Adrenocortical Carcinoma

  • Sara G. Creemers
  • Leo J. Hofland
  • Richard A. Feelders
Chapter
First Online:

Abstract

Adrenocortical carcinoma (ACC) is a rare malignancy with a poor prognosis. Incidence rates of 0.7–2.0 cases per million per year are reported. Approximately 40–60 % of patients present with symptoms due to hormone excess, while the remaining present with symptoms as a result of local or distant tumor growth. A growing proportion of ACC is incidentally discovered. The prediction of malignancy and the decision on adrenalectomy is supported by specific characteristics on CT scan, of which tumor size is the most important feature. Also, several radionucleotides have been evaluated and show promising results regarding differential diagnosis of adrenocortical tumors. The Weiss score, consisting of nine histopathological parameters, is currently considered the “gold standard” for ACC diagnosis. Successful tumor-directed surgery, performed by an experienced surgeon, is the only curative therapy. In patients with high risk of recurrence after resection (Ki67 > 10 % and stage III tumors), adjuvant mitotane treatment is recommended. In case of progression of advanced disease, mitotane can be combined with etoposide, doxorubicin, and cisplatin. However, mitotane is only effective in a subset of patients, indicating the need for predictive markers like CYP2W1, RRM1, or SOAT1 expression. Recently, also targeted therapies have been investigated, however, to date with discouraging results. Initial close surveillance by imaging and measurement of tumor markers is mandatory every 3 months. The staging system proposed by the European Network of the Study of Adrenal Tumors (ENSAT), the resection status, and the Ki67 index are important for prognostication. Research is focusing on molecular markers for stratification of survival outcome and on possibilities to use tumor and patient characteristics for a more personalized approach of patients with ACC.

Keywords

Clinical presentation Epidemiology Management Diagnosis Pathology Staging Mitotane Predictive markers Adjuvant treatment Follow-up Prognosis 
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References

  1. 1.
    Fassnacht M, Kroiss M, Allolio B. Update in adrenocortical carcinoma. J Clin Endocrinol Metab. 2013;98(12):4551–64.PubMedCrossRefGoogle Scholar
  2. 2.
    Kerkhofs TM, Verhoeven RH, Van der Zwan JM, Dieleman J, Kerstens MN, Links TP, et al. Adrenocortical carcinoma: a population-based study on incidence and survival in the Netherlands since 1993. Eur J Cancer. 2013;49(11):2579–86.PubMedCrossRefGoogle Scholar
  3. 3.
    Kebebew E, Reiff E, Duh QY, Clark OH, McMillan A. Extent of disease at presentation and outcome for adrenocortical carcinoma: have we made progress? World J Surg. 2006;30(5):872–8.PubMedCrossRefGoogle Scholar
  4. 4.
    Kleihues P, Schauble B, zur Hausen A, Esteve J, Ohgaki H. Tumors associated with p53 germline mutations: a synopsis of 91 families. Am J Pathol. 1997;150(1):1–13.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Wiedemann HR. Tumors and hemihypertrophy associated with Wiedemann-Beckwith syndrome. Eur J Pediatr. 1983;141(2):129.CrossRefGoogle Scholar
  6. 6.
    Waldmann J, Bartsch DK, Kann PH, Fendrich V, Rothmund M, Langer P. Adrenal involvement in multiple endocrine neoplasia type 1: results of 7 years prospective screening. Langenbeck Arch Surg. 2007;392(4):437–43.CrossRefGoogle Scholar
  7. 7.
    Luton JP, Cerdas S, Billaud L, Thomas G, Guilhaume B, Bertagna X, et al. Clinical features of adrenocortical carcinoma, prognostic factors, and the effect of mitotane therapy. N Engl J Med. 1990;322(17):1195–201.PubMedCrossRefGoogle Scholar
  8. 8.
    Fassnacht M, Allolio B. Clinical management of adrenocortical carcinoma. Best Pract Res Clin Endocrinol Metab. 2009;23(2):273–89.PubMedCrossRefGoogle Scholar
  9. 9.
    Allolio B, Fassnacht M. Clinical review: adrenocortical carcinoma: clinical update. J Clin Endocrinol Metab. 2006;91(6):2027–37.PubMedCrossRefGoogle Scholar
  10. 10.
    Berruti A, Fassnacht M, Haak H, Else T, Baudin E, Sperone P, et al. Prognostic role of overt hypercortisolism in completely operated patients with adrenocortical cancer. Eur Urol. 2014;65(4):832–8.PubMedCrossRefGoogle Scholar
  11. 11.
    Stewart PM, Walker BR, Holder G, Ohalloran D, Shackleton CHL. 11-Beta-hydroxysteroid dehydrogenase-activity in cushings-syndrome—explaining the mineralocorticoid excess state of the ectopic adrenocorticotropin syndrome. J Clin Endocr Metab. 1995;80(12):3617–20.PubMedGoogle Scholar
  12. 12.
    Seccia TM, Fassina A, Nussdorfer GG, Pessina AC, Rossi GP. Aldosterone-producing adrenocortical carcinoma: an unusual cause of Conn’s syndrome with an ominous clinical course. Endocr Relat Cancer. 2005;12(1):149–59.PubMedCrossRefGoogle Scholar
  13. 13.
    Ng L, Libertino JM. Adrenocortical carcinoma: diagnosis, evaluation and treatment. J Urol. 2003;169(1):5–11.PubMedCrossRefGoogle Scholar
  14. 14.
    Hyodo T, Megyesi K, Kahn CR, McLean JP, Friesen HG. Adrenocortical carcinoma and hypoglycemia: evidence for production of nonsuppressible insulin-like activity by the tumor. J Clin Endocrinol Metab. 1977;44(6):1175–84.PubMedCrossRefGoogle Scholar
  15. 15.
    Wajchenberg BL, Albergaria Pereira MA, Medonca BB, Latronico AC, Campos Carneiro P, Alves VA, et al. Adrenocortical carcinoma: clinical and laboratory observations. Cancer. 2000;88(4):711–36.PubMedCrossRefGoogle Scholar
  16. 16.
    Schteingart DE, Giordano TJ, Benitez RS, Burdick MD, Starkman MN, Arenberg DA, et al. Overexpression of CXC chemokines by an adrenocortical carcinoma: a novel clinical syndrome. J Clin Endocrinol Metab. 2001;86(8):3968–74.PubMedCrossRefGoogle Scholar
  17. 17.
