Diffuse intrinsic pontine glioma
- Mark W Kieran, MD, PhD
Mark W Kieran, MD, PhD
- Boston Children's Hospital
- Dana-Farber Cancer Institute
- Karen J Marcus, MD
Karen J Marcus, MD
- Associate Professor of Radiation Oncology
- Harvard Medical School
- Boston Children's Hospital
- Dana-Farber Cancer Institute
- Section Editors
- Jay S Loeffler, MD
Jay S Loeffler, MD
- Section Editor — Neurooncology
- Professor of Radiation Oncology
- Harvard Medical School
- Patrick Y Wen, MD
Patrick Y Wen, MD
- Section Editor — Neurooncology
- Professor of Neurology
- Harvard Medical School
- Amar Gajjar, MD
Amar Gajjar, MD
- Section Editor — Pediatric Neurooncology
- Scott and Tracie Hamilton Endowed Chair
- Director, Division of Neuro Oncology
- Co Leader Neurobiology and Brain Tumor Program
- Co Chair and Member, Department of Oncology
- St Jude Children’s Research Hospital
Brainstem gliomas are characterized by heterogeneous biologic behavior, ranging from low-grade tumors needing little treatment to those that are rapidly fatal despite aggressive therapy [1,2]. Prognosis and treatment depend upon both the clinical symptoms and their duration, the location of the tumor within the brainstem, and increasingly on the mutational profile.
Approximately 80 percent of pediatric brainstem gliomas arise within the pons, while the remaining 20 percent arise in the medulla, midbrain, or cervicomedullary junction (figure 1) [3-8]. The majority of pontine tumors are diffuse intrinsic brainstem gliomas, which are usually high-grade, locally infiltrative, and have a uniformly poor prognosis . Histologically, these tumors are usually anaplastic astrocytomas (World Health Organization [WHO] grade III) or glioblastoma (WHO grade IV). However, patients with WHO grade II tumors identified by biopsy do not have an improved prognosis. (See "Classification and pathologic diagnosis of gliomas".)
In contrast, most nonpontine tumors involving the cervicomedullary junction and tectum, as well as focal, cystic, and dorsal exophytic lesions, are low-grade astrocytomas, mostly grade I pilocytic astrocytomas . These are discrete, well-circumscribed tumors, often without evidence of locally invasive growth or edema . Approximately 10 to 20 percent of non-pontine gliomas will be high-grade and are treated similarly to diffuse intrinsic pontine gliomas.
Diffuse intrinsic pontine gliomas will be reviewed here. Gliomas arising from other sites within the brainstem are discussed separately. (See "Focal brainstem glioma".)
Gliomas arising in the brainstem (midbrain, pons, and medulla oblongata) account for 10 to 20 percent of all central nervous system (CNS) tumors in children. Brainstem gliomas are more common in children than adults [3,4,11,12]. In the United States, for example, there are approximately 300 pediatric cases and 100 adult cases reported each year. In children, the median age at diagnosis is five to nine years of age, and the incidence is approximately equal between males and females.
- Guillamo JS, Doz F, Delattre JY. Brain stem gliomas. Curr Opin Neurol 2001; 14:711.
- Monje M, Mitra SS, Freret ME, et al. Hedgehog-responsive candidate cell of origin for diffuse intrinsic pontine glioma. Proc Natl Acad Sci U S A 2011; 108:4453.
- Freeman CR, Farmer JP. Pediatric brain stem gliomas: a review. Int J Radiat Oncol Biol Phys 1998; 40:265.
- Rubin G, Michowitz S, Horev G, et al. Pediatric brain stem gliomas: an update. Childs Nerv Syst 1998; 14:167.
- Epstein FJ, Farmer JP. Brain-stem glioma growth patterns. J Neurosurg 1993; 78:408.
- Epstein F, Constantini S. Practical decisions in the treatment of pediatric brain stem tumors. Pediatr Neurosurg 1996; 24:24.
- Robertson PL, Allen JC, Abbott IR, et al. Cervicomedullary tumors in children: a distinct subset of brainstem gliomas. Neurology 1994; 44:1798.
- Pollack IF, Hoffman HJ, Humphreys RP, Becker L. The long-term outcome after surgical treatment of dorsally exophytic brain-stem gliomas. J Neurosurg 1993; 78:859.
- Fisher PG, Breiter SN, Carson BS, et al. A clinicopathologic reappraisal of brain stem tumor classification. Identification of pilocystic astrocytoma and fibrillary astrocytoma as distinct entities. Cancer 2000; 89:1569.
- Albright AL. Diffuse brainstem tumors: when is a biopsy necessary? Pediatr Neurosurg 1996; 24:252.
