Pediatric high-grade gliomas represent approximately 10% of all pediatric brain tumors. Similar to adult high-grade gliomas, they behave very aggressively, and these children have a very poor prognosis despite a variety of therapies that include chemotherapy and radiotherapy. In this review, we present an overview of both pediatric high-grade gliomas and diffuse intrinsic pontine gliomas with a focus on their epidemiology, etiology, presentation, prognostic factors, biology, treatment modalities, outcomes, and future research directions.
Bondy ML, Scheurer ME, Malmer B., et al. Brain tumor epidemiology: consensus from the Brain Tumor Epidemiology Consortium. Cancer. 2008;113(7 suppl):1953-1968.
2.
Davis FG, McCarthy BJ, Berger MSCentralized databases available for describing primary brain tumor incidence, survival, and treatment: Central Brain Tumor Registry of the United States; Surveillance, Epidemiology, and End Results; and National Cancer Data Base . Neuro Oncol. 1999;1(3):205-211.
3.
Louis DN, Ohgaki H., Wiestler OD, Cavenee WKWHO Classification of Tumours of the Central Nervous System. Albany, NY: WHO Publication Center; 2007.
4.
Geyer JR, Finlay JL, Boyett JM, et al. Survival of infants with malignant astrocytomas. A report from the Childrens Cancer Group. Cancer. 1995;75(4):1045-1050.
5.
Broniscer A. , Gajjar A.Supratentorial high-grade astrocytoma and diffuse brainstem glioma: two challenges for the pediatric oncologist . Oncologist. 2004;9(2):197-206.
6.
Wolff J., Chatagner P.Astrocytic Tumors, High Grade. London: Arnold; 2004.
7.
Hou LC, Bababeygy SR, Sarkissian V., et al. Congenital glioblastoma multiforme: case report and review of the literature. Pediatr Neurosur. 2008;44(4):304-312.
8.
Seker A., Ozek MMCongenital glioblastoma multiforme. Case report and review of the literature . J Neurosur. 2006; 105(6 suppl):473-479.
9.
Kranzinger M. , Jones N., Rittinger O., et al. Malignant glioma as a secondary malignant neoplasm after radiation therapy for craniopharyngioma: report of a case and review of reported cases. Onkologie. 2001;24(1):66-72.
10.
Salvati M., D’Elia A., Melone GA, et al. Radio-induced gliomas: 20-year experience and critical review of the pathology. J Neurooncol. 2008;89(2):169-177.
11.
Salvati M., Frati A., Russo N., et al. Radiation-induced gliomas: report of 10 cases and review of the literature. Surg Neurol. 2003;60(1):60-77; discussion 7.
12.
Neglia JP, Robison LL, Stovall M., et al. New primary neoplasms of the central nervous system in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J Natl Cancer Instit. 2006;98(21):1528-1537.
13.
Walter AW, Hancock ML, Pui CH, et al. Secondary brain tumors in children treated for acute lymphoblastic leukemia at St Jude Children’s Research Hospital. J Clin Oncol. 1998;16(12):3761-3767.
14.
Tsang RW, Laperriere NJ, Simpson WJ, Brierley J., Panzarella T., Smyth HSGlioma arising after radiation therapy for pituitary adenoma. A report of four patients and estimation of risk. Cancer. 1993;72(7):2227-2233.
15.
Nishio S., Morioka T., Inamura T., et al. Radiation-induced brain tumours: potential late complications of radiation therapy for brain tumours. Acta Neurochir. 1998;140(8):763-770.
16.
Melean G., Sestini R., Ammannati F., Papi L.Genetic insights into familial tumors of the nervous system. Am J Med Genet C Semin Med Genet. 2004;129C(1):74-84.
17.
Varley JMGermline TP53 mutations and Li-Fraumeni syndrome. Hum Mutat . 2003;21(3):313-320.
18.
Friedman JMEpidemiology of neurofibromatosis type 1. Am J Med Genet. 1999;89(1):1-6.
19.
Ward BA, Gutmann DHNeurofibromatosis 1: from lab bench to clinic. Pediatr Neurol . 2005;32(4):221-228.
20.
Guillamo JS , Creange A., Kalifa C., et al. Prognostic factors of CNS tumours in Neurofibromatosis 1 (NF1): a retrospective study of 104 patients. Brain. 2003;126(pt 1):152-160.
