Adrenocortical Cancer in Children

  • Carlos Rodriguez-Galindo
  • Gerard P. Zambetti
  • Raul C. Ribeiro


Adrenocortical cancer (ACC) is a rare but aggressive childhood endocrine neoplasm. Its incidence in children is extremely low (only 0.2% of pediatric cancers) [1], and most pediatric oncologists see few cases or none. Little is known about this malignancy and most available information has been learned from its more frequent adult counterpart. In recent years, an international registry has provided insight into the clinical characteristics and relevant management issues regarding pediatric ACC and tumor tissue for biological studies. These studies have resulted in the discovery of a novel mechanism of tumorigenesis [2], the gift to science by one of the rarest childhood cancers.


Congenital Adrenal Hyperplasia TP53 Mutation Adrenocortical Carcinoma Carney Complex Germline TP53 Mutation 
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.


  1. 1.
    Bernstein L, Gurney JG (1999) Carcinomas and other malignant epithelial neoplasms. In: Ries LAG et al (eds) Cancer and survival among children and adolescents: United States SEER program 1975–1995. National Cancer Institute, SEER program, Bethesda, MD, pp 139–147Google Scholar
  2. 2.
    Ribeiro RC et al (2001) An inherited p53 mutation that contributes in a tissue-specific manner to pediatric adrenal cortical carcinoma. Proc Natl Acad Sci USA 98:9330–9335PubMedCrossRefGoogle Scholar
  3. 3.
    Wooten MD, King DK (1993) Adrenal cortical carcinoma. Epidemiology and treatment with mitotane and a review of the literature. Cancer 72:3145–3155PubMedCrossRefGoogle Scholar
  4. 4.
    Figueiredo BC et al (2006) Penetrance of adrenocortical tumours associated with the germline TP53 R337H mutation. J Med Genet 43:91–96PubMedCrossRefGoogle Scholar
  5. 5.
    Pianovski MAD et al (2006) Mortality rate of adrenocortical tumors in children under 15 years of age in Curitiba, Brazil. Pediatr Blood Cancer 47:56–60PubMedCrossRefGoogle Scholar
  6. 6.
    Ribeiro RC, Figueiredo B (2004) Childhood adrenocortical tumours. Eur J Cancer 40:1117–1126PubMedCrossRefGoogle Scholar
  7. 7.
    Rodriguez-Galindo C et al (2005) Biology, clinical characteristics, and management of adrenocortical tumors in children. Pediatr Blood Cancer 45:265–273PubMedCrossRefGoogle Scholar
  8. 8.
    Hoyme HE et al (1998) Isolated hemihyperplasia (Hemihypertrophy): report of a prospective multicenter study of the incidence of neoplasia and review. Am J Med Genet 79:274–278PubMedCrossRefGoogle Scholar
  9. 9.
    Steenman M et al (2000) Genetics of Beckwith-Wiedeman syndrome-associated tumors: common genetic pathways. Genes Chromosomes Cancer 28:1–13PubMedCrossRefGoogle Scholar
  10. 10.
    Varan A et al (2000) Adrenocortical carcinoma associated with adrenogenital syndrome in a child. Med Pediatr Oncol 35:88–90PubMedCrossRefGoogle Scholar
  11. 11.
    Sutter JA, Grimberg A (2006) Adrenocortical tumors and hyperplasias in childhood – etiology, genetics, clinical presentation and therapy. Pediatr Endocrinol Rev 4:32–39PubMedGoogle Scholar
  12. 12.
    Langer P et al (2002) Adrenal involvement in multiple endocrine neoplasia type 1. World J Surg 26:891–896PubMedCrossRefGoogle Scholar
  13. 13.
    Kirschner LS (2002) Signaling pathways in adrenocortical cancer. Ann N Y Acad Sci 968:222–239PubMedCrossRefGoogle Scholar
  14. 14.
    Barlaskar FM, Hammer GD (2007) The molecular genetics of adrenocortical carcinoma. Rev Endocr Metab Disord 8:343–348PubMedCrossRefGoogle Scholar
  15. 15.
    Ilvesmaki V et al (1993) Insulin-like growth factors (IGFs) and their receptors in adrenal tumors: high IGF-II expression in functional adrenocortical carcinomas. J Clin Endocrinol Metab 77:852–858PubMedCrossRefGoogle Scholar
  16. 16.
    Boulle N et al (1998) Increased levels of insulin-like growth factor II (IGF-II) and IGF binding protein-2 are associated with malignancy in sporadic adrenocortical tumors. J Clin Endocrinol Metab 83:1713–1720PubMedCrossRefGoogle Scholar
  17. 17.
