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Prognostic and clinical significance of expressions of P53, Erbb2, c-Kit and Bcl2 in childhood medulloblastoma

Year 2019, Volume: 44 Issue: 1, 1 - 6, 31.03.2019
https://doi.org/10.17826/cumj.442463

Abstract

Purpose: The objective of this study is to evaluate prognostic implications of clinical, histopathological features and immuhistochemical expressions of p53, ERBB2, c-Kit and Bcl-2 in pediatric medulloblastoma. Materials and Methods: A total of 29 pediatric medulloblastoma cases were evaluated for prognostic association of demographic, clinical, histopathological features and immunohistochemical expressions of p53, ERBB2, c-Kit and Bcl-2.  Results: Median age at diagnosis was 69 months (21-122 months). Median duration of follow-up was 54 months (2-209 months). Fourteen of samples were diagnosed as classical (48%), thirteen cases as nodular/desmoplastic (45%) and two cases as anaplastic (7%) subtype. Staining for c-Kit, Bcl-2, p53 and ERBB2 was positive in 28, 10, 9 and 2 samples, respectively.  Overall  (OS) and event-free survival (EFS) were 62 % and 52%, respectively. Bcl-2 expression was found to be significantly increased in nodular/desmoplastic subtype. None of the clinical, histopathological and immunohistochemical features were related to survival.  Conclusion: This study reflects the earliest periods of current multimodal treatment protocols of medulloblastoma with similar survival rates in literature. Although none of the proposed factors have been associated with survival, future studies combining molecular and immunohistochemical methods would be more convenient for detecting new prognostic criteria in pediatric medulloblastoma.