21.
Leonard JR, Perry A., Rubin JB, King AA, Chicoine MR, Gutmann DHThe role of surgical biopsy in the diagnosis of glioma in individuals with neurofibromatosis-1. Neurology. 2006;67(8):1509-1512.
22.
Vinchon M., Soto-Ares G., Ruchoux MM, Dhellemmes P.Cerebellar gliomas in children with NF1: pathology and surgery. Childs Nerv Syst. 2000;16(7):417-420.
23.
Hamada H., Kurimoto M., Endo S., Ogiichi T., Akai T., Takaku A.Turcot’s syndrome presenting with medulloblastoma and familiar adenomatous polyposis: a case report and review of the literature. Acta Neurochir. 1998;140(6): 631-632.
24.
Reulecke BC , Erker CG, Fiedler BJ, Niederstadt TU, Kurlemann G.Brain tumors in children: initial symptoms and their influence on the time span between symptom onset and diagnosis. J Child Neurol. 2008;23(2):178-183.
25.
Reddy AT, Wellons JC 3rd.Pediatric high-grade gliomas. Cancer J.2003 ;9(2):107-112.
26.
Weissman Z. , Michowitz S., Shuper A., Kornreich L., Amir J.Dysembryoplastic neuroepithelial tumor: a curable cause of seizures. Pediatr Hematol Oncol. 1996;13(5):463-468.
27.
Khajavi K., Comair YG, Prayson RA, et al. Childhood ganglioglioma and medically intractable epilepsy. A clinicopathological study of 15 patients and a review of the literature . Pediatr Neurosur. 1995;22(4):181-188.
28.
Broniscer A.Past, present, and future strategies in the treatment of high-grade glioma in children. Cancer Invest . 2006;24(1): 77-81.
29.
Finlay JL, Zacharoulis S.The treatment of high grade gliomas and diffuse intrinsic pontine tumors of childhood and adolescence: a historical-and futuristic-perspective . J Neurooncol. 2005;75(3):253-266.
30.
Finlay JL, Boyett JM, Yates AJ, 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):112-123.
31.
Wolff JE, Gnekow AK, Kortmann RD, et al. Preradiation chemotherapy for pediatric patients with high-grade glioma. Cancer. 2002;94(1):264-271.
32.
Sposto R., Ertel IJ, Jenkin RD, 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): 165-177.
33.
Sanders RP, Kocak M., Burger PC, Merchant TE, Gajjar A., Broniscer A.High-grade astrocytoma in very young children. Pediatr Blood Cancer. 2007;49(7):888-893.
34.
Duffner PK, Krischer JP, Burger PC, et al. Treatment of infants with malignant gliomas: the Pediatric Oncology Group experience. J Neurooncol. 1996;28(2-3):245-256.
35.
Dufour C., Grill J., Lellouch-Tubiana A., 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):2939-2945.
Bredel M., Pollack IF, Hamilton RL, James CDEpidermal growth factor receptor expression and gene amplification in high-grade non-brainstem gliomas of childhood. Clin Cancer Res. 1999;5(7):1786-1792.
38.
Sung T., Miller DC, Hayes RL, Alonso M., Yee H., Newcomb EWPreferential inactivation of the p53 tumor suppressor pathway and lack of EGFR amplification distinguish de novo high grade pediatric astrocytomas from de novo adult astrocytomas. Brain Pathol. 2000;10(2):249-259.
39.
Libermann TA , Nusbaum HR, Razon N., et al. Amplification, enhanced expression and possible rearrangement of EGF receptor gene in primary human brain tumours of glial origin. Nature. 1985;313(5998):144-147.
40.
Libermann TA , Nusbaum HR, Razon N., et al. Amplification and overexpression of the EGF receptor gene in primary human glioblastomas . J Cell Sci Suppl. 1985;3:161-172.
41.
Khatua S., Peterson KM, Brown KM, et al. Overexpression of the EGFR/FKBP12/HIF-2alpha pathway identified in childhood astrocytomas by angiogenesis gene profiling. Cancer Res. 2003;63(8):1865-1870.
42.