    Gicquel C et al (2001) Molecular markers and long-term recurrences in a large cohort of patients with sporadic adrenocortical tumors. Cancer Res 61:6762–6767PubMedGoogle Scholar
  18. 18.
    Almeida MQ et al (2008) Expression of insulin-like growth factor-ii and its receptor in pediatric and adult adrenocortical tumors. J Clin Endocrinol Metab 93:3524–3531PubMedCrossRefGoogle Scholar
  19. 19.
    West AN et al (2007) Gene expression profiling of childhood adrenocortical tumors. Cancer Res 67:600–608PubMedCrossRefGoogle Scholar
  20. 20.
    Weber MM et al (2000) The role of the insulin-like growth factor system in adrenocortical tumorigenesis. Eur J Clin Invest 30(Suppl 3):69–75PubMedCrossRefGoogle Scholar
  21. 21.
    Weber MM et al (1999) Postnatal overexpression of insulin-like growth factor II in transgenic mice is associated with adrenocortical hyperplasia and enhanced steroidogenesis. Endocrinology 140:1537–1543PubMedCrossRefGoogle Scholar
  22. 22.
    Tissier F et al (2005) Mutations of {beta}-catenin in adrenocortical tumors: activation of the Wnt signaling pathway is a frequent event in both benign and malignant adrenocortical tumors. Cancer Res 65:7622–7627PubMedGoogle Scholar
  23. 23.
    Birch J et al (2001) Relative frequency and morphology of cancers in carriers of germline TP53 mutations. Oncogene 20:4621–4628PubMedCrossRefGoogle Scholar
  24. 24.
    Kleihues P et al (1997) Tumors associated with p53 germline mutations. A synopsis of 91 families. Am J Pathol 150:1–13PubMedGoogle Scholar
  25. 25.
    Gonzalez KD et al (2009) Beyond Li Fraumeni syndrome: clinical characteristics of families with p53 germline mutations. J Clin Oncol 27:1250–1256PubMedCrossRefGoogle Scholar
  26. 26.
    Varley JM et al (1999) Are there low-penetrance TP53 alleles? Evidence from childhood adrenocortical tumors. Am J Hum Genet 65:995–1006PubMedCrossRefGoogle Scholar
  27. 27.
    Wagner J et al (1994) High frequency of germline p53 mutations in childhood adrenocortical cancer. J Natl Cancer Inst 86:1707–1710PubMedCrossRefGoogle Scholar
  28. 28.
    Ariffin H et al (2008) Li-Fraumeni syndrome in a Malaysian kindred. Cancer Genet Cytogenet 186:49–53PubMedCrossRefGoogle Scholar
  29. 29.
    Khayat CM, Johnston DL (2004) Rhabdomyosarcoma, osteosarcoma, and adrenocortical carcinoma in a child with a germline p53 mutation. Pediatr Blood Cancer 43:683–686PubMedCrossRefGoogle Scholar
  30. 30.
    Rossbach H-C et al (2008) Composite adrenal anaplastic neuroblastoma and virilizing adrenocortical tumor with germline TP53 R248W mutation. Pediatr Blood Cancer 50:681–683PubMedCrossRefGoogle Scholar
  31. 31.
    Reincke M et al (1994) p53 mutations in human adrenocortical neoplasms: immunohistochemical and molecular studies. J Clin Endocrinol Metab 78:790–794PubMedCrossRefGoogle Scholar
  32. 32.
    DiGiammarino EL et al (2001) A novel mechanism of tumorigenesis involving pH-dependent destabilization of a mutant p53 tetramer. Nat Struct Biol 9:12–16CrossRefGoogle Scholar
  33. 33.
    West AN et al (2006) Identification of a novel germ line variant hotspot mutant p53-R175L in pediatric adrenal cortical carcinoma. Cancer Res 66:5056–5062PubMedCrossRefGoogle Scholar
  34. 34.
    Dohna M et al (2000) Adrenocortical carcinoma is characterized by a high frequency of chromosomal gains and high-level amplifications. Genes Chromosomes Cancer 28:145–152PubMedCrossRefGoogle Scholar
  35. 35.
    Figueiredo BC et al (1999) Comparative genomic hybridization analysis of adrenocortical tumors of childhood. J Clin Endocrinol Metab 84:1116–1121PubMedCrossRefGoogle Scholar
  36. 36.
    Loncarevic IF et al (2008) Number of genomic imbalances correlates with the overall survival for adrenocortical cancer in childhood. Pediatr Blood Cancer 51:356–362PubMedCrossRefGoogle Scholar
  37. 37.
    Doghman M et al (2007) Increased steroidogenic factor-1 dosage triggers adrenocortical cell proliferation and cancer. Mol Endocrinol 21:2968–2987PubMedCrossRefGoogle Scholar
  38. 38.