    Abiven G, Coste J, Groussin L, Anract P, Tissier F, Legmann P, et al. Clinical and biological features in the prognosis of adrenocortical cancer: poor outcome of cortisol-secreting tumors in a series of 202 consecutive patients. J Clin Endocr Metab. 2006;91(7):2650–5.PubMedCrossRefGoogle Scholar
  18. 18.
    Sturgeon C, Shen WT, Clark OH, Duh QY, Kebebew E. Risk assessment in 457 adrenal cortical carcinomas: how much does tumor size predict the likelihood of malignancy? J Am Coll Surgeons. 2006;202(3):423–30.CrossRefGoogle Scholar
  19. 19.
    Mansmann G, Lau J, Balk E, Rothberg M, Miyachi Y, Bornstein SR. The clinically inapparent adrenal mass: update in diagnosis and management. Endocr Rev. 2004;25(2):309–40.PubMedCrossRefGoogle Scholar
  20. 20.
    Nieman LK. Approach to the patient with an adrenal incidentaloma. J Clin Endocrinol Metab. 2010;95(9):4106–13.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Nogueira TM, Lirov R, Caoili EM, Lerario AM, Miller BS, Fragoso MC, et al. Radiographic characteristics of adrenal masses preceding the diagnosis of adrenocortical cancer. Horm Cancer. 2015;6(4):176–81.PubMedCrossRefGoogle Scholar
  22. 22.
    Zhang HM, Perrier ND, Grubbs EG, Sircar K, Ye ZX, Lee JE, et al. CT features and quantification of the characteristics of adrenocortical carcinomas on unenhanced and contrast-enhanced studies. Clin Radiol. 2012;67(1):38–46.PubMedCrossRefGoogle Scholar
  23. 23.
    Petersenn S, Richter PA, Broemel T, Ritter CO, Deutschbein T, Beil FU, et al. Computed tomography criteria for discrimination of adrenal adenomas and adrenocortical carcinomas: analysis of the German ACC registry. Eur J Endocrinol. 2015;172(4):415–22.PubMedCrossRefGoogle Scholar
  24. 24.
    Bharwani N, Rockall AG, Sahdev A, Gueorguiev M, Drake W, Grossman AB, et al. Adrenocortical carcinoma: the range of appearances on CT and MRI. AJR Am J Roentgenol. 2011;196(6):W706–14.PubMedCrossRefGoogle Scholar
  25. 25.
    Sangwaiya MJ, Boland GW, Cronin CG, Blake MA, Halpern EF, Hahn PF. Incidental adrenal lesions: accuracy of characterization with contrast-enhanced washout multidetector CT—10-minute delayed imaging protocol revisited in a large patient cohort. Radiology. 2010;256(2):504–10.PubMedCrossRefGoogle Scholar
  26. 26.
    Boland GW, Lee MJ, Gazelle GS, Halpern EF, McNicholas MM, Mueller PR. Characterization of adrenal masses using unenhanced CT: an analysis of the CT literature. AJR Am J Roentgenol. 1998;171(1):201–4.PubMedCrossRefGoogle Scholar
  27. 27.
    Blake MA, Kalra MK, Sweeney AT, Lucey BC, Maher MM, Sahani DV, et al. Distinguishing benign from malignant adrenal masses: multi-detector row CT protocol with 10-minute delay. Radiology. 2006;238(2):578–85.PubMedCrossRefGoogle Scholar
  28. 28.
    Arnold DT, Reed JB, Burt K. Evaluation and management of the incidental adrenal mass. Proc (Bayl Univ Med Cent). 2003;16(1):7–12.Google Scholar
  29. 29.
    Boland GWL, Dwamena BA, Sangwaiya MJ, Goehler AG, Blake MA, Hahn PF, et al. Characterization of adrenal masses by using FDG PET: a systematic review and meta-analysis of diagnostic test performance. Radiology. 2011;259(1):117–26.PubMedCrossRefGoogle Scholar
  30. 30.
    Leboulleux S, Dromain C, Bonniaud G, Auperin A, Caillou B, Lumbroso J, et al. Diagnostic and prognostic value of 18-fluorodeoxyglucose positron emission tomography in adrenocortical carcinoma: a prospective comparison with computed tomography. J Clin Endocrinol Metab. 2006;91(3):920–5.PubMedCrossRefGoogle Scholar
  31. 31.
    Ardito A, Massaglia C, Pelosi E, Zaggia B, Basile V, Brambilla R, et al. 18F-FDG PET/CT in the post-operative monitoring of patients with adrenocortical carcinoma. Eur J Endocrinol. 2015;173(6):749–56.PubMedCrossRefGoogle Scholar
  32. 32.
    Hahner S, Stuermer A, Kreissl M, Reiners C, Fassnacht M, Haenscheid H, et al. [I-123]iodometomidate for molecular imaging of adrenocortical cytochrome P450 family 11B enzymes. J Clin Endocr Metab. 2008;93(6):2358–65.PubMedCrossRefGoogle Scholar
  33. 33.
    Hennings J, Lindhe O, Bergstrom M, Langstrom B, Sundin A, Hellman P. [11C]metomidate positron emission tomography of adrenocortical tumors in correlation with histopathological findings. J Clin Endocrinol Metab. 2006;91(4):1410–4.PubMedCrossRefGoogle Scholar
  34. 34.
    Kreissl MC, Schirbel A, Fassnacht M, Haenscheid H, Verburg FA, Bock S, et al. [(1)(2)(3)I]Iodometomidate imaging in adrenocortical carcinoma. J Clin Endocrinol Metab. 2013;98(7):2755–64.PubMedCrossRefGoogle Scholar
  35. 35.
    Hahner S, Kreissl MC, Fassnacht M, Haenscheid H, Knoedler P, Lang K, et al. [131I]iodometomidate for targeted radionuclide therapy of advanced adrenocortical carcinoma. J Clin Endocrinol Metab. 2012;97(3):914–22.PubMedCrossRefGoogle Scholar
  36. 36.
    Faria JF, Goldman SM, Szejnfeld J, Melo H, Kater C, Kenney P, et al. Adrenal masses: characterization with in vivo proton MR spectroscopy—initial experience. Radiology. 2007;245(3):788–97.PubMedCrossRefGoogle Scholar
  37. 37.
