EnlargeCraniopharyngiomas are rare brain tumors that usually form near the pituitary gland and the hypothalamus. They are benign (not cancer) and do not spread to other parts of the brain or to other parts of the body. However, they may grow and press on nearby parts of the brain, including the pituitary gland, optic chiasm, and optic nerve. Craniopharyngiomas usually occur in children and young adults.
Craniopharyngiomas are usually part solid mass and part fluid-filled cyst. They are benign (not cancer) and do not spread to other parts of the brain or to other parts of the body. However, they may grow and press on nearby parts of the brain or other areas, including the pituitary gland, the optic chiasm, optic nerves, and fluid-filled spaces in the brain. Craniopharyngiomas may affect many functions of the brain. They may affect the hormone making process, growth, and vision. Benign brain tumors need treatment.
This summary is about the treatment of primary brain tumors (tumors that begin in the brain). Treatment of metastatic brain tumors, which are tumors formed by cancer cells that begin in other parts of the body and spread to the brain, is not covered in this summary.
Brain tumors can occur in both children and adults; however, treatment for children may be different than treatment for adults. For information about treatment for adults, see Adult Central Nervous System Tumors Treatment.
There are no known risk factors for childhood craniopharyngioma.
Craniopharyngiomas are rare in children younger than 2 years of age and are most often diagnosed in children aged 5 to 14 years. It is not known what causes these tumors.
Signs of childhood craniopharyngioma include vision changes and slow growth.
These and other signs and symptoms may be caused by craniopharyngiomas or by other conditions. Check with your child’s doctor if your child has any of the following:
headaches, including morning headache or headache that goes away after vomiting
Tests that examine the brain, vision, and hormone levels are used to detect (find) childhood craniopharyngiomas.
In addition to asking about your child’s personal and family health history and doing a physical exam, your child’s doctor may perform the following tests and procedures:
Neurological exam: A series of questions and tests to check the brain, spinal cord, and nerve function. The exam checks a person’s mental status, coordination, and ability to walk normally, and how well the muscles, senses, and reflexes work. This may also be called a neuro exam or a neurologic exam.
Visual field exam: An exam to check a person’s field of vision (the total area in which objects can be seen). This test measures both central vision (how much a person can see when looking straight ahead) and peripheral vision (how much a person can see in all other directions while staring straight ahead). Any loss of vision may be a sign of a tumor that has damaged or pressed on the parts of the brain that affect eyesight.
CT scan (CAT scan): A procedure that makes a series of detailed pictures of areas inside the body, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography.
MRI (magnetic resonance imaging) of the brain and spinal cord with gadolinium: A procedure that 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 tumor cells so they show up brighter in the picture. This procedure is also called nuclear magnetic resonance imaging (NMRI).
Blood chemistry studies: A procedure in which a blood sample is checked to measure the amounts of certain substances released into the blood by organs and tissues in the body. An unusual (higher or lower than normal) amount of a substance can be a sign of disease.
Blood hormone studies: A procedure in which a blood sample is checked to measure the amounts of certain hormones released into the blood by organs and tissues in the body. An unusual (higher or lower than normal) amount of a substance can be a sign of disease in the organ or tissue that makes it. For example, the blood may be checked for unusual levels of thyroid-stimulating hormone (TSH) or adrenocorticotropic hormone (ACTH). TSH and ACTH are made by the pituitary gland in the brain.
Childhood craniopharyngiomas may be diagnosed and removed in the same surgery.
Doctors may think a mass is a craniopharyngioma based on where it is in the brain and how it looks on a CT scan or MRI. In order to be sure, a sample of tissue is needed.
One of the following types of biopsy procedures may be used to take the sample of tissue:
Open biopsy: A hollow needle is inserted through a hole in the skull into the brain.
Computer-guided needle biopsy: A hollow needle guided by a computer is inserted through a small hole in the skull into the brain.
Transsphenoidal biopsy: Instruments are inserted through the nose and sphenoid bone (a butterfly-shaped bone at the base of the skull) and into the brain.
A pathologist views the tissue under a microscope to look for tumor cells. If tumor cells are found, as much tumor as safely possible may be removed during the same surgery.
The following laboratory test may be done on the sample of tissue that is removed:
Immunohistochemistry: A laboratory test that 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 of cancer.
Certain factors affect prognosis (chance of recovery) and treatment options.
The prognosis and treatment options depend on the following:
the size of the tumor
where the tumor is in the brain
whether there are tumor cells left after surgery
the child’s age
side effects that may occur months or years after treatment
whether the tumor has just been diagnosed or has recurred (come back)
Stages of Childhood Craniopharyngioma
Key Points
There is no standard staging system for childhood craniopharyngioma.
Sometimes childhood craniopharyngioma comes back after treatment.
There is no standard staging system for childhood craniopharyngioma.
The results of the tests and procedures done to diagnose craniopharyngioma are used to help make decisions about treatment.
Sometimes childhood craniopharyngioma comes back after treatment.
The tumor may come back in the same area of the brain where it was first found.
Treatment Option Overview
Key Points
There are different types of treatment for children with craniopharyngioma.
Children with craniopharyngioma should have their treatment planned by a team of health care providers who are experts in treating brain tumors in children.
Childhood brain tumors may cause signs or symptoms that begin before the cancer is diagnosed and continue for months or years.
The following types of treatment may be used:
Surgery (resection)
Radiation therapy
Cyst drainage
Chemotherapy
Immunotherapy
New types of treatment are being tested in clinical trials.
Treatment for childhood craniopharyngioma may cause side effects.
Patients may want to think about taking part in a clinical trial.
Patients can enter clinical trials before, during, or after starting their treatment.
Follow-up tests may be needed.
There are different types of treatment for children with craniopharyngioma.
Some treatments are standard (the currently used treatment), and some are being tested in clinical trials. A treatment clinical trial is a research study meant to help improve current treatments or obtain information on new treatments for patients with tumors. When clinical trials show that a new treatment is better than the standard treatment, the new treatment may become the standard treatment.
Because tumors in children are rare, taking part in a clinical trial should be considered. Clinical trials are taking place in many parts of the country. Information about ongoing clinical trials is available from the NCI website. Choosing the most appropriate treatment is a decision that ideally involves the patient, family, and health care team.
Children with craniopharyngioma should have their treatment planned by a team of health care providers who are experts in treating brain tumors in children.
Treatment will be overseen by a pediatric oncologist, a doctor who specializes in treating children with tumors. The pediatric oncologist works with other pediatrichealth care providers who are experts in treating children with brain tumors and who specialize in certain areas of medicine. These may include the following specialists:
Childhood brain tumors may cause signs or symptoms that begin before the cancer is diagnosed and continue for months or years.
Signs or symptoms caused by the tumor may begin before diagnosis and continue for months or years. It is important to talk with your child’s doctors about signs or symptoms caused by the tumor that may continue after treatment.
The following types of treatment may be used:
Surgery (resection)
The way the surgery is done depends on the size of the tumor, where it is in the brain, and whether the tumor has grown into nearby tissue in a finger-like way. It also depends on expected late effects after surgery.
The types of surgery that may be used to remove all of the tumor that can be seen with the eye include the following:
Transsphenoidal surgery: A type of surgery in which the instruments are inserted into part of the brain by going through an incision (cut) made under the upper lip or at the bottom of the nose between the nostrils and then through the sphenoid bone (a butterfly-shaped bone at the base of the skull) to reach the tumor near the pituitary gland and hypothalamus. EnlargeTranssphenoidal surgery. An endoscope and a curette are inserted through the nose and sphenoid sinus to remove the tumor.
Craniotomy: Surgery to remove the tumor through an opening made in the skull. EnlargeCraniotomy. An opening is made in the skull and a piece of the skull is removed to show part of the brain.
Partial resection may be used to diagnose the tumor. It can also be used as a treatment to remove fluid from tumors that are mostly fluid-filled cysts and relieve pressure on the optic nerves. If the tumor is near the pituitary gland or hypothalamus, it is not removed. This reduces the number of serious side effects after surgery.
Sometimes all of the tumor that can be seen is removed in surgery, and no further treatment is needed. At other times, it is hard to remove the tumor because it is growing into or pressing on nearby organs. If there is tumor remaining after the surgery, radiation therapy is usually given to kill any tumor cells that are left. Treatment given after the surgery, to lower the risk that the cancer will come back, is called adjuvant therapy.
Radiation therapy
Radiation therapy is a tumor treatment that uses high-energy x-rays or other types of radiation to kill tumor cells or keep them from growing. There are two types of radiation therapy:
External radiation therapy uses a machine outside the body to send radiation toward the area of the body with the tumor.
The way the radiation therapy is given depends on the type of tumor, whether the tumor is newly diagnosed or has come back, and where the tumor formed in the brain. External and internal radiation therapy are used to treat childhood craniopharyngioma.
Because radiation therapy to the brain can affect growth and development in young children, ways of giving radiation therapy that have fewer side effects are being used. These include:
Stereotactic radiosurgery: For very small craniopharyngiomas at the base of the brain, stereotactic radiosurgery may be used. Stereotactic radiosurgery is a type of external radiation therapy. A rigid head frame is attached to the skull to keep the head still during the radiation treatment. A machine aims a single large dose of radiation directly at the tumor. This procedure does not involve surgery. It is also called stereotaxic radiosurgery, radiosurgery, and radiation surgery.
Intracavitary radiation therapy: Intracavitary radiation therapy is a type of internal radiation therapy that may be used in tumors that are part solidmass and part fluid-filled cyst. Radioactive material is placed inside the tumor. This type of radiation therapy causes less damage to the nearby hypothalamus and optic nerves.
Intensity-modulated photon therapy: A type of radiation therapy that uses x-rays or gamma rays that come from a special machine called a linear accelerator (linac) to kill tumor cells. A computer is used to target the exact shape and location of the tumor. Thin beams of photons of different intensities are aimed at the tumor from many angles. This type of 3-dimensional radiation therapy may cause less damage to healthy tissue in the brain and other parts of the body. Photon therapy is different from proton therapy.
Proton-beam radiation therapy: A type of radiation therapy that uses streams of protons (tiny particles with a positive charge) to kill tumor cells. This treatment can reduce the amount of radiation damage to healthy tissue near a tumor. Proton radiation is different from x-ray radiation.
Cyst drainage
Surgery may be done to drain tumors that are mostly fluid-filled cysts. This lowers pressure in the brain and relieves symptoms. A catheter (thin tube) is inserted into the cyst, and a small container is placed under the skin. The fluid drains into the container and is later removed. Sometimes, after the cyst is drained, a drug is put through the catheter into the cyst. This causes the inside wall of the cyst to scar and stops the cyst from making fluid or increases the amount of time it takes for the fluid to build up again. Surgery to remove the tumor or radiation therapy may be done after the cyst is drained.
Chemotherapy
Chemotherapy is a treatment that uses anticancer drugs to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Intracavitary chemotherapy is a type of regional chemotherapy that places drugs directly into a cavity, such as a cyst. It is used for craniopharyngioma that has come back after treatment.
Immunotherapy
Immunotherapy uses the patient’s immune system to fight cancer. Substances made by the body or made in a laboratory are used to boost, direct, or restore the body’s natural defenses against cancer. For craniopharyngioma, the immunotherapy drug (interferon-alpha) is placed in a vein (intravenous) or inside the tumor using a catheter (intracavitary).
In newly diagnosed children, interferon-alpha may be placed directly into the cyst (intracystic) to delay the need for surgery or radiation therapy. In children whose tumor has recurred (come back), intracavitary interferon-alpha is used to treat the cyst part of the tumor.
New types of treatment are being tested in clinical trials.
This summary section describes treatments that are being studied in clinical trials. It may not mention every new treatment being studied. Information about clinical trials is available from the NCI website.
Treatment for childhood craniopharyngioma may cause side effects.
Side effects from tumor treatment that begin after treatment and continue for months or years are called late effects. Late effects of tumor treatment may include the following:
The following serious physical problems may occur if the pituitary gland, hypothalamus, optic nerves, or carotid artery are affected during surgery or radiation therapy:
Some late effects may be treated or controlled. Life-long hormone replacement therapy with several medicines may be needed. It is important to talk with your child’s doctors about the effects tumor treatment can have on your child. For more information, see Late Effects of Treatment for Childhood Cancer.
Patients may want to think about taking part in a clinical trial.
For some patients, taking part in a clinical trial may be the best treatment choice. Clinical trials are part of the medical research process. Clinical trials are done to find out if new treatments are safe and effective or better than the standard treatment.
Many of today’s standard treatments are based on earlier clinical trials. Patients who take part in a clinical trial may receive the standard treatment or be among the first to receive a new treatment.
Patients who take part in clinical trials also help improve the way diseases will be treated in the future. Even when clinical trials do not lead to effective new treatments, they often answer important questions and help move research forward.
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.
Patients can enter clinical trials before, during, or after starting their treatment.
Some clinical trials only include patients who have not yet received treatment. Other trials test treatments for patients who have not improved. There are also clinical trials that test new ways to stop a disease from recurring (coming back) or reduce the side effects of treatment.
Clinical trials are taking place in many parts of the country. Information about clinical trials supported by NCI can be found on NCI’s clinical trials search webpage. Clinical trials supported by other organizations can be found on the ClinicalTrials.gov website.
Follow-up tests may be needed.
Some of the tests that were done to diagnose the disease or decide how to treat it may be repeated. Some tests will be repeated in order 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 condition has changed. These tests are sometimes called follow-up tests or check-ups.
After treatment, follow-up testing with MRI will be done for several years to check if the tumor has come back.
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.
Treatment of Recurrent Childhood Craniopharyngioma
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.
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.
To Learn More About Childhood Craniopharyngioma and Other Childhood Brain Tumors
For more information about childhood craniopharyngioma and other childhood brain tumors, see the following:
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Purpose of This Summary
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Clinical Trial Information
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Clinical trials can be found online at NCI’s website. For more information, call the Cancer Information Service (CIS), NCI’s contact center, at 1-800-4-CANCER (1-800-422-6237).
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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.
Incidence
Craniopharyngiomas are relatively uncommon, accounting for about 3% of all intracranial tumors in children.[1,4,5]
No predisposing factors have been identified.
Anatomy
EnlargeFigure 1. Anatomy of the inside of the brain, showing the pineal and pituitary glands, optic nerve, ventricles (with cerebrospinal fluid shown in blue), and other parts of the brain. The tentorium separates the cerebrum from the cerebellum. The infratentorium (posterior fossa) is the region below the tentorium that contains the brain stem, cerebellum, and fourth ventricle. The supratentorium is the region above the tentorium and denotes the region that contains the cerebrum.
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]
EnlargeFigure 2. Drawing showing a coronal view of the inside of the brain where craniopharyngiomas may form. The tumor usually occurs in the region of the pituitary gland, near the optic chiasm and optic nerves.
Diagnostic Evaluation
CT and MRI scans are often diagnostic for childhood craniopharyngiomas, with most tumors demonstrating intratumoral calcifications and a solid and cystic component. MRI of the spinal axis is not routinely performed.
Craniopharyngiomas without calcification may be confused with other tumor types, including germ cell tumors, hypothalamic/chiasmatic astrocytomas, or Langerhans cell histiocytosis. Biopsy or resection is required to confirm the diagnosis.[17]
Apart from imaging, patients undergo endocrine testing and formal vision examination, including visual-field evaluation.
Prognosis
Regardless of the treatment modality, the 5-year and 10-year overall survival rates range from 80% to 90% in children between the ages of 0 and 14 years.[1,18–21] The event-free survival (EFS) rates can be more variable, depending on therapy and clinical characteristics of the patient and tumor. EFS rates range from 23% for younger children to 65% for school-aged children.[22,23]
References
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]
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]
WHO Classification of Tumours Editorial Board, ed.: WHO Classification of Tumours: Central Nervous System Tumours. Vol. 6. 5th ed. IARC Press; 2021.
Karavitaki N, Wass JA: Craniopharyngiomas. Endocrinol Metab Clin North Am 37 (1): 173-93, ix-x, 2008. [PUBMED Abstract]
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]
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]
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]
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]
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]
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]
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]
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]
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]
Felicetti F, Brignardello E, van Santen HM, eds.: Endocrine and Metabolic Late Effects in Cancer Survivors. Basel, Switzerland: Karger, 2021.
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]
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]
Muller HL: Childhood craniopharyngioma. Recent advances in diagnosis, treatment and follow-up. Horm Res 69 (4): 193-202, 2008. [PUBMED Abstract]
Müller HL: Childhood craniopharyngioma–current concepts in diagnosis, therapy and follow-up. Nat Rev Endocrinol 6 (11): 609-18, 2010. [PUBMED Abstract]
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]
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]
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]
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]
Histopathological Classification of Childhood Craniopharyngioma
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]
Adamantinomatous: Adamantinomatous craniopharyngiomas most frequently occur in children.[2] These tumors are typically composed of a solid portion formed by nests and trabeculae of epithelial tumor cells, with an abundance of calcification, and a cystic component that is filled with a dark, oily fluid. Wet keratin is also characteristic of this tumor type. Adamantinomatous craniopharyngiomas are more locally aggressive than are papillary craniopharyngiomas and have a significantly higher rate of recurrence.[3] Activating CTNNB1 gene variants are found in most adamantinomatous tumors.[1,4–6]
Papillary: Papillary craniopharyngiomas occur primarily in adults. BRAF V600E variants are observed in nearly all papillary craniopharyngiomas.[1,5,6]
References
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]
Karavitaki N, Wass JA: Craniopharyngiomas. Endocrinol Metab Clin North Am 37 (1): 173-93, ix-x, 2008. [PUBMED Abstract]
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]
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]
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]
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]
Stage Information for Childhood Craniopharyngioma
There is no generally applied staging system for childhood craniopharyngiomas. For treatment purposes, patients are grouped as having newly diagnosed or recurrent disease.
Treatment Option Overview for Childhood Craniopharyngioma
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.
Table 1. Treatment Options for Childhood Craniopharyngioma
Lohkamp LN, Kasper EM, Pousa AE, et al.: An update on multimodal management of craniopharyngioma in children. Front Oncol 13: 1149428, 2023. [PUBMED Abstract]
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]
Treatment of Newly Diagnosed Childhood Craniopharyngioma
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:
Tumor size.
Tumor location.
Extension of the tumor.
Potential short-term and long-term toxicity, partially related to baseline neuroendocrine and vision deficits (i.e., more conservative surgical approaches may be prioritized in patients who do not have existing neuroendocrine or visual deficits to mitigate the risk of surgical morbidity).[1]
Established treatment options for newly diagnosed childhood craniopharyngioma include the following:
Complete Resection With or Without Radiation Therapy
It may be possible to remove all visible tumor and achieve long-term disease control.[2–4][Level of evidence C1] A 5-year progression-free survival (PFS) rate of about 65% has been reported.[5] Reported recurrence rates range from less than 10% to nearly 50%.[6,7] Gross-total resection is often technically challenging because the tumor is surrounded by vital structures, including the optic nerves and chiasm, the carotid artery and its branches, the pituitary and hypothalamus, and the third cranial nerve. These structures may limit the ability to remove the entire tumor. Conservative surgical approaches are often used to preserve functional and quality-of-life outcomes.[8,9][Level of evidence C1]
Many surgical approaches have been described, and the choice is determined by tumor size, location, extension, and the patient’s baseline signs and symptoms of disease. Surgical approaches include the following:
Craniotomy: As noted above, gross-total resection may be technically challenging because the tumor is surrounded by vital structures. The surgeon often has a limited view of the hypothalamic and sellar regions, and portions of the mass may remain after surgery, accounting for some recurrences. An understanding of the complex variations in how the tumors grow anatomically may help facilitate gross-total resection.[10] Nonetheless, almost all craniopharyngiomas attach to the pituitary stalk. Of the patients who undergo complete resection, virtually all will require lifelong pituitary hormone replacement with multiple medications.[3,11]
Transsphenoidal approach: A transsphenoidal approach has been proven possible in patients of all ages and for tumors of various sizes localized within the sella.[12]; [13][Level of evidence C1] The development of expanded endonasal techniques with endoscopic visualization has allowed increased use of this approach, even for sizeable childhood tumors, which is similar to the experience in adults.[14] A complete resection can be obtained using this approach, with associated complications of panhypopituitarism and the risk of cerebrospinal fluid leaks.[15,16] When an endonasal approach is not possible, a craniotomy is required.
Complications of complete resection using either approach include the following:
Death from intraoperative hemorrhage, hypothalamic damage, or stroke (rare).
If the surgeon indicates that the tumor was not completely removed or if postoperative imaging reveals residual craniopharyngioma, radiation therapy may be recommended to prevent early progression.[19][Level of evidence C2] For more information, see the Subtotal Resection With Radiation Therapy section.
Routine surveillance using magnetic resonance imaging is performed for several years after complete resection because of the possibility of tumor recurrence.
Subtotal Resection With Radiation Therapy
The goal of limited surgery can be to establish a diagnosis, drain cystic components of the tumor, and decompress surrounding anatomical structures. In subtotal resections, removal of the tumor from the pituitary stalk or hypothalamus is typically avoided to minimize the late effects associated with complete resection.[20]
Surgery is often followed by radiation therapy, because radiation therapy can decrease the risk of recurrence after a subtotal resection.[21] With this approach, the 5-year PFS rates are approximately 70% to 90%,[5,22–25]; [26][Level of evidence C1] and the 10-year overall survival (OS) rates exceed 90%, which are similar to the rates in patients who undergo a gross-total resection.[27,28][Level of evidence C1]; [29][Level of evidence C2] Most often, radiation therapy is timed to immediately follow subtotal resection. However, in certain cases, such as in young patients or in patients without existing neuroendocrine or visual deficits, serial imaging may be used to delay or avoid radiation therapy for as long as feasible.[7,30] The standard approach to radiation therapy involves fractionated external-beam radiation, with a recommended dose of 50 to 54 Gy, in 1.8-Gy fractions, restricting the optic chiasm dose to 54 Gy.[31–34] Newer radiation technologies such as intensity-modulated photon therapy and proton-beam radiation therapy may reduce the radiation dose to uninvolved parts of the brain and spare normal tissue.[23,34–36] It is unknown whether such techniques reduce the late effects of radiation therapy.[26,34,36,37] Transient cyst enlargement may be noted during radiation therapy, and serial imaging may be required during radiation therapy to assess cyst changes and consider updates to radiation mapping.[38][Level of evidence C3]
Surgical complications with a subtotal resection can be similar to, but are less likely than, with a complete resection. If radiation therapy is used, additional complications must be considered, including the following:
Loss of pituitary hormonal function.
Cognitive dysfunction.
Development of late strokes and vascular malformations.
Delayed blindness.
Development of second tumors.
Malignant transformation of the primary tumor within the radiation field (rare).[39,40]
A phase II single-arm study included 94 patients (aged 12 months to 21 years) with craniopharyngiomas who were treated with proton-beam radiation therapy after individualized surgical resection. These patients were compared with a historical cohort of patients who were treated with photon-beam radiation therapy.[41] The survival outcomes of patients who received proton therapy were similar to those of patients who received photon therapy. The cumulative incidence rates of necrosis, vasculopathy, changes in vision, and severe complications were also similar between the two groups of patients. However, patients treated with proton therapy in the more recent cohort had superior cognitive outcomes.
A long-term study of 101 children who were treated for craniopharyngiomas evaluated visual, neurocognitive, and endocrine outcomes after photon radiation therapy. Race and presence of a shunt affected baseline scores.[42] For children who presented with lower intelligence quotient (IQ) scores at diagnosis, the impact of treatment often resulted in an IQ score reduction to the borderline mental disability range of 70 to 84. The investigators demonstrated that age at treatment (younger children had worse outcomes), radiation dose to the temporal lobes and hippocampi, and visual impairment significantly impacted neurocognitive function after radiation therapy. This study demonstrates the importance of these factors in the treatment and late effects of craniopharyngioma.
A report from the prospective registry study KiProReg examined the use of proton-beam therapy in 84 children younger than 18 years with craniopharyngioma.[43] The estimated 3-year OS rate was 98.2%, and the PFS 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.
Primary Cyst Drainage With or Without Radiation Therapy
For predominantly cystic craniopharyngiomas, stereotactic drainage of the cyst, insertion of a catheter from which drainage can be facilitated, or cyst fenestration are other therapeutic alternatives.[7,44] This can be followed by observation or radiation therapy, depending on clinical and tumor characteristics . This procedure may also allow the surgeon to use the following two-staged approach:[45]
Draining the cyst to relieve pressure and complicating symptoms.
Resecting the tumor or employing radiation therapy later.
A systematic review of publications on the treatment of cystic craniopharyngiomas with radioisotope brachytherapy from 2010 to 2021 identified 66 pediatric patients (N = 228).[55] With a minimum follow-up of 5 years, partial and complete responses were achieved in 89% of children with purely cystic lesions, compared with 58% of children with nonexclusively cystic lesions. Visual improvement was achieved in 64% of the patients with purely cystic lesions, and endocrine improvement was achieved in 20% of these patients. The observed progression rate was 3% for patients with purely cystic lesions. Treatment with intracystic brachytherapy, most commonly using 32P and yttrium Y 90, can be considered for patients with purely cystic craniopharyngiomas.
Treatment Options Under Clinical Evaluation
Information about NCI-supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.
Preclinical contemporary evaluations have identified active molecular and immune pathways in craniopharyngioma that may be targetable using commercially available or investigational agents. Specifically, MAPK and RAF pathways and immune/inflammatory targets such as PD-1 pathway components and IL-6 have been identified.[7,56–61][Level of evidence C1]
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
NCT05465174 (Nivolumab and Tovorafenib [DAY101] for Treatment of Craniopharyngioma in Children and Young Adults): This study assesses the tolerability and efficacy of combination therapy with PD-1 (nivolumab) and pan-RAF kinase (tovorafenib) inhibition for the treatment of children and young adults with craniopharyngioma.
References
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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]
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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]
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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]
Lohkamp LN, Kasper EM, Pousa AE, et al.: An update on multimodal management of craniopharyngioma in children. Front Oncol 13: 1149428, 2023. [PUBMED Abstract]
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]
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]
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]
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]
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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]
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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]
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]
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]
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]
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]
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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]
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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]
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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]
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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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
Barriger RB, Chang A, Lo SS, et al.: Phosphorus-32 therapy for cystic craniopharyngiomas. Radiother Oncol 98 (2): 207-12, 2011. [PUBMED Abstract]
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]
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]
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]
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]
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]
Linnert M, Gehl J: Bleomycin treatment of brain tumors: an evaluation. Anticancer Drugs 20 (3): 157-64, 2009. [PUBMED Abstract]
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]
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]
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]
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]
Hengartner AC, Prince E, Vijmasi T, et al.: Adamantinomatous craniopharyngioma: moving toward targeted therapies. Neurosurg Focus 48 (1): E7, 2020. [PUBMED Abstract]
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]
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]
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]
Treatment of Progressive or Recurrent Childhood Craniopharyngioma
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:
The management of recurrent craniopharyngioma is determined largely by previous therapy. Repeat attempts at gross-total resections are difficult, and long-term disease control is achieved less often.[4][Level of evidence C2]; [3] Complications are more frequent than with initial surgery.[5][Level of evidence C2]
Radiation Therapy
If not previously employed, external-beam radiation therapy remains an option, including the consideration of radiosurgery in selected circumstances.[6][Level of evidence C2] Repeat irradiation in different forms is also an option when considering prior radiation exposures and toxicities. Reirradiation has been shown to be feasible in regaining tumor control and providing symptom relief.[7][Level of evidence C3] The types of radiation therapy can range from standard conformal radiation approaches to Gamma Knife therapy.[8][Level of evidence C3]
Intracystic Therapy
Cystic recurrences may be treated with intracavitary instillation of varying agents via placement of an Ommaya catheter.[9] These agents have included radioactive 32P or other compounds,[10–12]; [13][Level of evidence B4] bleomycin,[14]; [15][Level of evidence C2] or, previously, interferon-alpha (which is no longer commercially available).[16]; [17][Level of evidence C1]; [18][Level of evidence C2] These strategies have been useful in certain cases, and a low risk of complications has been reported. However, none of these approaches has shown efficacy against solid portions of the tumor.
Systemic and Targeted Therapy
Although systemic therapy is generally not used, a small series has shown that the use of subcutaneous peginterferon alpha-2b to manage cystic recurrences can result in durable responses; however, this agent is no longer commercially available.[19][Level of evidence C2]
Observation
In select cases of asymptomatic patients with minimal (<25%) tumor progression, it may be possible to safely observe these patients. Intervention can begin when new symptoms develop or further tumor growth is identified on subsequent imaging.[20]
Treatment Options Under Clinical Evaluation
Information about NCI-supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.
Preclinical contemporary evaluations have identified active molecular and immune pathways in craniopharyngioma that may be targetable using commercially available or investigational agents. Specifically, MAPK and RAF pathways and immune/inflammatory targets such as PD-1 pathway components and IL-6 have been identified.[21–27][Level of evidence C1]
The following are examples of national and/or institutional clinical trials that are currently being conducted:
NCT05465174 (Nivolumab and Tovorafenib [DAY101] for Treatment of Craniopharyngioma in Children and Young Adults): This study assesses the tolerability and efficacy of combination therapy with PD-1 (nivolumab) and pan-RAF kinase (tovorafenib) inhibition for the treatment of children and young adults with craniopharyngioma.
NCT05286788 (Binimetinib [Mektovi] for the Treatment of Pediatric Adamantinomatous Craniopharyngioma): This phase II study will treat pediatric patients diagnosed with recurrent adamantinomatous craniopharyngioma with binimetinib (mektovi).
NCT05233397 (Tocilizumab [Actemra] for the Treatment of Progressive or Recurrent Pediatric Adamantinomatous Craniopharyngioma): This phase II study will treat pediatric patients diagnosed with recurrent adamantinomatous craniopharyngioma with tocilizumab (actemra).
References
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]
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]
Vinchon M, Dhellemmes P: Craniopharyngiomas in children: recurrence, reoperation and outcome. Childs Nerv Syst 24 (2): 211-7, 2008. [PUBMED Abstract]
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]
Xu Z, Yen CP, Schlesinger D, et al.: Outcomes of Gamma Knife surgery for craniopharyngiomas. J Neurooncol 104 (1): 305-13, 2011. [PUBMED Abstract]
Foran SJ, Laperriere N, Edelstein K, et al.: Reirradiation for recurrent craniopharyngioma. Adv Radiat Oncol 5 (6): 1305-1310, 2020. [PUBMED Abstract]
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]
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]
Barriger RB, Chang A, Lo SS, et al.: Phosphorus-32 therapy for cystic craniopharyngiomas. Radiother Oncol 98 (2): 207-12, 2011. [PUBMED Abstract]
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]
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]
Linnert M, Gehl J: Bleomycin treatment of brain tumors: an evaluation. Anticancer Drugs 20 (3): 157-64, 2009. [PUBMED Abstract]
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]
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]
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]
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]
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]
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]
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]
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]
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]
Hengartner AC, Prince E, Vijmasi T, et al.: Adamantinomatous craniopharyngioma: moving toward targeted therapies. Neurosurg Focus 48 (1): E7, 2020. [PUBMED Abstract]
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]
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]
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]
Late Effects in Patients Treated for Childhood Craniopharyngioma
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:
Behavioral issues and memory deficits. Although intelligence quotient is usually maintained, behavioral issues and other cognitive domains such as memory, executive function, and attention are commonly impacted.[4,6–8] Memory and neurocognitive effects may be mitigated by the use of proton radiation therapy and conformal plans to avoid surrounding normal brain anatomy such as the hypothalamus and hippocampus.[9]; [10][Level of evidence B3]
Visual disturbances. Visual disturbances, including visual field and acuity defects, have been reported. These deficits may be decreased with less aggressive surgical approaches or radiation therapy alone.[11][Level of evidence C1]; [6,10]
Endocrine abnormalities. Endocrine abnormalities result in the almost universal need for lifelong endocrine replacement with multiple pituitary hormones.[5,8]; [12–14][Level of evidence C1] Similar to visual disturbances, endocrine injury can be offset by limited surgical resection [5,6,15–17] and intracystic therapies that minimize invasive interventions.[18]
Decreased height. Growth hormone replacement therapy is used to improve growth in children treated for craniopharyngiomas. Growth hormone replacement initiated in childhood results in increases in height without impact on OS and progression-free survival when compared with children who did not receive growth hormone.[19][Level of evidence C1]; [20] Growth hormone administration beginning 1 year after diagnosis may be associated with early improvements in quality of life when measured at 3 years postdiagnosis.[21][Level of evidence C1] Published consensus guidelines do not support an increased risk of recurrence with use of growth hormones. They recommend considering growth hormone replacement therapy as early as 3 months after completing cancer therapy in patients who have stable disease and significant growth deficits.[22][Level of evidence D]
Obesity. Obesity, which can be life-threatening, and the development of metabolic syndrome, including nonalcoholic fatty liver disease, can occur.[23,24] Children who undergo complete resection or subtotal resection may develop obesity, suggesting that a predilection to obesity may be a component of the disease itself, not the result of direct hypothalamic injury.[25][Level of evidence C1] Severe obesity seen in patients with craniopharyngiomas is more likely a result of a combination of factors such as tumor location and treatment characteristics, with multifaceted downstream impacts.[26][Level of evidence C1] In a study of 709 patients with craniopharyngiomas, posterior hypothalamic involvement or operative injury to the posterior hypothalamus appeared to be a key factor in the development of severe obesity.[3]
Vasculopathies and stroke. Vasculopathies and subsequent strokes may result from local irradiation.[27,28] Previous studies have suggested that long-term growth hormone replacement may reduce the risk of stroke. Studies have also shown that pretreatment characteristics such as existing vascular injury, vessel location in the surgical field, and larger radiation doses to vascular structures increase the risk of long-term vessel stenosis.[28]; [29][Level of evidence C1] In a study of 94 pediatric patients with craniopharyngiomas who were treated with surgery and 54 Gy of proton therapy, the strongest predictor of postradiation therapy vasculopathy was preexisting vasculopathy.[29] The impact of proton radiation therapy was negligible within the operative corridor. Despite the high incidence (n = 27, 28.7%) of imaging-only evidence of subclinical stenosis events, only five patients required a revascularization procedure. In one of these patients, high-grade stenosis was present before radiation therapy. Two patients had previous tumor recurrences that required multiple resections before radiation therapy.
Subsequent neoplasms. Subsequent neoplasms may result from local irradiation.[27] Secondary malignancies related to radiation therapy that specifically involve the pituitary/sellar region can range from malignant tumors, such as high-grade gliomas, to meningiomas. This risk is increased in patients who are younger at the time of radiation therapy.[30]
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]
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]
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]
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]
Müller HL: Childhood craniopharyngioma: current controversies on management in diagnostics, treatment and follow-up. Expert Rev Neurother 10 (4): 515-24, 2010. [PUBMED Abstract]
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]
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]
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]
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]
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]
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]
Vinchon M, Weill J, Delestret I, et al.: Craniopharyngioma and hypothalamic obesity in children. Childs Nerv Syst 25 (3): 347-52, 2009. [PUBMED Abstract]
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]
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]
Müller HL: Consequences of craniopharyngioma surgery in children. J Clin Endocrinol Metab 96 (7): 1981-91, 2011. [PUBMED Abstract]
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]
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]
Lohkamp LN, Kasper EM, Pousa AE, et al.: An update on multimodal management of craniopharyngioma in children. Front Oncol 13: 1149428, 2023. [PUBMED Abstract]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
Latest Updates to This Summary (11/26/2024)
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.
