National Cancer Institute


Diffuse intrinsic pontine glioma (DIPG) is a fast-growing childhood brain stem glioma that is difficult to treat and has a poor prognosis. A focal glioma grows more slowly, is easier to treat, and has a better prognosis. Learn about the diagnosis, cellular classification, staging, treatment, and clinical trials for pediatric brain stem glioma in this expert-reviewed 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.

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).

Childhood Brain Stem Glioma Treatment

General Information About Childhood Brain Stem Glioma

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 is a generic description that refers to any tumor of glial origin arising in the brain stem, inclusive of the midbrain, pons, and medulla. The following two histologies predominate:

  • Diffuse (infiltrating) astrocytomas centered in the pons, also called diffuse intrinsic pontine glioma (DIPG).
  • Pilocytic astrocytomas, which occur throughout the brain stem.

Incidence

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

Drawing of the inside of the brain showing  the supratentorial area (the upper part of the brain) and the posterior fossa/infratentorial area (the lower back part of the brain). The supratentorial area contains the cerebrum, lateral ventricle, third ventricle, choroid plexus, hypothalamus, pineal gland, pituitary gland, and optic nerve. The posterior fossa/infratentorial area contains the cerebellum, tectum, fourth ventricle, and   brain stem (pons and medulla). The tentorium and spinal cord are also shown.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.

Clinical Features

In children with DIPG, a classic triad of symptoms (cranial neuropathies, long tract signs, and ataxia) is often described. However, children often present with only one or two of these findings. Obstructive hydrocephalus due to expansion of the pons can also be a presenting symptom. Nonspecific symptoms may also occur, including behavioral changes and decreased school performance.

Focal pilocytic astrocytomas in the brain stem present in multiple ways depending on tumor location. Common presenting symptoms include the following:

  • Raised intracranial pressure with associated hydrocephalus.
  • Unilateral hemiparesis.
  • Unilateral cranial neuropathies.
  • Ataxia.

Diagnosis

Primary tumors of the brain stem are most often diagnosed based on clinical findings and on neuroimaging studies using magnetic resonance imaging (MRI). Histologic confirmation of presumed DIPGs is usually unnecessary. However, histologic confirmation is currently performed for research studies and may be more routinely considered in the future. Biopsy or resection may be indicated for brain stem tumors that are not diffuse and intrinsic or when there is diagnostic uncertainty based on imaging findings. New approaches with stereotactic needle biopsy may make biopsy safer.

Children with neurofibromatosis type 1 (NF1) are at an increased risk of developing a brain stem glioma. 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. 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:

  • Histology/grade of the tumor: Astrocytic tumors predominate in the brain stem. WHO grade 1 tumors (e.g., pilocytic astrocytomas and gangliogliomas) have a favorable prognosis and can arise throughout the brain stem, including the tectum of the midbrain, focally within the pons, or at the cervicomedullary junction where they are often exophytic. In contrast, DIPGs are diffuse astrocytomas which, when biopsied at diagnosis, can range from a low-grade fibrillary astrocytoma (WHO grade 2) to glioblastoma (WHO grade 4). At postmortem evaluation, DIPGs are also generally anaplastic astrocytoma (WHO grade 3) or glioblastoma (WHO grade 4) by morphological criteria, although WHO grade 2 regions can also be identified. Low-grade fibrillary astrocytomas (WHO grade 2) occurring outside the pons in other brain stem locations tend to be focal tumors with a more favorable prognosis.
  • Age at diagnosis: Children younger than 3 years diagnosed with DIPG may have a more favorable prognosis, perhaps reflecting different biologic characteristics.
  • NF1: Children with NF1 and brain stem gliomas may have a better prognosis than other patients who have intrinsic lesions.

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 and the original histology of the tumor after treatment.

Cellular Classification of Childhood Brain Stem Glioma

Cytogenetic Characteristics of Diffuse Intrinsic Pontine Gliomas (DIPGs)

The genomic characteristics of DIPGs appear to differ from those of most other pediatric high-grade gliomas 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 mutation in histone H3.1 () or H3.3 ( and ), which led the World Health Organization to group these tumors together into a single entity. In one report of 64 children with thalamic tumors, 50% of high-grade gliomas (11 of 22) had an mutation, and approximately 10% of tumors with low-grade morphological characteristics (5 of 42) had an 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 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:

  • Histone H3 genes: Approximately 80% of DIPG tumors have a mutation in a specific amino acid in the histone H3.1 () or H3.3 ( and ) genes. This mutation is observed in pediatric high-grade gliomas at other midline locations but is uncommon in cortical pediatric high-grade gliomas and in adult high-grade gliomas. An autopsy study that examined multiple tumor sites (primary, contiguous, and metastatic) in seven DIPG patients found that the mutation was invariably present, supporting its role as a driver mutation for DIPG.
  • Activin A receptor, type I () gene: Approximately 20% of DIPG cases have activating mutations in the gene, with most occurring concurrently with H3.3 mutations. Germline mutations in cause the autosomal dominant syndrome fibrodysplasia ossificans progressiva (FOP), although there is no cancer predisposition in FOP.
  • Receptor tyrosine kinase amplification: amplification occurs in approximately 30% of cases, with lower rates of amplification observed for some other receptor tyrosine kinases (e.g., and ). An autopsy study that examined multiple tumor sites (primary, contiguous, and metastatic) in seven DIPG patients found that amplification was variably present across these sites, suggesting that this change is a secondary genomic alteration in DIPG.
  • deletion: DIPG tumors commonly show deletion of the gene on chromosome 17p. Additionally, is commonly mutated in DIPG tumors, particularly those with histone H3 gene mutations. Aneuploidy is commonly observed in cases with mutations.

