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Primary brain tumors, including brain stem gliomas, are a diverse group of diseases that together constitute the most common solid tumor of childhood. Immunohistochemical analysis, cytogenetic and molecular genetic findings, and measures of mitotic activity are increasingly used in tumor diagnosis and classification. Brain tumors are classified according to histology, but tumor location and extent of spread are important factors that affect treatment and prognosis.
The PDQ childhood brain tumor treatment summaries are organized primarily according to the World Health Organization (WHO) classification of nervous system tumors. For a full description of the classification of nervous system tumors and a link to the corresponding treatment summary for each type of brain tumor, refer to the PDQ summary on Childhood Brain and Spinal Cord Tumors Treatment Overview.
The term brain stem glioma is a generic description that refers to any tumor of glial origin arising in the brain stem, inclusive of the midbrain, pons, and medulla. While other histologies (e.g., ganglioglioma) can occur in the brain stem, the following two histologies predominate:
Approximately 300 to 400 pediatric brain stem tumors are diagnosed each year in the United States. DIPG accounts for approximately 75% to 80% of pediatric brain stem tumors. Most children with DIPG are diagnosed between the ages of 5 and 10 years. Focal pilocytic astrocytomas in the brain stem occur less frequently.
Anatomy of the inside of the brain, showing the pineal and pituitary glands, optic nerve, ventricles (with cerebrospinal fluid shown in blue), and other parts of the brain. The posterior fossa is the region below the tentorium, which separates the cortex from the cerebellum and essentially denotes the region containing the brain stem, cerebellum, and fourth ventricle.
Children with DIPG may present with the following classic triad of symptoms; however, children may present with only one or two of these symptoms at diagnosis:
Obstructive hydrocephalus caused by expansion of the pons can also be a presenting symptom. Nonspecific symptoms may also occur, including behavioral changes and decreased school performance.
The presentation of focal pilocytic astrocytomas in the brain stem depends on the tumor location. Common presenting symptoms include the following:
Primary tumors of the brain stem are most often diagnosed on the basis of clinical findings and on neuroimaging studies using magnetic resonance imaging (MRI), as follows:
Children with neurofibromatosis type 1 (NF1) are at an increased risk of developing brain stem gliomas, often pilocytic astrocytomas and not DIPGs. They may present with a long history of symptoms or be identified by screening tests.
Prognosis and Prognostic Factors
The median survival for children with DIPGs is less than 1 year, although about 10% of children will survive longer than 2 years.[9,10] In contrast, focal astrocytomas (e.g., pilocytic astrocytomas) have a markedly improved prognosis, with 5-year overall survival exceeding 90%.
Prognostic factors include the following:
DIPGs are diffuse astrocytomas that, when biopsied at diagnosis, can range from diffuse astrocytomas (WHO grade 2) to glioblastomas (WHO grade 4). At postmortem evaluation, DIPGs are also generally anaplastic astrocytomas (WHO grade 3) or glioblastomas (WHO grade 4) by morphological criteria, although WHO grade 2 regions can also be identified.[12,13,14,15,16]
Approximately 80% of DIPGs, regardless of histologic grade, demonstrate a histone H3.3 or H3.1 mutation and are now classified by the WHO as diffuse midline gliomas, H3 K27M-mutant (refer to the Cytogenetic Characteristics of Diffuse Intrinsic Pontine Gliomas section of this summary for more information). All diffuse midline gliomas, H3 K27M-mutant, are WHO grade 4, regardless of histologic grade, reflecting the poor prognosis of children with this diagnosis.
Follow-up After Treatment
For children with brain stem tumors and anticipated long-term survival, standard follow-up tends to include interval clinical assessments and periodic imaging with MRI. The required duration of follow-up with MRI varies; it largely depends on the presence or absence of residual imaging abnormalities after treatment, and the original histology of the tumor.
Cytogenetic Characteristics of Diffuse Intrinsic Pontine Gliomas (DIPGs)
The genomic characteristics of DIPGs appear to differ from those of many other pediatric high-grade gliomas of the cerebrum and from those of adult high-grade gliomas. The molecular and clinical characteristics of DIPGs align with those of other midline high-grade gliomas, with a specific H3 K27M mutation in histone H3.3 (H3F3A) or H3.1 (HIST1H3B and HIST1H3C), which led the World Health Organization to group these tumors together into a single entity, called diffuse midline glioma, H3 K27M-mutant.
