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Vol 69, No 2 (2018)
Original paper
Submitted: 2017-09-29
Accepted: 2017-12-05
Published online: 2018-01-12
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Markers of proliferation and invasiveness in somatotropinomas

Agata Baldys-Waligorska12, Iga Wierzbicka34, Grzegorz Sokolowski12, Dariusz Adamek56, Filip Golkowski12
DOI: 10.5603/EP.a2018.0001
·
Pubmed: 29334118
·
Endokrynol Pol 2018;69(2):182-189.
Affiliations
  1. Department of Endocrinology, Faculty of Medicine Jagiellonian University, Medical College, Mikolaja Kopernika 17, 31-501 Krakow, Poland
  2. Katedra i Klinika Endokrynologii, Uniwersytet Jagielloński, Collegium Medicum, Mikołaja Kopernika 17, 31-501 Kraków, Poland
  3. Chair of Gastroenterology, Hepatology and Infectious Diseases, Faculty of Medicine Jagiellonian University, Medical College, ul. Sniadeckich 5, 31-531 Krakow, Poland
  4. Katedra Gastroenterologii, Hepatologii i Chorób Zakaźnych, Uniwersytet Jagielloński, Collegium Medicum, ul. Śniadeckich 5, 31-531 Kraków, Poland
  5. Chair of Patomorphology, Faculty of Medicine Jagiellonian University, Medical College, Grzegórzecka 16, 31-531 Kraków, Poland
  6. Katedra Patomorfologii, Uniwersytet Jagielloński, Collegium Medicum, ul. Grzegórzecka 16, 31-531 Kraków, Poland

open access

Vol 69, No 2 (2018)
Original Paper
Submitted: 2017-09-29
Accepted: 2017-12-05
Published online: 2018-01-12

Abstract

Introduction In the search for markers of invasiveness of pituitary adenomas, we studied the expression of Ki-67 antigen, TOPO 2A (topoisomerase 2 alpha), AIP (Aryl Hydrocarbon Receptor-Interacting Protein) and VEGF (Vascular Endothelial Growth Factor) in somatotropinomas. Material and Methods We retrospectively studied a group of 31 patients who underwent pituitary tumour surgery. Expression of Ki-67, TOPO 2A, AIP and VEGF in surgical specimens was determined by immunohistochemistry. Relations between quantitatively determined markers and clinical symptoms, tumour features, and MR imaging, were analysed. Acromegaly was confirmed by hormonal tests in all patients studied. Local invasiveness (cavernous sinus penetration, optic chiasm compression or suprasellar extension) was observed in 18/31 patients (58,1%). Results Ki-67 was expressed in 77.4%, TOPO 2A in 87.1%, AIP in 83.8%, and VEGF in 87.1% of 31 cases of somatropinoma. Median values of Ki-67, TOPO 2A, AIP and cytoplasmic VEGF indices were 1.2% [IQR=2.2], 1.5% [IQR=1.6], 21.26% [IQR=20.1] and 20.4% [IQR=15.4], respectively. Ki-67, TOPO 2A, AIP and VEGF expression was not correlated with age nor with patient gender (p > 0.05). Only Ki-67 and TOPO 2A correlated with tumour size (for Ki-67: r=0.42, p=0.025; for TOPO 2A: r=0.53, p=0.003). Ki-67 and TOPO 2A levels were significantly higher in invasive compared to noninvasive somatropinomas (Ki67 mean values: 1.85±1.33% vs. 0.95±1.07%, p=0.024; TOPO 2A mean values: 2.19±1.63% vs. 1.45±1.23%, , p=0.011). Conclusions Ki-67, TOPO 2A, AIP and VEGF were expressed in over 70% of all somatotropinomas. Only Ki-67 and TOPO 2A expression correlated with tumour size and tumour invasiveness.

