Skip to main content

Advertisement

SpringerLink
Log in

PITX2 Expression in Non-functional Pituitary Neuroendocrine Tumor with Cavernous Sinus Invasion

  • Published:
Endocrine Pathology Aims and scope Submit manuscript

Abstract

Although most pituitary neuroendocrine tumors (PitNETs) show benign behavior, a significant number of PitNETs exhibit an aggressive course including cavernous sinus (CS) invasion. To date, the cause of CS invasion has not been fully elucidated. In this study, we analyzed the relationship between CS invasion in PitNETs and the expression of PITX2 and SNAIL1, which are the transcription factors associated with the morphogenesis of pituitary gland. Sixty cases with non-functional PitNETs were classified into four types: type 1a, none of CS invasion and suprasellar expansion; type 1b, suprasellar expansion without CS invasion; type 2a, CS invasion without suprasellar expansion; and type 2b, CS invasion with suprasellar expansion. We analyzed the expression of PITX2 and SNAIL1 employing quantitative real-time polymerase chain reaction (qPCR) and immunohistochemistry. Other parameters such as mitotic count, Ki-67 index, and p53 expression were also analyzed, which were previously reported as potential tumor proliferative markers in PitNETs. PITX2 expression was significantly higher in PitNETs with CS invasion than PitNETs without CS invasion (P = 0.019). Expression of SNAIL1 was significantly elevated in PitNETs with suprasellar expansion compared with PitNETs without suprasellar expansion (P = 0.02). There was no apparent relationship between CS invasion and mitotic count, Ki-67 index, and p53 expression (mitotic count, P = 0.11; Ki-67 index, P = 0.61; p53, P = 0.66). High PITX2 expression was observed in non-functional PitNETs with CS invasion, suggesting that PITX2 may be involved in CS invasion of PitNETs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Asa SL, Casar-Borota O, Chanson P, Delgrange E, Earls P, Ezzat S, Grossman A, Ikeda H, Inoshita N, Karavitaki N, Korbonits M, Laws ER Jr, Lopes MB, Maartens N, McCutcheon IE, Mete O, Nishioka H, Raverot G, Roncaroli F, Saeger W, Syro LV, Vasiljevic A, Villa C, Wierinckx A, Trouillas J (2017) From pituitary adenoma to pituitary neuroendocrine tumor (PitNET): an International Pituitary Pathology Club proposal. Endocr Relat Cancer.24:C5-C8.

    Article  CAS  PubMed  Google Scholar 

  2. Rindi G, Klimstra DS, Abedi-Ardekani B, Asa SL, Bosman FT, Brambilla E, Busam KJ, de Krijger RR, Dietel M, El-Naggar AK, Fernandez-Cuesta L, Klöppel G, McCluggage WG, Moch H, Ohgaki H, Rakha EA, Reed NS, Rous BA, Sasano H, Scarpa A, Scoazec JY, Travis WD, Tallini G, Trouillas J, van Krieken JH, Cree IA (2018) A common classification framework for neuroendocrine neoplasms: an International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal. Mod Pathol.31:1770–1786.

    Article  PubMed Central  PubMed  Google Scholar 

  3. Lloyd RV, Kovacs K, Young WF Jr, Farrel WE, Asa SL, Truillas J, Kontogeorgos G, Sano T, Scheithauer BW, Horvath E, DeLellis RA, Heitz PU (2004) Pituitary tumors. Introduction. In DeLellis RA, Lloyd RV, Heitz PU, Eng C (eds). WHO classification of tumours, Pathology and genetics of tumours of endocrine organs. IARC Press 8:10–13.

  4. Mete O, Lopes MB (2017) Overview of the 2017 WHO Classification of Pituitary Tumors. Endocr Pathol 28:228–243.

    Article  CAS  PubMed  Google Scholar 

  5. Shiratori H, Sakuma R, Watanabe M, Hashiguchi H, Mochida K, Sakai Y, Nishino J, Saijoh Y, Whitman M, Hamada H (2001) Two-step regulation of left-right asymmetric expression of Pitx2: initiation by nodal signaling and maintenance by Nkx2. Mol Cell 7:137–149.

    Article  CAS  PubMed  Google Scholar 

  6. Baek SH, Kioussi C, Briata P, Wang D, Nguyen HD, Ohgi KA, Glass CK, Wynshaw-Boris A, Rose DW, Rosenfeld MG (2003) Regulated subset of G1 growth-control genes in response to derepression by the Wnt pathway. Proc Natl Acad Sci U S A 100:3245–3250.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Hamada H, Meno C, Watanabe D, Saijoh Y. Establishment of vertebrate left-right asymmetry (2002) Nat. Rev. Genet 3:103–113.

