 41.
    Yamaji T, Ibayashi H (1969) Plasma dehydroepiandrosterone sulfate in normal and pathological conditions. J Clin Endocrinol Metab 29:273–280PubMedGoogle Scholar
  42. 42.
    Yamaji T, Ishibashi M, Sekihara H, Itabashi A, Yanaihara T (1984) Serum dehydroepiandrosterone sulfate in Cushing’s syndrome. J Clin Endocrinol Metab 59:1164–1168PubMedGoogle Scholar
  43. 43.
    Vaitukaitis JL, Dale SL, Melby JC (1969) Role of ACTH in the secretion of free dehydroepiandrosterone and its sulfate ester in man. J Clin Endocrinol Metab 29:1443–1447PubMedGoogle Scholar
  44. 44.
    Favre L, Jacot-des-Combes E, Morel P, Hausere H, Rindel AM, Megevaud R, Vallotton MB (1980) Primary aldosteronism with bilateral adrenal adenomas. Virchows Arch A Pathol Anat Histol 388:229–236PubMedGoogle Scholar
  45. 45.
    Honda M, Tsuchiya M, Tamura H (1982) In vivo and in vitro studies of steroid metabolism in a case of primary aldosteronism with multiple lesions of adenoma and nodular hyperplasia. Endocrinol Jpn 29:529–540PubMedGoogle Scholar
  46. 46.
    Imai T, Seo H, Murata Y, Funahashi H, Satoh Y, Sasano H, Matsui N, Takagi H (1991) Dexamethasone-nonsuppressible cortisol in two cases with aldosterone-producing adenoma. J Clin Endocrinol Metab 72:575–581PubMedGoogle Scholar
  47. 47.
    Gordon RD, Klemm SA, Tunny TJ, Stowasser M (1994) Genetics of primary aldosteronism. Clin Exp Pharmacol Physiol 21:915–918PubMedGoogle Scholar
  48. 48.
    Davies E, Bonnardeaux A, Plouin PF, Corvol P, Clauser E (1995) Somatic mutations of the angiotensin II (AT1) receptor gene are not present in aldosterone-producing adenoma. J Clin Endocrinol Metab 82:611–615Google Scholar
  49. 49.
    Sarzani R, Fallo F, Dessì-Fulgheri P, Pistorello M, Lanari A, Paci VM, Mantero F, Rappelli A (1992) Local renin–angiotensin system in human adrenals and aldosteronomas. Hypertension 19:702–707PubMedGoogle Scholar
  50. 50.
    Sarzani R, Opocher G, Dessì-Fulgheri P, Paci V, Cola G, Rocco S, Vianello B, Mantero F, Rappelli A (1995) Expression of type 1 angiotensin II receptors in human aldosteronomas. Endocr Res 21:189–195PubMedGoogle Scholar
  51. 51.
    Mazzocchi G, Malendowicz LK, Markowska A, Albertin G, Nussdorfer G (2000) Role of adrenal renin–angiotensin system in the control of aldosterone secretion in sodium restricted rats. Am J Physiol Endocrinol Metab 278:E1027–E1030PubMedGoogle Scholar
  52. 52.
    Sarzani R, Opocher G, Paci MV, Belloni AS, Mantero F, Dessì-Fulgheri P, Rappelli A (1999) Natriuretic peptides receptors in human aldosterone-secreting adenomas. J Endocrinol Invest 22:514–518PubMedGoogle Scholar
  53. 53.
    Sarzani R, Salvi F, Pietrucci F, Buglia L, Candelaresi C, Balducci B, Francioni M, Fazioli F, Letizia C, D’Erasmo E, Dessì-Fulgheri P, Rappelli A (2003) Absence of somatic mutations in natriuretic peptide receptor type-A gene in human aldosterone-secreting adenomas. J Mol Endocrinol 31:317–326PubMedGoogle Scholar
  54. 54.