Abstract

Introduction In the search for markers of invasiveness of pituitary adenomas, we studied the expression of Ki-67 antigen, TOPO 2A (topoisomerase 2 alpha), AIP (Aryl Hydrocarbon Receptor-Interacting Protein) and VEGF (Vascular Endothelial Growth Factor) in somatotropinomas. Material and Methods We retrospectively studied a group of 31 patients who underwent pituitary tumour surgery. Expression of Ki-67, TOPO 2A, AIP and VEGF in surgical specimens was determined by immunohistochemistry. Relations between quantitatively determined markers and clinical symptoms, tumour features, and MR imaging, were analysed. Acromegaly was confirmed by hormonal tests in all patients studied. Local invasiveness (cavernous sinus penetration, optic chiasm compression or suprasellar extension) was observed in 18/31 patients (58,1%). Results Ki-67 was expressed in 77.4%, TOPO 2A in 87.1%, AIP in 83.8%, and VEGF in 87.1% of 31 cases of somatropinoma. Median values of Ki-67, TOPO 2A, AIP and cytoplasmic VEGF indices were 1.2% [IQR=2.2], 1.5% [IQR=1.6], 21.26% [IQR=20.1] and 20.4% [IQR=15.4], respectively. Ki-67, TOPO 2A, AIP and VEGF expression was not correlated with age nor with patient gender (p > 0.05). Only Ki-67 and TOPO 2A correlated with tumour size (for Ki-67: r=0.42, p=0.025; for TOPO 2A: r=0.53, p=0.003). Ki-67 and TOPO 2A levels were significantly higher in invasive compared to noninvasive somatropinomas (Ki67 mean values: 1.85±1.33% vs. 0.95±1.07%, p=0.024; TOPO 2A mean values: 2.19±1.63% vs. 1.45±1.23%, , p=0.011). Conclusions Ki-67, TOPO 2A, AIP and VEGF were expressed in over 70% of all somatotropinomas. Only Ki-67 and TOPO 2A expression correlated with tumour size and tumour invasiveness.

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Keywords

pituitary adenoma, markers of proliferation, Ki-67, TOPO 2A, AIP, VEGF

About this article
Title

Markers of proliferation and invasiveness in somatotropinomas

Journal

Endokrynologia Polska

Issue

Vol 69, No 2 (2018)

Article type

Original paper

Pages

182-189

Published online

2018-01-12

Page views

3040

Article views/downloads

1343

DOI

10.5603/EP.a2018.0001

Pubmed

29334118

Bibliographic record

Endokrynol Pol 2018;69(2):182-189.

Keywords

pituitary adenoma
markers of proliferation
Ki-67
TOPO 2A
AIP
VEGF

Authors

Agata Baldys-Waligorska
Iga Wierzbicka
Grzegorz Sokolowski
Dariusz Adamek
Filip Golkowski

