DIPG is caused by certain changes to the way glial cells function, especially how they grow and divide into new cells. Often, the exact cause of the cell changes that lead to DIPG is unknown. To learn more about how cancer develops, see What Is Cancer?

A risk factor is anything that increases the chance of getting a disease. There are no known risk factors for DIPG.

The symptoms of DIPG depend on:

DIPG symptoms appear rapidly. It’s important to check with your child’s doctor immediately if your child has:

These symptoms may be caused by problems other than DIPG. The only way to know for sure is to see your child’s doctor.

If your child has symptoms that suggest a DIPG, their doctor will need to find out if these are due to DIPG or some other problem. The doctor will ask when the symptoms started and how often your child has been having them. They will also ask about your child’s personal and family medical history and do a physical exam, including a neurological exam. Depending on these results, they may recommend other tests. If your child is diagnosed with DIPG, the results of these tests will help you and your child’s doctor plan treatment.

The tests and procedures used to diagnose a DIPG may include:

Magnetic resonance imaging (MRI) with or without gadolinium

MRI uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the brain. A substance called gadolinium is injected into a vein. The gadolinium collects around the cancer cells so they show up brighter in the picture. This procedure is also called nuclear magnetic resonance imaging (NMRI).

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Biopsy

Your child’s doctor will discuss whether a biopsy is an option. A biopsy is a procedure in which a surgeon removes a sample of tumor tissue from the pons. A stereotactic biopsy, which involves using an imaging technique to help precisely find and remove the tumor tissue, is usually done. A pathologist will study the biopsy sample and provide the results of their analysis in a pathology report. If the pathologist finds that your child has DIPG, the pathology report will provide information about the cancer that can help guide treatment decisions.

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You may want to get a second opinion to confirm your child’s diagnosis and treatment plan. If you seek a second opinion, you will need to get medical test results and reports from the first doctor to share with the second doctor. The second doctor will review the pathology report, slides, and scans. They may agree with the first doctor, suggest changes to the treatment plan, or provide more information about your child’s cancer.

To learn more about choosing a doctor and getting a second opinion, see Finding Cancer Care. You can contact NCI’s Cancer Information Service via chat, email, or phone (both in English and Spanish) for help finding a doctor or hospital that can provide a second opinion. For questions you might want to ask at your child’s appointments, see Questions to Ask Your Doctor.

A pediatric oncologist, a doctor who specializes in treating children with cancer, oversees treatment for DIPG. The pediatric oncologist works with other health professionals who are experts in treating children with brain tumors and also specialize in other areas of medicine. Other specialists may include:

There are different types of treatment for children and adolescents with DIPG. You and your child’s care team will work together to decide treatment. Many factors will be considered, such as your child’s overall health and whether the cancer is newly diagnosed or has come back.

Your child’s treatment plan will include information about the cancer, the goals of treatment, treatment options, and the possible side effects. It will be helpful to talk with your child’s cancer care team before treatment begins about what to expect. For help every step of the way, see our booklet, Children with Cancer: A Guide for Parents.

Types of treatment your child might have include:

Surgery to place a shunt

Sometimes children with a DIPG have increased fluid around the brain or spinal cord. They may need surgery to place a shunt (long, thin tube) in a ventricle (fluid-filled space) of the brain and thread it under the skin to another part of the body, usually the abdomen. The shunt carries extra fluid away from the brain so it may be absorbed elsewhere in the body. This decreases the fluid and pressure on the brain or spinal cord.

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If your child has been diagnosed with DIPG, you likely have questions about your child’s chances of survival. The likely outcome or course of a disease is called prognosis.

Doctors consider these and other factors when making a prognosis for DIPG:

DIPG is a challenging cancer to treat because of its location in the brain, how fast it progresses, and the way it spreads into healthy tissue. Unfortunately, most children with DIPG do not live longer than 2 years after diagnosis. Your child’s cancer care team is in the best position to talk with you about your child’s prognosis.

As your child goes through treatment, they will have follow-up tests or check-ups. Some of the tests that were done to diagnose the cancer may be repeated to see how well the treatment is working. Decisions about whether to continue, change, or stop treatment may be based on the results of these tests.

Some of the tests will continue to be done from time to time after treatment has ended. The results of these tests can show if your child’s condition has changed or if the cancer has come back. If the results of imaging tests done after treatment for DIPG show a mass in the brain, a biopsy may be done to find out if it is made up of dead tumor cells or if new cancer cells are growing.

When your child has cancer, every member of the family needs support. Taking care of yourself during this time is important. Talk with your child’s treatment team and people in your family and community for support with coping with the emotional and physical stress that comes with a cancer diagnosis. To learn more, see Support for Families When a Child Has Cancer and the booklet Children with Cancer: A Guide for Parents.

For more childhood cancer information and other general cancer resources, see:

There are different types of ependymomas depending on where the tumor is located. Three main types of ependymoma are seen in children:

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Childhood ependymoma is caused by certain changes to the way ependymal cells function, especially how they grow and divide into new cells. The exact cause of these cell changes is unknown. Learn more about how cancer develops at What Is Cancer?

A risk factor is anything that increases the chance of getting a disease. Children with an inherited condition called neurofibromatosis type 2 (NF2) may have an increased risk of developing ependymoma along the optic pathway. Not every child with this risk factor will develop ependymoma. And it will develop in some children who don’t have a known risk factor.

Symptoms of ependymoma depend on the child’s age and where the tumor has formed. It’s important to check with your child’s doctor if your child has any of the symptoms below.

Symptoms of posterior fossa ependymoma in children can include:

Symptoms of supratentorial ependymomas in children can include:

Symptoms of spinal cord ependymomas in children can include:

These symptoms may be caused by problems other than an ependymoma. The only way to know is to see your child’s doctor.

If your child has symptoms that suggest an ependymoma, their doctor will need to find out if these are due to ependymoma or some other problem. The doctor will ask when the symptoms started and how often your child has been having them. They will also ask about your child’s personal and family medical history and do a physical exam, including a neurologic exam. Depending on these results, they may recommend other tests. If your child is diagnosed with an ependymoma, the results of these tests will help you and your child’s doctor plan treatment.

The tests used to diagnose ependymoma in children may include:

Magnetic resonance imaging (MRI) with or without gadolinium

MRI uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the brain and spinal cord. A substance called gadolinium is injected into a vein and travels through the bloodstream. The gadolinium may collect around the cancer cells so they show up brighter in the picture. This procedure is also called nuclear magnetic resonance imaging (NMRI).

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Biopsy

If the diagnostic tests show there may be a brain tumor, a biopsy can be done by removing part of the skull or making a small hole in the skull and using a needle or surgical device to remove a sample of the brain tissue. Sometimes, when a needle is used, it is guided by a computer to remove the tissue sample. A pathologist views the tissue under a microscope to look for cancer cells and determine the grade of the tumor. If cancer cells are found, the doctor will remove as much tumor as safely possible during the same surgery.

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The following laboratory tests may be done on the tissue that was removed during the biopsy:

• Immunohistochemistry uses antibodies to check for certain antigens (markers) in a sample of a patient’s tissue. The antibodies are usually linked to an enzyme or a fluorescent dye. After the antibodies bind to a specific antigen in the tissue sample, the enzyme or dye is activated, and the antigen can then be seen under a microscope. This type of test is used to help diagnose cancer and to help tell one type of cancer from another type.
• Next-generation sequencing uses computers to piece together DNA or RNA fragments in order to sequence a person or other organism’s entire DNA, large segments of DNA or RNA, or the DNA in specific types of cells from a sample of tissue. Next-generation sequencing can also identify changes in certain areas of the genome or in specific genes. There are many different types of next-generation sequencing methods, including whole-genome sequencing, whole-exome sequencing, multigene panel testing, and transcriptome sequencing. Next-generation sequencing may help researchers understand the cause of certain diseases, such as cancer. Also called massively parallel sequencing and NGS.

The Molecular Characterization Initiative offers free molecular testing to children, adolescents, and young adults with certain types of newly diagnosed cancer. The program is offered through NCI’s Childhood Cancer Data Initiative. To learn more, visit About the Molecular Characterization Initiative.

Lumbar puncture

Lumbar puncture is a procedure used to collect cerebrospinal fluid (CSF) from the spinal column. This is done by placing a needle between two bones in the spine and into the lining around the spinal cord to remove a sample of CSF. The sample of CSF is checked under a microscope for signs of tumor cells. The sample may also be checked for the amounts of protein and glucose.

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You may want to get a second opinion to confirm your child’s diagnosis and treatment plan. If you seek a second opinion, you will need to get medical test results and reports from the first doctor to share with the second doctor. The second doctor will review the pathology report, slides, and scans. This doctor may agree with the first doctor, suggest changes to the treatment plan, or provide more information about your child’s cancer.

To learn more about choosing a doctor and getting a second opinion, see Finding Cancer Care. You can contact NCI’s Cancer Information Service via chat, email, or phone (both in English and Spanish) for help finding a doctor or hospital that can provide a second opinion. For questions you might want to ask at your child’s appointments, see Questions to Ask Your Doctor About Cancer.

Staging is the process of learning the extent of the cancer in the body and is often used to help plan treatment and make a prognosis. There is no staging system used for childhood ependymoma, but it is given a tumor grade. Tumor grading is based on the World Health Organization (WHO) criteria.

Tumor grade describes how abnormal the cancer cells look under a microscope, how quickly the tumor is likely to grow and spread, and how likely the tumor is to come back after treatment. The WHO criteria also classifies ependymomas by their location in the brain or spinal cord (see the section on Types of childhood ependymoma) and the tumor’s molecular or genetic features.

Low-grade (grade I) cancer cells look more like normal cells than high-grade (grades II and III) cancer cells. Grade I cancer cells also tend to grow and spread more slowly than grade II and III cancer cells.

Childhood ependymoma often comes back after treatment, sometimes as long as 15 years after the initial treatment. The tumor commonly comes back at the original cancer site, although it can also spread to areas near the original site. It is rare for ependymoma to spread to areas far from the original cancer site.

There are different types of treatment for children and adolescents with ependymoma. You and your child’s care team will work together to decide treatment. Many factors will be considered, such as where the cancer is located, your child’s age and overall health, and the type and grade of the ependymoma.

Your child’s treatment plan will include information about the cancer, the goals of treatment, treatment options, and the possible side effects. It will be helpful to talk with your child’s care team before treatment begins about what to expect. For help every step of the way, see our booklet, Children with Cancer: A Guide for Parents.

The types of treatment your child might have include:

Treatment of newly diagnosed childhood ependymoma in the brain or brain stem includes surgery.

After surgery, the plan for further treatment depends on:

When the tumor is completely removed and cancer cells have not spread, treatment may include radiation therapy.

When part of the tumor remains after surgery, but cancer cells have not spread, treatment may include:

When cancer cells have spread within the brain and spinal cord, treatment may include:

Treatment for children younger than 1 year of age may include:

Radiation therapy is not given to children until they are older than 1 year.

To learn more about these treatments, see Types of treatment for childhood ependymoma.

Treatment of newly diagnosed childhood myxopapillary spinal ependymoma (grade 2) is surgery. Sometimes radiation therapy is given after surgery.

Treatment of newly diagnosed childhood nonmyxopapillary spinal ependymoma is surgery. Sometimes radiation therapy is given after surgery for children with grade 2 or grade 3 tumors.

To learn more about these treatments, see Types of treatment for childhood ependymoma.

Treatment of recurrent childhood ependymoma may include:

To learn more about these treatments, see Types of treatment for childhood ependymoma.

If your child has been diagnosed with ependymoma, you likely have questions about how serious the cancer is and your child’s chances of survival. The likely outcome or course of a disease is called prognosis. Your child’s prognosis depends on many factors, including:

Prognosis also depends on whether radiation therapy was given, the type and treatment dose, and whether chemotherapy alone was given.

No two people are alike, and responses to treatment can vary greatly. Your child’s cancer care team is in the best position to talk with you about your child’s prognosis.

Cancer treatments can cause side effects. Which side effects your child might have depends on the type of treatment they receive, the dose, and how their body reacts. Talk with your child’s treatment team about which side effects to look for and ways to manage them.

To learn more about side effects that begin during treatment for cancer, visit Side Effects.

Problems from cancer treatment that begin 6 months or later after treatment and continue for months or years are called late effects. Late effects of treatment for childhood ependymoma may include:

Some late effects may be treated or controlled. It is important to talk with your child’s doctors about the effects cancer treatment can have on your child. Learn more about Late Effects of Treatment for Childhood Cancer.

As your child goes through treatment, they will have follow-up tests or check-ups. Some of the tests that were done to diagnose the cancer may be repeated to see how well the treatment is working. Decisions about whether to continue, change, or stop treatment may be based on the results of these tests.

Childhood ependymoma may come back as long as 15 years or more after initial treatment. So once your child finishes treatment, they will continue to have certain tests from time to time. The results of these tests can show if your child’s condition has changed or if the cancer has come back.

Your child may receive an MRI of the brain and spinal cord at the following intervals:

When a child has cancer, every member of the family needs support. Taking care of yourself during this difficult time is important. Reach out to your child’s treatment team and to people in your family and community for support. To learn more, see Support for Families: Childhood Cancer and the booklet Children with Cancer: A Guide for Parents.

For more childhood cancer information and other general cancer resources, see:

For information about the treatments listed below, see the Treatment Option Overview section.

Treatment of newly diagnosed childhood craniopharyngioma may include the following:

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

For information about the treatments listed below, see the Treatment Option Overview section.

Treatment options for recurrent childhood craniopharyngioma depend on the type of treatment that was given when the tumor was first diagnosed and the needs of the child.

Treatment may include the following:

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

For more information about childhood craniopharyngioma and other childhood brain tumors, see the following:

For more childhood cancer information and other general cancer resources, visit:

Primary brain tumors, including craniopharyngiomas, are a diverse group of diseases that together constitute the most common solid tumors of childhood. Brain tumors are classified according to an integrated assessment of histology and molecular characteristics, with tumor location and extent of spread as important factors that affect treatment and prognosis.

Craniopharyngiomas are uncommon pediatric brain tumors. They are believed to be congenital in origin, arising from ectodermal remnants, Rathke cleft, or other embryonal epithelium. They often occur in the suprasellar region with an intrasellar portion. Magnetic resonance imaging (MRI) and computed tomography (CT) imaging are used to diagnose craniopharyngiomas, but histological confirmation is generally required before treatment.

The treatment of patients with newly diagnosed craniopharyngiomas may include surgery, radiation therapy, cyst drainage, and intracystic therapies. The treatment of patients with recurrent craniopharyngiomas depends on the initial treatment used. With current treatment strategies, the 5-year and 10-year survival rates reach 80% to 90% for children between the ages of 0 and 14 years.[1]

The PDQ childhood brain tumor treatment summaries are organized primarily according to the World Health Organization Classification of Central Nervous System (CNS) Tumours.[2,3] For a full description of the classification of CNS tumors and a link to the corresponding treatment summary for each type of brain tumor, see Childhood Brain and Spinal Cord Tumors Summary Index.

Anatomy

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Clinical Presentation

Craniopharyngiomas occur in the suprasellar region, near the pituitary gland, optic nerves, and optic chiasm (see Figure 2). This proximity commonly leads to injury of these surrounding structures, both by the tumor and interventions used to treat the tumor. Endocrine function is most frequently affected,[6–11] with patients suffering from neuroendocrine deficits such as growth hormone, thyroid, and cortisol deficiencies. Additionally, tumor proximity to the optic nerves and chiasm may result in visual compromise.[12][Level of evidence C1]; [7,13–15] Some patients present with obstructive hydrocephalus caused by tumor growth within the third ventricle. Rarely, tumors may extend into the posterior fossa, and patients may present with headache, diplopia, ataxia, and hearing loss.[16]

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References

1. Ostrom QT, Cioffi G, Waite K, et al.: CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2014-2018. Neuro Oncol 23 (12 Suppl 2): iii1-iii105, 2021. [PUBMED Abstract]
2. Louis DN, Perry A, Wesseling P, et al.: The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol 23 (8): 1231-1251, 2021. [PUBMED Abstract]
3. WHO Classification of Tumours Editorial Board, ed.: WHO Classification of Tumours: Central Nervous System Tumours. Vol. 6. 5th ed. IARC Press; 2021.
4. Karavitaki N, Wass JA: Craniopharyngiomas. Endocrinol Metab Clin North Am 37 (1): 173-93, ix-x, 2008. [PUBMED Abstract]
5. Garnett MR, Puget S, Grill J, et al.: Craniopharyngioma. Orphanet J Rare Dis 2: 18, 2007. [PUBMED Abstract]
6. van Schaik J, Hoving EW, Müller HL, et al.: Hypothalamic-Pituitary Outcome after Treatment for Childhood Craniopharyngioma. Front Horm Res 54: 47-57, 2021. [PUBMED Abstract]
7. Jimenez RB, Ahmed S, Johnson A, et al.: Proton Radiation Therapy for Pediatric Craniopharyngioma. Int J Radiat Oncol Biol Phys 110 (5): 1480-1487, 2021. [PUBMED Abstract]
8. Bogusz A, Müller HL: Childhood-onset craniopharyngioma: latest insights into pathology, diagnostics, treatment, and follow-up. Expert Rev Neurother 18 (10): 793-806, 2018. [PUBMED Abstract]
9. Tan TS, Patel L, Gopal-Kothandapani JS, et al.: The neuroendocrine sequelae of paediatric craniopharyngioma: a 40-year meta-data analysis of 185 cases from three UK centres. Eur J Endocrinol 176 (3): 359-369, 2017. [PUBMED Abstract]
10. Cohen M, Bartels U, Branson H, et al.: Trends in treatment and outcomes of pediatric craniopharyngioma, 1975-2011. Neuro Oncol 15 (6): 767-74, 2013. [PUBMED Abstract]
11. Fouda MA, Scott RM, Marcus KJ, et al.: Sixty years single institutional experience with pediatric craniopharyngioma: between the past and the future. Childs Nerv Syst 36 (2): 291-296, 2020. [PUBMED Abstract]
12. Nuijts MA, Veldhuis N, Stegeman I, et al.: Visual functions in children with craniopharyngioma at diagnosis: A systematic review. PLoS One 15 (10): e0240016, 2020. [PUBMED Abstract]
13. Wan MJ, Zapotocky M, Bouffet E, et al.: Long-term visual outcomes of craniopharyngioma in children. J Neurooncol 137 (3): 645-651, 2018. [PUBMED Abstract]
14. Ravindra VM, Okcu MF, Ruggieri L, et al.: Comparison of multimodal surgical and radiation treatment methods for pediatric craniopharyngioma: long-term analysis of progression-free survival and morbidity. J Neurosurg Pediatr 28 (2): 152-159, 2021. [PUBMED Abstract]
15. Felicetti F, Brignardello E, van Santen HM, eds.: Endocrine and Metabolic Late Effects in Cancer Survivors. Basel, Switzerland: Karger, 2021.
16. Zhou L, Luo L, Xu J, et al.: Craniopharyngiomas in the posterior fossa: a rare subgroup, diagnosis, management and outcomes. J Neurol Neurosurg Psychiatry 80 (10): 1150-4, 2009. [PUBMED Abstract]
17. Rossi A, Cama A, Consales A, et al.: Neuroimaging of pediatric craniopharyngiomas: a pictorial essay. J Pediatr Endocrinol Metab 19 (Suppl 1): 299-319, 2006. [PUBMED Abstract]
18. Muller HL: Childhood craniopharyngioma. Recent advances in diagnosis, treatment and follow-up. Horm Res 69 (4): 193-202, 2008. [PUBMED Abstract]
19. Müller HL: Childhood craniopharyngioma–current concepts in diagnosis, therapy and follow-up. Nat Rev Endocrinol 6 (11): 609-18, 2010. [PUBMED Abstract]
20. Zacharia BE, Bruce SS, Goldstein H, et al.: Incidence, treatment and survival of patients with craniopharyngioma in the surveillance, epidemiology and end results program. Neuro Oncol 14 (8): 1070-8, 2012. [PUBMED Abstract]
21. Ostrom QT, Cioffi G, Gittleman H, et al.: CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2012-2016. Neuro Oncol 21 (Suppl 5): v1-v100, 2019. [PUBMED Abstract]
22. Beckhaus J, Friedrich C, Boekhoff S, et al.: Outcome after pediatric craniopharyngioma: the role of age at diagnosis and hypothalamic damage. Eur J Endocrinol 188 (3): , 2023. [PUBMED Abstract]
23. Merchant TE, Dangda S, Hoehn ME, et al.: Pediatric Craniopharyngioma: The Effect of Visual Deficits and Hormone Deficiencies on Long-Term Cognitive Outcomes After Conformal Photon Radiation Therapy. Int J Radiat Oncol Biol Phys 115 (3): 581-591, 2023. [PUBMED Abstract]

Craniopharyngiomas are histologically benign and often occur in the suprasellar region, with an intrasellar portion. They may be locally invasive and typically do not metastasize to remote brain locations.

Craniopharyngiomas are classified under the category of tumors of the sella region according to the defined entities below. The two entities were previously described as subtypes of craniopharyngioma. However, based on the different populations they tend to affect, combined with distinct clinical, histological, and molecular characteristics, these are now considered unique diagnoses.[1]

References

1. Louis DN, Perry A, Wesseling P, et al.: The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol 23 (8): 1231-1251, 2021. [PUBMED Abstract]
2. Karavitaki N, Wass JA: Craniopharyngiomas. Endocrinol Metab Clin North Am 37 (1): 173-93, ix-x, 2008. [PUBMED Abstract]
3. Pekmezci M, Louie J, Gupta N, et al.: Clinicopathological characteristics of adamantinomatous and papillary craniopharyngiomas: University of California, San Francisco experience 1985-2005. Neurosurgery 67 (5): 1341-9; discussion 1349, 2010. [PUBMED Abstract]
4. Sekine S, Shibata T, Kokubu A, et al.: Craniopharyngiomas of adamantinomatous type harbor beta-catenin gene mutations. Am J Pathol 161 (6): 1997-2001, 2002. [PUBMED Abstract]
5. Brastianos PK, Taylor-Weiner A, Manley PE, et al.: Exome sequencing identifies BRAF mutations in papillary craniopharyngiomas. Nat Genet 46 (2): 161-5, 2014. [PUBMED Abstract]
6. Goschzik T, Gessi M, Dreschmann V, et al.: Genomic Alterations of Adamantinomatous and Papillary Craniopharyngioma. J Neuropathol Exp Neurol 76 (2): 126-134, 2017. [PUBMED Abstract]

There is no generally applied staging system for childhood craniopharyngiomas. For treatment purposes, patients are grouped as having newly diagnosed or recurrent disease.

Treatments for pediatric craniopharyngiomas have traditionally included maximal safe surgical resection and radiation therapy to treat residual tumor. Additionally, intracystic therapies such as radioactive phosphorus P 32, bleomycin, and interferon-alpha have been used. Evidence has demonstrated that conservative surgical approaches lead to better neuroendocrine and quality-of-life outcomes in patients.[1,2] Additionally, as the biological understanding of molecular and inflammatory drivers of these tumors have been identified, targeted therapies are now being studied.

Table 1 describes the treatment options for newly diagnosed and recurrent childhood craniopharyngioma.

References

1. Lohkamp LN, Kasper EM, Pousa AE, et al.: An update on multimodal management of craniopharyngioma in children. Front Oncol 13: 1149428, 2023. [PUBMED Abstract]
2. Bogusz A, Müller HL: Childhood-onset craniopharyngioma: latest insights into pathology, diagnostics, treatment, and follow-up. Expert Rev Neurother 18 (10): 793-806, 2018. [PUBMED Abstract]

There is no consensus on the optimal treatment for patients with newly diagnosed craniopharyngioma, in part because of the lack of prospective randomized trials that compare the different treatment options. Treatment is individualized on the basis of the following factors:

Established treatment options for newly diagnosed childhood craniopharyngioma include the following:

