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High-Grade Glioma

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Pediatric Neuro-oncology

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Abstract

High-grade gliomas (HGGs) constitute approximately 10 % of all childhood brain tumors and include AA (anaplastic astrocytoma), anaplastic oligodendroglioma (AO), and glioblastoma (GBM). Clinical symptomatology varies greatly with age and can be nonspecific, especially in younger children. Conventional MRI along with functional imaging has increased the diagnostic yield and improved surgical management of these patients. Routine histopathologic diagnosis is based on tissue obtained from biopsy or preferably resection of the tumor; central neuropathological review is recommended. The majority of pediatric HGGs are biologically distinct from adult malignant gliomas; these differences may explain responses to therapy and clinical outcomes. The recently proposed integrated genomic classification identifies six distinct biological subgroups of GBM in children and adults. Driver mutations in genes affecting histone H3.3 (K27M and G34R/V) coupled with mutations involving specific proteins (TP53, ATRX, DAXX) induce defects in chromatin remodeling and may play a central role in the genesis of pediatric HGGs. The current standard of care in pediatric HGGs include surgical resection followed by RT (in children >3years) with concurrent and adjuvant chemotherapy with temozolomide. However, these multimodality treatment strategies have had a minimal impact on improving survival. Ongoing clinical trials are investigating new molecular targets, chemoradiation sensitization of tumor cells, and immunotherapy. Future clinical trials of pediatric HGGs should incorporate the distinction between GBM subgroups and stratify patients using group-specific molecular markers.

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References

  1. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007;114(2):97–109.

    Article  PubMed Central  PubMed  Google Scholar 

  2. Dolecek TA, Propp JM, Stroup NE, Kruchko C. CBTRUS Statistical Report: primary brain and central nervous system tumors diagnosed in the United States in 2005–2009. Neuro Oncol. 2012;14:v1–49.

    Article  PubMed Central  PubMed  Google Scholar 

  3. Kaderali Z, Lamberti-Pasculli M, Rutka JT. The changing epidemiology of paediatric brain tumours: a review from the hospital for sick children. Childs Nerv Syst. 2009;25(7):787–93.

    Article  PubMed  Google Scholar 

  4. Kyritsis AP, Bondy ML, Rao JS, Sioka C. Inherited predisposition to glioma. Neuro Oncol. 2010;12(1):104–13.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Benesch M, Wagner S, Berthold F, Wolff JE. Primary dissemination of high-grade gliomas in children: experiences from four studies of the Pediatric Oncology and Hematology Society of the German Language Group (GPOH). J Neurooncol. 2005;72(2):179–83.

    Article  PubMed  Google Scholar 

  6. Wilne SH, Dineen RA, Dommett RM, Chu TP, Walker DA. Identifying brain tumours in children and young adults. BMJ. 2013;347:f5844.

    Article  CAS  PubMed  Google Scholar 

  7. Peet AC, Arvanitis TN, Leach MO, Waldman AD. Functional imaging in adult and paediatric brain tumors. Nat Rev Clin Oncol. 2012;9(12):700–11.

    Article  CAS  PubMed  Google Scholar 

  8. Wen PY, MacDonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, et al. Updated response assessment criteria for high-grade gliomas: response assessment in Neuro-Oncology Working Group. J Clin Oncol. 2010;28:1963–72.

    Article  PubMed  Google Scholar 

  9. Warren KE, Poussaint TY, Vezina G, Hargrave D, Packer RJ, Goldman S, et al. Challenges with defining response to antitumor agents in pediatric neuro-oncology: a report from the response assessment in pediatric neuro-oncology (RAPNO) working group. Pediatr Blood Cancer. 2013;60(9):1397–401.

    Article  PubMed  Google Scholar 

  10. Fouladi M, Hunt DL, Pollack IF, Dueckers G, Burger PC, Becker LE, et al. Outcome of children with centrally reviewed low-grade gliomas treated with chemotherapy with or without radiotherapy on Children’s Cancer Group high-grade glioma study CCG-945. Cancer. 2003;98(6):1243–52.