    Fassnacht M, Johanssen S, Quinkler M, Bucsky P, Willenberg HS, Beuschlein F, et al. Limited prognostic value of the 2004 International Union Against Cancer staging classification for adrenocortical carcinoma: proposal for a revised TNM classification. Cancer. 2009;115(2):243–50.PubMedCrossRefGoogle Scholar
  38. 38.
    Lughezzani G, Sun M, Perrotte P, Jeldres C, Alasker A, Isbarn H, et al. The European Network for the Study of Adrenal Tumors staging system is prognostically superior to the international union against cancer-staging system: a North American validation. Eur J Cancer. 2010;46(4):713–9.PubMedCrossRefGoogle Scholar
  39. 39.
    Weiss LM, Medeiros LJ, Vickery Jr AL. Pathologic features of prognostic significance in adrenocortical carcinoma. Am J Surg Pathol. 1989;13(3):202–6.PubMedCrossRefGoogle Scholar
  40. 40.
    Duregon E, Volante M, Bollito E, Goia M, Buttigliero C, Zaggia B, et al. Pitfalls in the diagnosis of adrenocortical tumors: a lesson from 300 consultation cases. Hum Pathol. 2015;46(12):1799–807.PubMedCrossRefGoogle Scholar
  41. 41.
    Aubert S, Wacrenier A, Leroy X, Devos P, Carnaille B, Proye C, et al. Weiss system revisited: a clinicopathologic and immunohistochemical study of 49 adrenocortical tumors. Am J Surg Pathol. 2002;26(12):1612–9.PubMedCrossRefGoogle Scholar
  42. 42.
    Pennanen M, Heiskanen I, Sane T, Remes S, Mustonen H, Haglund C, et al. Helsinki score-a novel model for prediction of metastases in adrenocortical carcinomas. Hum Pathol. 2015;46(3):404–10.PubMedCrossRefGoogle Scholar
  43. 43.
    Creemers SG, Hofland LJ, Korpershoek E, Franssen GJ, van Kemenade FJ, de Herder WW, et al. Future directions in the diagnosis and medical treatment of adrenocortical carcinoma. Endocr Relat Cancer. 2016;23(1):R43–69.PubMedGoogle Scholar
  44. 44.
    de Krijger RR, Papathomas TG. Adrenocortical neoplasia: evolving concepts in tumorigenesis with an emphasis on adrenal cortical carcinoma variants. Virchows Arch. 2012;460(1):9–18.PubMedCrossRefGoogle Scholar
  45. 45.
    Duregon E, Volante M, Cappia S, Cuccurullo A, Bisceglia M, Wong DD, et al. Oncocytic adrenocortical tumors: diagnostic algorithm and mitochondrial DNA profile in 27 cases. Am J Surg Pathol. 2011;35(12):1882–93.PubMedCrossRefGoogle Scholar
  46. 46.
    Papotti M, Volante M, Duregon E, Delsedime L, Terzolo M, Berruti A, et al. Adrenocortical tumors with myxoid features: a distinct morphologic and phenotypical variant exhibiting malignant behavior. Am J Surg Pathol. 2010;34(7):973–83.PubMedCrossRefGoogle Scholar
  47. 47.
    Grondal S, Eriksson B, Hagenas L, Werner S, Curstedt T. Steroid profile in urine—a useful tool in the diagnosis and follow-up of adrenocortical carcinoma. Acta Endocrinol-Cop. 1990;122(5):656–63.Google Scholar
  48. 48.
    Arlt W, Biehl M, Taylor AE, Hahner S, Libe R, Hughes BA, et al. Urine steroid metabolomics as a biomarker tool for detecting malignancy in adrenal tumors. J Clin Endocr Metab. 2011;96(12):3775–84.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Kerkhofs TM, Kerstens MN, Kema IP, Willems TP, Haak HR. Diagnostic value of urinary steroid profiling in the evaluation of adrenal tumors. Horm Cancer. 2015;6(4):168–75.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Libe R, Borget I, Ronchi CL, Zaggia B, Kroiss M, Kerkhofs T, et al. Prognostic factors in stage III-IV adrenocortical carcinomas (ACC): an European Network for the Study of Adrenal Tumor (ENSAT) study. Ann Oncol. 2015;26(10):2119–25.PubMedCrossRefGoogle Scholar
  51. 51.
    Bellantone R, Ferrante A, Boscherini M, Lombardi CP, Crucitti P, Crucitti F, et al. Role of reoperation in recurrence of adrenal cortical carcinoma: results from 188 cases collected in the Italian National Registry for Adrenal Cortical Carcinoma. Surgery. 1997;122(6):1212–8.PubMedCrossRefGoogle Scholar
  52. 52.
    Grubbs EG, Callender GG, Xing Y, Perrier ND, Evans DB, Phan AT, et al. Recurrence of adrenal cortical carcinoma following resection: surgery alone can achieve results equal to surgery plus mitotane. Ann Surg Oncol. 2010;17(1):263–70.PubMedCrossRefGoogle Scholar
  53. 53.
    Margonis GA, Kim Y, Tran TB, Postlewait LM, Maithel SK, Wang TS et al. Outcomes after resection of cortisol-secreting adrenocortical carcinoma. Am J Surg. 2015.Google Scholar
  54. 54.
    Livhits M, Li N, Yeh MW, Harari A. Surgery is associated with improved survival for adrenocortical cancer, even in metastatic disease. Surgery. 2014;156(6):1531–41.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Berruti A, Baudin E, Gelderblom H, Haak HR, Porpiglia F, Fassnacht M, et al. Adrenal cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012;23 Suppl 7:vii131–8.PubMedCrossRefGoogle Scholar
  56. 56.
    Else T, Kim AC, Sabolch A, Raymond VM, Kandathil A, Caoili EM, et al. Adrenocortical carcinoma. Endocr Rev. 2014;35(2):282–326.PubMedCrossRefGoogle Scholar
  57. 57.
    Fassnacht M, Libe R, Kroiss M, Allolio B. Adrenocortical carcinoma: a clinician’s update. Nat Rev Endocrinol. 2011;7(6):323–35.PubMedCrossRefGoogle Scholar
  58. 58.
