Glioma, Diffuse Pontine

  • Dana-Farber / Children's Hospital Cancer Center logo

    A diffuse pontine glioma or brain stem glioma is a malignant tumor that arises in the supportive tissue of the part of the brain that controls many vital functions. Learn about diffuse pontine glioma and find information on how we support and care for children and teens with brain stem glioma before, during, and after treatment.

The Brain Tumor Center at Dana-Farber/Boston Children's Cancer and Blood Disorders Center cares for children with many different types of common and rare brain and spinal tumors, including astrocytomas, medulloblastomas, ependymoma, glioblastomas, and primitive neuroectodermal tumors (PNET).

Your child will receive care from some of the world’s most experienced pediatric brain tumor doctors and internationally recognized pediatric subspecialists.

Our team works closely together to develop a care plan that offers your child the highest possible quality of life after treatment, and takes the needs of your child and your family into account.

Children treated at the Brain Tumor Center have access to some of the most advanced diagnostics and therapies, including:

  • Quick and accurate diagnosis from our dedicated pediatric neuropathologist
  • Access to advanced technologies like the intraoperative MRI, which allows our neurosurgeons to see detailed images of the brain during surgery
  • Advanced pediatric radiation oncology services, including targeted radiosurgery and low-dose radiation therapy that minimize exposure to radiation
  • Outpatient and oral chemotherapy, which may minimize the number of times your child will need to visit the hospital
  • Innovative therapies offered through clinical trials at Dana-Farber, Boston Children's Hospital, and nationally
  • Specialized programs for the treatment of low- and high-grade gliomas, and medulloblastoma

Thanks to refined surgical techniques and improved chemotherapy and radiation therapy, the majority of children with brain and spinal cord tumors are now long-term survivors. However, they may face physical, social, and intellectual challenges that require specialized care.

Learn more about our Brain Tumor Center.

Information for: Patients | Healthcare Professionals

Diffuse Pontine Glioma    

Overview

Having a tumor in the brain is always a very serious matter, and a diffuse pontine glioma – also called a brainstem glioma – is no exception. Diffuse pontine glioma is a highly aggressive and difficult to treat brain tumor and is found at the base of the brain in the pons, which controls vital body functions, such as breathing.

  • Diffuse pontine glioma is a glial tumor, meaning that it arises in the glial (supportive) tissue of the lowest, stem-like part of the brain, which controls many of the body’s most vital functions.
  • Diffuse pontine gliomas account for 10 to 15 percent of all childhood central nervous system tumors.
  • The median age at diagnosis is 5 to 9 years old but they can occur at any age in childhood.
  • These tumors occur with equal frequency in boys and girls and do not generally appear in adults.

As you read on, you’ll find detailed information about diffuse pontine gliomas.

How Dana-Farber/Boston Children's Cancer and Blood Disorders Center approaches diffuse pontine glioma

Children with diffuse pontine glioma are treated through the Glioma Program at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, an integrated pediatric hematology and oncology partnership between Dana-Farber Cancer Institute and Boston Children’s Hospital. Working together, we provide more specialists, more programs, and more clinical trials than almost any other pediatric center treating cancer and blood disorders in the world.

In-depth

We understand how overwhelming a diagnosis of diffuse pontine glioma can be. Right now, you probably have a lot of questions. How dangerous is diffuse pontine glioma? What is the very best treatment? What do we do next?

We’ve tried to provide some answers to those questions here, and our expert pediatric subspecialists can explain your child’s condition fully when you meet with us.

What causes diffuse pontine glioma?

As a parent, you undoubtedly want to know what may have caused your child’s tumor. However, the cause of diffuse pontine glioma is not currently understood.

There are no known factors or conditions that make your child more or less likely to develop this type of tumor. It might be reassuring to know that there’s nothing that you could have done or avoided doing that would have prevented the tumor from developing.

What are the symptoms of a diffuse pontine glioma?