References

1. Cohen M, Bartels U, Branson H, et al.: Trends in treatment and outcomes of pediatric craniopharyngioma, 1975-2011. Neuro Oncol 15 (6): 767-74, 2013. [PUBMED Abstract]
2. Mortini P, Losa M, Pozzobon G, et al.: Neurosurgical treatment of craniopharyngioma in adults and children: early and long-term results in a large case series. J Neurosurg 114 (5): 1350-9, 2011. [PUBMED Abstract]
3. Elliott RE, Hsieh K, Hochm T, et al.: Efficacy and safety of radical resection of primary and recurrent craniopharyngiomas in 86 children. J Neurosurg Pediatr 5 (1): 30-48, 2010. [PUBMED Abstract]
4. Zhang YQ, Ma ZY, Wu ZB, et al.: Radical resection of 202 pediatric craniopharyngiomas with special reference to the surgical approaches and hypothalamic protection. Pediatr Neurosurg 44 (6): 435-43, 2008. [PUBMED Abstract]
5. Yang I, Sughrue ME, Rutkowski MJ, et al.: Craniopharyngioma: a comparison of tumor control with various treatment strategies. Neurosurg Focus 28 (4): E5, 2010. [PUBMED Abstract]
6. Müller HL, Merchant TE, Puget S, et al.: New outlook on the diagnosis, treatment and follow-up of childhood-onset craniopharyngioma. Nat Rev Endocrinol 13 (5): 299-312, 2017. [PUBMED Abstract]
7. Apps JR, Muller HL, Hankinson TC, et al.: Contemporary Biological Insights and Clinical Management of Craniopharyngioma. Endocr Rev 44 (3): 518-538, 2023. [PUBMED Abstract]
8. Lohkamp LN, Kasper EM, Pousa AE, et al.: An update on multimodal management of craniopharyngioma in children. Front Oncol 13: 1149428, 2023. [PUBMED Abstract]
9. Bogusz A, Müller HL: Childhood-onset craniopharyngioma: latest insights into pathology, diagnostics, treatment, and follow-up. Expert Rev Neurother 18 (10): 793-806, 2018. [PUBMED Abstract]
10. Morisako H, Goto T, Goto H, et al.: Aggressive surgery based on an anatomical subclassification of craniopharyngiomas. Neurosurg Focus 41 (6): E10, 2016. [PUBMED Abstract]
11. Sands SA, Milner JS, Goldberg J, et al.: Quality of life and behavioral follow-up study of pediatric survivors of craniopharyngioma. J Neurosurg 103 (4 Suppl): 302-11, 2005. [PUBMED Abstract]
12. Bakhsheshian J, Jin DL, Chang KE, et al.: Risk factors associated with the surgical management of craniopharyngiomas in pediatric patients: analysis of 1961 patients from a national registry database. Neurosurg Focus 41 (6): E8, 2016. [PUBMED Abstract]
13. Locatelli D, Massimi L, Rigante M, et al.: Endoscopic endonasal transsphenoidal surgery for sellar tumors in children. Int J Pediatr Otorhinolaryngol 74 (11): 1298-302, 2010. [PUBMED Abstract]
14. Chivukula S, Koutourousiou M, Snyderman CH, et al.: Endoscopic endonasal skull base surgery in the pediatric population. J Neurosurg Pediatr 11 (3): 227-41, 2013. [PUBMED Abstract]
15. Mazzatenta D, Zoli M, Guaraldi F, et al.: Outcome of Endoscopic Endonasal Surgery in Pediatric Craniopharyngiomas. World Neurosurg 134: e277-e288, 2020. [PUBMED Abstract]
16. Lee JA, Cooper RL, Nguyen SA, et al.: Endonasal Endoscopic Surgery for Pediatric Sellar and Suprasellar Lesions: A Systematic Review and Meta-analysis. Otolaryngol Head Neck Surg 163 (2): 284-292, 2020. [PUBMED Abstract]
17. Müller HL, Gebhardt U, Teske C, et al.: Post-operative hypothalamic lesions and obesity in childhood craniopharyngioma: results of the multinational prospective trial KRANIOPHARYNGEOM 2000 after 3-year follow-up. Eur J Endocrinol 165 (1): 17-24, 2011. [PUBMED Abstract]
18. Clark AJ, Cage TA, Aranda D, et al.: Treatment-related morbidity and the management of pediatric craniopharyngioma: a systematic review. J Neurosurg Pediatr 10 (4): 293-301, 2012. [PUBMED Abstract]
19. Lin LL, El Naqa I, Leonard JR, et al.: Long-term outcome in children treated for craniopharyngioma with and without radiotherapy. J Neurosurg Pediatr 1 (2): 126-30, 2008. [PUBMED Abstract]
20. Elowe-Gruau E, Beltrand J, Brauner R, et al.: Childhood craniopharyngioma: hypothalamus-sparing surgery decreases the risk of obesity. J Clin Endocrinol Metab 98 (6): 2376-82, 2013. [PUBMED Abstract]
21. Müller HL: Childhood craniopharyngioma: current controversies on management in diagnostics, treatment and follow-up. Expert Rev Neurother 10 (4): 515-24, 2010. [PUBMED Abstract]
22. Winkfield KM, Tsai HK, Yao X, et al.: Long-term clinical outcomes following treatment of childhood craniopharyngioma. Pediatr Blood Cancer 56 (7): 1120-6, 2011. [PUBMED Abstract]
23. Jimenez RB, Ahmed S, Johnson A, et al.: Proton Radiation Therapy for Pediatric Craniopharyngioma. Int J Radiat Oncol Biol Phys 110 (5): 1480-1487, 2021. [PUBMED Abstract]
24. Eveslage M, Calaminus G, Warmuth-Metz M, et al.: The Postopera tive Quality of Life in Children and Adolescents with Craniopharyngioma. Dtsch Arztebl Int 116 (18): 321-328, 2019. [PUBMED Abstract]
25. Merchant TE, Hua CH, Shukla H, et al.: Proton versus photon radiotherapy for common pediatric brain tumors: comparison of models of dose characteristics and their relationship to cognitive function. Pediatr Blood Cancer 51 (1): 110-7, 2008. [PUBMED Abstract]
26. Merchant TE, Kun LE, Hua CH, et al.: Disease control after reduced volume conformal and intensity modulated radiation therapy for childhood craniopharyngioma. Int J Radiat Oncol Biol Phys 85 (4): e187-92, 2013. [PUBMED Abstract]
27. Schoenfeld A, Pekmezci M, Barnes MJ, et al.: The superiority of conservative resection and adjuvant radiation for craniopharyngiomas. J Neurooncol 108 (1): 133-9, 2012. [PUBMED Abstract]
28. Edmonston DY, Wu S, Li Y, et al.: Limited surgery and conformal photon radiation therapy for pediatric craniopharyngioma: long-term results from the RT1 protocol. Neuro Oncol 24 (12): 2200-2209, 2022. [PUBMED Abstract]
29. Clark AJ, Cage TA, Aranda D, et al.: A systematic review of the results of surgery and radiotherapy on tumor control for pediatric craniopharyngioma. Childs Nerv Syst 29 (2): 231-8, 2013. [PUBMED Abstract]
30. Beckhaus J, Friedrich C, Boekhoff S, et al.: Outcome after pediatric craniopharyngioma: the role of age at diagnosis and hypothalamic damage. Eur J Endocrinol 188 (3): , 2023. [PUBMED Abstract]
31. Kiehna EN, Merchant TE: Radiation therapy for pediatric craniopharyngioma. Neurosurg Focus 28 (4): E10, 2010. [PUBMED Abstract]
32. Harrabi SB, Adeberg S, Welzel T, et al.: Long term results after fractionated stereotactic radiotherapy (FSRT) in patients with craniopharyngioma: maximal tumor control with minimal side effects. Radiat Oncol 9: 203, 2014. [PUBMED Abstract]
33. Lo AC, Howard AF, Nichol A, et al.: Long-term outcomes and complications in patients with craniopharyngioma: the British Columbia Cancer Agency experience. Int J Radiat Oncol Biol Phys 88 (5): 1011-8, 2014. [PUBMED Abstract]
34. Bishop AJ, Greenfield B, Mahajan A, et al.: Proton beam therapy versus conformal photon radiation therapy for childhood craniopharyngioma: multi-institutional analysis of outcomes, cyst dynamics, and toxicity. Int J Radiat Oncol Biol Phys 90 (2): 354-61, 2014. [PUBMED Abstract]
35. Winkfield KM, Linsenmeier C, Yock TI, et al.: Surveillance of craniopharyngioma cyst growth in children treated with proton radiotherapy. Int J Radiat Oncol Biol Phys 73 (3): 716-21, 2009. [PUBMED Abstract]
36. Beltran C, Roca M, Merchant TE: On the benefits and risks of proton therapy in pediatric craniopharyngioma. Int J Radiat Oncol Biol Phys 82 (2): e281-7, 2012. [PUBMED Abstract]
37. Boehling NS, Grosshans DR, Bluett JB, et al.: Dosimetric comparison of three-dimensional conformal proton radiotherapy, intensity-modulated proton therapy, and intensity-modulated radiotherapy for treatment of pediatric craniopharyngiomas. Int J Radiat Oncol Biol Phys 82 (2): 643-52, 2012. [PUBMED Abstract]
38. Shi Z, Esiashvili N, Janss AJ, et al.: Transient enlargement of craniopharyngioma after radiation therapy: pattern of magnetic resonance imaging response following radiation. J Neurooncol 109 (2): 349-55, 2012. [PUBMED Abstract]
39. Ishida M, Hotta M, Tsukamura A, et al.: Malignant transformation in craniopharyngioma after radiation therapy: a case report and review of the literature. Clin Neuropathol 29 (1): 2-8, 2010 Jan-Feb. [PUBMED Abstract]
40. Aquilina K, Merchant TE, Rodriguez-Galindo C, et al.: Malignant transformation of irradiated craniopharyngioma in children: report of 2 cases. J Neurosurg Pediatr 5 (2): 155-61, 2010. [PUBMED Abstract]
41. Merchant TE, Hoehn ME, Khan RB, et al.: Proton therapy and limited surgery for paediatric and adolescent patients with craniopharyngioma (RT2CR): a single-arm, phase 2 study. Lancet Oncol 24 (5): 523-534, 2023. [PUBMED Abstract]
42. Merchant TE, Dangda S, Hoehn ME, et al.: Pediatric Craniopharyngioma: The Effect of Visual Deficits and Hormone Deficiencies on Long-Term Cognitive Outcomes After Conformal Photon Radiation Therapy. Int J Radiat Oncol Biol Phys 115 (3): 581-591, 2023. [PUBMED Abstract]
43. Bischoff M, Khalil DA, Frisch S, et al.: Outcome After Modern Proton Beam Therapy in Childhood Craniopharyngioma: Results of the Prospective Registry Study KiProReg. Int J Radiat Oncol Biol Phys 120 (1): 137-148, 2024. [PUBMED Abstract]
44. Cinalli G, Spennato P, Cianciulli E, et al.: The role of transventricular neuroendoscopy in the management of craniopharyngiomas: three patient reports and review of the literature. J Pediatr Endocrinol Metab 19 (Suppl 1): 341-54, 2006. [PUBMED Abstract]
45. Schubert T, Trippel M, Tacke U, et al.: Neurosurgical treatment strategies in childhood craniopharyngiomas: is less more? Childs Nerv Syst 25 (11): 1419-27, 2009. [PUBMED Abstract]
46. Julow J, Backlund EO, Lányi F, et al.: Long-term results and late complications after intracavitary yttrium-90 colloid irradiation of recurrent cystic craniopharyngiomas. Neurosurgery 61 (2): 288-95; discussion 295-6, 2007. [PUBMED Abstract]
47. Barriger RB, Chang A, Lo SS, et al.: Phosphorus-32 therapy for cystic craniopharyngiomas. Radiother Oncol 98 (2): 207-12, 2011. [PUBMED Abstract]
48. Maarouf M, El Majdoub F, Fuetsch M, et al.: Stereotactic intracavitary brachytherapy with P-32 for cystic craniopharyngiomas in children. Strahlenther Onkol 192 (3): 157-65, 2016. [PUBMED Abstract]
49. Kickingereder P, Maarouf M, El Majdoub F, et al.: Intracavitary brachytherapy using stereotactically applied phosphorus-32 colloid for treatment of cystic craniopharyngiomas in 53 patients. J Neurooncol 109 (2): 365-74, 2012. [PUBMED Abstract]
50. Ierardi DF, Fernandes MJ, Silva IR, et al.: Apoptosis in alpha interferon (IFN-alpha) intratumoral chemotherapy for cystic craniopharyngiomas. Childs Nerv Syst 23 (9): 1041-6, 2007. [PUBMED Abstract]
51. Cavalheiro S, Di Rocco C, Valenzuela S, et al.: Craniopharyngiomas: intratumoral chemotherapy with interferon-alpha: a multicenter preliminary study with 60 cases. Neurosurg Focus 28 (4): E12, 2010. [PUBMED Abstract]
52. Kilday JP, Caldarelli M, Massimi L, et al.: Intracystic interferon-alpha in pediatric craniopharyngioma patients: an international multicenter assessment on behalf of SIOPE and ISPN. Neuro Oncol 19 (10): 1398-1407, 2017. [PUBMED Abstract]
53. Linnert M, Gehl J: Bleomycin treatment of brain tumors: an evaluation. Anticancer Drugs 20 (3): 157-64, 2009. [PUBMED Abstract]
54. Hukin J, Steinbok P, Lafay-Cousin L, et al.: Intracystic bleomycin therapy for craniopharyngioma in children: the Canadian experience. Cancer 109 (10): 2124-31, 2007. [PUBMED Abstract]
55. Guimarães MM, Cardeal DD, Teixeira MJ, et al.: Brachytherapy in paediatric craniopharyngiomas: a systematic review and meta-analysis of recent literature. Childs Nerv Syst 38 (2): 253-262, 2022. [PUBMED Abstract]
56. Petralia F, Tignor N, Reva B, et al.: Integrated Proteogenomic Characterization across Major Histological Types of Pediatric Brain Cancer. Cell 183 (7): 1962-1985.e31, 2020. [PUBMED Abstract]
57. Apps JR, Carreno G, Gonzalez-Meljem JM, et al.: Tumour compartment transcriptomics demonstrates the activation of inflammatory and odontogenic programmes in human adamantinomatous craniopharyngioma and identifies the MAPK/ERK pathway as a novel therapeutic target. Acta Neuropathol 135 (5): 757-777, 2018. [PUBMED Abstract]
58. Hengartner AC, Prince E, Vijmasi T, et al.: Adamantinomatous craniopharyngioma: moving toward targeted therapies. Neurosurg Focus 48 (1): E7, 2020. [PUBMED Abstract]
59. Coy S, Rashid R, Lin JR, et al.: Multiplexed immunofluorescence reveals potential PD-1/PD-L1 pathway vulnerabilities in craniopharyngioma. Neuro Oncol 20 (8): 1101-1112, 2018. [PUBMED Abstract]
60. Grob S, Mirsky DM, Donson AM, et al.: Targeting IL-6 Is a Potential Treatment for Primary Cystic Craniopharyngioma. Front Oncol 9: 791, 2019. [PUBMED Abstract]
61. Donson AM, Apps J, Griesinger AM, et al.: Molecular Analyses Reveal Inflammatory Mediators in the Solid Component and Cyst Fluid of Human Adamantinomatous Craniopharyngioma. J Neuropathol Exp Neurol 76 (9): 779-788, 2017. [PUBMED Abstract]

Progression or recurrence of craniopharyngioma varies according to the type of up-front therapy, but it has been reported to be between 20% (patients who received a subtotal resection and radiation therapy) and 90% (patients who received a subtotal resection without radiation therapy).[1–3]

Treatment options for recurrent childhood craniopharyngioma include the following:

References

1. Yang I, Sughrue ME, Rutkowski MJ, et al.: Craniopharyngioma: a comparison of tumor control with various treatment strategies. Neurosurg Focus 28 (4): E5, 2010. [PUBMED Abstract]
2. Bogusz A, Müller HL: Childhood-onset craniopharyngioma: latest insights into pathology, diagnostics, treatment, and follow-up. Expert Rev Neurother 18 (10): 793-806, 2018. [PUBMED Abstract]
3. Liubinas SV, Munshey AS, Kaye AH: Management of recurrent craniopharyngioma. J Clin Neurosci 18 (4): 451-7, 2011. [PUBMED Abstract]
4. Vinchon M, Dhellemmes P: Craniopharyngiomas in children: recurrence, reoperation and outcome. Childs Nerv Syst 24 (2): 211-7, 2008. [PUBMED Abstract]
5. Jang WY, Lee KS, Son BC, et al.: Repeat operations in pediatric patients with recurrent craniopharyngiomas. Pediatr Neurosurg 45 (6): 451-5, 2009. [PUBMED Abstract]
6. Xu Z, Yen CP, Schlesinger D, et al.: Outcomes of Gamma Knife surgery for craniopharyngiomas. J Neurooncol 104 (1): 305-13, 2011. [PUBMED Abstract]
7. Foran SJ, Laperriere N, Edelstein K, et al.: Reirradiation for recurrent craniopharyngioma. Adv Radiat Oncol 5 (6): 1305-1310, 2020. [PUBMED Abstract]
8. Kobayashi T: Long-term results of gamma knife radiosurgery for 100 consecutive cases of craniopharyngioma and a treatment strategy. Prog Neurol Surg 22: 63-76, 2009. [PUBMED Abstract]
9. Steinbok P, Hukin J: Intracystic treatments for craniopharyngioma. Neurosurg Focus 28 (4): E13, 2010. [PUBMED Abstract]
10. Julow J, Backlund EO, Lányi F, et al.: Long-term results and late complications after intracavitary yttrium-90 colloid irradiation of recurrent cystic craniopharyngiomas. Neurosurgery 61 (2): 288-95; discussion 295-6, 2007. [PUBMED Abstract]
11. Barriger RB, Chang A, Lo SS, et al.: Phosphorus-32 therapy for cystic craniopharyngiomas. Radiother Oncol 98 (2): 207-12, 2011. [PUBMED Abstract]
12. Maarouf M, El Majdoub F, Fuetsch M, et al.: Stereotactic intracavitary brachytherapy with P-32 for cystic craniopharyngiomas in children. Strahlenther Onkol 192 (3): 157-65, 2016. [PUBMED Abstract]
13. Kickingereder P, Maarouf M, El Majdoub F, et al.: Intracavitary brachytherapy using stereotactically applied phosphorus-32 colloid for treatment of cystic craniopharyngiomas in 53 patients. J Neurooncol 109 (2): 365-74, 2012. [PUBMED Abstract]
14. Linnert M, Gehl J: Bleomycin treatment of brain tumors: an evaluation. Anticancer Drugs 20 (3): 157-64, 2009. [PUBMED Abstract]
15. Hukin J, Steinbok P, Lafay-Cousin L, et al.: Intracystic bleomycin therapy for craniopharyngioma in children: the Canadian experience. Cancer 109 (10): 2124-31, 2007. [PUBMED Abstract]
16. Ierardi DF, Fernandes MJ, Silva IR, et al.: Apoptosis in alpha interferon (IFN-alpha) intratumoral chemotherapy for cystic craniopharyngiomas. Childs Nerv Syst 23 (9): 1041-6, 2007. [PUBMED Abstract]
17. Cavalheiro S, Di Rocco C, Valenzuela S, et al.: Craniopharyngiomas: intratumoral chemotherapy with interferon-alpha: a multicenter preliminary study with 60 cases. Neurosurg Focus 28 (4): E12, 2010. [PUBMED Abstract]
18. Kilday JP, Caldarelli M, Massimi L, et al.: Intracystic interferon-alpha in pediatric craniopharyngioma patients: an international multicenter assessment on behalf of SIOPE and ISPN. Neuro Oncol 19 (10): 1398-1407, 2017. [PUBMED Abstract]
19. Yeung JT, Pollack IF, Panigrahy A, et al.: Pegylated interferon-α-2b for children with recurrent craniopharyngioma. J Neurosurg Pediatr 10 (6): 498-503, 2012. [PUBMED Abstract]
20. Fouda MA, Karsten M, Staffa SJ, et al.: Management strategies for recurrent pediatric craniopharyngioma: new recommendations. J Neurosurg Pediatr 27 (5): 548-555, 2021. [PUBMED Abstract]
21. Petralia F, Tignor N, Reva B, et al.: Integrated Proteogenomic Characterization across Major Histological Types of Pediatric Brain Cancer. Cell 183 (7): 1962-1985.e31, 2020. [PUBMED Abstract]
22. Apps JR, Muller HL, Hankinson TC, et al.: Contemporary Biological Insights and Clinical Management of Craniopharyngioma. Endocr Rev 44 (3): 518-538, 2023. [PUBMED Abstract]
23. Apps JR, Carreno G, Gonzalez-Meljem JM, et al.: Tumour compartment transcriptomics demonstrates the activation of inflammatory and odontogenic programmes in human adamantinomatous craniopharyngioma and identifies the MAPK/ERK pathway as a novel therapeutic target. Acta Neuropathol 135 (5): 757-777, 2018. [PUBMED Abstract]
24. Hengartner AC, Prince E, Vijmasi T, et al.: Adamantinomatous craniopharyngioma: moving toward targeted therapies. Neurosurg Focus 48 (1): E7, 2020. [PUBMED Abstract]
25. Coy S, Rashid R, Lin JR, et al.: Multiplexed immunofluorescence reveals potential PD-1/PD-L1 pathway vulnerabilities in craniopharyngioma. Neuro Oncol 20 (8): 1101-1112, 2018. [PUBMED Abstract]
26. Grob S, Mirsky DM, Donson AM, et al.: Targeting IL-6 Is a Potential Treatment for Primary Cystic Craniopharyngioma. Front Oncol 9: 791, 2019. [PUBMED Abstract]
27. Donson AM, Apps J, Griesinger AM, et al.: Molecular Analyses Reveal Inflammatory Mediators in the Solid Component and Cyst Fluid of Human Adamantinomatous Craniopharyngioma. J Neuropathol Exp Neurol 76 (9): 779-788, 2017. [PUBMED Abstract]

Quality-of-life issues are important to pediatric patients with craniopharyngiomas and are difficult to generalize because of the various treatment modalities. In one series of 261 patients diagnosed with craniopharyngiomas before 2000, hypothalamic involvement was associated with lower overall survival (OS), impaired quality of life, and severe obesity.[1][Level of evidence C1] Other studies investigating quality of life in large, multi-institutional cohorts have correlated worse quality-of-life outcomes with variables such as older age at diagnosis, hypothalamic involvement, degree of postoperative hypothalamic injury, and degree of tumor resection.[2,3] Regardless of therapy, most patients with craniopharyngiomas experience long-term effects from the tumor and associated therapies.[2–6][Level of evidence B3]

Late effects of treatment for childhood craniopharyngioma include the following:

For information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors, see Late Effects of Treatment for Childhood Cancer.

References

1. Sterkenburg AS, Hoffmann A, Gebhardt U, et al.: Survival, hypothalamic obesity, and neuropsychological/psychosocial status after childhood-onset craniopharyngioma: newly reported long-term outcomes. Neuro Oncol 17 (7): 1029-38, 2015. [PUBMED Abstract]
2. Eveslage M, Calaminus G, Warmuth-Metz M, et al.: The Postopera tive Quality of Life in Children and Adolescents with Craniopharyngioma. Dtsch Arztebl Int 116 (18): 321-328, 2019. [PUBMED Abstract]
3. Beckhaus J, Friedrich C, Boekhoff S, et al.: Outcome after pediatric craniopharyngioma: the role of age at diagnosis and hypothalamic damage. Eur J Endocrinol 188 (3): , 2023. [PUBMED Abstract]
4. Apps JR, Muller HL, Hankinson TC, et al.: Contemporary Biological Insights and Clinical Management of Craniopharyngioma. Endocr Rev 44 (3): 518-538, 2023. [PUBMED Abstract]
5. Müller HL: Childhood craniopharyngioma: current controversies on management in diagnostics, treatment and follow-up. Expert Rev Neurother 10 (4): 515-24, 2010. [PUBMED Abstract]
6. Bogusz A, Müller HL: Childhood-onset craniopharyngioma: latest insights into pathology, diagnostics, treatment, and follow-up. Expert Rev Neurother 18 (10): 793-806, 2018. [PUBMED Abstract]
7. Winkfield KM, Tsai HK, Yao X, et al.: Long-term clinical outcomes following treatment of childhood craniopharyngioma. Pediatr Blood Cancer 56 (7): 1120-6, 2011. [PUBMED Abstract]
8. Giese H, Haenig B, Haenig A, et al.: Neurological and neuropsychological outcome after resection of craniopharyngiomas. J Neurosurg 132 (5): 1425-1434, 2019. [PUBMED Abstract]
9. Özyurt J, Thiel CM, Lorenzen A, et al.: Neuropsychological outcome in patients with childhood craniopharyngioma and hypothalamic involvement. J Pediatr 164 (4): 876-881.e4, 2014. [PUBMED Abstract]
10. Merchant TE, Hoehn ME, Khan RB, et al.: Proton therapy and limited surgery for paediatric and adolescent patients with craniopharyngioma (RT2CR): a single-arm, phase 2 study. Lancet Oncol 24 (5): 523-534, 2023. [PUBMED Abstract]
11. Wan MJ, Zapotocky M, Bouffet E, et al.: Long-term visual outcomes of craniopharyngioma in children. J Neurooncol 137 (3): 645-651, 2018. [PUBMED Abstract]
12. Vinchon M, Weill J, Delestret I, et al.: Craniopharyngioma and hypothalamic obesity in children. Childs Nerv Syst 25 (3): 347-52, 2009. [PUBMED Abstract]
13. Dolson EP, Conklin HM, Li C, et al.: Predicting behavioral problems in craniopharyngioma survivors after conformal radiation therapy. Pediatr Blood Cancer 52 (7): 860-4, 2009. [PUBMED Abstract]
14. Kawamata T, Amano K, Aihara Y, et al.: Optimal treatment strategy for craniopharyngiomas based on long-term functional outcomes of recent and past treatment modalities. Neurosurg Rev 33 (1): 71-81, 2010. [PUBMED Abstract]
15. Müller HL: Consequences of craniopharyngioma surgery in children. J Clin Endocrinol Metab 96 (7): 1981-91, 2011. [PUBMED Abstract]
16. Marcus HJ, Rasul FT, Hussein Z, et al.: Craniopharyngioma in children: trends from a third consecutive single-center cohort study. J Neurosurg Pediatr 25 (3): 242-250, 2019. [PUBMED Abstract]
17. Clark AJ, Cage TA, Aranda D, et al.: Treatment-related morbidity and the management of pediatric craniopharyngioma: a systematic review. J Neurosurg Pediatr 10 (4): 293-301, 2012. [PUBMED Abstract]
18. Lohkamp LN, Kasper EM, Pousa AE, et al.: An update on multimodal management of craniopharyngioma in children. Front Oncol 13: 1149428, 2023. [PUBMED Abstract]
19. Boekhoff S, Bogusz A, Sterkenburg AS, et al.: Long-term Effects of Growth Hormone Replacement Therapy in Childhood-onset Craniopharyngioma: Results of the German Craniopharyngioma Registry (HIT-Endo). Eur J Endocrinol 179 (5): 331-341, 2018. [PUBMED Abstract]
20. Nguyen Quoc A, Beccaria K, González Briceño L, et al.: GH and Childhood-onset Craniopharyngioma: When to Initiate GH Replacement Therapy? J Clin Endocrinol Metab 108 (8): 1929-1936, 2023. [PUBMED Abstract]
21. Heinks K, Boekhoff S, Hoffmann A, et al.: Quality of life and growth after childhood craniopharyngioma: results of the multinational trial KRANIOPHARYNGEOM 2007. Endocrine 59 (2): 364-372, 2018. [PUBMED Abstract]
22. Boguszewski MCS, Boguszewski CL, Chemaitilly W, et al.: Safety of growth hormone replacement in survivors of cancer and intracranial and pituitary tumours: a consensus statement. Eur J Endocrinol 186 (6): P35-P52, 2022. [PUBMED Abstract]
23. Elowe-Gruau E, Beltrand J, Brauner R, et al.: Childhood craniopharyngioma: hypothalamus-sparing surgery decreases the risk of obesity. J Clin Endocrinol Metab 98 (6): 2376-82, 2013. [PUBMED Abstract]
24. Hoffmann A, Bootsveld K, Gebhardt U, et al.: Nonalcoholic fatty liver disease and fatigue in long-term survivors of childhood-onset craniopharyngioma. Eur J Endocrinol 173 (3): 389-97, 2015. [PUBMED Abstract]
25. Tan TS, Patel L, Gopal-Kothandapani JS, et al.: The neuroendocrine sequelae of paediatric craniopharyngioma: a 40-year meta-data analysis of 185 cases from three UK centres. Eur J Endocrinol 176 (3): 359-369, 2017. [PUBMED Abstract]
26. Otte A, Müller HL: Childhood-onset Craniopharyngioma. J Clin Endocrinol Metab 106 (10): e3820-e3836, 2021. [PUBMED Abstract]
27. Kiehna EN, Merchant TE: Radiation therapy for pediatric craniopharyngioma. Neurosurg Focus 28 (4): E10, 2010. [PUBMED Abstract]
28. Lo AC, Howard AF, Nichol A, et al.: A Cross-Sectional Cohort Study of Cerebrovascular Disease and Late Effects After Radiation Therapy for Craniopharyngioma. Pediatr Blood Cancer 63 (5): 786-93, 2016. [PUBMED Abstract]
29. Lucas JT, Faught AM, Hsu CY, et al.: Pre- and Posttherapy Risk Factors for Vasculopathy in Pediatric Patients With Craniopharyngioma Treated With Surgery and Proton Radiation Therapy. Int J Radiat Oncol Biol Phys 113 (1): 152-160, 2022. [PUBMED Abstract]
30. Burman P, van Beek AP, Biller BM, et al.: Radiotherapy, Especially at Young Age, Increases the Risk for De Novo Brain Tumors in Patients Treated for Pituitary/Sellar Lesions. J Clin Endocrinol Metab 102 (3): 1051-1058, 2017. [PUBMED Abstract]

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 of Newly Diagnosed Childhood Craniopharyngioma

Added text to state that a report from the prospective registry study KiProReg examined the use of proton-beam therapy in 84 children younger than 18 years with craniopharyngioma. The estimated 3-year overall survival rate was 98.2%, and the progression-free survival rate was 94.7%. With a median follow-up of 4.3 years, late toxicities appeared acceptable. Sixty-three of the patients were treated with pencil-beam scanning, which is considered an advancement in proton technology (cited Bischoff et al. as reference 43).

Late Effects in Patients Treated for Childhood Craniopharyngioma

Added Nguyen Quoc et al. as reference 20.

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® Cancer Information for Health Professionals pages.

For information about the treatments listed below, see the Treatment Option Overview section.

Treatment of newly diagnosed central nervous system (CNS) germinomas may include:

For information about the treatments listed below, see the Treatment Option Overview section.

It is not clear what treatment is best for newly diagnosed central nervous system (CNS) nongerminomas.

Treatment of choriocarcinoma, embryonal carcinoma, yolk sac tumor, or mixed germ cell tumor may include:

For information about the treatments listed below, see the Treatment Option Overview section.