References

  • 1. Zeltzer PM, Boyett JM, Finlay JL, Albright AL, Rorke LB, Milstein JM et al: Metastasis stage, adjuvant treatment, and residual tumor are prognostic factors for medulloblastoma inchildren: Conclusions from the Children’s Cancer Group 921 randomized phase III study. J Clin Oncol 1999;17:832-845.
  • 2. Chintagumpala M, Berg S, Blaney SM. Treatment contraversies in medulloblastoma. Curr Opin Oncol, 2001; 13: 154–159
  • 3. Edward C Schwalbe, Janet C Lindsey, Sirintra Nakjang, Stephen Crosier, Amanda J Smith, Debbie Hicks et al. Novel molecular subgroups for clinical classification and outcome prediction in childhood medulloblastoma: a cohort study. Lancet Oncol. 2017; 18(7): 958–971.
  • 4. Gajjar AJ, Robinson GW. Medulloblastoma-translating discoveries from the bench to the bedside. Nat Rev Clin Oncol. 2014;11(12):714-22
  • 5. Michael D. Taylor, Paul A. Northcott, Andrey Korshunov, Marc Remke, Yoon-Jae Cho, Steven C. Clifford et al. Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol. 2012;123(4):465-72.
  • 6. Robinson GW, Orr BA, Wu G, Gururangan S, Lin T, Qaddoumi I, et al. Vismodegib Exerts Targeted Efficacy Against Recurrent Sonic Hedgehog-Subgroup Medulloblastoma: Results From Phase II Pediatric Brain Tumor Consortium Studies PBTC-025B and PBTC-032. J Clin Oncol. 2015; 20;33(24):2646-54.
  • 7. Hashimoto Y, Penas-Prado M, Zhou S, Wei J, Khatua S, Hodges TR et al. Rethinking medulloblastoma from a targeted therapeutics perspective. J Neurooncol. 2018 ; 5
  • 8. Gessi M, von Bueren AO, Rutkowski S, Pietsch T. p53 expression predicts dismal outcome for medulloblastoma patients with metastatic disease. J Neurooncol. 2012;106(1):135-41
  • 9. Kleihues P, Louis DN, Scheithauer BW, Rorke LB, Reifenberger G, Burger PC, et al. The WHO classification of tumors of the nervous system. J Neuropathol Exp Neurol. 2002 ;61(3):215-25; discussion 226-9.
  • 10. Ramaswamy, V., M. Remke, J. Adamski, U. Bartels, U. Tabori, X. Wang, et al. 2016. Medulloblastoma subgroup-specificoutcomes in irradiated children: who are the true high-risk patients? Neuro. Oncol.18:291–297.
  • 11. Von Hoff K, Hinkes B, Gerber NU, Deinlein F, Mittler U, Urban C, et al. Long-term outcome and clinical prognosticfactors in children with medulloblastoma treated in the prospective randomized multicenter trial HIT’91. Eur J Cancer 45:1209–1217
  • 12. Johnston DL, Keene D, Kostova M, Lafay-Cousin L, Fryer C, Scheinemann K et al. Survival of children with medulloblastoma in Canada diagnosed between 1990 and 2009 inclusive. J Neurooncol. 2015 Sep;124(2):247-53.
  • 13. Stensvold E, Krossnes BK, Lundar T, Due-Tønnessen BJ, Frič R, Due-Tønnessen P et al. Outcome for children treated for medulloblastoma and supratentorial primitive neuroectodermal tumor (CNS-PNET) - a retrospective analysis spanning 40 years of treatment. Acta Oncol. 2017;56(5):698-705.
  • 14. Packer RJ, Zhou T, Holmes E, Vezina G, Gajjar A. Survival and secondary tumors in children with medulloblastoma receiving radiotherapy and adjuvant chemotherapy: results of Children's Oncology Group trial A9961. Neuro Oncol. 2013 ;15(1):97-103.
  • 15. Jakacki R, Burger PC, Zhou T, Holmes EJ, Kocak M, Onar A, et al. Outcome of children with metastatic medulloblastoma treated with carboplatin during craniospinal radiotherapy: a Children’s Oncology Group Phase I/II study. J Clin Oncol 30:2648–2653
  • 16. von Bueren AO, Kortmann RD, von Hoff K, Friedrich C, Mynarek M, Müller K, et al. Treatment of Children and Adolescents With Metastatic Medulloblastoma and Prognostic Relevance of Clinical and Biologic Parameters. J Clin Oncol. 2016 ;34(34):4151-4160
  • 17. Pietsch T, Schmidt R, Remke M, et al: Prognostic significance of clinical, histopathological, and molecular characteristics of medulloblastomas in the prospective HIT2000 multicenter clinical trial cohort. Acta Neuropathol 128:137-149, 2014
  • 18. Massimino M, Antonelli M, Gandola L, Miceli R, Pollo B, Biassoni V, et al. Histological variants of medulloblastoma are the most powerful clinical prognostic indicators. Pediatr Blood Cancer. 2013 Feb;60(2):210-6
  • 19. Jaros E, Lunec J, Perry RH, Kelly PJ, Pearson AD. p53 protein overexpression identifies a group of central primitive neuroectodermal tumours with poor prognosis. Br J Cancer, 1993; 68(4): 801–807
  • 20. Ray A, Ho M, Ma J, Parkes RK, Mainprize TG, Ueda S et al. A clinicobiological model predicting survival in medulloblastoma. Clin Cancer Res. 2004; 15;10(22):7613-20.
  • 21. Waye S, Naeem A, Choudhry MU, Parasido E, Tricoli L, Sivakumar A, et al. The p53 tumor suppressor protein protects against chemotherapeutic stress and apoptosis in human medulloblastoma cells. Aging (Albany NY). 2015 ;7(10):854-68.
  • 22. Miralbell R, Tolnay M, Bieri S, Probst A, Sappino AP, Berchtold W, et al. Pediatric medulloblastoma: prognostic value of p53, bcl–2, Mib-1, and microvessel density. J Neurooncol, 1999; 45(2):103–110
  • 23. Gilbertson RJ, Perry RH, Kelly PJ, Pearson ADJ, Lunec J (1997) Prognostic significance of HER2 and HER4 co expression in childhood medulloblastoma. Cancer Res 1997; 57:327
  • 24. Gilbertson RJ . ERBB2 in pediatric cancer: innocent until proven guilty. Oncologist,2005; 10(7):508–17
  • 25. Gajjar A, Hernan R, Kocak M, Fuller C, Lee Y, McKinnon PJ, et al. Clinical, histopathological and molecular markers of prognosis: toward a new disease stratification sysytem for medulloblastoma. J Clin Oncol, 2004; 22: 984–993
  • 26. Das P, Puri T, Suri V, Sharma MC, Sharma BS, Sarkar C. Medulloblastomas: a correlative study of MIB-1 proliferation index along with expression of c-Myc, ERBB2, and anti-apoptotic proteins along with histological typing and clinical outcome. Childs Nerv Syst. 2009;25(7):825-35.
  • 27. Chilton-Macneill S, Ho M, Hawkins C, Gassas A, Zielenska M, Baruchel S. C-kit expression and mutational analysis in medulloblastoma, Pediatr Dev Pathol, 2004; 7: 493-498
  • 28. Virág J, Kenessey I, Haberler C, Piurkó V, Bálint K, Döme B, et al. Angiogenesis and angiogenic tyrosine kinase receptor expression in pediatric brain tumors. Pathol Oncol Res. 2014 ;20(2):417-26.
  • 29. Blom T, Roselli A, Häyry V, Tynninen O, Wartiovaara K, Korja M, et al. Amplification and overexpression of KIT, PDGFRA, and VEGFR2 in medulloblastomas and primitive neuroectodermal tumors. J Neurooncol 2010; 97(2):217–224.
  • 30. Jenkins NC, Rao G, Eberhart CG, Pedone CA, Dubuc AM, Fults DW. Somatic cell transfer of c-Myc and Bcl-2 induces large-cell anaplastic medulloblastomas in mice. J Neurooncol. 2016 Feb;126(3):415-24. Oncol Rep. 2012 ;28(3):969-76.
  • 31. Sun P, Liu Y, Ying H, Li S. Action of db-cAMP on the bystander effect and chemosensitivity through connexin 43 and Bcl-2-mediated pathways in medulloblastoma cells. Oncol Rep. 2012;28(3):969-76.
  • 32. Schüller U, Schober F, Kretzschmar HA, Herms J. Bcl-2 expression inversely correlates with tumour cell differentiation in medulloblastoma. Neuropathol Appl Neurobiol. 2004;30(5):513-21.