- Packer RJ. Brain tumors in children. Arch Neurol 1999; 56:421.
- Guillamo JS, Monjour A, Taillandier L, et al. Brainstem gliomas in adults: prognostic factors and classification. Brain 2001; 124:2528.
- WHO Classification of Tumours of the Central Nervous System, Revised 4th Edition, Louis DN, Ohgaki H, Wiestler OD, Cavenee WK (Eds), IARC, Lyon 2016.
- Singh S, Bhutani R, Jalali R. Leptomeninges as a site of relapse in locally controlled, diffuse pontine glioma with review of literature. Childs Nerv Syst 2007; 23:117.
- Gururangan S, McLaughlin CA, Brashears J, et al. Incidence and patterns of neuraxis metastases in children with diffuse pontine glioma. J Neurooncol 2006; 77:207.
- Zarghooni M, Bartels U, Lee E, et al. 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 2010; 28:1337.
- Paugh BS, Broniscer A, Qu C, et al. Genome-wide analyses identify recurrent amplifications of receptor tyrosine kinases and cell-cycle regulatory genes in diffuse intrinsic pontine glioma. J Clin Oncol 2011; 29:3999.
- Wu G, Broniscer A, McEachron TA, et al. Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat Genet 2012; 44:251.
- Nikbakht H, Panditharatna E, Mikael LG, et al. Spatial and temporal homogeneity of driver mutations in diffuse intrinsic pontine glioma. Nat Commun 2016; 7:11185.
- Hoffman LM, DeWire M, Ryall S, et al. Spatial genomic heterogeneity in diffuse intrinsic pontine and midline high-grade glioma: implications for diagnostic biopsy and targeted therapeutics. Acta Neuropathol Commun 2016; 4:1.
- Lewis PW, Müller MM, Koletsky MS, et al. Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma. Science 2013; 340:857.
- Zhang L, Chen LH, Wan H, et al. Exome sequencing identifies somatic gain-of-function PPM1D mutations in brainstem gliomas. Nat Genet 2014; 46:726.
- Puget S, Philippe C, Bax DA, et al. Mesenchymal transition and PDGFRA amplification/mutation are key distinct oncogenic events in pediatric diffuse intrinsic pontine gliomas. PLoS One 2012; 7:e30313.
- Grill J, Puget S, Andreiuolo F, et al. Critical oncogenic mutations in newly diagnosed pediatric diffuse intrinsic pontine glioma. Pediatr Blood Cancer 2012; 58:489.
- Wu G, Diaz AK, Paugh BS, et al. The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma. Nat Genet 2014; 46:444.
- Taylor KR, Mackay A, Truffaux N, et al. Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma. Nat Genet 2014; 46:457.
- Fontebasso AM, Papillon-Cavanagh S, Schwartzentruber J, et al. Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma. Nat Genet 2014; 46:462.
- Buczkowicz P, Hoeman C, Rakopoulos P, et al. Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations. Nat Genet 2014; 46:451.
- Feng J, Hao S, Pan C, et al. The H3.3 K27M mutation results in a poorer prognosis in brainstem gliomas than thalamic gliomas in adults. Hum Pathol 2015; 46:1626.
- Hashizume R, Andor N, Ihara Y, et al. Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma. Nat Med 2014; 20:1394.
- Grasso CS, Tang Y, Truffaux N, et al. Functionally defined therapeutic targets in diffuse intrinsic pontine glioma. Nat Med 2015; 21:555.
- Broniscer A, Laningham FH, Kocak M, et al. Intratumoral hemorrhage among children with newly diagnosed, diffuse brainstem glioma. Cancer 2006; 106:1364.
- Shah NC, Ray A, Bartels U, et al. Diffuse intrinsic brainstem tumors in neonates. Report of two cases. J Neurosurg Pediatr 2008; 1:382.
- Schomerus L, Merkenschlager A, Kahn T, Hirsch W. Spontaneous remission of a diffuse brainstem lesion in a neonate. Pediatr Radiol 2007; 37:399.
- Krieger MD, Blüml S, McComb JG. Magnetic resonance spectroscopy of atypical diffuse pontine masses. Neurosurg Focus 2003; 15:E5.
- Hipp SJ, Steffen-Smith E, Hammoud D, et al. Predicting outcome of children with diffuse intrinsic pontine gliomas using multiparametric imaging. Neuro Oncol 2011; 13:904.
- Warren KE, Frank JA, Black JL, et al. Proton magnetic resonance spectroscopic imaging in children with recurrent primary brain tumors. J Clin Oncol 2000; 18:1020.
- Nadvi SS, Ebrahim FS, Corr P. The value of 201thallium-SPECT imaging in childhood brainstem gliomas. Pediatr Radiol 1998; 28:575.