In one report of 64 children with thalamic tumors, 50% of high-grade gliomas (11 of 22) had an H3 K27M mutation, and approximately 10% of tumors with low-grade morphological characteristics (5 of 42) had an H3 K27M mutation. Five-year overall survival (OS) was only 6% (1 of 16). In another study that included 202 children with glioblastoma, 68 of the tumors were midline (primarily thalamic) and had an H3 K27M mutation. Five-year OS for this group was only 5%, which was significantly inferior to the survival rates of the remaining patients in the study.
A number of chromosomal and genomic abnormalities have been reported for DIPG, including the following:
An autopsy study that examined multiple tumor sites (primary, contiguous, and metastatic) in seven DIPG patients found that the H3 K27M mutation was invariably present, supporting its role as a driver mutation for DIPG.
Patients with H3.1 K27M mutations have a longer median survival (15 months) than do patients with H3.3 K27M mutations (10.4 months).
An autopsy study that examined multiple tumor sites (primary, contiguous, and metastatic) in seven DIPG patients found that PDGFRA amplification was variably present across these sites, suggesting that this change is a secondary genomic alteration in DIPG.
The gene expression profile of DIPG differs from that of non–brain stem pediatric high-grade gliomas, further supporting a distinctive biology for this subset of pediatric gliomas. Pediatric H3 K27M-mutant tumors rarely show O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, which explains the lack of efficacy of temozolomide when it was tested in patients with DIPG.
There is no generally applied staging system for childhood brain stem glioma.
Brain stem gliomas are classified according to the following factors:
Brain stem gliomas may occur in the pons, midbrain, tectum, dorsum of the medulla at the cervicomedullary junction, or in multiple regions of the brain stem. The tumor may contiguously involve the cerebellar peduncles, cerebellum, the cervical spinal cord, and/or thalamus.[1,2]
Spread of diffuse intrinsic pontine gliomas (DIPGs), noted clinically, is usually contiguous, with metastasis via the subarachnoid space. Such dissemination may occur before local progression but usually occurs simultaneously with or after primary disease progression. However, subclinically, more widespread dissemination with extension to the brain stem, thalamus, cerebrum, and supratentorial leptomeninges is noted at autopsy.
Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2010, childhood cancer mortality decreased by more than 50%. Many of the improvements in survival in childhood cancer have been made as a result of clinical trials that have attempted to improve on the best available, accepted therapy. Clinical trials in pediatrics are designed to compare new therapy with therapy that is currently accepted as standard. This comparison may be done in a randomized study of two treatment arms or by evaluating a single new treatment and comparing the results with those that were previously obtained with existing therapy.
Because of the relative rarity of cancer in children, all patients with brain tumors should be considered for entry into a clinical trial. To determine and implement optimum treatment, planning by a multidisciplinary team of cancer specialists who have experience treating childhood brain tumors is required. Radiation therapy (including 3-dimensional conformal radiation therapy) of pediatric brain tumors is technically very demanding and should be carried out in centers that have experience in that area to ensure optimal results.
Table 1 describes the standard treatment options for newly diagnosed and progressive or recurrent childhood brain stem gliomas.
Standard Treatment Options for Newly Diagnosed Childhood Diffuse Intrinsic Pontine Gliomas (DIPGs)
Standard treatment options for newly diagnosed childhood DIPGs include the following:
While numerous clinical trials are available for children with newly diagnosed DIPGs, the utility of any therapy besides radiation therapy in the treatment of patients with newly diagnosed DIPG remains unproven.[1,2,3,4,5,6]; [7,8][Level of evidence: 2A]; [Level of evidence: 3iiiA]
No chemotherapeutic (including neoadjuvant, concurrent, postradiation chemotherapy) or immunotherapy strategy, when added to radiation therapy, has led to long-term survival for children with DIPGs.[10,11,12]; [Level of evidence: 2A] This includes therapy using high-dose, marrow-ablative chemotherapy with autologous hematopoietic stem cell rescue, which has been shown to be ineffective in extending survival. However, similar to the treatment of other brain tumors, radiation therapy is generally omitted for infants with DIPGs, and chemotherapy-only approaches are utilized. Published data supporting the utility of this approach are lacking.
Standard treatment for children with DIPGs is radiation therapy to involved areas. The conventional dose of radiation ranges between 54 Gy and 60 Gy given locally to the primary tumor site in single daily fractions. Such treatment will result in transient benefit for most patients, but more than 90% of patients will die within 18 months of diagnosis.
Radiation-induced changes may occur a few months after the completion of radiation therapy and may mimic tumor progression. When considering the efficacy of additional treatment, care needs to be taken to separate radiation-induced change from progressive disease.
