Immunohistochemical Biomarkers of Adrenal Cortical Neoplasms

  • Ozgur Mete
  • Sylvia L. Asa
  • Thomas J. Giordano
  • Mauro Papotti
  • Hironobu Sasano
  • Marco Volante


Careful morphological evaluation forms the basis of the workup of an adrenal cortical neoplasm. However, the adoption of immunohistochemical biomarkers has added tremendous value to enhance diagnostic accuracy. The authors provide a brief review of immunohistochemical biomarkers that have been used in the confirmation of adrenal cortical origin and in the detection of the source of functional adrenal cortical proliferations, as well as diagnostic, predictive, and prognostic biomarkers of adrenal cortical carcinoma. In addition, a brief section on potential novel theranostic biomarkers in the prediction of treatment response to mitotane and other relevant chemotherapeutic agents is also provided. In the era of precision and personalized medical practice, adoption of combined morphology and immunohistochemistry provides a new approach to the diagnostic workup of adrenal cortical neoplasms, reflecting the evolution of clinical responsibility of pathologists.


Immunohistochemistry SF-1 CYP11B2 CYP11B1 IGF-2 Ki67 p53 Beta-catenin Mitotane Adrenal cortical carcinoma 



The authors would like to thank Dr. Celso E. Gomez-Sanchez for providing the CYP11B1/2 monoclonal antibody for immunohistochemistry and Dr. Masao Doi and Dr. Hitoshi Okamura for providing the HSD3B1/2 monoclonal antibody.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflicts of interest.


  1. 1.
    Duan K, Giordano TJ, Mete O. Adrenal cortical proliferations. In: Mete O, Asa SL, eds. Endocrine Pathology. Cambridge: Cambridge University Press; 2016:602–627.Google Scholar
  2. 2.
    Duregon E, Volante M, Bollito E, et al. Pitfalls in the diagnosis of adrenocortical tumors: a lesson from 300 consultation cases. Hum Pathol. 2015; 46:1799–1807.PubMedCrossRefGoogle Scholar
  3. 3.
    Lapinski JE, Chen L, Zhou M. Distinguishing clear cell renal cell carcinoma, retroperitoneal paraganglioma, and adrenal cortical lesions on limited biopsy material: utility of immunohistochemical markers. Appl Immunohistochem Mol Morphol. 2010; 18:414–421.PubMedCrossRefGoogle Scholar
  4. 4.
    Ozisik G, Achermann JC, Meeks JJ, Jameson JL. SF1 in the development of the adrenal gland and gonads. Horm Res. 2003;59 Suppl 1:94–98.PubMedGoogle Scholar
  5. 5.
    Nishioka H, Inoshita N, Mete O, Asa SL, Hayashi K, et al. The Complementary Role of Transcription Factors in the Accurate Diagnosis of Clinically Nonfunctioning Pituitary Adenomas. Endocr Pathol. 2015; 26:349–355.PubMedCrossRefGoogle Scholar
  6. 6.
    Sbiera S, Schmull S, Assie G, et al. High diagnostic and prognostic value of steroidogenic factor-1 expression in adrenal tumors. J Clin Endocrinol Metab. 2010;95: E161–E171.PubMedCrossRefGoogle Scholar
  7. 7.
    Duregon E, Volante M, Giorcelli J, et al. Diagnostic and prognostic role of steroidogenic factor 1 in adrenocortical carcinoma: a validation study focusing on clinical and pathologic correlates. Hum Pathol. 2013; 44:822–828.PubMedCrossRefGoogle Scholar
  8. 8.
    Busam KJ, Iversen K, Coplan KA, et al. Immunoreactivity for A103, an antibody to melan-A (Mart-1), in adrenocortical and other steroid tumors. Am J Surg Pathol. 1998; 22:57–63.PubMedCrossRefGoogle Scholar
  9. 9.
    Mete O, van der Kwast TH. Epithelioid angiomyolipoma: a morphologically distinct variant that mimics a variety of intra-abdominal neoplasms. Arch Pathol Lab Med. 2011; 135:665–670.PubMedGoogle Scholar
  10. 10.