    Wajchenberg BL et al (2000) Adrenocortical carcinoma: clinical and laboratory observations. Cancer 88:711–736PubMedCrossRefGoogle Scholar
  39. 39.
    Ribeiro RC et al (1990) Adrenocortical carcinoma in children: a study of 40 cases. J Clin Oncol 8:67–74PubMedGoogle Scholar
  40. 40.
    Ciftci AO et al (2001) Adrenocortical tumors in children. J Pediatr Surg 36:549–554PubMedCrossRefGoogle Scholar
  41. 41.
    Driver CP et al (1998) Adrenal cortical tumors in childhood. Pediatr Hematol Oncol 15:527–532PubMedCrossRefGoogle Scholar
  42. 42.
    Wieneke JA et al (2003) Adrenal cortical neoplasms in the pediatric population: a clinicopathologic and immunophenotypic analysis of 83 patients. Am J Surg Pathol 27:867–881PubMedCrossRefGoogle Scholar
  43. 43.
    Sandrini R et al (1997) Childhood adrenocortical tumors. J Clin Endocrinol Metab 7:2027–2031CrossRefGoogle Scholar
  44. 44.
    Bugg MF et al (1994) Correlation of pathologic features with clinical outcome in pediatric adrenocortical neoplasia. Am J Clin Pathol 101:625–629PubMedGoogle Scholar
  45. 45.
    Teinturier C et al (1999) Clinical and prognostic aspects of adrenocortical neoplasms in childhood. Med Pediatr Oncol 32:106–111PubMedGoogle Scholar
  46. 46.
    Michalkiewicz E et al (2004) Clinical and outcome characteristics of children with adrenocortical tumors. An analysis of 254 cases from the international pediatric adrenocortical tumor registry. J Clin Oncol 22:838–845PubMedCrossRefGoogle Scholar
  47. 47.
    Narasimhan KL et al (2003) Adrenocortical tumors in childhood. Pediatr Surg Int 19:432–435PubMedCrossRefGoogle Scholar
  48. 48.
    Hanna AM et al (2008) Outcome of adrenocortical tumors in children. J Pediatr Surg 43:843–849PubMedCrossRefGoogle Scholar
  49. 49.
    Wang X et al (2007) Nine cases of childhood adrenal tumour presenting with hypertension and a review of the literature. Acta Paediatr 96:930–934PubMedCrossRefGoogle Scholar
  50. 50.
    Tucci JR et al (2005) The impact of tumor stage on prognosis in children with adrenocortical carcinoma. J Urol 174:2338–2342PubMedCrossRefGoogle Scholar
  51. 51.
    Ribeiro J et al (2000) Imaging findings in pediatric adrenocortical carcinoma. Pediatr Radiol 30:45–51PubMedCrossRefGoogle Scholar
  52. 52.
    Mackie GC et al (2006) Use of [18F]fluorodeoxyglucose positron emission tomography in evaluating locally recurrent and metastatic adrenocortical carcinoma. J Clin Endocrinol Metab 91:2665–2671PubMedCrossRefGoogle Scholar
  53. 53.
    Murphy JJ et al (2008) Early experience with PET/CT scan in the evaluation of pediatric abdominal neoplasms. J Pediatr Surg 43:2186–2192PubMedCrossRefGoogle Scholar
  54. 54.
    Weiss LM (1984) Comparative histologic study of 43 metastasizing and nonmetastasizing adrenocortical tumors. Am J Surg Pathol 8:163–169PubMedCrossRefGoogle Scholar
  55. 55.
    Slooten HV et al (1985) Morphologic characteristics of benign and malignant adrenocortical tumors. Cancer 55:766–773PubMedCrossRefGoogle Scholar
  56. 56.
    Weiss LM et al (1989) Pathologic features of prognostic significance in adrenocortical carcinoma. Am J Surg Pathol 13:202–206PubMedCrossRefGoogle Scholar
  57. 57.
    Kendrick ML et al (2001) Adrenocortical carcinoma: surgical progress or status quo? Arch Surg 136:543–549PubMedCrossRefGoogle Scholar
  58. 58.
    Stojadinovic A et al (2002) Adrenocortical carcinoma: clinical, morphologic, and molecular characterization. J Clin Oncol 20:941–950PubMedCrossRefGoogle Scholar
  59. 59.
    Harrison LE et al (1999) Pathologic features of prognostic significance for adrenocortical carcinoma after curative resection. Arch Surg 134:181–185PubMedCrossRefGoogle Scholar
  60. 60.
    Rosati R et al (2008) High frequency of loss of heterozygosity at 11p15 and IGF2 overexpression are not related to clinical outcome in childhood adrenocortical tumors positive for the R337H TP53 mutation. Cancer Genet Cytogenet 186:19–24PubMedCrossRefGoogle Scholar
  61. 61.
