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Original article

Vol. 143 No. 4546 (2013)

Expression of somatostatin receptors, angiogenesis and proliferation markers in pituitary adenomas: an immunohistochemical study with diagnostic and therapeutic implications

  • Alejandra Magagna-Poveda
  • Henning Leske
  • Christoph Schmid
  • René Bernays
  • Elisabeth Rushing
Cite this as:
Swiss Med Wkly. 2013;143:w13895


PRINCIPLES: Pituitary adenomas are common intracranial neoplasms that generate symptoms as a result of either mass effect or the increased production of pituitary hormones. Although mostly benign, these tumours can be associated with considerable morbidity. We investigated a panel of immunohistochemical preparations to identify potential therapeutic targets and surrogate markers of clinical outcome.

METHODS: Tumour tissue from 25 patients was evaluated for immunohistochemical expression of somatostatin receptors 1‒5, von Willebrand-factor (vWF), interleukin-8 (IL-8), vascular endothelial growth factor receptor 2 (VEGFR-2), kinesin spindle protein (Eg5) and MIB-1 (Ki-67), and its relationship with clinical features was analysed.

RESULTS: The proliferation marker MIB-1 (Ki-67) was the only marker predictive of adenoma recurrence. Of note, 67% of all relapses were associated with tumours showing luteinising hormone expression. All pituitary adenomas showed variable somatostatin receptor, IL-8, Eg5, vWF and VEGFR-2 expression; a relationship between these parameters and clinical outcome could not be demonstrated in this cohort.

CONCLUSIONS: This study validates MIB-1 (Ki-67) as a reliable marker of tumour recurrence in pituitary adenomas. Considering the consistently increased expression of Eg5, IL-8, VEGFR-2, somatostatin receptors and vWF in these tumours, further investigation as potential therapeutic targets is warranted.