    Sarzani R, Pietrucci F, Corinaldesi C, Francioni M, Letizia C, D’Erasmo E, Dessì-Fulgheri P, Rappelli A (2006) The functional HERG variant 897T is associated with Conn’s adenoma. J Hypertens 24:479–487PubMedGoogle Scholar
  55. 55.
    Kem DC, Tang K, Hanson CS, Brown RD, Painton R, Weinberger MH, Hollifield JW (1995) The prediction of anatomical morphology of primary aldosteronism using serum 18-hydroxycorticosterone levels. J Clin Endocrinol Metab 60:67–73Google Scholar
  56. 56.
    Streeten DHP, Tomycz N, Anderson GH Jr (1979) Reliability of screening methods for the diagnosis of primary aldosteronism. Am J Med 67:403–413PubMedGoogle Scholar
  57. 57.
    Herf SM, Teates DC, Tegtmeyer CJ, Vavghan ED Jr, Ayers CR, Carey RM (1979) Identification and differentiation of surgically correctable hypertension due to primary aldosteronism. Am J Med 67:397–402PubMedGoogle Scholar
  58. 58.
    Sutherland DJA, Ruse JL, Laidlaw JC (1966) Hypertension, increased aldosterone secretion and low plasma renin activity relieved by dexamethasone. Can Med Assoc J 95:1109–1119PubMedGoogle Scholar
  59. 59.
    New MI, Siegel EJ, Peterson RE (1973) Dexamethasone suppressible hyperaldosteronism. J Clin Endocrinol Metab 37:93–100PubMedGoogle Scholar
  60. 60.
    Grim CE, Weinberger MH (1980) Familial dexamethasone-suppressible normokalemic hyperaldosteronism. Pediatrics 65:597–604PubMedGoogle Scholar
  61. 61.
    New MI, Oberfield SE, Levine LS, Dupont B, Pollack MS, Gill JR Jr (1980) Autosomal dominant transmission and absence of HLA linkage in dexamethasone suppressible hyperaldosteronism. Lancet 1:550–551PubMedGoogle Scholar
  62. 62.
    Jonsson JR, Klemm SA, Tunny TJ, Stowasser M, Gordon RD (1995) A new genetic test for familial hyperaldosteronism type I aids in the detection of curable hypertension. Biochem Biophys Res Commun 207:565–571PubMedGoogle Scholar
  63. 63.
    Miyahara K, Kawamoto T, Mitsuuchi Y, Toda K, Imura H, Gordon RD, Shizuta Y (1992) The chimeric gene linked to glucocorticoid-suppressible hyperaldosteronism encodes a fused P-450 protein possessing aldosterone synthase activity. Biochem Biophys Res Commun 189:885–91PubMedGoogle Scholar
  64. 64.
    Lifton RP, Dluhy RG, Powers M, Rich GM, Ulick S, Lalouel JM (1992) A chimaeric 11 beta-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature 355:262–265PubMedGoogle Scholar
  65. 65.
    Pascoe L, Curnow KM, Slutsker L, Connell JM, Speiser PW, New MI, White PC (1992) Glucocorticoid-suppressible hyperaldosteronism results from hybrid genes created by unequal crossovers between CYP11B1 and CYP11B2. Proc Natl Acad Sci USA 89:8327–8331PubMedGoogle Scholar
  66. 66.
    Tang CK, Gray GF (1975) Adrenocortical neoplasms. Prognosis and morphology. Urology 5:691–695PubMedGoogle Scholar
  67. 67.
    Slooten HV, Schaberg A, Smeenk D, Meelenaar AJ (1985) Morphologic characteristics of benign and malignant adrenocortical tumors. Cancer 55:766–773PubMedGoogle Scholar
  68. 68.
    Gandour MJ, Grizzle WE (1986) A small adrenocortical carcinoma with aggressive behavior. An evaluation of criteria for malignancy. Arch Pathol Lab Med 110:1076–1079PubMedGoogle Scholar
  69. 69.