    Taskin OC, Gucer H, Mete O. An Unusual Adrenal Cortical Nodule: Composite Adrenal Cortical Adenoma and Adenomatoid Tumor. Endocr Pathol. 2015; 26:370–373.PubMedCrossRefGoogle Scholar
  11. 11.
    Papotti M, Volante M, Duregon E, et al. Adrenocortical tumors with myxoid features: a distinct morphologic and phenotypical variant exhibiting malignant behavior. Am J Surg Pathol. 2010; 34:973–983.PubMedCrossRefGoogle Scholar
  12. 12.
    Papathomas TG, Duregon E, Korpershoek E, et al. Sarcomatoid adrenocortical carcinoma: a comprehensive pathological, immunohistochemical, and targeted next-generation sequencing analysis. Hum Pathol. 2016; 58:113–122.PubMedCrossRefGoogle Scholar
  13. 13.
    Zheng S, Cherniack AD, Dewal N, et al. Comprehensive pangenomic characterization of adrenocortical carcinoma. Cancer Cell. 2016; 29:723–736.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Duan K, Mete O. Algorithmic approach to neuroendocrine tumors in targeted biopsies: Practical applications of immunohistochemical markers. Cancer Cytopathol. 2016; 124:871–884.PubMedCrossRefGoogle Scholar
  15. 15.
    Mete O, Kapran Y, Güllüoğlu MG, et al. Anti-CD10 (56C6) is expressed variably in adrenocortical tumors and cannot be used to discriminate clear cell renal cell carcinomas. Virchows Arch. 2010; 456:515–521.PubMedCrossRefGoogle Scholar
  16. 16.
    Sangoi AR, Fujiwara M, West RB, et al. Immunohistochemical distinction of primary adrenal cortical lesions from metastatic clear cell renal cell carcinoma: a study of 248 cases. Am J Surg Pathol. 2011; 35:678–686.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Xia QY, Wang XT, Zhan XM, et al. Xp11 Translocation Renal Cell Carcinomas (RCCs) With RBM10-TFE3 Gene Fusion Demonstrating Melanotic Features and Overlapping Morphology With t(6;11) RCC: Interest and Diagnostic Pitfall in Detecting a Paracentric Inversion of TFE3. Am J Surg Pathol. 2017; 41:663–676.PubMedCrossRefGoogle Scholar
  18. 18.
    Hayashi T, Gucer H, Mete O. A mimic of sarcomatoid adrenal cortical carcinoma: epithelioid angiosarcoma occurring in adrenal cortical adenoma. Endocr Pathol. 2014; 25:404–409.PubMedCrossRefGoogle Scholar
  19. 19.
    Takizawa K, Kohashi K, Negishi T, et al. A exceptional collision tumor of primary adrenal angiosarcoma and non-functioning adrenocortical adenoma. Pathol Res Pract. 2017; 213: 702–705.PubMedCrossRefGoogle Scholar
  20. 20.
    Ross JS, Wang K, Rand JV, et al. Next-generation sequencing of adrenocortical carcinoma reveals new routes to targeted therapies. J Clin Pathol. 2014; 67:968–973.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Duan K, Gomez Hernandez K, Mete O. Clinicopathological correlates of adrenal Cushing's syndrome. J Clin Pathol. 2015; 68:175–186.PubMedCrossRefGoogle Scholar
  22. 22.
    Mete O, Asa SL. Morphological distinction of cortisol-producing and aldosterone-producing adrenal cortical adenomas: not only possible but a critical clinical responsibility. Histopathology. 2012; 60:1015–1016; author reply 1016-7.PubMedCrossRefGoogle Scholar
  23. 23.
    Duan K, Mete O. Clinicopathologic Correlates of Primary Aldosteronism. Arch Pathol Lab Med. 2015; 139:948–954.PubMedCrossRefGoogle Scholar
  24. 24.
    Mete O, Duan K. The many faces of primary aldosteronism and Cushing syndrome: A reflection of Adrenocortical Tumour Heterogeneity. Front Med. 2018; 5:54. doi: CrossRefGoogle Scholar
  25. 25.
    Funder JW, Carey RM, Mantero F, et al. Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016; 101: 1889–1916.PubMedCrossRefGoogle Scholar
  26. 26.
    Mulatero P, Stowasser M, Loh KC, et al. Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from five continents. J Clin Endocrinol Metab. 2004; 89: 1045–1050.PubMedCrossRefGoogle Scholar
  27. 27.