    Article  PubMed  Google Scholar 

  11. Pollack IF, Boyett JM, Yates AJ, Burger PC, Gilles FH, Davis RL, Finlay JL, Children’s Cancer Group. The influence of central review on outcome associations in childhood malignant gliomas: results from the CCG-945 experience. Neuro Oncol. 2003;5(3):197–207.

    Article  PubMed Central  PubMed  Google Scholar 

  12. Gilles FH, Tavaré CJ, Becker LE, Burger PC, Yates AJ, Pollack IF, Finlay JL. Pathologist interobserver variability of histologic features in childhood brain tumors: results from the CCG-945 study. Pediatr Dev Pathol. 2008;11(2):108–17.

    Article  PubMed  Google Scholar 

  13. Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, et al. An integrated genomic analysis of human glioblastoma multiforme. Science. 2008;321(5897):1807–12.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Noushmehr H, Weisenberger DJ, Diefes K, Phillips HS, Pujara K, Berman BP, et al. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell. 2010;17(5):510–22.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Paugh BS, Zhu X, Qu C, Endersby R, Diaz AK, Zhang J, et al. Novel oncogenic PDGFRA mutations in pediatric high-grade gliomas. Cancer Res. 2013;73(20):6219–29.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Phillips JJ, Aranda D, Ellison DW, Judkins AR, Croul SE, Brat DJ, et al. PDGFRA amplification is common in pediatric and adult high-grade astrocytomas and identifies a poor prognostic group in IDH1 mutant glioblastoma. Brain Pathol. 2013;23(5):565–73.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Pollack IF, Hamilton RL, James CD, Finkelstein SD, Burnham J, Yates AJ, Children’s Oncology Group, et al. Rarity of PTEN deletions and EGFR amplification in malignant gliomas of childhood: results from the Children’s Cancer Group 945 cohort. J Neurosurg. 2006;105(5 Suppl):418–24.

    PubMed  Google Scholar 

  18. Bax DA, Gaspar N, Little SE, Marshall L, Perryman L, Regairaz M, et al. EGFRvIII deletion mutations in pediatric high-grade glioma and response to targeted therapy in pediatric glioma cell lines. Clin Cancer Res. 2009;15(18):5753–61.

    Article  CAS  PubMed  Google Scholar 

  19. Pollack IF, Hamilton RL, Sobol RW, Burnham J, Yates AJ, Holmes EJ, et al. O6-methylguanine-DNA methyltransferase expression strongly correlates with outcome in childhood malignant gliomas: results from the CCG-945 Cohort. J Clin Oncol. 2006;24(21):3431–7.

    Article  CAS  PubMed  Google Scholar 

  20. Cohen KJ, Pollack IF, Zhou T, Buxton A, Holmes EJ, Burger PC, et al. Temozolomide in the treatment of high-grade gliomas in children: a report from the Children’s Oncology Group. Neuro Oncol. 2011;13(3):317–23.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Schlosser S, Wagner S, Mühlisch J, Hasselblatt M, Gerss J, Wolff JE, Frühwald MC. MGMT as a potential stratification marker in relapsed high-grade glioma of children: the HIT-GBM experience. Pediatr Blood Cancer. 2010;54(2):228–37.

    PubMed  Google Scholar 

  22. Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352(10):997–1003.

    Article  CAS  PubMed  Google Scholar 

  23. Schwartzentruber J, Korshunov A, Liu XY, Jones DT, Pfaff E, Jacob K, et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature. 2012;482(7384):226–31.

    Article  CAS  PubMed  Google Scholar 

  24. Sturm D, Witt H, Hovestadt H, Khuong-Quang DA, Jones DTW, Konermann C, et al. Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell. 2012;22:425–37.