Çocukluk çağı medulloblastom olgularında P53, ERBB2, c-Kit ve BCL2 Ekspresyonunun prognostik ve klinik önemi

Year 2019, Volume: 44 Issue: 1, 1 - 6, 31.03.2019
https://doi.org/10.17826/cumj.442463

Abstract

Amaç: Bu çalışmanın amacı pediatrik medullbolastom olgularında p53, ERBB2, c-Kit ve Bcl-2 ekspresyonunun klinik ve prognostik öneminin araştırılmasıdır. Gereç ve Yöntem: Toplam 29 medulloblastom olgusu demografik, klinik, histopatolojik özellikler ve immünhistokimyasal olarak p53, ERBB2, c-Kit ve Bcl-2 ekspresyonlarının prognostik anlamı açısından değerlendirmeye alındı.  Bulgular: Ortanca tanı yaşı 69 aydı (21-122 ay). Ortalama takip süresi 54 ay (2-209 ay) olarak belirlendi. Ondört olgu klasik (%48), 13 olgu nodüler/dezmoplastik (%45) ve 2 olgu anaplastik (%7) olarak değerlendirildi. İmmünhistokimyasal olarak 28 olguda c-Kit, 10 olguda Bcl-2, 9 olguda p53 ve 2 olguda ERBB2 pozitifliği gösterildi. Genel sağkalım oranı %62 ve hastalıksız sağkalım oranı %52 olarak bulundu. Bcl-2 ekspresyonunun nodüler/dezmoplastik alt tipte arttığı gösterildi. Klinik, histopatolojik ve immünhistokimyasal özelliklerin herhangi birisinin prognoz üzerinde etkisi gösterilemedi. Sonuç:  Bu çalışma medulloblastom tedavisinde kombine tedavi protokollerinin kullanılmaya başladığı ilk yılları yansıtmaktadır. Sağkalım oranları tanı yıllarına göre literatür ile benzer saptanmıştır. Değerlendirilen klinik, histopatoloijk ve immünhistokimyasal özelliklerin prognozla ilişkisi gösterilemese de, gelecekte moleküler ve immünhistokimyasal yöntemlerin birlikte kullanıldığı çalışmalarla medulloblastom olgularında prognostik faktörlerin saptanmasının mümkün olacağı düşüncesindeyiz.