    Rossi GP, Bernini G, Caliumi C, et al. A prospective study of the prevalence of primary aldosteronism in 1,125 hypertensive patients. J Am Coll Cardiol. 2006; 48: 2293–2300.PubMedCrossRefGoogle Scholar
  28. 28.
    Nanba AT, Nanba K, Byrd JB, et al. Discordance between imaging and immunohistochemistry in unilateral primary aldosteronism. Clin Endocrinol (Oxf). 2017; 87:665–672.PubMedCrossRefGoogle Scholar
  29. 29.
    Dekkers T, ter Meer M, Lenders JW, et al. (2014). Adrenal nodularity and somatic mutations in primary aldosteronism: one node is the culprit? J Clin Endocrinol Metab. 99: E1341-EE135.PubMedCrossRefGoogle Scholar
  30. 30.
    Nakamura Y, Felizola SJ, Satoh F, Konosu-Fukaya S, Sasano H. Dissecting the molecular pathways of primary aldosteronism. Pathol. Int., 2014; 64: 482–489.PubMedCrossRefGoogle Scholar
  31. 31.
    Nanba K, Chen AX, Omata K, et al. Molecular heterogeneity in aldosterone-producing adenomas. J. Clin. Endocrinol. Metab. 2016; 101: 999–1007.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Seccia TM, Caroccia B, Gomez-Sanchez EP, et al. Review of Markers of Zona Glomerulosa and Aldosterone-Producing Adenoma Cells. Hypertension. 2017; 70:867–874.PubMedCrossRefGoogle Scholar
  33. 33.
    Doi M, Satoh F, Maekawa T, et al. Isoform-Specific Monoclonal Antibodies Against 3-Hydroxysteroid Dehydrogenase/Isomerase Family Provide Markers for Subclassification of Human Primary Aldosteronism. J Clin EndocrinolMetab, 2014: 99; E257–E262.CrossRefGoogle Scholar
  34. 34.
    Gomez-Sanchez CE, Qi X, Velarde-Miranda C, et al. Development of monoclonal antibodies against human CYP11B1 and CYP11B2. Mol Cell Endocrinol. 2014;383: 111–117.PubMedCrossRefGoogle Scholar
  35. 35.
    Nakamura Y, Maekawa T, Felizola S, et al. Adrenal CYP11B1/2 expression in primary aldosteronism: Immunohistochemical analysis using novel monoclonal antibodies. Moll Cell Endocrinol. 2014; 392: 73–79.CrossRefGoogle Scholar
  36. 36.
    Nishimoto K, Tomlins SA, Kuick R, et al. Aldosterone-stimulating somatic gene mutations are common in normal adrenal glands. Proc Natl Acad Sci U S A. 2015; 112(33): E4591–E4599.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Yamazaki Y, Nakamura Y, Omata K, et al. Histopathological classification of cross-sectional image negative hyperaldosteronism. J Clin Endocrinol Metab. 2017; 102: 1182–1192.PubMedGoogle Scholar
  38. 38.
    Konosu-Fukaya S, Nakamura Y, Satoh F, et al. 3β-hydroxysteroid dehydrogenase isoforms in human aldosterone-producing adenoma. Moll Cell Endocrinol, 2015; 408: 205–212.CrossRefGoogle Scholar
  39. 39.
    Weiss LM, Medeiros LJ, Vickery AL Jr. Pathologic features of prognostic significance in adrenocortical carcinoma. Am J Surg Pathol. 1989; 13:202–206.PubMedCrossRefGoogle Scholar
  40. 40.
    Aubert S, Wacrenier A, Leroy X, et al. Weiss system revisited: a clinicopathologic and immunohistochemical study of 49 adrenocortical tumors. Am J Surg Pathol. 2002; 26:1612–1619.PubMedCrossRefGoogle Scholar
  41. 41.
    Volante M, Bollito E, Sperone P, et al. Clinicopathological study of a series of 92 adrenocortical carcinomas: from a proposal of simplified diagnostic algorithm to prognostic stratification. Histopathology. 2009; 55:535–543.PubMedCrossRefGoogle Scholar
  42. 42.