- Kwon JW, Kim IO, Cheon JE, et al. Paediatric brain-stem gliomas: MRI, FDG-PET and histological grading correlation. Pediatr Radiol 2006; 36:959.
- Pichler R, Pichler J, Mustafa H, et al. Somatostatin-receptor positive brain stem glioma visualized by octreoscan. Neuro Endocrinol Lett 2007; 28:250.
- Hayward RM, Patronas N, Baker EH, et al. Inter-observer variability in the measurement of diffuse intrinsic pontine gliomas. J Neurooncol 2008; 90:57.
- Hargrave D, Chuang N, Bouffet E. Conventional MRI cannot predict survival in childhood diffuse intrinsic pontine glioma. J Neurooncol 2008; 86:313.
- Walker DA, Liu J, Kieran M, et al. 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 2013; 15:462.
- Salvati M, Cervoni L. Carcinoma of the prostate: brain stem metastasis as the only site of spread. Tumori 1997; 83:776.
- Liu AK, Macy ME, Foreman NK. Bevacizumab as therapy for radiation necrosis in four children with pontine gliomas. Int J Radiat Oncol Biol Phys 2009; 75:1148.
- Albright AL, Packer RJ, Zimmerman R, et al. Magnetic resonance scans should replace biopsies for the diagnosis of diffuse brain stem gliomas: a report from the Children's Cancer Group. Neurosurgery 1993; 33:1026.
- Pincus DW, Richter EO, Yachnis AT, et al. Brainstem stereotactic biopsy sampling in children. J Neurosurg 2006; 104:108.
- Chitnavis B, Phipps K, Harkness W, Hayward R. Intrinsic brainstem tumours in childhood: a report of 35 children followed for a minimum of 5 years. Br J Neurosurg 1997; 11:206.
- Franzini A, Allegranza A, Melcarne A, et al. Serial stereotactic biopsy of brain stem expanding lesions. Considerations on 45 consecutive cases. Acta Neurochir Suppl (Wien) 1988; 42:170.
- Dellaretti M, Reyns N, Touzet G, et al. Diffuse brainstem glioma: prognostic factors. J Neurosurg 2012; 117:810.
- Rajshekhar V, Chandy MJ. Computerized tomography-guided stereotactic surgery for brainstem masses: a risk-benefit analysis in 71 patients. J Neurosurg 1995; 82:976.
- Puget S, Beccaria K, Blauwblomme T, et al. Biopsy in a series of 130 pediatric diffuse intrinsic Pontine gliomas. Childs Nerv Syst 2015; 31:1773.
- Roujeau T, Machado G, Garnett MR, et al. Stereotactic biopsy of diffuse pontine lesions in children. J Neurosurg 2007; 107:1.
- Schild SE, Stafford SL, Brown PD, et al. The results of radiotherapy for brainstem tumors. J Neurooncol 1998; 40:171.
- Donahue B, Allen J, Siffert J, et al. Patterns of recurrence in brain stem gliomas: evidence for craniospinal dissemination. Int J Radiat Oncol Biol Phys 1998; 40:677.
- Sethi R, Allen J, Donahue B, et al. Prospective neuraxis MRI surveillance reveals a high risk of leptomeningeal dissemination in diffuse intrinsic pontine glioma. J Neurooncol 2011; 102:121.
- Janssens GO, Gidding CE, Van Lindert EJ, et al. The role of hypofractionation radiotherapy for diffuse intrinsic brainstem glioma in children: a pilot study. Int J Radiat Oncol Biol Phys 2009; 73:722.
- Negretti L, Bouchireb K, Levy-Piedbois C, et al. Hypofractionated radiotherapy in the treatment of diffuse intrinsic pontine glioma in children: a single institution's experience. J Neurooncol 2011; 104:773.
- Janssens GO, Jansen MH, Lauwers SJ, et al. Hypofractionation vs conventional radiation therapy for newly diagnosed diffuse intrinsic pontine glioma: a matched-cohort analysis. Int J Radiat Oncol Biol Phys 2013; 85:315.
- Zaghloul MS, Eldebawy E, Ahmed S, et al. Hypofractionated conformal radiotherapy for pediatric diffuse intrinsic pontine glioma (DIPG): a randomized controlled trial. Radiother Oncol 2014; 111:35.
- 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; 43:959.
- Fisher PG, Donaldson SS. Hyperfractionated radiotherapy in the management of diffuse intrinsic brainstem tumors: when is enough enough? Int J Radiat Oncol Biol Phys 1999; 43:947.