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).
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.
About This PDQ Summary
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood craniopharyngioma. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
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be cited with text, or
replace or update an existing article that is already cited.
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Childhood Craniopharyngioma Treatment are:
Kenneth J. Cohen, MD, MBA (Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital)
Karen J. Marcus, MD, FACR (Dana-Farber of Boston Children’s Cancer Center and Blood Disorders Harvard Medical School)
Roger J. Packer, MD (Children’s National Hospital)
D. Williams Parsons, MD, PhD (Texas Children’s Hospital)
Malcolm A. Smith, MD, PhD (National Cancer Institute)
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website’s Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
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PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Craniopharyngioma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/brain/hp/child-cranio-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389330]
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Childhood central nervous system (CNS) germ cell tumors form from germ cells.
There are different types of childhood CNS germ cell tumors.
Germinomas
Nongerminomas
Teratomas
Signs and symptoms of childhood CNS germ cell tumors include unusual thirst, frequent urination, or vision changes.
Imaging studies and other tests are used to help diagnose childhood CNS germ cell tumors.
A biopsy may be done to be sure of the diagnosis of a CNS germ cell tumor.
Certain factors affect prognosis (chance of recovery).
Childhood central nervous system (CNS) germ cell tumors form from germ cells.
Germ cells are the reproductive cells in a fetus. These cells later become sperm in the testicles or unfertilized eggs in the ovaries. Sometimes the germ cells travel to or from other parts of the fetus as it develops and later become germ cell tumors. Most germ cell tumors form in the testes or ovaries. Germ cell tumors that form in the brain or spinal cord are called CNS (central nervous system) germ cell tumors.
CNS germ cell tumors occur most often in young people aged 10 to 19 years. They are more common in males than in females. In older children, CNS germ cell tumors usually form in the brain near the pineal gland and in an area of the brain that includes the pituitary gland and the tissue just above it. Sometimes germ cell tumors form in other areas of the brain.
EnlargeAnatomy of the inside of the brain, showing the pineal and pituitary glands, optic nerve, ventricles (with cerebrospinal fluid shown in blue), and other parts of the brain.
The cause of most childhood CNS germ cell tumors is not known.
This summary is about germ cell tumors that start in the central nervous system (brain and spinal cord). Germ cell tumors may also form in other parts of the body. For information on germ cell tumors that are extracranial (outside the brain), see Childhood Extracranial Germ Cell Tumors Treatment.
Treatment of CNS germ cell tumors may be different for children and adults. For information about treatment for adults, see the following PDQ summaries:
There are different types of childhood CNS germ cell tumors.
Different types of CNS germ cell tumors can form from the germ cells that later become sperm or unfertilized eggs. The type of CNS germ cell tumor that is diagnosed depends on what the cells look like under a microscope and results of laboratory tests that check tumor marker levels.
This summary is about the treatment of several types of CNS germ cell tumors.
Germinomas
Germinomas are the most common type of CNS germ cell tumor and have a good prognosis. Tumor marker levels are not used to diagnose germinomas.
Mixed germ cell tumors are made of more than one kind of germ cell. They may make AFP and beta-hCG.
Teratomas
CNS teratomas are described as mature or immature, based on how normal the cells look under a microscope. Mature teratomas look almost like normal cells under a microscope and are made of different kinds of tissue, such as hair, muscle, and bone. Immature teratomas look very different from normal cells under a microscope and are made of cells that look like fetal cells. Some immature teratomas are a mix of mature and immature cells. Tumor marker levels are not used to diagnose teratomas.
Signs and symptoms of childhood CNS germ cell tumors include unusual thirst, frequent urination, or vision changes.
Imaging studies and other tests are used to help diagnose childhood CNS germ cell tumors.
In addition to asking about your child’s personal and family health history and doing a physical exam, your child’s doctor may perform the following tests and procedures:
Neurological exam: A series of questions and tests to check the brain, spinal cord, and nerve function. The exam checks a person’s mental status, coordination, and ability to walk normally, and how well the muscles, reflexes, and senses work. This may also be called a neuro exam or a neurologic exam.
Visual field exam: An exam to check a person’s field of vision (the total area in which objects can be seen). This test measures both central vision (how much a person can see when looking straight ahead) and peripheral vision (how much a person can see in all other directions while staring straight ahead). The eyes are tested one at a time. The eye not being tested is covered.
MRI (magnetic resonance imaging) with and without gadolinium: A procedure that 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. 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).
Lumbar puncture: 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 the CSF. The sample of CSF is checked under a microscope for signs of tumor cells and tested for tumor markers. The amount of protein and glucose in the sample may also be tested. This procedure is also called an LP or spinal tap. EnlargeLumbar puncture. A patient lies in a curled position on a table. After a small area on the lower back is numbed, a spinal needle (a long, thin needle) is inserted into the lower part of the spinal column to remove cerebrospinal fluid (CSF, shown in blue). The fluid may be sent to a laboratory for testing.
Tumor marker tests: A procedure in which a sample of blood or cerebrospinal fluid (CSF) is checked to measure the amounts of certain substances released into the blood or CSF normally by organs and tissues, or at abnormally high levels by tumor cells in the body. Certain substances are linked to specific types of cancer when found at increased levels in the blood or CSF. These are called tumor markers.
The following tumor markers are used to diagnose some CNS germ cell tumors:
Blood chemistry studies: A procedure in which a blood sample is checked to measure the amounts of certain substances released into the blood by organs and tissues in the body. An unusual (higher- or lower-than-normal) amount of a substance can be a sign of disease.
Blood hormone studies: A procedure in which a blood sample is checked to measure the amounts of certain hormones released into the blood by organs and tissues in the body. An unusual (higher- or lower-than-normal) amount of a substance can be a sign of disease in the organ or tissue that makes it. The blood will be checked for the levels of hormones made by the pituitary gland and other glands.
A biopsy may be done to be sure of the diagnosis of a CNS germ cell tumor.
If doctors think your child may have a CNS germ cell tumor, a biopsy may be done. For brain tumors, the 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 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. If cancer cells are found, the doctor may remove as much tumor as safely possible during the same surgery. The piece of skull is usually put back in place after the procedure.
EnlargeCraniotomy. An opening is made in the skull and a piece of the skull is removed to show part of the brain.
The following test may be done on the sample of tissue that is removed:
Immunohistochemistry: A laboratory test that 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 of cancer.
Sometimes the diagnosis can be made based on the results of imaging and tumor marker tests and a biopsy is not needed.
Certain factors affect prognosis (chance of recovery).
The prognosis depends on:
The type of germ cell tumor.
The type and level of any tumor markers.
Where the tumor is in the brain or in the spinal cord.
Whether the cancer has spread within the brain and spinal cord or to other parts of the body.
Whether the tumor is newly diagnosed or has recurred (come back) after treatment.
Stages of Childhood CNS Germ Cell Tumors
Key Points
Childhood central nervous system (CNS) germ cell tumors rarely spread outside of the brain and spinal cord.
Sometimes childhood central nervous system germ cell tumors come back after treatment.
Childhood central nervous system (CNS) germ cell tumors rarely spread outside of the brain and spinal cord.
Whether the tumor is newly diagnosed or has recurred (come back) after treatment.
Sometimes childhood central nervous system germ cell tumors come back after treatment.
The tumors usually recur (come back) where they first formed. The tumors may also come back in other places and/or in the meninges (thin layers of tissue that cover and protect the brain and spinal cord).
Treatment Option Overview
Key Points
There are different types of treatment for children with central nervous system (CNS) germ cell tumors.
Children with CNS germ cell tumors should have their treatment planned by a team of health care providers who are experts in treating cancer in children.
The following types of treatment are used:
Radiation therapy
Chemotherapy
Surgery
High-dose chemotherapy with stem cell rescue
New types of treatment are being tested in clinical trials.
Treatment for childhood CNS germ cell tumors may cause side effects.
Patients may want to think about taking part in a clinical trial.
Patients can enter clinical trials before, during, or after starting their cancer treatment.
Follow-up care may be needed.
There are different types of treatment for children with central nervous system (CNS) germ cell tumors.
Different types of treatment are available for children with central nervous system (CNS) germ cell tumors. Some treatments are standard (the currently used treatment), and some are being tested in clinical trials. A treatment clinical trial is a research study meant to help improve current treatments or obtain information on new treatments for people with cancer. When clinical trials show that a new treatment is better than the standard treatment, the new treatment may become the standard treatment.
Because cancer in children is rare, taking part in a clinical trial should be considered. Some clinical trials are open only to patients who have not started treatment.
Children with CNS germ cell tumors should have their treatment planned by a team of health care providers who are experts in treating cancer in children.
Treatment will be overseen by a pediatric oncologist and/or a radiation oncologist. A pediatric oncologist is a doctor who specializes in treating children with cancer. A radiation oncologist specializes in treating cancer with radiation therapy. These doctors work with other pediatrichealth care providers who are experts in treating children with CNS germ cell tumors and who specialize in certain areas of medicine. These may include the following specialists:
Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing.
External radiation therapy uses a machine outside the body to send radiation toward the area of the body with cancer. Certain ways of giving radiation therapy can help keep radiation from damaging nearby healthy tissue. This type of radiation therapy may include:
Stereotactic radiosurgery: Stereotactic radiosurgery is a type of external radiation therapy. A rigid head frame is attached to the skull to keep the head still during the radiation treatment. A machine aims a single large dose of radiation directly at the tumor. This procedure does not involve surgery. It is also called stereotaxic radiosurgery, radiosurgery, and radiation surgery.
Radiation therapy to the brain can affect growth and development in young children. Certain ways of giving radiation therapy can lessen the damage to healthy brain tissue. For children younger than 3 years, chemotherapy may be given instead. This can delay or reduce the need for radiation therapy.
Chemotherapy
Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy).
Surgery
Whether surgery to remove the tumor can be done depends on where the tumor is in the brain. Surgery to remove the tumor may cause severe, long-term side effects.
Surgery may be done to remove teratomas and may be used for germ cell tumors that come back. After the doctor removes all the cancer that can be seen at the time of the surgery, some patients may be given chemotherapy or radiation therapy after surgery to kill any cancer cells that are left. Treatment given after the surgery, to lower the risk that the cancer will come back, is called adjuvant therapy.
High-dose chemotherapy with stem cell rescue
High doses of chemotherapy are given to kill cancer cells. Healthy cells, including blood-forming cells, are also destroyed by the cancer treatment. Stem cell transplant is a treatment to replace the blood-forming cells. Stem cells (immature blood cells) are removed from the blood or bone marrow of the patient and are frozen and stored. After the patient completes chemotherapy, the stored stem cells are thawed and given back to the patient through an infusion. These reinfused stem cells grow into (and restore) the body’s blood cells.
New types of treatment are being tested in clinical trials.
Information about clinical trials is available from the NCI website.
Treatment for childhood CNS germ cell tumors may cause side effects.
Side effects from cancer treatment that begin after treatment and continue for months or years are called late effects. Late effects of cancer treatment may include:
Some late effects may be treated or controlled. Talk with your child’s doctors about the possible late effects caused by some treatments. Learn more at Late Effects of Treatment for Childhood Cancer.
Patients may want to think about taking part in a clinical trial.
For some patients, taking part in a clinical trial may be the best treatment choice. Clinical trials are part of the cancer research process. Clinical trials are done to find out if new cancer treatments are safe and effective or better than the standard treatment.
Many of today’s standard treatments for cancer are based on earlier clinical trials. Patients who take part in a clinical trial may receive the standard treatment or be among the first to receive a new treatment.
Patients who take part in clinical trials also help improve the way cancer will be treated in the future. Even when clinical trials do not lead to effective new treatments, they often answer important questions and help move research forward.
Patients can enter clinical trials before, during, or after starting their cancer treatment.
Some clinical trials only include patients who have not yet received treatment. Other trials test treatments for patients whose cancer has not gotten better. There are also clinical trials that test new ways to stop cancer from recurring (coming back) or reduce the side effects of cancer treatment.
Clinical trials are taking place in many parts of the country. Information about clinical trials supported by NCI can be found on NCI’s clinical trials search webpage. Clinical trials supported by other organizations can be found on the ClinicalTrials.gov website.
Follow-up care may be needed.
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 recurred (come back).
Children whose cancer affected their pituitary gland when the cancer was diagnosed will usually need to have their blood hormone levels checked. If the blood hormone level is low, replacement hormone medicine is given.
Children who had a high tumor marker level (alpha-fetoprotein or beta-human chorionic gonadotropin) when the cancer was diagnosed usually need to have their blood tumor marker level checked. If the tumor marker level increases after initial treatment, the tumor may have recurred.
Surgery. If a mass remains after chemotherapy that continues to grow and tumor marker levels are normal (called growing teratoma syndrome), surgery may be needed to check if the mass is part teratoma, fibrosis, or a growing tumor.
If the mass is a mature teratoma or fibrosis, radiation therapy is given.
If the mass is a growing tumor, other treatments may be given.
A clinical trial of chemotherapy with radiation therapy to treat patients with CNS nongerminomas that have not spread.
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.
To Learn More About Childhood CNS Germ Cell Tumors
For more information about childhood central nervous system germ cell tumors, see:
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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.
Incidence
In Western countries, GCTs represent 3% to 4% of primary brain tumors in children, with a peak incidence from age 10 to 19 years.[4,5] In Japan and other Asian countries, a series reported the incidence of CNS GCTs to be approximately 15% of all pediatric CNS tumors.[5–9] The genetic or environmental reasons for these differences remain unknown.
Overall, males have a higher incidence of GCTs than females. Male patients have a preponderance of pineal-region primary tumors.[10,11] However, male predominance is not noted in patients aged 10 years or younger at the time of diagnosis.[12]
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]
EnlargeFigure 1. Anatomy of the inside of the brain. The supratentorium contains the cerebrum, ventricles (with cerebrospinal fluid shown in blue), choroid plexus, hypothalamus, pineal gland, pituitary gland, and optic nerve. The infratentorium contains the cerebellum and brain stem.
Clinical Features
The signs and symptoms of CNS GCTs depend on the location of the tumor in the brain, as follows:
Suprasellar region. Patients with tumors arising in the suprasellar region often present with subtle or overt hormonal deficiencies and may experience a protracted prodrome lasting months to years. Diabetes insipidus caused by antidiuretic hormone deficiency occurs in 70% to 90% of patients and is the most common sentinel symptom. Patients can usually compensate for this deficiency by drinking excessive amounts of fluid for months to years. Eventually, other hormonal symptoms and visual deficits may emerge as the tumor expands dorsally and compresses or invades the optic chiasm and/or fills the third ventricle to cause hydrocephalus.[14–16]
Pineal region. Patients with tumors in the pineal region usually have a shorter history of symptoms than patients with tumors of the suprasellar or basal ganglionic region, with weeks to months of symptoms that include raised intracranial pressure and diplopia related to tectal and aqueductal compression. Signs and symptoms unique to masses in the pineal and posterior third ventricular region include Parinaud syndrome (vertical gaze impairment, convergence nystagmus, and light-near pupillary response dissociation), headache, and nausea and vomiting.
Bifocal tumors. Patients with bifocal primary tumors present with metasynchronous lesions in the suprasellar and pineal regions.[15] The secondary lesion is often asymptomatic and found on magnetic resonance imaging (MRI). In children with pineal primary tumors, the suprasellar lesion may also be associated with unexplained precocious puberty.
Nonspecific symptoms such as enuresis, anorexia, and psychiatric complaints [17] can lead to delays in a diagnosis. However, signs of increased intracranial pressure or visual changes tend to result in an earlier diagnosis.[18]
Diagnostic Evaluation and Prognostic Factors
Radiographic characteristics of CNS GCTs cannot reliably differentiate germinomas from NGGCTs or other CNS tumors. The diagnosis of GCTs is based on the following:
Characteristic clinical signs and symptoms supported by neuroimaging.
GCT marker analysis in the serum and lumbar cerebrospinal fluid (CSF).
Histology, if necessary.
The diagnosis of a suspected CNS GCT and an assessment of the clinical deficits and extent of metastases can usually be confirmed with the following tests:
MRI of brain and spine with and without gadolinium.
Alpha-fetoprotein (AFP) and beta subunit human chorionic gonadotropin (beta-HCG) levels in both serum and CSF, and cytology, if needed. If preoperative CSF can be obtained safely and tumor markers are found to be elevated, histological confirmation may not be needed. Before definitive therapy is initiated, a lumbar CSF assessment for cytology and tumor markers should be performed, if safe, to reconfirm the diagnosis and help monitor treatment response and control. The diagnostic utility of lumbar CSF is better validated and more reliable than that obtained from the ventricles (see Table 1).[18,19]
Evaluation of pituitary/hypothalamic function.
Visual-field and acuity examinations for suprasellar or hypothalamic tumors.
If possible, a baseline neuropsychological examination should be performed after symptoms of endocrine deficiency and raised intracranial pressure are resolved.
CNS GCTs can be diagnosed and classified on the basis of histology alone, tumor markers alone, or a combination of both.[19–21] A diagnosis of GCTs often requires a tumor biopsy, except when imaging characteristics are present and increased tumor markers (usually AFP and beta-HCG) are found in the serum and/or CSF. The tumor markers AFP and beta-HCG are the most useful, although other markers, such as placental alkaline phosphatase and c-kit, are being investigated (see Table 1). When the tumor markers are negative or mildly elevated but below diagnostic criteria, or if there are any atypical findings, an endoscopic or open biopsy is needed to make a definitive diagnosis.
Distinguishing between different GCT types by CSF protein marker levels alone is somewhat arbitrary, and standards vary across continents. Patients with pure germinomas and teratomas usually present with negative markers, but low levels of beta-HCG can be detected in patients with germinomas.[22] Current international efforts are directed at determining a marker threshold for beta-HCG–secreting germinomas because data suggest that the beta-HCG levels that are used to distinguish germinomas from NGGCTs (50 IU/L in Europe and 100 IU/L in North America) are questionable.
The use of tumor markers and histology in GCT clinical trials is evolving. For example, in the COG-ACNS1123 (NCT01602666) trial, patients were eligible for assignment to the germinoma regimen without biopsy confirmation if they had one of the following:
Either pineal region tumors or suprasellar primary tumors, normal AFP levels, and beta-HCG levels between 5 and 50 IU/L in serum and/or CSF.
Bifocal (pineal and suprasellar) involvement or pineal lesions with diabetes insipidus, normal AFP levels, and beta-HCG levels of 100 IU/L or lower in serum and/or CSF.
Table 1. Immunohistochemical Markers and Germ Cell Tumor Variants
There is also an effort to use tumor markers to determine prognosis on the basis of the presence and degree of elevation of AFP and beta-HCG. This is an evolving process, and cooperative groups in North America, Europe, and Japan have adopted slightly different criteria.[23]
Alternative classification schemes for CNS GCTs have been proposed by groups such as the Japanese Pediatric Brain Tumor Study Group for CNS GCTs. This group based their stratification on the prognostic grouping of the differing histological variants, as shown in Table 2.[9]
Table 2. Japanese Pediatric Brain Tumor Study Group Classification
Prognostic Group
Tumor Type
Good
Germinoma, pure
Mature teratoma
Intermediate
Germinoma with syncytiotrophoblastic giant cells
Immature teratoma
Mixed tumors mainly composed of germinoma or teratoma
Teratoma with malignant transformation
Poor
Choriocarcinoma
Embryonal carcinoma
Mixed tumors mainly composed of choriocarcinoma, yolk sac tumor, or embryonal carcinoma
Yolk sac tumor
It is crucial that appropriate staging is determined and that germinomas are distinguished from NGGCTs. Chemotherapy and radiation treatment plans differ significantly depending on GCT category and extent of disease.
Cellular and Molecular Classification
The pathogenesis of intracranial GCTs is unknown. The germ cell theory proposes that CNS GCTs arise from primordial germ cells that have aberrantly migrated and undergone malignant transformation. A genome-wide methylation profiling study of 61 GCTs supports this hypothesis.[24] Previous molecular studies that compared the genomic alterations in GCTs showed similar copy-number alterations in both CNS GCTs and systemic GCTs.[25]
An alternative hypothesis, the embryonic cell theory, proposes that GCTs arise from a pluripotent embryonic cell that escapes normal developmental signals and progresses to CNS GCTs.[26,27]
The WHO has classified CNS GCTs into the following groups:[1,2]
Germinoma.
Nongerminomatous GCTs.
Embryonal carcinoma.
Yolk sac tumor.
Choriocarcinoma.
Teratoma.
Mature teratoma.
Immature teratoma.
Teratoma with somatic-type malignancy.
Mixed GCT.
NGGCTs can consist of one malignant NGGCT type or contain multiple elements of GCT components, including teratomatous or germinomatous constituents.
Recurrent variants in KIT, genes in the MAPK pathway, and genes in the PI3K/mTOR signaling pathway have been identified in CNS GCTs.[28–30]
In a retrospective analysis of 82 children and adults with CNS GCTs, chromosome 12p gain was the most frequent copy number alteration. 12p gain was more frequent in NGGCTs (20 of 40, 50%) than germinomas (5 of 42, 12%). 12p gain was associated with worse survival in patients with NGGCTs (10-year overall survival rate, 47% for patients with 12p gain vs. 90% without; P = .02).[31]
Global hypomethylation that mirrors primordial germ cells in early development has also been observed in CNS GCTs.[30]
In an evaluation of 21 cases of CNS germinomas diagnosed between 2000 and 2016, programmed death-ligand 1 (PD-L1) and programmed cell death-1 (PD-1) expression was assessed by immunohistochemistry. Ninety percent of germinomas had germ cell components that stained positively for PD-L1. In addition, tumor-associated lymphocytes stained positive for PD-L1 in more than 75% of cases.[32]
References
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]
WHO Classification of Tumours Editorial Board, ed.: WHO Classification of Tumours: Central Nervous System Tumours. Vol. 6. 5th ed. IARC Press; 2021.
Louis DN, Ohgaki H, Wiestler OD: WHO Classification of Tumours of the Central Nervous System. 4th rev.ed. IARC Press, 2016.
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]
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]
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]
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.
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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.
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]
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.
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]
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]
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]
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]
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.
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]
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]
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]
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]
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]
Stage Information for Childhood CNS Germ Cell Tumors
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:
Magnetic resonance imaging (MRI). In addition to whole-brain MRI, MRI of the spine is required.
Lumbar cerebrospinal fluid (CSF). When medically permissible, lumbar CSF should be obtained for the measurement of tumor markers (alpha-fetoprotein [AFP] and beta subunit human chorionic gonadotropin [beta-HCG]) and for cytopathological review.
Ventricular tumor markers are obtained for AFP and beta-HCG in the presence of obstructive hydrocephalus and a necessary CSF diversion. However, ventricular CSF does not serve as a substitute for CSF tumor staging and cytopathological review. Both serum and CSF tumor markers should be obtained for a thorough staging and diagnostic evaluation.[2]
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
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]
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]
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]
Treatment Option Overview for Childhood CNS Germ Cell Tumors
Teratomas, germinomas, and other nongerminomatous germ cell tumors (NGGCTs) have differing prognoses and require different treatment regimens. Studies have observed the following:[1–5]
For children older than 3 years and adults, radiation therapy has been an important component of therapy for germinomas and NGGCTs, although the optimal dose and field of irradiation are debated.
Central nervous system (CNS) germ cell tumors (GCTs), similar to gonadal and extragonadal GCTs, have demonstrated sensitivity to chemotherapy.
Germinomas are highly chemosensitive and radiosensitive tumors. They are curable with craniospinal irradiation and local site–boost radiation therapy alone. However, the use of neoadjuvant or preirradiation chemotherapy allows reduced radiation therapy doses and volumes and, subsequently, reduced long-term radiation therapy–related effects.
In North America and Europe, patients with localized germinomas are effectively treated with whole-ventricular irradiation supplemented with tumor site–boost radiation therapy. Focal irradiation to the tumor bed, regardless of response to chemotherapy, is considered inadequate treatment.[6]
For NGGCTs, the combined use of more intensive neoadjuvant chemotherapy followed by either localized or craniospinal irradiation has resulted in improved survival rates in the last decade.[5,7,8]
Patients with bifocal intracranial GCTs limited to the suprasellar and pineal region were treated in the same manner as patients with localized, nonmetastatic tumors in studies in North America and Europe.[8]
Table 3 outlines the treatment options for patients with newly diagnosed and recurrent childhood CNS GCTs.
Table 3. Treatment Options for Childhood Central Nervous System (CNS) Germ Cell Tumors (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
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]
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]
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]
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]
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]
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]
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]
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]
Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014. [PUBMED Abstract]
Treatment of Newly Diagnosed Childhood CNS Germinomas
Treatment options for newly diagnosed childhood central nervous system (CNS) germinomas include the following:
Neoadjuvant Chemotherapy Followed by Response-Based Radiation Therapy
Chemotherapy has been explored to reduce radiation therapy doses and associated neurodevelopmental morbidity. Several studies have confirmed the feasibility of this approach for maintaining excellent survival rates.[1–4][Level of evidence B4]; [5–8][Level of evidence C1]
Chemotherapy agents such as cyclophosphamide, ifosfamide, etoposide, cisplatin, and carboplatin are highly active in CNS germinomas. Managing patients receiving chemotherapy agents that require hyperhydration (e.g., cyclophosphamide, ifosfamide, and cisplatin) can be quite challenging because of the possibility of diabetes insipidus in patients with primary tumors of the suprasellar region.[9]
An international group of investigators explored a chemotherapy-only approach primarily for younger children. A complete response was achieved in 84% of patients with germinomas who were treated with chemotherapy alone. However, 50% of these patients suffered tumor relapse or progression. Many recurrences were local, local plus ventricular, and ventricular alone and/or with leptomeningeal dissemination throughout the CNS, which required additional therapy, including radiation.[10]
Subsequent studies have continued to support the need for radiation therapy after chemotherapy and the likely requirement for whole-ventricular irradiation (24 Gy) with local tumor site–boost radiation therapy (total dose, 40 Gy).[11][Level of evidence B4]; [12][Level of evidence C1] Excellent results have also been reported for patients with metastatic germinomas who received craniospinal irradiation of 24 Gy with local tumor site–boost radiation therapy (total dose, 40 Gy).[1][Level of evidence B4]; [13]
Optimal management of bifocal lesions is less clear, but most investigators consider this presentation a form of metachronous primary disease to be staged as M0. A meta-analysis of 60 patients demonstrated excellent progression-free survival after craniospinal irradiation alone. Chemotherapy plus localized radiation therapy, including whole-ventricular irradiation, also resulted in excellent disease control.[14][Level of evidence C2] For germinomas that arise outside of the pineal or suprasellar region, the effectiveness of therapy, as used for pineal and/or suprasellar lesions, is not well delineated. However, one retrospective review of 47 patients with basal ganglion and thalamic tumors reported progression-free survival (PFS) and overall survival (OS) rates that were similar to those reported in patients with tumors arising in more common areas of the brain.[15]
Results have been reported for the ACNS1123 (NCT01602666) phase II trial (stratum 2) that investigated response-based radiation therapy for localized germinomas. Patients were aged 3 to 21 years. Patients who had a complete response to carboplatin and etoposide chemotherapy received 18 Gy of whole-ventricle irradiation and a 12-Gy boost to the tumor bed. Patients who had a partial response to chemotherapy proceeded to receive 24 Gy of whole-ventricle irradiation and a 12-Gy boost to the tumor bed. Longitudinal cognitive functioning was evaluated prospectively. There were 137 eligible patients. Among 90 evaluable patients, 74 were treated with 18 Gy of radiation, and 16 were treated with 24 Gy of whole-ventricle irradiation.[16]
The study failed to demonstrate noninferiority of the 18 Gy whole-ventricle irradiation regimen, compared with the study-specified threshold of a 95% 3-year PFS rate. The analysis was confounded by including any patient who could not be assessed for progression at 3 years as a treatment failure, which lead to a PFS rate of 86%. If these patients who could not be assessed were excluded, the Kaplan-Meier–based 3-year PFS estimates were 94.5% (± 2.7%) for the 18 Gy cohort.
Collectively, estimated mean IQ, attention, and concentration were within normal range. A lower mean attention score was observed at 9 months for patients who were treated with 24 Gy of radiation. Acute effects in processing speed were observed for patients who were treated with 18 Gy at 9 months, which improved at the 30-month assessment. However, the sample size was small and did not account for confounding variables such as surgical complications, hydrocephalus, and limited long-term follow-up data.
None of the evaluable patients had a relapse within the ventricular field or in the primary tumor region. All four disease progressions occurred outside of the radiation field, at a median time of 8.91 months after radiation therapy.
Of the eight relapses, three occurred along the biopsy tract.
Residual disease at the end of treatment was not associated with a worse prognosis.
Other studies have supported this treatment approach, reporting excellent outcomes in children with CNS germinomas.[17,18]
Radiation Therapy
CNS germinomas are highly radiosensitive and have been traditionally treated successfully with radiation therapy alone. Historically, patients with nondisseminated disease have been treated with craniospinal irradiation plus a boost to the region of the primary tumor. The dose of craniospinal irradiation has ranged from 24 Gy to 36 Gy, although studies have used lower doses. The local tumor dose of radiation therapy has ranged between 40 Gy and 50 Gy. Studies of lower-dose craniospinal irradiation have shown excellent outcomes.[19] This modification has resulted in 5-year OS rates exceeding 90%.[20]; [21][Level of evidence B4]; [22,23][Level of evidence C1] These excellent survival rates have allowed investigators to focus on reducing the radiation treatment volume and dose in an attempt to decrease late effects.[21,24,25]
Patterns of relapse after craniospinal irradiation versus reduced-volume radiation therapy (whole-brain or whole-ventricular radiation therapy) have supported the omission of craniospinal irradiation for localized germinomas.[26–28] On the basis of these results, the treatment for patients with localized germinomas has been modified to cover the whole ventricular system (24 Gy) followed by a boost to the primary site (30–40 Gy), rather than to deliver radiation therapy to the entire craniospinal axis or even to the whole brain. This change has not resulted in worse outcomes and is expected to minimize the acute and long-term toxicity of radiation therapy. Focal radiation therapy directed only to the tumor volume, even after neoadjuvant chemotherapy, results in ventricular relapses; therefore, focal radiation therapy is not recommended.[25]
Treatment Options Under Clinical Evaluation for Newly Diagnosed Childhood CNS Germinomas
Early-phase therapeutic trials may be available for selected patients. These trials may be available via the Children’s Oncology Group, the Pediatric Brain Tumor Consortium, or other entities. Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.
References
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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 of Newly Diagnosed Childhood CNS Nongerminomatous Germ Cell Tumors
Treatment options for newly diagnosed childhood central nervous system (CNS) nongerminomatous germ cell tumors (NGGCTs) include the following:
Surgery, for tumors that partially respond to chemotherapy or for tumors that increase in size during or after therapy (possible growing teratoma syndrome).
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]
Chemotherapy Followed by Radiation Therapy
The use of chemotherapy before radiation therapy has increased survival rates. However, the specific chemotherapy regimen, length of therapy, and the optimal radiation field, timing, and dose remain under investigation.[1,5,6] Anticancer agents that have been used include carboplatin, etoposide, bleomycin, ifosfamide, and vinblastine in different combinations. Some investigators have proposed radiation therapy fields that are smaller than those used for craniospinal irradiation (e.g., whole-ventricular irradiation with a boost to the local tumor site) for patients with nondisseminated NGGCT. Controversy exists over the pattern of tumor relapse in patients treated with chemotherapy and focal or whole-ventricular radiation therapy.[1,7–9]
Evidence (chemotherapy followed by radiation therapy):
A Children’s Oncology Group (COG) study (ACNS0122 [NCT00047320]) evaluated neoadjuvant chemotherapy followed by radiation therapy for children with localized NGGCTs.[2] Neoadjuvant chemotherapy consisted of six courses with carboplatin/etoposide alternating with ifosfamide/etoposide. After chemotherapy was completed, responding patients received 36 Gy of craniospinal radiation therapy, with 54 Gy to the tumor bed.
On the basis of a central review, 87% of patients showed either partial response (PR) or complete response (CR).
For the 102 eligible patients in the study, the 5-year event-free survival (EFS) rate was 84% (± 4%), and the OS rate was 93% (± 3%).
At 3 years, the EFS rate was 92% and the OS rate was 98% for all patients who achieved CR or PR either after induction chemotherapy or with the absence of malignant elements documented during second-look surgery.
The European SIOP-CNS-GCT-96 (NCT00293358) trial evaluated neoadjuvant chemotherapy consisting of four courses with cisplatin/etoposide/ifosfamide followed by focal radiation therapy (54 Gy) for patients with nonmetastatic disease.[3]
Patients with localized tumors (n = 116) demonstrated 5-year progression-free survival (PFS) rates of 72% (± 4%) and OS rates of 82% (± 4%).
Stratum 1 of the COG ACNS1123 (NCT01602666) study evaluated the efficacy of reduced-dose and reduced-volume radiation therapy in children and adolescents with localized NGGCTs who achieved PRs, CRs, and marker normalization after six cycles of chemotherapy. The main objective of this study was to evaluate the impact of reduced radiation therapy on PFS, with a goal of preserving neurocognitive function. Isolated spinal relapses occurred in 10% of patients in this trial, causing early stoppage of the protocol. This is compared with 8% of patients who developed a similar pattern of relapse in the ACNS0122 (NCT00047320) trial.
Patients in this study received six cycles of chemotherapy with carboplatin and etoposide alternating with ifosfamide and etoposide. If a CR or PR with or without second-look surgery was achieved, the patient was eligible for reduced radiation therapy, defined as 30.6 Gy to the whole-ventricular field and a 54-Gy boost to the tumor bed, compared with 36 Gy of craniospinal irradiation plus a 54-Gy tumor-bed boost used in the ACNS0122 trial.[4,10]
Of the 107 patients enrolled, 66 (61.7%) achieved a CR or PR and received reduced radiation therapy. The 3-year PFS rate was 87.8% (± 4.04%), and the OS rate was 92.4% (± 3.3%).
There were eight documented recurrences; six patients had distant spinal relapse alone and two patients had combined local-plus-distant relapse.
Patients with localized NGGCTs who achieved a CR or PR with chemotherapy and received reduced radiation therapy had a good PFS rate, similar to patients in the ACNS0122 trial who received craniospinal irradiation.
There was no significant difference in survival rates for NGGCT patients with localized disease in the two COG studies. The predominant site of relapse for patients in the ACNS1123 trial was in the spine, which was unique.[2,4]
A subgroup analysis compared protons with photons to the whole ventricles for treating patients with NGGCTs.[11] Mean radiation doses and the doses to 40% of volumes, including the supratentorial brain, cerebellum, bilateral temporal, parietal, and frontal lobes, were significantly lower among patients who were treated with protons than patients who were treated with photons. Late effects data confirming a clinical benefit are not available.