Pollack IF, Finkelstein SD, Woods J., et al. Expression of p53 and prognosis in children with malignant gliomas . N Engl J Med. 2002;346(6):420-427.
43.
Duffner PK, Horowitz ME, Krischer JP, et al. Postoperative chemotherapy and delayed radiation in children less than three years of age with malignant brain tumors. N Engl J Med. 1993;328(24):1725-1731.
44.
Palmer SL, Reddick WE, Gajjar A.Understanding the cognitive impact on children who are treated for medulloblastoma . J Pediatr Psychol. 2007 ;32(9):1040-1049.
45.
Schmiegelow M.Endocrinological late effects following radiotherapy and chemotherapy of childhood brain tumours. Dan Med Bull . 2006;53(3):326-341.
46.
Broniscer A. , Ke W., Fuller CE, Wu J., Gajjar A., Kun LESecond neoplasms in pediatric patients with primary central nervous system tumors: the St. Jude Children’s Research Hospital experience. Cancer. 2004;100(10):2246-2252.
47.
Marshall NE , Ballman KV, Michalak JC, et al. Ototoxicity of cisplatin plus standard radiation therapy vs. accelerated radiation therapy in glioblastoma patients . J Neurooncol. 2006;77(3):315-320.
48.
Wisoff JH, Boyett JM, Berger MS, 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 Neurosur. 1998;89(1):52-59.
49.
Pollack IF, Boyett JM, Yates AJ, et al. 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.
50.
Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma . N Engl J Med. 2005;352(10):987-996.
51.
Stupp R., Hegi ME, Mason WP, et al. 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):459-466.
52.
Hegi ME, Diserens AC, Gorlia T., et al. MGMT gene silencing and benefit from temozolomide in glioblastoma . N Engl J Med. 2005;352(10):997-1003.
53.
Pollack IF, Hamilton RL, Sobol RW, et al. O6-methylguanineDNA methyltransferase expression strongly correlates with outcome in childhood malignant gliomas: results from the CCG-945 cohort . J Clin Oncol. 2006;24(21):3431-3437.
54.
Broniscer A. , Chintagumpala M., Fouladi M., et al. Temozolomide after radiotherapy for newly diagnosed high-grade glioma and unfavorable low-grade glioma in children . J Neurooncol. 2006;76(3):313-319.
55.
Verschuur AC , Grill J., Lelouch-Tubiana A., Couanet D., Kalifa C., Vassal G.Temozolomide in paediatric high-grade glioma: a key for combination therapy? Br J Cancer. 2004;91(3):425-429.
56.
Finlay JL, Dhall G., Boyett JM, 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):806-811.
57.
Guruangan S. , Dunkel IJ, Goldman S., et al. Myeloablative chemotherapy with autologous bone marrow rescue in young children with recurrent malignant brain tumors . J Clin Oncol. 1998 ;16(7):2486-2493.
58.
Ali SA, McHayleh WM, Ahmad A., et al. Bevacizumab and irinotecan therapy in glioblastoma multiforme: a series of 13 cases. J Neurosur. 2008;109(2):268-272.
59.
Bokstein F. , Shpigel S., Blumenthal DTTreatment with bevacizumab and irinotecan for recurrent high-grade glial tumors. Cancer . 2008;112(10):2267-2273.
60.
Buie LW, Valgus J.Bevacizumab: a treatment option for recurrent glioblastoma multiforme . Ann Pharmacother. 2008;42(10): 1486-1490.
61.
Gururangan S., Chi S., Onar A., Packer R., Poussaint T., Gilbertson R., et al. Abstracts for the thirteenth annual meeting of the Society for Neuro-Oncology: phase II study of bevacizumab plus irinotecan in children with recurrent malignant glioma and diffuse intrinsic pontine glioma-a Pediatric Brain Tumor Consortium Study (PBTC-022). Neuro Oncol. 2008;10(3):759-915.
62.
Blum K., Godrich JTBrain Stem Tumors. New York: Thieme Medical Publishers; 2001.
63.
Walker DA, Punt JAG, Sokal M.Brainstem Tumors. London: Arnold ; 2004.
64.
Hargrave D. , Bartels U., Bouffet E.Diffuse brainstem glioma in children: critical review of clinical trials. Lancet Oncol. 2006;7(3):241-248.