    Article  CAS  PubMed  Google Scholar 

  8. Kioussi C, Briata P, Baek SH, Rose DW, Hamblet NS, Herman T, Ohgi KA, Lin C, Gleiberman A, Wang J, Brault V, Ruiz-Lozano P, Nguyen HD, Kemler R, Glass CK, Wynshaw-Boris A, Rosenfeld MG (2002) Identification of a Wnt/Dvl/beta-Catenin → Pitx2 pathway mediating cell-type-specific proliferation during development. Cell 111:673–685.

    Article  CAS  PubMed  Google Scholar 

  9. Maier S, Nimmrich I, Koenig T, Eppenberger-Castori S, Bohlmann I, Paradiso A, Spyratos F, Thomssen C, Mueller V, Nährig J, Schittulli F, Kates R, Lesche R, Schwope I, Kluth A, Marx A, Martens JW, Foekens JA, Schmitt M, Harbeck N (2007) DNA-methylation of the homeodomain transcription factor PITX2 reliably predicts risk of distant disease recurrence in tamoxifen-treated, node-negative breast cancer patients. Eur J Cancer 43:1679–1686.

    Article  CAS  PubMed  Google Scholar 

  10. Cox B, Roose H, Vennekens A, Vankelecom H (2017) Pituitary stem cell regulation: who is pulling the strings? J Endocrinol 234:R135-R158.

    Article  CAS  PubMed  Google Scholar 

  11. Rhee CS, Sen M, Lu D, Wu C, Leoni L, Rubin J, Corr M, Carson DA (2002) Wnt and frizzled receptors as potential targets for immunotherapy in head and neck squamous cell carcinomas. Oncogene 21:6598–6605.

    Article  CAS  PubMed  Google Scholar 

  12. Saeger W, Lüdecke DK, Buchfelder M, Fahlbusch R, Quabbe HJ, Petersenn S (2007) Pathohistological classification of pituitary tumors: 10 years of experience with the German Pituitary Tumor Registry. Eur J Endocrinol. 156:203–216.

    Article  CAS  PubMed  Google Scholar 

  13. Tamura R, Ohara K, Sasaki H, Morimoto Y, Yoshida K, Toda M (2018) Histopathological vascular investigation of the peritumoral brain zone of glioblastomas. J Neuro Oncol 136:233–224.

    Article  CAS  Google Scholar 

  14. Boeckx C, Wouters A, Pauwels B, Deschoolmeester V, Specenier P, Lukaszuk K, Vermorken JB, Pauwels P, Peeters M, Lardon F, Baay MF (2011) Expression analysis on archival material: comparison of 5 commercially available RNA isolation kits for FFPE material. Diagn Mol Pathol 20:203–211.

    Article  CAS  PubMed  Google Scholar 

  15. Knosp E, Steiner E, Kitz K, Matula C (1993) Pituitary adenomas with invasion of the cavernous sinus space: a magnetic resonance imaging classification compared with surgical findings. Neurosurgery 33:610–617.

    CAS  PubMed  Google Scholar 

  16. Rutkowski MJ, Alward RM, Chen R, Wagner J, Jahangiri A, Southwell DG, Kunwar S, Blevins L, Lee H, Aghi MK (2018) Atypical pituitary adenoma: a clinicopathologic case series. J Neurosurg 128:1058–1065.

    Article  PubMed  Google Scholar 

  17. Bates AS, Farrell WE, Bicknell EJ, McNicol AM, Talbot AJ, Broome JC, Perrett CW, Thakker RV, Clayton RN (1997) Allelic deletion in pituitary adenomas reflects aggressive biological activity and has potential value as a prognostic marker. J Clin Endocrinol Metab 82:818–824.

    CAS  PubMed  Google Scholar 

  18. Farrell WE (2005) Epigenetic mechanisms of tumorigenesis. Horm Metab Res 37:361–368.

    Article  CAS  PubMed  Google Scholar 

  19. Karga HJ, Alexander JM, Hedley-Whyte ET, Klibanski A, Jameson JL (1992) Ras mutations in human pituitary tumors. J Clin Endocrinol Metab 74:914–919.