The current and prevailing controversy in the management of patients with newly diagnosed, localized NGGCTs—who have no evidence of dissemination and either a complete radiographic response to chemotherapy or have no evidence of disease before and after the initiation of chemotherapy—is the radiation volume. The SIOP-CNS-GCT-96 (NCT00293358) trial employed involved fields of radiation only for these patients with no radiographic evidence of residual or disseminated disease. Two COG protocols used either craniospinal or whole-ventricular fields of radiation plus a boost to the primary tumor. The incidence of isolated spinal relapses was similar in all of these studies, ranging from 8% to 11%.
Patients with relapsed NGGCTs are difficult to treat with curative intent, and their prognosis is guarded. Whether craniospinal irradiation or whole-ventricular plus spinal radiation should be included for all newly diagnosed NGGCT patients is an unresolved controversy and a major question for future clinical trials.
Surgery
A small percentage of patients treated with chemotherapy may have normalization of tumor markers with a less-than-complete radiographic response. Occasionally, a mass continues to expand in size even though tumor markers may have normalized. This condition, designated as growing teratoma syndrome, represents an accelerated growth of the mature teratoma components during or after treatment.[2,12–14] In such circumstances, complete surgical resection is the treatment of choice, as it provides histological confirmation and exclusion of mixed germ cell tumor components.
A SIOP trial identified a significant OS advantage for patients without residual disease (5-year PFS rate, 85% ± 0.04% vs. 48% ± 0.07%), which underscores the important role of second-look surgery after chemotherapy and before irradiation.[3]
A second-look surgery can help determine whether the residual mass contains teratoma, fibrosis, or residual NGGCT.[7,15] If second-look surgery finds mature teratoma or fibrosis after chemotherapy, the general approach is to proceed with radiation therapy as if the patient had achieved a CR to chemotherapy. However, if an active tumor is observed, then alternative treatment approaches are generally considered.[2]
Treatment Options Under Clinical Evaluation for Newly Diagnosed Childhood CNS NGGCTs
Early-phase therapeutic trials may be available for selected patients. These trials may be available via the COG, the Pediatric Brain Tumor Consortium, or other entities. Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
ACNS2021 (NCT04684368) (A Study of a New Way to Treat Children and Young Adults With a Brain Tumor Called NGGCT): This phase II trial studies the effect of chemotherapy combined with radiation therapy in treating patients with localized NGGCTs. The purpose of this study is to examine the tumor response to induction chemotherapy. Tumor response will then determine additional treatment options, including radiation therapy or high-dose chemotherapy and a stem cell transplant followed by radiation therapy.
References
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]
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]
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]
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]
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]
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]
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.
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]
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]
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]
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]
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]
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]
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]
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]
Treatment of Newly Diagnosed Childhood CNS Teratomas
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:
The primary treatment for teratomas is gross-total resection.[1,2][Level of evidence C1]
Adjuvant treatment in the form of focal radiation therapy and/or adjuvant chemotherapy for patients with subtotally resected tumors is controversial. Small institutional series suggested a potential utility of stereotactic radiosurgery.[1,2][Level of evidence C1]
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.
Chemotherapy Followed by Additional Radiation Therapy
Patients with germinomas that were treated initially with chemotherapy only can benefit from chemotherapy followed by radiation therapy at the time of relapse.[4,5] Reirradiation, including radiosurgery, after chemotherapy at recurrence has been used.[5–9]
High-Dose Chemotherapy With Stem Cell Rescue With or Without Additional Radiation Therapy
For patients with pure germinomas who previously received radiation therapy, myeloablative chemotherapy with stem cell rescue has been used. High-dose chemotherapy and autologous stem cell rescue may also have curative potential for some patients with relapsed systemic NGGCTs.[7,9–13]
Treatment Options Under Clinical Evaluation for Recurrent Childhood CNS GCTs
There are limited clinical trials available for patients with recurrent NGGCTs. Early-phase therapeutic trials may be available for selected patients. These trials may be available via the Children’s Oncology Group (COG), the Pediatric Brain Tumor Consortium, or other entities. Information about NCI-supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.
References
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
Long-Term Effects of Childhood CNS Germ Cell Tumors
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:
Each chemotherapeutic agent has its own characteristic long-term side effects.
Radiation therapy to the areas commonly affected by GCTs is known to contribute to a decline in patient performance status, visual-field impairments, endocrine disorders, learning disabilities, stroke, and psychiatric conditions.[3–9]
Second tumors have been identified in this population, some of which are thought to be related to previous irradiation.[8,10,11]
Current clinical trials and therapeutic approaches are directed at minimizing the long-term sequelae that result from the treatment of CNS GCTs.
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.
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]
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]
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]
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]
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]
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]
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]
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]
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]
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
Latest Updates to This Summary (10/08/2024)
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.
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.
About This PDQ Summary
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood central nervous system germ cell tumors. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
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The lead reviewers for Childhood Central Nervous System Germ Cell Tumors Treatment are:
Kenneth J. Cohen, MD, MBA (Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital)
Karen J. Marcus, MD, FACR (Dana-Farber of Boston Children’s Cancer Center and Blood Disorders Harvard Medical School)
Roger J. Packer, MD (Children’s National Hospital)
D. Williams Parsons, MD, PhD (Texas Children’s Hospital)
Malcolm A. Smith, MD, PhD (National Cancer Institute)
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PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Central Nervous System Germ Cell Tumors Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/brain/hp/child-cns-germ-cell-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389498]
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Childhood Ependymoma Treatment (PDQ®)–Health Professional Version
General Information About Childhood Ependymoma
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]
Supratentorial ependymoma.
Supratentorial ependymoma, ZFTA fusion–positive (formerly called RELA fusion–positive).
Supratentorial ependymoma, YAP1 fusion–positive.
Posterior fossa ependymoma.
Posterior fossa ependymoma, group PFA.
Posterior fossa ependymoma, group PFB.
Spinal ependymoma.
Spinal ependymoma, MYCN-amplified.
Myxopapillary ependymoma.
Subependymoma (supratentorial, posterior fossa, and spinal locations).
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.
Incidence
Childhood ependymoma comprises approximately 9% of all childhood brain and spinal cord tumors, representing about 200 cases per year in the United States.[4,5]
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.
EnlargeFigure 1. Anatomy of the inside of the brain, showing the pineal and pituitary glands, optic nerve, ventricles (with cerebrospinal fluid shown in blue), and other parts of the brain. The tentorium separates the cerebrum from the cerebellum. The infratentorium (posterior fossa) is the region below the tentorium that contains the brain stem, cerebellum, and fourth ventricle. The supratentorium is the region above the tentorium and denotes the region that contains the cerebrum.
Clinical Features
The clinical presentation of ependymoma is dependent on tumor location.
Posterior fossa (infratentorial) ependymomas: Children with posterior fossa ependymomas may present with signs and symptoms of obstructive hydrocephalus caused by obstruction at the level of the fourth ventricle. They may also present with ataxia, neck pain, and/or cranial nerve palsies.
Supratentorial ependymomas: Supratentorial ependymomas may result in headaches, seizures, or location-dependent focal neurological deficits.
Spinal cord ependymomas: Spinal cord ependymomas, which are often the myxopapillary variant, tend to cause back pain, lower extremity weakness, and/or bowel and bladder dysfunction.
Diagnostic Evaluation
Every patient suspected of having an ependymoma is evaluated with diagnostic imaging of the whole brain and spinal cord. The most sensitive method available for evaluating spinal cord subarachnoid metastasis is spinal magnetic resonance imaging (MRI) performed with gadolinium. This is ideally done before surgery to avoid confusion with postoperative blood. If MRI is used, the entire spine is generally imaged in at least two planes with contiguous MRI slices performed after gadolinium enhancement.
If feasible, CSF cytological evaluation is conducted.[7] Despite the frequent finding of disseminated disease at the time of recurrence, metastatic disease at initial presentation is rare.[8][Level of evidence C2]
Prognostic Factors
Unfavorable factors affecting outcome (except as noted) include the following:
Molecular characteristics.
Posterior fossa ependymomas are divided into the following two primary molecular groups on the basis of distinctive patterns of gene expression.[9–12]
Posterior fossa A ependymoma (PF-EPN-A).
PF-EPN-A occurs primarily in young children and is characterized by a largely balanced genomic profile, with an increased occurrence of chromosome 1q gain [13–16] and expression of genes and proteins previously shown to be associated with poor prognosis, such as tenascin C and epidermal growth factor receptor.[13,17,18]
Gain of 1q confers a very poor prognosis despite complete resection and postoperative radiation therapy (5-year event-free survival rate, 81.5% for balanced 1q vs. 35.7% for gain 1q).[19][Level of evidence B4]
A combined retrospective analysis of 663 patients from five nonoverlapping cohorts identified loss of 6q as a poor prognostic factor for patients with PF-EPN-A.[20] Loss of 6q was observed in 8.6% of PF-EPN-A cases, and it is more common in tumors with 1q gain. The subset of patients (n = 22) with both 1q gain and 6q loss had a particularly poor prognosis.
A retrospective multi-institutional study compared patient-matched primary tumors with recurrent tumors. The study reported that the high-risk features of 1q gain and 6q loss were more frequent in recurrent tumors than in primary tumors, and these features remained associated with a poor prognosis.[21]
Posterior fossa B ependymoma (PF-EPN-B).
PF-EPN-B occurs primarily in older children and adults and is characterized by a more favorable prognosis and by numerous cytogenetic abnormalities involving whole chromosomes or chromosomal arms.[9,12,22]
Patients with PF-EPN-B have a favorable outcome when compared with patients with PF-EPN-A. Patients with PF-EPN-B have a 5-year progression-free survival (PFS) rate of 73% and an overall survival (OS) rate exceeding 90%.[11,12]
Gain of 1q is not a prognostic feature in patients with PF-EPN-B, whereas loss of chromosome 13q may confer a poor prognosis.[22]
Supratentorial ependymomas can be divided into the following two primary molecular groups on the basis of their gene fusion status:
While a retrospective analysis suggested that the RELA fusion predicted poorer prognosis,[11] subsequent reports suggest that patients with RELA fusions who undergo a complete resection and postoperative radiation have relatively favorable survival rates that are in the range of 80% at 5 years.[11,19,23,24] Retrospective studies suggest a poor outcome for patients who undergo complete surgical resections but do not receive postoperative radiation therapy.[11]
Homozygous deletion of CDKN2A has been associated with a poor prognosis in patients with ST-EPN-ZFTA.[25][Level of evidence B4] CDKN2A deletion has also been reported as a secondary event in recurrent ependymoma.[26]
Supratentorial ependymoma with YAP1 fusions (ST-EPN-YAP1).
Patients with ST-EPN-YAP1 have a favorable prognosis (although based on small numbers), with 5-year survival rates approaching 100%.[11,23,27]
Spinal ependymomas can be separated by methylome studies, but molecular classification does not provide any clinicopathological advantage over histopathological classification for myxopapillary ependymoma and subependymoma. However, molecular classification is useful for identifying spinal ependymoma with MYCN amplification, which has been associated with a poor prognosis. There is a paucity of data on the optimal risk stratification of spinal ependymoma in children, although inferring from adults, a complete resection confers a favorable prognosis.
Spinal ependymoma, MYCN-amplified (SP-EPN-MYCN).
This is a rare and aggressive ependymoma that predominantly affects young adults.
SP-EPN-MYCN tumors are typically grade 3, and they are characterized by aggressive behavior, with frequent leptomeningeal dissemination and high rate of recurrence.[28–31]
Younger age at diagnosis. Younger age at diagnosis has historically been a poor prognostic factor, although this could partially result from the common practice of avoiding or deferring radiation in children younger than 3 years. In a prospective Children’s Oncology Group (COG) trial (ACNS0121 [NCT00027846]), immediate postoperative radiation therapy was given to all children older than 1 year after gross-total resection or near-total resection. The study demonstrated that there was no significant difference in 5-year PFS or OS between patients aged 1 to 3 years and patients aged 3 to 21 years.[19]
Anaplastic histology. Anaplastic histology has been associated with a poor prognosis.[32][Level of evidence B4]; [33–36]; [37][Level of evidence C1]; [38][Level of evidence C2] However, the distinction between grade 2 and grade 3 disease has significant interobserver variability, confounding the use of anaplasia as a prognostic factor.[39] The 2021 WHO Classification of Tumors of the CNS no longer uses the term anaplastic ependymoma and allows only a histologically defined diagnosis of ependymoma in the integrated diagnosis. Within the layered report, a pathologist can still choose to assign either CNS WHO grade 2 or 3 to a tumor on the basis of its histological features.[2,3]
Lower doses of radiation. Lower doses of radiation or chemotherapy-only protocols confer a poor prognosis.[12,23,40,41]
Follow-Up After Treatment
Surveillance neuroimaging, coupled with clinical assessments, is generally recommended after treatment for ependymoma. In a report of 198 patients with ependymoma, 90 experienced a relapse. Patients whose relapsed tumor was detected by routine surveillance imaging had superior second PFS than patients whose relapsed tumor was detected by clinical symptomology. The latter were more likely to have metastatic disease at relapse. It is not known whether these patients also had more biologically aggressive disease, although the median time to relapse and the median time from last surveillance imaging was the same in both groups.[42]
Most practitioners obtain MRI of the brain and/or spinal cord at the following intervals:[43][Level of evidence B4]
First 2 to 3 years after treatment: Every 3 to 4 months.
Four to 5 years after treatment: Every 6 months.
More than 5 years after treatment: Annually because of the high incidence of late recurrences.
References
Louis DN, Ohgaki H, Wiestler OD: WHO Classification of Tumours of the Central Nervous System. 4th rev.ed. IARC Press, 2016.
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]
WHO Classification of Tumours Editorial Board, ed.: WHO Classification of Tumours: Central Nervous System Tumours. Vol. 6. 5th ed. IARC Press; 2021.
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.
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
Vaidya K, Smee R, Williams JR: Prognostic factors and treatment options for paediatric ependymomas. J Clin Neurosci 19 (9): 1228-35, 2012. [PUBMED Abstract]
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]
Klawinski D, Indelicato DJ, Hossain J, et al.: Surveillance imaging in pediatric ependymoma. Pediatr Blood Cancer 67 (11): e28622, 2020. [PUBMED Abstract]
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 Features of Childhood Ependymoma
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.
EnlargeFigure 2. Graphical summary of key molecular and clinical characteristics of ependymal tumor subgroups. Schematic representation of key genetic and epigenetic findings in the nine molecular subgroups of ependymal tumors as identified by methylation profiling. CIN, Chromosomal instability. Reprinted from Cancer Cell, Volume 27, Kristian W. Pajtler, Hendrik Witt, Martin Sill, David T.W. Jones, Volker Hovestadt, Fabian Kratochwil, Khalida Wani, Ruth Tatevossian, Chandanamali Punchihewa, Pascal Johann, Juri Reimand, Hans-Jorg Warnatz, Marina Ryzhova, Steve Mack, Vijay Ramaswamy, David Capper, Leonille Schweizer, Laura Sieber, Andrea Wittmann, Zhiqin Huang, Peter van Sluis, Richard Volckmann, Jan Koster, Rogier Versteeg, Daniel Fults, Helen Toledano, Smadar Avigad, Lindsey M. Hoffman, Andrew M. Donson, Nicholas Foreman, Ekkehard Hewer, Karel Zitterbart, Mark Gilbert, Terri S. Armstrong, Nalin Gupta, Jeffrey C. Allen, Matthias A. Karajannis, David Zagzag, Martin Hasselblatt, Andreas E. Kulozik, Olaf Witt, V. Peter Collins, Katja von Hoff, Stefan Rutkowski, Torsten Pietsch, Gary Bader, Marie-Laure Yaspo, Andreas von Deimling, Peter Lichter, Michael D. Taylor, Richard Gilbertson, David W. Ellison, Kenneth Aldape, Andrey Korshunov, Marcel Kool, and Stefan M. Pfister, Molecular Classification of Ependymal Tumors across All CNS Compartments, Histopathological Grades, and Age Groups, Pages 728–743, Copyright (2015), with permission from Elsevier.
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]
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:
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
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]
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]
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]
WHO Classification of Tumours Editorial Board, ed.: WHO Classification of Tumours: Central Nervous System Tumours. Vol. 6. 5th ed. IARC Press; 2021.
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
Histopathological Classification of Childhood Ependymal Tumors
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]
Subependymoma (WHO grade 1): A subependymoma is a slow-growing neoplasm, typically attached to the ventricle wall. It is composed of glial tumor cell clusters embedded in a fibrillary matrix.
The true incidence of subependymomas (WHO grade 1) is difficult to determine. These tumors are frequently asymptomatic and may be found incidentally at autopsy. Subependymomas probably comprise less than 5% of all ependymal tumors.
A diagnosis of subependymoma in a child is questionable, and further review or molecular analysis should be considered.[3]
Myxopapillary ependymoma (WHO grade 2): A myxopapillary ependymoma arises almost exclusively in the location of the conus medullaris, cauda equina, and filum terminale of the spinal cord. They are characterized histologically by tumor cells arranged in a papillary manner around vascularized myxoid stromal cores. Myxopapillary ependymoma is now considered WHO grade 2, rather than grade 1, because its recurrence rate is similar to conventional spinal ependymoma.[4]
Ependymoma: Ependymoma originates from the walls of the ventricles or from the spinal canal and are composed of neoplastic ependymal cells.
In the 2016 WHO revision, anaplastic ependymoma was eliminated as a subtype. In the 2021 WHO revision, papillary, clear cell, and tanycytic ependymoma were removed as subtypes because they were of no clinicopathologic utility. They are now included as patterns when describing the histopathology of an ependymoma.
Grading of ependymoma has been fraught with issues of reproducibility and clinical usefulness, especially in molecularly defined ependymoma. Therefore, the 2021 WHO classification allows only a histologically defined diagnosis of ependymoma in the integrated diagnosis (i.e., anaplastic ependymoma is no longer allowed), but a pathologist can choose to assign WHO grade 2 or 3 on the basis of the histopathological features. Grade 3 ependymoma, compared with grade 2 ependymoma, shows increased cellularity and mitotic activity, often associated with microvascular proliferation and necrosis. The distinction between grade 2 and grade 3 has significant interobserver variability and lacks uniformity across cooperative group studies.[5]
Histologically defined ependymoma can be further classified by molecular features, as follows:
Supratentorial ependymoma includes the molecular subtypes ST-EPN (NEC or NOS), ST-EPN-ZFTA, and ST-EPN-YAP1.
Posterior fossa ependymoma includes PF-EPN (NEC or NOS), PF-EPN-A, and PF-EPN-B.
Spinal ependymoma includes SP-EPN (NEC or NOS) and SP-EPN-MYCN.
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]
WHO Classification of Tumours Editorial Board, ed.: WHO Classification of Tumours: Central Nervous System Tumours. Vol. 6. 5th ed. IARC Press; 2021.
Louis DN, Ohgaki H, Wiestler OD: WHO Classification of Tumours of the Central Nervous System. 4th rev.ed. IARC Press, 2016.
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]
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]
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]
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]
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]
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]
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]
Stage Information for Childhood Ependymoma
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
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]
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]
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]
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]
Treatment Option Overview for Childhood Ependymoma
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:
Subtype of ependymoma.
Location of the tumor.
Whether the tumor was completely removed during the initial surgery.
Whether the tumor has disseminated throughout the central nervous system.
Child’s age.
Table 1 describes the standard treatment options for newly diagnosed and recurrent childhood ependymoma.
Table 1. Standard Treatment Options for 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
Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014. [PUBMED Abstract]
National Cancer Institute: NCCR*Explorer: An interactive website for NCCR cancer statistics. Bethesda, MD: National Cancer Institute. Available online. Last accessed February 25, 2025.
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.
Treatment of Childhood Myxopapillary Ependymoma
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:
Surgery with or without adjuvant radiation therapy.
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]
The study reported poor 5-year and 10-year event-free survival (EFS) rates of 52% and 26%, respectively.
However, these patients had an excellent 10-year overall survival (OS) rate of 100%.
Fifty percent of the patients had metastatic disease at diagnosis and 50% had subtotal resections, but only three patients received radiation therapy (two received focal and one received craniospinal).
The extent of resection did not affect the EFS rate.
Metastatic disease was associated with a worse EFS (10-year EFS rate, 13%), compared with localized disease (57%; P = .07).
This study concluded that despite the high risk of recurrence, patients with myxopapillary ependymoma have an excellent long-term survival. Therefore, radiation therapy should be reserved for patients with symptomatic recurrences to avoid long-term complications from radiation exposure.
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]
With a median follow-up of 3.6 years (range, 1.8–10.6 years), the 5-year local control rate was 100%, the PFS rate was 92%, and the OS rate was 100%.
One patient developed grade 3 spinal kyphosis after combined surgery and radiation therapy, and one patient developed grade 2 unilateral L5 neuropathy.
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]
At the time of radiation therapy, 45 patients (75.0%) had gross residual disease, and 35 patients (58.3%) had multifocal disease.
Forty-eight patients (80.0%) received involved-field radiation therapy (IFRT), seven (11.7%) received cranial-spinal radiation therapy, and five (8.3%) received whole-spine radiation therapy.
With a median follow-up of 6.2 years (range, 0.6–21.0 years), the 5-year OS rate was 100%, the PFS rate was 60.8%, and the cumulative incidence of local in-field progression rate was 4.1%.
The two local recurrences were in sites of gross residual disease. Of the 18 out-of-field recurrences after radiation therapy, all were superior to the initial treatment field. Nine of these patients experienced intracranial relapse (five of whom had isolated intracranial relapses).
For patients with metastatic myxopapillary ependymoma, there was no significant difference in PFS between patients treated with IFRT (to all sites) and those treated with whole-brain or craniospinal irradiation (P = .283).
On univariate analysis, distant-only recurrence before radiation therapy was significantly associated with shorter time to progression (HR, 4.00; 95% CI, 1.54–10.43; P = .005).
Conclusions from this report include: 1) the risk of recurrence within the radiation field is low, and 2) pediatric and AYA patients with high-risk myxopapillary ependymoma remain at risk for recurrences in the spine above the radiation fields and intracranially after radiation therapy.
References
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]
Bagley CA, Kothbauer KF, Wilson S, et al.: Resection of myxopapillary ependymomas in children. J Neurosurg 106 (4 Suppl): 261-7, 2007. [PUBMED Abstract]
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]
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]
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]
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]
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]
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]
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]
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]
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]
Treatment of Childhood Nonmyxopapillary Spinal Ependymoma
Standard treatment options for newly diagnosed childhood nonmyxopapillary spinal ependymoma include the following:
Surgery.
Radiation therapy.
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]
With a median follow-up of 6.3 years (range, 1.5–14.8 years), no tumors progressed.
Although most patients experienced neurological sequelae after surgery, only one developed additional neurological deficits after radiation therapy.
References
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]
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]
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.
Surgery
Surgery is performed in an attempt at maximal tumor reduction. Evidence suggests that more extensive surgical resection is related to an improved rate of survival.[1–5]; [6,7][Level of evidence C2] Magnetic resonance imaging (MRI) is performed postoperatively to confirm the extent of resection. If not obtained preoperatively, MRI of the entire neuraxis and cerebrospinal fluid cytopathology is performed to evaluate for disease dissemination.
Patients across all molecular subgroups who have residual tumor or disseminated disease are considered at high risk of relapse and may be treated on clinical trials specifically designed for them. Patients with no evidence of residual tumor still have an approximate 20% to 40% relapse risk despite receiving postoperative radiation therapy.[8][Level of evidence B4]
Anecdotal experience suggests that surgery alone for completely resected supratentorial World Health Organization (WHO) grade 2 tumors and spinal ependymomas may, in select cases, be an appropriate approach to treatment.[9–13][Level of evidence C2]
Evidence (surgery):
A prospective multi-institutional cooperative group trial (Children’s Oncology Group [COG] ACNS0121 [NCT00027846]) included patients with newly diagnosed intracranial ependymomas (N = 356). Surgery alone was used for the treatment of supratentorial, WHO grade 2, gross-totally resected ependymomas (n = 11).[8][Level of evidence B4]
The 5-year event-free survival (EFS) rate was 61.4%, and the overall survival (OS) rate was 100%.
Local failure occurred in four patients (36%), and local and distant failure occurred in one patient (9%).
In this study, the number of patients eligible for a surgery-alone approach was very small. Only a subset of these patients successfully avoided additional treatment.
Retrospective analysis of the outcome for patients with posterior fossa B ependymoma suggests that these patients might be sufficiently treated with gross-total resection alone,[7] but this approach has not been tested in a prospective randomized clinical trial.
Adjuvant Therapy
Treatment of no residual disease, no disseminated disease
Radiation therapy
The standard postsurgical treatment for these patients has been radiation therapy consisting of 54 Gy to 59.4 Gy to the tumor bed for children aged 3 years and older.[5,14] The ACNS0121 (NCT00027846) study extended the use of radiation therapy (54 Gy) to patients as young as 1 year, resulting in similar EFS and OS rates when compared with children older than 3 years.[8][Level of evidence B4]
It is not necessary to treat the entire CNS (whole brain and spine) because these tumors usually recur initially at the local site, although posterior fossa ependymomas may disseminate at recurrence, particularly in tumors with 1q gain.[15]; [16][Level of evidence C1]
Evidence (radiation therapy):
In one single-institution study, 74 patients aged 1 to 21 years were treated with conformal radiation therapy immediately after surgery.[17]
The 3-year progression-free survival (PFS) rate was 77.6% (± 5.8%).
In an expansion of the above series, 107 of 153 patients received conformal radiation therapy immediately after up-front resection.[5][Level of evidence C1]
The 7-year EFS rate was 76.9% (± 13.5%).
A COG prospective study (ACNS0121 [NCT00027846]) enrolled 356 patients between the ages of 1 and 21 years with newly diagnosed ependymoma into four strata.[8][Level of evidence B4]
Stratum 1: Patients with completely resected differentiated histology supratentorial ependymomas who were treated without radiation therapy.
The 5-year PFS rate was 61.4% (95% confidence interval, 34.5%–89.6%), with no deaths at 7 years, although only 11 patients were enrolled in this stratum.
Stratum 2: Patients with subtotally resected ependymomas (both supratentorial and infratentorial) with more than 5 mm residual disease. Treatment consisted of two cycles of chemotherapy followed by second-look surgery and conformal radiation therapy to the tumor bed (adding a 1-cm target clinical volume). Radiation doses were 54 Gy for patients aged 12 to 18 months and 59.4 Gy for patients older than 18 months.
The 5-year PFS rate was 25% for patients in whom a second surgery was not feasible, and 50% for patients in whom a second surgery resulted in a gross-total resection.
Stratum 3 and stratum 4: Patients with near-total resection (stratum 3) and gross-total resection (stratum 4). Patients aged 12 to 18 months received postoperative radiation therapy doses of 54 Gy, and patients older than 18 months received doses of 59.4 Gy (adding a 1-cm target clinical volume).
The 5-year PFS rate was 68.5% (range, 62.8%–74.2%).
Posterior fossa A ependymoma (PF-EPN-A), 1q balanced (without 1q gain): The 5-year PFS rate was 81.5% (range, 71.5%–91.5%).
PF-EPN-A, 1q gain: The 5-year PFS rate was 35.7% (range, 12.8%–58.6%).
For patients with PF-EPN-A, distant failure was more common in patients with 1q gain than in patients with 1q balanced (without 1q gain).
Supratentorial ependymomas: 30 of 39 patients with supratentorial ependymomas who were tested harbored ZFTA fusions, 23 of whom were in stratums 3 and 4. There was no significant difference in survival. The 5-year OS rates exceeded 80%.
Proton-beam radiation therapy (a type of charged-particle radiation therapy) provides a possible advantage for targeting the tumor (supratentorial or infratentorial) while avoiding critical normal brain and neuroendocrine tissues.
In a report from the Massachusetts General Hospital, 150 patients (aged <22 years) with WHO grade 2 and grade 3 ependymomas were treated with proton radiation therapy between 2001 and 2019. The median follow-up was 6.5 years.[18]
For the intracranial cohort (n = 145), the 7-year EFS rate was 63.4%, the OS rate was 82.6%, and the local control rate was 76.1%.
Fifty-one patients experienced a tumor recurrence: 26 patients (51%) had local failures, 19 patients (37.3%) had distant failures, and 6 patients (11.8%) had synchronous failures.
Of the 150 patients, 116 (77.3%) underwent gross-total resection, 5 (3.3%) underwent near-total resection, and 29 (19.3%) underwent subtotal resection.
For the intracranial cohort, the 7-year EFS rate was 70.3% for patients who underwent a gross-total resection or near-total resection and 35.2% for patients who underwent a subtotal resection.
With multivariate analysis, the effect of tumor excision persisted after controlling for tumor location.
In a combined Massachusetts General Hospital and University of Florida study, 386 children with nonmetastatic intracranial grade 2 and grade 3 ependymomas were treated with proton radiation therapy.[19]
With a median follow-up of 5 years, the 7-year local control rate was 77%, the PFS rate was 63.8%, and the OS rate was 82%.
As with the previous report, subtotal resection was associated with worse local control, PFS, and OS.
Radiation therapy doses of greater than 54 Gy were not associated with improved disease control or survival.
The rate of brain stem toxicity greater than grade 2 was 4%, and two children died of brain stem toxicity.
In the KiProReg study, 105 children with intracranial ependymomas were treated with a median total dose of 59.4 Gy of proton radiation therapy. Children younger than 4 years received 54 Gy. The median follow-up was 1.9 years.[20]
The estimated 3-year OS rate was 93.7%, the local control rate was 74.1%, and the PFS rate was 55.6%.
Multiple surgeries were identified as a risk factor for lower PFS.
There was a low rate of grade 3 toxicities and there were no episodes of symptomatic brain stem necrosis.
Concerns about brain stem toxicity in very young children (aged <3 years) after proton therapy to the posterior fossa have prompted the use of more conservative doses in these children at some centers.[21–23]
The International Society of Paediatric Oncology (SIOP) Ependymoma I study included 74 eligible pediatric patients with localized ependymomas. Thirty-three patients underwent a gross-total resection before receiving focal irradiation.[24][Level of evidence B4]
The 5-year EFS rate was 69%, and the 10-year EFS rate was 63%.
The 5-year OS rate was 81%, and the 10-year OS rate was 68%.
Post hoc analysis of known risk factors confirmed the impact of 1q gain, H3K27me3 loss, and hTERT expression.
Current treatment approaches do not include chemotherapy as a standard component of primary therapy for children with newly diagnosed ependymomas that are completely resected. The utility of adjuvant chemotherapy was studied in the completed COG ACNS0831 (NCT01096368) trial. Published results of this trial are forthcoming. There is no evidence that myeloablative chemotherapy [25] improves the outcome for patients with totally resected, nondisseminated ependymomas.
Treatment of residual disease, no disseminated disease
Second-look surgery
Second-look surgery should be considered because patients who have complete resections followed by irradiation have better disease control.[26] In some cases, further surgery can be undertaken after the initial attempted resection if the pediatric neurosurgeon believes that a gross-total resection could be obtained by an alternate surgical approach to the tumor. In other cases, additional up-front surgery is not anticipated to result in a gross-total resection; therefore, adjuvant therapy is initiated with future consideration of second-look surgery.[8]
Radiation therapy
The rationale for radiation therapy, as described in the Treatment of no residual disease, no disseminated disease section above, also pertains to the treatment of children with residual nondisseminated ependymoma. In patients who had a subtotal resection, treatment with radiation therapy results in a 5-year PFS rate of 25%. Outcome is particularly poor for patients with PF-EPN-A,[8] although the outcome may be better for patients with residual tumor within the spinal canal.[27]
Preirradiation chemotherapy
The rationale for using chemotherapy in patients with residual tumor is to attempt to achieve a state of no evidence of disease before the patients undergo radiation therapy, either by achieving a complete response (CR) to chemotherapy alone or by facilitating the likelihood of a gross-total resection at the time of second-look surgery after chemotherapy. The benefit of chemotherapy for residual tumor after up-front surgery is still being investigated.
Evidence (preirradiation chemotherapy with or without surgery):
One study demonstrated a benefit of preirradiation chemotherapy in children with near-total resection (>90% resection), with outcomes similar to those for children achieving a gross-total resection followed by radiation therapy.[28]
The COG ACNS0121 (NCT00027846) trial included two cycles of preirradiation chemotherapy for children with residual disease after up-front surgery (n = 64).[8][Level of evidence B4]
Second-look surgery occurred in 39% of patients (n = 25) (gross-total resection, 56%; near-total resection, 20%; subtotal resection, 24%).
For patients who underwent second-look surgery, the 5-year EFS rate was 50.5%, compared with 28.5% for patients who did not undergo second surgery (P = .12).
A multi-institutional trial for children younger than 3 years used preirradiation chemotherapy, followed by conformal radiation once the child was older than 12 months, followed by maintenance chemotherapy.[29][Level of evidence B4]
Fifty-four patients were enrolled, and 54% of patients (n = 29) underwent a gross-total resection at diagnosis.
Of the remaining 25 patients, 60% (n = 15) underwent a second-look surgery after chemotherapy, with 80% of patients achieving a gross-total resection.
At the time of radiation therapy, 76% of patients had a gross-total resection, 13% of patients had a near-total resection, and 11% of patients had a subtotal resection.
PFS (but not OS) was better for patients who underwent a gross-total resection or near-total resection before radiation therapy than it was for patients who underwent a subtotal resection (4-year PFS rate, 79% for gross-total resection/near-total resection vs. 41.7% for subtotal resection) (P = .024).
The SIOP Ependymoma I study enrolled 74 patients, 41 of whom had a subtotal resection after initial surgical management. The protocol specified that these patients were to receive up to four cycles of preirradiation vincristine, etoposide, and cyclophosphamide (VEC). Of the 41 patients, 10 did not receive the protocol-specified VEC therapy, and 3 patients opted for no further therapy and did not receive radiation therapy.[24][Level of evidence B4]
Of the 29 patients who received VEC, the combined complete response and partial response rate was 65%, which exceeded the prespecified 45% response rate threshold.
Eight of 29 patients had progressive disease at the completion of VEC chemotherapy. The 5-year and 10-year EFS rates were 34%. The 5-year OS rate was 60%, and the 10-year OS rate was 54%.
The study demonstrated chemoresponsiveness in most patients. However, the small number of patients precluded a determination of the added benefit of preirradiation VEC in either facilitating a subsequent gross-total resection or in a survival benefit, compared with patients with a subtotal resection who opted not to receive VEC before radiation therapy.
There is no evidence that high-dose chemotherapy with stem cell rescue is beneficial.[30]; [31][Level of evidence B4]
Treatment of CNS disseminated disease
Radiation therapy
Regardless of the degree of surgical resection, patients with CNS disseminated disease generally receive radiation therapy to the whole brain and spine, along with boosts to local disease and bulk areas of disseminated disease. The traditional local postsurgical radiation doses in these patients are 54 Gy to 55.8 Gy. Doses of approximately 36 Gy to the entire neuraxis (i.e., the whole brain and spine) are also administered but may be modulated depending on the age of the patient.[32] Boosts between 41.4 Gy and 50.4 Gy to bulk areas of spinal disease are administered, with doses depending on the age of the patient and the location of the tumor. However, there are no contemporary studies published to support this approach.
