Abstract
Diffuse intrinsic pontine glioma (DIPG) is a disease of childhood whose abysmal prognosis has remained unchanged for over 50 years. Biologic investigation has been stymied by lack of pretreatment tissue, as biopsy has been reserved for atypical cases. Recent advances in surgical and molecular-analytic techniques have increased the safety and potential utility of biopsy; brainstem biopsy has now been incorporated into several prospective clinical trials. These and other recent efforts have yielded new insights into DIPG molecular pathogenesis, and opened new avenues for investigation.
Similar content being viewed by others
References
Harris W (1926) A case of pontine glioma, with special reference to the paths of gustatory sensation. Proc R Soc Med 19:1–5
Lassman LP, Arjona VE (1967) Pontine gliomas of childhood. Lancet 1:913–915
Hargrave D, Bartels U, Bouffet E (2006) Diffuse brainstem glioma in children: critical review of clinical trials. Lancet Oncol 7:241–248
Bradley KA, Zhou T, McNall-Knapp RY, Jakacki RI, Levy AS, Vezina G, Pollack IF (2013) Motexafin-gadolinium and involved field radiation therapy for intrinsic pontine glioma of childhood: a children’s oncology group phase 2 study. Int J Radiat Oncol Biol Phys 85:e55–e60
Pollack IF, Stewart CF, Kocak M, Poussaint TY, Broniscer A, Banerjee A, Douglas JG, Kun LE, Boyett JM, Geyer JR (2011) A phase II study of gefitinib and irradiation in children with newly diagnosed brainstem gliomas: a report from the pediatric brain tumor consortium. Neuro Oncol 13:290–297
Jackson S, Patay Z, Howarth R, Pai Panandiker AS, Onar-Thomas A, Gajjar A, Broniscer A (2013) Clinico-radiologic characteristics of long-term survivors of diffuse intrinsic pontine glioma. J Neurooncol. doi:10.1007/s11060-013-1189-0
Zarghooni M, Bartels U, Lee E, Buczkowicz P, Morrison A, Huang A, Bouffet E, Hawkins C (2010) Whole-genome profiling of pediatric diffuse intrinsic pontine gliomas highlights platelet-derived growth factor receptor alpha and poly (ADP-ribose) polymerase as potential therapeutic targets. J Clin Oncol 28:1337–1344
Lassiter KR, Alexander E Jr, Davis CH Jr, Kelly DL Jr (1971) Surgical treatment of brain stem gliomas. J Neurosurg 34:719–725
Soler D, Borzyskowski M (1998) Lower urinary tract dysfunction in children with central nervous system tumours. Arch Dis Child 79:344–347
Zimmerman RA, Bilaniuk LT, Packer R, Sutton L, Samuel L, Johnson MH, Grossman RI, Goldberg HI (1985) Resistive NMR of brain stem gliomas. Neuroradiology 27:21–25
Ramos A, Hilario A, Lagares A, Salvador E, Perez-Nuñez A, Sepulveda J (2013) Brainstem gliomas. Semin Ultrasound CT MR 34:104–112
Yoshimura J, Onda K, Tanaka R, Takahashi H (2003) Clinicopathological study of diffuse type brainstem gliomas: analysis of 40 autopsy cases. Neurol Med Chir (Tokyo) 43:375–382; discussion 382
Prabhu SP, Ng S, Vajapeyam S, Kieran MW, Pollack IF, Geyer R, Haas-Kogan D, Boyett JM, Kun L, Poussaint TY (2011) DTI assessment of the brainstem white matter tracts in pediatric BSG before and after therapy: a report from the Pediatric Brain Tumor Consortium. Childs Nerv Syst 27:11–18
Zukotynski KA, Fahey FH, Kocak M et al (2011) Evaluation of 18F-FDG PET and MRI associations in pediatric diffuse intrinsic brain stem glioma: a report from the Pediatric Brain Tumor Consortium. J Nucl Med 52:188–195