    Duregon E, Fassina A, Volante M, et al. The reticulin algorithm for adrenocortical tumor diagnosis: a multicentric validation study on 245 unpublished cases. Am J Surg Pathol. 2013; 37:1433–1440.PubMedCrossRefGoogle Scholar
  43. 43.
    Pennanen M, Heiskanen I, Sane T, et al. Helsinki score-a novel model for prediction of metastases in adrenocortical carcinomas. Hum Pathol. 2015; 46:404–410.PubMedCrossRefGoogle Scholar
  44. 44.
    Duregon E, Cappellesso R, Maffeis V, et al. Validation of the prognostic role of the “Helsinki Score” in 225 cases of adrenocortical carcinoma. Hum Pathol. 2017; 62:1–7.PubMedCrossRefGoogle Scholar
  45. 45.
    Papotti M, Libè R, Duregon E, et al. The Weiss score and beyond histopathology for adrenocortical carcinoma. Horm Cancer. 2011; 2:333–340.PubMedCrossRefGoogle Scholar
  46. 46.
    Bisceglia M, Ludovico O, Di Mattia A, Ben-Dor D, Sandbank J, Pasquinelli G, Lau SK, Weiss LM. Adrenocortical oncocytic tumors: report of 10 cases and review of the literature. Int J Surg Pathol 2004; 12:231–243.PubMedCrossRefGoogle Scholar
  47. 47.
    Lloyd RV, Osamura RY, Kloppel G, Rosai J, editors. WHO Classification of Tumours of Endocrine Organs. 4th edn. Lyon: IARC; 2017.Google Scholar
  48. 48.
    Mete O, Gucer H, Kefeli M, Asa SL. Diagnostic and Prognostic Biomarkers of Adrenal Cortical Carcinoma. Am J Surg Pathol. 2018; 42:201–213.PubMedCrossRefGoogle Scholar
  49. 49.
    Fonseca D, Murthy SS, Tagore KR, et al. Diagnosis of Adrenocortical Tumors by Reticulin Algorithm. Indian J Endocrinol Metab. 2017;21(5):734–737.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Else T, Kim AC, Sabolch A, et al. Adrenocortical carcinoma. Endocr Rev. 2014; 35:282–326.PubMedCrossRefGoogle Scholar
  51. 51.
    Shenouda M, Brown LG, Denning KL, Pacioles T. A Case of Oncocytic Adrenocortical Neoplasm of Borderline (Uncertain) Malignant Potential. Cureus. 2016; 8: e638.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Tissier F. Classification of adrenal cortical tumors: what limits for the pathological approach? Best Pract Res Clin Endocrinol Metab. 2010; 24:877–885.PubMedCrossRefGoogle Scholar
  53. 53.
    Duregon E, Volante M, Rapa I, et al. Dissecting morphological and molecular heterogeneity in adrenocortical carcinoma. Turk Patoloji Derg. 2015;31 (suppl 1):98–104.PubMedGoogle Scholar
  54. 54.
    Mete O, Asa SL. Precursor lesions of endocrine system neoplasms. Pathology. 2013; 45:316–330.PubMedCrossRefGoogle Scholar
  55. 55.
    Heaton JH, Wood MA, Kim AC, et al. Progression to adrenocortical tumorigenesis in mice and humans through insulin-like growth factor 2 and β-catenin. Am J Pathol. 2012; 181:1017–1033.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Giordano TJ, Kuick R, Else T, et al. Molecular classification and prognostication of adrenocortical tumors by transcriptome profiling. Clin Cancer Res. 2009; 15:668–676.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    de Reyniès A, Assié G, Rickman DS, et al. Gene expression profiling reveals a new classification of adrenocortical tumors and identifies molecular predictors of malignancy and survival. J Clin Oncol. 2009; 27:1108–1115.PubMedCrossRefGoogle Scholar
  58. 58.
    Erickson LA, Jin L, Sebo TJ, et al. Pathologic features and expression of insulin-like growth factor-2 in adrenocortical neoplasms. Endocr Pathol. 2001; 12:429–435.PubMedCrossRefGoogle Scholar
  59. 59.
    Schmitt A, Saremaslani P, Schmid S, et al. IGFII and MIB1 immunohistochemistry is helpful for the differentiation of benign from malignant adrenocortical tumours. Histopathology. 2006;49: 298–307.PubMedCrossRefGoogle Scholar
  60. 60.