    Erickson LA et al (2001) Pathologic features and expression of insulin-like growth factor-2 in adrenocortical neoplasms. Endocr Pathol 12:429–435PubMedCrossRefGoogle Scholar
  62. 62.
    de Reynies A et al (2009) Gene expression profiling reveals a new classification of adrenocortical tumors and identifies molecular predictors of malignancy and survival. J Clin Oncol 27:1108–1115PubMedCrossRefGoogle Scholar
  63. 63.
    Michalkiewicz EL et al (1997) Clinical characteristics of small functioning adrenocortical tumors in children. Med Pediatr Oncol 28:175–178PubMedCrossRefGoogle Scholar
  64. 64.
    Zancanella P et al (2006) Mitotane associated with cisplatin, etoposide, and doxorubicin in advanced childhood adrenocortical carcinoma. Mitotane monitoring and tumor regression. J Pediatr Hematol Oncol 28:513–524PubMedCrossRefGoogle Scholar
  65. 65.
    Hovi L et al (2003) Adrenocortical carcinoma in children: a role for etoposide and cisplatin adjuvant therapy? Preliminary report. Med Pediatr Oncol 40:324–326PubMedCrossRefGoogle Scholar
  66. 66.
    Stewart JN et al (2004) A surgical approach to adrenocortical tumors in children: the mainstay of treatment. J Pediatr Surg 39:759–763PubMedCrossRefGoogle Scholar
  67. 67.
    Leung LYJ et al (2002) Ruptured adrenocortical carcinoma as a cause of paediatric acute abdomen. Pediatr Surg Int 18:730–732PubMedGoogle Scholar
  68. 68.
    Kardar AH (2001) Rupture of adrenal carcinoma after biopsy. J Urol 166:984PubMedCrossRefGoogle Scholar
  69. 69.
    Gonzalez RJ et al (2005) Laparoscopic resection of adrenal cortical carcinoma: a cautionary note. Surgery 138:1078–1086PubMedCrossRefGoogle Scholar
  70. 70.
    Crucitti F et al (1996) the Italian registry for adrenal cortical carcinoma: analysis of a multiinstitutional series of 129 patients. The ACC Italian registry study group. Surgery 119:161–170PubMedCrossRefGoogle Scholar
  71. 71.
    Lee JE et al (1995) Surgical management, DNA content, and patient survival in adrenal cortical carcinoma. Surgery 118:1090–1098PubMedCrossRefGoogle Scholar
  72. 72.
    Ayass M et al (1991) High-dose carboplatinum and VP-16 in treatment of metastatic adrenal carcinoma. Am J Pediatr Hematol Oncol 13:470–472PubMedCrossRefGoogle Scholar
  73. 73.
    Coelho Netto AS et al (1963) Treatment of adrenocortical cancer with o,p' -DDD. Ann Intern Med 59:74–78Google Scholar
  74. 74.
    Ostuni JA, Roginsky MS (1975) Metastatic adrenal cortical carcinoma: documented cure with combined chemotherapy. Arch Intern Med 135:1257–1258PubMedCrossRefGoogle Scholar
  75. 75.
    De Leon DD et al (2002) Long-Term (15 Years) outcome in an infant with metastatic adrenocortical carcinoma. J Clin Endocrinol Metab 87:4452–4456PubMedCrossRefGoogle Scholar
  76. 76.
    Wood BJ et al (2003) Radiofrequency ablation of adrenal tumors and adrenocortical carcinoma metastases. Cancer 97:554–560PubMedCrossRefGoogle Scholar
  77. 77.
    Hoffer FA et al (2009) A phase 1/pilot study of radiofrequency ablation for the treatment of recurrent pediatric solid tumors. Cancer 115:1328–1337PubMedCrossRefGoogle Scholar
  78. 78.
    Kirschner LS (2006) Emerging treatment strategies for adrenocortical carcinoma: a new hope. J Clin Endocrinol Metab 91:14–21PubMedCrossRefGoogle Scholar
  79. 79.
    Barlaskar FM et al (2009) Preclinical targeting of the type I insulin-like growth factor receptor in adrenocortical carcinoma. J Clin Endocrinol Metab 94:204–212PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Carlos Rodriguez-Galindo
    • 1
  • Gerard P. Zambetti
    • 2
  • Raul C. Ribeiro
    • 3
  1. 1.Department of Pediatric OncologyDana-Farber Cancer Institute and Children’s HospitalBostonUSA
  2. 2.Department of BiochemistrySt. Jude Children’s Research HospitalMemphisUSA
  3. 3.Department of OncologySt. Jude Children’s Research HospitalMemphisUSA

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