Albright AL, Packer RJ, Zimmerman R, Rorke LB, Boyett J, Hammond GD (1993) Magnetic resonance scans should replace biopsies for the diagnosis of diffuse brain stem gliomas: a report from the Children’s Cancer Group. Neurosurgery 33:1026–1029; discussion 1029–1030
Fried I, Hawkins C, Scheinemann K et al (2012) Favorable outcome with conservative treatment for children with low grade brainstem tumors. Pediatr Blood Cancer 58:556–560
Angelini P, Hawkins C, Laperriere N, Bouffet E, Bartels U (2011) Post mortem examinations in diffuse intrinsic pontine glioma: challenges and chances. J Neurooncol 101:75–81
Fangusaro J, Finlay J, Sposto R et al (2008) Intensive chemotherapy followed by consolidative myeloablative chemotherapy with autologous hematopoietic cell rescue (AuHCR) in young children with newly diagnosed supratentorial primitive neuroectodermal tumors (sPNETs): report of the Head Start I and II experience. Pediatr Blood Cancer 50:312–318
Giussani C, Poliakov A, Ferri RT et al (2010) DTI fiber tracking to differentiate demyelinating diseases from diffuse brain stem glioma. Neuroimage 52:217–223
Jansen MHA, van Vuurden DG, Vandertop WP, Kaspers GJL (2012) Diffuse intrinsic pontine gliomas: a systematic update on clinical trials and biology. Cancer Treat Rev 38:27–35
Mandell LR, Kadota R, Freeman C et al (1999) 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 43:959–964
Packer RJ, Boyett JM, Zimmerman RA, Albright AL, Kaplan AM, Rorke LB, Selch MT, Cherlow JM, Finlay JL, Wara WM (1994) Outcome of children with brain stem gliomas after treatment with 7800 cGy of hyperfractionated radiotherapy. A Childrens Cancer Group Phase I/II Trial. Cancer 74:1827–1834
Janssens GO, Jansen MH, Lauwers SJ et al (2013) Hypofractionation vs conventional radiation therapy for newly diagnosed diffuse intrinsic pontine glioma: a matched-cohort analysis. Int J Radiat Oncol Biol Phys 85:315–320
Bouffet E, Raquin M, Doz F, Gentet JC, Rodary C, Demeocq F, Chastagner P, Lutz P, Hartmann O, Kalifa C (2000) Radiotherapy followed by high dose busulfan and thiotepa: a prospective assessment of high dose chemotherapy in children with diffuse pontine gliomas. Cancer 88:685–692
Korones DN, Fisher PG, Kretschmar C, Zhou T, Chen Z, Kepner J, Freeman C (2008) Treatment of children with diffuse intrinsic brain stem glioma with radiotherapy, vincristine and oral VP-16: a Children’s Oncology Group phase II study. Pediatr Blood Cancer 50:227–230
Cohen KJ, Heideman RL, Zhou T, Holmes EJ, Lavey RS, Bouffet E, Pollack IF (2011) Temozolomide in the treatment of children with newly diagnosed diffuse intrinsic pontine gliomas: a report from the Children’s Oncology Group. Neuro Oncol 13:410–416
Michalski A, Bouffet E, Taylor RE, Hargrave D, Walker D, Picton S, Robinson K, Pizer B, Bujkiewicz S (2010) The addition of high-dose tamoxifen to standard radiotherapy does not improve the survival of patients with diffuse intrinsic pontine glioma. J Neurooncol 100:81–88
Packer RJ, Prados M, Phillips P et al (1996) 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 77:2150–2156
Walker DA, Liu J, Kieran M, Jabado N, Picton S, Packer R, St Rose C, CPN Paris 2011 Conference Consensus Group (2011) A multi-disciplinary consensus statement concerning surgical approaches to low-grade, high-grade astrocytomas and diffuse intrinsic pontine gliomas in childhood (CPN Paris 2011) using the Delphi method. Neuro Oncol 15:462–468