  1. Saeger W, Lüdecke DK, Buchfelder M, Fahlbusch R, QuabbeHJ, Petersenn S. Pathohistological classification of pituitary tumors: 10 years of experience with the German Pituitary Tumor. Registry. Eur J Endocrinol. 2007;156:203–16.
  2. Zada G, Woodmansee WW, Ramkissoon S, Amadio J, Nose V, Laws ER Jr. Atypical pituitary adenomas: incidence, clinical characteristics, and implications. Neurosurgery. 2011;114:336–44.
  3. Scheithauer BW, Gaffey TA, Lloyd RV, Sebo TJ, Kovacs KT, Horvath E, et al. Pathobiology of pituitary adenomas and carcinomas. Neurosurgery. 2006;59:341–53.
  4. Salehi F, Agur A, Scheithauer BW, Kovacs K, Lloyd RV, Cusimano M. Ki-67 in pituitary neoplasms: a review – part I. Neurosurgery. 2009;65:429–37.
  5. Salehi F, Agur A, Scheithauer BW, Kovacs K, Lloyd RV, Cusimano M. Biomarkers of pituitary neoplasms: a review (Part II). Neurosurgery. 2010;67:1790–8.
  6. Horvath E, Kovacs K, Singer W, Smyth HS, Killinger DW, Erzin C, et al. Acidophil stem cell adenoma of the human pituitary: clinicopathologic analysis of 15 cases. Cancer. 1981;47:761–71.
  7. Plöckinger U, Hoffmann U, Geese M, Lupp A, Buchfelder M, Flitsch J, et al. DG3173 (Somatoprim), a unique Somatostatin receptor subtype 2-, 4- and 5-selective analogue, effectively reduces GH-secretion in human growth hormone secreting pituitary adenomas even in Octreotide non-responsive tumours. Eur J Endocrinol. 2011;166:223–34.
  8. Duran-Prado M, Malagon MM, Gracia-Navarro F, Castano JP. Dimerization of G protein-coupled receptors: new avenues for somatostatin receptor signalling, control and functionning. Mol Cell Endocrinol. 2008;286:169–79.
  9. Olias G, Viollet C, Kusserow H, Epelbaum J, Meyerhof W. Regulation and function of somatostatin receptors. J Neurochem. 2004;89:1057–91.
  10. Poll F, Lehmann D, Illing S, Ginj M, Jacobs S, Lupp A, et al. Pasireotide and octreotide stimulate distinct patterns of sst2A somatostatin receptor phosphorylation. Mol Endocrinol. 2010;24:436–46.
  11. Petersenn S, Schopohl J, Barkan A, Mohideen P, Colao A, Abs R, et al. Pasireotide (SOM230) demonstrates efficacy and safety in patients with acromegaly: a randomized, multicenter, phase II trial. J Clin Endocrinol Metab. 2010;95:2781–9.
  12. Schmid HA. Pasireotide (SOM230): development, mechanism of action and potential applications. Mol Cell Endocrinol. 2008;286:69–74.
  13. Afargan M, Janson ET, Gelerman G, Rosenfeld R, Ziv O, Karpov O, et al. Novel long-acting somatostatin analog with endocrine selectivity: potent suppression of growth hormone but not of insulin. Endocrinology. 2001;142:477–86.
  14. Culler MD. Somatostatin-Dopamine Chimeras: A Novel Approach to Treatment of Neuroendocrine Tumors. Horm Metab Res. 2011;43:854–7.
  15. Colao A, Petersenn S, Newell-Price J, Findling JW, Gu F, Maldonado M, et al. A 12-month phase 3 study of pasireotide in Cushing’s disease. N Engl J Med. 2012;366(10):914–24.
  16. Ben-Shlomo A, Melmed S. Pasireotide – a somatostatin analog for the potential treatment of acromegaly, neuroendocrine tumors and Cushing’s disease. IDrugs. 2007;10:885–95.
  17. Ortiz LD, Syro LV, Scheithauer BW, Ersen A, Uribe H, Fadul CE, et al. Anti-VEGF therapy in pituitary carcinoma. Pituitary. 2012;15(3):445–9.
  18. Lloyd RV, Kovacs K, Young Jr WF, et al. Pituitary tumours: introduction. In: DeLellis RA, Lloyd RV, Heitz PU, Eng C (eds) World Health Organization Classification of Tumours: Pathology and Genetics – Tumours of Endocrine Organs. Lyon: IARC Press; 2004.
  19. Remmele W, Stegner H Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue. Pathologe. 1987;8:138–40.
  20. Ramírez C, Cheng S, Vargas G, Asa SL, Ezzat S, González B, et al. Expression of Ki-67, PTTG1, FGFR4, and SSTR 2, 3, and 5 in nonfunctioning pituitary adenomas: a high throughput TMA, immunohistochemical study. J Clin Endocrinol Metab. 2012;97(5):1745–51.
  21. Liu M, Wang X, Yang Y, Li D, Ren H, Zhu Q, et al. Ectopic expression of the microtubule-dependent motor protein Eg5 promotes pancreatic tumourigenesis. J Pathol. 2010;221:221–8.