Treatment of newly diagnosed mature and immature central nervous system (CNS) teratomas may include:

Treatment of recurrent childhood central nervous system (CNS) germ cell tumors may include:

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

For more information about childhood central nervous system germ cell tumors, see:

For more childhood cancer information and other general cancer resources, visit:

Primary brain tumors, including germ cell tumors (GCTs), are a diverse group of diseases that together constitute the most common solid tumors of childhood. The most recent World Health Organization (WHO) Classification of Central Nervous System Tumours implements some molecular parameters, in addition to histology, to define brain tumor entities.[1,2] Some CNS tumor types, such as embryonal tumors and gliomas, are organized according to molecular characterization. However, this updated classification schema does not yet categorize intracranial GCTs using molecular parameters. Tumor location, extent of disease (brain invasion and tumor spread), and type of CNS GCT histology remain important factors that affect treatment and prognosis.

CNS GCTs are broadly classified as germinomatous (commonly referred to as germinoma) and nongerminomatous germ cell tumors (NGGCTs) on the basis of clinicopathological and laboratory features, including tumor markers.[2,3] An alternative therapeutic classification in Japan distinguishes three groups on the basis of their prognosis: good prognosis (e.g., germinoma), intermediate prognosis (e.g., immature teratoma with malignant transformation), and poor prognosis (e.g., yolk sac tumor, choriocarcinoma, embryonal carcinoma, and mixed tumors of those entities).[3]

The PDQ childhood brain tumor treatment summaries are organized primarily according to the WHO Classification of Central Nervous System Tumours.[1–3] For a full description of the classification of CNS tumors and a link to the corresponding treatment summary for each type of brain tumor, see the Childhood Brain and Spinal Cord Tumors Summary Index.

Anatomy

CNS GCTs usually arise in the pineal and/or suprasellar regions of the brain as solitary or multiple lesions (see Figure 1). The most common site of origin is the pineal region (45%), and the second most common site is the suprasellar region (30%) within the infundibulum or pituitary stalk. Both of these sites are considered extra-axial or nonparenchymal CNS locations. Approximately 5% to 10% of patients present with synchronous tumors arising in both the suprasellar and pineal locations. Germinoma is the most frequently observed histology.[8] Other sites that may be involved include the basal ganglia, thalamus, and, less frequently, the ventricles, cerebral hemispheres, and brain stem.[10,11,13] Suprasellar tumors are most common in younger patients, whereas pineal or bifocal presentation predominates in older patients.[12]

Enlarge

References

1. Louis DN, Perry A, Wesseling P, et al.: The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol 23 (8): 1231-1251, 2021. [PUBMED Abstract]
2. WHO Classification of Tumours Editorial Board, ed.: WHO Classification of Tumours: Central Nervous System Tumours. Vol. 6. 5th ed. IARC Press; 2021.
3. Louis DN, Ohgaki H, Wiestler OD: WHO Classification of Tumours of the Central Nervous System. 4th rev.ed. IARC Press, 2016.
4. Matsutani M, Sano K, Takakura K, et al.: Primary intracranial germ cell tumors: a clinical analysis of 153 histologically verified cases. J Neurosurg 86 (3): 446-55, 1997. [PUBMED Abstract]
5. Ostrom QT, Gittleman H, Liao P, et al.: CBTRUS Statistical Report: Primary brain and other central nervous system tumors diagnosed in the United States in 2010-2014. Neuro Oncol 19 (suppl_5): v1-v88, 2017. [PUBMED Abstract]
6. Committee of Brain Tumor Registry of Japan: Report of Brain Tumor Registry of Japan (1969-1996). Neurol Med Chir (Tokyo) 43 (Suppl): i-vii, 1-111, 2003. [PUBMED Abstract]
7. The Committee of Brain Tumor Registry of Japan: Brain Tumor Registry of Japan (2001–2004). Neurol Med Chir (Tokyo) 54 (Suppl): 1-102, 2014. Also available online. Last accessed August 21, 2023.
8. Weksberg DC, Shibamoto Y, Paulino AC: Bifocal intracranial germinoma: a retrospective analysis of treatment outcomes in 20 patients and review of the literature. Int J Radiat Oncol Biol Phys 82 (4): 1341-51, 2012. [PUBMED Abstract]
9. Matsutani M; Japanese Pediatric Brain Tumor Study Group: Combined chemotherapy and radiation therapy for CNS germ cell tumors–the Japanese experience. J Neurooncol 54 (3): 311-6, 2001. [PUBMED Abstract]
10. Goodwin TL, Sainani K, Fisher PG: Incidence patterns of central nervous system germ cell tumors: a SEER Study. J Pediatr Hematol Oncol 31 (8): 541-4, 2009. [PUBMED Abstract]
11. Villano JL, Propp JM, Porter KR, et al.: Malignant pineal germ-cell tumors: an analysis of cases from three tumor registries. Neuro Oncol 10 (2): 121-30, 2008. [PUBMED Abstract]
12. Koh KN, Wong RX, Lee DE, et al.: Outcomes of intracranial germinoma-A retrospective multinational Asian study on effect of clinical presentation and differential treatment strategies. Neuro Oncol 24 (8): 1389-1399, 2022. [PUBMED Abstract]
13. Graham RT, Abu-Arja MH, Stanek JR, et al.: Multi-institutional analysis of treatment modalities in basal ganglia and thalamic germinoma. Pediatr Blood Cancer 68 (10): e29172, 2021. [PUBMED Abstract]
14. Kilday JP, Laughlin S, Urbach S, et al.: Diabetes insipidus in pediatric germinomas of the suprasellar region: characteristic features and significance of the pituitary bright spot. J Neurooncol 121 (1): 167-75, 2015. [PUBMED Abstract]
15. Hoffman HJ, Otsubo H, Hendrick EB, et al.: Intracranial germ-cell tumors in children. J Neurosurg 74 (4): 545-51, 1991. [PUBMED Abstract]
16. Sethi RV, Marino R, Niemierko A, et al.: Delayed diagnosis in children with intracranial germ cell tumors. J Pediatr 163 (5): 1448-53, 2013. [PUBMED Abstract]
17. Malbari F, Gershon TR, Garvin JH, et al.: Psychiatric manifestations as initial presentation for pediatric CNS germ cell tumors, a case series. Childs Nerv Syst 32 (8): 1359-62, 2016. [PUBMED Abstract]
18. Crawford JR, Santi MR, Vezina G, et al.: CNS germ cell tumor (CNSGCT) of childhood: presentation and delayed diagnosis. Neurology 68 (20): 1668-73, 2007. [PUBMED Abstract]
19. Allen J, Chacko J, Donahue B, et al.: Diagnostic sensitivity of serum and lumbar CSF bHCG in newly diagnosed CNS germinoma. Pediatr Blood Cancer 59 (7): 1180-2, 2012. [PUBMED Abstract]
20. Rosenblum MK, Nakazato Y, Matsutani M: Germ cell tumours. In: Louis DN, Ohgaki H, Wiestler OD: WHO Classification of Tumours of the Central Nervous System. 4th rev.ed. IARC Press, 2016, pp 286-91.
21. Murray MJ, Bartels U, Nishikawa R, et al.: Consensus on the management of intracranial germ-cell tumours. Lancet Oncol 16 (9): e470-e477, 2015. [PUBMED Abstract]
22. Frazier AL, Olson TA, Schneider DT, et al.: Germ cell tumors. In: Pizzo PA, Poplack DG, eds.: Principles and Practice of Pediatric Oncology. 7th ed. Lippincott Williams and Wilkins, 2015, pp 899-918.
23. Calaminus G, Bamberg M, Harms D, et al.: AFP/beta-HCG secreting CNS germ cell tumors: long-term outcome with respect to initial symptoms and primary tumor resection. Results of the cooperative trial MAKEI 89. Neuropediatrics 36 (2): 71-7, 2005. [PUBMED Abstract]
24. Fukushima S, Yamashita S, Kobayashi H, et al.: Genome-wide methylation profiles in primary intracranial germ cell tumors indicate a primordial germ cell origin for germinomas. Acta Neuropathol 133 (3): 445-462, 2017. [PUBMED Abstract]
25. Schneider DT, Zahn S, Sievers S, et al.: Molecular genetic analysis of central nervous system germ cell tumors with comparative genomic hybridization. Mod Pathol 19 (6): 864-73, 2006. [PUBMED Abstract]
26. Sano K, Matsutani M, Seto T: So-called intracranial germ cell tumours: personal experiences and a theory of their pathogenesis. Neurol Res 11 (2): 118-26, 1989. [PUBMED Abstract]
27. Teilum G: Embryology of ovary, testis, and genital ducts. In: Teilum G: Special Tumors of Ovary and Testis and Related Extragonadal Lesions: Comparative Pathology and Histological Identification. J. B. Lippincott, 1976, pp 15-30.
28. Wang L, Yamaguchi S, Burstein MD, et al.: Novel somatic and germline mutations in intracranial germ cell tumours. Nature 511 (7508): 241-5, 2014. [PUBMED Abstract]
29. Takami H, Fukuoka K, Fukushima S, et al.: Integrated clinical, histopathological, and molecular data analysis of 190 central nervous system germ cell tumors from the iGCT Consortium. Neuro Oncol 21 (12): 1565-1577, 2019. [PUBMED Abstract]
30. Schulte SL, Waha A, Steiger B, et al.: CNS germinomas are characterized by global demethylation, chromosomal instability and mutational activation of the Kit-, Ras/Raf/Erk- and Akt-pathways. Oncotarget 7 (34): 55026-55042, 2016. [PUBMED Abstract]
31. Satomi K, Takami H, Fukushima S, et al.: 12p gain is predominantly observed in non-germinomatous germ cell tumors and identifies an unfavorable subgroup of central nervous system germ cell tumors. Neuro Oncol 24 (5): 834-846, 2022. [PUBMED Abstract]
32. Wildeman ME, Shepard MJ, Oldfield EH, et al.: Central Nervous System Germinomas Express Programmed Death Ligand 1. J Neuropathol Exp Neurol 77 (4): 312-316, 2018. [PUBMED Abstract]

There is no universally accepted clinical staging system for germ cell tumors (GCTs), but a modified Chang staging system has traditionally been used.[1] Staging evaluation of central nervous system (CNS) GCTs includes the following:

Patients with localized disease and negative CSF cytology are considered to be metastatic negative (M0). Patients with positive CSF cytology or patients with drop metastasis (spinal or cranial subarachnoid metastases) are considered to be metastatic positive (M+). Appropriate staging is crucial because patients with metastatic disease require extended radiation fields.

GCTs may be disseminated throughout the neuraxis at the time of diagnosis or at any disease stage. Several patterns of spread may occur in germinomas, such as subependymal dissemination in the lateral or third ventricles and parenchymal infiltration. Extracranial spread to lung or bone is rare but has been reported.[3,4]

References

1. Calaminus G, Kortmann R, Worch J, et al.: SIOP CNS GCT 96: final report of outcome of a prospective, multinational nonrandomized trial for children and adults with intracranial germinoma, comparing craniospinal irradiation alone with chemotherapy followed by focal primary site irradiation for patients with localized disease. Neuro Oncol 15 (6): 788-96, 2013. [PUBMED Abstract]
2. Fujimaki T, Mishima K, Asai A, et al.: Levels of beta-human chorionic gonadotropin in cerebrospinal fluid of patients with malignant germ cell tumor can be used to detect early recurrence and monitor the response to treatment. Jpn J Clin Oncol 30 (7): 291-4, 2000. [PUBMED Abstract]
3. Jennings MT, Gelman R, Hochberg F: Intracranial germ-cell tumors: natural history and pathogenesis. J Neurosurg 63 (2): 155-67, 1985. [PUBMED Abstract]
4. Gay JC, Janco RL, Lukens JN: Systemic metastases in primary intracranial germinoma. Case report and literature review. Cancer 55 (11): 2688-90, 1985. [PUBMED Abstract]

Teratomas, germinomas, and other nongerminomatous germ cell tumors (NGGCTs) have differing prognoses and require different treatment regimens. Studies have observed the following:[1–5]

Table 3 outlines the treatment options for patients with newly diagnosed and recurrent childhood CNS GCTs.

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%.[9] Childhood and adolescent cancer survivors require close monitoring because side effects of cancer therapy may persist or develop months or years after treatment. For information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors, see Late Effects of Treatment for Childhood Cancer.

References

1. Osuka S, Tsuboi K, Takano S, et al.: Long-term outcome of patients with intracranial germinoma. J Neurooncol 83 (1): 71-9, 2007. [PUBMED Abstract]
2. Allen JC, Kim JH, Packer RJ: Neoadjuvant chemotherapy for newly diagnosed germ-cell tumors of the central nervous system. J Neurosurg 67 (1): 65-70, 1987. [PUBMED Abstract]
3. Kellie SJ, Boyce H, Dunkel IJ, et al.: Primary chemotherapy for intracranial nongerminomatous germ cell tumors: results of the second international CNS germ cell study group protocol. J Clin Oncol 22 (5): 846-53, 2004. [PUBMED Abstract]
4. Calaminus G, Kortmann R, Worch J, et al.: SIOP CNS GCT 96: final report of outcome of a prospective, multinational nonrandomized trial for children and adults with intracranial germinoma, comparing craniospinal irradiation alone with chemotherapy followed by focal primary site irradiation for patients with localized disease. Neuro Oncol 15 (6): 788-96, 2013. [PUBMED Abstract]
5. Fangusaro J, Wu S, MacDonald S, et al.: Phase II Trial of Response-Based Radiation Therapy for Patients With Localized CNS Nongerminomatous Germ Cell Tumors: A Children’s Oncology Group Study. J Clin Oncol 37 (34): 3283-3290, 2019. [PUBMED Abstract]
6. Joo JH, Park JH, Ra YS, et al.: Treatment outcome of radiation therapy for intracranial germinoma: adaptive radiation field in relation to response to chemotherapy. Anticancer Res 34 (10): 5715-21, 2014. [PUBMED Abstract]
7. Goldman S, Bouffet E, Fisher PG, et al.: Phase II Trial Assessing the Ability of Neoadjuvant Chemotherapy With or Without Second-Look Surgery to Eliminate Measurable Disease for Nongerminomatous Germ Cell Tumors: A Children’s Oncology Group Study. J Clin Oncol 33 (22): 2464-71, 2015. [PUBMED Abstract]
8. Calaminus G, Frappaz D, Kortmann RD, et al.: Outcome of patients with intracranial non-germinomatous germ cell tumors-lessons from the SIOP-CNS-GCT-96 trial. Neuro Oncol 19 (12): 1661-1672, 2017. [PUBMED Abstract]
9. Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014. [PUBMED Abstract]

Treatment options for newly diagnosed childhood central nervous system (CNS) germinomas include the following:

References

1. Calaminus G, Kortmann R, Worch J, et al.: SIOP CNS GCT 96: final report of outcome of a prospective, multinational nonrandomized trial for children and adults with intracranial germinoma, comparing craniospinal irradiation alone with chemotherapy followed by focal primary site irradiation for patients with localized disease. Neuro Oncol 15 (6): 788-96, 2013. [PUBMED Abstract]
2. Kretschmar C, Kleinberg L, Greenberg M, et al.: Pre-radiation chemotherapy with response-based radiation therapy in children with central nervous system germ cell tumors: a report from the Children’s Oncology Group. Pediatr Blood Cancer 48 (3): 285-91, 2007. [PUBMED Abstract]
3. Allen JC, DaRosso RC, Donahue B, et al.: A phase II trial of preirradiation carboplatin in newly diagnosed germinoma of the central nervous system. Cancer 74 (3): 940-4, 1994. [PUBMED Abstract]
4. Buckner JC, Peethambaram PP, Smithson WA, et al.: Phase II trial of primary chemotherapy followed by reduced-dose radiation for CNS germ cell tumors. J Clin Oncol 17 (3): 933-40, 1999. [PUBMED Abstract]
5. Khatua S, Dhall G, O’Neil S, et al.: Treatment of primary CNS germinomatous germ cell tumors with chemotherapy prior to reduced dose whole ventricular and local boost irradiation. Pediatr Blood Cancer 55 (1): 42-6, 2010. [PUBMED Abstract]
6. Cheng S, Kilday JP, Laperriere N, et al.: Outcomes of children with central nervous system germinoma treated with multi-agent chemotherapy followed by reduced radiation. J Neurooncol 127 (1): 173-80, 2016. [PUBMED Abstract]
7. O’Neil S, Ji L, Buranahirun C, et al.: Neurocognitive outcomes in pediatric and adolescent patients with central nervous system germinoma treated with a strategy of chemotherapy followed by reduced-dose and volume irradiation. Pediatr Blood Cancer 57 (4): 669-73, 2011. [PUBMED Abstract]
8. Lee DS, Lim DH, Kim IH, et al.: Upfront chemotherapy followed by response adaptive radiotherapy for intracranial germinoma: Prospective multicenter cohort study. Radiother Oncol 138: 180-186, 2019. [PUBMED Abstract]
9. Afzal S, Wherrett D, Bartels U, et al.: Challenges in management of patients with intracranial germ cell tumor and diabetes insipidus treated with cisplatin and/or ifosfamide based chemotherapy. J Neurooncol 97 (3): 393-9, 2010. [PUBMED Abstract]
10. Balmaceda C, Heller G, Rosenblum M, et al.: Chemotherapy without irradiation–a novel approach for newly diagnosed CNS germ cell tumors: results of an international cooperative trial. The First International Central Nervous System Germ Cell Tumor Study. J Clin Oncol 14 (11): 2908-15, 1996. [PUBMED Abstract]
11. da Silva NS, Cappellano AM, Diez B, et al.: Primary chemotherapy for intracranial germ cell tumors: results of the third international CNS germ cell tumor study. Pediatr Blood Cancer 54 (3): 377-83, 2010. [PUBMED Abstract]
12. Alapetite C, Brisse H, Patte C, et al.: Pattern of relapse and outcome of non-metastatic germinoma patients treated with chemotherapy and limited field radiation: the SFOP experience. Neuro Oncol 12 (12): 1318-25, 2010. [PUBMED Abstract]
13. Abu-Arja MH, Shatara MS, Okcu MF, et al.: The role of neoadjuvant chemotherapy in the management of metastatic central nervous system germinoma: A meta-analysis. Pediatr Blood Cancer 70 (10): e30601, 2023. [PUBMED Abstract]
14. Weksberg DC, Shibamoto Y, Paulino AC: Bifocal intracranial germinoma: a retrospective analysis of treatment outcomes in 20 patients and review of the literature. Int J Radiat Oncol Biol Phys 82 (4): 1341-51, 2012. [PUBMED Abstract]
15. Graham RT, Abu-Arja MH, Stanek JR, et al.: Multi-institutional analysis of treatment modalities in basal ganglia and thalamic germinoma. Pediatr Blood Cancer 68 (10): e29172, 2021. [PUBMED Abstract]
16. Bartels U, Onar-Thomas A, Patel SK, et al.: Phase II trial of response-based radiation therapy for patients with localized germinoma: a Children’s Oncology Group study. Neuro Oncol 24 (6): 974-983, 2022. [PUBMED Abstract]
17. Cappellano AM, Dassi N, Mançano B, et al.: Outcome of Children and Adolescents With Primary Intracranial Germinoma Treated With Chemotherapy and Reduced Dose-Field Irradiation: A Prospective Brazilian Experience. JCO Glob Oncol 9: e2200257, 2023. [PUBMED Abstract]
18. Li B, Feng J, Chen L, et al.: Relapse pattern and quality of life in patients with localized basal ganglia germinoma receiving focal radiotherapy, whole-brain radiotherapy, or craniospinal irradiation. Radiother Oncol 158: 90-96, 2021. [PUBMED Abstract]
19. Bamberg M, Kortmann RD, Calaminus G, et al.: Radiation therapy for intracranial germinoma: results of the German cooperative prospective trials MAKEI 83/86/89. J Clin Oncol 17 (8): 2585-92, 1999. [PUBMED Abstract]
20. Shibamoto Y, Abe M, Yamashita J, et al.: Treatment results of intracranial germinoma as a function of the irradiated volume. Int J Radiat Oncol Biol Phys 15 (2): 285-90, 1988. [PUBMED Abstract]
21. Cho J, Choi JU, Kim DS, et al.: Low-dose craniospinal irradiation as a definitive treatment for intracranial germinoma. Radiother Oncol 91 (1): 75-9, 2009. [PUBMED Abstract]
22. Huang PI, Chen YW, Wong TT, et al.: Extended focal radiotherapy of 30 Gy alone for intracranial synchronous bifocal germinoma: a single institute experience. Childs Nerv Syst 24 (11): 1315-21, 2008. [PUBMED Abstract]
23. Eom KY, Kim IH, Park CI, et al.: Upfront chemotherapy and involved-field radiotherapy results in more relapses than extended radiotherapy for intracranial germinomas: modification in radiotherapy volume might be needed. Int J Radiat Oncol Biol Phys 71 (3): 667-71, 2008. [PUBMED Abstract]
24. Chen MJ, Santos Ada S, Sakuraba RK, et al.: Intensity-modulated and 3D-conformal radiotherapy for whole-ventricular irradiation as compared with conventional whole-brain irradiation in the management of localized central nervous system germ cell tumors. Int J Radiat Oncol Biol Phys 76 (2): 608-14, 2010. [PUBMED Abstract]
25. Joo JH, Park JH, Ra YS, et al.: Treatment outcome of radiation therapy for intracranial germinoma: adaptive radiation field in relation to response to chemotherapy. Anticancer Res 34 (10): 5715-21, 2014. [PUBMED Abstract]
26. Rogers SJ, Mosleh-Shirazi MA, Saran FH: Radiotherapy of localised intracranial germinoma: time to sever historical ties? Lancet Oncol 6 (7): 509-19, 2005. [PUBMED Abstract]
27. Shikama N, Ogawa K, Tanaka S, et al.: Lack of benefit of spinal irradiation in the primary treatment of intracranial germinoma: a multiinstitutional, retrospective review of 180 patients. Cancer 104 (1): 126-34, 2005. [PUBMED Abstract]
28. Hardenbergh PH, Golden J, Billet A, et al.: Intracranial germinoma: the case for lower dose radiation therapy. Int J Radiat Oncol Biol Phys 39 (2): 419-26, 1997. [PUBMED Abstract]

Treatment options for newly diagnosed childhood central nervous system (CNS) nongerminomatous germ cell tumors (NGGCTs) include the following:

The optimal treatment regimen for CNS NGGCTs remains unclear.

The prognosis for children with CNS NGGCTs is inferior to that for children with germinomas, but the difference is diminishing with the addition of multimodality therapy. NGGCTs are radiosensitive, but patient survival rates after standard craniospinal irradiation alone has been poor, ranging from 20% to 45% at 5 years.[1] With the current treatment regimens, the 3-year to 5-year overall survival (OS) rates for patients with NGGCTs range from 75% to 90%.[2–4] In patients with NGGCTs who suffer tumor relapses, most occur within 3 years of diagnosis.[2]

References

1. Robertson PL, DaRosso RC, Allen JC: Improved prognosis of intracranial non-germinoma germ cell tumors with multimodality therapy. J Neurooncol 32 (1): 71-80, 1997. [PUBMED Abstract]
2. Goldman S, Bouffet E, Fisher PG, et al.: Phase II Trial Assessing the Ability of Neoadjuvant Chemotherapy With or Without Second-Look Surgery to Eliminate Measurable Disease for Nongerminomatous Germ Cell Tumors: A Children’s Oncology Group Study. J Clin Oncol 33 (22): 2464-71, 2015. [PUBMED Abstract]
3. Calaminus G, Frappaz D, Kortmann RD, et al.: Outcome of patients with intracranial non-germinomatous germ cell tumors-lessons from the SIOP-CNS-GCT-96 trial. Neuro Oncol 19 (12): 1661-1672, 2017. [PUBMED Abstract]
4. Fangusaro J, Wu S, MacDonald S, et al.: Phase II Trial of Response-Based Radiation Therapy for Patients With Localized CNS Nongerminomatous Germ Cell Tumors: A Children’s Oncology Group Study. J Clin Oncol 37 (34): 3283-3290, 2019. [PUBMED Abstract]
5. Matsutani M; Japanese Pediatric Brain Tumor Study Group: Combined chemotherapy and radiation therapy for CNS germ cell tumors–the Japanese experience. J Neurooncol 54 (3): 311-6, 2001. [PUBMED Abstract]
6. Calaminus G, Bamberg M, Jürgens H, et al.: Impact of surgery, chemotherapy and irradiation on long term outcome of intracranial malignant non-germinomatous germ cell tumors: results of the German Cooperative Trial MAKEI 89. Klin Padiatr 216 (3): 141-9, 2004 May-Jun. [PUBMED Abstract]
7. Baranzelli M, Patte C, Bouffet E, et al.: Carboplatin-based chemotherapy (CT) and focal irradiation (RT) in primary germ cell tumors (GCT): A French Society of Pediatric Oncology (SFOP) experience (meeting abstract). [Abstract] Proceedings of the American Society of Clinical Oncology 18: A-538, 140A, 1999.
8. Aoyama H, Shirato H, Ikeda J, et al.: Induction chemotherapy followed by low-dose involved-field radiotherapy for intracranial germ cell tumors. J Clin Oncol 20 (3): 857-65, 2002. [PUBMED Abstract]
9. Kim JW, Kim WC, Cho JH, et al.: A multimodal approach including craniospinal irradiation improves the treatment outcome of high-risk intracranial nongerminomatous germ cell tumors. Int J Radiat Oncol Biol Phys 84 (3): 625-31, 2012. [PUBMED Abstract]
10. Murphy ES, Dhall G, Fangusaro J, et al.: A Phase 2 Trial of Response-Based Radiation Therapy for Localized Central Nervous System Germ Cell Tumors: Patterns of Failure and Radiation Dosimetry for Nongerminomatous Germ Cell Tumors. Int J Radiat Oncol Biol Phys 113 (1): 143-151, 2022. [PUBMED Abstract]
11. Mak DY, Siddiqui Z, Liu ZA, et al.: Photon versus proton whole ventricular radiotherapy for non-germinomatous germ cell tumors: A report from the Children’s Oncology Group. Pediatr Blood Cancer 69 (9): e29697, 2022. [PUBMED Abstract]
12. Kim CY, Choi JW, Lee JY, et al.: Intracranial growing teratoma syndrome: clinical characteristics and treatment strategy. J Neurooncol 101 (1): 109-15, 2011. [PUBMED Abstract]
13. Kong DS, Nam DH, Lee JI, et al.: Intracranial growing teratoma syndrome mimicking tumor relapse: a diagnostic dilemma. J Neurosurg Pediatr 3 (5): 392-6, 2009. [PUBMED Abstract]
14. Michaiel G, Strother D, Gottardo N, et al.: Intracranial growing teratoma syndrome (iGTS): an international case series and review of the literature. J Neurooncol 147 (3): 721-730, 2020. [PUBMED Abstract]
15. Oya S, Saito A, Okano A, et al.: The pathogenesis of intracranial growing teratoma syndrome: proliferation of tumor cells or formation of multiple expanding cysts? Two case reports and review of the literature. Childs Nerv Syst 30 (8): 1455-61, 2014. [PUBMED Abstract]

Teratomas are designated as mature or immature on the basis of the absence or presence of differentiated tissues. The Japanese Pediatric Brain Tumor Study Group stratifies teratomas for classification and intensity of treatment (chemotherapy and radiation) into a good-prognosis group (mature teratomas) and an intermediate-prognosis group (immature teratomas) (see Table 2), while the Children’s Oncology Group includes immature teratomas with other nongerminomatous germ cell tumors.