    Hough AJ, Hollifield JW, Page DL, Hartmann WH (1979) Prognostic factors in adrenal cortex tumors: a mathematical analysis of clinical and morphological data. Am J Clin Pathol 72:390–399PubMedGoogle Scholar
  70. 70.
    Brown FM, Gaffey TA, Wold LE, Lloyd RV (2000) Myxoid neoplasms of the adrenal cortex: a rare histologic variant. Am J Surg Pathol 24:396–401PubMedGoogle Scholar
  71. 71.
    Weiss LM (1984) Comparable histologic study of 43 metastasizing and nonmetastasizing adrenocortical tumors. Am J Surg Pathol 8:163–169PubMedGoogle Scholar
  72. 72.
    Weiss LM, Medeiros LJ, Vickery AL (1989) Pathologic features of prognostic significance in adrenocortical carcinoma. Am J Surg Pathol 13:202–206PubMedGoogle Scholar
  73. 73.
    Amberson JB, Vaughan ED, Gray GF, Naus GJ (1987) Flow cytometric analysis of nuclear DNA from adrenocortical neoplasms. A retrospective study using paraffin-embedded tissue. Cancer 59:2091–2095PubMedGoogle Scholar
  74. 74.
    Suzuki T, Sasano H, Nishikawa T, Rhame J, Wilkinson DS, Nagura H (1992) Discerning malignancy in human adrenocortical neoplasms: utility of DNA flow cytometry and immunohistochemistry. Mod Pathol 5:224–231PubMedGoogle Scholar
  75. 75.
    Cibas ES, Medeiros LJ, Weinberg DS (1990) Cellular DNA profiles of benign and malignant adrenocortical tumors. Am J Surg Pathol 14:948–955PubMedGoogle Scholar
  76. 76.
    Bugg MF, Ribeiro RC, Roberson PK, Lloyd RV, Sanduni R, Silva JB, Epelman S, Shapiro DN, Paaham DM (1994) Correlation of pathologic features with clinical outcome in pediatric adrenocortical neoplasia: a study of a Brazilian population. Am J Clin Pathol 101:625–629PubMedGoogle Scholar
  77. 77.
    Haak HR, Cornelisse CJ, Hermans J, Cobben L, Fleuren GJ (1993) Nuclear DNA content and morphological characteristics in the prognosis of adrenocortical carcinoma. Br J Cancer 68:151–155PubMedGoogle Scholar
  78. 78.
    Camuto P, Schinella R, Gilchrist K, Citrin D, Fredrickson G (1991) Adrenal cortical carcinoma: flow cytometric study of 22 cases, an ECOG study. Urology 37:380–384PubMedGoogle Scholar
  79. 79.
    Sasano H, Watanabe K, Ito K, Sato S, Yajima A (1994) New concepts in the diagnosis and prognosis of endometrial carcinoma. Pathol Annu 29(Pt 2):31–49PubMedGoogle Scholar
  80. 80.
    Goldblum J, Shannon R, Kaldjian EP, Thiny M, Davenport R, Thompson N, Lloyd R (1993) Immunohistochemical assessment of proliferative activity in adrenal cortical neoplasms. Mod Pathol 6:663–668PubMedGoogle Scholar
  81. 81.
    Iino K, Sasano H, Yabuki N, Oki Y, Kikuchi A, Yoshimi T, Nagura H (1997) DNA topoisomerase IIα and Ki-67 in human adrenocortical neoplasms: a possible marker of differentiation between adenomas and carcinomas. Mod Pathol 10:901–907PubMedGoogle Scholar
  82. 82.
    Sasano H, Suzuki T, Shizawa S, Kato K, Nagura H (1994) Transforming growth factor alpha, epidermal growth factor, and epidermal growth factor receptor expression in normal and diseased human adrenal cortex by immunohistochemistry and in situ hybridization. Mod Pathol 7:741–746PubMedGoogle Scholar
  83. 83.