    Article  CAS  PubMed  Google Scholar 

  25. Chan KM, Fang D, Gan H, Hashizume R, Yu C, Schroeder M, et al. The histone H3.3K27M mutation in pediatric glioma reprograms H3K27 methylation and gene expression. Genes Dev. 2013;27(9):985–90.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Fontebasso AM, Liu XY, Sturm D, Jabado N. Chromatin remodeling defects in pediatric and young adult glioblastoma: a tale of a variant histone 3 tail. Brain Pathol. 2013;23(2):210–6.

    Article  CAS  PubMed  Google Scholar 

  27. Paugh BS, Qu C, Jones C, Liu Z, Adamowicz-Brice M, Zhang J, et al. Integrated molecular genetic profiling of pediatric high-grade gliomas reveals key differences with the adult disease. J Clin Oncol. 2010;28(18):3061–8.

    Article  PubMed Central  PubMed  Google Scholar 

  28. Bjerke L, Mackay A, Nandhabalan M, Burford A, Jury A, Popov S, et al. Histone H3.3 mutations drive pediatric glioblastoma through upregulation of MYCN. Cancer Discov 2013; Epub ahead of print.

    Google Scholar 

  29. Rheinbay E, Louis DN, Bernstein BE, Suvà ML. A tell-tail sign of chromatin: histone mutations drive pediatric glioblastoma. Cancer Cell. 2012;21(3):329–31.

    Article  CAS  PubMed  Google Scholar 

  30. Fontebasso AM, Schwartzentruber J, Khuong-Quang DA, Liu XY, Sturm D, Korshunov A, et al. Mutations in SETD2 and genes affecting histone H3K36 methylation target hemispheric high-grade gliomas. Acta Neuropathol. 2013;125(5):659–69.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Dasgupta T, Haas-Kogan DA. The combination of novel targeted molecular agents and radiation in the treatment of pediatric gliomas. Front Oncol. 2013;3:110.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Jones C, Perryman L, Hargrave D. Paediatric and adult malignant glioma: close relatives or distant cousins? Nat Rev Clin Oncol. 2012;9:400–13.

    Article  CAS  PubMed  Google Scholar 

  33. Wisoff JH, Boyett JM, Berger MS, Brant C, Li H, Yates AJ, et al. Current neurosurgical management and the impact of the extent of resection in the treatment of malignant gliomas of childhood: a report of the Children’s Cancer Group trial no. CCG-945. J Neurosurg. 1998;89(1):52–9.

    Article  CAS  PubMed  Google Scholar 

  34. Sposto R, Ertel IJ, Jenkin RD, Boesel CP, Venes JL, Ortega JA, et al. The effectiveness of chemotherapy for treatment of high grade astrocytoma in children: results of a randomized trial. A report from the Childrens Cancer Study Group. J Neurooncol. 1989;7(2):165–77.

    Article  CAS  PubMed  Google Scholar 

  35. Finlay JL, Boyett JM, Yates AJ, Wisoff JH, Milstein JM, Geyer JR, et al. Randomized phase III trial in childhood high-grade astrocytoma comparing vincristine, lomustine, and prednisone with the eight-drugs-in-1-day regimen. Childrens Cancer Group. J Clin Oncol. 1995;13(1):112–23.

    CAS  PubMed  Google Scholar 

  36. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups, National Cancer Institute of Canada Clinical Trials Group, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987–96.

    Article  CAS  PubMed  Google Scholar 

  37. Massimino M, Gandola L, Luksch R, Spreafico F, Riva D, Solero C, et al. Sequential chemotherapy, high-dose thiotepa, circulating progenitor cell rescue, and radiotherapy for childhood high-grade glioma. Neuro Oncol. 2005;7(1):41–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Finlay JL, Dhall G, Boyett JM, Dunkel IJ, Gardner SL, Goldman S, Children’s Cancer Group, et al. Myeloablative chemotherapy with autologous bone marrow rescue in children and adolescents with recurrent malignant astrocytoma: outcome compared with conventional chemotherapy: a report from the Children’s Oncology Group. Pediatr Blood Cancer. 2008;51(6):806–11.