    Margonis GA, Amini N, Kim Y, Tran TB, Postlewait LM, Maithel SK, et al. Incidence of perioperative complications following resection of adrenocortical carcinoma and its association with long-term survival. World J Surg. 2016;40(3):706–14.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Bellantone R, Lombardi CP, Raffaelli M. What is the appropriate role of minimally invasive vs. open surgery for small adrenocortical cancers? Curr Opin Oncol. 2015;27(1):44–9.PubMedCrossRefGoogle Scholar
  60. 60.
    Nelson AA, Woodard G. Severe adrenal cortical atrophy (cytotoxic) and hepatic damage produced in dogs by feeding 2,2-bis(parachlorophenyl)-1,1-dichloroethane (DDD or TDE). Arch Pathol (Chic). 1949;48(5):387–94.Google Scholar
  61. 61.
    Schteingart DE, Doherty GM, Gauger PG, Giordano TJ, Hammer GD, Korobkin M, et al. Management of patients with adrenal cancer: recommendations of an international consensus conference. Endocr Relat Cancer. 2005;12(3):667–80.PubMedCrossRefGoogle Scholar
  62. 62.
    Poli G, Guasti D, Rapizzi E, Fucci R, Canu L, Bandini A, et al. Morphofunctional effects of mitotane on mitochondria in human adrenocortical cancer cells. Endocr Relat Cancer. 2013;20(4):537–50.PubMedCrossRefGoogle Scholar
  63. 63.
    Sbiera S, Leich E, Liebisch G, Sbiera I, Schirbel A, Wiemer L et al. Mitotane inhibits sterol-O-acyl transferase 1 triggering lipid-mediated endoplasmic reticulum stress and apoptosis in adrenocortical carcinoma cells. Endocrinology. 2015:en20151367Google Scholar
  64. 64.
    Daffara F, De Francia S, Reimondo G, Zaggia B, Aroasio E, Porpiglia F, et al. Prospective evaluation of mitotane toxicity in adrenocortical cancer patients treated adjuvantly. Endocr Relat Cancer. 2008;15(4):1043–53.PubMedCrossRefGoogle Scholar
  65. 65.
    Hahner S, Fassnacht M. Mitotane for adrenocortical carcinoma treatment. Curr Opin Investig Drugs. 2005;6(4):386–94.PubMedGoogle Scholar
  66. 66.
    Zatelli MC, Gentilin E, Daffara F, Tagliati F, Reimondo G, Carandina G, et al. Therapeutic concentrations of mitotane (o, p′-DDD) inhibit thyrotroph cell viability and TSH expression and secretion in a mouse cell line model. Endocrinology. 2010;151(6):2453–61.PubMedCrossRefGoogle Scholar
  67. 67.
    Terzolo M, Berruti A. Adjunctive treatment of adrenocortical carcinoma. Curr Opin Endocrinol Diabetes Obes. 2008;15(3):221–6.PubMedCrossRefGoogle Scholar
  68. 68.
    Hermsen IG, Fassnacht M, Terzolo M, Houterman S, den Hartigh J, Leboulleux S, et al. Plasma concentrations of o, p′ DDD, o, p′ DDA, and o, p′ DDE as predictors of tumor response to mitotane in adrenocortical carcinoma: results of a retrospective ENS@T multicenter study. J Clin Endocr Metab. 2011;96(6):1844–51.PubMedCrossRefGoogle Scholar
  69. 69.
    Terzolo M, Baudin AE, Ardito A, Kroiss M, Leboulleux S, Daffara F, et al. Mitotane levels predict the outcome of patients with adrenocortical carcinoma treated adjuvantly following radical resection. Eur J Endocrinol. 2013;169(3):263–70.PubMedCrossRefGoogle Scholar
  70. 70.
    Baudin E, Pellegriti G, Bonnay M, Penfornis A, Laplanche A, Vassal G, et al. Impact of monitoring plasma 1,1-dichlorodiphenildichloroethane (o, p′DDD) levels on the treatment of patients with adrenocortical carcinoma. Cancer. 2001;92(6):1385–92.PubMedCrossRefGoogle Scholar
  71. 71.
    Kerkhofs TM, Baudin E, Terzolo M, Allolio B, Chadarevian R, Mueller HH, et al. Comparison of two mitotane starting dose regimens in patients with advanced adrenocortical carcinoma. J Clin Endocrinol Metab. 2013;98(12):4759–67.PubMedCrossRefGoogle Scholar
  72. 72.
    Cai W, Counsell RE, Schteingart DE, Sinsheimer JE, Vaz AD, Wotring LL. Adrenal proteins bound by a reactive intermediate of mitotane. Cancer Chemother Pharmacol. 1997;39(6):537–40.PubMedCrossRefGoogle Scholar
  73. 73.
    Lindhe O, Skogseid B, Brandt I. Cytochrome P450-catalyzed binding of 3-methylsulfonyl-DDE and o, p′-DDD in human adrenal zona fasciculata/reticularis. J Clin Endocrinol Metab. 2002;87(3):1319–26.PubMedGoogle Scholar
  74. 74.
    Kroiss M, Quinkler M, Lutz WK, Allolio B, Fassnacht M. Drug interactions with mitotane by induction of CYP3A4 metabolism in the clinical management of adrenocortical carcinoma. Clin Endocrinol (Oxf). 2011;75(5):585–91.CrossRefGoogle Scholar
  75. 75.
    Touitou Y, Bogdan A, Luton JP. Changes in corticosteroid synthesis of the human adrenal cortex in vitro, induced by treatment with o, p′-DDD for Cushing’s syndrome: evidence for the sites of action of the drug. J Steroid Biochem. 1978;9(12):1217–24.PubMedCrossRefGoogle Scholar
  76. 76.
    Ghataore L, Chakraborti I, Aylwin SJ, Schulte KM, Dworakowska D, Coskeran P, et al. Effects of mitotane treatment on human steroid metabolism: implications for patient management. Endocr Connect. 2012;1(1):37–47.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    van Seters AP, Moolenaar AJ. Mitotane increases the blood levels of hormone-binding proteins. Acta Endocrinol (Copenh). 1991;124(5):526–33.Google Scholar
  78. 78.
    Chortis V, Taylor AE, Schneider P, Tomlinson JW, Hughes BA, O’Neil DM, et al. Mitotane therapy in adrenocortical cancer induces CYP3A4 and inhibits 5alpha-reductase, explaining the need for personalized glucocorticoid and androgen replacement. J Clin Endocrinol Metab. 2013;98(1):161–71.PubMedCrossRefGoogle Scholar
  79. 79.