Symptoms usually develop very rapidly prior to diagnosis, reflecting the fast growth of these tumors. Most patients have less than three months and many less than three weeks of symptoms prior to diagnosis. While each child may experience symptoms of a diffuse pontine glioma differently, some of the most common include:

  • rapidly developing problems controlling eye movements, facial expressions, speech, chewing and swallowing (due to problems in the cranial nerves)
  • weakness in the arms and legs
  • problems with walking and coordination

Keep in mind that the symptoms of a brain tumor may resemble other, more common conditions or medical problems. Always consult your child's physician for a diagnosis.

How are diffuse pontine gliomas classified?

The World Health Organization classification scheme includes 4 grades of glioma, according to how the cells look under a microscope.grade I (benign)

  • grade II (fibrillary)
  • grade III (anaplastic – refers to lack of structure in the cell)
  • grade IV (glioblastoma multiforme – the most serious kind of tumor)

Since diffuse pontine gliomas are not generally biopsied, it can be difficult to assign a grade to one of these tumors. When biopsied, they are usually grade III or grade IV; occasionally they are grade II.

That being said, diffuse pontine gliomas usually progress like grade IV glioblastoma multiforme tumors. These are the most aggressive kind of astrocytic tumor, and they usually have the following characteristics:

  • an increased number of cells
  • abnormal cells and nuclei
  • the cells reproduce rapidly
  • the cells die quickly
  • increased growth of blood vessels

These tumors are aggressive, and will invade normal brain tissue.

Frequently Asked Questions

Q: What is the expected outcome after treatment?

A: Unfortunately, the prognosis for diffuse pontine glioma tumors remains poor. Experimental chemotherapy delivered concurrent to radiation therapy is actively being investigated in the treatment of diffuse pontine gliomas.

Q: Where will my child be treated?

A: Children treated through Dana-Farber/Boston Children's Cancer and Blood Disorders Center receive outpatient care at the Jimmy Fund Clinic on the third floor of Dana Farber Cancer Institute. If your child needs to be admitted to the hospital, she will stay at Boston Children's Hospital on the ninth floor of the Berthiaume building.

Q: What services are available to help my child and my family cope?

A: We offer many services to help you, your child and your family get through this difficult time.

Q: What kind of supportive or palliative care is available for my child?

A: When necessary, our Pediatric Advanced Care Team (PACT) is available to provide supportive treatments intended to optimize the quality of life and promote healing and comfort for children with life-threatening illness. In addition, PACT can provide psychosocial support and help arrange end-of-life care when necessary.

Questions to ask your child’s doctor

After your child is diagnosed with a brain tumor, you may feel overwhelmed with information. It can be easy to lose track of the questions that occur to you.  Lots of parents find it helpful to jot down questions as they arise – that way, when you talk to your child’s doctors, you can be sure that all of your concerns are addressed.  If your child is old enough, you may want to suggest that she write down what she wants to ask her health care provider, too. Some of the questions you may want to ask include:  

  • Has my child’s brain tumor spread?
  • How long will my child need to be in the hospital?
  • What are the possible short and long-term complications of treatment? How will they be addressed?
  • What is the likelihood of cure?
  • What services are available to help my child and my family cope?

Tests

The first step in treating your child is forming an accurate and complete diagnosis. Diffuse pontine glioma is most commonly diagnosed from radiologic studies such as a CT scan or more commonly MRI. The location of these tumors and their tendency to invade into normal tissue make biopsies complicated, although a biopsy may be performed if your child’s symptoms and other tests do not seem typical for the condition. Certain clinical trials require a biopsy as part of the therapy for diffuse pontine glioma.

Your child’s doctor will perform a complete medical and physical examination. In addition, your child’s physician may order some of the following tests: 

  • computerized tomography scan (also called a CT or CAT scan) - a diagnostic imaging procedure that uses a combination of x-rays and computer technology to produce cross-sectional images (often called slices), both horizontally and vertically, of the body. CT scans are more detailed than general x-rays.
     
  • magnetic resonance imaging (MRI) - a diagnostic procedure that uses a combination of large magnets, radiofrequencies, and a computer to produce detailed images of organs and structures within the body. MRI provides greater anatomical detail than CT scan and does a better job of distinguishing between tumors, tumor-related swelling and normal tissue.
     