    Article  PubMed Central  PubMed  Google Scholar 

  39. Geyer JR, Finlay JL, Boyett JM, Wisoff J, Yates A, Mao L, Packer RJ. Survival of infants with malignant astrocytomas. A Report from the Childrens Cancer Group. Cancer. 1995;75(4):1045–50.

    Article  CAS  PubMed  Google Scholar 

  40. Duffner PK, Krischer JP, Burger PC, Cohen ME, Backstrom JW, Horowitz ME, et al. Treatment of infants with malignant gliomas: the Pediatric Oncology Group experience. J Neurooncol. 1996;28(2–3):245–56.

    CAS  PubMed  Google Scholar 

  41. Dufour C, Grill J, Lellouch-Tubiana A, Puget S, Chastagner P, Frappaz D, et al. High-grade glioma in children under 5 years of age: a chemotherapy only approach with the BBSFOP protocol. Eur J Cancer. 2006;42(17):2939–45.

    Article  CAS  PubMed  Google Scholar 

  42. Tanaka S, Louis DN, Curry TW, Batchelor TT, Dietrich J. Diagnostic and therapeutic avenues for glioblastoma: no longer a dead end? Nat Rev Clin Oncol. 2013;10(1):14–26.

    Article  CAS  PubMed  Google Scholar 

  43. MacDonald TJ, Vezina G, Stewart CF, Turner D, Pierson CR, Chen L, et al. Phase II study of cilengitide in the treatment of refractory or relapsed high-grade gliomas in children: a report from the Children’s Oncology Group. Neuro Oncol. 2013;15(10):1438–44.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Gururangan S, Chi SN, Young Poussaint T, Onar-Thomas A, Gilbertson RJ, Vajapeyam S, et al. Lack of efficacy of bevacizumab plus irinotecan in children with recurrent malignant glioma and diffuse brainstem glioma: a Pediatric Brain Tumor Consortium study. J Clin Oncol. 2010;28(18):3069–75.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Geoerger B, Hargrave D, Thomas F, Ndiaye A, Frappaz D, Andreiuolo F, et al. ITCC (Innovative Therapies for Children with Cancer) European Consortium Innovative Therapies for Children with Cancer pediatric phase I study of erlotinib in brainstem glioma and relapsing/refractory brain tumors. Neuro Oncol. 2011;13(1):109–18.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Broniscer A, Baker SJ, Stewart CF, Merchant TE, Laningham FH, Schaiquevich P, et al. Phase I and pharmacokinetic studies of erlotinib administered concurrently with radiotherapy for children, adolescents, and young adults with high-grade glioma. Clin Cancer Res. 2009;15(2):701–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  47. Geyer JR, Stewart CF, Kocak M, Broniscer A, Phillips P, Douglas JG, et al. A phase I and biology study of gefitinib and radiation in children with newly diagnosed brain stem gliomas or supratentorial malignant gliomas. Eur J Cancer. 2010;46(18):3287–93.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Massimino M, Bode U, Biassoni V, Fleischhack G. Nimotuzumab for pediatric diffuse intrinsic pontine gliomas. Expert Opin Biol Ther. 2011;11(2):247–56.

    Article  CAS  PubMed  Google Scholar 

  49. Lam C, Bouffet E, Bartels U. Nimotuzumab in pediatric glioma. Future Oncol. 2009;5(9):1349–61.

    Article  CAS  PubMed  Google Scholar 

  50. Pollack IF, Jakacki RI, Blaney SM, Hancock ML, Kieran MW, Phillips P, et al. Phase I trial of imatinib in children with newly diagnosed brainstem and recurrent malignant gliomas: a Pediatric Brain Tumor Consortium report. Neuro Oncol. 2007;9(2):145–60.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  51. Baruchel S, Sharp JR, Bartels U, Hukin J, Odame I, Portwine C, et al. A Canadian paediatric brain tumour consortium (CPBTC) phase II molecularly targeted study of imatinib in recurrent and refractory paediatric central nervous system tumours. Eur J Cancer. 2009;45(13):2352–9.