65.
Sandri A., Sardi N., Genitori L., et al. Diffuse and focal brain stem tumors in childhood: prognostic factors and surgical outcome. Experience in a single institution. Childs Nerv Syst. 2006;22(9): 1127-1135.
66.
Panitch HS, Berg BOBrain stem tumors of childhood and adolescence. Am J Dis Chil . 1970;119(6):465-472.
67.
Frappaz D., Ricci AC, Kohler R., Bret P., Mottolese C.Diffuse brain stem tumor in an adolescent with multiple enchondromatosis (Ollier’s disease). Childs Nerv Syst. 1999;15(5):222-225.
68.
Freeman CR, Farmer JPPediatric brain stem gliomas: a review. Int J Radiat Oncol Biol Phys. 1998;40(2):265-271.
69.
Rubin G., Michowitz S., Horev G., et al. Pediatric brain stem gliomas: an update. Childs Nerv Syst. 1998;14(4-5):167-173.
70.
Albright ALDiffuse brainstem tumors: when is a biopsy necessary ? Pediatr Neurosur. 1996;24(5):252-255.
71.
Fangusaro JR , Jubran RF, Allen J., et al. Brainstem primitive neuroectodermal tumors (bstPNET): results of treatment with intensive induction chemotherapy followed by consolidative chemotherapy with autologous hematopoietic cell rescue. Pediatr Blood Cancer. 2008;50(3):715-717.
72.
Zagzag D., Miller DC, Knopp E., et al. Primitive neuroectodermal tumors of the brainstem: investigation of seven cases. Pediatrics. 2000;106(5):1045-1053.
73.
Keene DL, Hsu E., Ventureyra E., Nizalik E., Jimenez C.An unusual behavior of brainstem ependymoma. J Child Neurol . 1998;13(2):86-88.
74.
Sanford RA, Freeman CR, Burger P., Cohen MEPrognostic criteria for experimental protocols in pediatric brainstem gliomas . Surg Neurol. 1988;30(4):276-280.
75.
Bilaniuk LT , Molloy PT, Zimmerman RA, et al. Neurofibromatosis type 1: brain stem tumours. Neuroradiology. 1997;39(9): 642-653.
76.
Molloy PT, Bilaniuk LT, Vaughan SN, et al. Brainstem tumors in patients with neurofibromatosis type 1: a distinct clinical entity. Neurology. 1995 ;45(10):1897-1902.
77.
Gilbertson RJ, Hill DA, Hernan R., et al. ERBB1 is amplified and overexpressed in high-grade diffusely infiltrative pediatric brain stem glioma. Clin Cancer Res. 2003;9(10 pt 1):3620-3624.
78.
Louis DN, Rubio MP, Correa KM, Gusella JF, von Deimling A.Molecular genetics of pediatric brain stem gliomas. Application of PCR techniques to small and archival brain tumor specimens. J Neuropathol Exp Neurol. 1993; 52(5):507-515.
79.
Cartmill M. , Punt J.Diffuse brain stem glioma. A review of stereotactic biopsies. Childs Nerv Syst. 1999;15(5):235-237; discussion 8.
80.
Roujeau T., Machado G., Garnett MR, et al. Stereotactic biopsy of diffuse pontine lesions in children. J Neurosurg. 2007;107(1 suppl):1-4.
81.
Mandell LR, Kadota R., Freeman C., et al. There is no role for hyperfractionated radiotherapy in the management of children with newly diagnosed diffuse intrinsic brainstem tumors: results of a Pediatric Oncology Group phase III trial comparing conventional vs. hyperfractionated radiotherapy. Int J Radiat Oncol Biol Phys. 1999;43(5):959-964.
82.
Packer RJ, Prados M., Phillips P., et al. Treatment of children with newly diagnosed brain stem gliomas with intravenous recombinant beta-interferon and hyperfractionated radiation therapy: a childrens cancer group phase I/II study. Cancer . 1996;77(10):2150-2156.
83.
Finlay JL, Goldman S., Wong MC, et al. Pilot study of high-dose thiotepa and etoposide with autologous bone marrow rescue in children and young adults with recurrent CNS tumors . The Children’s Cancer Group. J Clin Oncol. 1996; 14(9):2495-2503.