    Ilvesmaki V, Kahri AI, Miettinen PJ, Voutilainen R (1993) Insulin-like growth factors (IGFs) and their receptors in adrenal tumors: high IGF-II expression in functional adrenocortical carcinomas. J Clin Endocrinol Metab 77:852–858PubMedGoogle Scholar
  84. 84.
    Wilkin F, Gagne N, Paquette J, Oligny LL, Deal C (2000) Pediatric adrenocortical tumors: molecular events leading to insulin-like growth factor II gene overexpression. J Clin Endocrinol Metab 85:2048–2056PubMedGoogle Scholar
  85. 85.
    Kamio T, Shigematsu K, Kawai K, Tsuchiyama H (1991) Immunoreactivity and receptor expression of insulin like growth factor I and insulin in human adrenal tumors. An Immunohistochemical study of 94 cases. Am J Pathol 138:83–91PubMedGoogle Scholar
  86. 86.
    Munro LM, Kennedy A, McNicol AM (1999) The expression of inhibin/activin subunits in the human adrenal cortex and its tumours. J Endocrinol 161:341–347PubMedGoogle Scholar
  87. 87.
    Fetsch PA, Powers CN, Zakowski MF, Abati A (1999) Anti-alpha-inhibin: marker of choice for the consistent distinction between adrenocortical carcinoma and renal cell carcinoma in fine-needle aspiration. Cancer 87:168–172PubMedGoogle Scholar
  88. 88.
    Arola J, Liu J, Heikkila P, Ilvesmaki V, Salmenkivi K, Voutilainen R, Kahri AI (2000) Expression of inhibin alpha in adrenocortical tumours reflects the hormonal status of the neoplasm. J Endocrinol 165:223–229PubMedGoogle Scholar
  89. 89.
    Martinerie C, Gicquel C, Louvel A, Laurent M, Schofield PN, Le Bouc Y (2001) Altered expression of novH is associated with human adrenocortical tumorigenesis. J Clin Endocrinol Metab 86:3929–3940PubMedGoogle Scholar
  90. 90.
    Boccuzzi A, Terzolo M, Cappia S, De Giuli P, De Risi C, Leonardo E, Bovio S, Borriero M, Paccotti P, Angeli A (1999) Different immunohistochemical patterns of TGF-beta 1 expression in benign and malignant adrenocortical tumours. Clin Endocrinol (Oxf) 50:801–808Google Scholar
  91. 91.
    Murray SA, Davis K, Fishman LM, Bornstein SR (2000) Alpha1 connexin 43 gap junctions are decreased in human adrenocortical tumors. J Clin Endocrinol Metab 85:890–895PubMedGoogle Scholar
  92. 92.
    Hanahan D, Folkman J (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86:353–364PubMedGoogle Scholar
  93. 93.
    de Fraipont F, El Atifi M, Gicquel C, Bertagna X, Chambaz EM, Feige JJ (2000) Expression of the angiogenesis markers vascular endothelial growth factor-A, thrombospondin-1, and platelet-derived endothelial cell growth factor in human sporadic adrenocortical tumors: correlation with genotypic alterations. J Clin Endocrinol Metab 85:4734–4741PubMedGoogle Scholar
  94. 94.
    Beckwith JP (1969) Macroglossia, omphalocele, adrenal cytomegaly, gigantism and hyperplastic visceromegaly. Birth Defects Orig Artic Ser 5:188–196Google Scholar
  95. 95.
    Wiedemann HR (1964) Complexe malformatif familial avec hernie ombilicale et macroglossie: un “syndrome nouveau”? J Genet Hum 13:223–233PubMedGoogle Scholar
  96. 96.
    Müller S, Gadner H, Weber B, Vogel M, Riehm H (1978) Wilms’ tumor and adrenocortical carcinoma with hemihypertrophy and hamartomas. Eur J Pediatr 127:219–226PubMedGoogle Scholar
  97. 97.
    Hayward NK, Little MH, Mortimer RH, Clouston WM, Smith PJ (1988) Generation of homozygosity at the c-Ha-ras-I locus on chromosome 11p in an adrenal adenoma from an adult with Wiedemann-Beckwith syndrome. Cancer Genet Cytogenet 30:127–132PubMedGoogle Scholar
  98. 98.