Chemotherapy
While chemotherapy is often used because of some degree of chemoresponsiveness, evidence demonstrating improvement in EFS and OS is lacking.[33]
Treatment of children younger than 1 year
Chemotherapy
Some, but not all, chemotherapy regimens induce objective responses in children younger than 3 years with newly diagnosed ependymomas.[34–37] The goal of chemotherapy is to avoid radiation, defer radiation until the child is older, or achieve a state of no evidence of disease before undergoing radiation therapy (either by a CR to chemotherapy or by a gross-total resection at time of second-look surgery after chemotherapy). Up to 25% of infants and young children with totally resected disease may achieve long-term survival. These studies have not been molecularly characterized, and it is unclear which patients may benefit from chemotherapy-only regimens. Survivors of chemotherapy-only protocols may eventually receive salvage radiation therapy.[38]; [39][Level of evidence B4]
Deferred radiation therapy
Historically, postoperative radiation therapy was omitted for children younger than 3 years with ependymomas. Two COG studies (POG-9233 and ACNS0121 [NCT00027846]) and many subsequent trials have lowered the age limit for postoperative radiation therapy to 1 year in an effort to improve outcomes for these younger children. The ACNS0121 trial showed that conformal radiation in children with completely resected tumors resulted in significantly improved outcomes compared with patients who received chemotherapy alone.[8][Level of evidence B4]
It is unclear which patients can benefit from radiation-sparing approaches. However, comparison of the POG-9233 trial results with the ACNS0121 (NCT00027846) trial results suggests a 50% to 60% improvement in survival for patients who were treated with radiation therapy.[8,38] A prospective evaluation of molecular markers may identify the infants who can be safely treated with radiation-sparing approaches and/or patients who may benefit from chemotherapy.
Evidence (radiation therapy):
Retrospective reviews based on Surveillance, Epidemiology, and End Results Program data from children younger than 3 years at diagnosis were accrued over a 50-year period.[40]
Results showed that patients who received local radiation therapy had better 10-year survival rates, even after adjusting for the extent of resection and tumor grade (WHO grade 2 vs. grade 3).
A large retrospective study, across 820 molecularly characterized posterior fossa ependymomas, demonstrated the following:[7]
Adjuvant first-line radiation therapy, along with complete resection and PF-EPN-B subgroup, were associated with an improved prognosis.
Radiation-sparing approaches were associated with dismal outcomes in children with PF-EPN-A tumors.
Conformal or charged-particle (e.g., proton) radiation therapy is an alternative approach for minimizing radiation-induced neurological damage in young children with ependymomas. The need and timing of radiation therapy for children who have successfully completed chemotherapy and have no residual disease is still to be determined.
The initial experience with this approach suggested that children younger than 3 years with ependymomas have neurological deficits at diagnosis that improve with time after conformal radiation treatment.[17]
Another study suggested that there was a trend for intellectual deterioration over time, even in older children treated with localized radiation therapy.[41]; [42][Level of evidence C1]
The COG ACNS0121 (NCT00027846) study showed that children aged 1 year to younger than 3 years who underwent a gross-total resection or near-total resection followed by immediate postoperative radiation therapy had the following results:[8][Level of evidence B4]
The 5-year EFS rate was 62.9%, and the OS rate was 87.4%.
These results were not statistically different from the results seen in patients aged 3 to 21 years, who had a 5-year EFS rate of 70.5% and an OS rate of 85.8%.
A multi-institutional trial of children younger than 3 years with newly diagnosed ependymomas (n = 54) who received four to six cycles of chemotherapy followed by radiation therapy (once they had reached the age of 12 months) resulted in the following:[29][Level of evidence B4]
The 4-year PFS rate was 75.1%, and the OS rate was 92.6%.
These results were comparable to the results seen in studies that treated children older than 3 years.
Of interest, there was no difference in outcomes between infants younger than 1 year and children aged 1 to 3 years at diagnosis.
Conformal radiation approaches, including 3-dimensional conformal radiation therapy that minimizes damage to normal brain tissue and charged-particle radiation therapy, such as proton-beam therapy, are under evaluation for infants and children with ependymomas.[17,43] When analyzing neurological outcomes after treatment of young children with ependymomas, it is important to consider that not all long-term deficits can be attributed to radiation therapy, because deficits may be present in young children before therapy begins.[17] For example, the presence of hydrocephalus at diagnosis is associated with a lower intelligence quotient, as measured after surgical resection and before administration of radiation therapy.[44]
Treatment Options Under Clinical Evaluation for Childhood Ependymoma
Early-phase therapeutic trials may be available for selected patients. These trials may be available via the COG, the Pediatric Brain Tumor Consortium, or other entities. Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
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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]
Kothbauer KF: Neurosurgical management of intramedullary spinal cord tumors in children. Pediatr Neurosurg 43 (3): 222-35, 2007. [PUBMED Abstract]
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]
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]
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]
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]
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]
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]
Hukin J, Epstein F, Lefton D, et al.: Treatment of intracranial ependymoma by surgery alone. Pediatr Neurosurg 29 (1): 40-5, 1998. [PUBMED Abstract]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
Indelicato DJ, Bradley JA, Rotondo RL, et al.: Outcomes following proton therapy for pediatric ependymoma. Acta Oncol 57 (5): 644-648, 2018. [PUBMED Abstract]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
Treatment of Recurrent Childhood Ependymoma
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:
The utility of further surgical intervention is individualized, based on the extent and location of the tumor. A study of 53 patients with recurrent ependymoma demonstrated an improved 5-year overall survival (OS) rate of 48.7% for patients who had gross-total or near-total resections at the time of surgery, compared with 5.3% for patients with less than gross-total or near-total resections.[4][Level of evidence B4]
In some cases, surgically accessible lesions may be treated alternatively with radiation therapy.
Radiation Therapy and/or Chemotherapy
Patients with recurrent ependymomas should be considered for treatment with the following modalities:[5][Level of evidence C1]
Craniospinal irradiation for both local and distant (spinal) recurrence could be considered.[15] A study of 101 reirradiated patients conducted at St. Jude Children’s Research Hospital observed the following results:[13][Level of evidence C2]
The median duration of OS was 75.1 months, and the median freedom from progression was 27.3 months.
The 1-, 2-, and 5-year estimates of OS rates were 95.5%, 74.9%, and 57.3%, respectively.
Among the 46 patients who received focal reirradiation for local failure, 13 had local failures, and 11 had distant-only failures.
Among the ten patients who received craniospinal irradiation for local failure, six had local failures, and none had distant-only failures.
Patients with distant-only failure who were treated with craniospinal irradiation had improved OS compared with individuals with local failure who were treated with focal radiation therapy (hazard ratio [HR], 0.37; 95% confidence interval [CI], 0.16–0.87).
The 10-year cumulative incidence of greater than grade 3 radiation necrosis after repeat radiation therapy was 7.9%.
Gain of chromosome 1q was associated with poorer OS (HR, 3.5; 95% CI, 1.1–10.6) for patients with distant failure (but not local failure) after initial radiation therapy. Other variables associated with reduced OS and freedom from progression included male sex, anaplastic histology at recurrence, and a short interval from initial radiation therapy to recurrence.
In a study of 31 children with locally recurrent ependymomas, patients received local (conformal) radiation at recurrence. They received various fractionation schemes using radiation doses similar to those used at initial diagnosis.[16]
The median local recurrence-free survival was 31 months (range, 2–63 months), and the median OS was 34 months (range, 3–63 months).
Patients who underwent surgery first had significantly higher survival rates than did patients who received reirradiation only.
In contrast, a study of 53 patients with recurrent ependymomas treated with radiation therapy after surgery showed no advantage with the addition of radiation therapy after a gross-total or near-total resection.[4][Level of evidence B4]
There was an improvement in the 5-year OS rate (22% vs. 7%) for patients treated with radiation therapy who had less than gross-total or near-total resections.
Three, and even four, courses of radiation therapy for patients with recurrences can prolong survival with acceptable minimal toxicity.[13][Level of evidence C2]
Active anticancer agents, including cyclophosphamide, cisplatin, carboplatin, lomustine, and etoposide, have been used in the recurrence setting. While older single-agent studies have demonstrated chemoresponsiveness with these agents, response is rarely durable.[17,18]
Regardless of treatment strategy, the prognosis for patients with recurrence is poor.[1] Entry into studies of novel therapeutic approaches should be considered.
Treatment Options Under Clinical Evaluation for Recurrent Childhood Ependymoma
Early-phase therapeutic trials may be available for selected patients. These trials may be available via the Children’s Oncology Group (COG), the Pediatric Brain Tumor Consortium, or other entities. Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
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]
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]
Wu J, Armstrong TS, Gilbert MR: Biology and management of ependymomas. Neuro Oncol 18 (7): 902-13, 2016. [PUBMED Abstract]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
Latest Updates to This Summary (01/06/2025)
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.
About This PDQ Summary
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood ependymoma. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
be discussed at a meeting,
be cited with text, or
replace or update an existing article that is already cited.
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Childhood Ependymoma Treatment are:
Kenneth J. Cohen, MD, MBA (Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital)
Louis S. Constine, MD (James P. Wilmot Cancer Center at University of Rochester Medical Center)
Roger J. Packer, MD (Children’s National Hospital)
D. Williams Parsons, MD, PhD (Texas Children’s Hospital)
Malcolm A. Smith, MD, PhD (National Cancer Institute)
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website’s Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
Permission to Use This Summary
PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”
The preferred citation for this PDQ summary is:
PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Ependymoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/brain/hp/child-ependymoma-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389373]
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Childhood Astrocytomas, Other Gliomas, and Glioneuronal/Neuronal Tumors Treatment (PDQ®)–Health Professional Version
General Information About Childhood Astrocytomas, Other Gliomas, and Glioneuronal/Neuronal Tumors
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.
EnlargeFigure 1. Anatomy of the inside of the brain, showing the cerebrum, cerebellum, brain stem, spinal cord, optic nerve, hypothalamus, and other parts of the brain.
Clinical Features
Presenting symptoms for childhood gliomas depend on the following:
Anatomical location.
Size of the tumor.
Rate of tumor growth.
Chronological and developmental age of the child.
Infants and young children with circumscribed gliomas (most commonly pilocytic astrocytomas) and, less frequently, diffuse astrocytomas, involving the hypothalamus may present with diencephalic syndrome. This syndrome is manifested by failure to thrive in an emaciated, seemingly euphoric child. Such children may have little in the way of other neurological findings but may present with macrocephaly, intermittent lethargy, and/or visual impairment.[3]
Children with diffuse midline gliomas centered in the pons (previously called diffuse intrinsic pontine gliomas [DIPGs]) may present with the following classic triad of symptoms; however, children may present with only one or two of these symptoms at diagnosis:
Obstructive hydrocephalus caused by expansion of the pons can also be a presenting symptom. Nonspecific symptoms may also occur, including behavioral changes and decreased school performance.
The presentation of circumscribed astrocytomas (e.g., pilocytic astrocytomas) in the brain stem depends on the tumor location. Common presenting symptoms include the following:[4]
Raised intracranial pressure with associated hydrocephalus.
Unilateral hemiparesis.
Unilateral cranial neuropathies.
Ataxia.
Diagnostic Evaluation
The initial diagnostic evaluation of patients with gliomas includes magnetic resonance imaging (MRI) with and without contrast of the brain and/or spine. The risk of neuraxis dissemination is tumor type dependent, and complete neuraxis imaging, including MRIs of the brain and total spine, may be performed in select patients. In most cases, the specific diagnosis is determined after surgical intervention and pathological classification.
Primary tumors of the brain stem are most often diagnosed based on clinical findings and neuroimaging studies using MRI, as follows:[5]
Diffuse midline glioma centered in the pons (DIPG). A presumptive diagnosis of DIPG based on classic imaging and clinical features, in the absence of a histological diagnosis, has been routinely employed. Increasingly however, histological confirmation is obtained for both entry into research studies and molecular characterization of the tumor.[6] Given the technical challenges of pontine biopsies, the procedure is best undertaken by an experienced pediatric neurosurgeon to minimize the risk of irreversible neurological complications.[7–11] Biopsy is recommended for pontine tumors when the diagnosis is uncertain based on imaging findings.
Non-DIPG brain stem tumors. Biopsy or resection is generally indicated for non-DIPG brain stem tumors.
Lumbar punctures examining the cerebrospinal fluid for circulating tumor cells are not commonly performed in children with these tumor types.
WHO Classification of Childhood CNS Astrocytomas, Gliomas, and Glioneuronal/Neuronal Tumors
The pathological classification of pediatric brain tumors is a highly specialized area that continues to evolve. Rapid advances in molecular genetics have led to major improvements in the accurate diagnosis of brain tumors over the past decade. At the same time, many novel brain tumor entities have been recognized based on unique molecular features. Examination of the diagnostic tissue by an experienced neuropathologist is strongly recommended, along with molecular testing, if available.
According to the 2021 WHO CNS classification, gliomas and glioneuronal/neuronal tumors occurring predominantly in childhood are broadly classified as follows:
Within each tumor type, various subtypes are recognized based on histological and molecular features.
The 2021 WHO CNS classification recommends a layered report structure as follows:[1,2]
Integrated diagnosis (combined tissue-based histological and molecular diagnosis).
Histological diagnosis.
CNS WHO grade.
Molecular information (listed).
WHO CNS tumor grading
Whereas CNS tumors were previously graded on histopathological grounds and clinical behavior alone (clinicopathological grading), the 2021 WHO CNS grading scheme employs combined histological and molecular grading for many tumor types.[1] Histological grading ranges from 1 to 4, but not all grades are applied to all tumor types, and some tumor types are not graded.
The 2021 WHO CNS classification and grading of the most common types/subtypes of gliomas, glioneuronal tumors, and neuronal tumors (excluding ependymal tumors) occurring in childhood and adolescence are shown in Table 1.
Table 1. World Health Organization (WHO) Classification and Grading of the Most Common Types and Subtypes of Gliomas, Glioneuronal Tumors, and Neuronal Tumors Occurring in Childhood and Adolescence (Excluding Ependymal Tumors)
Tumor Type/Subtype
WHO CNS Grades
Pediatric-type diffuse high-grade gliomas:
Diffuse midline glioma, H3 K27-altered
4
Diffuse pediatric-type high-grade glioma, H3-wild type and IDH-wild type
Childhood gliomas can occur anywhere in the CNS, although each tumor type tends to occur in specific anatomical locations (see Table 2).
Table 2. Common Central Nervous System (CNS) Locations for Childhood Gliomas
Tumor Type
Common CNS Location
Circumscribed astrocytic gliomas
Cerebellum, optic nerve, optic chiasm/hypothalamus, thalamus and basal ganglia, brain stem, cerebral hemispheres, and spinal cord (rare)
Ganglioglioma
Cerebrum, brain stem; occasionally other locations
Diffuse midline glioma, H3 K27-altered
Pons, thalamus, spinal cord, and other midline structures
Diffuse pediatric-type high-grade glioma, H3-wild type and IDH-wild type
Cerebrum; occasionally other locations
Cerebellum: More than 80% of gliomas located in the cerebellum are pilocytic astrocytomas (WHO grade 1) and often cystic; most of the remainder represent pediatric-type diffuse low-grade gliomas.[12] High-grade gliomas in the cerebellum are rare.
Brain stem: The term brain stem glioma is a generic description that refers to any tumor of glial origin arising in the brain stem, inclusive of the midbrain, pons, and medulla. While other histologies (e.g., ganglioglioma) can occur in the brain stem, the following two histologies predominate:
Diffuse midline glioma, H3 K27-altered, which are centered in the pons.[13] These were commonly referred to as diffuse intrinsic pontine gliomas (DIPG) due to their anatomical location. For more information about diffuse midline glioma, H3 K27-altered, see the Genomics of Gliomas, Glioneuronal Tumors, and Neuronal tumors section.
Pilocytic astrocytomas, which occur throughout the brain stem.
Tumors with exophytic components are overwhelmingly pilocytic astrocytomas.[14] DIPG accounts for approximately 75% to 80% of pediatric brain stem tumors.[15] Most children with DIPGs are diagnosed between the ages of 5 and 10 years. Focal pilocytic astrocytomas in the brain stem occur less frequently.[4]
Optic pathway and hypothalamus: Most tumors arising within the optic pathway (i.e., optic nerve, chiasm, and optic radiations) represent pilocytic astrocytomas, and rarely pediatric-type diffuse low-grade gliomas.[12]
Cerebrum: Most tumors arising in the cerebral hemispheres comprise circumscribed astrocytic gliomas and pediatric-type diffuse low-grade gliomas, followed by pediatric-type diffuse high-grade gliomas.[12]
Genomics of Gliomas, Glioneuronal Tumors, and Neuronal Tumors
Selected cancer susceptibility syndromes associated with pediatric glioma
Neurofibromatosis type 1 (NF1)
Children with NF1 have an increased propensity to develop low-grade gliomas, especially in the optic pathway. Up to 20% of patients with NF1 will develop an optic pathway glioma. Most children with NF1-associated optic nerve gliomas are asymptomatic and/or have nonprogressive symptoms and do not require antitumor treatment. Screening magnetic resonance imaging (MRI) in asymptomatic patients with NF1 is usually not indicated, although some investigators perform baseline MRI for young children who cannot undergo detailed ophthalmologic examinations.[16]
The diagnosis is often based on compatible clinical findings and imaging features. Histological confirmation is rarely needed at the time of diagnosis. When biopsies are performed, these tumors are predominantly pilocytic astrocytomas.[12]
Indications for treatment vary and are often based on the goal of preserving vision.
Very rarely, patients with NF1 develop high-grade gliomas. Sometimes, this tumor is the result of a transformation of a lower-grade tumor.[17]
Tuberous sclerosis
Patients with tuberous sclerosis have a predilection for developing subependymal giant cell astrocytoma (SEGA). Variants in either TSC1 or TSC2 cause constitutive activation of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, leading to increases in proliferation. SEGAs are responsive to molecularly targeted approaches with mTORC1 pathway inhibitors.[18][Level of evidence C2] Patients with tuberous sclerosis are also at risk of developing cortical tubers and subependymal nodules.
Molecular features and recurrent genomic alterations
Recurrent genomic alterations resulting in constitutive activation of the mitogen-activated protein kinase (MAPK) pathway, most commonly involving the BRAF gene, represent the primary (and often sole) oncogenic driver in the vast majority of pediatric low-grade gliomas, including pilocytic/pilomyxoid astrocytomas, gangliogliomas, and others.[12] As a result, most of these tumors are amenable to molecular targeted therapies.
More complex tumor genomes are characteristic of pediatric diffuse high-grade gliomas. These complex genomes include recurrent genomic alterations in the H3 histone encoding genes (e.g., H3F3A, HIST1H3B), DNA damage repair pathways (e.g., TP53, PPM1D, ATM, MDM2), chromatin modifiers (e.g., ATRX, BCOR, SETD2), cell cycle pathways (e.g., CDKN2A, CDKN2B, RB1), and/or oncogene amplifications (PDGFR, VEGFR2, KIT, MYC, MYCN).[19] For most of these tumors, existing conventional and molecular targeted therapies have limited efficacy.
A rare subset of pediatric high-grade gliomas arising in patients with inheritable biallelic mismatch repair deficiency (bMMRD) is characterized by an extraordinarily high mutational burden. Correctly identifying these patients at the time of diagnosis is critical because of intrinsic resistance to temozolomide and responsiveness to treatment with immune checkpoint inhibitors.[20][Level of evidence C3]; [21]
BRAF::KIAA1549
BRAF activation in pilocytic astrocytoma occurs most commonly through a BRAF::KIAA1549 gene fusion, resulting in a fusion protein that lacks the BRAF autoregulatory domain.[22] This fusion is seen in most infratentorial and midline pilocytic astrocytomas but is present at lower frequency in supratentorial (hemispheric) tumors.[12]
Presence of the BRAF::KIAA1549 fusion is associated with improved clinical outcome (progression-free survival [PFS] and overall survival [OS]) in patients with pilocytic astrocytoma.[23]; [24][Level of evidence C1] Progression to high-grade gliomas is very rare for pediatric gliomas with the BRAF::KIAA1549 fusion.[24]
BRAF variants
Activating single nucleotide variants in BRAF, most commonly BRAF V600E, are present in a subset of pediatric gliomas and glioneuronal tumors across a wide spectrum of histologies, including pleomorphic xanthoastrocytoma, pilocytic astrocytoma, ganglioglioma, desmoplastic infantile ganglioglioma/astrocytoma, and others.[12] Some low-grade, infiltrative, pediatric gliomas with an alteration in a MAPK pathway gene, including BRAF, and often resembling diffuse low-grade astrocytoma or oligodendroglioma histologically, are now classified as diffuse low-grade glioma, MAPK pathway altered.[1,25]
Retrospective clinical studies have shown the following:
In a retrospective series of more than 400 children with low-grade gliomas, 17% of tumors had BRAF V600E variants. The 10-year PFS rate was 27% for patients with BRAF V600E variants, compared with 60% for patients whose tumors did not harbor that variant. Additional factors associated with this poor prognosis included subtotal resection and CDKN2A deletion.[26][Level of evidence C2] Even in patients who underwent a gross-total resection, recurrence was noted in one-third, suggesting that BRAF V600E tumors have a more invasive phenotype than do other low-grade glioma variants.
In a similar analysis, children with diencephalic low-grade astrocytomas with a BRAF V600E variant had a 5-year PFS rate of 22%, compared with a PFS rate of 52% in children with wild-type BRAF.[27][Level of evidence C2]
The frequency of the BRAF V600E variant was significantly higher in pediatric low-grade gliomas that transformed to high-grade gliomas (8 of 18 patients) than was the frequency of the variant in tumors that did not transform to high-grade gliomas (10 of 167 cases).[24]
NF1 variants
Somatic alterations in NF1 are seen most frequently in children with NF1 and are associated with germline alterations in the tumor suppressor NF1. Loss of heterozygosity for NF1 represents the most common somatic alteration in these patients followed by inactivating variants in the second NF1 allele, and consistent with a second hit required for tumorigenesis. While most NF1 patients with low-grade gliomas have an excellent long-term prognosis, secondary transformation into high-grade glioma may occur in a small subset. Genomically, transformation is associated with the acquisition of additional oncogenic drivers, such as loss of function alterations in CDKN2A, CDKN2B and/or ATRX. Primary high-grade gliomas may also occur in patients with NF1 but are exceedingly rare. Genomic alterations involving the MAPK signaling pathway other than NF1 are very uncommon in gliomas occurring in children with NF1.[17]
ALK, NTRK1, NTRK2, NTRK3, or ROS1 gene fusions
High-grade gliomas with distinctive molecular characteristics arise in infants, typically in those diagnosed during the first year of life.[28–30] These tumors are characterized by recurrent oncogenic gene fusions involving ALK, NTRK1, NTRK2, NTRK3, or ROS1 as the primary and, typically, sole oncogenic driver. Infants with this type of glioma, now classified as infant-type hemispheric glioma, have a much better prognosis compared with older children with high-grade gliomas. Remarkably, these tumors may evolve from high-grade to low-grade histology over time, and it remains unclear how much this phenomenon is a consequence of natural disease history versus treatment-induced changes.[28]
ROS1 gene fusions have also been reported in gliomas occurring in older children and adults. A retrospective meta-analysis that included 40 children older than 1 year revealed that ROS1 gene fusions occurred in diverse glioma histologies, including diffuse high-grade and low-grade gliomas and glioneuronal tumors.[30] Similar to ROS1-altered cases occurring in infants, tumor variants in other known driver genes were rare. However, tumor copy number alterations were more frequent in older children than infants.
Other genomic alterations
As an alternative to BRAF activation or NF1 loss, other primary oncogenic driver alterations along the MAPK signaling pathway have been observed in pilocytic astrocytomas and other pediatric-type gliomas. These include oncogenic variants and/or fusions involving FGFR1, FGFR2, PTPN11, RAF1,NTRK2, and others.[12,31,32]
Low-grade gliomas with rearrangements in the MYB family of transcription factors [12,33,34] have been classified as a separate entity: diffuse astrocytoma, MYB– or MYBL1-altered, WHO grade 1.[1] Prognosis is generally favorable for patients with these tumors, particularly when a gross-total resection or near-total resection is obtained at the time of surgery.[35]
Angiocentric gliomas
Angiocentric gliomas typically arise in children and young adults as cerebral tumors presenting with seizures.[36]
Two reports in 2016 identified MYB gene alterations as being present in almost all cases diagnosed as angiocentric glioma, with QKI being the primary fusion partner in cases where fusion-partner testing was possible.[32,37] While angiocentric gliomas most commonly occur supratentorially, brain stem angiocentric gliomas with MYB::QKI fusions have also been reported.[38,39]
Astroblastomas, MN1-altered
Astroblastomas are defined histologically as glial neoplasms composed of GFAP-positive cells and contain astroblastic pseudorosettes that often demonstrate sclerosis. Astroblastomas are diagnosed primarily in childhood through young adulthood.[36]
The following studies have described genomic alterations associated with astroblastoma:
A report describing a molecular classification of CNS primitive neuroectodermal tumors (PNETs) identified an entity called CNS high-grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1) that was characterized by gene fusions involving MN1.[40] Most tumors with a histological diagnosis of astroblastoma (16 of 23) belonged to this molecularly defined entity.
A report of 27 histologically defined astroblastomas found that 10 cases had MN1 rearrangements, 7 cases had BRAF rearrangements, and 2 cases had RELA rearrangements.[41] Methylation array analysis showed that the cases with MN1 rearrangements clustered with CNS HGNET-MN1, the BRAF-altered cases clustered with pleomorphic xanthoastrocytomas, and the RELA cases clustered with ependymomas.
Genomic evaluation of eight cases of astroblastoma identified four with MN1 alterations. Of the remaining four cases, two had genomic alterations consistent with high-grade glioma and two cases could not be classified based on their molecular characteristics.[42]
One study described eight cases of astroblastoma. All five cases that underwent fluorescence in situ hybridization analysis showed MN1 rearrangements.[43]
These reports suggest that the histological diagnosis of astroblastoma encompasses a heterogeneous group of genomically defined entities. Astroblastomas with MN1 fusions represent a distinctive subset of histologically diagnosed cases.[44]
IDH1 and IDH2 variants
IDH1– and IDH2-altered tumors occur in the pediatric population as low-grade gliomas (WHO Grade 2), high-grade gliomas (WHO Grade 3 and 4), and oligodendrogliomas with codeletion of 1p and 19q. For more information about IDH1– and IDH2-altered gliomas, see the IDH1 and IDH2 variants section in the Molecular features of pediatric-type high-grade gliomas section.
Molecular features of pediatric-type high-grade gliomas
Pediatric high-grade gliomas are biologically distinct from those arising in adults.[45–48]
Subgroups identified using DNA methylation patterns
Pediatric-type high-grade gliomas can be separated into distinct subgroups based on epigenetic patterns (DNA methylation). These subgroups show distinguishing chromosome copy number gains/losses and gene variants in the tumor.[19,49,50] Particularly distinctive subtypes of pediatric high-grade gliomas are those with recurring variants at specific amino acids in histone genes, and together these account for approximately one-half of pediatric high-grade gliomas.[19]
The following pediatric-type high-grade glioma subgroups were identified based on their DNA methylation patterns, and they show distinctive molecular and clinical characteristics:[19]
Genomic alterations associated with diffuse midline gliomas
The histone K27 variants: H3.3 (H3F3A) and H3.1 (HIST1H3B and, rarely, HIST1H3C) variants at K27 and EZHIP
The histone K27–altered cases occur predominantly in middle childhood (median age, approximately 10 years), are almost exclusively midline (thalamus, brain stem, and spinal cord), and carry a very poor prognosis. The 2021 WHO classification groups these cancers into a single entity: diffuse midline glioma, H3 K27-altered. However, there are clinical and biological distinctions between cases with H3.3 and H3.1 variants, as described below.[1]
Diffuse midline glioma, H3 K27-altered, is defined by loss of H3 K27 trimethylation either due to an H3 K27M variant or, less commonly, overexpression of EZHIP. This entity includes most high-grade gliomas located in the thalamus, pons (diffuse intrinsic pontine gliomas [DIPGs]), and spinal cord, predominantly in children, but also in adults.[51]
H3.3 K27M: H3.3 K27M cases occur throughout the midline and pons, account for approximately 60% of cases in these locations, and commonly present between the ages of 5 and 10 years.[19] The prognosis for H3.3 K27M patients is especially poor, with a median survival of less than 1 year; the 2-year survival rate is less than 5%.[19] Leptomeningeal dissemination is frequently observed in H3.3 K27M patients.[52]
H3.1 K27M: H3.1 K27M cases are approximately fivefold less common than H3.3 K27M cases. They occur primarily in the pons and present at a younger age than other H3.3 K27M patients (median age, 5 years vs. 6–10 years). These patients have a slightly more favorable prognosis than do H3.3 K27M patients (median survival, 15 months vs. 11 months). Variants in ACVR1, which is also the variant observed in the genetic condition fibrodysplasia ossificans progressiva, are present in a high proportion of H3.1 K27M cases.[19,53,54]
H3.2 K27M: Rarely, K27M variants are also identified in H3.2 (HIST2H3C) cases.[19]
A subset of tumors with H3 K27 variants will have a BRAF V600E or FGFR1 co-variant.[55] A retrospective cohort of 29 tumors combined with 31 cases previously reported in the literature demonstrated a somewhat higher propensity for a thalamic location. These cases exhibit a unique DNA methylation cluster that is distinct from other diffuse midline glioma subgroups and glioma subtypes with BRAF or FGFR1 alterations. The median survival for these patients exceeded 3 years.[56] A separate retrospective study of pediatric and adult patients with H3 K27-altered gliomas revealed BRAF V600E variants in 5.8% (9 of 156) and FGFR1 variants in 10.9% (17 of 156) of patients younger than 20 years.[57] Other recurrent genetic alterations detected in pediatric patients included variants in TP53, ATRX, PIK3CA, and amplifications of PDGFRA and KIT. FGFR1 variants were noted to be more frequent in patients older than 20 years (31.8%, 47 of 148).
EZHIP overexpression: The small minority of patients with diffuse midline gliomas lacking histone H3 variants often show EZHIP overexpression.[51] EZHIP inhibits PRC2 activity, leading to the same loss of H3 K27 trimethylation that is induced by H3 K27M variants.[58] Overexpression of EZHIP is likewise observed in posterior fossa type A ependymomas, which also shows loss of H3 K27 methylation.[59]
H3.3 (H3F3A) variant at G34
The H3.3 G34 subtype arises from H3.3 glycine 34 to arginine/valine (G34R/V) variants.[49,50] This subtype presents in older children and young adults (median age, 14–18 years) and arises exclusively in the cerebral cortex.[49,50] H3.3 G34 cases commonly have variants in TP53 and ATRX (95% and 84% of cases, respectively, in one large series) and show widespread hypomethylation across the whole genome. In a series of 95 patients with the H3.3 G34 subtype, 44% of patients also had a variant in PDGFRA at the time of diagnosis, and 81% of patients had PDGFRA variants observed at relapse.[60]
Patients with H3F3A variants are at high risk of treatment failure,[61] but the prognosis is not as poor as that of patients with histone 3.1 or 3.3 K27M variants.[50] O-6-methylguanine-DNA methyltransferase (MGMT) methylation is observed in approximately two-thirds of cases, and aside from the IDH1-altered subtype (see below), the H3.3 G34 subtype is the only pediatric high-grade glioma subtype that demonstrates MGMT methylation rates exceeding 20%.[19]
IDH1 and IDH2 variants
IDH1– and IDH2-altered tumors occur in the pediatric population as low-grade gliomas (WHO grade 2), high-grade gliomas (WHO grades 3 and 4), and oligodendrogliomas with codeletion of 1p and 19q.[62]
IDH1 variants are much more common than IDH2 variants, accounting for approximately 90% of pediatric IDH-altered CNS tumors.
IDH-altered low-grade gliomas are more common than IDH-altered high-grade gliomas, accounting for approximately three-fourths of IDH-altered pediatric glioma cases.
Oligodendrogliomas with IDH variants represent approximately 20% of pediatric CNS tumors with IDH variants.
The median age at diagnosis for pediatric patients with IDH-altered tumors is approximately 16 years, and IDH-altered CNS tumors are very uncommon in children aged 10 years and younger.
Like astrocytomas with IDH variants in adults, those in affected children commonly have TP53 variants (approximately 90% of cases) and ATRX variants (approximately 50%).
Like IDH-altered, low-grade gliomas in adults, low-grade tumors in pediatric patients can also show progression to high-grade gliomas.
IDH1-altered cases represent a small percentage of high-grade gliomas (approximately 5%–10%) seen in pediatrics, and are almost exclusively older adolescents (median age in a pediatric population, 16 years) with hemispheric tumors.[19,62] These tumors are classified under adult-type diffuse glioma, as astrocytoma, IDH-altered in the 2021 WHO CNS classification. IDH1-altered cases often show TP53 variants, MGMT promoter methylation, and a glioma-CpG island methylator phenotype (G-CIMP).[49,50]
Pediatric patients with IDH1 variants have a more favorable prognosis than patients with other types of high-grade gliomas.[19] A retrospective multi-institutional review of pediatric patients with IDH-altered gliomas and available outcome data (n = 76) reported a 5-year PFS rate of 44% (95% CI, 25%–59%) and a 5-year OS rate of 92% (95% CI, 79%–97%).[62] Approximately 25% of the gliomas in the cohort were classified as high grade. There was no difference in 5-year PFS rates observed between tumor grades. However, patients with high-grade tumors had a worse 5-year OS rate of 75% (95% CI, 40%–91%).
Rare, IDH-altered, high-grade gliomas have been reported to occur in children with mismatch repair–deficiency syndromes (Lynch syndrome or constitutional mismatch repair deficiency syndrome).[63] These tumors, termed primary mismatch repair–deficient IDH-altered astrocytomas (PMMRDIAs), could be distinguished from other IDH-altered gliomas by methylation profiling. PMMRDIAs have molecular features that are distinct from most IDH-altered gliomas, including a hypervariant phenotype and frequent activation of receptor tyrosine kinase pathways. Patients with PMMRDIAs have a markedly worse prognosis than patients with other IDH-altered gliomas, with a median survival of 15 months.