References (42)
  1. Dworakowska D, Grossman AB. The pathophysiology of pituitary adenomas. Best Pract Res Clin Endocrinol Metab. 2009; 23(5): 525–541.
    CrossRefPubMed
  2. Bałdys-Waligórska A, Krzentowska-Korek A, Gołkowski F, et al. The predictive value of the IGF-1 level in acromegaly patients treated by surgery and a somatostatin analogue. Endokrynol Pol. 2011; 62(5): 401–408.
    PubMed
  3. Meij BP, Lopes MBS, Ellegala DB, et al. The long-term significance of microscopic dural invasion in 354 patients with pituitary adenomas treated with transsphenoidal surgery. J Neurosurg. 2002; 96(2): 195–208.
    CrossRefPubMed
  4. Trouillas J, Roy P, Sturm N, et al. members of HYPOPRONOS. A new prognostic clinicopathological classification of pituitary adenomas: a multicentric case-control study of 410 patients with 8 years post-operative follow-up. Acta Neuropathol. 2013; 126(1): 123–135.
    CrossRefPubMed
  5. DeLellis RA, Lloyd RV, Heitz PU. Pathology and Genetics of Tumors of Endocrine Organs. In: World Health Organisation Classification of Tumors. IARC Press, Lyon 2004: 9–47.
  6. Wolfsberger S, Knosp E. Comments on the WHO 2004 classification of pituitary tumors. Acta Neuropathol. 2006; 111(1): 66–67.
    CrossRefPubMed
  7. Zada G, Woodmansee WW, Ramkissoon S, et al. Atypical pituitary adenomas: incidence, clinical characteristics, and implications. J Neurosurg. 2011; 114(2): 336–344.
    CrossRefPubMed
  8. Gruppetta M, Formosa R, Falzon S, et al. Expression of cell cycle regulators and biomarkers of proliferation and regrowth in human pituitary adenomas. Pituitary. 2017; 20(3): 358–371.
    CrossRefPubMed
  9. Al-Shraim M, Asa SL. The 2004 World Health Organization classification of pituitary tumors: what is new? Acta Neuropathol. 2006; 111(1): 1–7.
    CrossRefPubMed
  10. Clarke DJ, Vas AC, Andrews CA, et al. Topoisomerase II checkpoints: universal mechanisms that regulate mitosis. Cell Cycle. 2006; 5(17): 1925–1928.
    CrossRefPubMed
  11. Vidal S, Kovacs K, Horvath E, et al. Topoisomerase IIalpha expression in pituitary adenomas and carcinomas: relationship to tumor behavior. Mod Pathol. 2002; 15(11): 1205–1212.
    CrossRefPubMed
  12. Cao Yi, Ke R, Wang S, et al. DNA topoisomerase IIα and Ki67 are prognostic factors in patients with hepatocellular carcinoma. Oncol Lett. 2017; 13(6): 4109–4116.
    CrossRefPubMed
  13. Trofimiuk-Müldner M, Bałdys-Waligórska A, Sokołowski G, et al. Topoisomerase IIα as a prognostic factor in pituitary tumors. Pol Arch Med Wewn. 2014; 124(10): 500–508.
    PubMed
  14. Wolfsberger S, Wunderer J, Zachenhofer I, et al. Expression of cell proliferation markers in pituitary adenomas--correlation and clinical relevance of MIB-1 and anti-topoisomerase-IIalpha. Acta Neurochir (Wien). 2004; 146(8): 831–839.
    CrossRefPubMed
  15. Hernández-Ramírez LC, Martucci F, Morgan RML, et al. Rapid Proteasomal Degradation of Mutant Proteins Is the Primary Mechanism Leading to Tumorigenesis in Patients With Missense AIP Mutations. J Clin Endocrinol Metab. 2016; 101(8): 3144–3154.
    CrossRefPubMed
  16. Sav A, Rotondo F, Syro LV, et al. Biomarkers of pituitary neoplasms. Anticancer Res. 2012; 32(11): 4639–4654.
    PubMed
  17. Schöfl C, Honegger J, Droste M, et al. Frequency of AIP gene mutations in young patients with acromegaly: a registry-based study. J Clin Endocrinol Metab. 2014; 99(12): E2789–E2793.
    CrossRefPubMed
  18. Kasuki L, Vieira Neto L, Wildemberg LE, et al. AIP expression in sporadic somatotropinomas is a predictor of the response to octreotide LAR therapy independent of SSTR2 expression. Endocr Relat Cancer. 2012; 19(3): L25–L29.
    CrossRefPubMed
  19. Siveen KS, Prabhu K, Krishnankutty R, et al. Vascular Endothelial Growth Factor (VEGF) Signaling in Tumour Vascularization: Potential and Challenges. Curr Vasc Pharmacol. 2017; 15(4): 339–351.
    CrossRefPubMed
  20. McCabe CJ, Boelaert K, Tannahill LA, et al. Vascular endothelial growth factor, its receptor KDR/Flk-1, and pituitary tumor transforming gene in pituitary tumors. J Clin Endocrinol Metab. 2002; 87(9): 4238–4244.
    CrossRefPubMed
  21. Knosp E, Steiner E, Kitz K, et al. Pituitary adenomas with invasion of the cavernous sinus space: a magnetic resonance imaging classification compared with surgical findings. Neurosurgery. 1993; 33(4): 610–7; discussion 617.
    PubMed
  22. Zada G, Lin N, Laws ER. Patterns of extrasellar extension in growth hormone-secreting and nonfunctional pituitary macroadenomas. Neurosurg Focus. 2010; 29(4): E4.
    CrossRefPubMed
