Nestin as a Marker in the Classification of Adrenocortical Tumors

Abstract

Expression of the intermediate filament, nestin, was long believed to be restricted to neuroectodermal stem cells. However, nestin expression has recently been detected in several tumors. Since adrenocortical carcinoma, a tumor entity still very difficult to classify, may gain the ability to aberrantly express neuroectodermal proteins including chromogranin A and synaptophysin, we asked the question whether nestin might also be detected in adrenocortical carcinomas, and if so, whether it might serve as a tool for clinical pathology. Therefore, we studied the expression of nestin in normal adrenal glands, adrenocortical adenomas, and adrenocortical cancers using specific immunohistochemistry and semi-quantitative reverse transcriptase-polymerase chain reaction. Immunostaining was nestin-positive in 1 out of 9 normal adrenal glands (11%), 2 out of 20 adrenocortical adenomas (10%), and 13 out of 16 adrenocortical carcinomas (81%). Expression of nestin mRNA could be detected in all microdissected tissues, independently of their grade of dedifferentiation. We conclude that our findings provide further evidence that nestin, as a marker, is not restricted to neuronal stem cells and nestin expression is worth to be studied in adrenocortical tumors.

Key words

fetal adrenal gland - nestin - tumor - adrenal adenoma - adrenocortical carcinoma