    Nader N, Raverot G, Emptoz-Bonneton A, Dechaud H, Bonnay M, Baudin E, et al. Mitotane has an estrogenic effect on sex hormone-binding globulin and corticosteroid-binding globulin in humans. J Clin Endocr Metab. 2006;91(6):2165–70.PubMedCrossRefGoogle Scholar
  80. 80.
    Terzolo M, Angeli A, Fassnacht M, Daffara F, Tauchmanova L, Conton PA, et al. Adjuvant mitotane treatment for adrenocortical carcinoma. N Engl J Med. 2007;356(23):2372–80.PubMedCrossRefGoogle Scholar
  81. 81.
    Beuschlein F, Weigel J, Saeger W, Kroiss M, Wild V, Daffara F, et al. Major prognostic role of Ki67 in localized adrenocortical carcinoma after complete resection. J Clin Endocrinol Metab. 2015;100(3):841–9.PubMedCrossRefGoogle Scholar
  82. 82.
    Ronchi CL, Sbiera S, Volante M, Steinhauer S, Scott-Wild V, Altieri B, et al. CYP2W1 is highly expressed in adrenal glands and is positively associated with the response to mitotane in adrenocortical carcinoma. PLoS One. 2014;9(8), e105855.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Volante M, Terzolo M, Fassnacht M, Rapa I, Germano A, Sbiera S, et al. Ribonucleotide reductase large subunit (RRM1) gene expression may predict efficacy of adjuvant mitotane in adrenocortical cancer. Clin Cancer Res. 2012;18(12):3452–61.PubMedCrossRefGoogle Scholar
  84. 84.
    Germano A, Rapa I, Volante M, De Francia S, Migliore C, Berruti A, et al. RRM1 modulates mitotane activity in adrenal cancer cells interfering with its metabolization. Mol Cell Endocrinol. 2015;401(C):105–10.PubMedCrossRefGoogle Scholar
  85. 85.
    Berruti A, Ferrero A, Sperone P, Daffara F, Reimondo G, Papotti M, et al. Emerging drugs for adrenocortical carcinoma. Expert Opin Emerg Drugs. 2008;13(3):497–509.PubMedCrossRefGoogle Scholar
  86. 86.
    Gagliano T, Gentilin E, Benfini K, Di Pasquale C, Tassinari M, Falletta S, et al. Mitotane enhances doxorubicin cytotoxic activity by inhibiting P-gp in human adrenocortical carcinoma cells. Endocrine. 2014;47(3):943–51.PubMedCrossRefGoogle Scholar
  87. 87.
    Flynn SD, Murren JR, Kirby WM, Honig J, Kan L, Kinder BK. P-glycoprotein expression and multidrug resistance in adrenocortical carcinoma. Surgery. 1992;112(6):981–6.PubMedGoogle Scholar
  88. 88.
    Fassnacht M, Terzolo M, Allolio B, Baudin E, Haak H, Berruti A, et al. Combination chemotherapy in advanced adrenocortical carcinoma. N Engl J Med. 2012;366(23):2189–97.PubMedCrossRefGoogle Scholar
  89. 89.
    Sperone P, Ferrero A, Daffara F, Priola A, Zaggia B, Volante M, et al. Gemcitabine plus metronomic 5-fluorouracil or capecitabine as a second-/third-line chemotherapy in advanced adrenocortical carcinoma: a multicenter phase II study. Endocr Relat Cancer. 2010;17(2):445–53.PubMedCrossRefGoogle Scholar
  90. 90.
    Chacon R, Tossen G, Loria FS, Chacon M. CASE 2. Response in a patient with metastatic adrenal cortical carcinoma with thalidomide. J Clin Oncol. 2005;23(7):1579–80.PubMedCrossRefGoogle Scholar
  91. 91.
    Berruti A, Sperone P, Bellini E, Daffara F, Perotti P, Ardito A, et al. Metronomic therapy concepts in the management of adrenocortical carcinoma. Horm Cancer. 2011;2(6):378–84.PubMedCrossRefGoogle Scholar
  92. 92.
    Germano A, Rapa I, Volante M, Lo Buono N, Carturan S, Berruti A, et al. Cytotoxic activity of gemcitabine, alone or in combination with mitotane, in adrenocortical carcinoma cell lines. Mol Cell Endocrinol. 2014;382(1):1–7.PubMedCrossRefGoogle Scholar
  93. 93.
    Ronchi CL, Sbiera S, Kraus L, Wortmann S, Johanssen S, Adam P, et al. Expression of excision repair cross complementing group 1 and prognosis in adrenocortical carcinoma patients treated with platinum-based chemotherapy. Endocr Relat Cancer. 2009;16(3):907–18.PubMedCrossRefGoogle Scholar
  94. 94.
    Hermsen IGC, Groenen YE, Dercksen MW, Theuws J, Haak HR. Response to radiation therapy in adrenocortical carcinoma. J Endocrinol Invest. 2010;33(10):712–4.PubMedCrossRefGoogle Scholar
  95. 95.
    Fassnacht M, Hahner S, Polat B, Koschker AC, Kenn W, Flentje M, et al. Efficacy of adjuvant radiotherapy of the tumor bed on local recurrence of adrenocortical carcinoma. J Clin Endocrinol Metab. 2006;91(11):4501–4.PubMedCrossRefGoogle Scholar
  96. 96.
    Sabolch A, Feng M, Griffith K, Hammer G, Doherty G, Ben-Josef E. Adjuvant and definitive radiotherapy for adrenocortical carcinoma. Int J Radiat Oncol Biol Phys. 2011;80(5):1477–84.PubMedCrossRefGoogle Scholar
  97. 97.
    Sabolch A, Else T, Griffith KA, Ben-Josef E, Williams A, Miller BS, et al. Adjuvant radiation therapy improves local control after surgical resection in patients with localized adrenocortical carcinoma. Int J Radiat Oncol Biol Phys. 2015;92(2):252–9.PubMedCrossRefGoogle Scholar
  98. 98.
    Polat B, Fassnacht M, Pfreundner L, Guckenberger M, Bratengeier K, Johanssen S, et al. Radiotherapy in adrenocortical carcinoma. Cancer. 2009;115(13):2816–23.PubMedCrossRefGoogle Scholar
  99. 99.