- Freeman CR, Kepner J, Kun LE, et al. A detrimental effect of a combined chemotherapy-radiotherapy approach in children with diffuse intrinsic brain stem gliomas? Int J Radiat Oncol Biol Phys 2000; 47:561.
- Marcus KJ, Dutton SC, Barnes P, et al. A phase I trial of etanidazole and hyperfractionated radiotherapy in children with diffuse brainstem glioma. Int J Radiat Oncol Biol Phys 2003; 55:1182.
- Walter AW, Gajjar A, Ochs JS, et al. Carboplatin and etoposide with hyperfractionated radiotherapy in children with newly diagnosed diffuse pontine gliomas: a phase I/II study. Med Pediatr Oncol 1998; 30:28.
- Jennings MT, Sposto R, Boyett JM, et al. Preradiation chemotherapy in primary high-risk brainstem tumors: phase II study CCG-9941 of the Children's Cancer Group. J Clin Oncol 2002; 20:3431.
- Broniscer A, Iacono L, Chintagumpala M, et al. Role of temozolomide after radiotherapy for newly diagnosed diffuse brainstem glioma in children: results of a multiinstitutional study (SJHG-98). Cancer 2005; 103:133.
- Chuba PJ, Zamarano L, Hamre M, et al. Permanent I-125 brain stem implants in children. Childs Nerv Syst 1998; 14:570.
- Fuchs I, Kreil W, Sutter B, et al. Gamma Knife radiosurgery of brainstem gliomas. Acta Neurochir Suppl 2002; 84:85.
- Fontanilla HP, Pinnix CC, Ketonen LM, et al. Palliative reirradiation for progressive diffuse intrinsic pontine glioma. Am J Clin Oncol 2012; 35:51.
- Hargrave D, Bartels U, Bouffet E. Diffuse brainstem glioma in children: critical review of clinical trials. Lancet Oncol 2006; 7:241.
- Korones DN, Fisher PG, Kretschmar C, et al. 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 2008; 50:227.
- Massimino M, Spreafico F, Biassoni V, et al. Diffuse pontine gliomas in children: changing strategies, changing results? A mono-institutional 20-year experience. J Neurooncol 2008; 87:355.
- Cohen KJ, Heideman RL, Zhou T, et al. Temozolomide in the treatment of children with newly diagnosed diffuse intrinsic pontine gliomas: a report from the Children's Oncology Group. Neuro Oncol 2011; 13:410.
- Bailey S, Howman A, Wheatley K, et al. Diffuse intrinsic pontine glioma treated with prolonged temozolomide and radiotherapy--results of a United Kingdom phase II trial (CNS 2007 04). Eur J Cancer 2013; 49:3856.
- Sirachainan N, Pakakasama S, Visudithbhan A, et al. Concurrent radiotherapy with temozolomide followed by adjuvant temozolomide and cis-retinoic acid in children with diffuse intrinsic pontine glioma. Neuro Oncol 2008; 10:577.
- Lonser RR, Warren KE, Butman JA, et al. Real-time image-guided direct convective perfusion of intrinsic brainstem lesions. Technical note. J Neurosurg 2007; 107:190.
- Anderson RC, Kennedy B, Yanes CL, et al. Convection-enhanced delivery of topotecan into diffuse intrinsic brainstem tumors in children. J Neurosurg Pediatr 2013; 11:289.
- Jackson S, Patay Z, Howarth R, et al. Clinico-radiologic characteristics of long-term survivors of diffuse intrinsic pontine glioma. J Neurooncol 2013; 114:339.
- Broniscer A, Laningham FH, Sanders RP, et al. Young age may predict a better outcome for children with diffuse pontine glioma. Cancer 2008; 113:566.
- Sanford RA, Freeman CR, Burger P, Cohen ME. Prognostic criteria for experimental protocols in pediatric brainstem gliomas. Surg Neurol 1988; 30:276.
- Freeman CR, Bourgouin PM, Sanford RA, et al. Long term survivors of childhood brain stem gliomas treated with hyperfractionated radiotherapy. Clinical characteristics and treatment related toxicities. The Pediatric Oncology Group. Cancer 1996; 77:555.
- Selvapandian S, Rajshekhar V, Chandy MJ. Brainstem glioma: comparative study of clinico-radiological presentation, pathology and outcome in children and adults. Acta Neurochir (Wien) 1999; 141:721.
- Landolfi JC, Thaler HT, DeAngelis LM. Adult brainstem gliomas. Neurology 1998; 51:1136.
- Histopathology and grade
- Molecular pathogenesis
- H3 K27M-mutant diffuse midline glioma
- CLINICAL PRESENTATION
- Differential diagnosis
- Radiation therapy
- Alternative RT techniques
- Investigational therapies
- SUMMARY AND RECOMMENDATIONS