    Article  CAS  PubMed  Google Scholar 

  20. Yoshimoto K, Iwahana H, Fukuda A, Sano T, Katsuragi K, Kinoshita M, Saito S, Itakura M (1992) ras mutations in endocrine tumors:mutation detection by polymerase chain reaction-single strand conformation polymorphism. Jpn J Cancer Res 83:1057–1062.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Aylwin SJ, Welch JP, Davey CL, Geddes JF, WoodDF, Besser GM, Grossman AB, Monson JP, Burrin JM (2001) The relationship between steroidogenic factor 1 and DAX-1 expression and invitro gonadotropin secretion in human pituitary adenomas. J Clin Endocrinol Metab 86:2476–2483.

    CAS  PubMed  Google Scholar 

  22. Cushman LJ, Watkins-Chow DE, Brinkmeier ML, Raetzman LT, Radak AL, Lloyd RV, Camper SA (2001) Persistent Prop1 expression delays gonadotrope differentiation and enhances pituitary tumor susceptibility. Hum Mol Genet 10:1141–1153.

    Article  CAS  PubMed  Google Scholar 

  23. Dasen JS, O’Connell SM, Flynn SE, Treier M, Gleiberman AS, Szeto DP, Hooshmand F, Aggarwal AK, Rosenfeld MG (1999) Reciprocal interactions of Pit1 and GATA2 mediate signaling gradient-induced determination of pituitary cell types. Cell 97:587–598.

    Article  CAS  PubMed  Google Scholar 

  24. Egashira N, Minematsu T, Miyai S, Takekoshi S, Camper SA, Osamura RY (2008) Pituitary changes in Prop1 transgenic mice:hormone producing tumor sandsignetring type gonadotropes. Acta Histochem Cytochem 41:47–57.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Ishii Y, Suzuki M, Takekoshi S, Egashira N, Yamazaki M, Miyai S, Sanno N, Teramoto A, Osamura RY (2006) Immunonegative “null cell” adenomas and gonadotropin (Gn) subunit (SUs) immunopositive adenomas share frequent expression of multiple transcription factors. Endocr Pathol 17:35–43.

    Article  CAS  PubMed  Google Scholar 

  26. Basu M, Bhattacharya R, Ray U, Mukhopadhyay S, Chatterjee U, Roy SS (2015) Invasion of ovarian cancer cells is induced byPITX2-mediated activation of TGF-β and Activin-A. Mol Cancer 14:162.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Carreno G, Gonzalez-Meljem JM, Haston S, Martinez-Barbera JP (2017) Stem cells and their role in pituitary tumorigenesis. Mol Cell Endocrinol 445:27–34.

    Article  CAS  PubMed  Google Scholar 

  28. Fung FK, Chan DW, Liu VW, Leung TH, Cheung AN, Ngan HY (2012) Increased Expression of PITX2 Transcription Factor Contributes to Ovarian Cancer Progression. PLoS One 7:e37076.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Suh H, Gage PJ, Drouin J, Camper SA (2002) Pitx2 is required at multiple stages of pituitary organogenesis: pituitary primordium formation and cell specification. Development 129:329–337.

    CAS  PubMed  Google Scholar 

  30. Sun Z, Yu W, Sanz Navarro M, Sweat M, Eliason S, Sharp T, Liu H, Seidel K, Zhang L, Moreno M, Lynch T, Holton NE, Rogers L, Neff T, Goodheart MJ, Michon F, Klein OD, Chai Y, Dupuy A, Engelhardt JF, Chen Z, Amendt BA (2016) Sox2 and Lef-1 interact with Pitx2 to regulate incisor development and stem cell renewal. Development 143:4115–4126.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Camper SA (2011) Beta-catenin stimulates pituitary stem cells to form aggressive tumors. Proc Natl Acad Sci U S A 108:11303–11304.

    Article  PubMed Central  PubMed  Google Scholar 

  32. Sharp T, Wang J, Li X, Cao H, Gao S, Moreno M, Amendt BA (2014) A pituitary homeobox 2 (Pitx2):microRNA-200a-3p:β-catenin pathway converts mesenchymal cells to amelogenin-expressing dental epithelial cells. J Biol Chem 289:27327–27341.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Tian R, Wang J, Yan H, Wu J, Xu Q, Zhan X, Gui Z, Ding M, He J (2017) Differential expression of miR16 in glioblastoma and glioblastoma stem cells: their correlation with proliferation, differentiation, metastasis and prognosis. Oncogene 36:5861–5173.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Xu Q, Yuan X, Tunici P, Liu G, Fan X, Xu M, Hu J, Hwang JY, Farkas DL, Black KL, Yu JS (2009) Isolation of tumour stem-like cells from benign tumours. Br J Cancer. 101:303–311.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Moreno CS, Evans CO, Zhan X, Okor M, Desiderio DM, Oyesiku NM (2005) Novel molecular signaling and classification of human clinically nonfunctional pituitary adenomas identified by gene expression profiling and proteomic analyses. Cancer Res 65:10214–10222.