    Wang C, Sun Y, Wu H, et al. Distinguishing adrenal cortical carcinomas and adenomas: a study of clinicopathological features and biomarkers. Histopathology. 2014; 64:567–576.PubMedCrossRefGoogle Scholar
  61. 61.
    McNicol AM, Nolan CE, Struthers AJ, et al. Expression of p53 in adrenocortical tumours: clinicopathological correlations. J Pathol. 1997; 181:146–152.PubMedCrossRefGoogle Scholar
  62. 62.
    Reincke M, Karl M, Travis WH, et al. p53 mutations in human adrenocortical neoplasms: immunohistochemical and molecular studies. J Clin Endocrinol Metab. 1994; 78:790–794.PubMedGoogle Scholar
  63. 63.
    Stojadinovic A, Brennan MF, Hoos A, et al. Adrenocortical adenoma and carcinoma: histopathological and molecular comparative analysis. Mod Pathol. 2003; 16:742–751.PubMedCrossRefGoogle Scholar
  64. 64.
    Das S, Sengupta M, Islam N, et al. Weineke criteria, Ki-67 index and p53 status to study pediatric adrenocortical tumors: is there a correlation? J Pediatr Surg. 2016; 51:1795–1800.PubMedCrossRefGoogle Scholar
  65. 65.
    Stojadinovic A, Ghossein RA, Hoos A, et al. Adrenocortical carcinoma: clinical, morphologic, and molecular characterization. J Clin Oncol. 2002; 20:941–950.PubMedCrossRefGoogle Scholar
  66. 66.
    Edgren M, Eriksson B, Wilander E, et al. Biological characteristics of adrenocortical carcinoma: a study of p53, IGF, EGF-r, Ki-67 and PCNA in 17 adrenocortical carcinomas. Anticancer Res. 1997; 17:1303–1309.PubMedGoogle Scholar
  67. 67.
    Arola J, Salmenkivi K, Liu J, et al. p53 and Ki67 in adrenocortical tumors. Endocr Res. 2000; 26:861–865.PubMedCrossRefGoogle Scholar
  68. 68.
    Morimoto R, Satoh F, Murakami O, 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; 55:49–55.PubMedCrossRefGoogle Scholar
  69. 69.
    Pereira SS, Morais T, Costa MM, Monteiro MP, Pignatelli D. The emerging role of the molecular marker p27 in the differential diagnosis of adrenocortical tumors. Endocr Connect. 2013; 2:137–145.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Han VK, Lu F, Bassett N, et al. Insulin-like growth factor-II (IGF-II) messenger ribonucleic acid is expressed in steroidogenic cells of the developing ovine adrenal gland: evidence of an autocrine/paracrine role for IGF-II. Endocrinology. 1992; 131:3100–3109.PubMedCrossRefGoogle Scholar
  71. 71.
    Nielsen HM, How-Kit A, Guerin C, et al. Copy number variations alter methylation and parallel IGF2 overexpression in adrenal tumors. Endocr Relat Cancer. 2015; 22:953–967.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Boulle N, Logié A, Gicquel C, et al. 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. 1998; 83:1713–1720.PubMedGoogle Scholar
  73. 73.
    Boulle N, Gicquel C, Logie A, et al. Fibroblast growth factor-2 inhibits the maturation of pro-insulin-like growth factor-II (Pro-IGF-II) and the expression of insulin-like growth factor binding protein-2 (IGFBP-2) in the human adrenocortical tumor cell line NCI-H295R. Endocrinology. 2000; 141:3127–3136.PubMedCrossRefGoogle Scholar
  74. 74.
    Pinto EM, Chen X, Easton J, et al. Genomic landscape of paediatric adrenocortical tumours. Nat Commun. 2015; 6:6302.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Tissier F, Cavard C, Groussin L, et al. 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. 2005; 65:7622–7627.PubMedCrossRefGoogle Scholar
  76. 76.
    Åkerström T, Maharjan R, Sven Willenberg H, et al. Activating mutations in CTNNB1 in aldosterone producing adenomas. Sci Rep. 2016; 6:19546.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Assie G, Giordano TJ, Bertherat J. Gene expression profiling in adrenocortical neoplasia. Mol Cell Endocrinol. 2012; 351:111–117.PubMedCrossRefGoogle Scholar
  78. 78.