References

• 1 Miettinen M. Neuroendocrine differentiation in adrenocortical carcinoma. New immunohistochemical findings supported by electron microscopy.  Lab Invest. 1992;  66 169-174
• 2 Tartour E, Caillou B, Tenenbaum F, Schroder S, Luciani S, Talbot M, Schlumberger M. Immunohistochemical study of adrenocortical carcinoma. Predictive value of the D11 monoclonal antibody.  Cancer. 1993;  72 3296-3303
• 3 Haak HR, Fleuren GJ. Neuroendocrine differentiation of adrenocortical tumors.  Cancer. 1995;  75 860-864
• 4 Komminoth P, Roth J, Schroder S, Saremaslani P, Heitz PU. Overlapping expression of immunohistochemical markers and synaptophysin mRNA in pheochromocytomas and adrenocortical carcinomas. Implications for the differential diagnosis of adrenal gland tumors.  Lab Invest. 1995;  72 424-431
• 5 Liu AM, Maeda S, Hosone M, Azuma K, Katayama H, Yokoyama M. Use of electron microscopic evaluation for the diagnosis of adrenal cortical carcinoma in fine needle aspiration cytology: a case report and review of the literature.  Med Electron Microsc. 2001;  34 190-197
• 6 Stratakis CA, Carney JA, Kirschner LS, Willenberg HS, Brauer S, Ehrhart-Bornstein M, Bornstein SR. Synaptophysin immunoreactivity in primary pigmented nodular adrenocortical disease: neuroendocrine properties of tumors associated with Carney complex.  J Clin Endocrinol Metab. 1999;  84 1122-1128
• 7 Bourdeau I, Lacroix A, Schurch W, Caron P, Antakly T, Stratakis CA. Primary pigmented nodular adrenocortical disease: paradoxical responses of cortisol secretion to dexamethasone occur in vitro and are associated with increased expression of the glucocorticoid receptor.  J Clin Endocrinol Metab. 2003;  88 3931-3937
• 8 Weiss LM, Medeiros LJ, Vickery AL. Pathologic features of prognostic significance in adrenocortical carcinoma.  Am J Surg Pathol. 1989;  13 202-206
• 9 Grumbach MM, Biller BM, Braunstein GD, Campbell KK, Carney JA, Godley PA, Harris EL, Lee JK, Oertel YC, Posner MC, Schlechte JA, Wieand HS. Management of the Clinically Inapparent Adrenal Mass (“Incidentaloma”).  Ann Intern Med. 2003;  138 424-430
• 10 Ho CL, Liem RK. Intermediate filaments in the nervous system: implications in cancer.  Cancer Metastasis Rev. 1996;  15 483-497
• 11 Prasad S, Soldatenkov VA, Srinivasarao G, Dritschilo A. Intermediate filament proteins during carcinogenesis and apoptosis.  Int J Oncol. 1999;  14 563-570
• 12 Lendahl U, Zimmerman LB, MacKay RD. CNS stem cells express a new class of intermediate filament protein.  Cell. 1990;  60 585-595
• 13 Zimmerman L, Parr B, Lendahl U, Cunningham M, MacKay R, Gavin B, Mann J, Vassileva G, MacMahon A. Independent regulatory elements in the nestin gene direct transgene expression to neural stem cells or muscle precursors.  Neuron. 1994;  12 11-24
• 14 Dahlstrand J, Lardelli M, Lendahl U. Nestin mRNA expression correlates with the central nervous system progenitor cell state in many, but not all, regions of developing central nervous system.  Brain Res Dev Brain Res. 1995;  84 109-129
• 15 Sejersen T, Lendahl U. Transient expression of the intermediate filament nestin during skeletal muscle development.  J Cell Sci. 1993;  106 1291-1300
• 16 Kachinsky AM, Dominov JA, Miller JB. Myogenesis and the intermediate filament protein, nestin.  Dev Biol. 1994;  165 216-228
• 17 Dahlstrand J, Collins VP, Lendahl U. Expression of the class VI intermediate filament nestin in human central nervous system tumors.  Cancer Res. 1992;  52 5334-5341
• 18 Tohyama T, Lee VM, Rorke LB, Marvin M, MacKay RD, Trojanowski JQ. Nestin expression in embryonic human neuroepithelium and in human neuroepithelial tumor cells.  Lab Invest. 1992;  66 303-313
• 19 Tohyama T, Lee VM, Rorke LB, Marvin M, MacKay RD, Trojanowski JQ. Monoclonal antibodies to a rat nestin fusion protein recognize a 220-kDa polypeptide in subsets of fetal and adult human central nervous system neurons and in primitive neuroectodermal tumor cells.  Am J Pathol. 1993;  143 258-268
• 20 Kobayashi M, Sjoberg G, Soderhall S, Lendahl U, Sandstedt B, Sejersen T. Pediatric rhabdomyosarcomas express the intermediate filament nestin.  Pediatr Res. 1998;  43 386-392
• 21 Smits A, van Grieken D, Hartman M, Lendahl U, Funa K, Nister M. Coexpression of platelet-derived growth factor alpha and beta receptors on medulloblastomas and other primitive neuroectodermal tumors is consistent with an immature stem cell and neuronal derivation.  Lab Invest. 1996;  74 188-198
• 22 Tsujimura T, Makiishi-Shimobayashi C, Lundkvist J, Lendahl U, Nakasho K, Sugihara A, Iwasaki T, Mano M, Yamada N, Yamashita K, Toyosaka A, Terada N. Expression of the intermediate filament nestin in gastrointestinal stromal tumors and interstitial cells of Cajal.  Am J Pathol. 2001;  158 817-823
• 23 Valtz NL, Hayes TE, Norregaard T, Liu SM, MacKay RD. An embryonic origin for medulloblastoma.  New Biol. 1991;  3 364-371
• 24 Ehrhart-Bornstein M, Breidert M, Guadanucci P, Wozniak W, Bocian-Sobkowska J, Malendowicz LK, Bornstein SR. 17 alpha-Hydroxylase and chromogranin A in 6th week human fetal adrenals.  Horm Metab Res. 1997;  29 30-32
• 25 Haase M, Schott M, Bornstein SR, Malendowicz LK, Scherbaum WA, Willenberg HS. CITED2 is expressed in human adrenocortical cells and regulated by basic fibroblast growth factor.  J Endocrinol. 2007;  192 459-465
• 26 Bertelli E, Regoli M, Lucattelli M, Bastianini A, Fonzi L. Nestin expression in rat adrenal gland.  Histochem Cell Biol. 2002;  117 371-377
• 27 Willenberg HS, Walters R, Bornstein SR. Use of laser microdissection in complex tissue.  Methods Enzymol. 2002;  356 216-223
• 28 Latronico AC, Almeida MQ. The molecular pathogenesis of childhood adrenocortical tumors.  Horm Metab Res. 2007;  39 461-466
• 29 Stratakis CA. Adrenocortical tumors, primary pigmented adrenocortical disease(PPNAD)/Carney complex, and other bilateral hyperplasias: the NIH studies.  Horm Metab Res. 2007;  39 467-473
• 30 Ehrhart-Bornstein M, Hilbers U. Neuroendocrine properties of adrenocortical cells.  Horm Metab Res. 1998;  30 436-439
• 31 Toti P, Regoli M, Nesi G, Occhini R, Bartolommei S, Fonzi L, Bertelli E. Nestin expression in normal adrenal gland and adrenocortical tumors.  Histol Histopathol. 2005;  20 1115-1120
• 32 Marx C, Wolkersdörfer GW, Brown JW, Scherbaum WA, Bornstein SR. MHC class II expression – a new tool to asses dignity in adrenocortical tumors.  J Clin Endocrinol Metab. 1996;  81 4488-4491

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