Pleomorphic xanthoastrocytoma (PXA)–like
Approximately 10% of pediatric high-grade gliomas have DNA methylation patterns that are PXA-like.[50] PXA-like cases commonly have BRAF V600E variants and a relatively favorable outcome (approximately 50% survival at 5 years).[19,61]
High-grade astrocytoma with piloid features
This entity was included in the 2016 WHO classification (called pilocytic astrocytoma with anaplasia) to describe tumors with histological features of pilocytic astrocytoma, increased mitotic activity, and additional high-grade features. The current nomenclature was adopted in the 2021 WHO classification. A more recent publication described a cohort of 83 cases with these histological features (referred to as anaplastic astrocytoma with piloid features) that shared a common DNA methylation profile, which is distinct from the methylation profiles of other gliomas. These tumors occurred more often in adults (median age, 41 years), and they harbored frequent deletions of CDKN2A/B, MAPK pathway alterations (most often in the NF1 gene), and variants or deletions of ATRX. They are associated with a clinical course that is intermediate between pilocytic astrocytoma and IDH–wild-type glioblastoma.[64]
Other variants
Pediatric patients with glioblastoma multiforme high-grade glioma whose tumors lack both histone variants and IDH1 variants represent approximately 40% of pediatric glioblastoma multiforme cases.[19,65] This is a heterogeneous group, with higher rates of gene amplifications than other pediatric high-grade glioma subtypes. The most commonly amplified genes are PDGFRA, EGFR, CCND/CDK, and MYC/MYCN.[49,50] MGMT promoter methylation rates are low in this group.[65] One report divided this group into three subtypes. The subtype characterized by high rates of MYCN amplification showed the poorest prognosis, while the subtype characterized by TERT promoter variants and EGFR amplification showed the most favorable prognosis. The third group was characterized by PDGFRA amplification.[65]
High-grade gliomas in infants
Infants and young children with high-grade gliomas appear to have tumors with distinctive molecular characteristics [28,29] when compared with tumors of older children and adults with high-grade gliomas. An indication of this difference was noted with the application of DNA methylation analysis to pediatric high-grade tumors, which found that approximately 7% of pediatric patients with a histological diagnosis of high-grade glioma had tumors with methylation patterns more closely resembling those of low-grade gliomas.[19] Ten of 16 infants (younger than 1 year) with a high-grade glioma diagnosis were in this methylation array–defined group.[19] The 5-year survival rate for patients in this report diagnosed at younger than 1 year exceeded 60%, while the 5-year survival rate for patients aged 1 to 3 years and older was less than 20%.
Two studies of the molecular characteristics of high-grade gliomas in infants and young children have further defined the distinctive nature of tumors arising in children younger than 1 year. A key finding from both studies is the importance of gene fusions involving tyrosine kinases (e.g., ALK, NTRK1, NTRK2, NTRK3, and ROS1) in patients in this age group. Both studies also found that infants with high-grade gliomas whose tumors have these gene fusions have survival rates much higher than those of older children with high-grade gliomas.[28,29]
The first study presented data for 118 children younger than 1 year with a low-grade or high-grade glioma diagnosis who had tumor tissue available for genomic characterization.[28] Approximately 75% of the cases were classified as low grade, but the diminished utility of histological classification in this age group was illustrated by the relatively low OS rate for the low-grade cohort (71%) and the relatively favorable survival for the high-grade cohort (55%). Rates of surgical resection were higher for patients with high-grade tumors, a result of many of the low-grade tumors occurring in midline locations while the high-grade tumors were found in supratentorial locations. This finding may also help to explain the relative outcomes for the two groups. Genomic characterization divided the infant glioma population into the following three groups, the first of which included patients with high-grade gliomas:
Group 1 tumors were receptor tyrosine kinase driven and primarily high grade (83%). These tumors harbored lesions in ALK, ROS1, NTRK, and MET. The median age at diagnosis was 3 months, and OS rates were approximately 60%.
Group 2 tumors were RAS/MAPK driven and were all hemispheric low-grade gliomas, representing one-fourth of hemispheric gliomas in infants. BRAF V600E was the most common alteration, followed by FGFR1 alterations and BRAF fusions. This group had a median age at presentation of 8 months and had the most favorable outcome (10-year OS rate, 93%).
Group 3 tumors were RAS/MAPK driven with low-grade histology and midline presentation (approximately 80% optic pathway/hypothalamic gliomas). Most group 3 tumors showed either BRAF fusions or BRAF V600E. Median age at diagnosis was 7.5 months. The 5-year progression-free survival (PFS) rate was approximately 20%, and the 10-year OS rate was approximately 50% (far inferior to that of optic pathway/hypothalamic gliomas in children aged >1 year).
The second study focused on tumors from children younger than 4 years with a pathological diagnosis of WHO grades 2, 3, and 4 gliomas, astrocytomas, or glioneuronal tumors. Among the 191 tumors studied that met inclusion criteria, 61 had methylation profiles consistent with glioma subtypes that occur in older children (e.g., IDH1, diffuse midline glioma H3 K27-altered, SEGA, pleomorphic xanthoastrocytoma, etc.). The remaining 130 cases were called the intrinsic set and were the focus of additional molecular characterization:[29]
The intrinsic set contained most of the patients diagnosed before age 1 year (49 of 63 patients, 78%) and had a median age of 7.2 months. Tumors were frequently in a superficial hemispheric location, often involving the meninges, and had a well-defined border with adjacent normal brain.
The methylation classifier placed most of these cases in either the desmoplastic infantile ganglioglioma/astrocytoma (DIG/DIA) subgroup or in the infantile hemispheric glioma subgroup.
For 41 tumors from the intrinsic set in which tissue was available for gene panel and RNA sequencing, 25 tumors had fusions involving either ALK (n = 10), NTRK1 (n = 2), NTRK2 (n = 2), NTRK3 (n = 8), ROS1 (n = 2), or MET (n = 1). BRAF variants (n = 3) were observed in cases that were high scoring by methylation array for the DIG/DIA or DIG/DIA-like subgroups.
For patients in the intrinsic set, the 5-year survival rate was higher for patients whose tumors had gene fusions when compared with patients whose tumors lacked fusions (approximately 80% vs. 60%, respectively). However, both of these groups of patients had much higher survival rates than other children with high-grade gliomas.
Secondary high-grade glioma
Childhood secondary high-grade glioma (high-grade glioma that is preceded by a low-grade glioma) is uncommon (2.9% in a study of 886 patients). No pediatric low-grade gliomas with the BRAF::KIAA1549 fusion transformed to a high-grade glioma, whereas low-grade gliomas with the BRAF V600E variants were associated with increased risk of transformation. Seven of 18 patients (approximately 40%) with secondary high-grade glioma had BRAF V600E variants, with CDKN2A alterations present in 8 of 14 cases (57%).[24]
Molecular features of glioneuronal and neuronal tumors
Glioneuronal and neuronal tumors are generally low-grade tumors. Select histologies recognized by the 2021 WHO classification include the following:[1]
Ganglioglioma presents during childhood and into adulthood. It most commonly arises in the cerebral cortex and is associated with seizures, but it also presents in other sites, including the spinal cord.[66,67]
The unifying theme for the molecular pathogenesis of ganglioglioma is genomic alterations leading to MAPK pathway activation.[32,68] BRAF alterations are observed in approximately 50% of ganglioglioma cases, with V600E being by far the most common alteration. However, other BRAF variants and gene fusions are also observed. Other less commonly altered genes in ganglioglioma include KRAS, FGFR1, FGFR2, RAF1, NTRK2, and NF1.[32,68]
Desmoplastic infantile astrocytomas (DIA) and desmoplastic infantile gangliogliomas (DIG)
DIA and DIG most often present in the first year of life and show a characteristic imaging appearance in which a contrast-enhancing solid nodule accompanies a large cystic component.[69,70] DIG is more common than DIA,[69] and by methylation array analysis, both diagnoses cluster together.[71] Survival outcome is generally favorable with surgical resection.[69]
The most commonly observed genomic alterations in DIA and DIG are BRAF variants involving V600. Gene fusions involving kinase genes are observed less frequently.
Among 16 cases confirmed by histology and DNA methylation profiling to be DIA and DIG, BRAF variants were observed in seven cases (43.8%): four BRAF V600E variants and three BRAF V600D variants.[71] One additional case had an EML4::ALK fusion. BRAF variants were present in 4 of 12 DIG cases (25%) (with 3 of 4 altered cases having BRAF V600D) and in 3 of 4 DIA cases (75%) (all 3 altered cases with BRAF V600E).
One study of seven DIG cases found MAPK pathway alterations in four (57%).[72] Three alterations involved BRAF (V600E, V600D, and one deletion/insertion centered at V600) and one was a TPM3::NTRK1 in-frame fusion. Notably, the variant allele frequency was low (8%–27%), suggesting that DIG is characterized by a prominent nonneoplastic component resulting in low clonal driver variant allele frequencies.
Another report also described the BRAF V600D variant in a DIG case.[73] As the V600D variant is far less common than V600E in other cancers, its detection in multiple DIG cases suggests an association between the variant and DIG.
Dysembryoplastic neuroepithelial tumor (DNET)
DNET presents in children and adults, with the median age at diagnosis in mid-to-late adolescence. It is characterized histopathologically by the presence of columns of oligodendroglial-like cells and cortical ganglion cells floating in mucin.[74] The temporal lobe is the most common location, and it is associated with drug-refractory epilepsy.[67,75]
FGFR1 alterations have been reported in 60% to 80% of DNETs, and include FGFR1 activating single nucleotide variants, internal tandem duplication of the kinase domain, and activating gene fusions.[32,76,77] BRAF variants are uncommon in DNET.
Papillary glioneuronal tumor
Papillary glioneuronal tumor is a low-grade biphasic neoplasm with astrocytic and neuronal differentiation that primarily arises in the supratentorial compartment.[36] The median age at presentation is in the early 20s, but it can be observed during childhood through adulthood.
The primary genomic alteration associated with papillary glioneuronal tumor is a gene fusion, SLC44A1::PRKCA, that is associated with the t(9:17)(q31;q24) translocation.[78,79] In one study of 28 cases diagnosed histologically as papillary glioneuronal tumor using methylation arrays, 11 of the cases clustered in a distinctive methylation class, while the remaining cases showed methylation profiles typical for other tumor entities. Molecular analysis of the cases in the distinctive methylation cluster showed that all of them had the SLC44A1::PRKCA gene fusion except for a single case with a NOTCH1::PRKCA gene fusion.[80] This suggests that molecular methods for identifying the presence of a PRKCA fusion are less susceptible to misclassification in diagnosing papillary glioneuronal tumor than are morphology-based methods.
Rosette-forming glioneuronal tumor (RGNT)
RGNT presents in adolescents and adults, with tumors generally located infratentorially, although tumors can arise in mesencephalic or diencephalic regions.[81] The typical histological appearance shows both a glial component and a neurocytic component arranged in rosettes or perivascular pseudorosettes.[36] Outcome for patients with RGNT is generally favorable, consistent with the WHO grade 1 designation.[81]
DNA methylation profiling shows that RGNT has a distinct epigenetic profile that distinguishes it from other low-grade glial/glioneuronal tumor entities.[81] A study of 30 cases of RGNT observed FGFR1 hotspot variants in all analyzed tumors.[81] In addition, PIK3CA activating variants were concurrently observed in 19 of 30 cases (63%). Missense or damaging variants in NF1 were identified in 10 of 30 cases (33%), with 7 tumors having variants in FGFR1, PIK3CA, and NF1. The co-occurrence of variants that activate both the MAPK pathway and the PI3K pathway makes the variant profile of RGNT distinctive among astrocytic and glioneuronal tumors.
Diffuse leptomeningeal glioneuronal tumor (DLGNT)
DLGNT is a rare CNS tumor that has been characterized radiographically by leptomeningeal enhancement on MRI that may involve the posterior fossa, brain stem region, and spinal cord.[82] Intraparenchymal lesions, when present, typically involve the spinal cord.[82] Localized intramedullary glioneuronal tumors without leptomeningeal dissemination and with histomorphological, immunophenotypic, and genomic characteristics similar to DLGNT have been reported.[83]
DLGNT showed a distinctive epigenetic profile on DNA methylation arrays, and unsupervised clustering of array data applied to 30 cases defined two subclasses of DLGNT: methylation class (MC)-1 (n = 17) and MC-2 (n = 13).[82] Of note, many of the array-defined cases had originally been diagnosed as other entities (e.g., primitive neuroectodermal tumors, pilocytic astrocytoma, and anaplastic astrocytoma). Patients with DLGNT-MC-1 were diagnosed at an earlier age than were patients with DLGNT-MC-2 (5 years vs. 14 years, respectively). The 5-year OS rate was higher for patients with DLGNT-MC-1 than for those with DLGNT-MC-2 (100% vs. 43%, respectively). Genomic findings from the 30 cases of methylation array–defined DLGNT are provided below:
All 30 cases showed loss of chromosome 1p, but only 6 of 17 DLGNT-MC-1 cases showed additional gain of chromosome 1q, compared with all cases of DLGNT-MC-2.[82] A separate report found that chromosome 1q gain was an adverse prognostic factor in patients with DLGNT (including cases with localized disease),[84] which is consistent with the inferior outcome for patients with DLGNT-MC-2.
Co-deletions of 1p/19q were more frequent in the DLGNT-MC-1 group (7 of 13, 54%) than in the DLGNT-MC-2 group (2 of 13, 15%). In contrast to oligodendroglioma, variants of IDH1 and IDH2 were not identified.[82]
MAPK pathway activation is common in DLGNT cases.[82] The KIAA1549::BRAF fusion was present in 11 of 15 DLGNT-MC-1 cases (65%) and in 9 of 13 DLGNT-MC-2 cases (69%). Fusions involving NTRK1, NTRK2, or NTRK3 were present in one case each, and another case had a TRIM33::RAF1 fusion.
Extraventricular neurocytoma
Extraventricular neurocytoma is histologically similar to central neurocytoma, consisting of small uniform cells that demonstrate neuronal differentiation. However, extraventricular neurocytoma arises in the brain parenchyma rather than in association with the ventricular system.[36] It presents during childhood through adulthood.
In a study of 40 tumors histologically classified as extraventricular neurocytoma and subjected to methylation array analysis, only 26 formed a separate cluster distinctive from reference tumors of other histologies.[85] Among cases with an extraventricular neurocytoma methylation array classification for which genomic characterization could be performed, 11 of 15 (73%) showed rearrangements affecting members of the FGFR family, with FGFR1::TACC1 being the most common alteration.[85]
Prognosis
Circumscribed astrocytic gliomas, pediatric-type diffuse low-grade gliomas, and glioneuronal/neuronal tumors
These tumors generally carry a relatively favorable prognosis, particularly for well-circumscribed lesions where a radical resection may be possible.[86,87] With the exception of diffuse leptomeningeal glioneuronal tumors, disseminated or multifocal disease is rare.[88]
Unfavorable clinical prognostic features include the following:[89–91]
Young age.
Inability to obtain a complete resection.
Diencephalic syndrome.
Disseminated or multifocal disease, which is associated with a poorer long-term outcome.
On a molecular level, presence of a BRAF V600E variant, especially in conjunction with a CDKN2A or CDKN2B homozygous deletion, has been recognized as a negative prognostic factor, with risk of transformation to a higher-grade tumor. Conversely, the presence of a BRAF::KIAA1549 fusion confers a better clinical outcome in patients with circumscribed astrocytic gliomas.[26][Level of evidence C2]
In children with tumors of the visual pathway, both visual outcomes and clinical assessments are important. Children with isolated optic nerve tumors have a better prognosis than do children with lesions that involve the chiasm or that extend along the optic pathway.[92,93]; [94][Level of evidence C1] Children with NF1 also have a better prognosis, especially when the tumor is found in asymptomatic patients.[95] Better visual acuity at diagnosis, older age at diagnosis, and presence of NF1 are associated with better visual outcomes.[96]
Pediatric-type diffuse high-grade gliomas
These tumors carry a very poor prognosis with currently available therapies.
Patients with diffuse midline glioma, H3 K27-altered have the poorest prognosis, with 3-year survival rates below 5%.[50]
Diffuse brain stem tumors
The following definitions of brain stem tumors are used:
Brain stem glioma: A general term describing an astrocytoma arising in the brain stem. Such tumors can be circumscribed or diffuse and can occur in any location in the brain stem, including the midbrain, pons, and medulla.
Diffuse intrinsic pontine glioma (DIPG): A term used to describe an infiltrating astrocytoma (presumed diffuse midline glioma) centered in the pons.
Diffuse midline glioma, H3 K27-altered: The pathological diagnosis of most tumors that present with imaging features consistent with a DIPG.
The median survival for children with DIPGs is less than 1 year, although about 10% of children will survive longer than 2 years.[97,98] In contrast, patients with focal astrocytomas (e.g., pilocytic astrocytomas) have a markedly improved prognosis, with 5-year OS rates exceeding 90%.[4]
One report from a clinical trial included 42 children and adolescents with newly diagnosed midline thalamic high-grade gliomas. The study found that tumor location, enhancement pattern, diffusion restriction, and variant status did not significantly affect survival.[99] Leptomeningeal metastatic dissemination and lower surgical resection rates were associated with poorer outcomes.
Prognostic factors include the following:
Histology/grade of the tumor: Astrocytic tumors predominate in the brain stem. WHO grade 1 tumors (e.g., pilocytic astrocytomas and gangliogliomas) have a favorable prognosis and can arise throughout the brain stem, including the tectum of the midbrain, focally within the pons, or at the cervicomedullary junction where they are often exophytic. Low-grade diffuse astrocytomas (WHO grade 2) occurring outside the pons in other brain stem locations tend to be tumors with a more favorable prognosis.[100]
DIPGs are diffuse astrocytomas that, when biopsied at diagnosis, can range from diffuse astrocytomas (WHO grade 2) to glioblastomas (WHO grade 4). At postmortem evaluation, DIPGs are also generally anaplastic astrocytomas (WHO grade 3) or glioblastomas (WHO grade 4) by morphological criteria, although WHO grade 2 regions can also be identified.[53,54,101–103]
Approximately 80% of DIPGs, regardless of histological grade, demonstrate a histone H3.3 or H3.1 variant and are now classified by the WHO as diffuse midline gliomas, H3 K27M-altered. All diffuse midline gliomas, H3 K27M-altered, are WHO grade 4, regardless of histological grade, reflecting the poor prognosis of children with this diagnosis.
Age at diagnosis: Slightly prolonged survival has been found in those either very young (≤3 years) or older (≥10 years) at diagnosis. Approximately 4% of children with DIPGs are diagnosed when younger than 3 years. The prognosis of these children is less dismal than that of older children, with 28% of younger children alive at 2 years compared with 8% of children aged 3 to 10 years at diagnosis and 14% of children older than 10 years at diagnosis. For children aged 10 years and older, long-term survival was associated with older age at presentation and a longer duration of symptoms.[104] The more favorable prognosis for young children may reflect the presence of different biological characteristics in different age groups.[97,105]
NF1: Children with NF1 and brain stem gliomas may have a better prognosis than other patients who have intrinsic lesions.[106,107]
Clinical and imaging features present at diagnosis: For children with DIPGs, features associated with surviving less than 2 years include the presence at diagnosis of cranial nerve palsies, ring enhancement, necrosis, and extrapontine extension.[97] The 2-year survival rate is less than 10% for patients with these characteristics.
Duration of symptoms at diagnosis: Longer duration of symptoms is associated with a more favorable prognosis. The 2-year survival rates range from 7% for patients with duration of symptoms less than 6 months to 29% for patients with duration of symptoms of 24 months or longer.[97]
Histone variants: Patients with H3.1 K27M variants have a longer median survival (15 months) than do patients with H3.3 K27M variants (10.4 months) or patients without a histone variant (10.5 months).[97]
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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]
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]
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]
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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Reinhardt A, Stichel D, Schrimpf D, et al.: Anaplastic astrocytoma with piloid features, a novel molecular class of IDH wildtype glioma with recurrent MAPK pathway, CDKN2A/B and ATRX alterations. Acta Neuropathol 136 (2): 273-291, 2018. [PUBMED Abstract]
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]
Becker AJ: Ganglioglioma. In: Louis DN, Ohgaki H, Wiestler OD: WHO Classification of Tumours of the Central Nervous System. 4th rev.ed. IARC Press, 2016, pp 138-41.
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]
Pekmezci M, Villanueva-Meyer JE, Goode B, et al.: The genetic landscape of ganglioglioma. Acta Neuropathol Commun 6 (1): 47, 2018. [PUBMED Abstract]
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]
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]
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]
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]
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]
Louis DN, Ohgaki H, Wiestler OD: WHO Classification of Tumours of the Central Nervous System. 4th rev.ed. IARC Press, 2016.
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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Albers AC, Gutmann DH: Gliomas in patients with neurofibromatosis type 1. Expert Rev Neurother 9 (4): 535-9, 2009. [PUBMED Abstract]
Stage Information for Childhood Astrocytomas, Other Gliomas, and Glioneuronal/Neuronal Tumors
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
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Caretti V, Bugiani M, Freret M, et al.: Subventricular spread of diffuse intrinsic pontine glioma. Acta Neuropathol 128 (4): 605-7, 2014. [PUBMED Abstract]
Treatment Option Overview for Childhood Astrocytomas, Other Gliomas, and Glioneuronal/Neuronal Tumors
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.
Table 3. Standard Treatment Options for Childhood Astrocytomas, Other Gliomas, and Glioneuronal/Neuronal Tumors
Treatment Group
Standard Treatment Options
Circumscribed astrocytic gliomas, pediatric-type diffuse low-grade gliomas, and glioneuronal/neuronal tumors:
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.
Treatment of Circumscribed Astrocytic Gliomas, Pediatric-Type Diffuse Low-Grade Gliomas, and Glioneuronal/Neuronal Tumors
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:
Observation, without any intervention, is an option for patients with neurofibromatosis type 1 (NF1) or incidentally found, asymptomatic tumors.[2] Spontaneous regressions of optic pathway gliomas have been reported in children with and without NF1.[3,4]
Surgery
Surgical resection is a primary treatment,[5,6] and surgical feasibility depends on tumor location. For example, safe surgical resection may not be feasible in many patients with optic pathway gliomas, because even a biopsy may present risks to the patient’s vision. As a result, a diagnosis of an optic pathway glioma may rely on a compatible history and imaging findings alone. This is especially true in patients with NF1.[5] For other clinical presentations of an optic pathway tumor, particularly when the tumor is more infiltrative, a biopsy may be considered for molecular characterization of the tumor.
For patients presenting with obstructive hydrocephalus, a shunt or other cerebrospinal fluid diversion procedure may also be needed.
Cerebellum: Complete or near-complete removal can be obtained in 90% to 95% of patients with pilocytic astrocytomas located in the cerebellum.[6]
Optic nerve: For children with isolated optic nerve lesions and progressive symptoms, complete surgical resection, while curative, generally results in blindness in the affected eye. In the absence of retained vision in the affected eye, complete surgical resection may be considered when cosmesis related to proptosis is of concern.
Midline structures (hypothalamus, thalamus, and brain stem): Circumscribed astrocytic gliomas located in midline structures can sometimes be aggressively resected, with resultant long-term disease control.[3] Despite the increasing surgical accessibility of these tumors, such resection may result in significant neurological sequelae, especially in children younger than 2 years at diagnosis.[7][Level of evidence C1] For pediatric-type diffuse low-grade gliomas in deep-seated lesions, extensive surgical resection may not be appropriate and biopsy only should be considered.[8][Level of evidence C2]
In general, for focal brain stem gliomas, particularly those arising in the pons and medulla, maximal safe surgical resection is attempted.[9] While a greater extent of resection is associated with a higher progression-free survival (PFS), this must be balanced with the risk of new postsurgical complications. In a series of 116 patients with low-grade gliomas of the brain stem, 100 patients had some surgical intervention. Twenty-seven patients underwent a biopsy, only one of whom had new postoperative deficits. Seventy-three patients underwent a complete or partial resection, and almost 30% of this group had significant postoperative complications, including respiratory insufficiency (five patients), cerebellar mutism (three patients), and cranial nerve palsies or paresis (15 patients).[10]
Cerebrum: Hemispheric circumscribed astrocytic gliomas are often amenable to complete surgical resection.
Spine: Surgical resection of spinal tumors is generally attempted but it often cannot be completed. In a cohort of 128 patients with primary spinal cord low-grade gliomas, gross-total resection was achieved in a minority of the patients (24 of 128). For the entire cohort, long-term disease control was achieved in about 87% of patients, but subsequent treatment in the form of repeat resection, chemotherapy, and/or radiation therapy was frequently required. Notably, disease progression was common (51 of 128 patients), with late-progression events occurring often. Neurological sequelae and orthopedic complications were common.[11][Level of evidence C2]
After resection, immediate (within 48 hours of resection per Children’s Oncology Group [COG] criteria) postoperative magnetic resonance imaging is obtained. Surveillance scans are then obtained periodically for completely resected tumors, although the value following the initial 3- to 6-month postoperative period is uncertain.[12]; [13][Level of evidence C2]
Factors related to outcome for children with low-grade gliomas treated with surgery followed by observation were identified in a COG study that included 518 evaluable patients.[6] Overall outcome for the entire group was an 8-year PFS rate of 78% and an 8-year overall survival (OS) rate of 96%. The following factors were related to prognosis:[6]
Tumor location: Children with cerebellar and cerebral tumors showed a higher PFS rate at 8 years compared with patients with midline and chiasmatic tumors (84% ± 1.9% vs. 51% ± 5.9%, respectively).
Histology: Approximately three-fourths of patients had pilocytic astrocytoma; PFS and OS were superior for these patients when compared with children with nonpilocytic tumors.
Extent of resection: Patients with gross-total resection had 8-year PFS rates exceeding 90% and OS rates of 99%. By comparison, approximately one-half of patients with any degree of residual tumor (as assessed by operative report and by postoperative imaging) showed disease progression by 8 years, although OS rates exceeded 90%.[6]
A multivariate analysis examined 100 patients with confirmed diagnoses of World Health Organization (WHO) grade 2 diffuse gliomas treated in an International Society of Paediatric Oncology (SIOP) study. The extent of glioma resection had the greatest impact on event-free survival (EFS) rates. The 5-year EFS rates were 75% to 76% for patients who underwent a complete or subtotal resection. In comparison, 5-year EFS rates were 56% for patients who had a partial resection and 19% for patients who had a biopsy.[14][Level of evidence B4]
The extent of resection necessary for cure is unknown because patients with microscopic and even gross residual tumor after surgery may experience long-term PFS without postoperative therapy.[5,6]
Age: Younger children (age <5 years) showed higher rates of tumor progression but there was no significant age effect for OS in multivariate analysis. In a retrospective review of a different series of pediatric patients, children younger than 1 year with low-grade gliomas demonstrated an inferior PFS compared with children aged 1 year and older.[15]
The long-term functional outcome of patients with cerebellar pilocytic astrocytomas is relatively favorable. Full-scale mean intelligence quotients (IQs) of patients with low-grade gliomas treated with surgery alone are close to the normative population. However, these patients may have long-term medical, psychological, and educational deficits.[16]; [17,18][Level of evidence C1]
Adjuvant Therapy
Adjuvant therapy following complete resection is generally not required unless there is a subsequent recurrence of disease. Treatment options for patients with incompletely resected tumor must be individualized and may include one or more of the following:
Patients whose tumors have been partially resected may be observed without further disease-directed treatment, particularly if the pace of tumor regrowth is anticipated to be very slow. Approximately 50% of patients with less-than-gross total resections have disease that does not progress in 5 to 8 years, supporting the observation strategy in selected patients.[6]
A multi-institutional retrospective study of children with IDH-altered low-grade gliomas revealed that 39 of 45 patients (87%) were managed with observation after surgery, including 20 patients who underwent biopsy or subtotal resection only. For these 39 patients, the 5-year 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.[19]
Chemotherapy
Given the long-term side effects associated with radiation therapy, chemotherapy is recommended as first-line therapy for most pediatric patients who require adjuvant therapy after surgery.
Chemotherapy may result in objective tumor shrinkage and help avoid, or at least delay, the need for radiation therapy in most patients.[20–22] Chemotherapy is also an option for adolescents with optic nerve pathway gliomas to delay or avoid radiation therapy.[23][Level of evidence C2] Chemotherapy has been shown to shrink tumors in children with hypothalamic gliomas and the diencephalic syndrome, resulting in weight gain in those who respond to treatment.[24]
The most widely used regimens to treat tumor progression or symptomatic nonresectable, pediatric low-grade gliomas are the following:
A combination of thioguanine, procarbazine, lomustine, and vincristine (TPCV).[30]; [20][Level of evidence A1]
The COG reported the results of a randomized phase III trial (COG-A9952) that treated children younger than 10 years with low-grade chiasmatic/hypothalamic gliomas without NF1 using one of two regimens: carboplatin and vincristine (CV) or TPCV. The 5-year EFS rate was 39% (± 4%) for patients who received the CV regimen and 52% (± 5%) for patients who received the TPCV regimen. Toxicity rates between the two regimens were relatively comparable.[20] In the same study, children with NF1 were nonrandomly assigned to receive treatment with CV. The 5-year EFS rate for children with NF1 was markedly better, at 69% (± 4%), than it was for children without NF1 who received CV. In multivariate analysis, NF1 was an independent predictor of better EFS but not OS.[31] In a separate study that included 100 patients with WHO grade 2 diffuse gliomas, a subset of patients (n = 16) were treated with CV, and some patients also received etoposide. This subset of patients had a 5-year PFS rate of 38% when patients with histone H3 variants were excluded.[14][Level of evidence B4]
Other chemotherapy approaches that have been employed to treat children with progressive or symptomatic nonresectable, low-grade astrocytomas include the following:
Multiagent, platinum-based regimens.[21,22,32]; [33][Level of evidence B4]; [34][Level of evidence C1] Reported 5-year PFS rates have ranged from approximately 35% to 60% for children who received platinum-based chemotherapy for optic pathway gliomas,[21,22] but most patients ultimately require further treatment. This is particularly true for children who initially present with hypothalamic/chiasmatic gliomas that have neuraxis dissemination.[35][Level of evidence C2]
Among children who received chemotherapy for optic pathway gliomas, those without NF1 had higher rates of disease progression than those with NF1, and infants had higher rates of disease progression than children older than 1 year.[21,22,29] Visual status (including acuity and field) is an important measure of outcome and response to treatment. Vision function can be impaired; it is variable even in patients with radiographic responses and is often less than optimal. More than one-third of patients successfully treated with chemotherapy have poor vision in one or both eyes, and some patients lose vision despite radiographic evidence of tumor control (response or stability). In most series, children with sporadic visual pathway gliomas have poorer visual outcomes than do children with NF1.[29]; [38,39][Level of evidence C1] Better initial visual acuity, older age, and absence of postchiasmatic involvement are associated with improved or stable vision after chemotherapy.[40,41]
Radiation therapy
Radiation therapy is usually reserved for patients with disease that does not durably respond to chemotherapy.[21,22,42,43]
For children with low-grade gliomas for whom radiation therapy is indicated, approaches that contour the radiation distribution to the tumor and avoid normal brain tissue (3-D conformal radiation therapy, intensity-modulated radiation therapy (IMRT), stereotactic radiation therapy, and proton radiation therapy [charged-particle radiation therapy]) can reduce the acute and long-term toxicities associated with these modalities.[44,45]; [46][Level of evidence C2] Radiation doses of 54 Gy in 1.8 Gy fractions are typically used.[47,48] In a prospective study of 174 patients treated with proton therapy, the 5-year actuarial rate of local control was 85% (95% confidence interval [CI], 78%–90%), the PFS rate was 84% (95% CI, 77%–89%), and the OS rate was 92% (95% CI, 85%–95%). Brain stem and spinal cord tumor locations and a dose of 54 Gy relative biological effectiveness (RBE) or less were associated with inferior local control (P < .01 for both).[49] In a separate study that included 100 patients with WHO grade 2 diffuse gliomas, a subset of patients (n = 16) were treated with radiation therapy. These patients had a 5-year PFS rate of 74% when patients with histone H3 variants were excluded.[14][Level of evidence B4]
Subsequent to radiation therapy administration, care must be taken to distinguish radiation-induced imaging changes, termed pseudoprogression or spurious progression,[50] from disease progression. The peak time to radiation therapy–induced imaging changes, often presenting as an apparent enlargement of the irradiated mass, is 4 to 6 months, but they can manifest even later.[51–54]; [55,56][Level of evidence B4]; [8,57,58][Level of evidence C2] In a report of 83 patients with low-grade astrocytomas, pseudoprogression was more common after radiation doses of higher than 50.4 Gy (RBE) (hazard ratio [HR], 2.61; P = .16). Pseudoprogression was also more common after proton radiation therapy than after photon IMRT (HR, 2.15; P = .048), presumably because of increased effects on the vasculature. Patients with pilocytic histology had lower rates of pseudoprogression than those with nonpilocytic low-grade gliomas (HR, 0.47; P = .037). There was no association with overall disease control.[50]
A report from the SIOP-LGG 2004 (NCT00276640) study and LGG-registry cohorts evaluated the following radiological criteria for pseudoprogression:[59]
Increasing total tumor–associated T2 lesion.
Increasing focal tumor–associated T2 lesion.
Increasing contrast-enhancing tumor in the first 24 months after radiation therapy.
The following results were observed:
Definite pseudoprogression was radiologically determined in 54 of 136 patients (39.7%) without differences in frequency between radiation therapy modalities: iodine-interstitial radiation therapy (22 of 48 patients) versus photon radiation therapy (24 of 54 patients) versus proton-beam radiation therapy (11 of 20 patients) (P = .780).
Definite pseudoprogression occurred at median 6.3 months (iodine-interstitial radiation therapy, 7.2 months; photon radiation therapy, 4.4 months; proton-beam radiation therapy, 6.5 months) after radiation therapy initiation and persisted for a median of 7.2 months (iodine-interstitial radiation therapy, 8.5 months; photon radiation therapy, 7 months; proton-beam radiation therapy, 7.4 months).
Appearance of necrosis within the focal tumor–associated T2 lesion proved to be a relevant predictor of definite pseudoprogression (P < .001).
Radiation therapy results in long-term radiographic disease control for most children with chiasmatic and posterior pathway chiasmatic gliomas. However, despite radiological control, visual outcomes are variable.