Saratsis AM, Kambhampati M, Snyder K et al (2013) Comparative multidimensional molecular analyses of pediatric diffuse intrinsic pontine glioma reveals distinct molecular subtypes. Acta Neuropathol (Berl). doi:10.1007/s00401-013-1218-2
Schwartzentruber J, Korshunov A, Liu X-Y et al (2012) Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 482:226–231
Khuong-Quang D-A, Buczkowicz P, Rakopoulos P et al (2012) K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas. Acta Neuropathol (Berl) 124:439–447
Wu G, Broniscer A, McEachron TA et al (2012) Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat Genet. doi:10.1038/ng.1102
Lewis PW, Müller MM, Koletsky MS, Cordero F, Lin S, Banaszynski LA, Garcia BA, Muir TW, Becher OJ, Allis CD (2013) Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma. Science 340:857–861
Paugh BS, Broniscer A, Qu C et al (2011) Genome-wide analyses identify recurrent amplifications of receptor tyrosine kinases and cell-cycle regulatory genes in diffuse intrinsic pontine glioma. J Clin Oncol 29:3999–4006
Barrow J, Adamowicz-Brice M, Cartmill M, MacArthur D, Lowe J, Robson K, Brundler M-A, Walker DA, Coyle B, Grundy R (2011) Homozygous loss of ADAM3A revealed by genome-wide analysis of pediatric high-grade glioma and diffuse intrinsic pontine gliomas. Neuro Oncol 13:212–222
Cage TA, Samagh SP, Mueller S, Nicolaides T, Haas-Kogan D, Prados M, Banerjee A, Auguste KI, Gupta N (2013) Feasibility, safety, and indications for surgical biopsy of intrinsic brainstem tumors in children. Childs Nerv Syst. doi:10.1007/s00381-013-2101-0
Grill J, Puget S, Andreiuolo F, Philippe C, Macconaill L, Kieran MW (2011) Critical oncogenic mutations in newly diagnosed pediatric diffuse intrinsic pontine glioma. Pediatr Blood Cancer. doi:10.1002/pbc.24060
Kieran MW, Roberts CWM, Chi SN, Ligon KL, Rich BE, Macconaill LE, Garraway LA, Biegel JA (2012) Absence of oncogenic canonical pathway mutations in aggressive pediatric rhabdoid tumors. Pediatr Blood Cancer 59:1155–1157
Lee RS, Stewart C, Carter SL et al (2012) A remarkably simple genome underlies highly malignant pediatric rhabdoid cancers. J Clin Invest 122:2983–2988
Puget S, Philippe C, Bax DA et al (2012) Mesenchymal transition and PDGFRA amplification/mutation are key distinct oncogenic events in pediatric diffuse intrinsic pontine gliomas. PLoS One 7:e30313
Becher OJ, Hambardzumyan D, Walker TR et al (2010) Preclinical evaluation of radiation and perifosine in a genetically and histologically accurate model of brainstem glioma. Cancer Res 70:2548–2557
Masui K, Suzuki SO, Torisu R, Goldman JE, Canoll P, Iwaki T (2010) Glial progenitors in the brainstem give rise to malignant gliomas by platelet-derived growth factor stimulation. Glia 58:1050–1065
Monje M, Mitra SS, Freret ME et al (2011) Hedgehog-responsive candidate cell of origin for diffuse intrinsic pontine glioma. Proc Natl Acad Sci USA 108:4453–4458
Geoerger B, Aerts I, Casanova M et al (2012) A phase I/II study of LDE225, a smoothened (Smo) antagonist, in pediatric patients with recurrent medulloblastoma (MB) or other solid tumors. In: 2012 ASCO Annual Meeting. J Clin Oncol 30:suppl; abstr 9519
Pollack IF, Jakacki RI, Blaney SM et al (2007) Phase I trial of imatinib in children with newly diagnosed brainstem and recurrent malignant gliomas: a Pediatric Brain Tumor Consortium report. Neuro Oncol 9:145–160