    Duregon E, Molinaro L, Volante M, 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; 27:1246–1254.PubMedCrossRefGoogle Scholar
  79. 79.
    Giordano TJ. The argument for mitotic rate-based grading for the prognostication of adrenocortical carcinoma. Am J Surg Pathol. 2011;35: 471–473.PubMedCrossRefGoogle Scholar
  80. 80.
    Mouat IC, Giordano TJ. Assessing Biological Aggression in Adrenocortical Neoplasia. Surg Pathol Clin. 2014; 7:533–541.PubMedCrossRefGoogle Scholar
  81. 81.
    Beuschlein F, Weigel J, Saeger W, et al. Major prognostic role of Ki67 in localized adrenocortical carcinoma after complete resection. J Clin Endocrinol Metab. 2015; 100:841–849.PubMedCrossRefGoogle Scholar
  82. 82.
    Sasano H, Satoh F, Nakamura Y. Roles of the pathologist in evaluating surrogate markers for medical therapy in adrenocortical carcinoma. Endocr Pathol 2014; 25:366–370.PubMedCrossRefGoogle Scholar
  83. 83.
    Stigliano A, Chiodini I, Giordano R, et al. Management of adrenocortical carcinoma: a consensus statement of the Italian Society of Endocrinology (SIE). J Endocrinol Invest. 2016 Jan;39(1):103–121.PubMedCrossRefGoogle Scholar
  84. 84.
    Papathomas TG, Pucci E, Giordano TJ, et al. An International Ki67 Reproducibility Study in Adrenal Cortical Carcinoma. Am J Surg Pathol. 2016; 40:569–576.PubMedCrossRefGoogle Scholar
  85. 85.
    Lu H, Papathomas TG, van Zessen D, et al. Automated Selection of Hotspots (ASH): enhanced automated segmentation and adaptive step finding for Ki67 hotspot detection in adrenal cortical cancer. Diagn Pathol. 2014;9: 216.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Logarinho E, Bousbaa H. Kinetochore-microtubule interactions “in check” by Bub1, Bub3 and BubR1: the dual task of attaching and signalling. Cell Cycle. 2008; 7:1763–1768.PubMedCrossRefGoogle Scholar
  87. 87.
    Song L, Craney A, Rape M. Microtubule-dependent regulation of mitotic protein degradation. Mol Cell. 2014; 53:179–192.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Wrighton KH. Mitosis: microtubules protect spindle assembly factors. Nat Rev Mol Cell Biol. 2014; 15:150–151.PubMedCrossRefGoogle Scholar
  89. 89.
    Fry AM. The Nek2 protein kinase: a novel regulator of centrosome structure. Oncogene. 2002; 21:6184–6194.PubMedCrossRefGoogle Scholar
  90. 90.
    Fletcher L, Cerniglia GJ, Nigg EA, et al. Inhibition of centrosome separation after DNA damage: a role for Nek2. Radiat Res. 2004; 162:128–135.PubMedCrossRefGoogle Scholar
  91. 91.
    Duan K, Mete O. Familial endocrine tumor syndromes: Clinical and predictive roles of molecular histopathology. AJSP: Reviews and Reports. 2017; 22:246–268.Google Scholar
  92. 92.
    Raymond VM, Everett JN, Furtado LV, et al. Adrenocortical carcinoma is a lynch syndrome-associated cancer. J Clin Oncol. 2013; 31:3012–3018.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Else T, Lerario AM, Everett J, et al. Adrenocortical carcinoma and succinate dehydrogenase gene mutations: an observational case series. Eur J Endocrinol. 2017; 177:439–444.PubMedCrossRefGoogle Scholar
  94. 94.
    Fassnacht M, Terzolo M, Allolio B, et al. Combination chemotherapy in advanced adrenocortical carcinoma. N Engl J Med. 2012 Jun 7; 366(:2189–2197.Google Scholar
  95. 95.
    Creemers SG, Hofland LJ, Korpershoek E, et al. Future directions in the diagnosis and medical treatment of adrenocortical carcinoma. Endocr Relat Cancer. 2016; 23: R43–R69.PubMedCrossRefGoogle Scholar
  96. 96.