Treatment options for newly diagnosed childhood central nervous system (CNS) teratomas include the following:

References

1. Huang X, Zhang R, Zhou LF: Diagnosis and treatment of intracranial immature teratoma. Pediatr Neurosurg 45 (5): 354-60, 2009. [PUBMED Abstract]
2. Lee YH, Park EK, Park YS, et al.: Treatment and outcomes of primary intracranial teratoma. Childs Nerv Syst 25 (12): 1581-7, 2009. [PUBMED Abstract]

Treatment options for recurrent childhood central nervous system (CNS) germ cell tumors (GCTs) include the following:

For patients who had localized germinomas at diagnosis and were treated with craniospinal and local boost radiation therapy, the most common form of relapse is at the primary site.[1] In contrast, the site of relapse is more variable in patients who relapse after chemotherapy and focal radiation therapy with or without whole-ventricular radiation to the primary site of disease. These patients have different combinations of local, disseminated ventricular, cerebral, leptomeningeal, and spinal relapse.[1,2]

Patients with disseminated germinomas and nongerminomatous germ cell tumors (NGGCTs) also may have complex patterns of relapse, including local and/or disseminated intracranial or intraspinal relapse after treatment with craniospinal radiation therapy alone or preirradiation chemotherapy with various volumes and doses of radiation therapy.[1–3]

Enrollment on clinical trials should be considered for all patients with recurrent disease. Information about ongoing National Cancer Institute (NCI)–supported clinical trials is available from the NCI website.

References

1. Calaminus G, Kortmann R, Worch J, et al.: SIOP CNS GCT 96: final report of outcome of a prospective, multinational nonrandomized trial for children and adults with intracranial germinoma, comparing craniospinal irradiation alone with chemotherapy followed by focal primary site irradiation for patients with localized disease. Neuro Oncol 15 (6): 788-96, 2013. [PUBMED Abstract]
2. Calaminus G, Frappaz D, Kortmann RD, et al.: Outcome of patients with intracranial non-germinomatous germ cell tumors-lessons from the SIOP-CNS-GCT-96 trial. Neuro Oncol 19 (12): 1661-1672, 2017. [PUBMED Abstract]
3. Goldman S, Bouffet E, Fisher PG, et al.: Phase II Trial Assessing the Ability of Neoadjuvant Chemotherapy With or Without Second-Look Surgery to Eliminate Measurable Disease for Nongerminomatous Germ Cell Tumors: A Children’s Oncology Group Study. J Clin Oncol 33 (22): 2464-71, 2015. [PUBMED Abstract]
4. Merchant TE, Sherwood SH, Mulhern RK, et al.: CNS germinoma: disease control and long-term functional outcome for 12 children treated with craniospinal irradiation. Int J Radiat Oncol Biol Phys 46 (5): 1171-6, 2000. [PUBMED Abstract]
5. Sawamura Y, Ikeda JL, Tada M, et al.: Salvage therapy for recurrent germinomas in the central nervous system. Br J Neurosurg 13 (4): 376-81, 1999. [PUBMED Abstract]
6. Hu YW, Huang PI, Wong TT, et al.: Salvage treatment for recurrent intracranial germinoma after reduced-volume radiotherapy: a single-institution experience and review of the literature. Int J Radiat Oncol Biol Phys 84 (3): 639-47, 2012. [PUBMED Abstract]
7. Murray MJ, Bailey S, Heinemann K, et al.: Treatment and outcomes of UK and German patients with relapsed intracranial germ cell tumors following uniform first-line therapy. Int J Cancer 141 (3): 621-635, 2017. [PUBMED Abstract]
8. Wong K, Opimo AB, Olch AJ, et al.: Re-irradiation of Recurrent Pineal Germ Cell Tumors with Radiosurgery: Report of Two Cases and Review of Literature. Cureus 8 (4): e585, 2016. [PUBMED Abstract]
9. Callec L, Lardy-Cleaud A, Guerrini-Rousseau L, et al.: Relapsing intracranial germ cell tumours warrant retreatment. Eur J Cancer 136: 186-194, 2020. [PUBMED Abstract]
10. Beyer J, Kramar A, Mandanas R, et al.: High-dose chemotherapy as salvage treatment in germ cell tumors: a multivariate analysis of prognostic variables. J Clin Oncol 14 (10): 2638-45, 1996. [PUBMED Abstract]
11. Motzer RJ, Mazumdar M, Bosl GJ, et al.: High-dose carboplatin, etoposide, and cyclophosphamide for patients with refractory germ cell tumors: treatment results and prognostic factors for survival and toxicity. J Clin Oncol 14 (4): 1098-105, 1996. [PUBMED Abstract]
12. Mabbott DJ, Monsalves E, Spiegler BJ, et al.: Longitudinal evaluation of neurocognitive function after treatment for central nervous system germ cell tumors in childhood. Cancer 117 (23): 5402-11, 2011. [PUBMED Abstract]
13. Acharya S, DeWees T, Shinohara ET, et al.: Long-term outcomes and late effects for childhood and young adulthood intracranial germinomas. Neuro Oncol 17 (5): 741-6, 2015. [PUBMED Abstract]

A significant proportion of children with central nervous system (CNS) germ cell tumors (GCTs) present with endocrinopathies, including diabetes insipidus and panhypopituitarism. In most cases, these endocrinopathies are permanent despite tumor control, and patients will need continuous hormone replacement therapy.[1,2]

Although significant improvements in the overall survival of patients with CNS GCTs have occurred, patients face significant late effects based on the location of the primary tumor and its treatment. These sequelae are not only limited to children, but they can also occur in adolescents and young adults. Treatment-related late effects include the following:

Current clinical trials and therapeutic approaches are directed at minimizing the long-term sequelae that result from the treatment of CNS GCTs.

For information about the incidence, type, and monitoring of late effects in survivors of childhood and adolescent cancer, see Late Effects of Treatment for Childhood Cancer.

References

1. Rosenblum MK, Matsutani M, Van Meir EG: CNS germ cell tumours. In: Kleihues P, Cavenee WK, eds.: Pathology and Genetics of Tumours of the Nervous System. International Agency for Research on Cancer, 2000, pp 208-14.
2. Hoffman HJ, Otsubo H, Hendrick EB, et al.: Intracranial germ-cell tumors in children. J Neurosurg 74 (4): 545-51, 1991. [PUBMED Abstract]
3. Osuka S, Tsuboi K, Takano S, et al.: Long-term outcome of patients with intracranial germinoma. J Neurooncol 83 (1): 71-9, 2007. [PUBMED Abstract]
4. Balmaceda C, Finlay J: Current advances in the diagnosis and management of intracranial germ cell tumors. Curr Neurol Neurosci Rep 4 (3): 253-62, 2004. [PUBMED Abstract]
5. Odagiri K, Omura M, Hata M, et al.: Treatment outcomes, growth height, and neuroendocrine functions in patients with intracranial germ cell tumors treated with chemoradiation therapy. Int J Radiat Oncol Biol Phys 84 (3): 632-8, 2012. [PUBMED Abstract]
6. Liang SY, Yang TF, Chen YW, et al.: Neuropsychological functions and quality of life in survived patients with intracranial germ cell tumors after treatment. Neuro Oncol 15 (11): 1543-51, 2013. [PUBMED Abstract]
7. Mabbott DJ, Monsalves E, Spiegler BJ, et al.: Longitudinal evaluation of neurocognitive function after treatment for central nervous system germ cell tumors in childhood. Cancer 117 (23): 5402-11, 2011. [PUBMED Abstract]
8. Acharya S, DeWees T, Shinohara ET, et al.: Long-term outcomes and late effects for childhood and young adulthood intracranial germinomas. Neuro Oncol 17 (5): 741-6, 2015. [PUBMED Abstract]
9. Wong J, Goddard K, Laperriere N, et al.: Long term toxicity of intracranial germ cell tumor treatment in adolescents and young adults. J Neurooncol 149 (3): 523-532, 2020. [PUBMED Abstract]
10. Jabbour SK, Zhang Z, Arnold D, et al.: Risk of second tumor in intracranial germinoma patients treated with radiation therapy: the Johns Hopkins experience. J Neurooncol 91 (2): 227-32, 2009. [PUBMED Abstract]
11. Sands SA, Kellie SJ, Davidow AL, et al.: Long-term quality of life and neuropsychologic functioning for patients with CNS germ-cell tumors: from the First International CNS Germ-Cell Tumor Study. Neuro Oncol 3 (3): 174-83, 2001. [PUBMED Abstract]

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.

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 of Newly Diagnosed Childhood Central Nervous System (CNS) Germinomas

Added text to state that other studies have supported the treatment approach of chemotherapy and response-based radiation therapy, reporting excellent outcomes in children with CNS germinomas (cited Cappellano et al. as reference 17).

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® Cancer Information for Health Professionals pages.

Primary brain tumors, including ependymomas, 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, extent of spread, molecular features, and age are important factors that affect treatment and prognosis.

According to the 2021 revision to the World Health Organization (WHO) Classification of Tumors of the Central Nervous System (CNS), ependymal tumors are classified into the following ten main subtypes based on anatomical site and histopathological and molecular features:[1–3]

The PDQ childhood brain tumor treatment summaries are organized primarily according to the WHO Classification of Tumors of the CNS.[1,3] For a description of the classification of nervous system tumors and a link to the corresponding treatment summary for each type of brain tumor, see Childhood Brain and Spinal Cord Tumors Summary Index.

Anatomy

Ependymomas arise from ependymal cells that line the ventricles and passageways in the brain and the center of the spinal cord (see Figure 1). Ependymal cells produce cerebrospinal fluid (CSF). These tumors are classified as supratentorial, posterior fossa (infratentorial), or spinal. In children, 65% to 75% of ependymomas arise in the posterior fossa around the fourth ventricle.[6] Less commonly, ependymomas present in the supratentorial compartment. Spinal ependymomas are rare in childhood.

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References

1. Louis DN, Ohgaki H, Wiestler OD: WHO Classification of Tumours of the Central Nervous System. 4th rev.ed. IARC Press, 2016.
2. Louis DN, Perry A, Wesseling P, et al.: The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol 23 (8): 1231-1251, 2021. [PUBMED Abstract]
3. WHO Classification of Tumours Editorial Board, ed.: WHO Classification of Tumours: Central Nervous System Tumours. Vol. 6. 5th ed. IARC Press; 2021.
4. Gurney JG, Smith MA, Bunin GR: CNS and miscellaneous intracranial and intraspinal neoplasms. In: Ries LA, Smith MA, Gurney JG, et al., eds.: Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. National Cancer Institute, SEER Program, 1999. NIH Pub.No. 99-4649, Chapter 3, pp 51-63. Also available online. Last accessed February 9, 2024.
5. Ostrom QT, Gittleman H, Truitt G, et al.: CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2011-2015. Neuro Oncol 20 (suppl_4): iv1-iv86, 2018. [PUBMED Abstract]
6. Andreiuolo F, Puget S, Peyre M, et al.: Neuronal differentiation distinguishes supratentorial and infratentorial childhood ependymomas. Neuro Oncol 12 (11): 1126-34, 2010. [PUBMED Abstract]
7. Moreno L, Pollack IF, Duffner PK, et al.: Utility of cerebrospinal fluid cytology in newly diagnosed childhood ependymoma. J Pediatr Hematol Oncol 32 (6): 515-8, 2010. [PUBMED Abstract]
8. Benesch M, Mynarek M, Witt H, et al.: Newly Diagnosed Metastatic Intracranial Ependymoma in Children: Frequency, Molecular Characteristics, Treatment, and Outcome in the Prospective HIT Series. Oncologist 24 (9): e921-e929, 2019. [PUBMED Abstract]
9. Wani K, Armstrong TS, Vera-Bolanos E, et al.: A prognostic gene expression signature in infratentorial ependymoma. Acta Neuropathol 123 (5): 727-38, 2012. [PUBMED Abstract]
10. Witt H, Mack SC, Ryzhova M, et al.: Delineation of two clinically and molecularly distinct subgroups of posterior fossa ependymoma. Cancer Cell 20 (2): 143-57, 2011. [PUBMED Abstract]
11. Pajtler KW, Witt H, Sill M, et al.: Molecular Classification of Ependymal Tumors across All CNS Compartments, Histopathological Grades, and Age Groups. Cancer Cell 27 (5): 728-43, 2015. [PUBMED Abstract]
12. Ramaswamy V, Hielscher T, Mack SC, et al.: Therapeutic Impact of Cytoreductive Surgery and Irradiation of Posterior Fossa Ependymoma in the Molecular Era: A Retrospective Multicohort Analysis. J Clin Oncol 34 (21): 2468-77, 2016. [PUBMED Abstract]
13. Mendrzyk F, Korshunov A, Benner A, et al.: Identification of gains on 1q and epidermal growth factor receptor overexpression as independent prognostic markers in intracranial ependymoma. Clin Cancer Res 12 (7 Pt 1): 2070-9, 2006. [PUBMED Abstract]
14. Korshunov A, Witt H, Hielscher T, et al.: Molecular staging of intracranial ependymoma in children and adults. J Clin Oncol 28 (19): 3182-90, 2010. [PUBMED Abstract]
15. Kilday JP, Mitra B, Domerg C, et al.: Copy number gain of 1q25 predicts poor progression-free survival for pediatric intracranial ependymomas and enables patient risk stratification: a prospective European clinical trial cohort analysis on behalf of the Children’s Cancer Leukaemia Group (CCLG), Societe Francaise d’Oncologie Pediatrique (SFOP), and International Society for Pediatric Oncology (SIOP). Clin Cancer Res 18 (7): 2001-11, 2012. [PUBMED Abstract]
16. Godfraind C, Kaczmarska JM, Kocak M, et al.: Distinct disease-risk groups in pediatric supratentorial and posterior fossa ependymomas. Acta Neuropathol 124 (2): 247-57, 2012. [PUBMED Abstract]
17. Korshunov A, Golanov A, Timirgaz V: Immunohistochemical markers for intracranial ependymoma recurrence. An analysis of 88 cases. J Neurol Sci 177 (1): 72-82, 2000. [PUBMED Abstract]
18. Andreiuolo F, Le Teuff G, Bayar MA, et al.: Integrating Tenascin-C protein expression and 1q25 copy number status in pediatric intracranial ependymoma prognostication: A new model for risk stratification. PLoS One 12 (6): e0178351, 2017. [PUBMED Abstract]
19. Merchant TE, Bendel AE, Sabin ND, et al.: Conformal Radiation Therapy for Pediatric Ependymoma, Chemotherapy for Incompletely Resected Ependymoma, and Observation for Completely Resected, Supratentorial Ependymoma. J Clin Oncol 37 (12): 974-983, 2019. [PUBMED Abstract]
20. Baroni LV, Sundaresan L, Heled A, et al.: Ultra high-risk PFA ependymoma is characterized by loss of chromosome 6q. Neuro Oncol 23 (8): 1360-1370, 2021. [PUBMED Abstract]
21. Donson AM, Bertrand KC, Riemondy KA, et al.: Significant increase of high-risk chromosome 1q gain and 6q loss at recurrence in posterior fossa group A ependymoma: A multicenter study. Neuro Oncol 25 (10): 1854-1867, 2023. [PUBMED Abstract]
22. Cavalli FMG, Hübner JM, Sharma T, et al.: Heterogeneity within the PF-EPN-B ependymoma subgroup. Acta Neuropathol 136 (2): 227-237, 2018. [PUBMED Abstract]
23. Upadhyaya SA, Robinson GW, Onar-Thomas A, et al.: Molecular grouping and outcomes of young children with newly diagnosed ependymoma treated on the multi-institutional SJYC07 trial. Neuro Oncol 21 (10): 1319-1330, 2019. [PUBMED Abstract]
24. Fukuoka K, Kanemura Y, Shofuda T, et al.: Significance of molecular classification of ependymomas: C11orf95-RELA fusion-negative supratentorial ependymomas are a heterogeneous group of tumors. Acta Neuropathol Commun 6 (1): 134, 2018. [PUBMED Abstract]
25. Jünger ST, Andreiuolo F, Mynarek M, et al.: CDKN2A deletion in supratentorial ependymoma with RELA alteration indicates a dismal prognosis: a retrospective analysis of the HIT ependymoma trial cohort. Acta Neuropathol 140 (3): 405-407, 2020. [PUBMED Abstract]
26. Milde T, Pfister S, Korshunov A, et al.: Stepwise accumulation of distinct genomic aberrations in a patient with progressively metastasizing ependymoma. Genes Chromosomes Cancer 48 (3): 229-38, 2009. [PUBMED Abstract]
27. Andreiuolo F, Varlet P, Tauziède-Espariat A, et al.: Childhood supratentorial ependymomas with YAP1-MAMLD1 fusion: an entity with characteristic clinical, radiological, cytogenetic and histopathological features. Brain Pathol 29 (2): 205-216, 2019. [PUBMED Abstract]
28. Ghasemi DR, Sill M, Okonechnikov K, et al.: MYCN amplification drives an aggressive form of spinal ependymoma. Acta Neuropathol 138 (6): 1075-1089, 2019. [PUBMED Abstract]
29. Swanson AA, Raghunathan A, Jenkins RB, et al.: Spinal Cord Ependymomas With MYCN Amplification Show Aggressive Clinical Behavior. J Neuropathol Exp Neurol 78 (9): 791-797, 2019. [PUBMED Abstract]
30. Scheil S, Brüderlein S, Eicker M, et al.: Low frequency of chromosomal imbalances in anaplastic ependymomas as detected by comparative genomic hybridization. Brain Pathol 11 (2): 133-43, 2001. [PUBMED Abstract]
31. Raffeld M, Abdullaev Z, Pack SD, et al.: High level MYCN amplification and distinct methylation signature define an aggressive subtype of spinal cord ependymoma. Acta Neuropathol Commun 8 (1): 101, 2020. [PUBMED Abstract]
32. Massimino M, Miceli R, Giangaspero F, et al.: Final results of the second prospective AIEOP protocol for pediatric intracranial ependymoma. Neuro Oncol 18 (10): 1451-60, 2016. [PUBMED Abstract]
33. Merchant TE, Jenkins JJ, Burger PC, et al.: Influence of tumor grade on time to progression after irradiation for localized ependymoma in children. Int J Radiat Oncol Biol Phys 53 (1): 52-7, 2002. [PUBMED Abstract]
34. Korshunov A, Golanov A, Sycheva R, et al.: The histologic grade is a main prognostic factor for patients with intracranial ependymomas treated in the microneurosurgical era: an analysis of 258 patients. Cancer 100 (6): 1230-7, 2004. [PUBMED Abstract]
35. Tamburrini G, D’Ercole M, Pettorini BL, et al.: Survival following treatment for intracranial ependymoma: a review. Childs Nerv Syst 25 (10): 1303-12, 2009. [PUBMED Abstract]
36. Massimino M, Barretta F, Modena P, et al.: Second series by the Italian Association of Pediatric Hematology and Oncology of children and adolescents with intracranial ependymoma: an integrated molecular and clinical characterization with a long-term follow-up. Neuro Oncol 23 (5): 848-857, 2021. [PUBMED Abstract]
37. Amirian ES, Armstrong TS, Aldape KD, et al.: Predictors of survival among pediatric and adult ependymoma cases: a study using Surveillance, Epidemiology, and End Results data from 1973 to 2007. Neuroepidemiology 39 (2): 116-24, 2012. [PUBMED Abstract]
38. Tihan T, Zhou T, Holmes E, et al.: The prognostic value of histological grading of posterior fossa ependymomas in children: a Children’s Oncology Group study and a review of prognostic factors. Mod Pathol 21 (2): 165-77, 2008. [PUBMED Abstract]
39. Ellison DW, Kocak M, Figarella-Branger D, et al.: Histopathological grading of pediatric ependymoma: reproducibility and clinical relevance in European trial cohorts. J Negat Results Biomed 10: 7, 2011. [PUBMED Abstract]
40. Vaidya K, Smee R, Williams JR: Prognostic factors and treatment options for paediatric ependymomas. J Clin Neurosci 19 (9): 1228-35, 2012. [PUBMED Abstract]
41. Zapotocky M, Beera K, Adamski J, et al.: Survival and functional outcomes of molecularly defined childhood posterior fossa ependymoma: Cure at a cost. Cancer 125 (11): 1867-1876, 2019. [PUBMED Abstract]
42. Klawinski D, Indelicato DJ, Hossain J, et al.: Surveillance imaging in pediatric ependymoma. Pediatr Blood Cancer 67 (11): e28622, 2020. [PUBMED Abstract]
43. Massimino M, Barretta F, Modena P, et al.: Pediatric intracranial ependymoma: correlating signs and symptoms at recurrence with outcome in the second prospective AIEOP protocol follow-up. J Neurooncol 140 (2): 457-465, 2018. [PUBMED Abstract]

Molecular Subgroups of Ependymoma

Molecular characterization studies have previously identified nine molecular subgroups of ependymoma, six of which predominate in childhood. The subgroups are determined by their distinctive DNA methylation and gene expression profiles and unique spectrum of genomic alterations (see Figure 2).[1–4]

One new molecularly defined ependymoma was added to the 2021 World Health Organization (WHO) Classification of Tumours of the Central Nervous System: spinal ependymoma with MYCN amplification. The 2021 classification further described ependymal tumors defined by anatomical location and histology but not by molecular alteration. These tumors are called posterior fossa ependymoma (PF-EPN), supratentorial ependymoma (ST-EPN), and spinal ependymoma (SP-EPN). These tumors either contain a unique molecular alteration (not elsewhere classified [NEC]) or their molecular analysis failed or was not obtained (not otherwise specified [NOS]).[5]

• Infratentorial tumors.
  • Posterior fossa ependymoma (PF-EPN).
  • Posterior fossa A (PF-EPN-A), loss of H3 K27 trimethylation mark.
  • Posterior fossa B (PF-EPN-B), retained H3 K27 trimethylation mark.
• Supratentorial tumors.
  • Supratentorial ependymoma (ST-EPN).
  • ZFTA fusion–positive ependymoma (ST-EPN-ZFTA). This was previously called RELA fusion–positive ependymoma (ST-EPN-RELA), but it was renamed because ZFTA is the new designation for C11orf95, and ZFTA may be fused with a partner gene other than RELA.[6]
  • YAP1 fusion–positive ependymoma (ST-EPN-YAP1).
• Spinal tumors.
  • Spinal ependymoma (SP-EPN).
  • Spinal ependymoma, MYCN-amplified (SP-EPN-MYCN).
  • Myxopapillary ependymoma (SP-EPN-MPE).

Subependymoma—whether supratentorial, infratentorial, or spinal—accounts for the remaining three molecular variants, and it is rarely, if ever, seen in children.

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Infratentorial tumors

Posterior fossa A ependymoma (PF-EPN-A)

The most common posterior fossa ependymoma subgroup is PF-EPN-A and is characterized by the following:

• Presentation in young children (median age, 3 years).[1,7]
• Low rates of variants that affect protein structure, approximately five per genome.[2]
• Gain of chromosome 1q, a known poor prognostic factor for patients with ependymoma,[8] in approximately 25% of cases.[1,3,9]
• Loss of chromosome 6q, reported to be a poor prognostic factor for patients with PF-EPN-A, in 8% to 10% of cases.[10]
• A balanced chromosomal profile with few chromosomal gains or losses.[1,2]
• Loss of the H3 K27 trimethylation mark and globally hypomethylated DNA.[11] A prospective multi-institutional study analyzed 147 patients with ependymoma. The study reported high sensitivity and specificity for immunohistochemical detection of loss of the H3 K27 trimethylation mark in identifying PF-EPN-A cases.[12] Loss of this mark occurs through multiple mechanisms, including the following:
  • Recurrent variants of EZHIP in 10% of cases, with high EZHIP mRNA expression across almost all PF-EPN-A.[13,14] EZHIP expression (with or without alteration) results in inhibition of the methyltransferase EZH2 leading to loss of the H3 K27 trimethylation mark.[14,15]
  • Recurrent K27M variants in histone H3 variants in a small proportion of cases.[16,17] Unlike diffuse midline gliomas, variants in H3.1 (H3C2 and H3C3) are more common than variants in H3.3 (H3-3A).[13] Histone variants are mutually exclusive with high expression of EZHIP,[13] and they also lead to loss of the H3 K27 trimethylation mark through EZH2 inhibition.

A study that included over 600 cases of PF-EPN-A used methylation array profiling to divide this population into two distinctive subgroups, PFA-1 and PFA-2.[13] Gene expression profiling suggested that these two subtypes may arise in different anatomical locations in the hindbrain. Within both PFA-1 and PFA-2 groups, distinctive minor subtypes could be identified, suggesting the presence of heterogeneity. Additional study will be required to define the clinical significance of these subtypes.

Posterior fossa B ependymoma (PF-EPN-B)

The PF-EPN-B subgroup is less common than the PF-EPN-A subgroup, representing 15% to 20% of all posterior fossa ependymomas in children. PF-EPN-B is characterized by the following:

• Presentation primarily in adolescents and young adults (median age, 30 years).[1,7]
• Low rates of variants that affect protein structure (approximately five per genome), with no recurring variants.[3]
• Numerous cytogenetic abnormalities, primarily involving the gain/loss of whole chromosomes.[1,3]
• Retained H3 K27 trimethylation.[11]
• 1q gain and 6q loss occur in PF-EPN-B but have not been reported as prognostic in this subgroup (unlike in PF-EPN-A).[18]

Supratentorial tumors

Supratentorial ependymomas with ZFTA fusions (ST-EPN-ZFTA)

ST-EPN-ZFTA is the largest subset of pediatric supratentorial ependymomas and is predominantly characterized by gene fusions involving RELA,[19,20] a transcriptional factor important in NF-κB pathway activity. ST-EPN-ZFTA is characterized by the following:

• Represents approximately 70% of supratentorial ependymomas in children,[19,20] and presents at a median age of 8 years.[1]
• Presence of ZFTA fusions result from chromothripsis involving chromosome 11q13.1.[19]
• Low rates of variants that affect protein structure and near absence of recurring variants outside of ZFTA::RELA fusions.[19]
• Evidence of NF-κB pathway activation at the protein and RNA level.[19]
• Gain of chromosome 1q, in approximately one-quarter of cases, with an indeterminate effect on survival.[1]
• The concordance was high between immunohistochemistry for nuclear p65-RelA, fluorescence in situ hybridization for ZFTA and RELA, and DNA methylation-based classification for defining ST-EPN-ZFTA.[21]
• Homozygous deletion of CDKN2A has been associated with a poor prognosis in patients with ZFTA fusion–positive ependymoma.[22][Level of evidence B4] CDKN2A deletion has also been reported as a secondary event in recurrent ependymoma.[23]

Supratentorial ependymomas with YAP1 fusions (ST-EPN-YAP1)

ST-EPN-YAP1 is the second, less common subset of supratentorial ependymomas and has fusions involving YAP1 on chromosome 11. ST-EPN-YAP1 is characterized by the following:

• Median age at diagnosis of 1.4 years.[1]
• Presence of a gene fusion involving YAP1, with MAMLD1 being the most common fusion partner.[1,19]
• A relatively stable genome with few chromosomal changes other than the YAP1 fusion.[1]

Tumors mimicking supratentorial ependymomas

Supratentorial ependymomas without ZFTA or YAP1 fusions (on chromosome 11) are an undefined entity, and it is unclear what these samples represent. By DNA methylation analysis, these samples often cluster with other entities such as high-grade gliomas and embryonal tumors. As one example, a retrospective methylation analysis of supratentorial brain tumors identified a group of tumors distinct from supratentorial ependymoma that harbor recurrent PLAGL1 fusions.[24] The histological lineage of these PLAGL1-altered tumors is not yet clear. Nineteen of the 32 tumors (59%) had previously been reported as ependymomas. Caution should be taken when diagnosing a supratentorial ependymoma that does not harbor a fusion involving chromosome 11.[6,25,26]

Spinal ependymoma with MYCN amplification (SP-EPN-MYCN)

SP-EPN-MYCN is rare, with only 27 cases reported.[27–30]

• Median age at presentation was 31 years (range, 12–56 years).
• High level of MYCN amplification was present at diagnosis and relapse.
• SP-EPN-MYCN has a unique methylation profile compared with other spinal cord ependymomas, MYCN-amplified pediatric-type glioblastoma, and neuroblastoma.