A study from St. Jude Children’s Research Hospital reported on long-term visual acuity outcomes after radiation therapy. For the worse eye, the 5-year cumulative incidence of visual acuity decline was 17.9% and improvement was 13.5%. For the better eye, the 5-year cumulative incidence of visual acuity decline was 11.5% and improvement was 10.6%. After radiation therapy, most patients had stabilization of their vision. Visual change after radiation therapy was most likely to occur within 2 years, supporting the importance of visual assessments during this period.[60]
Another study of 38 patients (mean age, 3 years; median follow-up, 8.5 years) with optic pathway gliomas treated between 2000 and 2018 complemented the previous data on preservation of long-term visual acuity. For patients treated with early radiation therapy (either up-front or as first salvage), blindness-free survival rates were 100% at 5 and 8 years. In comparison, blindness-free survival rates were 81% at 5 years and 60% at 8 years for patients treated primarily with chemotherapy.[61]
Other sequelae include intellectual and endocrinologic deterioration, cerebrovascular damage, late death, and possibly an increased risk of secondary tumors.[62–64]; [56][Level of evidence B4] A population-based study identified radiation therapy as the most significant risk factor associated with late mortality, although the patients who required radiation therapy may have reflected a higher-risk population.[64]
The management of unresectable circumscribed astrocytic gliomas, pediatric-type diffuse low-grade gliomas, glioneuronal tumors, and neuronal tumors is controversial. To identify negative prognostic features in patients treated with radiation therapy, the St. Jude Children’s Research Hospital assessed 150 children (median age, 8 years; range, 1.2–20 years) who received radiation therapy and were monitored for a median of 11.4 years (range, 0.24–29.4 years). Recursive positioning analysis yielded low-risk and high-risk prognostic groups. The 10-year OS rate was 95.6% for patients in the low-risk group, versus 76.4% for patients in the high-risk group. Low-risk tumors included pilocytic astrocytoma/ganglioglioma located outside of the midbrain/thalamus, while high-risk tumors included diffuse astrocytoma or those located in the midbrain/thalamus. Within the high-risk group of patients, delayed radiation therapy (defined as after at least one line of chemotherapy) was associated with a decrement in OS.[65]
Children with NF1 may be at higher risk of radiation-associated secondary tumors and morbidity resulting from vascular changes. Radiation therapy is used as a last resort in these patients, given the heightened risk of inducing neurological toxic effects and second malignancy.[66]
Targeted therapy
The U.S. Food and Drug Administration (FDA) approved the combination of trametinib (MEK inhibitor) plus dabrafenib (BRAF inhibitor) for the treatment of pediatric patients aged 1 year and older with low-grade gliomas and a BRAF V600E variant who require systemic therapy. The approval was based on a randomized clinical trial that compared the dabrafenib-plus-trametinib combination with the carboplatin-plus-vincristine combination. The median age of enrolled patients was 9.5 years, and the most common histological subtypes were ganglioglioma (about 25%) and pilocytic astrocytoma (about 30%). Patients were randomly assigned in a 2-to-1 ratio, with 73 receiving dabrafenib plus trametinib and 37 receiving carboplatin plus vincristine. Patients received dabrafenib and trametinib until loss of clinical benefit or until unacceptable toxicity, and the carboplatin-plus-vincristine combination was given as a 10-week induction course, followed by eight 6-week cycles of therapy.[67]
The objective response rate was assessed by independent review using Response Assessment in Neuro-Oncology (RANO) 2017 response criteria for low-grade glioma that employ T2-fluid attenuated inversion recovery (FLAIR) rather than contrast enhancement.
Patients randomly assigned to dabrafenib plus trametinib had a significantly higher objective response rate compared with patients who received carboplatin plus vincristine (47% vs. 11%). An additional 41% of patients in each treatment group had stable disease.
Patients randomly assigned to dabrafenib plus trametinib had a significantly longer PFS compared with patients who received carboplatin plus vincristine (20.1 months vs. 7.4 months).
Grade 3 or higher adverse events were more common in patients who received carboplatin plus vincristine compared with patients who received dabrafenib plus trametinib (94% vs. 47%).
IDH inhibitors are being studied for the treatment of patients with IDH-altered low-grade and high-grade gliomas. One agent, vorasidenib, has shown preliminary evidence of activity in delaying the time to progression when compared with placebo in newly diagnosed adults with IDH1– or IDH2-altered low-grade gliomas.[68] The 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.
For children with tuberous sclerosis (TS) and symptomatic subependymal giant cell astrocytomas (SEGAs), agents that inhibit mammalian target of rapamycin (mTOR) (e.g., everolimus and sirolimus) have been studied.
Evidence (treatment of SEGA with an mTOR inhibitor):
A multicenter, phase III, placebo-controlled trial of 117 patients confirmed these earlier findings.[73][Level of evidence B3]
Thirty-five percent of the patients in the everolimus group had at least a 50% reduction in the size of the SEGA, versus no reduction in the placebo group.
In a study of patients who were treated with everolimus for 5 years, the following results were observed:[74]
A reduction in the size of the mass was observed in about 50% of patients; in many cases, the reduction was sustained.
These patients also had a reduction in seizure frequency.
Treatment Options Under Clinical Evaluation
Early-phase therapeutic trials may be available for selected patients. These trials may be available via the COG, the Pediatric Brain Tumor Consortium, or other entities. Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.
The following are examples of national and/or institutional clinical trials that are currently being conducted:
ACNS1831 (NCT03871257) (A Study of the Drugs Selumetinib Versus Carboplatin/Vincristine in Patients With NF1 and Low-Grade Glioma): This phase III trial investigates the use of selumetinib compared with the standard treatment of CV for treating patients with NF1-associated low-grade gliomas, and improving vision in patients with low-grade gliomas of the optic pathway (vision nerves).
ACNS1833 (NCT04166409) (A Study of the Drugs Selumetinib Versus Carboplatin and Vincristine in Patients With Low-Grade Glioma): This phase III trial compares the effect of selumetinib with the standard of care treatment using carboplatin and vincristine in treating patients with newly diagnosed or previously untreated low-grade glioma that does not have a BRAF V600E variant and is not associated with systemic NF1.
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
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Treatment of Progressive/Recurrent Circumscribed Astrocytic Gliomas, Pediatric-Type Diffuse Low-Grade Gliomas, and Glioneuronal/Neuronal Tumors
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:
Consideration of surgical intervention must be individualized based on the following:
Initial tumor type.
Length of time between initial treatment and tumor recurrence/progression.
Clinical picture.
Utility of second surgery is impacted by site of recurrence and the probability of obtaining a near-total resection/gross-total resection without significant neurological injury.[6]
Radiation Therapy
The rationale for the use of radiation therapy is essentially the same for first-line therapy or at the time of recurrence. For more information, see the Radiation therapy section. If the child has never received radiation therapy, local radiation therapy may be a treatment option, although chemotherapy in lieu of radiation should be considered, depending on the child’s age and the extent and location of the tumor.[7][Level of evidence C1]; [8][Level of evidence C2]
For children with low-grade gliomas for whom radiation therapy is indicated, conformal radiation therapy (including proton-beam therapy) approaches appear effective and offer the potential for reducing the acute and long-term toxicities associated with this modality.[9–12]
Chemotherapy
If there is recurrence or progression at an unresectable site, chemotherapy should be considered.
Chemotherapy may result in relatively long-term disease control.[13,14] The choice of regimen depends on the type of and response to prior chemotherapy. Numerous options can be considered, most commonly including carboplatin with or without vincristine (CV); thioguanine, procarbazine, lomustine, and vincristine (TPCV); or vinblastine alone; temozolomide alone; temozolomide in combination with carboplatin and vincristine; irinotecan and bevacizumab; or lenalidomide.[13–17] When a therapeutically actionable molecular alteration is identified in the tumor, molecular targeted therapy is increasingly being used as second-line therapy.
Targeted Therapy
mTOR inhibitors
For children with tuberous sclerosis (TS) and symptomatic subependymal giant cell astrocytomas (SEGAs) or low-grade gliomas,[18] mammalian target of rapamycin (mTOR) inhibitors (e.g., everolimus and sirolimus) have been studied.
A multicenter, phase III, placebo-controlled trial of 117 patients confirmed these earlier findings.[23][Level of evidence B3]
Thirty-five percent of the patients in the everolimus group had at least a 50% reduction in the size of the SEGA, versus no reduction in the placebo group.
In a study of patients who were treated with everolimus for 5 years, the following results were observed:[24]
A reduction in the size of the mass was observed in about 50% of patients; in many cases, the reduction was sustained.
These patients also had a reduction in seizure frequency.
In a series of 23 patients with recurrent low-grade gliomas who were treated with everolimus, the following was observed:[25]
Everolimus demonstrated modest activity, with a 2-year progression-free survival (PFS) rate of 39% and an overall survival rate of 93%.
A companion study completed by the Neurofibromatosis Clinical Trials Consortium evaluated 23 children with neurofibromatosis type 1 (NF1) and progressive low-grade gliomas who were treated with everolimus.[26]
Of the 22 evaluable patients, 15 demonstrated either a partial response or tumor stabilization, 10 of whom remained free of progression for a median follow-up of 33 months.
VEGF inhibitors
Antitumor activity has also been observed for bevacizumab given in combination with irinotecan, which, in some cases, also results in clinical or visual improvement.[27]
Evidence (targeted therapy [bevacizumab]):
In a phase II study of bevacizumab plus irinotecan for children with recurrent low-grade gliomas, the following results were observed:[28]
Sustained partial responses were observed in only two patients (5.7%).
The 6-month PFS rate was 85.4% (standard error [SE] ± 5.96%).
The 2-year PFS rate was 47.8% (SE ± 9.27%).
A pilot study of 14 patients with recurrent low-grade gliomas also evaluated bevacizumab-based therapies and observed the following:[29][Level of evidence C2]; [30][Level of evidence C3]
Objective responses were seen in 12 patients (86%).
No patients progressed on therapy (median treatment duration, 12 months), but 13 of 14 progressed after stopping bevacizumab at a median of 5 months.
A retrospective pooled analysis included 88 children with low-grade gliomas who received bevacizumab-based treatment along with additional therapy.[31]
A partial response was observed in 40% of patients, and stable disease was seen in 49% of patients.
Sixty-five percent of the patients progressed at a median of 8 months after discontinuation of bevacizumab-based treatment. The radiographic PFS rate was 29% at 3 years.
Stability in visual function was seen in 49% of patients, and visual function improved in 29% of patients. Despite radiographic progression in many patients, the 3-year visual-PFS rate was 53%.
Bevacizumab has also been employed for children with low-grade gliomas and symptomatic radiation-induced tumor enlargement.[32,33]
Treatment with bevacizumab produced imaging improvement (five of five patients) and allowed weaning off steroids (four of four patients).
BRAF and MEK inhibitors
With the identification of BRAF variants driving a significant proportion of low-grade gliomas, inhibition of various elements of this molecular pathway (e.g., MEK and BRAF) are actively being tested in ongoing clinical trials, with early reports suggesting substantial activity. While first-generation BRAF inhibitors like vemurafenib and dabrafenib are active against tumors with BRAF V600E variants, they are contraindicated for tumors with BRAF gene fusions because of the potential for paradoxical activation of the MAPK pathway.[34,35] As described below, the U.S. Food and Drug Administration (FDA) approved the dabrafenib-plus-trametinib combination for use in pediatric patients aged 1 year and older with relapsed or refractory low-grade gliomas with BRAF V600E variants.
For patients whose tumors have BRAF V600E variants, the focus of clinical research efforts is on the evaluation of BRAF inhibitors in combination with MEK inhibitors. Such combinations are approved for the treatment of adult cancers with BRAF V600E variants and are more effective than either BRAF inhibitors or MEK inhibitors used as single agents.[36]
Results on the use of the BRAF V600E inhibitor dabrafenib demonstrated a 44% overall response rate (1 complete response and 13 partial responses) by central review in children with BRAF V600 variants and relapsed or refractory low-grade gliomas. The median duration of response was 26 months. The disease control rate (complete response plus partial response plus stable disease) was 78%. The therapy was well tolerated, although 91% of patients experienced side effects such as fatigue (34%), rash (31%), and pyrexia (28%). Nine of 32 patients had grade 3 to grade 4 toxicities, 10 patients required dose modifications, and 2 patients discontinued treatment, including 1 child who had disseminated intravascular coagulation with hypertension. In this pediatric study, no cases of squamous cell carcinoma of the skin or keratoacanthoma were encountered.[37]
A phase I/II study of trametinib as a single agent for patients with BRAF V600E variants and low-grade gliomas enrolled 13 pediatric patients. The objective response rate for these 13 patients was assessed by independent review using Response Assessment in Neuro-Oncology (RANO) 2017 response criteria for low-grade gliomas that employ T2-fluid attenuated inversion recovery (FLAIR) rather than contrast enhancement.[38]
Two of 13 patients (15%) achieved partial responses, and 6 patients (46%) had stable disease.
The 24-month PFS rate was 50%.
A phase I/II study that evaluated the combination of dabrafenib and trametinib enrolled 34 patients with BRAF V600E variants and low-grade gliomas and 2 patients with BRAF V600E variants and high-grade gliomas. The objective response rate for these 36 patients was assessed by independent review using RANO 2017 response criteria for low-grade glioma that employ T2-FLAIR rather than contrast enhancement.[38]
Nine of 36 patients (25%) achieved partial responses, and 23 patients (64%) had stable disease.
The 24-month PFS rate was 80%.
The most common treatment-related adverse events in the dabrafenib-plus-trametinib group were pyrexia (50%) and dry skin (42%). Adverse events leading to discontinuation of therapy occurred in 22% of patients, a lower rate than observed for patients who received single-agent trametinib (54%).
The FDA approved the trametinib-plus-dabrafenib combination for adult and pediatric patients aged 1 year and older with unresectable or metastatic solid tumors with BRAF V600E variants who have progressed following prior treatment and have no satisfactory alternative treatment options. This indication includes pediatric patients aged 1 year and older with BRAF V600E variants and low-grade gliomas.
The MEK inhibitor selumetinib has been studied in a phase I/II clinical trial for children with low-grade gliomas (PBTC-029 [NCT01089101]).
The phase I component of the PBTC-029 trial showed the following results:[39]
Selumetinib was tolerated at a daily dose of 25 mg/m2.
The most common adverse events leading to patient discontinuation of treatment were rash, paronychia, and asymptomatic creatine phosphokinase (CPK) elevation.
Stratum 1 of the phase II component of this trial was for patients with BRAF genomic alterations.[40]
Nine of 25 patients (36%) achieved a partial response, with responses occurring for both BRAF V600E patients and for patients with BRAF gene fusions.
The 2-year PFS rate was 70% for stratum 1 patients.
Stratum 3 of the phase II component of this trial was for patients with NF1-associated low-grade gliomas.[40]
The 2-year event-free survival rate for this group was 96%.
10 of 25 patients (40%) achieved partial responses.
Stratum 4 of the phase II component of this trial was for patients with recurrent optic pathway and hypothalamic low-grade gliomas.[41]
Six of 25 patients (24%) had a partial response, and an additional 14 of 25 patients (56%) had stable disease.
The 2-year PFS rate was 78%.
Of the 19 patients evaluable for visual acuity, 4 had improvements in visual acuity, with an additional 13 having stable findings.
The most common toxicities across all strata were grade 1 and grade 2 CPK elevation, diarrhea, hypoalbuminemia, elevated aspartate aminotransferase (AST), and rash. Rare grade 3 and grade 4 toxicities included elevated CPK, rash, neutropenia, emesis, and paronychia.
In 2024, the FDA granted accelerated approval to tovorafenib (a type 2 RAF inhibitor) 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. Approval was based on the results of a study of 137 patients (77 patients in the primary cohort [arm 1] and 60 patients in an extension cohort [arm 2]) who were treated with tovorafenib. The study was designed using Response Assessment in Neuro-Oncology High-Grade Glioma (RANO-HGG) criteria, which defines response as the reduction in the T1-Gd positive measurements.[42]
Using the RANO-HGG criteria, the overall response rate (ORR) was 67% for patients in arm 1, with a median duration of response (DOR) of 16.6 months.
When the data was analyzed using Response Assessment in Pediatric Neuro-Oncology (RAPNO) criteria, which defines response as the reduction in the T2/FLAIR signal, the ORR was 51%, with a median DOR of 13.8 months.
Treatment Options Under Clinical Evaluation
Early-phase therapeutic trials may be available for selected patients. These trials may be available via the COG, the Pediatric Brain Tumor Consortium, or other entities. Information about NCI-supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
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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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
Treatment of Pediatric-Type Diffuse High-Grade Gliomas
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:
The extent of tumor resection at initial diagnosis is positively associated with survival. Therefore, maximal safe resection is recommended for children with nonpontine tumors.[4,10,11]
For children with diffuse midline glioma in the pons (DIPG), histological confirmation is increasingly obtained for both entry into research studies and molecular characterization of the tumor.[12] New approaches with stereotactic needle biopsy may make biopsy safer.[13–16] Given the technical challenges of pontine biopsies, the procedure is best undertaken by an experienced pediatric neurosurgeon to minimize the risk of irreversible neurological complications.[13–17] Biopsy is recommended for pontine tumors when the diagnosis is uncertain based on imaging findings.
Adjuvant Therapy
Radiation therapy
For patients with diffuse midline glioma, H3 K27-altered and diffuse pediatric-type high-grade glioma, H3-wild type and IDH-wild type, focal radiation therapy is routinely administered to a field that widely encompasses the entire tumor. The radiation therapy dose to the tumor bed is usually at least 54 Gy. Despite such therapy, the prognosis is dismal. Similarly poor survival is seen in children with spinal cord primary tumors and children with thalamic high-grade gliomas (i.e., diffuse midline gliomas, H3 K27M-altered tumors) treated with radiation therapy.[18,19]; [20,21][Level of evidence C1]
Standard treatment for children with diffuse midline gliomas centered in the pons is radiation therapy to the involved site. The conventional dose of radiation ranges between 54 Gy and 60 Gy, given locally to the primary tumor site in single daily fractions. Such treatment will result in transient benefit for most patients, but more than 90% of patients will die within 18 months of diagnosis.[22]
Radiation-induced changes may occur a few months after the completion of radiation therapy and may mimic tumor progression. When considering the efficacy of additional treatment, care needs to be taken to separate radiation-induced change from progressive disease.[23]
Research studies that evaluated the efficacy of hyperfractionated and hypofractionated radiation therapy and radiosensitizers have not demonstrated improved outcomes using these radiation techniques.
Hyperfractionated (twice daily) radiation therapy. Studies using doses as high as 78 Gy have been completed. Evidence demonstrates that these increased radiation therapy doses do not improve the duration or rate of survival for patients with DIPGs, whether given alone [24,25] or in combination with chemotherapy, and they were associated with increased toxicity at the highest dose levels.[26]
Hypofractionated radiation therapy. This technique results in survival rates comparable with conventional fractionated radiation therapy techniques, possibly with less treatment burden.[27]; [28][Level of evidence A1]; [22,29][Level of evidence B4] One randomized study compared three radiation therapy fractions (39 Gy in 13 fractions; 45 Gy in 15 fractions; and 54 Gy in 30 fractions). The study concluded that the higher hypofractionated regimen was inferior, possibly due to increased toxicity.[30]
Radiosensitizers. Studies evaluating the efficacy of various radiosensitizers as a means for enhancing the therapeutic effect of radiation therapy have been completed but have failed to show any significant improvement in outcome.[25,26,31–34]
Chemotherapy
For patients with diffuse pediatric-type high-grade glioma, H3-wild type and IDH-wild type, the benefit from radiation therapy with adjuvant chemotherapy compared with radiation therapy alone has not been formally proven in a randomized prospective trial. However, the aggregate data from numerous nonrandomized prospective clinical trials for children with high-grade gliomas suggest a benefit from alkylating chemotherapy, similar to adults with primary glioblastoma. Therefore, adjuvant therapy with a combination of radiation therapy and alkylating chemotherapy can be considered standard of care. Commonly used chemotherapy regimens include temozolomide alone or in combination with lomustine.[5,6]
Prospective, randomized clinical trials in adults with primary glioblastoma have established MGMT promoter hypermethylation as an independent prognostic biomarker regardless of therapy, as well as a predictive biomarker for benefit from temozolomide.[35,36] However, in children with diffuse pediatric-type high-grade glioma, H3-wild type and IDH-wild type, MGMT promoter methylation status is not prognostic,[8,37] and its predictive value for benefit from alkylator chemotherapy is unknown given the lack of applicable randomized data.
In a prospective randomized trial, the use of adjuvant bevacizumab after radiation therapy did not prolong overall survival (OS) or progression-free survival (PFS) in pediatric patients with newly diagnosed high-grade gliomas.[7]
No chemotherapy (including neoadjuvant, concurrent, postradiation chemotherapy) or immunotherapy strategy, when added to radiation therapy, has led to long-term survival for children with DIPGs.[38–40]; [41][Level of evidence B4] This includes therapy using high-dose, marrow-ablative chemotherapy with autologous hematopoietic stem cell rescue, which has been shown to be ineffective in extending survival.[42] However, similar to the treatment of other brain tumors, radiation therapy is generally omitted for infants with DIPGs, and chemotherapy-only approaches are used. Published data supporting the utility of this approach are lacking.
Children with infant-type hemispheric gliomas have been categorized into three groups.[43] Group 1 tumors include high-grade gliomas that are hemispheric and receptor tyrosine kinase (RTK) driven, including ALK, NTRK, ROS1, and MET gene fusions. Previously, infants with such tumors were treated with adjuvant multiagent chemotherapy instead of radiation therapy, with relatively favorable outcomes.[9,44]
Targeted Therapy
Therapeutically targetable somatic BRAF V600E variants are present in a small subset of patients with pediatric-type diffuse high-grade gliomas. Data from a nonrandomized retrospective study suggest that up-front inclusion of BRAF and/or MEK inhibitor therapy in place of chemotherapy may result in improved survival.[45][Level of evidence C2]
There is evidence that infants with group 1 hemispheric high-grade gliomas that have specific RTK-driven gene fusions are responsive to RTK-targeted therapeutics.[43,46] A subset analysis included 33 patients with NTRK fusion–positive central nervous system tumors who were treated with larotrectinib (included in two larger trials that enrolled children and adults with solid tumors and NTRK fusions).[47] The objective response rate was 30%, and 82% of patients with measurable disease had tumor shrinkage. The 12-month duration of response rate was 75%, the PFS rate was 56%, and the OS rate was 85%.[47] The role of RTK inhibitors in the up-front treatment of infants with pediatric-type high-grade glioma remains under study.
Immunotherapy
Children with inheritable biallelic mismatch repair deficiency have a very high mutational burden and neoantigen expression. These patients are at risk of developing a variety of cancers, including hematologic malignancies, gastrointestinal cancers, and high-grade gliomas. The high variant and neoantigen load have been associated with responsiveness to immune checkpoint inhibition. Early case reports have demonstrated clinical imaging responses in children who are treated with an anti-programmed death-1 inhibitor.[48]
Treatment Options Under Clinical Evaluation
Therapeutic clinical trials may be available for selected patients. These trials may be available via the Children’s Oncology Group (COG), the Pediatric Brain Tumor Consortium, or other entities. Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
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]
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]
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]
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]
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]
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]
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]
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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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
Treatment of Recurrent Pediatric-Type Diffuse High-Grade Gliomas
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:
The use of surgical intervention must be individualized based on the following:
Initial tumor type.
Length of time between initial treatment and the reappearance of the mass lesion.
Location of the recurrent tumor.
Consideration of therapeutics based on the requirement for fresh tumor tissue or to deliver therapy to the operative bed.
In most cases of diffuse midline gliomas centered in the pons (diffuse intrinsic pontine glioma [DIPG]), biopsy at the time of clinical or radiological progression is neither necessary nor recommended. Biopsy may be considered for confirmation of relapse when treatment-related brain stem damage, which may be clinically indistinguishable from tumor recurrence, is in the differential diagnosis. Other tests, including positron emission tomography, magnetic resonance spectroscopy, and single-photon emission computed tomography, are not reliable in distinguishing necrosis from tumor recurrence in previously irradiated patients with DIPG.
Radiation Therapy
Radiation therapy is appropriate for patients who have not previously been irradiated. Radiation doses and volumes are similar to those used for newly diagnosed patients. Generally, this is limited to young children initially treated with radiation-avoiding strategies.
For previously irradiated patients with non–brain stem pediatric-type high-grade gliomas, reirradiation has been used, although the data demonstrating benefit are sparse. Stereotactic radiosurgery (SRS) or stereotactic radiation therapy (SRT) techniques using either hypofractionated radiation therapy or standard fraction sizes may be considered. For small volume distinct lesions, SRS allows for maximum sparing of normal tissues. For more infiltrative lesions, fractionated radiation therapy may better spare normal tissues.[1]
For patients with DIPG, reirradiation has been shown to prolong survival and can be considered at progression in children who have had an initial response to radiation therapy.[2,3] In a phase I/II study of 12 patients treated at three dose levels (24 Gy/12 fractions, 26.5 Gy/12 fractions, or 30.8 Gy/14 fractions), almost all patients improved. Clinical utility analysis showed that the 24-Gy regimen was preferable.[4] A recent survey confirms the effective use of even lower doses (e.g., 12 Gy fractionated). These doses are beneficial, and they allow for additional radiation therapy courses.[5]
Targeted Therapy
Somatic BRAF V600E variants are present in a small subset of patients. While many of these tumors are responsive to BRAF and/or MEK inhibitors, responses in the recurrent setting are typically not sustained long term. A median progression-free survival of approximately 3 months was reported in one retrospective series.[6] In a multicenter, open-label, single-arm, phase II trial that evaluated dabrafenib plus trametinib, 15 of 45 adult patients with BRAF V600E variants and high-grade gliomas had an objective response. There were three complete responses and 12 partial responses, with a median overall survival of 17.6 months.[7]
The U.S. Food and Drug Administration (FDA) approved the combination of dabrafenib (BRAF inhibitor) plus trametinib (MEK inhibitor) for adult and pediatric patients aged 1 year and older with unresectable or metastatic solid tumors with BRAF V600E variants who have progressed following prior treatment and have no satisfactory alternative treatment options.[8,9] This approval includes pediatric patients aged 1 year and older with BRAF V600E variants and high-grade gliomas. The approval for this patient population was based on the results described below:[8–10]
The dabrafenib-plus-trametinib combination was studied in 41 pediatric patients with relapsed or progressive high-grade gliomas.
The median age of enrolled patients was 13 years.
The objective response rate was 56% (95% confidence interval [CI], 39.7%–71.5%).
For the 23 patients who achieved objective responses, 48% of patients had a duration of response of 12 months and longer and 22% of patients had a duration of response of 24 months or longer.
Activating gene fusions (ALK, NTRK1, NTRK2, NTRK3, ROS1, and MET) are characteristic of infant-type diffuse gliomas.[11,12] Data from case reports and recent prospective clinical trials suggest that these tumors are highly responsive to targeted therapies.[13]
Tumor sample sequencing was done in pediatric (n = 54) and young adult patients (n = 15) with recurrent or refractory high-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 36 of 69 tumors (52.2%).[14] Alterations in MAPK pathway genes were detected in 17 of 69 tumors (24.6%), most frequently BRAF V600E variants or fusions (n = 11, 15.9%). FGFR1 variants or fusions were identified in 6 of 69 tumors (8.7%).
Immunotherapy
Numerous studies are investigating a variety of immunotherapy strategies, including checkpoint inhibitors,[15] oncolytic viruses, chimeric antigen receptor (CAR) T cells, and other immune-modulating strategies. GD2-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 (ICANS) and tumor inflammation–associated neurotoxicity.[16]
Treatment Options Under Clinical Evaluation
The role of immune checkpoint inhibition in the treatment of children with recurrent high-grade astrocytoma is currently under study. Children with biallelic mismatch repair deficiency have a very high mutational burden and neoantigen expression and are at risk of developing a variety of cancers, including hematologic malignancies, gastrointestinal cancers, and brain tumors. The high variant and neoantigen load has been correlated with improved response to immune checkpoint inhibition. Early case reports have demonstrated clinical and radiographic responses in children who are treated with an anti–programmed death-1 inhibitor.[17]
Patients for whom initial treatment fails may benefit from additional treatment, including entry into clinical trials of novel therapeutic approaches.[18] Early-phase therapeutic trials may be available for selected patients. These trials may be available via the COG, the Pediatric Brain Tumor Consortium, or other entities. Information about NCI-supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
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]
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]
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]
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]
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]
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]
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]
Novartis Pharmaceuticals Corporation: TAFINLAR (dabrafenib): Prescribing Information. East Hanover, New Jersey: Novartis Pharmaceuticals Corporation, 2023. Available online. Last accessed February 7, 2024.
Novartis Pharmaceuticals Corporation: MEKINIST (trametinib): Prescribing Information. East Hanover, New Jersey: Novartis Pharmaceuticals Corporation, 2023. Available online. Last accessed February 7, 2024.
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]
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]
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]
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]
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]
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]
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]
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]
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]
Latest Updates to This Summary (04/14/2025)
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.
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 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.
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).
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.
About This PDQ Summary
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood astrocytomas, other gliomas, and glioneuronal/neuronal tumors. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
be discussed at a meeting,
be cited with text, or
replace or update an existing article that is already cited.
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Childhood Astrocytomas, Other Gliomas, and Glioneuronal/Neuronal Tumors Treatment are:
Kenneth J. Cohen, MD, MBA (Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital)
Louis S. Constine, MD (James P. Wilmot Cancer Center at University of Rochester Medical Center)
Karen J. Marcus, MD, FACR (Dana-Farber of Boston Children’s Cancer Center and Blood Disorders Harvard Medical School)
Roger J. Packer, MD (Children’s National Hospital)
Malcolm A. Smith, MD, PhD (National Cancer Institute)
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website’s Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
Permission to Use This Summary
PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”
The preferred citation for this PDQ summary is:
PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Astrocytomas, Other Gliomas, and Glioneuronal/Neuronal Tumors Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/brain/hp/child-astrocytoma-glioma-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389382]
Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.
Disclaimer
Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.
Contact Us
More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.
Childhood Brain and Spinal Cord Tumors Summary Index (PDQ®)–Health Professional Version
General Information About Childhood Brain and Spinal Cord Tumors
Primary brain tumors are a diverse group of diseases that together constitute the most common solid tumor of childhood. The Central Brain Tumor Registry of the United States (CBTRUS) estimates that approximately 4,300 U.S. children are diagnosed each year.[1]
Brain tumors are classified by histology, but tumor location and extent of spread are also important factors that affect treatment and prognosis. Immunohistochemical analysis, cytogenetic and molecular genetic findings, and measures of proliferative activity are increasingly used in tumor diagnosis and classification.[2]
References
Ostrom QT, Gittleman H, Farah P, et al.: CBTRUS statistical report: Primary brain and central nervous system tumors diagnosed in the United States in 2006-2010. Neuro Oncol 15 (Suppl 2): ii1-56, 2013. [PUBMED Abstract]
Louis DN, Perry A, Reifenberger G, et al.: The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol 131 (6): 803-20, 2016. [PUBMED Abstract]
Type of Childhood Brain and Spinal Cord Tumors
For information about the type of childhood brain and spinal cord tumor and its related PDQ summary, see the table below. If a tumor type is not listed, a corresponding PDQ treatment summary is not available.
CNS Tumor Type, Pathological Subtype, and Its Related PDQ Treatment Summary
Tumor Type (Based on the 2021 WHO Classification)a
Pathological Subtype (Based on the 2021 WHO Classification)a
Related PDQ Treatment Summary
CNS = central nervous system; NEC = not elsewhere classified; NOS = not otherwise specified; WHO = World Health Organization.
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]
Latest Updates to This Summary (12/19/2023)
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
This summary was comprehensively reviewed and extensively revised.
This summary was renamed from Childhood Brain and Spinal Cord Tumors Treatment Overview.
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.
About This PDQ Summary
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood brain and spinal cord tumors. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
be discussed at a meeting,
be cited with text, or
replace or update an existing article that is already cited.
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Childhood Brain and Spinal Cord Tumors Summary Index are:
Kenneth J. Cohen, MD, MBA (Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital)
Louis S. Constine, MD (James P. Wilmot Cancer Center at University of Rochester Medical Center)
Roger J. Packer, MD (Children’s National Hospital)
D. Williams Parsons, MD, PhD (Texas Children’s Hospital)
Malcolm A. Smith, MD, PhD (National Cancer Institute)
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website’s Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
Permission to Use This Summary
PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”
The preferred citation for this PDQ summary is:
PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Brain and Spinal Cord Tumors Summary Index. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/brain/hp/child-brain-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389453]
Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.
Disclaimer
Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.
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Central nervous system (CNS) atypical teratoid/rhabdoid tumor (AT/RT) is a cancer that forms in the tissues of the brain.
Certain genetic changes may increase the risk of AT/RT.
The symptoms of AT/RT are not the same in every person.
CNS AT/RT is found with tests that examine the brain and spinal cord.
Childhood AT/RT is diagnosed using a biopsy, and the tumor may be removed in the same surgery.
Certain factors affect prognosis (chance of recovery) and treatment options.
Central nervous system (CNS) atypical teratoid/rhabdoid tumor (AT/RT) is a cancer that forms in the tissues of the brain.
Central nervous system (CNS) atypical teratoid/rhabdoid tumor (AT/RT) is a very rare, fast-growing cancer that begins in the brain and spinal cord. It usually occurs in children aged 3 years and younger, although it can occur in older children and adults.
About half of these tumors form in the cerebellum or brain stem. The cerebellum is the part of the brain that controls movement, balance, and posture. The brain stem controls breathing, heart rate, and the nerves and muscles used in seeing, hearing, walking, talking, and eating. AT/RT can also begin in other parts of the brain and spinal cord.
EnlargeAnatomy of the brain. The supratentorial area (the upper part of the brain) contains the cerebrum, lateral ventricle and third ventricle (with cerebrospinal fluid shown in blue), choroid plexus, pineal gland, hypothalamus, pituitary gland, and optic nerve. The posterior fossa/infratentorial area (the lower back part of the brain) contains the cerebellum, tectum, fourth ventricle, and brain stem (midbrain, pons, and medulla). The skull and meninges protect the brain and spinal cord.
Certain genetic changes may increase the risk of AT/RT.
A risk factor is anything that increases the chance of getting a disease. Not every child with one or more of these risk factors will develop AT/RT. And it will develop in some children who don’t have a known risk factor.
AT/RT may be linked to changes in the tumor suppressor genes SMARCB1 or SMARCA4. Tumor suppressor genes make a protein that helps control how and when cells grow. Changes in the DNA of tumor suppressor genes like SMARCB1 or SMARCA4 may lead to cancer.
The changes in the SMARCB1 or SMARCA4 genes may be inherited (passed on from parents to offspring). When this gene change is inherited, tumors may form in two parts of the body at the same time (for example, in the brain and the kidney). For children with AT/RT, genetic counseling (a discussion with a trained professional about inherited diseases and a possible need for gene testing) may be recommended.
Talk with your child’s doctor if you think your child may be at risk.
The symptoms of AT/RT are not the same in every person.
Because AT/RT is fast growing, symptoms may develop quickly and get worse over a period of days or weeks. It’s important to check with your child’s doctor if your child has:
a morning headache or headache that goes away after vomiting
nausea and vomiting
unusual sleepiness or change in activity level
loss of balance, lack of coordination, or trouble walking
an increase in head size (in infants)
pain, tingling, numbness, or paralysis in the face
These symptoms may be caused by problems other than AT/RT. The only way to know is to see your child’s doctor.
CNS AT/RT is found with tests that examine the brain and spinal cord.
If your child has symptoms that suggest AT/RT, the doctor will need to find out if these are due to cancer or another 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 health 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 AT/RT, the results of these tests will help you and your child’s doctor plan treatment.
The tests used to diagnose AT/RT may include:
Magnetic resonance imaging (MRI) uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the brain and spinal cord. This procedure is also called nuclear magnetic resonance imaging (NMRI).
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 the 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. This procedure is also called an LP or spinal tap.
SMARCB1 and SMARCA4 gene testing is a laboratory test in which a sample of blood or tissue is tested for certain changes in the SMARCB1 and SMARCA4 genes. Children with AT/RT may be eligible for gene testing through the Molecular Characterization Initiative.