References

  • 1. Zeltzer PM, Boyett JM, Finlay JL, Albright AL, Rorke LB, Milstein JM et al: Metastasis stage, adjuvant treatment, and residual tumor are prognostic factors for medulloblastoma inchildren: Conclusions from the Children’s Cancer Group 921 randomized phase III study. J Clin Oncol 1999;17:832-845.
  • 2. Chintagumpala M, Berg S, Blaney SM. Treatment contraversies in medulloblastoma. Curr Opin Oncol, 2001; 13: 154–159
  • 3. Edward C Schwalbe, Janet C Lindsey, Sirintra Nakjang, Stephen Crosier, Amanda J Smith, Debbie Hicks et al. Novel molecular subgroups for clinical classification and outcome prediction in childhood medulloblastoma: a cohort study. Lancet Oncol. 2017; 18(7): 958–971.
  • 4. Gajjar AJ, Robinson GW. Medulloblastoma-translating discoveries from the bench to the bedside. Nat Rev Clin Oncol. 2014;11(12):714-22
  • 5. Michael D. Taylor, Paul A. Northcott, Andrey Korshunov, Marc Remke, Yoon-Jae Cho, Steven C. Clifford et al. Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol. 2012;123(4):465-72.
  • 6. Robinson GW, Orr BA, Wu G, Gururangan S, Lin T, Qaddoumi I, et al. Vismodegib Exerts Targeted Efficacy Against Recurrent Sonic Hedgehog-Subgroup Medulloblastoma: Results From Phase II Pediatric Brain Tumor Consortium Studies PBTC-025B and PBTC-032. J Clin Oncol. 2015; 20;33(24):2646-54.
  • 7. Hashimoto Y, Penas-Prado M, Zhou S, Wei J, Khatua S, Hodges TR et al. Rethinking medulloblastoma from a targeted therapeutics perspective. J Neurooncol. 2018 ; 5
  • 8. Gessi M, von Bueren AO, Rutkowski S, Pietsch T. p53 expression predicts dismal outcome for medulloblastoma patients with metastatic disease. J Neurooncol. 2012;106(1):135-41
  • 9. Kleihues P, Louis DN, Scheithauer BW, Rorke LB, Reifenberger G, Burger PC, et al. The WHO classification of tumors of the nervous system. J Neuropathol Exp Neurol. 2002 ;61(3):215-25; discussion 226-9.
  • 10. Ramaswamy, V., M. Remke, J. Adamski, U. Bartels, U. Tabori, X. Wang, et al. 2016. Medulloblastoma subgroup-specificoutcomes in irradiated children: who are the true high-risk patients? Neuro. Oncol.18:291–297.
  • 11. Von Hoff K, Hinkes B, Gerber NU, Deinlein F, Mittler U, Urban C, et al. Long-term outcome and clinical prognosticfactors in children with medulloblastoma treated in the prospective randomized multicenter trial HIT’91. Eur J Cancer 45:1209–1217
  • 12. Johnston DL, Keene D, Kostova M, Lafay-Cousin L, Fryer C, Scheinemann K et al. Survival of children with medulloblastoma in Canada diagnosed between 1990 and 2009 inclusive. J Neurooncol. 2015 Sep;124(2):247-53.
  • 13. Stensvold E, Krossnes BK, Lundar T, Due-Tønnessen BJ, Frič R, Due-Tønnessen P et al. Outcome for children treated for medulloblastoma and supratentorial primitive neuroectodermal tumor (CNS-PNET) - a retrospective analysis spanning 40 years of treatment. Acta Oncol. 2017;56(5):698-705.
  • 14. Packer RJ, Zhou T, Holmes E, Vezina G, Gajjar A. Survival and secondary tumors in children with medulloblastoma receiving radiotherapy and adjuvant chemotherapy: results of Children's Oncology Group trial A9961. Neuro Oncol. 2013 ;15(1):97-103.
  • 15. Jakacki R, Burger PC, Zhou T, Holmes EJ, Kocak M, Onar A, et al. Outcome of children with metastatic medulloblastoma treated with carboplatin during craniospinal radiotherapy: a Children’s Oncology Group Phase I/II study. J Clin Oncol 30:2648–2653
  • 16. von Bueren AO, Kortmann RD, von Hoff K, Friedrich C, Mynarek M, Müller K, et al. Treatment of Children and Adolescents With Metastatic Medulloblastoma and Prognostic Relevance of Clinical and Biologic Parameters. J Clin Oncol. 2016 ;34(34):4151-4160
  • 17. Pietsch T, Schmidt R, Remke M, et al: Prognostic significance of clinical, histopathological, and molecular characteristics of medulloblastomas in the prospective HIT2000 multicenter clinical trial cohort. Acta Neuropathol 128:137-149, 2014