References

1. Pajtler KW, Witt H, Sill M, et al.: Molecular Classification of Ependymal Tumors across All CNS Compartments, Histopathological Grades, and Age Groups. Cancer Cell 27 (5): 728-43, 2015. [PUBMED Abstract]
2. Witt H, Mack SC, Ryzhova M, et al.: Delineation of two clinically and molecularly distinct subgroups of posterior fossa ependymoma. Cancer Cell 20 (2): 143-57, 2011. [PUBMED Abstract]
3. Mack SC, Witt H, Piro RM, et al.: Epigenomic alterations define lethal CIMP-positive ependymomas of infancy. Nature 506 (7489): 445-50, 2014. [PUBMED Abstract]
4. Pajtler KW, Mack SC, Ramaswamy V, et al.: The current consensus on the clinical management of intracranial ependymoma and its distinct molecular variants. Acta Neuropathol 133 (1): 5-12, 2017. [PUBMED Abstract]
5. WHO Classification of Tumours Editorial Board, ed.: WHO Classification of Tumours: Central Nervous System Tumours. Vol. 6. 5th ed. IARC Press; 2021.
6. Zschernack V, Jünger ST, Mynarek M, et al.: Supratentorial ependymoma in childhood: more than just RELA or YAP. Acta Neuropathol 141 (3): 455-466, 2021. [PUBMED Abstract]
7. Ramaswamy V, Hielscher T, Mack SC, et al.: Therapeutic Impact of Cytoreductive Surgery and Irradiation of Posterior Fossa Ependymoma in the Molecular Era: A Retrospective Multicohort Analysis. J Clin Oncol 34 (21): 2468-77, 2016. [PUBMED Abstract]
8. Korshunov A, Witt H, Hielscher T, et al.: Molecular staging of intracranial ependymoma in children and adults. J Clin Oncol 28 (19): 3182-90, 2010. [PUBMED Abstract]
9. Merchant TE, Bendel AE, Sabin ND, et al.: Conformal Radiation Therapy for Pediatric Ependymoma, Chemotherapy for Incompletely Resected Ependymoma, and Observation for Completely Resected, Supratentorial Ependymoma. J Clin Oncol 37 (12): 974-983, 2019. [PUBMED Abstract]
10. Baroni LV, Sundaresan L, Heled A, et al.: Ultra high-risk PFA ependymoma is characterized by loss of chromosome 6q. Neuro Oncol 23 (8): 1360-1370, 2021. [PUBMED Abstract]
11. Panwalkar P, Clark J, Ramaswamy V, et al.: Immunohistochemical analysis of H3K27me3 demonstrates global reduction in group-A childhood posterior fossa ependymoma and is a powerful predictor of outcome. Acta Neuropathol 134 (5): 705-714, 2017. [PUBMED Abstract]
12. Chapman RJ, Ghasemi DR, Andreiuolo F, et al.: Optimizing biomarkers for accurate ependymoma diagnosis, prognostication, and stratification within International Clinical Trials: A BIOMECA study. Neuro Oncol 25 (10): 1871-1882, 2023. [PUBMED Abstract]
13. Pajtler KW, Wen J, Sill M, et al.: Molecular heterogeneity and CXorf67 alterations in posterior fossa group A (PFA) ependymomas. Acta Neuropathol 136 (2): 211-226, 2018. [PUBMED Abstract]
14. Hübner JM, Müller T, Papageorgiou DN, et al.: EZHIP/CXorf67 mimics K27M mutated oncohistones and functions as an intrinsic inhibitor of PRC2 function in aggressive posterior fossa ependymoma. Neuro Oncol 21 (7): 878-889, 2019. [PUBMED Abstract]
15. Jain SU, Do TJ, Lund PJ, et al.: PFA ependymoma-associated protein EZHIP inhibits PRC2 activity through a H3 K27M-like mechanism. Nat Commun 10 (1): 2146, 2019. [PUBMED Abstract]
16. Gessi M, Capper D, Sahm F, et al.: Evidence of H3 K27M mutations in posterior fossa ependymomas. Acta Neuropathol 132 (4): 635-7, 2016. [PUBMED Abstract]
17. Ryall S, Guzman M, Elbabaa SK, et al.: H3 K27M mutations are extremely rare in posterior fossa group A ependymoma. Childs Nerv Syst 33 (7): 1047-1051, 2017. [PUBMED Abstract]
18. Cavalli FMG, Hübner JM, Sharma T, et al.: Heterogeneity within the PF-EPN-B ependymoma subgroup. Acta Neuropathol 136 (2): 227-237, 2018. [PUBMED Abstract]
19. Parker M, Mohankumar KM, Punchihewa C, et al.: C11orf95-RELA fusions drive oncogenic NF-κB signalling in ependymoma. Nature 506 (7489): 451-5, 2014. [PUBMED Abstract]
20. Pietsch T, Wohlers I, Goschzik T, et al.: Supratentorial ependymomas of childhood carry C11orf95-RELA fusions leading to pathological activation of the NF-κB signaling pathway. Acta Neuropathol 127 (4): 609-11, 2014. [PUBMED Abstract]
21. Pagès M, Pajtler KW, Puget S, et al.: Diagnostics of pediatric supratentorial RELA ependymomas: integration of information from histopathology, genetics, DNA methylation and imaging. Brain Pathol 29 (3): 325-335, 2019. [PUBMED Abstract]
22. Jünger ST, Andreiuolo F, Mynarek M, et al.: CDKN2A deletion in supratentorial ependymoma with RELA alteration indicates a dismal prognosis: a retrospective analysis of the HIT ependymoma trial cohort. Acta Neuropathol 140 (3): 405-407, 2020. [PUBMED Abstract]
23. Milde T, Pfister S, Korshunov A, et al.: Stepwise accumulation of distinct genomic aberrations in a patient with progressively metastasizing ependymoma. Genes Chromosomes Cancer 48 (3): 229-38, 2009. [PUBMED Abstract]
24. Sievers P, Henneken SC, Blume C, et al.: Recurrent fusions in PLAGL1 define a distinct subset of pediatric-type supratentorial neuroepithelial tumors. Acta Neuropathol 142 (5): 827-839, 2021. [PUBMED Abstract]
25. Sturm D, Orr BA, Toprak UH, et al.: New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs. Cell 164 (5): 1060-72, 2016. [PUBMED Abstract]
26. Fukuoka K, Kanemura Y, Shofuda T, et al.: Significance of molecular classification of ependymomas: C11orf95-RELA fusion-negative supratentorial ependymomas are a heterogeneous group of tumors. Acta Neuropathol Commun 6 (1): 134, 2018. [PUBMED Abstract]
27. Ghasemi DR, Sill M, Okonechnikov K, et al.: MYCN amplification drives an aggressive form of spinal ependymoma. Acta Neuropathol 138 (6): 1075-1089, 2019. [PUBMED Abstract]
28. Swanson AA, Raghunathan A, Jenkins RB, et al.: Spinal Cord Ependymomas With MYCN Amplification Show Aggressive Clinical Behavior. J Neuropathol Exp Neurol 78 (9): 791-797, 2019. [PUBMED Abstract]
29. Scheil S, Brüderlein S, Eicker M, et al.: Low frequency of chromosomal imbalances in anaplastic ependymomas as detected by comparative genomic hybridization. Brain Pathol 11 (2): 133-43, 2001. [PUBMED Abstract]
30. Raffeld M, Abdullaev Z, Pack SD, et al.: High level MYCN amplification and distinct methylation signature define an aggressive subtype of spinal cord ependymoma. Acta Neuropathol Commun 8 (1): 101, 2020. [PUBMED Abstract]

For the first time, the 2016 World Health Organization (WHO) Classification of Tumours of the Central Nervous System (CNS) incorporated genotypic findings into the classification of select CNS tumors. This integrated classification is intended to define more homogeneous entities that will improve the accuracy of diagnoses, refine prognoses, and more reliably reach conclusions regarding treatment strategies.

The 2021 WHO classification continues to classify ependymal tumors on the basis of anatomical site (i.e., supratentorial, posterior fossa, spinal), histopathological features (i.e., subependymoma, myxopapillary ependymoma, ependymoma), and molecular features (i.e., supratentorial ependymoma with ZFTA [formerly called C11orf95] or YAP1 fusions, posterior fossa A or B, and spinal ependymoma with MYCN amplification). The updated classification also includes ependymal tumors defined by anatomical location and histology but not by molecular alteration. Examples include cases where the tumor contains a unique molecular alteration (in such cases, the term not elsewhere classified [NEC] is used) or when molecular analysis fails or is not feasible (in these cases, the term not otherwise specified [NOS] is used).[1]

Ependymal tumors are now classified into the following three main histological subtypes:[1,2]

Histologically defined ependymoma can be further classified by molecular features, as follows:

Subependymoma and myxopapillary ependymoma are usually considered to be clinically and pathologically distinct from spinal ependymoma.

Although supratentorial and infratentorial ependymoma are believed to arise from radial glia cells, they have different genomics, genomic landscapes, gene expression, and immunohistochemical signatures.[6–9] Supratentorial tumors are more often characterized by neuronal differentiation.[7] It is clear that supratentorial and infratentorial ependymomas should be considered separate biological entities.[6,9–12]

Ependymoblastoma is no longer recognized in the WHO classification and is now classified as an embryonal tumor with multilayered rosettes. For more information, see Childhood Medulloblastoma and Other Central Nervous System Embryonal Tumors Treatment.

References

1. WHO Classification of Tumours Editorial Board, ed.: WHO Classification of Tumours: Central Nervous System Tumours. Vol. 6. 5th ed. IARC Press; 2021.
2. Louis DN, Ohgaki H, Wiestler OD: WHO Classification of Tumours of the Central Nervous System. 4th rev.ed. IARC Press, 2016.
3. Pajtler KW, Mack SC, Ramaswamy V, et al.: The current consensus on the clinical management of intracranial ependymoma and its distinct molecular variants. Acta Neuropathol 133 (1): 5-12, 2017. [PUBMED Abstract]
4. Louis DN, Perry A, Wesseling P, et al.: The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol 23 (8): 1231-1251, 2021. [PUBMED Abstract]
5. Ellison DW, Kocak M, Figarella-Branger D, et al.: Histopathological grading of pediatric ependymoma: reproducibility and clinical relevance in European trial cohorts. J Negat Results Biomed 10: 7, 2011. [PUBMED Abstract]
6. Taylor MD, Poppleton H, Fuller C, et al.: Radial glia cells are candidate stem cells of ependymoma. Cancer Cell 8 (4): 323-35, 2005. [PUBMED Abstract]
7. Andreiuolo F, Puget S, Peyre M, et al.: Neuronal differentiation distinguishes supratentorial and infratentorial childhood ependymomas. Neuro Oncol 12 (11): 1126-34, 2010. [PUBMED Abstract]
8. Grill J, Bergthold G, Ferreira C: Pediatric ependymomas: will molecular biology change patient management? Curr Opin Oncol 23 (6): 638-42, 2011. [PUBMED Abstract]
9. Mack SC, Pajtler KW, Chavez L, et al.: Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling. Nature 553 (7686): 101-105, 2018. [PUBMED Abstract]
10. Mack SC, Witt H, Piro RM, et al.: Epigenomic alterations define lethal CIMP-positive ependymomas of infancy. Nature 506 (7489): 445-50, 2014. [PUBMED Abstract]
11. Pajtler KW, Witt H, Sill M, et al.: Molecular Classification of Ependymal Tumors across All CNS Compartments, Histopathological Grades, and Age Groups. Cancer Cell 27 (5): 728-43, 2015. [PUBMED Abstract]
12. Johnson RA, Wright KD, Poppleton H, et al.: Cross-species genomics matches driver mutations and cell compartments to model ependymoma. Nature 466 (7306): 632-6, 2010. [PUBMED Abstract]

Although there is no formal staging system, ependymomas are divided into supratentorial, posterior fossa (infratentorial), and spinal tumors. Approximately 20% of childhood ependymomas arise in the spine, and 80% arise in the brain (30% in the supratentorial region and 70% in the posterior fossa).[1]

Ependymomas usually originate in the ependymal linings of ventricles or central canal or ventriculus terminalis of the spinal cord and have access to the cerebrospinal fluid. Therefore, these tumors may spread throughout the neuraxis, although leptomeningeal dissemination is noted in less than 10% of patients with intracranial ependymomas at initial diagnosis.

Myxopapillary ependymoma may disseminate,[2,3] and spinal ependymoma with MYCN amplification shows a high rate of metastasis, with up to 50% of pediatric patients demonstrating leptomeningeal seeding at presentation.[4]

Magnetic resonance imaging of the brain and entire spine, along with lumbar puncture for cytology, is performed at diagnosis to assess for metastatic disease.

References

1. Villano JL, Parker CK, Dolecek TA: Descriptive epidemiology of ependymal tumours in the United States. Br J Cancer 108 (11): 2367-71, 2013. [PUBMED Abstract]
2. Fassett DR, Pingree J, Kestle JR: The high incidence of tumor dissemination in myxopapillary ependymoma in pediatric patients. Report of five cases and review of the literature. J Neurosurg 102 (1 Suppl): 59-64, 2005. [PUBMED Abstract]
3. Bandopadhayay P, Silvera VM, Ciarlini PDSC, et al.: Myxopapillary ependymomas in children: imaging, treatment and outcomes. J Neurooncol 126 (1): 165-174, 2016. [PUBMED Abstract]
4. Raffeld M, Abdullaev Z, Pack SD, et al.: High level MYCN amplification and distinct methylation signature define an aggressive subtype of spinal cord ependymoma. Acta Neuropathol Commun 8 (1): 101, 2020. [PUBMED Abstract]

Many of the improvements in survival in patients with 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 previously obtained with existing therapy.

Because of the relative rarity of cancer in children, all patients with aggressive brain tumors should be considered for entry into a clinical trial. To determine and implement optimum treatment, review of each case by a multidisciplinary team of cancer specialists who have experience treating childhood brain tumors is required. Radiation therapy for pediatric brain tumors is technically demanding and should be performed in centers that have pediatric experience to ensure optimal results.

Treatment of childhood ependymoma begins with surgery. The type of adjuvant therapy given, such as a second surgery, chemotherapy, or radiation therapy, depends on the following:

Table 1 describes the standard treatment options for newly diagnosed and recurrent childhood ependymoma.

Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2020, childhood cancer mortality decreased by more than 50%.[1–3] Childhood and adolescent cancer survivors require close monitoring because cancer therapy side effects may persist or develop months or years after treatment. For specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors, see Late Effects of Treatment for Childhood Cancer.

References

1. Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014. [PUBMED Abstract]
2. National Cancer Institute: NCCR*Explorer: An interactive website for NCCR cancer statistics. Bethesda, MD: National Cancer Institute. Available online. Last accessed February 25, 2025.
3. Surveillance Research Program, National Cancer Institute: SEER*Explorer: An interactive website for SEER cancer statistics. Bethesda, MD: National Cancer Institute. Available online. Last accessed December 30, 2024.

Myxopapillary ependymoma, considered to be a histological subtype of ependymoma, has a relatively high incidence of central nervous system (CNS) tumor dissemination at diagnosis and at follow-up. Imaging of the complete craniospinal axis at the time of diagnosis and during follow-up is indicated.[1,2] According to the 2021 World Health Organization (WHO) Classification of Tumors of the CNS, myxopapillary ependymoma is now considered WHO grade 2 rather than grade 1 because its recurrence rate is similar to conventional spinal ependymoma and exceeds the rate typical of grade 1 tumors.[3]

Standard treatment options for newly diagnosed childhood myxopapillary ependymoma include the following:

Historically, the management of myxopapillary ependymoma consisted of an attempt at en bloc resection of the tumor with no further treatment in the case of a gross-total resection.[4]; [5][Level of evidence C2] However, some practitioners now favor the use of radiation therapy after surgical resection of the primary mass. This practice is based on the finding that dissemination of these tumors to other parts of the neuraxis can occur, particularly after partial resection, and evidence that focal radiation therapy may improve progression-free survival (PFS).[1,4]; [6–8][Level of evidence C2]

With the exception of an en bloc gross-total resection where the utility of adjuvant radiation therapy has been debated, radiation therapy is often considered for patients with less than a gross-total resection, a piecemeal resection, or locally recurrent disease after surgery alone. A retrospective single-institution review included 18 pediatric patients with myxopapillary ependymoma.[9]

However, two reports provided some support for the use of radiation therapy for patients with multifocal spinal myxopapillary ependymoma. The first study included 12 children (aged <21 years) who were treated with limited-volume brain-sparing proton radiation therapy. The median age of patients was 13.5 years. Radiation therapy was given as adjuvant therapy after primary surgery in five patients and for recurrence in seven patients. No patient had previously received radiation therapy. Of the 12 patients, 11 (92%) had evidence of gross disease at the time of radiation therapy, and all but one patient received 54 Gy relative biological effectiveness (RBE) of radiation therapy.[10]

A second multi-institutional retrospective study of 60 pediatric and adolescent and young adult (AYA) patients also suggested a benefit of radiation therapy (2000–2020). The median age at radiation therapy was 14.8 years (range, 7.1–26.5 years). The population was high risk because the indications for radiation therapy included gross residual disease, microscopic residual disease, or recurrent or multifocal disease.[11]

References

1. Fassett DR, Pingree J, Kestle JR: The high incidence of tumor dissemination in myxopapillary ependymoma in pediatric patients. Report of five cases and review of the literature. J Neurosurg 102 (1 Suppl): 59-64, 2005. [PUBMED Abstract]
2. Bagley CA, Kothbauer KF, Wilson S, et al.: Resection of myxopapillary ependymomas in children. J Neurosurg 106 (4 Suppl): 261-7, 2007. [PUBMED Abstract]
3. Louis DN, Perry A, Wesseling P, et al.: The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol 23 (8): 1231-1251, 2021. [PUBMED Abstract]
4. Akyurek S, Chang EL, Yu TK, et al.: Spinal myxopapillary ependymoma outcomes in patients treated with surgery and radiotherapy at M.D. Anderson Cancer Center. J Neurooncol 80 (2): 177-83, 2006. [PUBMED Abstract]
5. Bagley CA, Wilson S, Kothbauer KF, et al.: Long term outcomes following surgical resection of myxopapillary ependymomas. Neurosurg Rev 32 (3): 321-34; discussion 334, 2009. [PUBMED Abstract]
6. Pica A, Miller R, Villà S, et al.: The results of surgery, with or without radiotherapy, for primary spinal myxopapillary ependymoma: a retrospective study from the rare cancer network. Int J Radiat Oncol Biol Phys 74 (4): 1114-20, 2009. [PUBMED Abstract]
7. Agbahiwe HC, Wharam M, Batra S, et al.: Management of pediatric myxopapillary ependymoma: the role of adjuvant radiation. Int J Radiat Oncol Biol Phys 85 (2): 421-7, 2013. [PUBMED Abstract]
8. Jeibmann A, Egensperger R, Kuchelmeister K, et al.: Extent of surgical resection but not myxopapillary versus classical histopathological subtype affects prognosis in lumbo-sacral ependymomas. Histopathology 54 (2): 260-2, 2009. [PUBMED Abstract]
9. Bandopadhayay P, Silvera VM, Ciarlini PDSC, et al.: Myxopapillary ependymomas in children: imaging, treatment and outcomes. J Neurooncol 126 (1): 165-174, 2016. [PUBMED Abstract]
10. Looi WS, Indelicato DJ, Mailhot Vega RB, et al.: Outcomes following limited-volume proton therapy for multifocal spinal myxopapillary ependymoma. Pediatr Blood Cancer 68 (3): e28820, 2021. [PUBMED Abstract]
11. Liu KX, Indelicato DJ, Paulino AC, et al.: Multi-institutional Characterization of Outcomes for Pediatric and Young Adult Patients With High-Risk Myxopapillary Ependymoma After Radiation Therapy. Int J Radiat Oncol Biol Phys 117 (5): 1174-1180, 2023. [PUBMED Abstract]

Standard treatment options for newly diagnosed childhood nonmyxopapillary spinal ependymoma include the following:

Although studies suggest that surgery alone may be adequate for many grade 1 tumors, adjuvant radiation therapy may improve survival in patients with nonmyxopapillary high-grade (2/3) tumors. A bicentric report from the University of Florida and Massachusetts General Hospital supports the use of radiation therapy for tumor control.[1–3]

Between 2008 and 2019, 14 pediatric patients with nonmetastatic nonmyxopapillary grade 2 (n = 6) and grade 3 (n = 8) spinal ependymomas were treated with radiation therapy doses between 50.4 Gy relative biological effectiveness (RBE) and 54 Gy RBE (protons). The median age for patients at the time of radiation therapy was 14 years (range, 1.5–18 years). Before radiation therapy, 3 patients underwent subtotal resection, and 11 patients had gross-total or near-total resections.[4]

References

1. Oh MC, Ivan ME, Sun MZ, et al.: Adjuvant radiotherapy delays recurrence following subtotal resection of spinal cord ependymomas. Neuro Oncol 15 (2): 208-15, 2013. [PUBMED Abstract]
2. Volpp PB, Han K, Kagan AR, et al.: Outcomes in treatment for intradural spinal cord ependymomas. Int J Radiat Oncol Biol Phys 69 (4): 1199-204, 2007. [PUBMED Abstract]
3. Merchant TE, Kiehna EN, Thompson SJ, et al.: Pediatric low-grade and ependymal spinal cord tumors. Pediatr Neurosurg 32 (1): 30-6, 2000. [PUBMED Abstract]
4. Indelicato DJ, Ioakeim-Ioannidou M, Grippin AJ, et al.: Bicentric Treatment Outcomes After Proton Therapy for Nonmyxopapillary High-Grade Spinal Cord Ependymoma in Children. Int J Radiat Oncol Biol Phys 112 (2): 335-341, 2022. [PUBMED Abstract]

Standard treatment options for newly diagnosed childhood intracranial ependymoma include the following:

Typically, all patients undergo surgery to remove the tumor. Whether additional treatment is given depends on the ependymoma subtype, age of the child, extent of tumor resection, and whether disseminated disease is present.