  • magnetic resonance spectroscopy (MRS) - a test done along with an MRI. It can detect the presence of organic compounds within sample tissue that can identify the tissue as normal or tumor, and may also be able to tell if the tumor is a glial tumor or if it is of neuronal origin (originating in a neuron, instead of an astrocytic cell).

Surgical biopsies are not routinely performed in cases of diffuse pontine glioma because of the location of the tumor. Diffuse pontine gliomas occur in the brainstem, which controls the body’s vital functions.

After we complete all necessary tests, our experts meet to review and discuss what they have learned about your child's condition. Then we will meet with you and your family to discuss the results and outline the best treatment options.

Treatment and care

We know how difficult a diagnosis of a pediatric brain tumor can be, both for your child and for your whole family. That’s why our physicians are focused on family-centered care: From your first visit, you’ll work with a team of professionals who are committed to supporting all of your family’s physical and psychosocial needs. We’ll work with you to create a care plan that’s best for your child.

If your child has been diagnosed with a diffuse pontine glioma, you’ll naturally be eager to know how your child’s physician will treat the tumor. Your child’s physician will determine a specific course of treatment based on several factors, including:

  • your child's age, overall health and medical history
  • type, location, and size of the tumor
  • extent of the disease
  • your child's tolerance for specific medications, procedures or therapies
  • how your child's doctors expects the disease to progress

There are a number of treatments we may recommend. Some of them help to treat the tumor while others are intended to address complications of the disease or side effects of the treatment.

Learn more about our pediatric Glioma Program.

What are the treatments for a diffuse pontine glioma?

If your child has been diagnosed with a diffuse pontine glioma, treatment may include:

  • Radiation therapy – This is the primary therapy for newly diagnosed diffuse pontine glioma. It uses high-energy rays (radiation) from a specialized machine to damage or kill cancer cells and shrink tumors.Conventional limited-field radiation produces responses in over 90 percent of children with diffuse pontine gliomas. These responses are short-lived however, with a median duration of about 6 months. Several trials to increase the dose of radiation therapy have been performed and none has improved survival.
  • Experimental chemotherapy – Chemotherapy and biologic therapy in combination with radiation therapy is actively being investigated as a treatment of this condition. Several trials evaluating new agents are either underway or have been recently completed.

In addition, there are trials evaluating whether new ways of delivering the traditional drugs might improve responses. We should know more about the results of these tests soon. Unfortunately, no currently available chemotherapy regimen has been shown to increase survival rates in this condition.

Unfortunately, complete surgical resection is not an option in the treatment of these tumors because of where the tumor is located. Diffuse pontine gliomas occur in the brainstem, which controls the body’s most vital functions. Surgery in this part of the brain can cause severe neurological damage.

How are side effects managed?

Side effects in the treatment of diffuse pontine glioma can arise from radiation and chemotherapy. 

  • Procedures should be performed in specialized centers where experienced specialists work in the most technologically advanced settings.
  • Radiation therapy often produces inflammation, which can temporarily exacerbate symptoms and dysfunction. To control this inflammation, steroids are sometimes necessary.
  • Some of the chemotherapy agents are associated with fatigue, diarrhea, constipation and headache. These side effects can be effectively managed under most circumstances.

Many specialized brain tumor treatment centers have now specialists who deliver complementary or alternative medicines. These treatments, which may help control pain and side effects of therapy include the following.

  • acupuncture/acupressure
  • therapeutic touch
  • massage
  • herbs
  • dietary recommendations

Talk to your child’s physician about whether complementary or alternative medicine might be a viable option.

In the event that end-of-life care is necessary, our Pediatric Advanced Care Team is available to ease symptoms and help your child maintain quality-of-life as much as possible.

What is the expected outcome after treatment for diffuse pontine glioma?

Unfortunately, the prognosis for diffuse pontine gliomas remains very poor although a small percentage of patients can survive this disease. Your child’s physician will discuss treatment options with you, including experimental clinical trials, and supportive care.

What about progressive or recurrent disease?

Clinical trials and experimental therapies are available for patients with relapsed diffuse pontine glioma. Current trials include novel medications as well as new methods for the delivery of more traditional agents.

Resources and support

We understand that you may have a lot of questions if your child is diagnosed with a diffuse pontine glioma. Will it affect my child long-term? What do we do next? We’ve tried to provide some answers to those questions here, but there are also a number of resources and support services to help you and your family through this difficult time.