    Steenman M, Westerveld A, Mannens M (2000) Genetics of Beckwith-Wiedemann syndrome-associated tumors: common genetic pathways. Genes Chromosomes Cancer 28:1–13PubMedGoogle Scholar
  99. 99.
    Barlaskar FM, Hammer GD (2007) The molecular genetics of adrenocortical carcinoma. Rev Endocr Metab Disord 8:343–348PubMedGoogle Scholar
  100. 100.
    Koch CA, Pacak K, Chrousos GP (2002) The molecular pathogenesis of hereditary and sporadic adrenocortical and adrenomedullary tumors. J Clin Endocrinol Metab 87:5367–5384PubMedGoogle Scholar
  101. 101.
    Li FP, Fraumeni JF Jr (1982) Prospective study of a family cancer syndrome. JAMA 247:2692–2694PubMedGoogle Scholar
  102. 102.
    Lynch HT, Katz DA, Bogard PJ, Lynch JF (1985) The sarcoma, breast cancer, lung cancer, and adrenocortical carcinoma syndrome revisited. Am J Dis Child 139:134–136PubMedGoogle Scholar
  103. 103.
    Sidhu S, Gicquel C, Bambach CP, Campbell P, Magarey C, Robinson BG, Delbridge LW (2003) Clinical and molecular aspects of adrenocortical tumourigenesis. ANZ J Surg 73:727–738PubMedGoogle Scholar
  104. 104.
    Yano T, Linehan M, Anglard P, Lerman MI, Daniel LN, Stein CA, Robertson CN, LaRocca RL, Zbar B (1989) Genetic changes in human adrenocortical carcinomas. J Natl Cancer Inst 81:518–523PubMedGoogle Scholar
  105. 105.
    Herrmann ME, Rydstedt LL, Talpos GB, Ratner S, Wolman SR, Lalley PA (1994) Chromosomal aberrations in two adrenocortical tumors, one with a rearrangement at 11p15. Cancer Genet Cytogenet 75:111–116PubMedGoogle Scholar
  106. 106.
    Dohna M, Reincke M, Mincheva A, Allolio B, Solinas-Toldo S, Lichter P (2000) Adrenocortical carcinoma is characterized by a high frequency of chromosomal gains and high-level amplifications. Genes Chromosomes Cancer 28:145–152PubMedGoogle Scholar
  107. 107.
    Zhao J, Speel EJ, Muletta-Feurer S, Rutimann K, Saremasiani P, Roth J, Heitz PU, Komminoth P (1999) Analysis of genomic alterations in sporadic adrenocortical lesions. Gain of chromosome 17 is an early event in adrenocortical tumorigenesis. Am J Pathol 155:1039–1045PubMedGoogle Scholar
  108. 108.
    Russell AJ, Sibbald J, Haak H, Keith WN, McNicol AM (1999) Increasing genome instability in adrenocortical carcinoma progression with involvement of chromosomes 3, 9 and X at the adenoma stage. Br J Cancer 81:684–689PubMedGoogle Scholar
  109. 109.
    Sameshima Y, Mizoguchi H, Sugimura T, Terada M, Yokota J (1992) Detection of novel germ-line p53 mutations in diverse-cancer-prone families identified by selecting patients with childhood adrenocortical carcinoma. J Natl Cancer Inst 84:703–707PubMedGoogle Scholar
  110. 110.
    Hamelin R, Barichard F, Henry I, Junien C, Thomas G (1994) Single base pair germ-line deletion in the p53 gene in a cancer predisposed family. Hum Genet 94:88–90PubMedGoogle Scholar
  111. 111.
    Soussi T, Leblanc T, Baruchel A, Schaison G (1993) Germline mutations of the p53 tumor-suppressor gene in cancer-prone families: a review. Nouv Rev Fr Hematol 35:33–36PubMedGoogle Scholar
  112. 112.