  • 18. Massimino M, Antonelli M, Gandola L, Miceli R, Pollo B, Biassoni V, et al. Histological variants of medulloblastoma are the most powerful clinical prognostic indicators. Pediatr Blood Cancer. 2013 Feb;60(2):210-6
  • 19. Jaros E, Lunec J, Perry RH, Kelly PJ, Pearson AD. p53 protein overexpression identifies a group of central primitive neuroectodermal tumours with poor prognosis. Br J Cancer, 1993; 68(4): 801–807
  • 20. Ray A, Ho M, Ma J, Parkes RK, Mainprize TG, Ueda S et al. A clinicobiological model predicting survival in medulloblastoma. Clin Cancer Res. 2004; 15;10(22):7613-20.
  • 21. Waye S, Naeem A, Choudhry MU, Parasido E, Tricoli L, Sivakumar A, et al. The p53 tumor suppressor protein protects against chemotherapeutic stress and apoptosis in human medulloblastoma cells. Aging (Albany NY). 2015 ;7(10):854-68.
  • 22. Miralbell R, Tolnay M, Bieri S, Probst A, Sappino AP, Berchtold W, et al. Pediatric medulloblastoma: prognostic value of p53, bcl–2, Mib-1, and microvessel density. J Neurooncol, 1999; 45(2):103–110
  • 23. Gilbertson RJ, Perry RH, Kelly PJ, Pearson ADJ, Lunec J (1997) Prognostic significance of HER2 and HER4 co expression in childhood medulloblastoma. Cancer Res 1997; 57:327
  • 24. Gilbertson RJ . ERBB2 in pediatric cancer: innocent until proven guilty. Oncologist,2005; 10(7):508–17
  • 25. Gajjar A, Hernan R, Kocak M, Fuller C, Lee Y, McKinnon PJ, et al. Clinical, histopathological and molecular markers of prognosis: toward a new disease stratification sysytem for medulloblastoma. J Clin Oncol, 2004; 22: 984–993
  • 26. Das P, Puri T, Suri V, Sharma MC, Sharma BS, Sarkar C. Medulloblastomas: a correlative study of MIB-1 proliferation index along with expression of c-Myc, ERBB2, and anti-apoptotic proteins along with histological typing and clinical outcome. Childs Nerv Syst. 2009;25(7):825-35.
  • 27. Chilton-Macneill S, Ho M, Hawkins C, Gassas A, Zielenska M, Baruchel S. C-kit expression and mutational analysis in medulloblastoma, Pediatr Dev Pathol, 2004; 7: 493-498
  • 28. Virág J, Kenessey I, Haberler C, Piurkó V, Bálint K, Döme B, et al. Angiogenesis and angiogenic tyrosine kinase receptor expression in pediatric brain tumors. Pathol Oncol Res. 2014 ;20(2):417-26.
  • 29. Blom T, Roselli A, Häyry V, Tynninen O, Wartiovaara K, Korja M, et al. Amplification and overexpression of KIT, PDGFRA, and VEGFR2 in medulloblastomas and primitive neuroectodermal tumors. J Neurooncol 2010; 97(2):217–224.
  • 30. Jenkins NC, Rao G, Eberhart CG, Pedone CA, Dubuc AM, Fults DW. Somatic cell transfer of c-Myc and Bcl-2 induces large-cell anaplastic medulloblastomas in mice. J Neurooncol. 2016 Feb;126(3):415-24. Oncol Rep. 2012 ;28(3):969-76.
  • 31. Sun P, Liu Y, Ying H, Li S. Action of db-cAMP on the bystander effect and chemosensitivity through connexin 43 and Bcl-2-mediated pathways in medulloblastoma cells. Oncol Rep. 2012;28(3):969-76.
  • 32. Schüller U, Schober F, Kretzschmar HA, Herms J. Bcl-2 expression inversely correlates with tumour cell differentiation in medulloblastoma. Neuropathol Appl Neurobiol. 2004;30(5):513-21.
There are 32 citations in total.

Details

Primary Language English
Subjects Health Care Administration
Journal Section Research
Authors

Süheyla Ocak 0000-0001-7479-7444

Mustafa Alp Özkan 0000-0003-1578-2757

Ferda Ozkan This is me 0000-0002-9919-0582

Büge Öz This is me 0000-0003-3201-1313

Tülin Tiraje Celkan 0000-0001-7287-1276

Hilmi Apak This is me 0000-0003-4102-6402

Publication Date March 31, 2019
Acceptance Date July 31, 2018
Published in Issue Year 2019 Volume: 44 Issue: 1

Cite

MLA Ocak, Süheyla et al. “Prognostic and Clinical Significance of Expressions of P53, Erbb2, C-Kit and Bcl2 in Childhood Medulloblastoma”. Cukurova Medical Journal, vol. 44, no. 1, 2019, pp. 1-6, doi:10.17826/cumj.442463.