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.
Ultrasound exam uses high-energy sound waves (ultrasound) that bounce off internal tissues or organs, such as the kidney, and make echoes. The echoes form a picture of body tissues called a sonogram. This procedure is done to check for tumors that may also have formed in the kidney.
Childhood AT/RT is diagnosed using a biopsy, and the tumor may be removed in the same surgery.
If doctors think there might be a brain tumor, a biopsy may be done to remove a sample of tissue. For brain tumors, the 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 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. If cancer cells are found, the doctor may remove as much tumor as safely possible during the same surgery. The pathologist checks the cancer cells to find out the type of brain tumor. It is often difficult to completely remove AT/RT because of where the tumor is in the brain and because it may already have spread at the time of diagnosis. The piece of skull is usually put back in place after the procedure.
EnlargeCraniotomy. An opening is made in the skull and a piece of the skull is removed to show part of the brain.
The following test may be done on the sample of tissue that is removed:
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 of cancer.
Certain factors affect prognosis (chance of recovery) and treatment options.
If your child has been diagnosed with AT/RT, 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.
The prognosis depends on:
whether your child has certain inherited gene changes
whether the tumor has certain gene changes
your child’s age
the amount of tumor remaining after surgery
whether the cancer has spread to other parts of the brain and spinal cord or to the kidney at the time of diagnosis
whether the cancer has just been diagnosed or has recurred (come back)
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.
Stages of Childhood Central Nervous System Atypical Teratoid/Rhabdoid Tumor
Key Points
There is no standard staging system for central nervous system (CNS) atypical teratoid/rhabdoid tumor (AT/RT).
There is no standard staging system for central nervous system (CNS) atypical teratoid/rhabdoid tumor (AT/RT).
The process used to find out if cancer has spread to other parts of the body is called staging. There is no standard staging system for central nervous system (CNS) atypical teratoid/rhabdoid tumor (AT/RT).
For treatment, this tumor is grouped as newly diagnosed or recurrent. Treatment depends on:
your child’s age
how much cancer remains after surgery to remove the tumor
whether the cancer has spread to other parts of the CNS
the results of tests and procedures done to diagnose the cancer
Treatment Option Overview
Key Points
There are different types of treatment for children with central nervous system (CNS) atypical teratoid/rhabdoid tumor (AT/RT).
Children with AT/RT should have their treatment planned by a team of health care providers who are experts in treating cancer in children.
Childhood brain tumors may cause symptoms that begin before the cancer is diagnosed and continue for months or years.
The following types of treatment may be used:
Surgery
Chemotherapy
Radiation therapy
Stem cell transplant
Clinical trials
Treatment for childhood CNS AT/RT may cause side effects.
Follow-up care may be needed.
Resources and support are available to help you cope with your child’s cancer.
There are different types of treatment for children with central nervous system (CNS) atypical teratoid/rhabdoid tumor (AT/RT).
There are different types of treatment for children with AT/RT. 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 and your child’s age and overall health.
Your child’s treatment plan will include information about the tumor, 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.
Children with AT/RT should have their treatment planned by a team of health care providers who are experts in treating cancer in children.
A pediatric oncologist, a doctor who specializes in treating children with cancer, oversees treatment of AT/RT. The pediatric oncologist works with other health care providers who are experts in treating children with CNS cancer and also specialize in other areas of medicine. Other specialists may include:
Childhood brain tumors may cause symptoms that begin before the cancer is diagnosed and continue for months or years.
Symptoms caused by the tumor may begin before diagnosis. These signs or symptoms may continue for months or years. It is important to talk with your child’s doctors about symptoms caused by the tumor that may continue after treatment.
The following types of treatment may be used:
Surgery
Surgery is used to treat CNS AT/RT. Learn more about how this tumor is diagnosed.
After the doctor removes all the cancer that can be seen at the time of the surgery, most children will receive chemotherapy and possibly radiation therapy to try to kill any cancer cells that are left. Treatment given after surgery to lower the risk that the cancer will come back is called adjuvant therapy.
Chemotherapy
Chemotherapy uses drugs to stop the growth of cancer cells. Chemotherapy either kills the cells or stops them from dividing. Chemotherapy may be given with other types of treatments.
Chemotherapy for AT/RT is injected into a vein. When given this way, the drugs enter the bloodstream and can reach tumor cells throughout the body. High doses of some chemotherapy drugs given into a vein can cross the blood-brain barrier and reach the tumor. Chemotherapy for AT/RT is also placed directly into the cerebrospinal fluid (intrathecal chemotherapy). Combination chemotherapy uses more than one anticancer drug.
EnlargeIntrathecal chemotherapy. Anticancer drugs are injected into the intrathecal space, which is the space that holds the cerebrospinal fluid (CSF, shown in blue). There are two different ways to do this. One way, shown in the top part of the figure, is to inject the drugs into an Ommaya reservoir (a dome-shaped container that is placed under the scalp during surgery; it holds the drugs as they flow through a small tube into the brain). The other way, shown in the bottom part of the figure, is to inject the drugs directly into the CSF in the lower part of the spinal column, after a small area on the lower back is numbed.
Chemotherapy drugs used alone or in combination to treat AT/RT in children include:
Other chemotherapy drugs not listed here may also be used.
Learn more about how chemotherapy works, how it is given, and common side effects at Chemotherapy to Treat Cancer.
Radiation therapy
Radiation therapy uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing. External radiation therapy uses a machine outside the body to send radiation toward the area of the body with cancer.
Because radiation therapy can affect growth and brain development in young children, especially children who are 3 years old or younger, the dose of radiation therapy may be lower than in older children.
High doses of chemotherapy are given to kill cancer cells. This treatment destroys healthy cells, including blood-forming cells. Stem cell transplant is a treatment to replace the blood-forming cells. Stem cells (immature blood cells) are removed from the blood or bone marrow of the patient and are frozen and stored. After the patient completes chemotherapy, the stored stem cells are thawed and given back to the patient through an infusion. These reinfused stem cells grow into (and restore) the body’s blood cells.
Clinical trials
For some children, joining a clinical trial may be an option. There are different types of clinical trials for childhood cancer. For example, a treatment trial tests new treatments or new ways of using current treatments. Supportive care and palliative care trials look at ways to improve quality of life, especially for those who have side effects from cancer and its treatment.
You can find clinical trials for people with atypical teratoid/rhabdoid tumor at Treatment Clinical Trials for Atypical Teratoid/Rhabdoid Tumor or use the clinical trial search to find NCI-supported cancer clinical trials accepting participants. The search allows you to filter trials based on the type of cancer, your child’s age, and where the trials are being done. Clinical trials supported by other organizations can be found on the ClinicalTrials.gov website.
Treatment for childhood CNS AT/RT may cause side effects.
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.
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 cancer treatment may include:
physical problems
changes in mood, feelings, thinking, learning, or memory
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.
Follow-up care may be needed.
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. Some tests will 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 recurred (come back).
Resources and support are available to help you cope with your child’s cancer.
When your 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.
Treatment of Childhood Central Nervous System Atypical Teratoid/Rhabdoid Tumor
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.
Treatment of Recurrent Childhood Central Nervous System Atypical Teratoid/Rhabdoid Tumor
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.
To Learn More about Childhood Central Nervous System Atypical Teratoid/Rhabdoid Tumor and Other Childhood Brain Tumors
For more information about childhood central nervous system atypical teratoid/rhabdoid tumor and other childhood brain tumors, visit:
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Purpose of This Summary
This PDQ cancer information summary has current information about the treatment of childhood central nervous system atypical teratoid and rhabdoid tumor. It is meant to inform and help patients, families, and caregivers. It does not give formal guidelines or recommendations for making decisions about health care.
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Clinical Trial Information
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Clinical trials can be found online at NCI’s website. For more information, call the Cancer Information Service (CIS), NCI’s contact center, at 1-800-4-CANCER (1-800-422-6237).
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PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Central Nervous System Atypical Teratoid/Rhabdoid Tumor Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/brain/patient/child-cns-atrt-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389341]
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Primary brain tumors, including atypical teratoid/rhabdoid tumors (AT/RTs), are a diverse group of diseases that together constitute the most common solid tumors of childhood. The PDQ childhood brain tumor treatment summaries are primarily organized according to the World Health Organization classification of nervous system tumors.[1,2] Brain tumors are classified according to histology, but immunohistochemical analysis, cytogenetic and molecular genetic findings, and measures of mitotic activity are increasingly used in tumor diagnosis and classification. Tumor location, extent of spread, and age at diagnosis are important factors that affect treatment and prognosis.[3–5] 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.
CNS AT/RT is a rare, clinically aggressive tumor that most often affects children aged 3 years and younger but can occur in older children and adults. Approximately one-half of AT/RTs arise in the posterior fossa.[6] The diagnostic evaluation includes magnetic resonance imaging (MRI) of the neuraxis and lumbar cerebrospinal fluid examination. AT/RT has been linked to somatic and germline variants of SMARCB1 and, less commonly, SMARCA4, both of which act as tumor suppressor genes.[7] There is no evidence-based standard treatment for children with AT/RT. Multimodality treatment consisting of surgery, chemotherapy (including high-dose chemotherapy), and radiation therapy is under evaluation in controlled clinical trials.
Based on current biological understanding, AT/RT is part of a larger family of rhabdoid tumors. In this summary, the term AT/RT refers to CNS tumors only, and the term rhabdoid tumor reflects the possibility of both CNS and non-CNS tumors. Unless specifically noted in the text, this summary refers to CNS AT/RT.
Childhood and adolescent cancer survivors require close monitoring because side effects of cancer therapy 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.
Incidence
The exact incidence of childhood CNS AT/RT is difficult to determine because the tumor is rare and has only been recognized since 1996.[8]
In two prospective studies performed by the Children’s Cancer Group and the Pediatric Oncology Group in North America, retrospective review disclosed that approximately 10% of children aged 3 years or younger at diagnosis with brain tumors had AT/RTs.[9]
A study completed in Taiwan found that AT/RTs account for 26% of primitive or embryonal tumors in children younger than 3 years.[10]
The Austrian Brain Tumor Registry (recruitment period, 1996–2006) confirmed that AT/RTs represented the sixth most common malignant brain tumor among 311 newly diagnosed children (6.1%), with a peak incidence during the first 2 years of life.[11]
The incidence in older patients is unknown. However, in the Central Nervous System Atypical Teratoid/Rhabdoid Tumor Registry (AT/RT Registry), 12 of the 42 patients (29%) were older than 36 months at the time of diagnosis.[12]
Anatomy
EnlargeAnatomy of the inside of the brain, showing the pineal and pituitary glands, optic nerve, ventricles (with cerebrospinal fluid shown in blue), and other parts of the brain. The tentorium separates the cerebrum from the cerebellum. The infratentorium (posterior fossa) is the region below the tentorium that contains the brain stem, cerebellum, and fourth ventricle. The supratentorium is the region above the tentorium and denotes the region that contains the cerebrum.
Clinical Presentation
Childhood AT/RT is a clinically aggressive tumor that primarily occurs in children younger than 3 years, but it also can occur in older children and adults.[13,14]
Approximately one-half of all AT/RTs arise in the posterior fossa, although they can occur anywhere in the CNS.[6,9] Tumors of the posterior fossa may occur in the cerebellopontine angle or more midline. Involvement of individual cranial nerves has been noted.[15]
Because AT/RTs grow rapidly, patients often have a fairly short history of progressive symptoms, measured in days to weeks. Signs and symptoms depend on tumor location. Young patients with posterior fossa tumors usually present with symptoms related to hydrocephalus, which include the following:
Early-morning headaches.
Vomiting.
Lethargy.
Increased head circumference.
They may also develop ataxia, regression of motor skills, or localizing symptoms related to cranial nerve dysfunction.
Registry data suggest that 25% to 30% of patients present with disseminated disease.[5,12,16] Dissemination is typically through leptomeningeal pathways seeding the spine and other areas of the brain. Up to 35% of patients present with germline variants and may be prone to synchronous, multifocal tumors.[17–20]
Diagnostic Evaluation
All patients with suspected AT/RT should undergo MRI of the brain and spine. Unless medically contraindicated, the lumbar cerebrospinal fluid should be inspected for evidence of tumor. Patients may also undergo renal ultrasonography to detect synchronous tumors. Germline testing is also indicated.
AT/RTs cannot be reliably distinguished from other malignant brain tumors on the basis of clinical history or radiographic evaluation alone. Surgery is necessary to obtain tissue and confirm the diagnosis. Immunohistochemical staining for loss of SMARCB1 protein expression is also used to confirm the diagnosis.[21,22] Methylation array analysis has become an important adjunct to confirm the AT/RT subtype.[3,4]
Prognosis
Prognostic factors that affect survival for patients with AT/RTs are not fully delineated.
Known factors associated with a poor outcome include the following:
Most published data on outcomes of patients with AT/RT are from small series and are retrospective in nature. Initial retrospective studies reported an average survival from diagnosis of only about 12 months.[8,9,13,25,27] In a retrospective report, 2-year overall survival (OS) was better for patients who underwent a gross-total resection than for those who had a subtotal resection. However, in this study, the effect of radiation therapy on survival was less clear.[25]
There are reports of long-term survivors.[28] Notably, improved survival has been reported for those who received intensive multimodality therapy.[16,19]
Children aged 3 years and older with AT/RT who received postoperative craniospinal irradiation and high-dose, alkylator-based chemotherapy had improved survival compared with patients younger than 3 years. In this report, the incidence of leptomeningeal metastases was also higher in the infant patients.[29]
In one prospective study of 25 children with AT/RT who received intensive multimodality therapy, including radiation and intrathecal chemotherapy, the reported 2-year progression-free survival rate was 53%, and the OS rate was 70%.[30]
For patients in the prospective ACNS0333 (NCT00653068) trial, the 4-year event-free survival rate was 37%, and the 4-year OS rate was 43%.[31]
In the prospective European Rhabdoid Registry series, patients aged 1 year and older with an AT/RT tyrosinase (TYR) subgroup designation demonstrated a 5-year OS rate of 71%, while those younger than 1 year with a non-TYR AT/RT had a very poor survival rate.[5] These data were confirmed in two other trials.[26]
References
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WHO Classification of Tumours Editorial Board, ed.: WHO Classification of Tumours: Central Nervous System Tumours. Vol. 6. 5th ed. IARC Press; 2021.
Federico A, Thomas C, Miskiewicz K, et al.: ATRT-SHH comprises three molecular subgroups with characteristic clinical and histopathological features and prognostic significance. Acta Neuropathol 143 (6): 697-711, 2022. [PUBMED Abstract]
Lu VM, Di L, Eichberg DG, et al.: Age of diagnosis clinically differentiates atypical teratoid/rhabdoid tumors diagnosed below age of 3 years: a database study. Childs Nerv Syst 37 (4): 1077-1085, 2021. [PUBMED Abstract]
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Packer RJ, Biegel JA, Blaney S, et al.: Atypical teratoid/rhabdoid tumor of the central nervous system: report on workshop. J Pediatr Hematol Oncol 24 (5): 337-42, 2002 Jun-Jul. [PUBMED Abstract]
Ho DM, Hsu CY, Wong TT, et al.: Atypical teratoid/rhabdoid tumor of the central nervous system: a comparative study with primitive neuroectodermal tumor/medulloblastoma. Acta Neuropathol 99 (5): 482-8, 2000. [PUBMED Abstract]
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Hilden JM, Meerbaum S, Burger P, et al.: Central nervous system atypical teratoid/rhabdoid tumor: results of therapy in children enrolled in a registry. J Clin Oncol 22 (14): 2877-84, 2004. [PUBMED Abstract]
Burger PC, Yu IT, Tihan T, et al.: Atypical teratoid/rhabdoid tumor of the central nervous system: a highly malignant tumor of infancy and childhood frequently mistaken for medulloblastoma: a Pediatric Oncology Group study. Am J Surg Pathol 22 (9): 1083-92, 1998. [PUBMED Abstract]
Lutterbach J, Liegibel J, Koch D, et al.: Atypical teratoid/rhabdoid tumors in adult patients: case report and review of the literature. J Neurooncol 52 (1): 49-56, 2001. [PUBMED Abstract]
Lobón-Iglesias MJ, Andrianteranagna M, Han ZY, et al.: Imaging and multi-omics datasets converge to define different neural progenitor origins for ATRT-SHH subgroups. Nat Commun 14 (1): 6669, 2023. [PUBMED Abstract]
Bartelheim K, Nemes K, Seeringer A, et al.: Improved 6-year overall survival in AT/RT – results of the registry study Rhabdoid 2007. Cancer Med 5 (8): 1765-75, 2016. [PUBMED Abstract]
Biegel JA, Fogelgren B, Wainwright LM, et al.: Germline INI1 mutation in a patient with a central nervous system atypical teratoid tumor and renal rhabdoid tumor. Genes Chromosomes Cancer 28 (1): 31-7, 2000. [PUBMED Abstract]
Bourdeaut F, Lequin D, Brugières L, et al.: Frequent hSNF5/INI1 germline mutations in patients with rhabdoid tumor. Clin Cancer Res 17 (1): 31-8, 2011. [PUBMED Abstract]
Seeringer A, Reinhard H, Hasselblatt M, et al.: Synchronous congenital malignant rhabdoid tumor of the orbit and atypical teratoid/rhabdoid tumor–feasibility and efficacy of multimodal therapy in a long-term survivor. Cancer Genet 207 (9): 429-33, 2014. [PUBMED Abstract]
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Kordes U, Gesk S, Frühwald MC, et al.: Clinical and molecular features in patients with atypical teratoid rhabdoid tumor or malignant rhabdoid tumor. Genes Chromosomes Cancer 49 (2): 176-81, 2010. [PUBMED Abstract]
Dufour C, Beaugrand A, Le Deley MC, et al.: Clinicopathologic prognostic factors in childhood atypical teratoid and rhabdoid tumor of the central nervous system: a multicenter study. Cancer 118 (15): 3812-21, 2012. [PUBMED Abstract]
Lafay-Cousin L, Hawkins C, Carret AS, et al.: Central nervous system atypical teratoid rhabdoid tumours: the Canadian Paediatric Brain Tumour Consortium experience. Eur J Cancer 48 (3): 353-9, 2012. [PUBMED Abstract]
Upadhyaya SA, Robinson GW, Onar-Thomas A, et al.: Relevance of Molecular Groups in Children with Newly Diagnosed Atypical Teratoid Rhabdoid Tumor: Results from Prospective St. Jude Multi-institutional Trials. Clin Cancer Res 27 (10): 2879-2889, 2021. [PUBMED Abstract]
Athale UH, Duckworth J, Odame I, et al.: Childhood atypical teratoid rhabdoid tumor of the central nervous system: a meta-analysis of observational studies. J Pediatr Hematol Oncol 31 (9): 651-63, 2009. [PUBMED Abstract]
Olson TA, Bayar E, Kosnik E, et al.: Successful treatment of disseminated central nervous system malignant rhabdoid tumor. J Pediatr Hematol Oncol 17 (1): 71-5, 1995. [PUBMED Abstract]
Tekautz TM, Fuller CE, Blaney S, et al.: Atypical teratoid/rhabdoid tumors (ATRT): improved survival in children 3 years of age and older with radiation therapy and high-dose alkylator-based chemotherapy. J Clin Oncol 23 (7): 1491-9, 2005. [PUBMED Abstract]
Chi SN, Zimmerman MA, Yao X, et al.: Intensive multimodality treatment for children with newly diagnosed CNS atypical teratoid rhabdoid tumor. J Clin Oncol 27 (3): 385-9, 2009. [PUBMED Abstract]
Reddy AT, Strother DR, Judkins AR, et al.: Efficacy of High-Dose Chemotherapy and Three-Dimensional Conformal Radiation for Atypical Teratoid/Rhabdoid Tumor: A Report From the Children’s Oncology Group Trial ACNS0333. J Clin Oncol 38 (11): 1175-1185, 2020. [PUBMED Abstract]
Tumor Biology of Childhood CNS Atypical Teratoid/Rhabdoid Tumor
Childhood central nervous system (CNS) atypical teratoid/rhabdoid tumor (AT/RT) was first described as a discrete clinical entity in 1987 [1] based on its distinctive pathological and genetic characteristics. Before then, it was most often classified as a medulloblastoma, CNS primitive neuroectodermal tumor (CNS PNET), or choroid plexus carcinoma. The World Health Organization (WHO) classifies AT/RT as an embryonal grade IV neoplasm.[2]
Histologically, AT/RT is morphologically heterogeneous, typically containing sheets of large epithelioid cells with abundant eosinophilic cytoplasm and scattered rhabdoid cells, most often with accompanying components of primitive neuroectodermal cells (small round blue cells), mesenchymal cells, and/or glial cells.[3]
Immunohistochemical staining for epithelial markers (cytokeratin or epithelial membrane antigen), glial fibrillary acidic protein, synaptophysin (or neurofilament), and smooth muscle (desmin) may help to identify the heterogeneity of differentiation, but will vary depending on the cellular composition.[4] Rhabdoid cells, while not present in all AT/RTs, will express vimentin, epithelial membrane antigen, and smooth muscle actin.
Immunohistochemical staining for the SMARCB1 protein is useful in establishing the diagnosis of AT/RT. A loss of SMARCB1 staining is noted in neoplastic cells, but staining is retained in non-neoplastic cells (e.g., vascular endothelial cells).[5–7]
AT/RT is a rapidly growing tumor that can have an MIB-1 labeling index of 50% to 100%.[8]
Genomics of CNS Atypical Teratoid/Rhabdoid Tumor (AT/RT)
SMARCB1 and SMARCA4 genes
AT/RT was the first primary pediatric brain tumor in which a candidate tumor suppressor gene, SMARCB1, was identified.[9] SMARCB1 is genomically altered in most rhabdoid tumors, including CNS, renal, and extrarenal rhabdoid malignancies.[9] SMARCB1 is a component of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin-remodeling complex.[10]
Rare cases of rhabdoid tumors expressing SMARCB1 and lacking SMARCB1 variants have also been associated with somatic or germline variants of SMARCA4, another member of the SWI/SNF chromatin-remodeling complex.[7,11,12]
Less commonly, SMARCA4-negative (with retained SMARCB1) tumors have been described.[7,11,12] Loss of SMARCB1 or SMARCA4 staining is a defining marker for AT/RT.
The 2021 WHO classification defines AT/RT by the presence of either SMARCB1 or SMARCA4 alterations. Tumors with histological features of AT/RT that lack these genomic alterations are termed CNS embryonal tumors with rhabdoid features.[13]
Despite the absence of recurring genomic alterations beyond SMARCB1 and SMARCA4,[14–16] biologically, relatively distinctive subsets of AT/RT have been identified.[17–19] In one study, three distinctive subsets of AT/RT were identified through the use of DNA methylation arrays for 150 AT/RT tumors and gene expression arrays for 67 AT/RT tumors:[18]
AT/RT tyrosinase (TYR): This subset represented approximately one-third of cases and was characterized by elevated expression of melanosomal markers such as TYR (the gene encoding tyrosinase). Cases in this subset were primarily infratentorial, with most presenting in children aged 0 to 1 year and showing chromosome 22q loss.[18] For patients with AT/RT TYR, the mean overall survival (OS) was 37 months in a clinically heterogeneous group (95% confidence interval [CI], 18–56 months).[20] In the prospective European Rhabdoid Registry (EU-RHAB) series, patients aged 1 year and older with AT/RT TYR demonstrated a 5-year OS rate of 71%, while those younger than 1 year with a non-TYR AT/RT had a very poor survival rate.[21]
AT/RT sonic hedgehog (SHH): This subset represented approximately 40% of cases and was characterized by elevated expression of genes in the SHH pathway (e.g., GLI2 and MYCN). Cases in this subset occurred with similar frequency in the supratentorium and infratentorium. While most patients presented before the age of 2 years, approximately one-third of patients presented between the ages of 2 and 5 years.[18] For patients with AT/RT SHH, the mean OS was 16 months (95% CI, 8–25 months).[20]
In a subsequent study, the AT/RT SHH subgroup was further divided into three subtypes: SHH-1A, SHH-1B, and SHH-2.[22] Children older than 3 years who harbored the SHH-1B signature experienced the most favorable outcomes.
AT/RT MYC: This subset represented approximately one-fourth of cases and was characterized by elevated expression of MYC. AT/RT MYC cases tended to occur in the supratentorial compartment. While most AT/RT MYC cases occurred by the age of 5 years, AT/RT MYC represented the most common subset diagnosed at age 6 years and older. Focal deletions of SMARCB1 were the most common mechanism of SMARCB1 loss for this subset.[18] For patients with AT/RT MYC, the mean OS was 13 months (95% CI, 5–22 months).[20]
Loss of SMARCB1 or SMARCA4 protein expression has therapeutic significance, because this loss creates a dependence of the cancer cells on EZH2 activity.[23] Preclinical studies have shown that some AT/RT xenograft lines with SMARCB1 loss respond to EZH2 inhibitors with tumor growth inhibition and occasional tumor regression.[24,25] In a study of the EZH2 inhibitor tazemetostat, objective responses were observed in adult patients whose tumors had either SMARCB1 or SMARCA4 loss (non-CNS malignant rhabdoid tumors and epithelioid sarcoma).[26] For more information, see the Treatment of Recurrent Childhood CNS Atypical Teratoid/Rhabdoid Tumor section.
Cribriform Neuroepithelial Tumor
Cribriform neuroepithelial tumor has genomic and epigenomic characteristics that are very similar to those of AT/RT TYR.[20] The 2021 WHO Classification lists cribriform neuroepithelial tumor as a provisional entity. Like AT/RT, cribriform neuroepithelial tumor occurs in young children (median age, 1–2 years) and tumor cells lack SMARCB1 expression. Histologically, cribriform neuroepithelial tumor is characterized by the presence of cribriform strands and ribbons, but there is an absence of rhabdoid tumor cells with abundant eosinophilic cytoplasm. Like AT/RT TYR, tyrosinase expression is commonly observed. The outcome of patients with cribriform neuroepithelial tumor is more favorable than the outcome of patients with AT/RT TYR. In one study, only one death was reported among ten children with cribriform neuroepithelial tumor.[20]
Rhabdoid Tumor Predisposition Syndrome (RTPS)
RTPS, which is primarily related to germline SMARCB1 alterations (and less commonly to germline SMARCA4 alterations), has been clearly defined.[9,27] RTPS caused by SMARCB1 germline alterations is termed RTPS Type 1, while RTPS due to a SMARCA4 germline variant is called RTPS Type 2. RTPS is highly suggested in patients with synchronous occurrence of extracranial malignant rhabdoid tumor (kidney or soft tissue) and AT/RT, bilateral malignant rhabdoid tumors of the kidney, or malignant rhabdoid tumors in two or more siblings.
This syndrome is manifested by a marked predisposition to the development of malignant rhabdoid tumors in infancy and early childhood. Up to one-third of AT/RTs are thought to arise in the setting of RTPS, and most of these occur within the first year of life. The most common non-CNS malignancy of RTPS is malignant rhabdoid tumor of the kidney, which is also noted in infancy.[28,29]
A study of 65 children with rhabdoid tumors found that 23 (35%) had germline variants and/or deletions of SMARCB1.[5] Children with germline alterations in SMARCB1 presented at an earlier age than did sporadic cases (median age, approximately 5 months vs. 18 months) and were more likely to present with synchronous, multifocal tumors.[5] One parent was found to be a carrier of the SMARCB1 germline abnormality in 7 of 22 evaluated cases showing germline alterations, with four of the carrier parents being unaffected by SMARCB1-associated cancers.[5] This finding indicates that AT/RT shows an autosomal dominant inheritance pattern with incomplete penetrance.
Gonadal mosaicism has also been observed, as evidenced by families in which multiple siblings are affected by AT/RT and have identical SMARCB1 alterations, but both parents lack a SMARCB1 variant/deletion.[5,6] Screening for germline SMARCB1 variants in children diagnosed with AT/RT is suggested for counseling families on the genetic implications of their child’s AT/RT diagnosis.[5] Preliminary recommendations for the genetic evaluation and subsequent presymptomatic screening of nonaffected variant carriers (including parents and siblings of affected patients) have been reported and are likely to evolve as the understanding of RTPS improves.[28–30] In patients with a predisposition to AT/RT, whole-body magnetic resonance imaging may help to identify synchronous rhabdoid tumors outside of the CNS.
Rorke LB, Packer RJ, Biegel JA: Central nervous system atypical teratoid/rhabdoid tumors of infancy and childhood: definition of an entity. J Neurosurg 85 (1): 56-65, 1996. [PUBMED Abstract]
Oztek MA, Noda SM, Romberg EK, et al.: Changes to pediatric brain tumors in 2021 World Health Organization classification of tumors of the central nervous system. Pediatr Radiol 53 (3): 523-543, 2023. [PUBMED Abstract]
Louis DN, Ohgaki H, Wiestler OD: WHO Classification of Tumours of the Central Nervous System. 4th rev.ed. IARC Press, 2016.
McLendon RE, Adekunle A, Rajaram V, et al.: Embryonal central nervous system neoplasms arising in infants and young children: a pediatric brain tumor consortium study. Arch Pathol Lab Med 135 (8): 984-93, 2011. [PUBMED Abstract]
Eaton KW, Tooke LS, Wainwright LM, et al.: Spectrum of SMARCB1/INI1 mutations in familial and sporadic rhabdoid tumors. Pediatr Blood Cancer 56 (1): 7-15, 2011. [PUBMED Abstract]
Bruggers CS, Bleyl SB, Pysher T, et al.: Clinicopathologic comparison of familial versus sporadic atypical teratoid/rhabdoid tumors (AT/RT) of the central nervous system. Pediatr Blood Cancer 56 (7): 1026-31, 2011. [PUBMED Abstract]
Hasselblatt M, Gesk S, Oyen F, et al.: Nonsense mutation and inactivation of SMARCA4 (BRG1) in an atypical teratoid/rhabdoid tumor showing retained SMARCB1 (INI1) expression. Am J Surg Pathol 35 (6): 933-5, 2011. [PUBMED Abstract]
Kleihues P, Louis DN, Scheithauer BW, et al.: The WHO classification of tumors of the nervous system. J Neuropathol Exp Neurol 61 (3): 215-25; discussion 226-9, 2002. [PUBMED Abstract]
Biegel JA, Tan L, Zhang F, et al.: Alterations of the hSNF5/INI1 gene in central nervous system atypical teratoid/rhabdoid tumors and renal and extrarenal rhabdoid tumors. Clin Cancer Res 8 (11): 3461-7, 2002. [PUBMED Abstract]
Biegel JA, Kalpana G, Knudsen ES, et al.: The role of INI1 and the SWI/SNF complex in the development of rhabdoid tumors: meeting summary from the workshop on childhood atypical teratoid/rhabdoid tumors. Cancer Res 62 (1): 323-8, 2002. [PUBMED Abstract]
Schneppenheim R, Frühwald MC, Gesk S, et al.: Germline nonsense mutation and somatic inactivation of SMARCA4/BRG1 in a family with rhabdoid tumor predisposition syndrome. Am J Hum Genet 86 (2): 279-84, 2010. [PUBMED Abstract]
Hasselblatt M, Nagel I, Oyen F, et al.: SMARCA4-mutated atypical teratoid/rhabdoid tumors are associated with inherited germline alterations and poor prognosis. Acta Neuropathol 128 (3): 453-6, 2014. [PUBMED Abstract]
WHO Classification of Tumours Editorial Board, ed.: WHO Classification of Tumours: Central Nervous System Tumours. Vol. 6. 5th ed. IARC Press; 2021.
Lee RS, Stewart C, Carter SL, et al.: A remarkably simple genome underlies highly malignant pediatric rhabdoid cancers. J Clin Invest 122 (8): 2983-8, 2012. [PUBMED Abstract]
Kieran MW, Roberts CW, Chi SN, et al.: Absence of oncogenic canonical pathway mutations in aggressive pediatric rhabdoid tumors. Pediatr Blood Cancer 59 (7): 1155-7, 2012. [PUBMED Abstract]
Hasselblatt M, Isken S, Linge A, et al.: High-resolution genomic analysis suggests the absence of recurrent genomic alterations other than SMARCB1 aberrations in atypical teratoid/rhabdoid tumors. Genes Chromosomes Cancer 52 (2): 185-90, 2013. [PUBMED Abstract]
Torchia J, Picard D, Lafay-Cousin L, et al.: Molecular subgroups of atypical teratoid rhabdoid tumours in children: an integrated genomic and clinicopathological analysis. Lancet Oncol 16 (5): 569-82, 2015. [PUBMED Abstract]
Johann PD, Erkek S, Zapatka M, et al.: Atypical Teratoid/Rhabdoid Tumors Are Comprised of Three Epigenetic Subgroups with Distinct Enhancer Landscapes. Cancer Cell 29 (3): 379-93, 2016. [PUBMED Abstract]
Upadhyaya SA, Robinson GW, Onar-Thomas A, et al.: Relevance of Molecular Groups in Children with Newly Diagnosed Atypical Teratoid Rhabdoid Tumor: Results from Prospective St. Jude Multi-institutional Trials. Clin Cancer Res 27 (10): 2879-2889, 2021. [PUBMED Abstract]
Johann PD, Hovestadt V, Thomas C, et al.: Cribriform neuroepithelial tumor: molecular characterization of a SMARCB1-deficient non-rhabdoid tumor with favorable long-term outcome. Brain Pathol 27 (4): 411-418, 2017. [PUBMED Abstract]
Frühwald MC, Hasselblatt M, Nemes K, et al.: Age and DNA methylation subgroup as potential independent risk factors for treatment stratification in children with atypical teratoid/rhabdoid tumors. Neuro Oncol 22 (7): 1006-1017, 2020. [PUBMED Abstract]
Federico A, Thomas C, Miskiewicz K, et al.: ATRT-SHH comprises three molecular subgroups with characteristic clinical and histopathological features and prognostic significance. Acta Neuropathol 143 (6): 697-711, 2022. [PUBMED Abstract]
Wilson BG, Wang X, Shen X, et al.: Epigenetic antagonism between polycomb and SWI/SNF complexes during oncogenic transformation. Cancer Cell 18 (4): 316-28, 2010. [PUBMED Abstract]
Knutson SK, Warholic NM, Wigle TJ, et al.: Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2. Proc Natl Acad Sci U S A 110 (19): 7922-7, 2013. [PUBMED Abstract]
Kurmasheva RT, Sammons M, Favours E, et al.: Initial testing (stage 1) of tazemetostat (EPZ-6438), a novel EZH2 inhibitor, by the Pediatric Preclinical Testing Program. Pediatr Blood Cancer 64 (3): , 2017. [PUBMED Abstract]
Italiano A, Soria JC, Toulmonde M, et al.: Tazemetostat, an EZH2 inhibitor, in relapsed or refractory B-cell non-Hodgkin lymphoma and advanced solid tumours: a first-in-human, open-label, phase 1 study. Lancet Oncol 19 (5): 649-659, 2018. [PUBMED Abstract]
Biegel JA, Fogelgren B, Wainwright LM, et al.: Germline INI1 mutation in a patient with a central nervous system atypical teratoid tumor and renal rhabdoid tumor. Genes Chromosomes Cancer 28 (1): 31-7, 2000. [PUBMED Abstract]
Frühwald MC, Nemes K, Boztug H, et al.: Current recommendations for clinical surveillance and genetic testing in rhabdoid tumor predisposition: a report from the SIOPE Host Genome Working Group. Fam Cancer 20 (4): 305-316, 2021. [PUBMED Abstract]
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Stage Information for Childhood CNS Atypical Teratoid/Rhabdoid Tumor
There is no evidence-based staging system for childhood central nervous system atypical teratoid/rhabdoid tumor. For treatment purposes, patients are classified as having newly diagnosed or recurrent disease, with or without neuraxis dissemination.