  22. Onofri C, Theodoropoulou M, Losa M, Uhl E, Lange M, Arzt E, et al. Localization of vascular endothelial growth factor (VEGF) receptors in normal and adenomatous pituitaries: detection of a non-endothelial function of VEGF in pituitary tumours. J Endocrinol. 2006;191:249–61.
  23. Ben-Shlomo A, Melmed S. Somatostatin agonists for treatment of acromegaly. Mol cell Endocrinol. 2008;286:192–8.
  24. Gerecitano JF, Stephenson JJ, Lewis NL, Osmukhina A, Li J, Wu K, et al. A Phase I trial of the kinesin spindle protein (Eg5) inhibitor AZD4877 in patients with solid and lymphoid malignancies. Invest New Drugs.2012;doi: 10.1007/s10637-012-9821-y.
  25. Folkman J, Watson K, Ingber D, Hanahan D. Induction of angiogenesis during the transition from hyperplasia to neoplasia. Nature. 1989;339:58–61.
  26. Weidner N, Folkman J, Pozza F et al. Tumor angiogenesis: a new significant and independent prognostic indicator early stage breast cancer. J Natl Cancer Inst. 1992;84:1875–87.
  27. Fidler IJ, Ellis LM. The implications of angiogenesis for the biology and therapy of cancer metastasis. Cell. 1994;79:185–8.
  28. Chung AS, Lee J, Ferrara N. Targeting the tumour vasculature: insights from physiological angiogenesis. Nat Rev Cancer. 2010;10:505–14.
  29. Olsson AK, Dimberg A, Kreuger J, Claesson- Welsh L. VEGF receptor signalling – in control of vascular function. Nat Rev Mol Cell Biol. 2006;7:359–71.
  30. Lloyd Lloyd RV, Scheithauer BW, Kuroki T, Vidal S, Kovacs K, Stefaneanu L. Vascular Endothelial Growth Factor (VEGF) Expression in Human Pituitary Adenomas and Carcinomas. Endocr Pathol. 1999;10:229–35.
  31. McCabe CJ, Boelaert K, Tannahill LA, Heaney AP, Stratford AL, Khaira JS, et al. Vascular endothelial growth factor, its receptor KDR/Flk-1, and pituitary tumor transforming gene in pituitary tumours. J Clin Endocr Metab. 2002;87:4238–44.
  32. Christina C, Perez-Millan MI, Luque G, Dulce RA, Sevlever G, Berner SI, et al. VEGF and CD31 association in pituitary adenomas. Endocr Pathol. 2010;21:154–60.
  33. Gorczyca W, Hardy J. Microadenomas of the human pituitary and their vascularization. Neurosurgery. 1988;22:1–6.
  34. Turner HE, Nagy Z, Gatter KC, Esiri MM, Harris AL, Wass JA. Angiogenesis in pituitary adenomas and the normal pituitary gland. J Clin Endocr Metab. 2000;85:1159–62.
  35. Vidal S, Kovacs K, Horvath E, Scheithauer BW, Kuroki T, Lloyd RV. Microvessel density in pituitary adenomas and carcinomas. Virchows Arch. 2001;438:595–602.
  36. De la Torre NG, Turner HE, Wass JA. Angiogenesis in prolactinomas: regulation and relationship with tumour behaviour. Pituitary. 2005;8:17–23.
  37. Banerjee SK, Sarkar DK, Weston AP, De A, Campbell DR. Over expression of vascular endothelial growth factor and its receptor during the development of estrogen-induced rat pituitary tumours may mediate estrogen-initiated tumour angiogenesis. Carcinogenesis. 1997;18:1155–61.
  38. Banerjee SK, Zoubine MN, Tran TM, Weston AP, Campbell DR. Over-expression of vascular endothelial growth factor164 and its co-receptor neuropilin-1 in estrogen-induced rat pituitary tumours and GH3 rat pituitary tumour cells. Int J Oncol. 2000;16:253–60.
  39. Kuczynski EA, Patten SG, Coomber BL. VEGFR2 expression and TGF-β signaling in initial and recurrent high-grade human glioma. Oncology. 2011;81(2):126–34.
  40. Kitadai Y, Haruma K, Sumii K et al. Expression of interleukin-8 correlates with vascularity in human gastric carcinomas. Am J Pathol. 1998;152:93–100.
  41. Mete O, Asa SL. Clinicopathological correlations in pituitary adenomas. Brain Pathol. 2012;22(4):443–53.
  42. Gadelha MR, Kasuki L, Korbonits M. Novel pathway for somatostatin analogs in patients with acromegaly. Trends Endocrinol Metab. 2013;24(5):238–46.
  43. Thoma CR, Toso A, Meraldi P, Krek W. Mechanisms of aneuploidy and its suppression by tumour suppressor proteins. Swiss Med Wkly. 2011;141:w13170.

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