Research and innovation

Clinical and basic scientists at Dana-Farber/Boston Children's are conducting numerous research studies to help clinicians better understand and treat diffuse pontine gliomas.

What is the latest research on diffuse pontine gliomas and malignant gliomas?
Dana-Farber/Boston Children's is a member of the Pediatric Oncology Therapeutic Experimental Investigators Consortium (POETIC), a collaborative clinical research group offering experimental therapies to patients with relapsed or refractory disease. It is also the New England Phase I Center of the Children's Oncology Group (COG) and the Department of Defense (DOD) Neurofibromatosis Clinical Trial Consortium.

Through these groups, a number of novel therapies are available for children with both newly diagnosed and current brain tumors. Two new protocols include a phase II trial of radiation therapy, cetuximab and irinotecan for children with newly diagnosed malignant glioma and diffuse intrinsic pontine glioma.

A second trial for newly diagnosed malignant gliomas is a Phase I gene therapy immunotherapy trial combined with radiation therapy and temozolomide. This combination is toxic to malignant glioma cells and thus stops their growth. More importantly, it can induce an immune response to malignant cells located outside of the tumor's primary site, thus targeting the infiltrative boundary of the tumor that typically results in recurrence.

We are also leading an international phase II clinical trial on the genetics of diffuse pontine glioma. Using advanced surgical techniques, a surgical biopsy of the tumor is performed on participating patients. Samples are then analyzed at the Broad Institute of Harvard and MIT in order to understand the unique molecular characteristics of each tumor. This research will allow us to tailor treatment to each individual patient and hopefully improve outcomes for children with diffuse pontine glioma.

Clinical trials 

For many children with rare or hard-to-treat conditions, clinical trials provide new options.


General Information About Childhood Brain Stem Glioma

Primary brain tumors 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.[1][2] 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. 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.[3] Most children with DIPG are diagnosed between the ages of 5 and 10 years. Focal pilocytic astrocytomas in the brain stem occur less frequently.[4]

Anatomy

Drawing of the inside of the brain showing  the lateral ventricle, third ventricle, and fourth ventricle, cerebrum, choroid plexus, hypothalamus, pineal gland, pituitary gland, optic nerve, tentorium, cerebellum,  brain stem, pons, medulla, and spinal cord.
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:[4]

  • 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).[5] Histologic confirmation of presumed DIPGs is usually unnecessary. However, histologic confirmation is currently performed for research studies and may be more routinely recommended in the future.[6] 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.[7][8]

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.[9] In contrast, focal pilocytic astrocytomas have a markedly improved prognosis, with 5-year overall survival exceeding 90%.[4]

Prognostic factors include the following:

  • Histology/grade of the tumor: Astrocytic tumors predominate in the brain stem. Pilocytic astrocytomas (WHO grade 1) 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 or at postmortem evaluation, are often anaplastic astrocytoma (WHO grade 3) or glioblastoma (WHO grade 4).[10][11][12][13] Low-grade fibrillary astrocytomas (WHO grade 2) can occur as focal tumors throughout the brain stem, with a good prognosis. Conversely, some children with imaging features supportive of a diagnosis of DIPG in whom tissue is eventually obtained may also show low-grade fibrillary histology.[14]
  • Age at diagnosis: Children younger than 3 years may have a more favorable prognosis, perhaps reflecting different biologic characteristics.[15]
  • NF1: Children with NF1 and brain stem gliomas may have a better prognosis than other patients who have intrinsic lesions.[16][17]

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.

References:

  1. Louis DN, Ohgaki H, Wiestler OD, et al., eds.: WHO Classification of Tumours of the Central Nervous System. 4th ed. Lyon, France: IARC Press, 2007.

  2. Louis DN, Ohgaki H, Wiestler OD, et al.: The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114 (2): 97-109, 2007.

  3. Warren KE: Diffuse intrinsic pontine glioma: poised for progress. Front Oncol 2: 205, 2012.

  4. Klimo P Jr, Pai Panandiker AS, Thompson CJ, et al.: Management and outcome of focal low-grade brainstem tumors in pediatric patients: the St. Jude experience. J Neurosurg Pediatr 11 (3): 274-81, 2013.