    Wagner J, Portwine C, Rabin K, Leclerc JM, Narod SA, Malkin D (1994) High frequency of germline p53 mutations in childhood adrenocortical cancer. J Natl Cancer Inst 86:1707–1710PubMedGoogle Scholar
  113. 113.
    Barzon L, Chilosi M, Fallo F, Martignoni G, Montagna L, Palu G, Boscaro M (2001) Molecular analysis of CDKN1C and TP53 in sporadic adrenal tumors. Eur J Endocrinol 145:207–212PubMedGoogle Scholar
  114. 114.
    Reincke M, Karl M, Travis WH, Mastorakos G, Allolio B, Linehan HM, Chrousos GP (1994) p53 mutations in human adrenocortical neoplasms: immunohistochemical and molecular studies. J Clin Endocrinol Metab 78:790–794PubMedGoogle Scholar
  115. 115.
    McNicol AM, Nolan CE, Struthers AJ, Farquharson MA, Hermans J, Haak HR (1997) Expression of p53 in adrenocortical tumours: clinicopathological correlations. J Pathol 181:146–152PubMedGoogle Scholar
  116. 116.
    Gortz B, Roth J, Speel EJ, Krahenmann A, De Krijger RR, Matlas-Gulu X, Muletta-Feurer S, Rutmann K, Saremaslani P, Heitz PU, Komminoth P (1999) MEN1 gene mutation analysis of sporadic adrenocortical lesions. Int J Cancer 80:373–379PubMedGoogle Scholar
  117. 117.
    Heppner C, Reincke M, Agarwal SK, Mora P, Allolio B, Burns AL, Spiegel AM, Marx SJ (1999) MEN1 gene analysis in sporadic adrenocortical neoplasms. J Clin Endocrinol Metab 84:216–219PubMedGoogle Scholar
  118. 118.
    Nakazumi H, Sasano H, Iino K, Orikasa S (1998) Expression of cell cycle inhibitor p27 and Ki67 in human adrenocortical neoplasms. Mod Pathol 11:1165–1170PubMedGoogle Scholar
  119. 119.
    Pilon C, Pistorello M, Moscon A, Altavilla G, Pagotto U, Boscaro M, Fallo F (1999) Inactivation of the p16 tumor suppressor gene in adrenocortical tumors. J Clin Endocrinol Metab 84:2776–2779PubMedGoogle Scholar
  120. 120.
    Hirano Y, Fujita K, Suzuki K, Ushiyama T, Ohtawara Y, Tsuda F (1998) Telomerase activity as an indicator of potentially malignant adrenal tumors. Cancer 83:772–776PubMedGoogle Scholar
  121. 121.
    Mantovani G, Lania AG, Bondioni S, Peverelli E, Pedroni C, Ferrero S, Pellegrini C, Vicentini L, Arnaldi G, Bosari S, Beck-Peccoz P, Spada A (2008) Different expression of protein kinase A (PKA) regulatory subunits in cortisol-secreting adrenocortical tumors: relationship with cell proliferation. Exp Cell Res 314:123–130PubMedGoogle Scholar
  122. 122.
    Babinska A, Sworczak K, Wisniewski P, Nałecz A, Jaskiewicz K (2008) The role of immunohistochemistry in histopathological diagnostics of clinically “silent” incidentally detected adrenal masses. Exp Clin Endocrinol Diabetes 116:246–251PubMedGoogle Scholar
  123. 123.
    Barzon L, Masi G, Pacenti M, Trevisan M, Fallo F, Remo A, Martignoni G, Montanaro D, Pezzi V, Palù G (2008) Expression of aromatase and estrogen receptors in human adrenocortical tumors. Virchows Arch 452:181–191PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Hironobu Sasano
    • 1
  • Yasuhiro Nakamura
  • Takuya Moriya
  • Takashi Suzuki
  1. 1.Department of PathologyTohoku University School of MedicineAoba-ku, Sendai-ShiJapan

Personalised recommendations