    Article  CAS  PubMed  Google Scholar 

  36. Acunzo J, Roche C, Defilles C, Thirion S, Quentien MH, Figarella-Branger D, Graillon T, Dufour H, Brue T, Pellegrini I, Enjalbert A, Barlier A (2011) Inactivation of PITX2 transcription factor induced apoptosis of gonadotroph tumoral cells. Endocrinology 152:3884–3892.

    Article  CAS  PubMed  Google Scholar 

  37. Cui M, Zhang M, Liu HF, Wang JP (2017) Effects of microRNA-21 targeting PITX2 on proliferation and apoptosis of pituitary tumor cells. Eur Rev Med Pharmacol Sci 21:2995–3004.

    CAS  PubMed  Google Scholar 

  38. Batlle E, Sancho E, Francí C, Domínguez D, Monfar M, Baulida J, García De Herreros A (2000) The transcription factor Snail is a repressor of E-cadherin gene expression in epithelial tumor cells. Nature Cell Biol 2: 84–89.

    Article  CAS  PubMed  Google Scholar 

  39. Perez-Moreno MA, Locascio A, Rodrigo I, Dhondt G, Portillo F, Nieto MA, Cano A (2001) A new role for E12/E47 in the repression of E-cadherin expression and epithelial-mesenchymal transitions. J Biol Chem 276:27424–27431.

    Article  CAS  PubMed  Google Scholar 

  40. Cano A, Pérez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, del Barrio MG, Portillo F, Nieto MA (2000) The transcription factor Snail controls epithelial-mesenchymal transition by repressing E-cadherin expression. Nature Cell Biol 2:76–83.

    Article  CAS  PubMed  Google Scholar 

  41. Miermeister CP, Petersenn S, Buchfelder M, Fahlbusch R, Lüdecke DK, Hölsken A, Bergmann M, Knappe HU, Hans VH, Flitsch J, Saeger W, Buslei R (2015) Histological criteria for atypical pituitary adenomas - data from the German pituitary adenoma registry suggests modifications. Acta Neuropathol Commun 3:50.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Miyoshi A, Kitajima Y, Kido S, Shimonishi T, Matsuyama S, Kitahara K, Miyazaki K (2005) Snail accelerates cancer invasion by upregulating MMP expression and is associated with poor prognosis of hepatocellular carcinoma. Br J Cancer 92:252–258.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. Yokoyama K, Kamata N, Hayashi E, Hoteiya T, Ueda N, Fujimoto R, Nagayama M (2001) Reverse correlation of E-cadherin and Snail in oral squamous cell carcinoma cells in vitro. Oral Oncology 7:65–71.

    Article  Google Scholar 

  44. Jia W, Zhu J, Martin TA, Jiang A, Sanders AJ, Jiang WG (2015) Epithelial-mesenchymal Transition (EMT) Markers in Human Pituitary Adenomas Indicate a Clinical Course. Anticancer Res 35:2635–2643.

    PubMed  Google Scholar 

  45. Shah PP, Kakar SS (2011) Pituitary tumor transforming gene induces epithelial to mesenchymal transition by regulation of Twist, Snail, Slug, and E-cadherin. Cancer Lett 311:66–76.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Manojlovic-Gacic E, Engström BE, Casar-Borota O (2018) Histopathological classification of non-functioning pituitary neuroendocrine tumors. Pituitary. 21:119–129.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

The authors greatly thank Ms. Naoko Tsuzaki at Department of Neurosurgery, Keio University School of Medicine, for technical assistance of laboratory works.

Author information

Authors and Affiliations

  1. Department of Neurosurgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Ryota Tamura, Yukina Morimoto, Kenzo Kosugi, Yumiko Oishi, Mizuto Sato, Kazunari Yoshida & Masahiro Toda

  2. Department of Pathology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Kentaro Ohara

Authors
  1. Ryota Tamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kentaro Ohara
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yukina Morimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kenzo Kosugi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yumiko Oishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mizuto Sato
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kazunari Yoshida
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Masahiro Toda
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Masahiro Toda.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed Consent

Informed consent was obtained from all individual participants included in the study.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tamura, R., Ohara, K., Morimoto, Y. et al. PITX2 Expression in Non-functional Pituitary Neuroendocrine Tumor with Cavernous Sinus Invasion. Endocr Pathol 30, 81–89 (2019). https://doi.org/10.1007/s12022-019-9573-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12022-019-9573-8

Keywords

Search

Navigation