  5. Liu AK, Brandon J, Foreman NK, et al.: Conventional MRI at presentation does not predict clinical response to radiation therapy in children with diffuse pontine glioma. Pediatr Radiol 39 (12): 1317-20, 2009.

  6. 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 15 (4): 462-8, 2013.

  7. Cage TA, Samagh SP, Mueller S, et al.: Feasibility, safety, and indications for surgical biopsy of intrinsic brainstem tumors in children. Childs Nerv Syst 29 (8): 1313-9, 2013.

  8. Grill J, Puget S, Andreiuolo F, et al.: Critical oncogenic mutations in newly diagnosed pediatric diffuse intrinsic pontine glioma. Pediatr Blood Cancer 58 (4): 489-91, 2012.

  9. Cohen KJ, Pollack IF, Zhou T, et al.: Temozolomide in the treatment of high-grade gliomas in children: a report from the Children's Oncology Group. Neuro Oncol 13 (3): 317-23, 2011.

  10. Ballester LY, Wang Z, Shandilya S, et al.: Morphologic characteristics and immunohistochemical profile of diffuse intrinsic pontine gliomas. Am J Surg Pathol 37 (9): 1357-64, 2013.

  11. 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 46 (5): 444-50, 2014.

  12. Taylor KR, Mackay A, Truffaux N, et al.: Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma. Nat Genet 46 (5): 457-61, 2014.

  13. 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 46 (5): 451-6, 2014.

  14. Warren KE, Killian K, Suuriniemi M, et al.: Genomic aberrations in pediatric diffuse intrinsic pontine gliomas. Neuro Oncol 14 (3): 326-32, 2012.

  15. Broniscer A, Laningham FH, Sanders RP, et al.: Young age may predict a better outcome for children with diffuse pontine glioma. Cancer 113 (3): 566-72, 2008.

  16. Pascual-Castroviejo I, Pascual-Pascual SI, Viaño J, et al.: Posterior fossa tumors in children with neurofibromatosis type 1 (NF1). Childs Nerv Syst 26 (11): 1599-603, 2010.

  17. Albers AC, Gutmann DH: Gliomas in patients with neurofibromatosis type 1. Expert Rev Neurother 9 (4): 535-9, 2009.

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. 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 (H3F3A) or H3.3 (HIST1H3B) genes.[1][2][3][4][5] These same mutations are observed in pediatric high-grade gliomas at other midline locations but are uncommon in cortical pediatric high-grade gliomas and in adult high-grade gliomas.[1][2][3][4][5][6]
  • Activin A receptor, type I (ACVR1) gene: Approximately 20% of DIPG cases have activating mutations in the ACVR1 gene, with most occurring concurrently with H3.3 mutations.[2][3][4][5] Germline mutations in ACVR1 cause the autosomal dominant syndrome fibrodysplasia ossificans progressiva (FOP), although there is no cancer predisposition in FOP.[7]
  • Receptor tyrosine kinase amplification:PDGFRA amplification occurs in approximately 30% of cases, with lower rates of amplification observed for some other receptor tyrosine kinases (e.g., MET and IGF1R).[8][9]
  • TP53 deletion: DIPG tumors commonly show deletion of the TP53 gene on chromosome 17p.[9] Additionally, TP53 is commonly mutated in DIPG tumors, particularly those with histone H3 gene mutations.[2][3][4][5][10] Aneuploidy is commonly observed in cases with TP53 mutations.[5]

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.[9]

References:

  1. Wu G, Broniscer A, McEachron TA, et al.: Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat Genet 44 (3): 251-3, 2012.

  2. 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 46 (5): 444-50, 2014.

  3. Fontebasso AM, Papillon-Cavanagh S, Schwartzentruber J, et al.: Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma. Nat Genet 46 (5): 462-6, 2014.

  4. Taylor KR, Mackay A, Truffaux N, et al.: Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma. Nat Genet 46 (5): 457-61, 2014.

  5. 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 46 (5): 451-6, 2014.