    Article  CAS  PubMed  Google Scholar 

  52. Geoerger B, Kieran MW, Grupp S, Perek D, Clancy J, Krygowski M, et al. Phase II trial of temsirolimus in children with high-grade glioma, neuroblastoma and rhabdomyosarcoma. Eur J Cancer. 2012;48(2):253–62.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. Warren KE, Gururangan S, Geyer JR, McLendon RE, Poussaint TY, Wallace D, et al. A phase II study of O6-benzylguanine and temozolomide in pediatric patients with recurrent or progressive high-grade gliomas and brainstem gliomas: a Pediatric Brain Tumor Consortium study. J Neurooncol. 2012;106(3):643–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  54. Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, European Organisation for Research and Treatment of Cancer Brain Tumour and Radiation Oncology Groups, National Cancer Institute of Canada Clinical Trials Group. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009;10(5):459–66.

    Article  CAS  PubMed  Google Scholar 

  55. Merchant TE, Pollack IF, Loeffler JS. Brain tumors across the age spectrum: biology, therapy and late effects. Semin Radiat Oncol. 2010;20(1):58–66.

    Article  PubMed Central  PubMed  Google Scholar 

  56. Sands SA, Zhou T, O’Neil SH, Patel SK, Allen J, McGuire Cullen P, et al. Long-term follow-up of children treated for high-grade gliomas: children's oncology group L991 final study report. J Clin Oncol. 2012;30(9):943–9.

    Article  PubMed Central  PubMed  Google Scholar 

  57. Fontebasso AM, Bechet D, Jabado N. Molecular biomarkers in pediatric glial tumors: a needed wind of change. Curr Opin Oncol. 2013;25(6):665–73.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

Dr. Issai Vanan is the Father Peter J Mckenna St. Baldrick’s Cancer Research Scholar, supported by the St. Baldrick’s Foundation, USA. Dr. Eisenstat holds the Muriel and Ada Hole Kids with Cancer Society Chair in Pediatric Oncology, University of Alberta.

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Authors and Affiliations

  1. Departments of Pediatrics and Child Health, Oncology and Cell Biology, Cancer Care Manitoba, Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, MB, Canada

    Magimairajan Issai Vanan M.D., M.P.H., F.A.A.P.

  2. Division of Neurosurgery, Department of Surgery, Stollery Children’s Hospital/University of Alberta, Edmonton, AB, Canada

    Vivek Mehta M.D., M.Sc.

  3. Departments of Pediatrics, Medical Genetics and Oncology, Stollery Children’s Hospital, University of Alberta, Edmonton Clinic Health Academy, Edmonton, AB, Canada

    David D. Eisenstat M.D., M.A., F.R.C.P.C.

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  1. Magimairajan Issai Vanan M.D., M.P.H., F.A.A.P.
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  2. Vivek Mehta M.D., M.Sc.
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  3. David D. Eisenstat M.D., M.A., F.R.C.P.C.
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Correspondence to David D. Eisenstat M.D., M.A., F.R.C.P.C. .

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  1. Division of Hematology/Oncology, Department of Pediatrics, Associate Professor of Pediatrics, McMaster Children's Hospital, McMaster University, Hamilton, Ontario, Canada

    Katrin Scheinemann

  2. Department of Haematology/Oncology, Garron Family Chair in Childhood Cancer Research, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

    Eric Bouffet

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Vanan, M.I., Mehta, V., Eisenstat, D.D. (2015). High-Grade Glioma. In: Scheinemann, K., Bouffet, E. (eds) Pediatric Neuro-oncology. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1541-5_10

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  • DOI: https://doi.org/10.1007/978-1-4939-1541-5_10

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