    Corcuff JB, Young J, Masquefa-Giraud P, Chanson P, Baudin E, Tabarin A. Rapid control of severe neoplastic hypercortisolism with metyrapone and ketoconazole. Eur J Endocrinol. 2015;172(4):473–81.PubMedCrossRefGoogle Scholar
  100. 100.
    Creemers SG, Hofland LJ, Lamberts SW, Feelders RA. Cushing’s syndrome: an update on current pharmacotherapy and future directions. Expert Opin Pharmacother. 2015;16(12):1829–44.PubMedCrossRefGoogle Scholar
  101. 101.
    Lacroix A, Feelders RA, Stratakis CA, Nieman LK. Cushing’s syndrome. Lancet. 2015;386(9996):913–27.PubMedCrossRefGoogle Scholar
  102. 102.
    Fleseriu M, Biller BM, Findling JW, Molitch ME, Schteingart DE, Gross C, et al. Mifepristone, a glucocorticoid receptor antagonist, produces clinical and metabolic benefits in patients with Cushing’s syndrome. J Clin Endocrinol Metab. 2012;97(6):2039–49.PubMedCrossRefGoogle Scholar
  103. 103.
    Hunter MH, Carek PJ. Evaluation and treatment of women with hirsutism. Am Fam Physician. 2003;67(12):2565–72.PubMedGoogle Scholar
  104. 104.
    de Reynies A, Assie G, Rickman DS, Tissier F, Groussin L, Rene-Corrail F, et al. Gene expression profiling reveals a new classification of adrenocortical tumors and identifies molecular predictors of malignancy and survival. J Clin Oncol. 2009;27(7):1108–15.PubMedCrossRefGoogle Scholar
  105. 105.
    Wang C, Sun Y, Wu H, Zhao D, Chen J. Distinguishing adrenal cortical carcinomas and adenomas: a study of clinicopathological features and biomarkers. Histopathology. 2014;64(4):567–76.PubMedCrossRefGoogle Scholar
  106. 106.
    Giordano TJ, Thomas DG, Kuick R, Lizyness M, Misek DE, Smith AL, et al. Distinct transcriptional profiles of adrenocortical tumors uncovered by DNA microarray analysis. Am J Pathol. 2003;162(2):521–31.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    De Martino MC, Feelders RA, de Herder WW, van Koetsveld PM, Dogan F, Janssen JA, et al. Characterization of the mTOR pathway in human normal adrenal and adrenocortical tumors. Endocr Relat Cancer. 2014;21(4):601–13.PubMedCrossRefGoogle Scholar
  108. 108.
    Jones RL, Kim ES, Nava-Parada P, Alam S, Johnson FM, Stephens AW, et al. Phase I study of intermittent oral dosing of the insulin-like growth factor-1 and insulin receptors inhibitor OSI-906 in patients with advanced solid tumors. Clin Cancer Res. 2015;21(4):693–700.PubMedCrossRefGoogle Scholar
  109. 109.
    Lerario AM, Worden FP, Ramm CA, Hasseltine EA, Stadler WM, Else T, et al. The combination of insulin-like growth factor receptor 1 (IGF1R) antibody cixutumumab and mitotane as a first-line therapy for patients with recurrent/metastatic adrenocortical carcinoma: a multi-institutional NCI-sponsored trial. Horm Cancer. 2014;5(4):232–9.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Naing A, LoRusso P, Fu S, Hong D, Chen HX, Doyle LA, et al. Insulin growth factor receptor (IGF-1R) antibody cixutumumab combined with the mTOR inhibitor temsirolimus in patients with metastatic adrenocortical carcinoma. Br J Cancer. 2013;108(4):826–30.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Fassnacht M, Berruti A, Baudin E, Demeure MJ, Gilbert J, Haak H, et al. Linsitinib (OSI-906) versus placebo for patients with locally advanced or metastatic adrenocortical carcinoma: a double-blind, randomised, phase 3 study. Lancet Oncol. 2015;16(4):426–35.PubMedCrossRefGoogle Scholar
  112. 112.
    Sasano H, Suzuki T, Shizawa S, Kato K, Nagura H. 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. 1994;7(7):741–6.PubMedGoogle Scholar
  113. 113.
    de Fraipont F, El Atifi M, Cherradi N, Le Moigne G, Defaye G, Houlgatte R, et al. Gene expression profiling of human adrenocortical tumors using complementary deoxyribonucleic acid microarrays identifies several candidate genes as markers of malignancy. J Clin Endocr Metab. 2005;90(3):1819–29.PubMedCrossRefGoogle Scholar
  114. 114.
    Xu YZ, Zhu Y, Shen ZJ, Sheng JY, He HC, Ma G, et al. Significance of heparanase-1 and vascular endothelial growth factor in adrenocortical carcinoma angiogenesis: potential for therapy. Endocrine. 2011;40(3):445–51.PubMedCrossRefGoogle Scholar
  115. 115.
    Zacharieva S, Atanassova I, Orbetzova M, Nachev E, Kalinov K, Kirilov G, et al. Circulating vascular endothelial growth factor and active renin concentrations and prostaglandin E2 urinary excretion in patients with adrenal tumours. Eur J Endocrinol. 2004;150(3):345–9.PubMedCrossRefGoogle Scholar
  116. 116.
    O’Sullivan C, Edgerly M, Velarde M, Wilkerson J, Venkatesan AM, Pittaluga S, et al. The VEGF inhibitor axitinib has limited effectiveness as a therapy for adrenocortical cancer. J Clin Endocr Metab. 2014;99(4):1291–7.PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Kroiss M, Quinkler M, Johanssen S, van Erp NP, Lankheet N, Pollinger A, et al. Sunitinib in refractory adrenocortical carcinoma: a phase II, single-arm, open-label trial. J Clin Endocrinol Metab. 2012;97(10):3495–503.PubMedCrossRefGoogle Scholar
  118. 118.
    Gross DJ, Munter G, Bitan M, Siegal T, Gabizon A, Weitzen R, et al. The role of imatinib mesylate (Glivec) for treatment of patients with malignant endocrine tumors positive for c-kit or PDGF-R. Endocr-Relat Cancer. 2006;13(2):535–40.PubMedCrossRefGoogle Scholar
  119. 119.