References

1. van Veelen-Vincent ML, Pierre-Kahn A, Kalifa C, et al.: Ependymoma in childhood: prognostic factors, extent of surgery, and adjuvant therapy. J Neurosurg 97 (4): 827-35, 2002. [PUBMED Abstract]
2. Abdel-Wahab M, Etuk B, Palermo J, et al.: Spinal cord gliomas: A multi-institutional retrospective analysis. Int J Radiat Oncol Biol Phys 64 (4): 1060-71, 2006. [PUBMED Abstract]
3. Kothbauer KF: Neurosurgical management of intramedullary spinal cord tumors in children. Pediatr Neurosurg 43 (3): 222-35, 2007. [PUBMED Abstract]
4. Zacharoulis S, Ji L, Pollack IF, et al.: Metastatic ependymoma: a multi-institutional retrospective analysis of prognostic factors. Pediatr Blood Cancer 50 (2): 231-5, 2008. [PUBMED Abstract]
5. Merchant TE, Li C, Xiong X, et al.: Conformal radiotherapy after surgery for paediatric ependymoma: a prospective study. Lancet Oncol 10 (3): 258-66, 2009. [PUBMED Abstract]
6. Cage TA, Clark AJ, Aranda D, et al.: A systematic review of treatment outcomes in pediatric patients with intracranial ependymomas. J Neurosurg Pediatr 11 (6): 673-81, 2013. [PUBMED Abstract]
7. Ramaswamy V, Hielscher T, Mack SC, et al.: Therapeutic Impact of Cytoreductive Surgery and Irradiation of Posterior Fossa Ependymoma in the Molecular Era: A Retrospective Multicohort Analysis. J Clin Oncol 34 (21): 2468-77, 2016. [PUBMED Abstract]
8. Merchant TE, Bendel AE, Sabin ND, et al.: Conformal Radiation Therapy for Pediatric Ependymoma, Chemotherapy for Incompletely Resected Ependymoma, and Observation for Completely Resected, Supratentorial Ependymoma. J Clin Oncol 37 (12): 974-983, 2019. [PUBMED Abstract]
9. Volpp PB, Han K, Kagan AR, et al.: Outcomes in treatment for intradural spinal cord ependymomas. Int J Radiat Oncol Biol Phys 69 (4): 1199-204, 2007. [PUBMED Abstract]
10. Hukin J, Epstein F, Lefton D, et al.: Treatment of intracranial ependymoma by surgery alone. Pediatr Neurosurg 29 (1): 40-5, 1998. [PUBMED Abstract]
11. Little AS, Sheean T, Manoharan R, et al.: The management of completely resected childhood intracranial ependymoma: the argument for observation only. Childs Nerv Syst 25 (3): 281-4, 2009. [PUBMED Abstract]
12. Venkatramani R, Dhall G, Patel M, et al.: Supratentorial ependymoma in children: to observe or to treat following gross total resection? Pediatr Blood Cancer 58 (3): 380-3, 2012. [PUBMED Abstract]
13. Ghia AJ, Mahajan A, Allen PK, et al.: Supratentorial gross-totally resected non-anaplastic ependymoma: population based patterns of care and outcomes analysis. J Neurooncol 115 (3): 513-20, 2013. [PUBMED Abstract]
14. Koshy M, Rich S, Merchant TE, et al.: Post-operative radiation improves survival in children younger than 3 years with intracranial ependymoma. J Neurooncol 105 (3): 583-90, 2011. [PUBMED Abstract]
15. Combs SE, Kelter V, Welzel T, et al.: Influence of radiotherapy treatment concept on the outcome of patients with localized ependymomas. Int J Radiat Oncol Biol Phys 71 (4): 972-8, 2008. [PUBMED Abstract]
16. Schroeder TM, Chintagumpala M, Okcu MF, et al.: Intensity-modulated radiation therapy in childhood ependymoma. Int J Radiat Oncol Biol Phys 71 (4): 987-93, 2008. [PUBMED Abstract]
17. Merchant TE, Mulhern RK, Krasin MJ, et al.: Preliminary results from a phase II trial of conformal radiation therapy and evaluation of radiation-related CNS effects for pediatric patients with localized ependymoma. J Clin Oncol 22 (15): 3156-62, 2004. [PUBMED Abstract]
18. Patteson BE, Baliga S, Bajaj BVM, et al.: Clinical outcomes in a large pediatric cohort of patients with ependymoma treated with proton radiotherapy. Neuro Oncol 23 (1): 156-166, 2021. [PUBMED Abstract]
19. Indelicato DJ, Ioakeim-Ioannidou M, Bradley JA, et al.: Proton Therapy for Pediatric Ependymoma: Mature Results From a Bicentric Study. Int J Radiat Oncol Biol Phys 110 (3): 815-820, 2021. [PUBMED Abstract]
20. Peters S, Merta J, Schmidt L, et al.: Evaluation of dose, volume, and outcome in children with localized, intracranial ependymoma treated with proton therapy within the prospective KiProReg Study. Neuro Oncol 24 (7): 1193-1202, 2022. [PUBMED Abstract]
21. Indelicato DJ, Flampouri S, Rotondo RL, et al.: Incidence and dosimetric parameters of pediatric brainstem toxicity following proton therapy. Acta Oncol 53 (10): 1298-304, 2014. [PUBMED Abstract]
22. Sato M, Gunther JR, Mahajan A, et al.: Progression-free survival of children with localized ependymoma treated with intensity-modulated radiation therapy or proton-beam radiation therapy. Cancer 123 (13): 2570-2578, 2017. [PUBMED Abstract]
23. Indelicato DJ, Bradley JA, Rotondo RL, et al.: Outcomes following proton therapy for pediatric ependymoma. Acta Oncol 57 (5): 644-648, 2018. [PUBMED Abstract]
24. Ritzmann TA, Chapman RJ, Kilday JP, et al.: SIOP Ependymoma I: Final results, long-term follow-up, and molecular analysis of the trial cohort-A BIOMECA Consortium Study. Neuro Oncol 24 (6): 936-948, 2022. [PUBMED Abstract]
25. Zacharoulis S, Levy A, Chi SN, et al.: Outcome for young children newly diagnosed with ependymoma, treated with intensive induction chemotherapy followed by myeloablative chemotherapy and autologous stem cell rescue. Pediatr Blood Cancer 49 (1): 34-40, 2007. [PUBMED Abstract]
26. Massimino M, Solero CL, Garrè ML, et al.: Second-look surgery for ependymoma: the Italian experience. J Neurosurg Pediatr 8 (3): 246-50, 2011. [PUBMED Abstract]
27. Wahab SH, Simpson JR, Michalski JM, et al.: Long term outcome with post-operative radiation therapy for spinal canal ependymoma. J Neurooncol 83 (1): 85-9, 2007. [PUBMED Abstract]
28. Garvin JH, Selch MT, Holmes E, et al.: Phase II study of pre-irradiation chemotherapy for childhood intracranial ependymoma. Children’s Cancer Group protocol 9942: a report from the Children’s Oncology Group. Pediatr Blood Cancer 59 (7): 1183-9, 2012. [PUBMED Abstract]
29. Upadhyaya SA, Robinson GW, Onar-Thomas A, et al.: Molecular grouping and outcomes of young children with newly diagnosed ependymoma treated on the multi-institutional SJYC07 trial. Neuro Oncol 21 (10): 1319-1330, 2019. [PUBMED Abstract]
30. Grill J, Kalifa C, Doz F, et al.: A high-dose busulfan-thiotepa combination followed by autologous bone marrow transplantation in childhood recurrent ependymoma. A phase-II study. Pediatr Neurosurg 25 (1): 7-12, 1996. [PUBMED Abstract]
31. Venkatramani R, Ji L, Lasky J, et al.: Outcome of infants and young children with newly diagnosed ependymoma treated on the “Head Start” III prospective clinical trial. J Neurooncol 113 (2): 285-91, 2013. [PUBMED Abstract]
32. Merchant TE, Boop FA, Kun LE, et al.: A retrospective study of surgery and reirradiation for recurrent ependymoma. Int J Radiat Oncol Biol Phys 71 (1): 87-97, 2008. [PUBMED Abstract]
33. Bouffet E, Capra M, Bartels U: Salvage chemotherapy for metastatic and recurrent ependymoma of childhood. Childs Nerv Syst 25 (10): 1293-301, 2009. [PUBMED Abstract]
34. Duffner PK, Horowitz ME, Krischer JP, et al.: The treatment of malignant brain tumors in infants and very young children: an update of the Pediatric Oncology Group experience. Neuro-oncol 1 (2): 152-61, 1999. [PUBMED Abstract]
35. Duffner PK, Horowitz ME, Krischer JP, et al.: Postoperative chemotherapy and delayed radiation in children less than three years of age with malignant brain tumors. N Engl J Med 328 (24): 1725-31, 1993. [PUBMED Abstract]
36. Geyer JR, Sposto R, Jennings M, et al.: Multiagent chemotherapy and deferred radiotherapy in infants with malignant brain tumors: a report from the Children’s Cancer Group. J Clin Oncol 23 (30): 7621-31, 2005. [PUBMED Abstract]
37. Grill J, Le Deley MC, Gambarelli D, et al.: Postoperative chemotherapy without irradiation for ependymoma in children under 5 years of age: a multicenter trial of the French Society of Pediatric Oncology. J Clin Oncol 19 (5): 1288-96, 2001. [PUBMED Abstract]
38. Strother DR, Lafay-Cousin L, Boyett JM, et al.: Benefit from prolonged dose-intensive chemotherapy for infants with malignant brain tumors is restricted to patients with ependymoma: a report of the Pediatric Oncology Group randomized controlled trial 9233/34. Neuro Oncol 16 (3): 457-65, 2014. [PUBMED Abstract]
39. Grundy RG, Wilne SA, Weston CL, et al.: Primary postoperative chemotherapy without radiotherapy for intracranial ependymoma in children: the UKCCSG/SIOP prospective study. Lancet Oncol 8 (8): 696-705, 2007. [PUBMED Abstract]
40. Snider CA, Yang K, Mack SC, et al.: Impact of radiation therapy and extent of resection for ependymoma in young children: A population-based study. Pediatr Blood Cancer 65 (3): , 2018. [PUBMED Abstract]
41. Zapotocky M, Beera K, Adamski J, et al.: Survival and functional outcomes of molecularly defined childhood posterior fossa ependymoma: Cure at a cost. Cancer 125 (11): 1867-1876, 2019. [PUBMED Abstract]
42. von Hoff K, Kieffer V, Habrand JL, et al.: Impairment of intellectual functions after surgery and posterior fossa irradiation in children with ependymoma is related to age and neurologic complications. BMC Cancer 8: 15, 2008. [PUBMED Abstract]
43. MacDonald SM, Safai S, Trofimov A, et al.: Proton radiotherapy for childhood ependymoma: initial clinical outcomes and dose comparisons. Int J Radiat Oncol Biol Phys 71 (4): 979-86, 2008. [PUBMED Abstract]
44. Merchant TE, Lee H, Zhu J, et al.: The effects of hydrocephalus on intelligence quotient in children with localized infratentorial ependymoma before and after focal radiation therapy. J Neurosurg 101 (2 Suppl): 159-68, 2004. [PUBMED Abstract]

Recurrence is not uncommon for all grades of ependymoma and may develop many years after initial treatment.[1,2] Late recurrence beyond 10 to 15 years has been reported.[3] Disease generally recurs at the primary tumor site, although concomitant neuraxis dissemination may also be seen. Systemic relapse is extremely rare.

At the time of relapse, a complete evaluation for the extent of recurrence is indicated for all patients.

Treatment options for recurrent childhood ependymoma include the following:

References

1. Zacharoulis S, Ashley S, Moreno L, et al.: Treatment and outcome of children with relapsed ependymoma: a multi-institutional retrospective analysis. Childs Nerv Syst 26 (7): 905-11, 2010. [PUBMED Abstract]
2. Ritzmann TA, Rogers HA, Paine SML, et al.: A retrospective analysis of recurrent pediatric ependymoma reveals extremely poor survival and ineffectiveness of current treatments across central nervous system locations and molecular subgroups. Pediatr Blood Cancer 67 (9): e28426, 2020. [PUBMED Abstract]
3. Wu J, Armstrong TS, Gilbert MR: Biology and management of ependymomas. Neuro Oncol 18 (7): 902-13, 2016. [PUBMED Abstract]
4. Adolph JE, Fleischhack G, Mikasch R, et al.: Local and systemic therapy of recurrent ependymoma in children and adolescents: short- and long-term results of the E-HIT-REZ 2005 study. Neuro Oncol 23 (6): 1012-1023, 2021. [PUBMED Abstract]
5. Messahel B, Ashley S, Saran F, et al.: Relapsed intracranial ependymoma in children in the UK: patterns of relapse, survival and therapeutic outcome. Eur J Cancer 45 (10): 1815-23, 2009. [PUBMED Abstract]
6. Kano H, Yang HC, Kondziolka D, et al.: Stereotactic radiosurgery for pediatric recurrent intracranial ependymomas. J Neurosurg Pediatr 6 (5): 417-23, 2010. [PUBMED Abstract]
7. Bouffet E, Hawkins CE, Ballourah W, et al.: Survival benefit for pediatric patients with recurrent ependymoma treated with reirradiation. Int J Radiat Oncol Biol Phys 83 (5): 1541-8, 2012. [PUBMED Abstract]
8. Desrousseaux J, Claude L, Chaltiel L, et al.: Respective Roles of Surgery, Chemotherapy, and Radiation Therapy for Recurrent Pediatric and Adolescent Ependymoma: A National Multicentric Study. Int J Radiat Oncol Biol Phys 117 (2): 404-415, 2023. [PUBMED Abstract]
9. Merchant TE, Boop FA, Kun LE, et al.: A retrospective study of surgery and reirradiation for recurrent ependymoma. Int J Radiat Oncol Biol Phys 71 (1): 87-97, 2008. [PUBMED Abstract]
10. Kano H, Niranjan A, Kondziolka D, et al.: Outcome predictors for intracranial ependymoma radiosurgery. Neurosurgery 64 (2): 279-87; discussion 287-8, 2009. [PUBMED Abstract]
11. Lin YY, Wu HM, Yang HC, et al.: Repeated gamma knife radiosurgery enables longer tumor control in cases of highly-recurrent intracranial ependymoma. J Neurooncol 148 (2): 363-372, 2020. [PUBMED Abstract]
12. Kano H, Su YH, Wu HM, et al.: Stereotactic Radiosurgery for Intracranial Ependymomas: An International Multicenter Study. Neurosurgery 84 (1): 227-234, 2019. [PUBMED Abstract]
13. Tsang DS, Burghen E, Klimo P, et al.: Outcomes After Reirradiation for Recurrent Pediatric Intracranial Ependymoma. Int J Radiat Oncol Biol Phys 100 (2): 507-515, 2018. [PUBMED Abstract]
14. Eaton BR, Chowdhry V, Weaver K, et al.: Use of proton therapy for re-irradiation in pediatric intracranial ependymoma. Radiother Oncol 116 (2): 301-8, 2015. [PUBMED Abstract]
15. Tsang DS, Murray L, Ramaswamy V, et al.: Craniospinal irradiation as part of re-irradiation for children with recurrent intracranial ependymoma. Neuro Oncol 21 (4): 547-557, 2019. [PUBMED Abstract]
16. Régnier E, Laprie A, Ducassou A, et al.: Re-irradiation of locally recurrent pediatric intracranial ependymoma: Experience of the French society of children’s cancer. Radiother Oncol 132: 1-7, 2019. [PUBMED Abstract]
17. Bouffet E, Capra M, Bartels U: Salvage chemotherapy for metastatic and recurrent ependymoma of childhood. Childs Nerv Syst 25 (10): 1293-301, 2009. [PUBMED Abstract]
18. Jakacki RI, Foley MA, Horan J, et al.: Single-agent erlotinib versus oral etoposide in patients with recurrent or refractory pediatric ependymoma: a randomized open-label study. J Neurooncol 129 (1): 131-8, 2016. [PUBMED Abstract]

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.

Editorial changes were made to this summary.

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® Cancer Information for Health Professionals pages.

Primary brain tumors, including gliomas, are a diverse group of diseases that together constitute the most common solid tumors of childhood. Brain tumors are classified according to histology and molecular features, but tumor location and extent of spread are also important factors that affect treatment and prognosis. Histological features, immunohistochemical analysis, and cytogenetic and molecular genetic findings are used in tumor diagnosis and classification.

Gliomas are thought to arise from neural stem and progenitor cells that are present in the brain and spinal cord. Gliomas are classified based on histological and molecular features, and they represent the most common type of central nervous system (CNS) tumor in children.

Historically, pediatric gliomas were classified into low-grade (World Health Organization [WHO] grades 1–2) and high-grade (WHO grades 3–4) gliomas based on histological features. However, the incorporation of molecular biomarkers has led to a new classification scheme. According to the 2021 WHO Classification of Tumours: Central Nervous System Tumours (5th edition), gliomas, glioneuronal tumors, and neuronal tumors are broadly classified into adult-type diffuse gliomas, pediatric-type diffuse low-grade gliomas, pediatric-type diffuse high-grade gliomas, circumscribed astrocytic gliomas, glioneuronal and neuronal tumors, and ependymal tumors.[1,2] Within these tumor types, various subtypes are recognized, and histological grading ranging from grade 1 to grade 4 is applied to some. Most children with circumscribed astrocytic gliomas, pediatric-type diffuse low-grade gliomas, and glioneuronal and neuronal tumors have a relatively favorable prognosis, especially when a complete surgical resection can be accomplished. Children with pediatric-type diffuse high-grade gliomas generally have a poor prognosis. For information about ependymal tumors, see Childhood Ependymoma Treatment.

The PDQ childhood brain tumor treatment summaries are organized primarily according to the 2021 WHO CNS classification.[1,2]

Anatomy

Childhood gliomas can occur anywhere in the CNS (see Figure 1). For the most common CNS location for each tumor type, see Table 2.

Enlarge

References

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4. Klimo P, 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. [PUBMED Abstract]
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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. [PUBMED Abstract]
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10. Gupta N, Goumnerova LC, Manley P, et al.: Prospective feasibility and safety assessment of surgical biopsy for patients with newly diagnosed diffuse intrinsic pontine glioma. Neuro Oncol 20 (11): 1547-1555, 2018. [PUBMED Abstract]
11. Pfaff E, El Damaty A, Balasubramanian GP, et al.: Brainstem biopsy in pediatric diffuse intrinsic pontine glioma in the era of precision medicine: the INFORM study experience. Eur J Cancer 114: 27-35, 2019. [PUBMED Abstract]
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14. Holzapfel J, Kandels D, Schmidt R, et al.: Favorable prognosis in pediatric brainstem low-grade glioma: Report from the German SIOP-LGG 2004 cohort. Int J Cancer 146 (12): 3385-3396, 2020. [PUBMED Abstract]
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18. Franz DN, Agricola K, Mays M, et al.: Everolimus for subependymal giant cell astrocytoma: 5-year final analysis. Ann Neurol 78 (6): 929-38, 2015. [PUBMED Abstract]
19. Mackay A, Burford A, Carvalho D, et al.: Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma. Cancer Cell 32 (4): 520-537.e5, 2017. [PUBMED Abstract]
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23. Hawkins C, Walker E, Mohamed N, et al.: BRAF-KIAA1549 fusion predicts better clinical outcome in pediatric low-grade astrocytoma. Clin Cancer Res 17 (14): 4790-8, 2011. [PUBMED Abstract]
24. Mistry M, Zhukova N, Merico D, et al.: BRAF mutation and CDKN2A deletion define a clinically distinct subgroup of childhood secondary high-grade glioma. J Clin Oncol 33 (9): 1015-22, 2015. [PUBMED Abstract]
25. López GY, Van Ziffle J, Onodera C, et al.: The genetic landscape of gliomas arising after therapeutic radiation. Acta Neuropathol 137 (1): 139-150, 2019. [PUBMED Abstract]
26. Lassaletta A, Zapotocky M, Mistry M, et al.: Therapeutic and Prognostic Implications of BRAF V600E in Pediatric Low-Grade Gliomas. J Clin Oncol 35 (25): 2934-2941, 2017. [PUBMED Abstract]
27. Ho CY, Mobley BC, Gordish-Dressman H, et al.: A clinicopathologic study of diencephalic pediatric low-grade gliomas with BRAF V600 mutation. Acta Neuropathol 130 (4): 575-85, 2015. [PUBMED Abstract]
28. Guerreiro Stucklin AS, Ryall S, Fukuoka K, et al.: Alterations in ALK/ROS1/NTRK/MET drive a group of infantile hemispheric gliomas. Nat Commun 10 (1): 4343, 2019. [PUBMED Abstract]
29. Clarke M, Mackay A, Ismer B, et al.: Infant High-Grade Gliomas Comprise Multiple Subgroups Characterized by Novel Targetable Gene Fusions and Favorable Outcomes. Cancer Discov 10 (7): 942-963, 2020. [PUBMED Abstract]
30. Meredith DM, Cooley LD, Dubuc A, et al.: ROS1 Alterations as a Potential Driver of Gliomas in Infant, Pediatric, and Adult Patients. Mod Pathol 36 (11): 100294, 2023. [PUBMED Abstract]
31. Jones DT, Hutter B, Jäger N, et al.: Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma. Nat Genet 45 (8): 927-32, 2013. [PUBMED Abstract]
32. Qaddoumi I, Orisme W, Wen J, et al.: Genetic alterations in uncommon low-grade neuroepithelial tumors: BRAF, FGFR1, and MYB mutations occur at high frequency and align with morphology. Acta Neuropathol 131 (6): 833-45, 2016. [PUBMED Abstract]
33. Zhang J, Wu G, Miller CP, et al.: Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas. Nat Genet 45 (6): 602-12, 2013. [PUBMED Abstract]
34. Ramkissoon LA, Horowitz PM, Craig JM, et al.: Genomic analysis of diffuse pediatric low-grade gliomas identifies recurrent oncogenic truncating rearrangements in the transcription factor MYBL1. Proc Natl Acad Sci U S A 110 (20): 8188-93, 2013. [PUBMED Abstract]
35. Moreira DC, Qaddoumi I, Spiller S, et al.: Comprehensive analysis of MYB/MYBL1-altered pediatric-type diffuse low-grade glioma. Neuro Oncol 26 (7): 1327-1334, 2024. [PUBMED Abstract]
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37. Bandopadhayay P, Ramkissoon LA, Jain P, et al.: MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism. Nat Genet 48 (3): 273-82, 2016. [PUBMED Abstract]
38. D’Aronco L, Rouleau C, Gayden T, et al.: Brainstem angiocentric gliomas with MYB-QKI rearrangements. Acta Neuropathol 134 (4): 667-669, 2017. [PUBMED Abstract]
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40. Sturm D, Orr BA, Toprak UH, et al.: New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs. Cell 164 (5): 1060-72, 2016. [PUBMED Abstract]
41. Lehman NL, Usubalieva A, Lin T, et al.: Genomic analysis demonstrates that histologically-defined astroblastomas are molecularly heterogeneous and that tumors with MN1 rearrangement exhibit the most favorable prognosis. Acta Neuropathol Commun 7 (1): 42, 2019. [PUBMED Abstract]
42. Wood MD, Tihan T, Perry A, et al.: Multimodal molecular analysis of astroblastoma enables reclassification of most cases into more specific molecular entities. Brain Pathol 28 (2): 192-202, 2018. [PUBMED Abstract]
43. Hirose T, Nobusawa S, Sugiyama K, et al.: Astroblastoma: a distinct tumor entity characterized by alterations of the X chromosome and MN1 rearrangement. Brain Pathol 28 (5): 684-694, 2018. [PUBMED Abstract]
44. Lucas CG, Solomon DA, Perry A: A review of recently described genetic alterations in central nervous system tumors. Hum Pathol 96: 56-66, 2020. [PUBMED Abstract]
45. Paugh BS, Qu C, Jones C, et al.: Integrated molecular genetic profiling of pediatric high-grade gliomas reveals key differences with the adult disease. J Clin Oncol 28 (18): 3061-8, 2010. [PUBMED Abstract]
46. Bax DA, Mackay A, Little SE, et al.: A distinct spectrum of copy number aberrations in pediatric high-grade gliomas. Clin Cancer Res 16 (13): 3368-77, 2010. [PUBMED Abstract]
47. Ward SJ, Karakoula K, Phipps KP, et al.: Cytogenetic analysis of paediatric astrocytoma using comparative genomic hybridisation and fluorescence in-situ hybridisation. J Neurooncol 98 (3): 305-18, 2010. [PUBMED Abstract]
48. Pollack IF, Hamilton RL, Sobol RW, et al.: IDH1 mutations are common in malignant gliomas arising in adolescents: a report from the Children’s Oncology Group. Childs Nerv Syst 27 (1): 87-94, 2011. [PUBMED Abstract]
49. Sturm D, Witt H, Hovestadt V, et al.: Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell 22 (4): 425-37, 2012. [PUBMED Abstract]
50. Korshunov A, Ryzhova M, Hovestadt V, et al.: Integrated analysis of pediatric glioblastoma reveals a subset of biologically favorable tumors with associated molecular prognostic markers. Acta Neuropathol 129 (5): 669-78, 2015. [PUBMED Abstract]
51. Castel D, Kergrohen T, Tauziède-Espariat A, et al.: Histone H3 wild-type DIPG/DMG overexpressing EZHIP extend the spectrum diffuse midline gliomas with PRC2 inhibition beyond H3-K27M mutation. Acta Neuropathol 139 (6): 1109-1113, 2020. [PUBMED Abstract]
52. Rodriguez Gutierrez D, Jones C, Varlet P, et al.: Radiological Evaluation of Newly Diagnosed Non-Brainstem Pediatric High-Grade Glioma in the HERBY Phase II Trial. Clin Cancer Res 26 (8): 1856-1865, 2020. [PUBMED Abstract]
53. 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. [PUBMED Abstract]
54. Taylor KR, Mackay A, Truffaux N, et al.: Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma. Nat Genet 46 (5): 457-61, 2014. [PUBMED Abstract]
55. Gestrich C, Grieco K, Lidov HG, et al.: H3K27-altered diffuse midline gliomas with MAPK pathway alterations: Prognostic and therapeutic implications. J Neuropathol Exp Neurol 83 (1): 30-35, 2023. [PUBMED Abstract]
56. Auffret L, Ajlil Y, Tauziède-Espariat A, et al.: A new subtype of diffuse midline glioma, H3 K27 and BRAF/FGFR1 co-altered: a clinico-radiological and histomolecular characterisation. Acta Neuropathol 147 (1): 2, 2023. [PUBMED Abstract]
57. Williams EA, Brastianos PK, Wakimoto H, et al.: A comprehensive genomic study of 390 H3F3A-mutant pediatric and adult diffuse high-grade gliomas, CNS WHO grade 4. Acta Neuropathol 146 (3): 515-525, 2023. [PUBMED Abstract]
58. Jain SU, Do TJ, Lund PJ, et al.: PFA ependymoma-associated protein EZHIP inhibits PRC2 activity through a H3 K27M-like mechanism. Nat Commun 10 (1): 2146, 2019. [PUBMED Abstract]
59. Hübner JM, Müller T, Papageorgiou DN, et al.: EZHIP/CXorf67 mimics K27M mutated oncohistones and functions as an intrinsic inhibitor of PRC2 function in aggressive posterior fossa ependymoma. Neuro Oncol 21 (7): 878-889, 2019. [PUBMED Abstract]
60. Chen CCL, Deshmukh S, Jessa S, et al.: Histone H3.3G34-Mutant Interneuron Progenitors Co-opt PDGFRA for Gliomagenesis. Cell 183 (6): 1617-1633.e22, 2020. [PUBMED Abstract]
61. Mackay A, Burford A, Molinari V, et al.: Molecular, Pathological, Radiological, and Immune Profiling of Non-brainstem Pediatric High-Grade Glioma from the HERBY Phase II Randomized Trial. Cancer Cell 33 (5): 829-842.e5, 2018. [PUBMED Abstract]
62. Yeo KK, Alexandrescu S, Cotter JA, et al.: Multi-institutional study of the frequency, genomic landscape, and outcome of IDH-mutant glioma in pediatrics. Neuro Oncol 25 (1): 199-210, 2023. [PUBMED Abstract]
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65. Korshunov A, Schrimpf D, Ryzhova M, et al.: H3-/IDH-wild type pediatric glioblastoma is comprised of molecularly and prognostically distinct subtypes with associated oncogenic drivers. Acta Neuropathol 134 (3): 507-516, 2017. [PUBMED Abstract]
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67. Blumcke I, Spreafico R, Haaker G, et al.: Histopathological Findings in Brain Tissue Obtained during Epilepsy Surgery. N Engl J Med 377 (17): 1648-1656, 2017. [PUBMED Abstract]
68. Pekmezci M, Villanueva-Meyer JE, Goode B, et al.: The genetic landscape of ganglioglioma. Acta Neuropathol Commun 6 (1): 47, 2018. [PUBMED Abstract]
69. Bianchi F, Tamburrini G, Massimi L, et al.: Supratentorial tumors typical of the infantile age: desmoplastic infantile ganglioglioma (DIG) and astrocytoma (DIA). A review. Childs Nerv Syst 32 (10): 1833-8, 2016. [PUBMED Abstract]
70. Trehan G, Bruge H, Vinchon M, et al.: MR imaging in the diagnosis of desmoplastic infantile tumor: retrospective study of six cases. AJNR Am J Neuroradiol 25 (6): 1028-33, 2004 Jun-Jul. [PUBMED Abstract]
71. Wang AC, Jones DTW, Abecassis IJ, et al.: Desmoplastic Infantile Ganglioglioma/Astrocytoma (DIG/DIA) Are Distinct Entities with Frequent BRAFV600 Mutations. Mol Cancer Res 16 (10): 1491-1498, 2018. [PUBMED Abstract]
72. Blessing MM, Blackburn PR, Krishnan C, et al.: Desmoplastic Infantile Ganglioglioma: A MAPK Pathway-Driven and Microglia/Macrophage-Rich Neuroepithelial Tumor. J Neuropathol Exp Neurol 78 (11): 1011-1021, 2019. [PUBMED Abstract]
73. Greer A, Foreman NK, Donson A, et al.: Desmoplastic infantile astrocytoma/ganglioglioma with rare BRAF V600D mutation. Pediatr Blood Cancer 64 (6): , 2017. [PUBMED Abstract]
74. Louis DN, Ohgaki H, Wiestler OD: WHO Classification of Tumours of the Central Nervous System. 4th rev.ed. IARC Press, 2016.
75. Stone TJ, Keeley A, Virasami A, et al.: Comprehensive molecular characterisation of epilepsy-associated glioneuronal tumours. Acta Neuropathol 135 (1): 115-129, 2018. [PUBMED Abstract]
76. Rivera B, Gayden T, Carrot-Zhang J, et al.: Germline and somatic FGFR1 abnormalities in dysembryoplastic neuroepithelial tumors. Acta Neuropathol 131 (6): 847-63, 2016. [PUBMED Abstract]
77. Matsumura N, Nobusawa S, Ito J, et al.: Multiplex ligation-dependent probe amplification analysis is useful for detecting a copy number gain of the FGFR1 tyrosine kinase domain in dysembryoplastic neuroepithelial tumors. J Neurooncol 143 (1): 27-33, 2019. [PUBMED Abstract]
78. Pages M, Lacroix L, Tauziede-Espariat A, et al.: Papillary glioneuronal tumors: histological and molecular characteristics and diagnostic value of SLC44A1-PRKCA fusion. Acta Neuropathol Commun 3: 85, 2015. [PUBMED Abstract]
79. Bridge JA, Liu XQ, Sumegi J, et al.: Identification of a novel, recurrent SLC44A1-PRKCA fusion in papillary glioneuronal tumor. Brain Pathol 23 (2): 121-8, 2013. [PUBMED Abstract]
80. Hou Y, Pinheiro J, Sahm F, et al.: Papillary glioneuronal tumor (PGNT) exhibits a characteristic methylation profile and fusions involving PRKCA. Acta Neuropathol 137 (5): 837-846, 2019. [PUBMED Abstract]
81. Sievers P, Appay R, Schrimpf D, et al.: Rosette-forming glioneuronal tumors share a distinct DNA methylation profile and mutations in FGFR1, with recurrent co-mutation of PIK3CA and NF1. Acta Neuropathol 138 (3): 497-504, 2019. [PUBMED Abstract]
82. Deng MY, Sill M, Chiang J, et al.: Molecularly defined diffuse leptomeningeal glioneuronal tumor (DLGNT) comprises two subgroups with distinct clinical and genetic features. Acta Neuropathol 136 (2): 239-253, 2018. [PUBMED Abstract]
83. Chiang JCH, Harreld JH, Orr BA, et al.: Low-grade spinal glioneuronal tumors with BRAF gene fusion and 1p deletion but without leptomeningeal dissemination. Acta Neuropathol 134 (1): 159-162, 2017. [PUBMED Abstract]
84. Chiang J, Dalton J, Upadhyaya SA, et al.: Chromosome arm 1q gain is an adverse prognostic factor in localized and diffuse leptomeningeal glioneuronal tumors with BRAF gene fusion and 1p deletion. Acta Neuropathol 137 (1): 179-181, 2019. [PUBMED Abstract]
85. Sievers P, Stichel D, Schrimpf D, et al.: FGFR1:TACC1 fusion is a frequent event in molecularly defined extraventricular neurocytoma. Acta Neuropathol 136 (2): 293-302, 2018. [PUBMED Abstract]
86. Wisoff JH, Sanford RA, Heier LA, et al.: Primary neurosurgery for pediatric low-grade gliomas: a prospective multi-institutional study from the Children’s Oncology Group. Neurosurgery 68 (6): 1548-54; discussion 1554-5, 2011. [PUBMED Abstract]
87. Bandopadhayay P, Bergthold G, London WB, et al.: Long-term outcome of 4,040 children diagnosed with pediatric low-grade gliomas: an analysis of the Surveillance Epidemiology and End Results (SEER) database. Pediatr Blood Cancer 61 (7): 1173-9, 2014. [PUBMED Abstract]
88. Lu VM, Di L, Gernsback J, et al.: Contemporary outcomes of diffuse leptomeningeal glioneuronal tumor in pediatric patients: A case series and literature review. Clin Neurol Neurosurg 218: 107265, 2022. [PUBMED Abstract]
89. Stokland T, Liu JF, Ironside JW, et al.: A multivariate analysis of factors determining tumor progression in childhood low-grade glioma: a population-based cohort study (CCLG CNS9702). Neuro Oncol 12 (12): 1257-68, 2010. [PUBMED Abstract]
90. Gnekow AK, Walker DA, Kandels D, et al.: A European randomised controlled trial of the addition of etoposide to standard vincristine and carboplatin induction as part of an 18-month treatment programme for childhood (≤16 years) low grade glioma - A final report. Eur J Cancer 81: 206-225, 2017. [PUBMED Abstract]
91. Chamdine O, Broniscer A, Wu S, et al.: Metastatic Low-Grade Gliomas in Children: 20 Years’ Experience at St. Jude Children’s Research Hospital. Pediatr Blood Cancer 63 (1): 62-70, 2016. [PUBMED Abstract]
92. Due-Tønnessen BJ, Helseth E, Scheie D, et al.: Long-term outcome after resection of benign cerebellar astrocytomas in children and young adults (0-19 years): report of 110 consecutive cases. Pediatr Neurosurg 37 (2): 71-80, 2002. [PUBMED Abstract]
93. Massimi L, Tufo T, Di Rocco C: Management of optic-hypothalamic gliomas in children: still a challenging problem. Expert Rev Anticancer Ther 7 (11): 1591-610, 2007. [PUBMED Abstract]
94. Campagna M, Opocher E, Viscardi E, et al.: Optic pathway glioma: long-term visual outcome in children without neurofibromatosis type-1. Pediatr Blood Cancer 55 (6): 1083-8, 2010. [PUBMED Abstract]
95. Hernáiz Driever P, von Hornstein S, Pietsch T, et al.: Natural history and management of low-grade glioma in NF-1 children. J Neurooncol 100 (2): 199-207, 2010. [PUBMED Abstract]
96. Falzon K, Drimtzias E, Picton S, et al.: Visual outcomes after chemotherapy for optic pathway glioma in children with and without neurofibromatosis type 1: results of the International Society of Paediatric Oncology (SIOP) Low-Grade Glioma 2004 trial UK cohort. Br J Ophthalmol 102 (10): 1367-1371, 2018. [PUBMED Abstract]
97. Hoffman LM, Veldhuijzen van Zanten SEM, Colditz N, et al.: Clinical, Radiologic, Pathologic, and Molecular Characteristics of Long-Term Survivors of Diffuse Intrinsic Pontine Glioma (DIPG): A Collaborative Report From the International and European Society for Pediatric Oncology DIPG Registries. J Clin Oncol 36 (19): 1963-1972, 2018. [PUBMED Abstract]
98. 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. [PUBMED Abstract]
99. Rodriguez D, Calmon R, Aliaga ES, et al.: MRI and Molecular Characterization of Pediatric High-Grade Midline Thalamic Gliomas: The HERBY Phase II Trial. Radiology 304 (1): 174-182, 2022. [PUBMED Abstract]
100. McAbee JH, Modica J, Thompson CJ, et al.: Cervicomedullary tumors in children. J Neurosurg Pediatr 16 (4): 357-66, 2015. [PUBMED Abstract]
101. 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. [PUBMED Abstract]
102. 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. [PUBMED Abstract]
103. Hoffman LM, DeWire M, Ryall S, et al.: Spatial genomic heterogeneity in diffuse intrinsic pontine and midline high-grade glioma: implications for diagnostic biopsy and targeted therapeutics. Acta Neuropathol Commun 4: 1, 2016. [PUBMED Abstract]
104. Erker C, Lane A, Chaney B, et al.: Characteristics of patients ≥10 years of age with diffuse intrinsic pontine glioma: a report from the International DIPG/DMG Registry. Neuro Oncol 24 (1): 141-152, 2022. [PUBMED Abstract]
105. 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. [PUBMED Abstract]
106. 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. [PUBMED Abstract]
107. Albers AC, Gutmann DH: Gliomas in patients with neurofibromatosis type 1. Expert Rev Neurother 9 (4): 535-9, 2009. [PUBMED Abstract]