  6. Schwartzentruber J, Korshunov A, Liu XY, et al.: Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 482 (7384): 226-31, 2012.

  7. Shore EM, Xu M, Feldman GJ, et al.: A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat Genet 38 (5): 525-7, 2006.

  8. 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 28 (8): 1337-44, 2010.

  9. 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 29 (30): 3999-4006, 2011.

  10. Khuong-Quang DA, Buczkowicz P, Rakopoulos P, et al.: K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas. Acta Neuropathol 124 (3): 439-47, 2012.

Stage Information for Childhood Brain Stem Glioma

There is no generally applied staging system for childhood brain stem glioma.[1]

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.[2][3]

It is uncommon for these tumors to have spread outside the brain stem itself at the time of initial diagnosis. 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.[4]

References:

  1. Freeman CR, Farmer JP: Pediatric brain stem gliomas: a review. Int J Radiat Oncol Biol Phys 40 (2): 265-71, 1998.

  2. Laigle-Donadey F, Doz F, Delattre JY: Brainstem gliomas in children and adults. Curr Opin Oncol 20 (6): 662-7, 2008.

  3. Khatua S, Moore KR, Vats TS, et al.: Diffuse intrinsic pontine glioma-current status and future strategies. Childs Nerv Syst 27 (9): 1391-7, 2011.

  4. 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 102 (1): 121-7, 2011.

Treatment Option Overview for Childhood Brain Stem Glioma

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. Standard Treatment Options for Childhood Brain Stem Gliomas

Stage

Standard Treatment Options

Newly diagnosed childhood brain stem gliomas:

Diffuse intrinsic pontine gliomas

Radiation therapy

Focal or low-grade brain stem gliomas

Surgical resection (with or without radiation therapy and chemotherapy)

Observation (with or without cerebrospinal fluid diversion)

Radiation therapy, chemotherapy, and alternative approaches for inoperable focal or low-grade tumors

Recurrent/progressive childhood brain stem gliomas:

Diffuse intrinsic pontine gliomas

Palliative care

Focal or low-grade brain stem gliomas

Repeat surgical resection

Radiation therapy

Chemotherapy

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.[1][2][3][4][5][6]; [7][8][Level of evidence: 2A]; [9][Level of evidence: 3iiiA]

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.[10][11][12]; [13][Level of evidence: 2A] This includes studies utilizing high-dose, marrow-ablative chemotherapy with autologous hematopoietic stem cell rescue, which have also been ineffective in extending survival.[14]

Standard treatment options for newly diagnosed DIPGs include the following:

  1. Radiation therapy.

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.[15]

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.[16]

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

  1. Hyperfractionated (twice daily) radiation therapy techniques have been used to deliver a higher dose, and studies using doses as high as 78 Gy have been completed. Evidence demonstrates that these increased radiation therapy doses do not improve the duration or rate of survival for patients with DIPGs, whether given alone [1][17] or in combination with chemotherapy.[3]
  2. Hypofractionated radiation therapy results in survival rates comparable to conventional fractionated radiation therapy techniques, possibly with less treatment burden.[15][18][Level of evidence: 2A]
  3. Studies evaluating the efficacy of various radiosensitizers as a means for enhancing the therapeutic effect of radiation therapy have been undertaken but to date have failed to show any significant improvement in outcome.[1][3][4][5][19][20]

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 Children’s Oncology Group phase I institutions, the Pediatric Brain Tumor Consortium, or other entities.

Standard Treatment Options for Focal or Low-Grade Brain Stem Gliomas

Standard treatment options for newly diagnosed focal or low-grade brain stem gliomas include the following:

  1. Surgical resection (with or without radiation therapy and chemotherapy).
  2. Observation (with or without cerebrospinal fluid diversion).
  3. Radiation therapy, chemotherapy, and alternative approaches for inoperable focal or low-grade tumors.

Surgical resection (with or without radiation therapy and chemotherapy)

In general, maximal surgical resection is attempted.[21][22]

Patients with residual tumor may be candidates for additional therapy, including 3-dimensional conformal radiation therapy approaches, with or without adjuvant chemotherapy.