    Samnotra V, Vassilopoulou-Sellin R, Fojo AT, Oh WK, LaRocca RV, Ernstoff MS, et al. A phase II trial of gefitinib monotherapy in patients with unresectable adrenocortical carcinoma (ACC). J Clin Oncol. 2007;25:15527.Google Scholar
  120. 120.
    Quinkler M, Hahner S, Wortmann S, Johanssen S, Adam P, Ritter C, et al. Treatment of advanced adrenocortical carcinoma with erlotinib plus gemcitabine. J Clin Endocrinol Metab. 2008;93(6):2057–62.PubMedCrossRefGoogle Scholar
  121. 121.
    Berruti A, Sperone P, Ferrero A, Germano A, Ardito A, Priola AM, et al. Phase II study of weekly paclitaxel and sorafenib as second/third-line therapy in patients with adrenocortical carcinoma. Eur J Endocrinol. 2012;166(3):451–8.PubMedCrossRefGoogle Scholar
  122. 122.
    Gaujoux S, Tissier F, Groussin L, Libe R, Ragazzon B, Launay P, et al. Wnt/beta-catenin and 3′,5′-cyclic adenosine 5′-monophosphate/protein kinase a signaling pathways alterations and somatic beta-catenin gene mutations in the progression of adrenocortical tumors. J Clin Endocr Metab. 2008;93(10):4135–40.PubMedCrossRefGoogle Scholar
  123. 123.
    Doghman M, Cazareth J, Lalli E. The T cell factor/beta-catenin antagonist PKF115-584 inhibits proliferation of adrenocortical carcinoma cells. J Clin Endocrinol Metab. 2008;93(8):3222–5.PubMedCrossRefGoogle Scholar
  124. 124.
    Stommel JM, Kimmelman AC, Ying H, Nabioullin R, Ponugoti AH, Wiedemeyer R, et al. Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies. Science. 2007;318(5848):287–90.PubMedCrossRefGoogle Scholar
  125. 125.
    Ip JC, Pang TC, Glover AR, Soon P, Zhao JT, Clarke S, et al. Immunohistochemical validation of overexpressed genes identified by global expression microarrays in adrenocortical carcinoma reveals potential predictive and prognostic biomarkers. Oncologist. 2015;20(3):247–56.PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Duregon E, Molinaro L, Volante M, Ventura L, Righi L, Bolla S, et al. Comparative diagnostic and prognostic performances of the hematoxylin-eosin and phospho-histone H3 mitotic count and Ki-67 index in adrenocortical carcinoma. Mod Pathol. 2014;27(9):1246–54.PubMedCrossRefGoogle Scholar
  127. 127.
    Morimoto R, Satoh F, Murakami O, Suzuki T, Abe T, Tanemoto M, et al. Immunohistochemistry of a proliferation marker Ki67/MIB1 in adrenocortical carcinomas: Ki67/MIB1 Labeling index is a predictor for recurrence of adrenocortical carcinomas. Endocr J. 2008;55(1):49–55.PubMedCrossRefGoogle Scholar
  128. 128.
    Papathomas TG, Pucci E, Giordano TJ, Lu H, Duregon E, Volante M, et al. An international Ki67 reproducibility study in adrenal cortical carcinoma. Am J Surg Pathol. 2015.Google Scholar
  129. 129.
    Bilimoria KY, Shen WT, Elaraj D, Bentrem DJ, Winchester DJ, Kebebew E, et al. Adrenocortical carcinoma in the United States: treatment utilization and prognostic factors. Cancer. 2008;113(11):3130–6.PubMedCrossRefGoogle Scholar
  130. 130.
    Tissier F, Aubert S, Leteurtre E, Al Ghuzlan A, Patey M, Decaussin M, et al. Adrenocortical tumors: improving the practice of the Weiss system through virtual microscopy a national program of the French network INCa-COMETE. Am J Surg Pathol. 2012;36(8):1194–201.PubMedCrossRefGoogle Scholar
  131. 131.
    Berruti A, Terzolo M, Sperone P, Pia A, Della Casa S, Gross DJ, et al. Etoposide, doxorubicin and cisplatin plus mitotane in the treatment of advanced adrenocortical carcinoma: a large prospective phase II trial. Endocr Relat Cancer. 2005;12(3):657–66.PubMedCrossRefGoogle Scholar
  132. 132.
    Else T, Williams AR, Sabolch A, Jolly S, Miller BS, Hammer GD. Adjuvant therapies and patient and tumor characteristics associated with survival of adult patients with adrenocortical carcinoma. J Clin Endocrinol Metab. 2014;99(2):455–61.PubMedCrossRefGoogle Scholar
  133. 133.
    Bertherat J, Coste J, Bertagna X. Adjuvant mitotane in adrenocortical carcinoma. N Engl J Med. 2007;357(12):1256–7. author reply 9.PubMedCrossRefGoogle Scholar
  134. 134.
    Stojadinovic A, Ghossein RA, Hoos A, Nissan A, Marshall D, Dudas M, et al. Adrenocortical carcinoma: clinical, morphologic, and molecular characterization. J Clin Oncol. 2002;20(4):941–50.PubMedCrossRefGoogle Scholar
  135. 135.
    Kim Y, Margonis GA, Prescott JD, Tran TB, Postlewait LM, Maithel SK, et al. Nomograms to predict recurrence-free and overall survival after curative resection of adrenocortical carcinoma. JAMA Surg. 2015:1–9.Google Scholar
  136. 136.
    Giordano TJ, Kuick R, Else T, Gauger PG, Vinco M, Bauersfeld J, et al. Molecular classification and prognostication of adrenocortical tumors by transcriptome profiling. Clin Cancer Res. 2009;15(2):668–76.PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Assie G, Guillaud-Bataille M, Ragazzon B, Bertagna X, Bertherat J, Clauser E. The pathophysiology, diagnosis and prognosis of adrenocortical tumors revisited by transcriptome analyses. Trends Endocrinol Metab. 2010;21(5):325–34.PubMedCrossRefGoogle Scholar
  138. 138.
    Laurell C, Velazquez-Fernandez D, Lindsten K, Juhlin C, Enberg U, Geli J, et al. Transcriptional profiling enables molecular classification of adrenocortical tumours. Eur J Endocrinol. 2009;161(1):141–52.PubMedCrossRefGoogle Scholar
  139. 139.