Broniscer A, Baker JN, Tagen M et al (2010) Phase I study of vandetanib during and after radiotherapy in children with diffuse intrinsic pontine glioma. J Clin Oncol 28:4762–4768
Haas-Kogan DA, Banerjee A, Poussaint TY et al (2011) Phase II trial of tipifarnib and radiation in children with newly diagnosed diffuse intrinsic pontine gliomas. Neuro Oncol 13:298–306
Paugh BS, Qu C, Jones C et al (2010) Integrated molecular genetic profiling of pediatric high-grade gliomas reveals key differences with the adult disease. J Clin Oncol 28:3061–3068
Buczkowicz P, Zarghooni M, Bartels U, Morrison A, Misuraca KL, Chan T, Bouffet E, Huang A, Becher O, Hawkins C (2013) Aurora kinase B is a potential therapeutic target in pediatric diffuse intrinsic pontine glioma. Brain Pathol Zurich Switz 23:244–253
Vivanco I, Robins HI, Rohle D et al (2012) Differential sensitivity of glioma- versus lung cancer-specific EGFR mutations to EGFR kinase inhibitors. Cancer Discov 2:458–471
Broniscer A, Baker SD, Wetmore C et al (2013) Phase I trial, pharmacokinetics, and pharmacodynamics of vandetanib and dasatinib in children with newly diagnosed diffuse intrinsic pontine glioma. Clin Cancer Res 19:3050–3058
Veringa SJE, Biesmans D, van Vuurden DG et al (2013) In vitro drug response and efflux transporters associated with drug resistance in pediatric high grade glioma and diffuse intrinsic pontine glioma. PLoS One 8:e61512
Chittiboina P, Heiss JD, Warren KE, Lonser RR (2014) Magnetic resonance imaging properties of convective delivery in diffuse intrinsic pontine gliomas. J Neurosurg Pediatr. doi:10.3171/2013.11.PEDS136
Takakura K, Miki Y, Kubo O (1975) Adjuvant immunotherapy for malignant brain tumors in infants and children. Childs Brain 1:141–147
Joshi BH, Puri RA, Leland P, Varricchio F, Gupta G, Kocak M, Gilbertson RJ, Puri RK (2008) Identification of interleukin-13 receptor alpha2 chain overexpression in situ in high-grade diffusely infiltrative pediatric brainstem glioma. Neuro Oncol 10:265–274
Li G, Mitra SS, Monje M, Henrich KN, Bangs CD, Nitta RT, Wong AJ (2012) Expression of epidermal growth factor variant III (EGFRvIII) in pediatric diffuse intrinsic pontine gliomas. J Neurooncol 108:395–402
Gilbertson RJ, Hill DA, Hernan R et al (2003) ERBB1 is amplified and overexpressed in high-grade diffusely infiltrative pediatric brain stem glioma. Clin Cancer Res 9:3620–3624
Warren KE, Killian K, Suuriniemi M, Wang Y, Quezado M, Meltzer PS (2011) Genomic aberrations in pediatric diffuse intrinsic pontine gliomas. Neuro Oncol. doi:10.1093/neuonc/nor190
Geoerger B, Hargrave D, Thomas F et al (2011) Innovative therapies for children with cancer pediatric phase I study of erlotinib in brainstem glioma and relapsing/refractory brain tumors. Neuro Oncol 13:109–118
Acknowledgments
Support was obtained from the Ellie Kavalieros DIPG Foundation (MWK) and the Ryan Harvey Fund (MWK).
Conflict of interest
NJR: none. MWK: Consulting/advisory board agreements with Novartis, Sanofi, Incyte, Boehringer, SigmaTau, and Merck Pharmaceutical.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Robison, N.J., Kieran, M.W. Diffuse intrinsic pontine glioma: a reassessment. J Neurooncol 119, 7–15 (2014). https://doi.org/10.1007/s11060-014-1448-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11060-014-1448-8