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.[21]

A period of observation may be indicated before instituting any treatment for patients with neurofibromatosis type 1.[23] Brain stem gliomas in these children may be indolent and may require no specific treatment for years.[24]

Radiation therapy, chemotherapy, and alternative approaches for inoperable focal or low-grade 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 or low-grade brain stem glioma.[25][26][Level of evidence: 3iDi] 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 for the treatment of inoperable brain stem gliomas include the following:

  • Stereotactic iodine I-125 brachytherapy approaches, with or without adjuvant chemotherapy.[27]
  • The use of BRAF inhibitors for tumors harboring a V600E mutation.[28]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with untreated childhood brain stem glioma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

  1. 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 43 (5): 959-64, 1999.

  2. 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 20 (16): 3431-7, 2002.

  3. Allen J, Siffert J, Donahue B, et al.: A phase I/II study of carboplatin combined with hyperfractionated radiotherapy for brainstem gliomas. Cancer 86 (6): 1064-9, 1999.

  4. Broniscer A, Leite CC, Lanchote VL, et al.: Radiation therapy and high-dose tamoxifen in the treatment of patients with diffuse brainstem gliomas: results of a Brazilian cooperative study. Brainstem Glioma Cooperative Group. J Clin Oncol 18 (6): 1246-53, 2000.

  5. Doz F, Neuenschwander S, Bouffet E, et al.: Carboplatin before and during radiation therapy for the treatment of malignant brain stem tumours: a study by the Société Française d'Oncologie Pédiatrique. Eur J Cancer 38 (6): 815-9, 2002.

  6. Wolff JE, Westphal S, Mölenkamp G, et al.: Treatment of paediatric pontine glioma with oral trophosphamide and etoposide. Br J Cancer 87 (9): 945-9, 2002.

  7. 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 50 (2): 227-30, 2008.

  8. 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 13 (4): 410-6, 2011.

  9. Jalali R, Raut N, Arora B, et al.: Prospective evaluation of radiotherapy with concurrent and adjuvant temozolomide in children with newly diagnosed diffuse intrinsic pontine glioma. Int J Radiat Oncol Biol Phys 77 (1): 113-8, 2010.

  10. Frappaz D, Schell M, Thiesse P, et al.: Preradiation chemotherapy may improve survival in pediatric diffuse intrinsic brainstem gliomas: final results of BSG 98 prospective trial. Neuro Oncol 10 (4): 599-607, 2008.

  11. Frazier JL, Lee J, Thomale UW, et al.: Treatment of diffuse intrinsic brainstem gliomas: failed approaches and future strategies. J Neurosurg Pediatr 3 (4): 259-69, 2009.

  12. Hargrave D, Bartels U, Bouffet E: Diffuse brainstem glioma in children: critical review of clinical trials. Lancet Oncol 7 (3): 241-8, 2006.

  13. Warren K, Bent R, Wolters PL, et al.: A phase 2 study of pegylated interferon α-2b (PEG-Intron(®)) in children with diffuse intrinsic pontine glioma. Cancer 118 (14): 3607-13, 2012.

  14. Bouffet E, Raquin M, Doz F, et al.: Radiotherapy followed by high dose busulfan and thiotepa: a prospective assessment of high dose chemotherapy in children with diffuse pontine gliomas. Cancer 88 (3): 685-92, 2000.

  15. 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 85 (2): 315-20, 2013.

  16. Liu AK, Macy ME, Foreman NK: Bevacizumab as therapy for radiation necrosis in four children with pontine gliomas. Int J Radiat Oncol Biol Phys 75 (4): 1148-54, 2009.

  17. Freeman CR, Krischer JP, Sanford RA, et al.: Final results of a study of escalating doses of hyperfractionated radiotherapy in brain stem tumors in children: a Pediatric Oncology Group study. Int J Radiat Oncol Biol Phys 27 (2): 197-206, 1993.

  18. 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 104 (3): 773-7, 2011.

  19. 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 47 (3): 561-4, 2000.

  20. Bradley KA, Zhou T, McNall-Knapp RY, et al.: 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 (1): e55-60, 2013.