    Ragazzon B, Libe R, Gaujoux S, Assie G, Fratticci A, Launay P, et al. Transcriptome analysis reveals that p53 and beta-catenin alterations occur in a group of aggressive adrenocortical cancers. Cancer Res. 2010;70(21):8276–81.PubMedCrossRefGoogle Scholar
  140. 140.
    Assie G, Letouze E, Fassnacht M, Jouinot A, Luscap W, Barreau O, et al. Integrated genomic characterization of adrenocortical carcinoma. Nat Genet. 2014;46(6):607–12.PubMedCrossRefGoogle Scholar
  141. 141.
    Barreau O, Assie G, Wilmot-Roussel H, Ragazzon B, Baudry C, Perlemoine K, et al. Identification of a CpG island methylator phenotype in adrenocortical carcinomas. J Clin Endocrinol Metab. 2013;98(1):E174–84.PubMedCrossRefGoogle Scholar
  142. 142.
    Volante M, Sperone P, Bollito E, Frangipane E, Rosas R, Daffara F, et al. Matrix metalloproteinase type 2 expression in malignant adrenocortical tumors: diagnostic and prognostic significance in a series of 50 adrenocortical carcinomas. Mod Pathol. 2006;19(12):1563–9.PubMedCrossRefGoogle Scholar
  143. 143.
    Fenske W, Volker HU, Adam P, Hahner S, Johanssen S, Wortmann S, et al. Glucose transporter GLUT1 expression is an stage-independent predictor of clinical outcome in adrenocortical carcinoma. Endocr Relat Cancer. 2009;16(3):919–28.PubMedCrossRefGoogle Scholar
  144. 144.
    Demeure MJ, Coan KE, Grant CS, Komorowski RA, Stephan E, Sinari S, et al. PTTG1 overexpression in adrenocortical cancer is associated with poor survival and represents a potential therapeutic target. Surgery. 2013;154(6):1405–16.PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Parviainen H, Schrade A, Kiiveri S, Prunskaite-Hyyrylainen R, Haglund C, Vainio S, et al. Expression of Wnt and TGF-beta pathway components and key adrenal transcription factors in adrenocortical tumors: association to carcinoma aggressiveness. Pathol Res Pract. 2013;209(8):503–9.PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Duregon E, Volante M, Giorcelli J, Terzolo M, Lalli E, Papotti M. Diagnostic and prognostic role of steroidogenic factor 1 in adrenocortical carcinoma: a validation study focusing on clinical and pathologic correlates. Hum Pathol. 2013;44(5):822–8.PubMedCrossRefGoogle Scholar
  147. 147.
    McAteer JP, Huaco JA, Gow KW. Predictors of survival in pediatric adrenocortical carcinoma: a surveillance, epidemiology, and end results (SEER) program study. J Pediatr Surg. 2013;48(5):1025–31.PubMedCrossRefGoogle Scholar
  148. 148.
    Wieneke JA, Thompson LD, Heffess CS. Adrenal cortical neoplasms in the pediatric population: a clinicopathologic and immunophenotypic analysis of 83 patients. Am J Surg Pathol. 2003;27(7):867–81.PubMedCrossRefGoogle Scholar
  149. 149.
    Ribeiro RC, Sandrini Neto RS, Schell MJ, Lacerda L, Sambaio GA, Cat I. Adrenocortical carcinoma in children: a study of 40 cases. J Clin Oncol. 1990;8(1):67–74.PubMedGoogle Scholar
  150. 150.
    Hayles AB, Hahn Jr HB, Sprague RG, Bahn RC, Priestley JT. Hormone-secreting tumors of the adrenal cortex in children. Pediatrics. 1966;37(1):19–25.PubMedGoogle Scholar
  151. 151.
    Li FP, Fraumeni Jr JF. Rhabdomyosarcoma in children: epidemiologic study and identification of a familial cancer syndrome. J Natl Cancer Inst. 1969;43(6):1365–73.PubMedGoogle Scholar
  152. 152.
    Choong SS, Latiff ZA, Mohamed M, Lim LL, Chen KS, Vengidasan L, et al. Childhood adrenocortical carcinoma as a sentinel cancer for detecting families with germline TP53 mutations. Clin Genet. 2012;82(6):564–8.PubMedCrossRefGoogle Scholar
  153. 153.
    Sandrini R, Ribeiro RC, DeLacerda L. Childhood adrenocortical tumors. J Clin Endocrinol Metab. 1997;82(7):2027–31.PubMedGoogle Scholar
  154. 154.
    Michalkiewicz E, Sandrini R, Figueiredo B, Miranda ECM, Caran E, Oliveira-Filho AG, et al. Clinical and outcome characteristics of children with adrenocortical tumors: a report from the international pediatric adrenocortical tumor registry. J Clin Oncol. 2004;22(5):838–45.PubMedCrossRefGoogle Scholar
  155. 155.
    Ribeiro RC, Michalkiewicz EL, Figueiredo BC, DeLacerda L, Sandrini F, Pianovsky MD, et al. Adrenocortical tumors in children. Braz J Med Biol Res. 2000;33(10):1225–34.PubMedCrossRefGoogle Scholar
  156. 156.
    Teinturier C, Pauchard MS, Brugieres L, Landais P, Chaussain JL, Bougneres PF. Clinical and prognostic aspects of adrenocortical neoplasms in childhood. Med Pediatr Oncol. 1999;32(2):106–11.PubMedCrossRefGoogle Scholar
  157. 157.
    Bugg MF, Ribeiro RC, Roberson PK, Lloyd RV, Sandrini R, Silva JB, et al. Correlation of pathological features with clinical outcome in pediatric adrenocortical neoplasia—a study of a Brazilian population. Am J Clin Pathol. 1994;101(5):625–9.PubMedCrossRefGoogle Scholar
  158. 158.
    Sabbaga CC, Avilla SG, Schulz C, Garbers JC, Blucher D. Adrenocortical carcinoma in children: clinical aspects and prognosis. J Pediatr Surg. 1993;28(6):841–3.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2017

Authors and Affiliations

  • Sara G. Creemers
    • 1
  • Leo J. Hofland
    • 1
  • Richard A. Feelders
    • 1
  1. 1.Department of Internal Medicine, Division of EndocrinologyErasmus MC, University Medical Center RotterdamRotterdamThe Netherlands

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