There is no recognized staging system for childhood astrocytomas, other gliomas, and glioneuronal/neuronal tumors. Unifocal disease represents by far the most common initial clinical presentation, followed by multifocal and/or diffuse disease, including leptomeningeal disease. Disease spread outside the central nervous system (CNS) is exceedingly rare.

Spread of diffuse midline glioma in the pons, 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.[1] However, subclinically, more widespread dissemination with extension to the brain stem, thalamus, cerebrum, and supratentorial leptomeninges has been noted at autopsy.[2]

References

1. 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. [PUBMED Abstract]
2. Caretti V, Bugiani M, Freret M, et al.: Subventricular spread of diffuse intrinsic pontine glioma. Acta Neuropathol 128 (4): 605-7, 2014. [PUBMED Abstract]

Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2020, childhood cancer mortality decreased by more than 50%.[1] 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 previously obtained results that assessed an 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. Information about ongoing National Cancer Institute (NCI)–supported clinical trials is available from the NCI website.

To determine and implement optimal treatment, planning by a multidisciplinary team of cancer specialists who have experience treating childhood brain tumors is required. Irradiation 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.

Long-term management of patients with brain tumors is complex and requires a multidisciplinary approach. For information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors, see Late Effects of Treatment for Childhood Cancer.

Table 3 describes the standard treatment options for childhood astrocytomas, other gliomas, and glioneuronal/neuronal tumors.

References

1. Surveillance Research Program, National Cancer Institute: SEER*Explorer: An interactive website for SEER cancer statistics. Bethesda, MD: National Cancer Institute. Available online. Last accessed December 30, 2024.

To determine and implement optimal management, treatment is best guided by a multidisciplinary team of specialists experienced in treating pediatric patients with brain tumors.

For children with optic pathway gliomas, an important primary goal of treatment is preservation of visual function.[1]

Standard treatment options for newly diagnosed circumscribed astrocytic gliomas, pediatric-type diffuse low-grade gliomas, and glioneuronal/neuronal tumors include the following:

References

1. Nicolin G, Parkin P, Mabbott D, et al.: Natural history and outcome of optic pathway gliomas in children. Pediatr Blood Cancer 53 (7): 1231-7, 2009. [PUBMED Abstract]
2. Listernick R, Ferner RE, Liu GT, et al.: Optic pathway gliomas in neurofibromatosis-1: controversies and recommendations. Ann Neurol 61 (3): 189-98, 2007. [PUBMED Abstract]
3. Albright AL: Feasibility and advisability of resections of thalamic tumors in pediatric patients. J Neurosurg 100 (5 Suppl Pediatrics): 468-72, 2004. [PUBMED Abstract]
4. Piccirilli M, Lenzi J, Delfinis C, et al.: Spontaneous regression of optic pathways gliomas in three patients with neurofibromatosis type I and critical review of the literature. Childs Nerv Syst 22 (10): 1332-7, 2006. [PUBMED Abstract]
5. Due-Tønnessen BJ, Helseth E, Scheie D, et al.: Long-term outcome after resection of benign cerebellar astrocytomas in children and young adults (0-19 years): report of 110 consecutive cases. Pediatr Neurosurg 37 (2): 71-80, 2002. [PUBMED Abstract]
6. Wisoff JH, Sanford RA, Heier LA, et al.: Primary neurosurgery for pediatric low-grade gliomas: a prospective multi-institutional study from the Children’s Oncology Group. Neurosurgery 68 (6): 1548-54; discussion 1554-5, 2011. [PUBMED Abstract]
7. Scheinemann K, Bartels U, Huang A, et al.: Survival and functional outcome of childhood spinal cord low-grade gliomas. Clinical article. J Neurosurg Pediatr 4 (3): 254-61, 2009. [PUBMED Abstract]
8. Sawamura Y, Kamada K, Kamoshima Y, et al.: Role of surgery for optic pathway/hypothalamic astrocytomas in children. Neuro Oncol 10 (5): 725-33, 2008. [PUBMED Abstract]
9. Kestle J, Townsend JJ, Brockmeyer DL, et al.: Juvenile pilocytic astrocytoma of the brainstem in children. J Neurosurg 101 (1 Suppl): 1-6, 2004. [PUBMED Abstract]
10. Holzapfel J, Kandels D, Schmidt R, et al.: Favorable prognosis in pediatric brainstem low-grade glioma: Report from the German SIOP-LGG 2004 cohort. Int J Cancer 146 (12): 3385-3396, 2020. [PUBMED Abstract]
11. Perwein T, Benesch M, Kandels D, et al.: High frequency of disease progression in pediatric spinal cord low-grade glioma (LGG): management strategies and results from the German LGG study group. Neuro Oncol 23 (7): 1148-1162, 2021. [PUBMED Abstract]
12. Sutton LN, Cnaan A, Klatt L, et al.: Postoperative surveillance imaging in children with cerebellar astrocytomas. J Neurosurg 84 (5): 721-5, 1996. [PUBMED Abstract]
13. Dorward IG, Luo J, Perry A, et al.: Postoperative imaging surveillance in pediatric pilocytic astrocytomas. J Neurosurg Pediatr 6 (4): 346-52, 2010. [PUBMED Abstract]
14. Falkenstein F, Gessi M, Kandels D, et al.: Prognostic impact of distinct genetic entities in pediatric diffuse glioma WHO-grade II-Report from the German/Swiss SIOP-LGG 2004 cohort. Int J Cancer 147 (8): 2159-2175, 2020. [PUBMED Abstract]
15. Mirow C, Pietsch T, Berkefeld S, et al.: Children <1 year show an inferior outcome when treated according to the traditional LGG treatment strategy: a report from the German multicenter trial HIT-LGG 1996 for children with low grade glioma (LGG). Pediatr Blood Cancer 61 (3): 457-63, 2014. [PUBMED Abstract]
16. Beebe DW, Ris MD, Armstrong FD, et al.: Cognitive and adaptive outcome in low-grade pediatric cerebellar astrocytomas: evidence of diminished cognitive and adaptive functioning in National Collaborative Research Studies (CCG 9891/POG 9130). J Clin Oncol 23 (22): 5198-204, 2005. [PUBMED Abstract]
17. Turner CD, Chordas CA, Liptak CC, et al.: Medical, psychological, cognitive and educational late-effects in pediatric low-grade glioma survivors treated with surgery only. Pediatr Blood Cancer 53 (3): 417-23, 2009. [PUBMED Abstract]
18. Daszkiewicz P, Maryniak A, Roszkowski M, et al.: Long-term functional outcome of surgical treatment of juvenile pilocytic astrocytoma of the cerebellum in children. Childs Nerv Syst 25 (7): 855-60, 2009. [PUBMED Abstract]
19. Yeo KK, Alexandrescu S, Cotter JA, et al.: Multi-institutional study of the frequency, genomic landscape, and outcome of IDH-mutant glioma in pediatrics. Neuro Oncol 25 (1): 199-210, 2023. [PUBMED Abstract]
20. 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. [PUBMED Abstract]
21. Gnekow AK, Falkenstein F, von Hornstein S, et al.: Long-term follow-up of the multicenter, multidisciplinary treatment study HIT-LGG-1996 for low-grade glioma in children and adolescents of the German Speaking Society of Pediatric Oncology and Hematology. Neuro Oncol 14 (10): 1265-84, 2012. [PUBMED Abstract]
22. Laithier V, Grill J, Le Deley MC, et al.: Progression-free survival in children with optic pathway tumors: dependence on age and the quality of the response to chemotherapy–results of the first French prospective study for the French Society of Pediatric Oncology. J Clin Oncol 21 (24): 4572-8, 2003. [PUBMED Abstract]
23. Chong AL, Pole JD, Scheinemann K, et al.: Optic pathway gliomas in adolescence–time to challenge treatment choices? Neuro Oncol 15 (3): 391-400, 2013. [PUBMED Abstract]
24. Gropman AL, Packer RJ, Nicholson HS, et al.: Treatment of diencephalic syndrome with chemotherapy: growth, tumor response, and long term control. Cancer 83 (1): 166-72, 1998. [PUBMED Abstract]
25. Gururangan S, Cavazos CM, Ashley D, et al.: Phase II study of carboplatin in children with progressive low-grade gliomas. J Clin Oncol 20 (13): 2951-8, 2002. [PUBMED Abstract]
26. Mahoney DH, Cohen ME, Friedman HS, et al.: Carboplatin is effective therapy for young children with progressive optic pathway tumors: a Pediatric Oncology Group phase II study. Neuro Oncol 2 (4): 213-20, 2000. [PUBMED Abstract]
27. Dodgshun AJ, Maixner WJ, Heath JA, et al.: Single agent carboplatin for pediatric low-grade glioma: A retrospective analysis shows equivalent efficacy to multiagent chemotherapy. Int J Cancer 138 (2): 481-8, 2016. [PUBMED Abstract]
28. Bouffet E, Jakacki R, Goldman S, et al.: Phase II study of weekly vinblastine in recurrent or refractory pediatric low-grade glioma. J Clin Oncol 30 (12): 1358-63, 2012. [PUBMED Abstract]
29. Lassaletta A, Scheinemann K, Zelcer SM, et al.: Phase II Weekly Vinblastine for Chemotherapy-Naïve Children With Progressive Low-Grade Glioma: A Canadian Pediatric Brain Tumor Consortium Study. J Clin Oncol 34 (29): 3537-3543, 2016. [PUBMED Abstract]
30. Prados MD, Edwards MS, Rabbitt J, et al.: Treatment of pediatric low-grade gliomas with a nitrosourea-based multiagent chemotherapy regimen. J Neurooncol 32 (3): 235-41, 1997. [PUBMED Abstract]
31. Ater JL, Xia C, Mazewski CM, et al.: Nonrandomized comparison of neurofibromatosis type 1 and non-neurofibromatosis type 1 children who received carboplatin and vincristine for progressive low-grade glioma: A report from the Children’s Oncology Group. Cancer 122 (12): 1928-36, 2016. [PUBMED Abstract]
32. Massimino M, Spreafico F, Cefalo G, et al.: High response rate to cisplatin/etoposide regimen in childhood low-grade glioma. J Clin Oncol 20 (20): 4209-16, 2002. [PUBMED Abstract]
33. Massimino M, Spreafico F, Riva D, et al.: A lower-dose, lower-toxicity cisplatin-etoposide regimen for childhood progressive low-grade glioma. J Neurooncol 100 (1): 65-71, 2010. [PUBMED Abstract]
34. Mora J, Perez-Jaume S, Cruz O: Treatment of childhood astrocytomas with irinotecan and cisplatin. Clin Transl Oncol 20 (4): 500-507, 2018. [PUBMED Abstract]
35. von Hornstein S, Kortmann RD, Pietsch T, et al.: Impact of chemotherapy on disseminated low-grade glioma in children and adolescents: report from the HIT-LGG 1996 trial. Pediatr Blood Cancer 56 (7): 1046-54, 2011. [PUBMED Abstract]
36. Gururangan S, Fisher MJ, Allen JC, et al.: Temozolomide in children with progressive low-grade glioma. Neuro Oncol 9 (2): 161-8, 2007. [PUBMED Abstract]
37. Khaw SL, Coleman LT, Downie PA, et al.: Temozolomide in pediatric low-grade glioma. Pediatr Blood Cancer 49 (6): 808-11, 2007. [PUBMED Abstract]
38. Moreno L, Bautista F, Ashley S, et al.: Does chemotherapy affect the visual outcome in children with optic pathway glioma? A systematic review of the evidence. Eur J Cancer 46 (12): 2253-9, 2010. [PUBMED Abstract]
39. Shofty B, Ben-Sira L, Freedman S, et al.: Visual outcome following chemotherapy for progressive optic pathway gliomas. Pediatr Blood Cancer 57 (3): 481-5, 2011. [PUBMED Abstract]
40. Falzon K, Drimtzias E, Picton S, et al.: Visual outcomes after chemotherapy for optic pathway glioma in children with and without neurofibromatosis type 1: results of the International Society of Paediatric Oncology (SIOP) Low-Grade Glioma 2004 trial UK cohort. Br J Ophthalmol 102 (10): 1367-1371, 2018. [PUBMED Abstract]
41. Rakotonjanahary J, Gravier N, Lambron J, et al.: Long-term visual acuity in patients with optic pathway glioma treated during childhood with up-front BB-SFOP chemotherapy-Analysis of a French pediatric historical cohort. PLoS One 14 (3): e0212107, 2019. [PUBMED Abstract]
42. Fisher BJ, Leighton CC, Vujovic O, et al.: Results of a policy of surveillance alone after surgical management of pediatric low grade gliomas. Int J Radiat Oncol Biol Phys 51 (3): 704-10, 2001. [PUBMED Abstract]
43. Tsang DS, Murphy ES, Merchant TE: Radiation Therapy for Optic Pathway and Hypothalamic Low-Grade Gliomas in Children. Int J Radiat Oncol Biol Phys 99 (3): 642-651, 2017. [PUBMED Abstract]
44. Greenberger BA, Pulsifer MB, Ebb DH, et al.: Clinical outcomes and late endocrine, neurocognitive, and visual profiles of proton radiation for pediatric low-grade gliomas. Int J Radiat Oncol Biol Phys 89 (5): 1060-8, 2014. [PUBMED Abstract]
45. Paulino AC, Mazloom A, Terashima K, et al.: Intensity-modulated radiotherapy (IMRT) in pediatric low-grade glioma. Cancer 119 (14): 2654-9, 2013. [PUBMED Abstract]
46. Müller K, Gnekow A, Falkenstein F, et al.: Radiotherapy in pediatric pilocytic astrocytomas. A subgroup analysis within the prospective multicenter study HIT-LGG 1996 by the German Society of Pediatric Oncology and Hematology (GPOH). Strahlenther Onkol 189 (8): 647-55, 2013. [PUBMED Abstract]
47. Bitterman DS, MacDonald SM, Yock TI, et al.: Revisiting the Role of Radiation Therapy for Pediatric Low-Grade Glioma. J Clin Oncol 37 (35): 3335-3339, 2019. [PUBMED Abstract]
48. Cherlow JM, Shaw DWW, Margraf LR, et al.: Conformal Radiation Therapy for Pediatric Patients with Low-Grade Glioma: Results from the Children’s Oncology Group Phase 2 Study ACNS0221. Int J Radiat Oncol Biol Phys 103 (4): 861-868, 2019. [PUBMED Abstract]
49. Indelicato DJ, Rotondo RL, Uezono H, et al.: Outcomes Following Proton Therapy for Pediatric Low-Grade Glioma. Int J Radiat Oncol Biol Phys 104 (1): 149-156, 2019. [PUBMED Abstract]
50. Ludmir EB, Mahajan A, Paulino AC, et al.: Increased risk of pseudoprogression among pediatric low-grade glioma patients treated with proton versus photon radiotherapy. Neuro Oncol 21 (5): 686-695, 2019. [PUBMED Abstract]
51. Chawla S, Korones DN, Milano MT, et al.: Spurious progression in pediatric brain tumors. J Neurooncol 107 (3): 651-7, 2012. [PUBMED Abstract]
52. Marcus KJ, Goumnerova L, Billett AL, et al.: Stereotactic radiotherapy for localized low-grade gliomas in children: final results of a prospective trial. Int J Radiat Oncol Biol Phys 61 (2): 374-9, 2005. [PUBMED Abstract]
53. Combs SE, Schulz-Ertner D, Moschos D, et al.: Fractionated stereotactic radiotherapy of optic pathway gliomas: tolerance and long-term outcome. Int J Radiat Oncol Biol Phys 62 (3): 814-9, 2005. [PUBMED Abstract]
54. Naftel RP, Pollack IF, Zuccoli G, et al.: Pseudoprogression of low-grade gliomas after radiotherapy. Pediatr Blood Cancer 62 (1): 35-9, 2015. [PUBMED Abstract]
55. Merchant TE, Kun LE, Wu S, et al.: Phase II trial of conformal radiation therapy for pediatric low-grade glioma. J Clin Oncol 27 (22): 3598-604, 2009. [PUBMED Abstract]
56. Merchant TE, Conklin HM, Wu S, et al.: Late effects of conformal radiation therapy for pediatric patients with low-grade glioma: prospective evaluation of cognitive, endocrine, and hearing deficits. J Clin Oncol 27 (22): 3691-7, 2009. [PUBMED Abstract]
57. Kano H, Niranjan A, Kondziolka D, et al.: Stereotactic radiosurgery for pilocytic astrocytomas part 2: outcomes in pediatric patients. J Neurooncol 95 (2): 219-29, 2009. [PUBMED Abstract]
58. Hallemeier CL, Pollock BE, Schomberg PJ, et al.: Stereotactic radiosurgery for recurrent or unresectable pilocytic astrocytoma. Int J Radiat Oncol Biol Phys 83 (1): 107-12, 2012. [PUBMED Abstract]
59. Stock A, Hancken CV, Kandels D, et al.: Pseudoprogression Is Frequent After Front-Line Radiation Therapy in Pediatric Low-Grade Glioma: Results From the German Low-Grade Glioma Cohort. Int J Radiat Oncol Biol Phys 112 (5): 1190-1202, 2022. [PUBMED Abstract]
60. Acharya S, Quesada S, Coca K, et al.: Long-term visual acuity outcomes after radiation therapy for sporadic optic pathway glioma. J Neurooncol 144 (3): 603-610, 2019. [PUBMED Abstract]
61. Hanania AN, Paulino AC, Ludmir EB, et al.: Early radiotherapy preserves vision in sporadic optic pathway glioma. Cancer 127 (13): 2358-2367, 2021. [PUBMED Abstract]
62. Jenkin D, Angyalfi S, Becker L, et al.: Optic glioma in children: surveillance, resection, or irradiation? Int J Radiat Oncol Biol Phys 25 (2): 215-25, 1993. [PUBMED Abstract]
63. Khafaga Y, Hassounah M, Kandil A, et al.: Optic gliomas: a retrospective analysis of 50 cases. Int J Radiat Oncol Biol Phys 56 (3): 807-12, 2003. [PUBMED Abstract]
64. Krishnatry R, Zhukova N, Guerreiro Stucklin AS, et al.: Clinical and treatment factors determining long-term outcomes for adult survivors of childhood low-grade glioma: A population-based study. Cancer 122 (8): 1261-9, 2016. [PUBMED Abstract]
65. Acharya S, Liu JF, Tatevossian RG, et al.: Risk stratification in pediatric low-grade glioma and glioneuronal tumor treated with radiation therapy: an integrated clinicopathologic and molecular analysis. Neuro Oncol 22 (8): 1203-1213, 2020. [PUBMED Abstract]
66. Grill J, Couanet D, Cappelli C, et al.: Radiation-induced cerebral vasculopathy in children with neurofibromatosis and optic pathway glioma. Ann Neurol 45 (3): 393-6, 1999. [PUBMED Abstract]
67. Bouffet E, Hansford JR, Garrè ML, et al.: Dabrafenib plus Trametinib in Pediatric Glioma with BRAF V600 Mutations. N Engl J Med 389 (12): 1108-1120, 2023. [PUBMED Abstract]
68. Mellinghoff IK, van den Bent MJ, Blumenthal DT, et al.: Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma. N Engl J Med 389 (7): 589-601, 2023. [PUBMED Abstract]
69. Franz DN, Agricola KD, Tudor CA, et al.: Everolimus for tumor recurrence after surgical resection for subependymal giant cell astrocytoma associated with tuberous sclerosis complex. J Child Neurol 28 (5): 602-7, 2013. [PUBMED Abstract]
70. Krueger DA, Care MM, Holland K, et al.: Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med 363 (19): 1801-11, 2010. [PUBMED Abstract]
71. Weidman DR, Pole JD, Bouffet E, et al.: Dose-level response rates of mTor inhibition in tuberous sclerosis complex (TSC) related subependymal giant cell astrocytoma (SEGA). Pediatr Blood Cancer 62 (10): 1754-60, 2015. [PUBMED Abstract]
72. Franz DN, Leonard J, Tudor C, et al.: Rapamycin causes regression of astrocytomas in tuberous sclerosis complex. Ann Neurol 59 (3): 490-8, 2006. [PUBMED Abstract]
73. Franz DN, Belousova E, Sparagana S, et al.: Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet 381 (9861): 125-32, 2013. [PUBMED Abstract]
74. Franz DN, Agricola K, Mays M, et al.: Everolimus for subependymal giant cell astrocytoma: 5-year final analysis. Ann Neurol 78 (6): 929-38, 2015. [PUBMED Abstract]

There is no single standard treatment option for progressive/recurrent circumscribed astrocytic gliomas, pediatric-type diffuse low-grade gliomas, glioneuronal tumors, and neuronal tumors. To determine and implement optimal management, treatment is best guided by a multidisciplinary team of specialists with experience treating pediatric patients with brain tumors.

An individual plan needs to be tailored based on the following:

Recurrent disease is usually at the primary tumor site, although multifocal or widely disseminated disease to other intracranial sites and to the spinal leptomeninges has been documented.[1,2] Most recurrences are of the same tumor entity; however, transformation into a higher grade tumor is possible and associated with the molecular profile.[3] Surveillance imaging will frequently identify asymptomatic recurrences.[4] At the time of recurrence, a complete evaluation to determine the extent of the relapse is indicated.

Tumor sample sequencing was done in pediatric (n = 48) and young adult patients (n = 6) with recurrent or refractory low-grade gliomas who were enrolled in the National Cancer Institute (NCI)–Children’s Oncology Group (COG) Pediatric MATCH trial. The test revealed genomic alterations that were considered actionable for treatment on MATCH study arms in 39 of 54 tumors (72.2%).[5] Alterations in MAPK pathway genes (most commonly BRAF and NF1) were detected in 26 of 54 tumors (48.1%). FGFR1 variants (n = 11) or fusions (n = 1) were identified in 12 of 54 tumors (22.2%).