    Scheidt HA, Haralampiev I, Theisgen S, et al. The adrenal specific toxicant mitotane directly interacts with lipid membranes and alters membrane properties depending on lipid composition. Mol Cell Endocrinol. 2016; 428:68–81.PubMedCrossRefGoogle Scholar
  97. 97.
    Kroiss M, Plonné D, Kendl S, et al. Association of mitotane with chylomicrons and serum lipoproteins: practical implications for treatment of adrenocortical carcinoma. Eur J Endocrinol. 2016; 174:343–353.PubMedCrossRefGoogle Scholar
  98. 98.
    Ronchi CL, Sbiera S, Volante M, 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: e105855.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Volante M, Terzolo M, Fassnacht M, et al. Ribonucleotide reductase large subunit (RRM1) gene expression may predict efficacy of adjuvant mitotane in adrenocortical cancer. Clin Cancer Res. 2012; 18:3452–3461.PubMedCrossRefGoogle Scholar
  100. 100.
    Jordheim LP, Sève P, Trédan O, Dumontet C. The ribonucleotide reductase large subunit (RRM1) as a predictive factor in patients with cancer. Lancet Oncol. 2011; 12:693–702.PubMedCrossRefGoogle Scholar
  101. 101.
    Germano A, Rapa I, Volante M, et al. RRM1 modulates mitotane activity in adrenal cancer cells interfering with its metabolization. Mol Cell Endocrinol. 2015; 401:105–110.PubMedCrossRefGoogle Scholar
  102. 102.
    Barsanti-Innes B, Hey SP, Kimmelman J. The Challenges of Validating in Precision Medicine: The Case of Excision Repair Cross-Complement Group 1 Diagnostic Testing. Oncologist. 2017; 22:89–96.PubMedCrossRefGoogle Scholar
  103. 103.
    Laufs V, Altieri B, Sbiera S, et al. ERCC1 as predictive biomarker to platinum-based chemotherapy in adrenocortical carcinomas. Eur J Endocrinol. 2017 Nov 29. pii: EJE-17-0788. doi:
  104. 104.
    Roca E, Berruti A, Sbiera S, et al. Topoisomerase 2α and thymidylate synthase expression in adrenocortical cancer. Endocr Relat Cancer. 2017; 24:299–307.PubMedCrossRefGoogle Scholar
  105. 105.
    Henning JEK, Deutschbein T, Altieri B, et al. Gemcitabine-Based Chemotherapy in Adrenocortical Carcinoma: A Multicenter Study of Efficacy and Predictive Factors. J Clin Endocrinol Metab. 2017; 102:4323–4332.PubMedCrossRefGoogle Scholar
  106. 106.
    Ruggiero C, Doghman-Bouguerra M, Sbiera S, et al. Dosage-dependent regulation of VAV2 expression by steroidogenic factor-1 drives adrenocortical carcinoma cell invasion. Sci Signal. 2017;10(469).Google Scholar
  107. 107.
    Sbiera S, Sbiera I, Ruggiero C, et al. Assessment of VAV2 Expression Refines Prognostic Prediction in Adrenocortical Carcinoma. J Clin Endocrinol Metab. 2017; 102:3491–3498.PubMedCrossRefGoogle Scholar
  108. 108.
    Ruggiero C, Lalli E. VAV2: a novel prognostic marker and a druggable target for adrenocortical carcinoma. Oncotarget. 2017; 8:88257–88258.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Ozgur Mete
    • 1
  • Sylvia L. Asa
    • 1
  • Thomas J. Giordano
    • 2
  • Mauro Papotti
    • 3
  • Hironobu Sasano
    • 4
  • Marco Volante
    • 5
  1. 1.Department of PathologyUniversity Health NetworkTorontoCanada
  2. 2.Departments of Pathology and Internal MedicineUniversity of Michigan Health SystemAnn ArborUSA
  3. 3.Department of PathologyTurin University at Molinette HospitalTurinItaly
  4. 4.Department of PathologyTohoku University School of MedicineSendaiJapan
  5. 5.Department of Oncology, University of Turin at San Luigi HospitalTurin UniversityTurinItaly

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