  21. Vandertop WP, Hoffman HJ, Drake JM, et al.: Focal midbrain tumors in children. Neurosurgery 31 (2): 186-94, 1992.

  22. Kestle J, Townsend JJ, Brockmeyer DL, et al.: Juvenile pilocytic astrocytoma of the brainstem in children. J Neurosurg 101 (1 Suppl): 1-6, 2004.

  23. Bilaniuk LT, Molloy PT, Zimmerman RA, et al.: Neurofibromatosis type 1: brain stem tumours. Neuroradiology 39 (9): 642-53, 1997.

  24. Molloy PT, Bilaniuk LT, Vaughan SN, et al.: Brainstem tumors in patients with neurofibromatosis type 1: a distinct clinical entity. Neurology 45 (10): 1897-902, 1995.

  25. Klimo P Jr, Pai Panandiker AS, Thompson CJ, et al.: Management and outcome of focal low-grade brainstem tumors in pediatric patients: the St. Jude experience. J Neurosurg Pediatr 11 (3): 274-81, 2013.

  26. Ronghe M, Hargrave D, Bartels U, et al.: Vincristine and carboplatin chemotherapy for unresectable and/or recurrent low-grade astrocytoma of the brainstem. Pediatr Blood Cancer 55 (3): 471-7, 2010.

  27. Ruge MI, Kickingereder P, Simon T, et al.: Stereotactic iodine-125 brachytherapy for treatment of inoperable focal brainstem gliomas of WHO grades I and II: feasibility and long-term outcome. J Neurooncol 109 (2): 273-83, 2012.

  28. Rush S, Foreman N, Liu A: Brainstem ganglioglioma successfully treated with vemurafenib. J Clin Oncol 31 (10): e159-60, 2013.

Recurrent/Progressive Childhood Brain Stem Glioma Treatment

Treatment Options for Recurrent Diffuse Intrinsic Pontine Gliomas (DIPGs)

Given the dismal prognosis for patients with DIPGs, progression of the pontine lesion 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 should be considered for entry into trials of novel therapeutic approaches because there are no standard agents that have demonstrated a clinically significant activity.

Palliative Care

Palliative care is provided for these patients whether or not disease-directed therapy is administered.

Treatment options under clinical evaluation

Early-phase therapeutic trials may be available for selected patients. These trials may be available via Children’s Oncology Group phase I institutions, the Pediatric Brain Tumor Consortium, or other entities.

Treatment Options for Recurrent Focal or Low-Grade Brain Stem Gliomas

At the time of recurrence, a complete evaluation to determine the extent of the relapse may be indicated for selected low-grade 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 or low-grade brain stem gliomas include the following:

  1. Repeat surgical resection: 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.[1]
  2. Radiation therapy including 3-dimensional conformal radiation therapy.
  3. Chemotherapy: Chemotherapy with agents such as a carboplatin and vincristine may be effective in children with recurrent low-grade exophytic gliomas.[2][3]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent childhood brain stem glioma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

  1. Bowers DC, Krause TP, Aronson LJ, et al.: Second surgery for recurrent pilocytic astrocytoma in children. Pediatr Neurosurg 34 (5): 229-34, 2001.

  2. Packer RJ, Lange B, Ater J, et al.: Carboplatin and vincristine for recurrent and newly diagnosed low-grade gliomas of childhood. J Clin Oncol 11 (5): 850-6, 1993.

  3. Ater JL, Zhou T, Holmes E, et al.: Randomized study of two chemotherapy regimens for treatment of low-grade glioma in young children: a report from the Children's Oncology Group. J Clin Oncol 30 (21): 2641-7, 2012.


This information is provided by the National Cancer Institute.

This information was last updated on May 19, 2014.

  • Email
  • Print
  • Share
  • Text
Highlight Glossary Terms
  • Make an Appointment

    • For adults:
      877-442-3324 (877-442-DFCI)
    • For children:
      888-733-4662 (888-PEDI-ONC)
    • Or complete the online form.
  • DIPG Clinical Trial

  • Find a Clinical Trial

  • Ranked #1

    • U.S. News and World Report Best Children's Hospital Cancer logo Dana-Farber/
      Boston Children's is ranked the #1 pediatric cancer hospital by the U.S. News & World Report 2014-15 Best Children's Hospitals guide.