  23. Wierzbicka-Tutka I, Sokołowski G, Bałdys-Waligórska A, et al. PTTG and Ki-67 expression in pituitary adenomas. Przegl Lek. 2016; 73(2): 53–58.
    PubMed
  24. Landeiro JA, Fonseca EO, Monnerat AL, et al. Nonfunctioning giant pituitary adenomas: Invasiveness and recurrence. Surg Neurol Int. 2015; 6: 179.
    CrossRefPubMed
  25. Sarkar S, Chacko AG, Chacko G. An analysis of granulation patterns, MIB-1 proliferation indices and p53 expression in 101 patients with acromegaly. Acta Neurochir (Wien). 2014; 156(12): 2221–30; discussion 2230.
    CrossRefPubMed
  26. Chacko G, Chacko AG, Lombardero M, et al. Clinicopathologic correlates of giant pituitary adenomas. J Clin Neurosci. 2009; 16(5): 660–665.
    CrossRefPubMed
  27. Jaffrain-Rea ML, Angelini M, Gargano D, et al. Expression of aryl hydrocarbon receptor (AHR) and AHR-interacting protein in pituitary adenomas: pathological and clinical implications. Endocr Relat Cancer. 2009; 16(3): 1029–1043.
    CrossRefPubMed
  28. Lloyd RV, Scheithauer BW, Kuroki T, et al. Vascular Endothelial Growth Factor (VEGF) Expression in Human Pituitary Adenomas and Carcinomas. Endocr Pathol. 1999; 10(3): 229–235.
    PubMed
  29. Sánchez-Ortiga R, Sánchez-Tejada L, Moreno-Perez O, et al. Over-expression of vascular endothelial growth factor in pituitary adenomas is associated with extrasellar growth and recurrence. Pituitary. 2013; 16(3): 370–377.
    CrossRefPubMed
  30. Wang Y, Li J, Tohti M, et al. The expression profile of Dopamine D2 receptor, MGMT and VEGF in different histological subtypes of pituitary adenomas: a study of 197 cases and indications for the medical therapy. J Exp Clin Cancer Res. 2014; 33: 56.
    CrossRefPubMed
  31. Kurosaki M, Saegert W, Abe T, et al. Expression of vascular endothelial growth factor in growth hormone-secreting pituitary adenomas: special reference to the octreotide treatment. Neurol Res. 2008; 30(5): 518–522.
    CrossRefPubMed
  32. Alimohamadi M, Ownagh V, Mahouzi L, et al. The impact of immunohistochemical markers of Ki-67 and p53 on the long-term outcome of growth hormone-secreting pituitary adenomas: A cohort study. Asian J Neurosurg. 2014; 9(3): 130–136.
    CrossRefPubMed
  33. Jaffrain-Rea ML, Rotondi S, Turchi A, et al. Somatostatin analogues increase AIP expression in somatotropinomas, irrespective of Gsp mutations. Endocr Relat Cancer. 2013; 20(5): 753–766.
    CrossRefPubMed
  34. Kasuki Jomori de Pinho L, Vieira Neto L, Armondi Wildemberg LE, et al. Low aryl hydrocarbon receptor-interacting protein expression is a better marker of invasiveness in somatotropinomas than Ki-67 and p53. Neuroendocrinology. 2011; 94(1): 39–48.
    CrossRefPubMed
  35. Yilmaz M, Vural E, Koc K, et al. Cavernous sinus invasion and effect of immunohistochemical features on remission in growth hormone secreting pituitary adenomas. Turk Neurosurg. 2015; 25(3): 380–388.
    CrossRefPubMed
  36. Yarman S, Kurtulmus N, Canbolat A, et al. Expression of Ki-67, p53 and vascular endothelial growth factor (VEGF) concomitantly in growth hormone-secreting pituitary adenomas; which one has a role in tumor behavior ? Neuro Endocrinol Lett. 2010; 31(6): 823–828.
    PubMed
  37. Sen A, Das C, Mukhopadhyay M, et al. Cytohistological correlation in pituitary tumor and immunological assessment with the help of Ki-67. J Postgrad Med. 2017; 63(2): 96–99.
    CrossRefPubMed
  38. Dénes J, Kasuki L, Trivellin G, et al. Regulation of aryl hydrocarbon receptor interacting protein (AIP) protein expression by MiR-34a in sporadic somatotropinomas. PLoS One. 2015; 10(2): e0117107.
    CrossRefPubMed
  39. Magagna-Poveda A, Leske H, Schmid C, et al. Expression of somatostatin receptors, angiogenesis and proliferation markers in pituitary adenomas: an immunohistochemical study with diagnostic and therapeutic implications. Swiss Med Wkly. 2013; 143: w13895.
    CrossRefPubMed
  40. Ritvonen E, Pitkänen E, Karppinen A, et al. Impact of AIP and inhibitory G protein alpha 2 proteins on clinical features of sporadic GH-secreting pituitary adenomas. Eur J Endocrinol. 2017; 176(2): 243–252.
    CrossRefPubMed
  41. Chahal HS, Trivellin G, Leontiou CA, et al. Somatostatin analogs modulate AIP in somatotroph adenomas: the role of the ZAC1 pathway. J Clin Endocrinol Metab. 2012; 97(8): E1411–E1420.
    CrossRefPubMed
  42. Zawada NB, Kunert-Radek J, Pawlikowski M, et al. An evaluation of the effects of somatostatin analogue therapy in non-functioning pituitary adenomas in comparison to acromegaly. Endokrynol Pol. 2016; 67(3): 292–298.
    CrossRefPubMed

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