Research studies that evaluated the efficacy of hyperfractionated and hypofractionated radiation therapy and radiosensitizers have not demonstrated improved outcomes using these radiation techniques.
Treatment options under clinical evaluation for newly diagnosed childhood DIPGs
Early-phase therapeutic trials may be available for selected patients. These trials may be available via the Children's Oncology Group (COG), the Pediatric Brain Tumor Consortium (PBTC), or other entities. Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
Standard Treatment Options for Newly Diagnosed Childhood Focal Brain Stem Gliomas
Standard treatment options for newly diagnosed childhood focal brain stem gliomas include the following:
Surgical resection (with or without chemotherapy and/or radiation therapy)
In general, maximal surgical resection is attempted.
Patients with residual tumor may be candidates for additional therapy. Treatment options include chemotherapy and/or radiation therapy.
Observation (with or without cerebrospinal fluid diversion)
Patients with small tectal lesions and hydrocephalus but no other neurological deficits may be treated with cerebrospinal fluid diversion alone and undergo monitoring with sequential neuroradiographic studies unless there is evidence of progressive disease.
For patients with neurofibromatosis type 1, a period of observation may be indicated before instituting any treatment. Brain stem gliomas in these children may be indolent and may require no specific treatment for years.
Radiation therapy, chemotherapy, or alternative approaches for unresectable tumors
In selected circumstances, adjuvant therapy in the form of radiation therapy or chemotherapy can be considered in a child with a newly diagnosed focal brain stem glioma.[26,27][Level of evidence: 3iDi] Decisions regarding the need for such therapy depend on the age of the child, the extent of resection obtained, and associated neurologic deficits.
Stereotactic iodine I 125 brachytherapy, with or without adjuvant chemotherapy, is a rarely used alternative approach that has proven beneficial in select cases.
Treatment options under clinical evaluation for newly diagnosed childhood focal brain stem gliomas
Early-phase therapeutic trials may be available for selected patients. These trials may be available via the COG, the PBTC, or other entities. Information about NCI-supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
Treatment Options for Progressive Childhood Diffuse Intrinsic Pontine Gliomas (DIPGs)
Progression of the DIPG tumor is anticipated generally within 1 year of completing radiation therapy. Radiation-induced changes may occur a few months after the completion of radiation therapy and may mimic tumor progression.
In most cases, biopsy at the time of clinical or radiologic progression is neither necessary nor recommended. Biopsy may be considered for confirmation of relapse when treatment-related brain stem damage, which may be clinically indistinguishable from tumor recurrence, is in the differential diagnosis. Other tests, including positron emission tomography, magnetic resonance spectroscopy, and single-photon emission computed tomography, have not yet been shown to be reliable in distinguishing necrosis from tumor recurrence in previously irradiated DIPG patients.
When considering the efficacy of additional treatment, care needs to be taken to separate radiation-induced changes from progressive disease.
There is no standard treatment. Treatment options for progressive childhood DIPGs include the following:
Reirradiation has been shown to prolong survival and can be considered at progression in children who have had an initial response to radiation therapy.[1,2]
Patients or families who desire additional disease-directed therapy should consider entering trials of novel therapeutic approaches because no standard agents have demonstrated clinically significant activity.
Regardless of whether a decision is made to pursue disease-directed therapy at the time of progression, palliative care remains a central focus of management. This ensures that quality of life is maximized while attempting to reduce symptoms and stress related to the terminal illness.
Treatment options under clinical evaluation for progressive childhood DIPGs
The following are examples of national and/or institutional clinical trials that are currently being conducted:
Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.
Treatment Options for Recurrent Childhood Focal Brain Stem Gliomas
At the time of tumor recurrence, a complete evaluation to determine the extent of the relapse may be indicated for selected focal lesions. Treatment considerations at the time of recurrence or progression are dependent on prior treatment.
Treatment options for recurrent childhood focal brain stem gliomas include the following:
The need for surgical intervention must be individualized on the basis of the initial tumor type, the location within the brain stem, the length of time between initial treatment, the appearance of the mass lesion, and the clinical picture.
Chemotherapy with agents such as carboplatin and vincristine may be effective in children with recurrent focal exophytic gliomas.
Treatment options under clinical evaluation for recurrent childhood focal brain stem gliomas
Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
This summary was comprehensively reviewed and reformatted.
This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood brain stem glioma. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Childhood Brain Stem Glioma Treatment are:
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Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
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PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Brain Stem Glioma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/brain/hp/child-glioma-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389253]
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Last Revised: 2019-06-19
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