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 -mutant tumors rarely show MGMT promoter methylation, which explains the lack of efficacy of temozolomide when it was tested in patients with DIPG.

Stage Information for Childhood Brain Stem Glioma

There is no generally applied staging system for childhood brain stem glioma.

Brain stem gliomas are classified according to the following:

  • Location.
  • Radiographic appearance.
  • Histology (when obtained).

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. The majority of childhood brain stem gliomas are diffuse astrocytomas that involve the pons (diffuse intrinsic pontine gliomas [DIPGs]), often with contiguous involvement of other brain stem sites.

Spread of malignant brain stem tumors is usually contiguous, with metastasis via the subarachnoid space. Such dissemination may occur prior to local relapse but usually occurs simultaneously with or after local disease relapse.

Treatment Option Overview for Childhood Brain Stem Glioma

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 in order to ensure optimal results.

Table 1 describes the standard treatment options for newly diagnosed and recurrent or progressive childhood brain stem gliomas.

Newly Diagnosed Childhood Brain Stem Glioma Treatment

Standard Treatment Options for Diffuse Intrinsic Pontine Gliomas (DIPGs)

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.; []; []

Currently, no chemotherapeutic strategy—including neoadjuvant, concurrent, postradiation therapy, or immunotherapy—when added to radiation therapy has led to long-term survival for children with DIPGs.; [] This includes studies utilizing high-dose, marrow-ablative chemotherapy with autologous hematopoietic stem cell rescue, which have also been ineffective in extending survival.

Standard treatment options for newly diagnosed DIPGs include the following:

Radiation therapy

Conventional 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 evaluating the efficacy of hyperfractionated and hypofractionated radiation therapy and radiosensitizers have not demonstrated improved outcomes using these radiation techniques.

Chemotherapy only (infants)

Similar to the treatment of other brain tumors, radiation therapy is often omitted for infants with DIPGs, and chemotherapy-only approaches are utilized. However, published data supporting the utility of this approach is lacking.

Treatment options under clinical evaluation

Early-phase therapeutic trials may be available for selected patients. These trials may be available via the Children’s Oncology Group, the Pediatric Brain Tumor Consortium, 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 Focal Brain Stem Gliomas

Standard treatment options for newly diagnosed 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 have follow-up with sequential neuroradiographic studies unless there is evidence of progressive disease.

A period of observation may be indicated before instituting any treatment for patients with neurofibromatosis type 1. 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.[] Decisions regarding the need for such therapy depend on the age of the child, the extent of resection obtainable, and associated neurologic deficits.

Alternative approaches that have proven beneficial in selected cases include the following:

  • Stereotactic iodine I 125 brachytherapy approaches, with or without adjuvant chemotherapy.
  • The use of inhibitors for tumors harboring a V600E mutation.

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.

Progressive/Recurrent Childhood Brain Stem Glioma Treatment

Treatment Options for Progressive Diffuse Intrinsic Pontine Gliomas (DIPGs)

Progression of the tumor is anticipated generally within 1 year of completing radiation therapy. In most cases, biopsy at the time of clinical or radiologic progression is neither necessary nor recommended. To date, no salvage regimen has been shown to extend survival. 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 for Recurrent Focal Brain Stem Gliomas

At the time of recurrence, a complete evaluation to determine the extent of the relapse may be indicated for selected focal lesions. Biopsy or surgical resection should be considered for confirmation of relapse when other entities such as secondary tumor and treatment-related brain necrosis, which may be clinically indistinguishable from tumor recurrence, are 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 brain stem gliomas. 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.

Treatment considerations at the time of recurrence or progression are dependent on prior treatment. Treatment options for recurrent focal brain stem gliomas include the following:

Treatment Options Under Clinical Evaluation

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, 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.

The following is an example of a national and/or institutional clinical trial that is currently being conducted:

  • (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 3,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.

    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 ClinicalTrials.gov website for APEC1621 (NCT03155620).

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.

Changes to This Summary (09/28/2017)

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.

Treatment Option Overview for Childhood Brain Stem Glioma

Added text to state that 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% (cited Smith et al. as reference 1).

Progressive/Recurrent Childhood Brain Stem Glioma Treatment

Added Treatment Options Under Clinical Evaluation as a new subsection for progressive/recurrent childhood brain stem glioma.

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.

About This PDQ Summary

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:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

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:

  • Kenneth J. Cohen, MD, MBA (Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital)
  • Karen J. Marcus, MD (Dana-Farber Cancer Institute/Boston Children's Hospital)
  • Roger J. Packer, MD (Children's National Health System)
  • Malcolm A. Smith, MD, PhD (National Cancer Institute)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

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.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

The preferred citation for this PDQ summary is:

PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Brain Stem Glioma Treatment. Bethesda, MD: National Cancer Institute. Updated . Available at: https://www.cancer.gov/types/brain/hp/child-glioma-treatment-pdq. Accessed . [PMID: 26389253]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

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