Hormonal aggressiveness according to the expression of cellular markers in corticotroph adenomas
- 104 Downloads
The molecular mechanisms underlying tumor growth in Cushing’s disease (CD) still remain a challenge. Moreover, clinical manifestations of CD may vary depending on hormonal activity; however, factors involved in the hormonal aggressiveness of adrenocorticotropic hormone (ACTH)-secreting pituitary tumors have not been fully clarified. We investigated the association between the expression of cellular markers regarding pituitary tumor progression and initial or postoperative hormone levels in patients with CD.
Tumor tissues from 28 corticotroph adenomas (female 26, male 2, mean age 39.21 ± 10.39 years) were subject to immunohistochemical study using the following antibodies: pituitary tumor-transforming gene 1 (PTTG1), cyclin D1, p16, p27, brahma related-gene 1 (Brg1), and Ki-67. We then analyzed the relationship between each cellular marker expression and hormone levels, including 24 h urinary free cortisol (UFC), plasma ACTH, and serum cortisol.
PTTG1 and Ki-67 were expressed in 100% and 50% of patients, respectively. However, the levels did not reflect initial hormonal activity. The cyclin D1-negative group showed higher serum cortisol levels compared to the cyclin D1-positive group (p = 0.01). The 24 h UFC levels were significantly higher in the p27-negative group than in the p27-positive group (p = 0.04), whereas the Brg1-positive group revealed higher serum cortisol levels than in the Brg1-negative group (p = 0.02).
Although PTTG1 and Ki-67 play an essential role in developing ACTH-secreting tumors, cyclin D1, p27, and Brg1 may be better biomarkers to determine hormonal aggressiveness of the tumor. Further research is needed to understand the influence of cellular markers on hormonal activity in CD.
KeywordsCushing syndrome ACTH-secreting pituitary adenoma Hormones Biomarkers
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
- 6.B.M. Biller, A.B. Grossman, P.M. Stewart, S. Melmed, X. Bertagna, J. Bertherat, M. Buchfelder, A. Colao, A.R. Hermus, L.J. Hofland, A. Klibanski, A. Lacroix, J.R. Lindsay, J. Newell-Price, L.K. Nieman, S. Petersenn, N. Sonino, G.K. Stalla, B. Swearingen, M.L. Vance, J.A. Wass, M. Boscaro, Treatment of adrenocorticotropin-dependent Cushing’s syndrome: a consensus statement. J. Clin. Endocrinol. Metab. 93, 2454–2462 (2008)CrossRefGoogle Scholar
- 8.N. Hameed, C.G. Yedinak, J. Brzana, S.H. Gultekin, N.D. Coppa, A. Dogan, J.B. Delashaw, M. Fleseriu, Remission rate after transsphenoidal surgery in patients with pathologically confirmed Cushing’s disease, the role of cortisol, ACTH assessment and immediate reoperation: a large single center experience. Pituitary 16, 452–458 (2013)CrossRefGoogle Scholar
- 11.N. Sonino, M. Zielezny, G.A. Fava, F. Fallo, M. Boscaro, Risk factors and long-term outcome in pituitary-dependent Cushing’s disease. J. Clin. Endocrinol. Metab. 81, 2647–2652 (1996)Google Scholar
- 17.J.S. Lim, S.K. Lee, S.H. Kim, E.J. Lee, S.H. Kim, Intraoperative multiple-staged resection and tumor tissue identification using frozen sections provide the best result for the accurate localization and complete resection of tumors in Cushing’s disease. Endocrine 40, 452–461 (2011)CrossRefGoogle Scholar
- 25.H. Cushing, The basophil adenomas of the pituitary body and their clinical manifestations (pituitary basophilism). Bull. Johns. Hopkins Hosp. 50, 137 (1932)Google Scholar
- 32.S. Bilodeau, S. Vallette-Kasic, Y. Gauthier, D. Figarella-Branger, T. Brue, F. Berthelet, A. Lacroix, D. Batista, C. Stratakis, J. Hanson, B. Meij, J. Drouin, Role of Brg1 and HDAC2 in GR trans-repression of the pituitary POMC gene and misexpression in Cushing disease. Genes Dev. 20, 2871–2886 (2006)CrossRefGoogle Scholar
- 33.X. Liu, M. Feng, Y. Zhang, C. Dai, B. Sun, X. Bao, K. Deng, Y. Yao, R. Wang, Expression of Matrix Metalloproteinase-9, Pituitary Tumor Transforming Gene, High Mobility Group A 2, and Ki-67 in Adrenocorticotropic Hormone-Secreting Pituitary Tumors and Their Association with Tumor Recurrence. World Neurosurg. 113, e213–e221 (2018)CrossRefGoogle Scholar
- 34.A. Wierinckx, C. Auger, P. Devauchelle, A. Reynaud, P. Chevallier, M. Jan, G. Perrin, M. Fevre-Montange, C. Rey, D. Figarella-Branger, G. Raverot, M.F. Belin, J. Lachuer, J. Trouillas, A diagnostic marker set for invasion, proliferation, and aggressiveness of prolactin pituitary tumors. Endocr. Relat. Cancer 14, 887–900 (2007)CrossRefGoogle Scholar
- 35.M. Filippella, F. Galland, M. Kujas, J. Young, A. Faggiano, G. Lombardi, A. Colao, G. Meduri, P. Chanson, Pituitary tumour transforming gene (PTTG) expression correlates with the proliferative activity and recurrence status of pituitary adenomas: a clinical and immunohistochemical study. Clin. Endocrinol. 65, 536–543 (2006)CrossRefGoogle Scholar
- 41.D. Reisman, E.A. Thompson, Glucocorticoid regulation of cyclin D3 gene transcription and mRNA stability in lymphoid cells. Mol. Endocrinol. 9, 1500–1509 (1995)Google Scholar
- 44.M. Korbonits, H.S. Chahal, G. Kaltsas, S. Jordan, Y. Urmanova, Z. Khalimova, P.E. Harris, W.E. Farrell, F.X. Claret, A.B. Grossman, Expression of phosphorylatedp27(Kip1) protein and Jun activation domain-binding protein 1 in human pituitary tumors. J. Clin. Endocrinol. Metab. 87, 2635–2643 (2002)CrossRefGoogle Scholar