Treatment options for progressive/recurrent circumscribed astrocytic gliomas, pediatric-type diffuse low-grade gliomas, and glioneuronal/neuronal tumors include the following:

References

1. Perilongo G, Carollo C, Salviati L, et al.: Diencephalic syndrome and disseminated juvenile pilocytic astrocytomas of the hypothalamic-optic chiasm region. Cancer 80 (1): 142-6, 1997. [PUBMED Abstract]
2. Leibel SA, Sheline GE, Wara WM, et al.: The role of radiation therapy in the treatment of astrocytomas. Cancer 35 (6): 1551-7, 1975. [PUBMED Abstract]
3. Ryall S, Zapotocky M, Fukuoka K, et al.: Integrated Molecular and Clinical Analysis of 1,000 Pediatric Low-Grade Gliomas. Cancer Cell 37 (4): 569-583.e5, 2020. [PUBMED Abstract]
4. Udaka YT, Yeh-Nayre LA, Amene CS, et al.: Recurrent pediatric central nervous system low-grade gliomas: the role of surveillance neuroimaging in asymptomatic children. J Neurosurg Pediatr 11 (2): 119-26, 2013. [PUBMED Abstract]
5. Parsons DW, Janeway KA, Patton DR, et al.: Actionable Tumor Alterations and Treatment Protocol Enrollment of Pediatric and Young Adult Patients With Refractory Cancers in the National Cancer Institute-Children’s Oncology Group Pediatric MATCH Trial. J Clin Oncol 40 (20): 2224-2234, 2022. [PUBMED Abstract]
6. Bowers DC, Krause TP, Aronson LJ, et al.: Second surgery for recurrent pilocytic astrocytoma in children. Pediatr Neurosurg 34 (5): 229-34, 2001. [PUBMED Abstract]
7. Scheinemann K, Bartels U, Tsangaris E, et al.: Feasibility and efficacy of repeated chemotherapy for progressive pediatric low-grade gliomas. Pediatr Blood Cancer 57 (1): 84-8, 2011. [PUBMED Abstract]
8. de Haas V, Grill J, Raquin MA, et al.: Relapses of optic pathway tumors after first-line chemotherapy. Pediatr Blood Cancer 52 (5): 575-80, 2009. [PUBMED Abstract]
9. Merchant TE, Conklin HM, Wu S, et al.: Late effects of conformal radiation therapy for pediatric patients with low-grade glioma: prospective evaluation of cognitive, endocrine, and hearing deficits. J Clin Oncol 27 (22): 3691-7, 2009. [PUBMED Abstract]
10. Marcus KJ, Goumnerova L, Billett AL, et al.: Stereotactic radiotherapy for localized low-grade gliomas in children: final results of a prospective trial. Int J Radiat Oncol Biol Phys 61 (2): 374-9, 2005. [PUBMED Abstract]
11. Bitterman DS, MacDonald SM, Yock TI, et al.: Revisiting the Role of Radiation Therapy for Pediatric Low-Grade Glioma. J Clin Oncol 37 (35): 3335-3339, 2019. [PUBMED Abstract]
12. Cherlow JM, Shaw DWW, Margraf LR, et al.: Conformal Radiation Therapy for Pediatric Patients with Low-Grade Glioma: Results from the Children’s Oncology Group Phase 2 Study ACNS0221. Int J Radiat Oncol Biol Phys 103 (4): 861-868, 2019. [PUBMED Abstract]
13. 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. [PUBMED Abstract]
14. Gnekow AK, Falkenstein F, von Hornstein S, et al.: Long-term follow-up of the multicenter, multidisciplinary treatment study HIT-LGG-1996 for low-grade glioma in children and adolescents of the German Speaking Society of Pediatric Oncology and Hematology. Neuro Oncol 14 (10): 1265-84, 2012. [PUBMED Abstract]
15. Lassaletta A, Scheinemann K, Zelcer SM, et al.: Phase II Weekly Vinblastine for Chemotherapy-Naïve Children With Progressive Low-Grade Glioma: A Canadian Pediatric Brain Tumor Consortium Study. J Clin Oncol 34 (29): 3537-3543, 2016. [PUBMED Abstract]
16. de Marcellus C, Tauziède-Espariat A, Cuinet A, et al.: The role of irinotecan-bevacizumab as rescue regimen in children with low-grade gliomas: a retrospective nationwide study in 72 patients. J Neurooncol 157 (2): 355-364, 2022. [PUBMED Abstract]
17. Warren KE, Vezina G, Krailo M, et al.: Phase II Randomized Trial of Lenalidomide in Children With Pilocytic Astrocytomas and Optic Pathway Gliomas: A Report From the Children’s Oncology Group. J Clin Oncol 41 (18): 3374-3383, 2023. [PUBMED Abstract]
18. Haas-Kogan DA, Aboian MS, Minturn JE, et al.: Everolimus for Children With Recurrent or Progressive Low-Grade Glioma: Results From the Phase II PNOC001 Trial. J Clin Oncol 42 (4): 441-451, 2024. [PUBMED Abstract]
19. Franz DN, Agricola KD, Tudor CA, et al.: Everolimus for tumor recurrence after surgical resection for subependymal giant cell astrocytoma associated with tuberous sclerosis complex. J Child Neurol 28 (5): 602-7, 2013. [PUBMED Abstract]
20. Krueger DA, Care MM, Holland K, et al.: Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med 363 (19): 1801-11, 2010. [PUBMED Abstract]
21. Weidman DR, Pole JD, Bouffet E, et al.: Dose-level response rates of mTor inhibition in tuberous sclerosis complex (TSC) related subependymal giant cell astrocytoma (SEGA). Pediatr Blood Cancer 62 (10): 1754-60, 2015. [PUBMED Abstract]
22. Franz DN, Leonard J, Tudor C, et al.: Rapamycin causes regression of astrocytomas in tuberous sclerosis complex. Ann Neurol 59 (3): 490-8, 2006. [PUBMED Abstract]
23. Franz DN, Belousova E, Sparagana S, et al.: Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet 381 (9861): 125-32, 2013. [PUBMED Abstract]
24. Franz DN, Agricola K, Mays M, et al.: Everolimus for subependymal giant cell astrocytoma: 5-year final analysis. Ann Neurol 78 (6): 929-38, 2015. [PUBMED Abstract]
25. Wright KD, Yao X, London WB, et al.: A POETIC Phase II study of continuous oral everolimus in recurrent, radiographically progressive pediatric low-grade glioma. Pediatr Blood Cancer 68 (2): e28787, 2021. [PUBMED Abstract]
26. Ullrich NJ, Prabhu SP, Reddy AT, et al.: A phase II study of continuous oral mTOR inhibitor everolimus for recurrent, radiographic-progressive neurofibromatosis type 1-associated pediatric low-grade glioma: a Neurofibromatosis Clinical Trials Consortium study. Neuro Oncol 22 (10): 1527-1535, 2020. [PUBMED Abstract]
27. Avery RA, Hwang EI, Jakacki RI, et al.: Marked recovery of vision in children with optic pathway gliomas treated with bevacizumab. JAMA Ophthalmol 132 (1): 111-4, 2014. [PUBMED Abstract]
28. Gururangan S, Fangusaro J, Poussaint TY, et al.: Efficacy of bevacizumab plus irinotecan in children with recurrent low-grade gliomas–a Pediatric Brain Tumor Consortium study. Neuro Oncol 16 (2): 310-7, 2014. [PUBMED Abstract]
29. Hwang EI, Jakacki RI, Fisher MJ, et al.: Long-term efficacy and toxicity of bevacizumab-based therapy in children with recurrent low-grade gliomas. Pediatr Blood Cancer 60 (5): 776-82, 2013. [PUBMED Abstract]
30. Packer RJ, Jakacki R, Horn M, et al.: Objective response of multiply recurrent low-grade gliomas to bevacizumab and irinotecan. Pediatr Blood Cancer 52 (7): 791-5, 2009. [PUBMED Abstract]
31. Green K, Panagopoulou P, D’Arco F, et al.: A nationwide evaluation of bevacizumab-based treatments in pediatric low-grade glioma in the UK: Safety, efficacy, visual morbidity, and outcomes. Neuro Oncol 25 (4): 774-785, 2023. [PUBMED Abstract]
32. Foster KA, Ares WJ, Pollack IF, et al.: Bevacizumab for symptomatic radiation-induced tumor enlargement in pediatric low grade gliomas. Pediatr Blood Cancer 62 (2): 240-245, 2015. [PUBMED Abstract]
33. Zhukova N, Rajagopal R, Lam A, et al.: Use of bevacizumab as a single agent or in adjunct with traditional chemotherapy regimens in children with unresectable or progressive low-grade glioma. Cancer Med 8 (1): 40-50, 2019. [PUBMED Abstract]
34. Sievert AJ, Lang SS, Boucher KL, et al.: Paradoxical activation and RAF inhibitor resistance of BRAF protein kinase fusions characterizing pediatric astrocytomas. Proc Natl Acad Sci U S A 110 (15): 5957-62, 2013. [PUBMED Abstract]
35. Karajannis MA, Legault G, Fisher MJ, et al.: Phase II study of sorafenib in children with recurrent or progressive low-grade astrocytomas. Neuro Oncol 16 (10): 1408-16, 2014. [PUBMED Abstract]
36. Odogwu L, Mathieu L, Blumenthal G, et al.: FDA Approval Summary: Dabrafenib and Trametinib for the Treatment of Metastatic Non-Small Cell Lung Cancers Harboring BRAF V600E Mutations. Oncologist 23 (6): 740-745, 2018. [PUBMED Abstract]
37. Hargrave DR, Bouffet E, Tabori U, et al.: Efficacy and Safety of Dabrafenib in Pediatric Patients with BRAF V600 Mutation-Positive Relapsed or Refractory Low-Grade Glioma: Results from a Phase I/IIa Study. Clin Cancer Res 25 (24): 7303-7311, 2019. [PUBMED Abstract]
38. Bouffet E, Geoerger B, Moertel C, et al.: Efficacy and Safety of Trametinib Monotherapy or in Combination With Dabrafenib in Pediatric BRAF V600-Mutant Low-Grade Glioma. J Clin Oncol 41 (3): 664-674, 2023. [PUBMED Abstract]
39. Banerjee A, Jakacki RI, Onar-Thomas A, et al.: A phase I trial of the MEK inhibitor selumetinib (AZD6244) in pediatric patients with recurrent or refractory low-grade glioma: a Pediatric Brain Tumor Consortium (PBTC) study. Neuro Oncol 19 (8): 1135-1144, 2017. [PUBMED Abstract]
40. Fangusaro J, Onar-Thomas A, Young Poussaint T, et al.: Selumetinib in paediatric patients with BRAF-aberrant or neurofibromatosis type 1-associated recurrent, refractory, or progressive low-grade glioma: a multicentre, phase 2 trial. Lancet Oncol 20 (7): 1011-1022, 2019. [PUBMED Abstract]
41. Fangusaro J, Onar-Thomas A, Poussaint TY, et al.: A phase II trial of selumetinib in children with recurrent optic pathway and hypothalamic low-grade glioma without NF1: a Pediatric Brain Tumor Consortium study. Neuro Oncol 23 (10): 1777-1788, 2021. [PUBMED Abstract]
42. Kilburn LB, Khuong-Quang DA, Hansford JR, et al.: The type II RAF inhibitor tovorafenib in relapsed/refractory pediatric low-grade glioma: the phase 2 FIREFLY-1 trial. Nat Med 30 (1): 207-217, 2024. [PUBMED Abstract]

To determine and implement optimal management, treatment is best guided by a multidisciplinary team of specialists experienced in treating pediatric patients with brain tumors.

The outcome for pediatric patients with the most common types of high-grade glioma (i.e., diffuse midline glioma, H3 K27-altered and diffuse pediatric-type high-grade glioma, H3-wild type and IDH-wild type) remains dismal.[1] In contrast, the prognosis for children with infant-type hemispheric glioma is relatively favorable.[2,3]

Maximal safe surgical resection can be considered standard of care for all patients with pediatric-type diffuse high-grade glioma.[4]

Standard adjuvant therapy for children with diffuse pediatric-type high-grade glioma, H3-wild type and IDH-wild type, includes radiation therapy and alkylator chemotherapy.[5–7]

For children with diffuse midline glioma, H3 K27-altered (the most common subtype), including those with diffuse intrinsic pontine glioma (DIPG), adjuvant radiation therapy alone can be considered standard of care given the apparent lack of benefit of chemotherapy.[8,9]

Standard treatment options for newly diagnosed pediatric-type diffuse high-grade gliomas include the following:

References

1. Mackay A, Burford A, Carvalho D, et al.: Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma. Cancer Cell 32 (4): 520-537.e5, 2017. [PUBMED Abstract]
2. Clarke M, Mackay A, Ismer B, et al.: Infant High-Grade Gliomas Comprise Multiple Subgroups Characterized by Novel Targetable Gene Fusions and Favorable Outcomes. Cancer Discov 10 (7): 942-963, 2020. [PUBMED Abstract]
3. Guerreiro Stucklin AS, Ryall S, Fukuoka K, et al.: Alterations in ALK/ROS1/NTRK/MET drive a group of infantile hemispheric gliomas. Nat Commun 10 (1): 4343, 2019. [PUBMED Abstract]
4. Hatoum R, Chen JS, Lavergne P, et al.: Extent of Tumor Resection and Survival in Pediatric Patients With High-Grade Gliomas: A Systematic Review and Meta-analysis. JAMA Netw Open 5 (8): e2226551, 2022. [PUBMED Abstract]
5. 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. [PUBMED Abstract]
6. Jakacki RI, Cohen KJ, Buxton A, et al.: Phase 2 study of concurrent radiotherapy and temozolomide followed by temozolomide and lomustine in the treatment of children with high-grade glioma: a report of the Children’s Oncology Group ACNS0423 study. Neuro Oncol 18 (10): 1442-50, 2016. [PUBMED Abstract]
7. Grill J, Massimino M, Bouffet E, et al.: Phase II, Open-Label, Randomized, Multicenter Trial (HERBY) of Bevacizumab in Pediatric Patients With Newly Diagnosed High-Grade Glioma. J Clin Oncol 36 (10): 951-958, 2018. [PUBMED Abstract]
8. Korshunov A, Ryzhova M, Hovestadt V, et al.: Integrated analysis of pediatric glioblastoma reveals a subset of biologically favorable tumors with associated molecular prognostic markers. Acta Neuropathol 129 (5): 669-78, 2015. [PUBMED Abstract]
9. Macy ME, Birks DK, Barton VN, et al.: Clinical and molecular characteristics of congenital glioblastoma. Neuro Oncol 14 (7): 931-41, 2012. [PUBMED Abstract]
10. Wisoff JH, Boyett JM, Berger MS, et al.: Current neurosurgical management and the impact of the extent of resection in the treatment of malignant gliomas of childhood: a report of the Children’s Cancer Group trial no. CCG-945. J Neurosurg 89 (1): 52-9, 1998. [PUBMED Abstract]
11. Yang T, Temkin N, Barber J, et al.: Gross total resection correlates with long-term survival in pediatric patients with glioblastoma. World Neurosurg 79 (3-4): 537-44, 2013 Mar-Apr. [PUBMED Abstract]
12. 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. [PUBMED Abstract]
13. 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. [PUBMED Abstract]
14. 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. [PUBMED Abstract]
15. Puget S, Beccaria K, Blauwblomme T, et al.: Biopsy in a series of 130 pediatric diffuse intrinsic Pontine gliomas. Childs Nerv Syst 31 (10): 1773-80, 2015. [PUBMED Abstract]
16. Gupta N, Goumnerova LC, Manley P, et al.: Prospective feasibility and safety assessment of surgical biopsy for patients with newly diagnosed diffuse intrinsic pontine glioma. Neuro Oncol 20 (11): 1547-1555, 2018. [PUBMED Abstract]
17. Pfaff E, El Damaty A, Balasubramanian GP, et al.: Brainstem biopsy in pediatric diffuse intrinsic pontine glioma in the era of precision medicine: the INFORM study experience. Eur J Cancer 114: 27-35, 2019. [PUBMED Abstract]
18. Kramm CM, Butenhoff S, Rausche U, et al.: Thalamic high-grade gliomas in children: a distinct clinical subset? Neuro Oncol 13 (6): 680-9, 2011. [PUBMED Abstract]
19. Tendulkar RD, Pai Panandiker AS, Wu S, et al.: Irradiation of pediatric high-grade spinal cord tumors. Int J Radiat Oncol Biol Phys 78 (5): 1451-6, 2010. [PUBMED Abstract]
20. Wolff B, Ng A, Roth D, et al.: Pediatric high grade glioma of the spinal cord: results of the HIT-GBM database. J Neurooncol 107 (1): 139-46, 2012. [PUBMED Abstract]
21. Ononiwu C, Mehta V, Bettegowda C, et al.: Pediatric spinal glioblastoma multiforme: current treatment strategies and possible predictors of survival. Childs Nerv Syst 28 (5): 715-20, 2012. [PUBMED Abstract]
22. 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. [PUBMED Abstract]
23. 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. [PUBMED Abstract]
24. 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. [PUBMED Abstract]
25. 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. [PUBMED Abstract]
26. 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. [PUBMED Abstract]
27. Izzuddeen Y, Gupta S, Haresh KP, et al.: Hypofractionated radiotherapy with temozolomide in diffuse intrinsic pontine gliomas: a randomized controlled trial. J Neurooncol 146 (1): 91-95, 2020. [PUBMED Abstract]
28. Zaghloul MS, Eldebawy E, Ahmed S, et al.: Hypofractionated conformal radiotherapy for pediatric diffuse intrinsic pontine glioma (DIPG): a randomized controlled trial. Radiother Oncol 111 (1): 35-40, 2014. [PUBMED Abstract]
29. 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. [PUBMED Abstract]
30. Zaghloul MS, Nasr A, Tolba M, et al.: Hypofractionated Radiation Therapy For Diffuse Intrinsic Pontine Glioma: A Noninferiority Randomized Study Including 253 Children. Int J Radiat Oncol Biol Phys 113 (2): 360-368, 2022. [PUBMED Abstract]
31. 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. [PUBMED Abstract]
32. 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. [PUBMED Abstract]
33. 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. [PUBMED Abstract]
34. 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. [PUBMED Abstract]
35. Stupp R, Mason WP, van den Bent MJ, et al.: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352 (10): 987-96, 2005. [PUBMED Abstract]
36. Hegi ME, Diserens AC, Gorlia T, et al.: MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352 (10): 997-1003, 2005. [PUBMED Abstract]
37. Mackay A, Burford A, Molinari V, et al.: Molecular, Pathological, Radiological, and Immune Profiling of Non-brainstem Pediatric High-Grade Glioma from the HERBY Phase II Randomized Trial. Cancer Cell 33 (5): 829-842.e5, 2018. [PUBMED Abstract]
38. 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. [PUBMED Abstract]
39. 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. [PUBMED Abstract]
40. Hargrave D, Bartels U, Bouffet E: Diffuse brainstem glioma in children: critical review of clinical trials. Lancet Oncol 7 (3): 241-8, 2006. [PUBMED Abstract]
41. 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. [PUBMED Abstract]
42. 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. [PUBMED Abstract]
43. Waters TW, Moore SA, Sato Y, et al.: Refractory infantile high-grade glioma containing TRK-fusion responds to larotrectinib. Pediatr Blood Cancer 68 (5): e28868, 2021. [PUBMED Abstract]
44. Duffner PK, Horowitz ME, Krischer JP, et al.: Postoperative chemotherapy and delayed radiation in children less than three years of age with malignant brain tumors. N Engl J Med 328 (24): 1725-31, 1993. [PUBMED Abstract]
45. Nobre L, Zapotocky M, Ramaswamy V, et al.: Outcomes of BRAF V600E Pediatric Gliomas Treated With Targeted BRAF Inhibition. JCO Precis Oncol 4: , 2020. [PUBMED Abstract]
46. Ziegler DS, Wong M, Mayoh C, et al.: Brief Report: Potent clinical and radiological response to larotrectinib in TRK fusion-driven high-grade glioma. Br J Cancer 119 (6): 693-696, 2018. [PUBMED Abstract]
47. Doz F, van Tilburg CM, Geoerger B, et al.: Efficacy and safety of larotrectinib in TRK fusion-positive primary central nervous system tumors. Neuro Oncol 24 (6): 997-1007, 2022. [PUBMED Abstract]
48. Bouffet E, Larouche V, Campbell BB, et al.: Immune Checkpoint Inhibition for Hypermutant Glioblastoma Multiforme Resulting From Germline Biallelic Mismatch Repair Deficiency. J Clin Oncol 34 (19): 2206-11, 2016. [PUBMED Abstract]

To determine and implement optimal management, treatment is best guided by a multidisciplinary team of specialists experienced in treating pediatric patients with brain tumors.

Treatment options for recurrent pediatric-type diffuse high-grade gliomas include the following:

References

1. Tsang DS, Oliveira C, Bouffet E, et al.: Repeat irradiation for children with supratentorial high-grade glioma. Pediatr Blood Cancer 66 (9): e27881, 2019. [PUBMED Abstract]
2. Janssens GO, Gandola L, Bolle S, et al.: Survival benefit for patients with diffuse intrinsic pontine glioma (DIPG) undergoing re-irradiation at first progression: A matched-cohort analysis on behalf of the SIOP-E-HGG/DIPG working group. Eur J Cancer 73: 38-47, 2017. [PUBMED Abstract]
3. Lassaletta A, Strother D, Laperriere N, et al.: Reirradiation in patients with diffuse intrinsic pontine gliomas: The Canadian experience. Pediatr Blood Cancer 65 (6): e26988, 2018. [PUBMED Abstract]
4. Amsbaugh MJ, Mahajan A, Thall PF, et al.: A Phase 1/2 Trial of Reirradiation for Diffuse Intrinsic Pontine Glioma. Int J Radiat Oncol Biol Phys 104 (1): 144-148, 2019. [PUBMED Abstract]
5. Cacciotti C, Liu KX, Haas-Kogan DA, et al.: Reirradiation practices for children with diffuse intrinsic pontine glioma. Neurooncol Pract 8 (1): 68-74, 2021. [PUBMED Abstract]
6. Nobre L, Zapotocky M, Ramaswamy V, et al.: Outcomes of BRAF V600E Pediatric Gliomas Treated With Targeted BRAF Inhibition. JCO Precis Oncol 4: , 2020. [PUBMED Abstract]
7. Wen PY, Stein A, van den Bent M, et al.: Dabrafenib plus trametinib in patients with BRAFV600E-mutant low-grade and high-grade glioma (ROAR): a multicentre, open-label, single-arm, phase 2, basket trial. Lancet Oncol 23 (1): 53-64, 2022. [PUBMED Abstract]
8. Novartis Pharmaceuticals Corporation: TAFINLAR (dabrafenib): Prescribing Information. East Hanover, New Jersey: Novartis Pharmaceuticals Corporation, 2023. Available online. Last accessed February 7, 2024.
9. Novartis Pharmaceuticals Corporation: MEKINIST (trametinib): Prescribing Information. East Hanover, New Jersey: Novartis Pharmaceuticals Corporation, 2023. Available online. Last accessed February 7, 2024.
10. Hargrave DR, Terashima K, Hara J, et al.: Phase II Trial of Dabrafenib Plus Trametinib in Relapsed/Refractory BRAF V600-Mutant Pediatric High-Grade Glioma. J Clin Oncol 41 (33): 5174-5183, 2023. [PUBMED Abstract]
11. Clarke M, Mackay A, Ismer B, et al.: Infant High-Grade Gliomas Comprise Multiple Subgroups Characterized by Novel Targetable Gene Fusions and Favorable Outcomes. Cancer Discov 10 (7): 942-963, 2020. [PUBMED Abstract]
12. Guerreiro Stucklin AS, Ryall S, Fukuoka K, et al.: Alterations in ALK/ROS1/NTRK/MET drive a group of infantile hemispheric gliomas. Nat Commun 10 (1): 4343, 2019. [PUBMED Abstract]
13. Desai AV, Robinson GW, Gauvain K, et al.: Entrectinib in children and young adults with solid or primary CNS tumors harboring NTRK, ROS1, or ALK aberrations (STARTRK-NG). Neuro Oncol 24 (10): 1776-1789, 2022. [PUBMED Abstract]
14. Parsons DW, Janeway KA, Patton DR, et al.: Actionable Tumor Alterations and Treatment Protocol Enrollment of Pediatric and Young Adult Patients With Refractory Cancers in the National Cancer Institute-Children’s Oncology Group Pediatric MATCH Trial. J Clin Oncol 40 (20): 2224-2234, 2022. [PUBMED Abstract]
15. Dunkel IJ, Doz F, Foreman NK, et al.: Nivolumab with or without ipilimumab in pediatric patients with high-grade CNS malignancies: Safety, efficacy, biomarker, and pharmacokinetics-CheckMate 908. Neuro Oncol 25 (8): 1530-1545, 2023. [PUBMED Abstract]
16. Monje M, Mahdi J, Majzner R, et al.: Intravenous and intracranial GD2-CAR T cells for H3K27M+ diffuse midline gliomas. Nature 637 (8046): 708-715, 2025. [PUBMED Abstract]
17. Bouffet E, Larouche V, Campbell BB, et al.: Immune Checkpoint Inhibition for Hypermutant Glioblastoma Multiforme Resulting From Germline Biallelic Mismatch Repair Deficiency. J Clin Oncol 34 (19): 2206-11, 2016. [PUBMED Abstract]
18. Warren KE, Gururangan S, Geyer JR, et al.: A phase II study of O6-benzylguanine and temozolomide in pediatric patients with recurrent or progressive high-grade gliomas and brainstem gliomas: a Pediatric Brain Tumor Consortium study. J Neurooncol 106 (3): 643-9, 2012. [PUBMED Abstract]

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.

General Information About Childhood Astrocytomas, Other Gliomas, and Glioneuronal/Neuronal Tumors

Added text to state that prognosis is generally favorable for patients with MYB/MYBL1-altered tumors, particularly when a gross-total resection or near-total resection is obtained at the time of surgery (cited Moreira et al. as reference 35).

Added Gestrich et al. as reference 55.

Treatment of Circumscribed Astrocytic Gliomas, Pediatric-Type Diffuse Low-Grade Gliomas, and Glioneuronal/Neuronal Tumors

Added text to state that a multi-institutional retrospective study of children with IDH-altered low-grade gliomas revealed that 39 of 45 patients were managed with observation after surgery, including 20 patients who underwent biopsy or subtotal resection only. For these 39 patients, the 5-year progression-free survival (PFS) rate was 42%, and the 10-year PFS rate was 0%, with a median PFS of 4.76 years. The extent of resection did not significantly impact survival (cited Yeo et al. as reference 19).

Added text to state that the U.S. Food and Drug Administration (FDA) approved vorasidenib for adult and pediatric patients aged 12 years and older with grade 2 astrocytomas or oligodendrogliomas and a susceptible IDH1 or IDH2 variant after surgery, which includes biopsy, subtotal resection, or gross-total resection.

Treatment of Progressive/Recurrent Circumscribed Astrocytic Gliomas, Pediatric-Type Diffuse Low-Grade Gliomas, and Glioneuronal/Neuronal Tumors

Added text to state that in 2024, the FDA granted accelerated approval to tovorafenib for the treatment of patients aged 6 months or older with relapsed or refractory low-grade glioma harboring a BRAF fusion or rearrangement or BRAF V600 variant. Also added text about the results of a study of 137 patients who were treated with tovorafenib, which led to the FDA approval (cited Kilburn et al. as reference 42).

Treatment of Recurrent Pediatric-Type Diffuse High-Grade Gliomas

Added Dunkel et al. as reference 15. Also added text to state that GD2-chimeric antigen receptor (CAR) T cells were administered intravenously and intraventricularly in a small study of 11 patients to treat H3 K27M-altered diffuse midline gliomas. The paper describes a reduction in tumor volume for some patients. However, in a number of cases, the contribution of the CAR T-cell therapy to the tumor reduction is difficult to separate from the effects of the antecedent radiation therapy treatment. This treatment required substantial supportive care, including early placement of an Ommaya reservoir to manage central nervous system complications, which included both immune effector cell acute neurotoxicity syndrome and tumor inflammation–associated neurotoxicity (cited Monje et al. as reference 16).

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® Cancer Information for Health Professionals pages.