Treatment of Childhood CNS Atypical Teratoid/Rhabdoid Tumor
An evidence-based standard treatment for children with newly diagnosed central nervous system (CNS) atypical teratoid/rhabdoid tumor (AT/RT) has not yet been defined. Given the highly aggressive nature of the tumor, most patients have been treated with intensive multimodality therapy. However, the extent of treatment, particularly for radiation therapy, is limited because of the young age of most patients.
Treatment options for newly diagnosed CNS AT/RT include the following:
Surgery, Chemotherapy, and Radiation Therapy (Multimodality Therapy)
The extent of surgical resection may affect survival. Data from the Central Nervous System Atypical Teratoid/Rhabdoid Tumor Registry (AT/RT Registry) suggest that patients who have had a complete resection may have a longer median survival. However, complete surgical resection is often difficult because of the invasive nature of the tumor.[1]
Chemotherapy has been the main adjuvant therapy for very young children with AT/RT. Cooperative group studies that included children younger than 36 months demonstrated poor survival with standard chemotherapeutic regimens alone.[2] The Children’s Cancer Group reported a 2-year event-free survival (EFS) rate of 14% for 28 children younger than 36 months who were treated with multiagent chemotherapy.[3]
Intensive regimens that use varying combinations of high-dose chemotherapy,[4][Level of evidence C1]; [5,6][Level of evidence C2] intrathecal chemotherapy, and radiation therapy have led to prolonged survival for some patients.
Only two prospective trials for children with CNS AT/RT have been completed. In an institutional prospective trial, children were treated with a modified Intergroup Rhabdomyosarcoma Study-III (IRS-III) protocol, using intrathecal chemotherapy and radiation therapy. Of the subset of 20 children who completed therapy, the 2-year progression-free survival (PFS) rate was 53%, and the overall survival (OS) rate was 70%. Survival was better for patients who had a complete resection.[7][Level of evidence C1] In the Children’s Oncology Group (COG) ACNS0333 (NCT00653068) study, patients were treated with intensive induction chemotherapy, followed by high-dose chemotherapy with autologous stem cell rescue and radiation therapy. The 4-year PFS rate was 37%, and the OS rate was 43%.[8][Level of evidence B4]
Thirteen patients in the AT/RT Registry were treated with high-dose chemotherapy with hematopoietic stem cell rescue as part of initial therapy.[1] Four of these patients, two of whom also received radiation, were alive without progressive disease 21.5 to 90 months after diagnosis at last report. Of 15 evaluable children (all younger than 32 months at diagnosis) who were on a chemotherapy Head Start III protocol, 2 survived for more than 47 months.[9][Level of evidence C1]
Radiation therapy appears to have a positive impact on survival for patients with AT/RT.[10,11]
Evidence (radiation therapy):
Of the 42 patients in the AT/RT Registry, 13 (31%) received radiation therapy in addition to chemotherapy as part of their primary therapy.[1] The radiation field was to the primary tumor bed in nine children, and the radiation field was to the tumor bed and the craniospinal axis in four children.
The median survival of these patients was 48 months, compared with 16.75 months for all patients in the registry.
In a retrospective series of 31 patients with AT/RT from the St. Jude Children’s Research Hospital, the following results were reported:[12]
The 2-year EFS rate was 78% for patients older than 3 years, which was considerably better than the EFS rate of 11% for patients younger than 3 years.
All but one of the surviving patients (seven of eight) in the older group received craniospinal irradiation and intensive chemotherapy with hematopoietic stem cell transplant.
Only 3 of the 22 younger patients received any form of radiation therapy, 2 of whom were disease free.
In a Surveillance, Epidemiology, and End Results (SEER) Program registry review, radiation therapy was associated with improved survival in children younger than 3 years.[13]
In the European Registry for rhabdoid tumors series, the following results were observed:[14][Level of evidence C1]
Radiation therapy was also associated with improved survival, with a 6-year OS rate of 66% (± 0.1%) in patients who received this treatment.
The significant benefit of radiation therapy was corroborated in an extension of this series.[15]
Evidence (multimodality therapy):
The IRS-III study used radiation therapy, intrathecal methotrexate, cytarabine, hydrocortisone, and systemic multiagent chemotherapy. The results of this small retrospective series were encouraging,[16,17] leading to the first prospective study of multimodality treatment in this group of patients.
On the basis of the previous pilot series, a prospective multi-institutional trial was conducted for children with newly diagnosed CNS AT/RT. Treatment was divided into five phases: preirradiation, chemoradiation, consolidation, maintenance, and continuation therapy. Intrathecal chemotherapy was administered, alternating intralumbar and intraventricular routes. Radiation therapy was either focal (54 Gy) or craniospinal (36 Gy, plus primary boost), depending on the child’s age and extent of disease at diagnosis.[7]
The 2-year PFS rate was 53% (± 13%), and the 2-year OS rate was 70% (± 10%).
Results were most favorable for children who were older, had a gross-total resection, and had no metastatic disease at presentation.
Six of the eight children without progressive disease at the time of the report had received conformal radiation therapy, and two children had received craniospinal radiation therapy. Seven children had a gross-total resection, and only one child had metastatic disease (this child had persistent, stable disease 1.5 years from diagnosis).
The COG performed a prospective single-arm study of 65 children. Fifty-four of the children were younger than 36 months and received two courses of methotrexate, cyclophosphamide, cisplatin, and etoposide followed by three courses of high-dose carboplatin and thiotepa supported by peripheral stem cell rescue. For patients with nondisseminated disease, focal involved-field radiation therapy was mandated after either induction or consolidation, depending on age. For patients with disseminated disease, craniospinal radiation at the end of therapy was recommended but not mandated.[8]
For all patients, the 4-year EFS rate was 37%, and the 4-year OS rate was 43%.
For children younger than 36 months at diagnosis, the 4-year EFS rate was 35%, compared with 6.4% in a historical cohort of patients who received chemotherapy alone (P < .0005).
For the 11 children aged 36 months or older at diagnosis, the 4-year EFS rate was 48%, and the 4-year OS rate was 57%.
Toxicity from this regimen was significant. Four treatment-related deaths (6% of the patients) resulting from sepsis, respiratory failure, or CNS necrosis were reported.
On the basis of the two prospective studies summarized above, multimodality therapy with surgery, radiation therapy, and chemotherapy seems to be the best treatment to optimize the survival of children with AT/RT. However, toxicities can be significant, and the most effective regimen and the optimal sequencing of therapies still need to be determined.
Treatment Options Under Clinical Evaluation
Early-phase therapeutic trials may be available for selected patients. These trials may be available via the Children’s Oncology Group, the Pediatric Brain Tumor Consortium, or other entities. Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.
References
Hilden JM, Meerbaum S, Burger P, et al.: Central nervous system atypical teratoid/rhabdoid tumor: results of therapy in children enrolled in a registry. J Clin Oncol 22 (14): 2877-84, 2004. [PUBMED Abstract]
Packer RJ, Biegel JA, Blaney S, et al.: Atypical teratoid/rhabdoid tumor of the central nervous system: report on workshop. J Pediatr Hematol Oncol 24 (5): 337-42, 2002 Jun-Jul. [PUBMED Abstract]
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]
Nicolaides T, Tihan T, Horn B, et al.: High-dose chemotherapy and autologous stem cell rescue for atypical teratoid/rhabdoid tumor of the central nervous system. J Neurooncol 98 (1): 117-23, 2010. [PUBMED Abstract]
Gardner SL, Asgharzadeh S, Green A, et al.: Intensive induction chemotherapy followed by high dose chemotherapy with autologous hematopoietic progenitor cell rescue in young children newly diagnosed with central nervous system atypical teratoid rhabdoid tumors. Pediatr Blood Cancer 51 (2): 235-40, 2008. [PUBMED Abstract]
Finkelstein-Shechter T, Gassas A, Mabbott D, et al.: Atypical teratoid or rhabdoid tumors: improved outcome with high-dose chemotherapy. J Pediatr Hematol Oncol 32 (5): e182-6, 2010. [PUBMED Abstract]
Chi SN, Zimmerman MA, Yao X, et al.: Intensive multimodality treatment for children with newly diagnosed CNS atypical teratoid rhabdoid tumor. J Clin Oncol 27 (3): 385-9, 2009. [PUBMED Abstract]
Reddy AT, Strother DR, Judkins AR, et al.: Efficacy of High-Dose Chemotherapy and Three-Dimensional Conformal Radiation for Atypical Teratoid/Rhabdoid Tumor: A Report From the Children’s Oncology Group Trial ACNS0333. J Clin Oncol 38 (11): 1175-1185, 2020. [PUBMED Abstract]
Zaky W, Dhall G, Ji L, et al.: Intensive induction chemotherapy followed by myeloablative chemotherapy with autologous hematopoietic progenitor cell rescue for young children newly-diagnosed with central nervous system atypical teratoid/rhabdoid tumors: the Head Start III experience. Pediatr Blood Cancer 61 (1): 95-101, 2014. [PUBMED Abstract]
Aridgides PD, Mahajan A, Eaton B, et al.: Focal versus craniospinal radiation for disseminated atypical teratoid/rhabdoid tumor following favorable response to systemic therapy. Pediatr Blood Cancer 70 (7): e30351, 2023. [PUBMED Abstract]
Frisch S, Libuschewski H, Peters S, et al.: Radiation Therapy Plays an Important Role in the Treatment of Atypical Teratoid/Rhabdoid Tumors: Analysis of the EU-RHAB Cohorts and Their Precursors. Int J Radiat Oncol Biol Phys 119 (4): 1147-1157, 2024. [PUBMED Abstract]
Tekautz TM, Fuller CE, Blaney S, et al.: Atypical teratoid/rhabdoid tumors (ATRT): improved survival in children 3 years of age and older with radiation therapy and high-dose alkylator-based chemotherapy. J Clin Oncol 23 (7): 1491-9, 2005. [PUBMED Abstract]
Buscariollo DL, Park HS, Roberts KB, et al.: Survival outcomes in atypical teratoid rhabdoid tumor for patients undergoing radiotherapy in a Surveillance, Epidemiology, and End Results analysis. Cancer 118 (17): 4212-9, 2012. [PUBMED Abstract]
Bartelheim K, Nemes K, Seeringer A, et al.: Improved 6-year overall survival in AT/RT – results of the registry study Rhabdoid 2007. Cancer Med 5 (8): 1765-75, 2016. [PUBMED Abstract]
Frühwald MC, Hasselblatt M, Nemes K, et al.: Age and DNA methylation subgroup as potential independent risk factors for treatment stratification in children with atypical teratoid/rhabdoid tumors. Neuro Oncol 22 (7): 1006-1017, 2020. [PUBMED Abstract]
Olson TA, Bayar E, Kosnik E, et al.: Successful treatment of disseminated central nervous system malignant rhabdoid tumor. J Pediatr Hematol Oncol 17 (1): 71-5, 1995. [PUBMED Abstract]
Zimmerman MA, Goumnerova LC, Proctor M, et al.: Continuous remission of newly diagnosed and relapsed central nervous system atypical teratoid/rhabdoid tumor. J Neurooncol 72 (1): 77-84, 2005. [PUBMED Abstract]
Treatment of Recurrent Childhood CNS Atypical Teratoid/Rhabdoid Tumor
There is no standard treatment for children with recurrent central nervous system (CNS) atypical teratoid/rhabdoid tumor (AT/RT), and their outcomes are poor.[1]
Trials of molecularly targeted therapy are ongoing. In a study of the EZH2 inhibitor tazemetostat in adult patients with epithelioid sarcoma and non-CNS malignant rhabdoid tumors with SMARCB1 or SMARCA4 loss, prolonged stable disease and objective responses were observed.[2] In the National Cancer Institute (NCI)–Children’s Oncology Group Pediatric MATCH APEC1621C (NCT03213665) trial, eight children with AT/RT received tazemetostat. One patient demonstrated disease stabilization.[3][Level of evidence B4]
Patients or families who desire additional disease-directed therapy should consider entering trials of novel therapeutic approaches because no standard agents have demonstrated clinically significant activity.
Regardless of whether a decision is made to pursue disease-directed therapy at the time of progression, palliative care remains a central focus of management. This ensures that quality of life is maximized while attempting to reduce symptoms and stress related to the terminal illness.
Treatment Options Under Clinical Evaluation
Early-phase therapeutic trials may be available for selected patients. These trials may be available via the Children’s Oncology Group (COG), the Pediatric Brain Tumor Consortium, or other entities. Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
PEPN2121 (NCT05286801) (Tiragolumab and Atezolizumab for the Treatment of Relapsed or Refractory SMARCB1– or SMARCA4-Deficient Tumors): This study is evaluating the combination of a PD-L1 targeting antibody (atezolizumab) with a TIGIT targeting antibody (tiragolumab) for patients with SMARCB1– or SMARCA4-deficient tumors. Patients with AT/RT may be eligible for this study.
References
Carey SS, Huang J, Myers JR, et al.: Outcomes for children with recurrent/refractory atypical teratoid rhabdoid tumor: A single-institution study with molecular correlation. Pediatr Blood Cancer 71 (10): e31208, 2024. [PUBMED Abstract]
Italiano A, Soria JC, Toulmonde M, et al.: Tazemetostat, an EZH2 inhibitor, in relapsed or refractory B-cell non-Hodgkin lymphoma and advanced solid tumours: a first-in-human, open-label, phase 1 study. Lancet Oncol 19 (5): 649-659, 2018. [PUBMED Abstract]
Chi SN, Yi JS, Williams PM, et al.: Tazemetostat for tumors harboring SMARCB1/SMARCA4 or EZH2 alterations: results from NCI-COG pediatric MATCH APEC1621C. J Natl Cancer Inst 115 (11): 1355-1363, 2023. [PUBMED Abstract]
Spina A, Gagliardi F, Boari N, et al.: Does Stereotactic Radiosurgery Positively Impact the Local Control of Atypical Teratoid Rhabdoid Tumors? World Neurosurg 104: 612-618, 2017. [PUBMED Abstract]
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
Latest Updates to This Summary (03/03/2025)
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.
About This PDQ Summary
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood central nervous system atypical teratoid and rhabdoid tumor. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
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be cited with text, or
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Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Childhood Central Nervous System Atypical Teratoid/Rhabdoid Tumor Treatment are:
Kenneth J. Cohen, MD, MBA (Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital)
Karen J. Marcus, MD, FACR (Dana-Farber of Boston Children’s Cancer Center and Blood Disorders Harvard Medical School)
Roger J. Packer, MD (Children’s National Hospital)
Malcolm A. Smith, MD, PhD (National Cancer Institute)
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Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
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The preferred citation for this PDQ summary is:
PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Central Nervous System Atypical Teratoid/Rhabdoid Tumor Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/brain/hp/child-cns-atrt-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389426]
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World Health Organization (WHO) Classification for CNS Embryonal Tumors and Pineoblastoma
Embryonal tumors are a collection of biologically heterogeneous lesions that share the tendency to disseminate throughout the nervous system via cerebrospinal fluid (CSF) pathways. Although there is significant variability, histologically these tumors are grouped together because they are at least partially composed of hyperchromatic cells (blue cell tumors on standard staining) with little cytoplasm, which are densely packed and demonstrate a high degree of mitotic activity. Other histological and immunohistochemical features, such as the degree of apparent cellular transformation along identifiable cell lineages (e.g., ependymal or glial), can be used to separate these tumors to some degree. However, a convention, which has been accepted by the WHO, also separates these tumors based on presumed location of origin within the CNS. Molecular studies have substantiated the differences between tumors arising in different areas of the brain and give partial credence to this classification approach.[1]
In 2016, the WHO proposed an integrated phenotypic and genotypic classification system for CNS tumors in which diagnoses are layered with WHO grade, histological classification, and molecular classification.[2] The term primitive neuroectodermal tumor (PNET) has been removed from the WHO diagnostic lexicon, although some rare entities (e.g., medulloepithelioma) have remained. A molecularly distinct entity, embryonal tumor with multilayered rosettes (ETMR), C19MC-altered, was added, encompassing embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma, and medulloepithelioma. The WHO classification will be updated as other molecularly distinct entities are defined.
The pathological diagnosis of embryonal tumors is based primarily on histological and immunohistological microscopic features. However, molecular genetic studies are employed increasingly to subclassify embryonal tumors. These molecular genetic findings are also being used for risk stratification and treatment planning.[3–6]
The 2021 WHO classification of embryonal tumors is as follows:[7,8]
Medulloblastoma, SHH-activated and TP53-wild type.
Medulloblastoma, SHH-activated and TP53-altered.
Medulloblastoma, non-WNT/non-SHH.
Medulloblastomas, histologically defined.
Desmoplastic nodular medulloblastoma.
Medulloblastoma with extensive nodularity.
Large cell medulloblastoma.
Anaplastic medulloblastoma.
Other CNS embryonal tumors.
Atypical teratoid/rhabdoid tumor.
Cribriform neuroepithelial tumor.
Embryonal tumor with multilayered rosettes.
CNS neuroblastoma, FOXR2-activated.
CNS tumor with BCOR internal tandem duplication.
CNS embryonal tumor NEC/NOS.
Pineoblastoma was previously conventionally grouped with embryonal tumors. However, it is now categorized by the WHO as a pineal parenchymal tumor. The 2021 WHO classification of these tumors is as follows:[7,8]
Pineocytoma.
Pineal parenchymal tumor of intermediate differentiation.
Pineoblastoma.
Papillary tumor of the pineal region.
Desmoplastic myxoid tumor of the pineal region, SMARCB1-altered.
Given that therapies for pineoblastomas are quite similar to those for embryonal tumors, pineoblastomas are discussed in this summary. A somewhat closely aligned tumor, pineal parenchymal tumor of intermediate differentiation (PPTID), has been identified but is not considered an embryonal tumor and primarily arises in adults.[2]
Anatomy
EnlargeFigure 1. Anatomy of the inside of the brain, showing the pineal and pituitary glands, optic nerve, ventricles (with cerebrospinal fluid shown in blue), and other parts of the brain. The posterior fossa is the region below the tentorium, which separates the cortex from the cerebellum and essentially denotes the region containing the brain stem, cerebellum, and fourth ventricle.
Incidence
Embryonal tumors account for approximately 20% of primary CNS tumors (malignant CNS neoplasms and pilocytic astrocytomas) arising in children. These tumors occur along the pediatric age spectrum but tend to cluster early in life. The incidence of embryonal tumors in children aged 1 to 9 years is fivefold to tenfold higher than in adults (see Table 1).[9,10]
Table 1. Annual Incidence Rates for Childhood Central Nervous System Embryonal Tumors According to Agea
Medulloblastomas comprise the vast majority of pediatric embryonal tumors. By definition, they arise in the posterior fossa (see Figure 1), where they constitute approximately 40% of all posterior fossa tumors. Other forms of embryonal tumors each make up 2% or less of all childhood brain tumors.
Diagnostic and Staging Evaluation
Imaging studies and CSF analysis are included in the diagnostic and staging evaluation.
Imaging studies
Diagnosis is usually made by either magnetic resonance imaging (MRI) or computed tomography (CT) scan. MRI is preferable because the anatomical relationship between the tumor and surrounding brain and tumor dissemination is better visualized with this method.[11,12]
After diagnosis, evaluation of embryonal tumors is quite similar, essentially independent of the histological subtype and the location of the tumor. Given the tendency of these tumors to disseminate throughout the CNS early in the course of illness, imaging evaluation of the neuraxis by MRI of the entire brain and spine is indicated. Preferably, this is done before surgery to avoid postoperative artifacts, especially blood. Such imaging can be difficult to interpret and must be performed in at least two planes, with and without the use of contrast enhancement (gadolinium).[13] A study of the significance of equivocal findings on spinal MRIs in children with medulloblastoma identified equivocal findings in 48 of 100 patients (48%). The study reported the following results:[14]
Analysis by subgroup identified a higher proportion of equivocal findings in the SHH subgroup (P = .007).
The 5-year overall survival (OS) rate in children with equivocal MRI findings (80%) was not different from the 5-year OS in patients who had normal MRI findings (84.8%), while OS in patients with M3 metastases was worse (54.7%) (P = .02).
In contrast, a Children’s Oncology Group (COG) prospective study treated over 400 children without metastatic disease with a reduced dose (23.4 Gy) of craniospinal radiation therapy. Nearly 20% of patients with central neuroradiographic review were found to have either evidence of possible excessive residual disease and/or metastatic disease or were considered to have imaging inadequate to fully evaluate the neuroaxis. For patients with centrally reviewed imaging, children considered to have metastatic disease had poor OS compared with those with nondisseminated disease. The subgroup found to have inadequate imaging by central review had an intermediate survival rate between the children with adequate imaging and those who had metastatic disease.[13] In a subsequent prospective COG study that treated over 500 children with reduced-dose craniospinal radiation therapy (23.4 Gy or 18 Gy), patients with inadequate imaging had poorer survival.[15] Consensus guidelines for timing and neuroimaging techniques have been recommended and include details that outline standards for preoperative assessment of the entire neuroaxis and postoperative assessment of the amount of residual disease.[16]
After surgery, imaging of the primary tumor site is indicated to determine the extent of residual disease.
CSF analysis
After surgery, lumbar CSF analysis is performed, if deemed safe. Neuroimaging and CSF evaluation are considered complementary because as many as 10% of patients have evidence of free-floating tumor cells in the CSF without clear evidence of leptomeningeal disease on MRI scan.[17]
CSF analysis is conventionally done 14 to 21 days after surgery. If CSF is obtained within 14 days of the operation, detection of tumor cells within the spinal fluid is possibly related to the surgical procedure. In most staging systems, if fluid is obtained in the first few days after surgery and found to be positive for tumor cells, the positivity must be confirmed by a subsequent spinal tap to be considered diagnostically significant. In contrast, if CSF is negative for tumor cells at that time, then no confirmation is needed. When obtaining fluid by lumbar spinal tap is deemed unsafe, ventricular fluid can be obtained. However, this method may not be as sensitive as lumbar fluid assessment.[17]
Because embryonal tumors are very rarely metastatic to the bone, bone marrow, or other body sites at the time of diagnosis, studies such as bone marrow aspirates, chest x-rays, or bone scans are not indicated, unless there are symptoms or signs suggesting organ involvement.
Prognostic Factors
Various clinical and biological parameters have been associated with the likelihood of disease control of embryonal tumors after treatment.[4] Many of these factors have been shown to be predictive for medulloblastomas, although some are used to assign risk, to some degree, for other embryonal tumors. Parameters that are most frequently used to predict outcome include the following:[18,19]
It has become increasingly clear, especially for medulloblastomas, that outcome is also related to the molecular characteristics of the tumor, but this has not been definitively shown for other embryonal tumors.[1,5,6,20–23] OS rates range from 30% to 90%, depending on the molecular subtype of the medulloblastoma, extent of dissemination at time of diagnosis, and possibly other factors, such as the degree of resection. Children with medulloblastoma who survive for 5 years are considered cured of their tumor. Survival rates for other embryonal tumors are generally poorer, ranging from less than 5% to 50%. Specific survival rates are discussed within each subgroup in the summary.[24–27]
In older studies, the presence of brain stem involvement in children with medulloblastoma was found to be a prognostic factor. It has not been found to be of predictive value in subsequent studies that treated patients with both radiation and chemotherapy.[13,18]
An accurate diagnosis is critical for patients with embryonal tumors. For example, in the ACNS0332 (NCT00392327) trial that enrolled 80 patients with high-risk medulloblastoma, supratentorial CNS-PNET tumors, and pineoblastoma, 60 patients had sufficient tissue for evaluation. Thirty-one tumors were nonpineal in location, 22 (71%) of which represented tumors that were not intended for trial inclusion, including 18 high-grade gliomas, 2 atypical teratoid/rhabdoid tumors, and 2 ependymomas. Outcomes across tumor types were strikingly different. Patients with supratentorial embryonal tumors/pineoblastomas exhibited a 5-year event-free survival (EFS) rate of 62.8% (95% confidence interval [CI], 43.4%–82.2%) and an OS rate of 78.5% (95% CI, 62.2%–94.8%), whereas patients with molecularly classified high-grade gliomas had a 5-year EFS rate of 5.6% (95% CI, 0%–13%) and an OS rate of 12% (95% CI, 0%–24.7%). Survival rates for patients with high-grade gliomas were similar to those of patients who were enrolled in historical studies that avoided craniospinal irradiation and intensive chemotherapy. Thus, for patients with CNS-PNET/pineoblastoma, prognosis is considerably better than previously assumed when molecularly confirmed high-grade gliomas are removed.[28]
Prognosis is poor for patients with medulloepithelioma and ETMR, with 5-year survival rates ranging between 0% and 30%.[29–31] In a retrospective multivariate analysis of 38 patients, total or near-total resection, the use of radiation therapy, and the use of high-dose chemotherapy were associated with an improved prognosis.[32][Level of evidence C1] Another retrospective analysis included 159 patients with confirmed molecular diagnoses of primary ETMRs from the Rare Brain Tumor Registry (median age at diagnosis, 26 months; IQR, 18–36 months). The study revealed an EFS rate of 57% (95% CI, 47%–68%) at 6 months and 31% (95% CI, 21%–42%) at 2 years. The OS rate was 29% (95% CI, 20%–38%) at 2 years and 27% (95% CI, 18%–37%) at 4 years. OS was associated with nonmetastatic disease (hazard ratio [HR], 0.48; 95% CI, 0.28–0.80; P = .0057) and nonbrainstem location (HR, 0.42; 95% CI, 0.22–0.81; P = .013) on univariate analysis, as well as with gross-total resection (HR, 0.30; 95% CI, 0.16–0.58; P = .0014), use of high-dose chemotherapy (HR, 0.35; 95% CI, 0.19–0.67; P = .0020), and use of radiation therapy (HR, 0.21; 95% CI, 0.10–0.41; P < .0001) on multivariable analysis.[33][Level of evidence C1]
Extent of CNS disease at diagnosis
Patients with disseminated CNS disease at diagnosis are at highest risk of disease relapse.[17–19] Ten percent to 40% of patients with medulloblastoma have CNS dissemination at diagnosis. Infants have the highest incidence and adolescents and adults have the lowest incidence of CNS dissemination.
Nonmedulloblastoma embryonal tumors and pineoblastomas may also be disseminated at the time of diagnosis, although the incidence may be somewhat less than for medulloblastomas, with dissemination at diagnosis in approximately 10% to 20% of patients.[24,25] Patients with nonmedulloblastoma embryonal tumors and pineoblastomas who have disseminated disease at the time of diagnosis have a poor OS, with reported survival rates at 5 years ranging from 10% to 30%.[24–27,34]
Age at diagnosis
Age younger than 3 years at diagnosis portends an unfavorable outcome for those with medulloblastoma and, possibly, other embryonal tumors.[35–40] The exception is for those diagnosed with desmoplastic medulloblastoma/medulloblastoma with extensive nodularity (MBEN).
Amount of residual disease after definitive surgery
As a predictor of outcome, postoperative MRI measurement of the amount of residual disease after definitive surgery has been supplanted by extent of resection after surgery.[13]
In older studies, the extent of resection for medulloblastomas was found to be related to survival.[18,19,41,42] A Hirntumor and International Society of Paediatric Oncology study of 340 children reported that residual disease (>1.5 cm2) connoted a poorer 5-year EFS rate.[43] Extent of resection after surgery is still used to separate patients into risk groups, with patients having more than 1.5 cm2 of residual disease stratified into high-risk groups, with intensification of craniospinal irradiation to 36 Gy.
An international, retrospective, collaborative study included 787 patients of all ages with medulloblastoma who were treated in a variety of ways. The study incorporated molecular subgrouping and clinical factors in the analysis. The multivariate analysis found that subtotal resection (>1.5 cm2 residual), but not near-total resection (<1.5 cm2 residual), was associated with inferior progression-free survival compared with gross-total resection. This study suggested that attempts to completely remove the tumor, especially when the likelihood of neurological morbidity is high, are not warranted because there appears to be little or no benefit to gross-total resection when compared with near-total resection. It gives some credence to the present approach, in which patients with more than 1.5 cm2 of disease are considered higher-risk patients.[44] In a retrospective analysis of 1,100 patients with molecularly characterized medulloblastoma, subtotal resection was associated with worse survival in univariable analysis (P < .0001). However, subtotal resection was not independently prognostic in multivariable analyses and not prognostic in patients who did not have metastatic disease and received up-front craniospinal irradiation.[45] Prospective studies are needed to better define the impact of extent of resection on outcome within molecularly defined subgroups.
In patients with other forms of embryonal tumors, the extent of resection has not been definitively shown to impact survival.[26] However, in a COG study of 66 children with supratentorial embryonal tumors, extent of resection was found to be prognostic for those with localized disease at the time of diagnosis.[46]
Tumor histopathology
For medulloblastomas, histopathological features such as large cell variant, anaplasia, and desmoplasia have been shown in retrospective analyses to correlate with outcome.[36,47,48] In prospective studies, immunohistochemical and histopathological findings have not predicted outcome in children older than 3 years at diagnosis, with the exception of the large cell/anaplastic variant, which has been associated with poorer prognosis.[13,22,49] Several studies have observed that the histological finding of desmoplasia, seen in patients aged 3 years and younger with desmoplastic medulloblastoma, especially MBEN, connotes a significantly better prognosis compared with outcomes for infants and young children with classic or large cell/anaplastic medulloblastoma.[22,35–37,50]; [38][Level of evidence B4] Within the SHH group with TP53 variants, both somatic and constitutional (called Li-Fraumeni syndrome) TP53 variants may occur. Both of these variants connote a poor prognosis, compared with other SHH pathway–activated tumors.[23]
For other embryonal tumors, histological variations have not been associated with differing outcomes.
Biological/molecular tumor cell characteristics
Measure of minimal residual disease
In one study, CSF copy number variations, similar to those found in the primary tumors, were prognostic of relapse when present after radiation therapy or during or after chemotherapy. If this finding is replicated in prospective clinical trials and the technique becomes available, it will be an important measure of minimal residual disease and likely will become part of the baseline evaluation, as well as part of surveillance testing.[51]
Genomic analyses
For medulloblastoma, genomic analyses (including RNA gene expression and DNA methylation profiles, as well as DNA sequencing to identify variants) on both fresh-frozen and formalin-fixed, paraffin-embedded sections, have identified molecular subtypes.[3–6,20,21,52–59] These subtypes include those characterized by WNT pathway activation and SHH pathway activation, as well as additional subgroups characterized by MYC or MYCN alterations and other genomic alterations.[3–6,20,21,52–58] Children with medulloblastoma whose tumors show WNT pathway activation usually have an excellent prognosis. Within the non-WNT, non-SHH medulloblastoma group, there are subsets of patients with differing prognoses. For example, patients with chromosome 11 loss have an excellent prognosis, similar to those with WNT tumors.[15,60,61] Patients with SHH pathway–activated tumors have a prognosis that is influenced by the presence or absence of TP53 variants (favorable vs. unfavorable prognosis, respectively).[61] The outcome for the remaining patients is less favorable than for patients with WNT pathway activation. Variants in medulloblastoma are observed in a subtype-specific manner. CTNNB1 variants are observed in most WNT-subtype tumors. PTCH1, SMO, and SUFU variants are observed in the SHH-subtype tumors. The prognostic significance of recurring variants is closely aligned with that of the molecular subtype with which they are associated.[4,62] At recurrence, the subtype remains unchanged from the original molecular subtype at diagnosis.[63]
For nonmedulloblastoma embryonal tumors, integrative genomic analysis has also identified molecular subtypes with different outcomes. For more detailed information, see the Subtypes of nonmedulloblastoma embryonal tumors section.
Follow-Up After Treatment
Relapse in children with embryonal tumors is most likely to occur within the first 18 months of diagnosis.[43,64] Surveillance imaging of the brain and spine is usually undertaken at routine intervals during and after treatment (see Table 2). The frequency of such imaging, designed to detect recurrent disease at an early, asymptomatic state, has been arbitrarily determined and has not been shown to clearly influence survival.[65–68] Growth hormone replacement therapy has not been shown to increase the likelihood of disease relapse and should not impact the frequency of surveillance testing.[37]
Table 2. Surveillance Testing During and After Treatment for Medulloblastoma and Other Central Nervous System Embryonal Tumors
Surveillance Period
Frequency of Visits During Surveillance Period
Testing
MRI = magnetic resonance imaging.
aFor pineoblastoma, continue spinal evaluations every 6 months until 5 years from diagnosis. Although these suggestions are based on a small sample size, there is evidence for continuing surveillance testing of the spine until 5 years after diagnosis.[69]
First 3 years after diagnosis
Every 3 months
Physical examination
Imaging of the brain every 3 months for the first 3 years, then every 6 months for the ensuing 2 years, and then as per preference of the treating physician or per protocol; MRI of the spine every 3 months for the first 2 years, then every 6 months for 1 year, and then as per preference of the treating physician or per protocola
Endocrinology evaluation once a year
Neuropsychological testing every 1–2 years
3–5 years after diagnosis
Every 6 months
Physical examination
Imaging of the brain and spine once a year
Endocrinology evaluation once a year
Neuropsychological testing every 1–2 years
More than 5 years after diagnosis
Once a year
Physical examination
Imaging of the brain once a year
Endocrinology evaluation once a year
Neuropsychological testing every 1–2 years (optional)
The development of surveillance strategies other than imaging for patients with medulloblastoma is the subject of ongoing research. In one study of 134 children with newly diagnosed medulloblastoma, copy number variants were detected at baseline in 123 patients (92%) by primary tumor testing and in 65 patients (49%) by CSF testing. Copy number variants were detected more frequently in the CSF of patients with disseminated disease and in those with subsequent progression. Prospective studies will be necessary to evaluate the potential for CSF copy number analysis to become a component of surveillance testing, as a measure of medulloblastoma minimal residual disease and early relapse.[51]
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.
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von Bueren AO, von Hoff K, Pietsch T, et al.: Treatment of young children with localized medulloblastoma by chemotherapy alone: results of the prospective, multicenter trial HIT 2000 confirming the prognostic impact of histology. Neuro Oncol 13 (6): 669-79, 2011. [PUBMED Abstract]
Rutkowski S, Gerber NU, von Hoff K, et al.: Treatment of early childhood medulloblastoma by postoperative chemotherapy and deferred radiotherapy. Neuro Oncol 11 (2): 201-10, 2009. [PUBMED Abstract]
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Mynarek M, Pizer B, Dufour C, et al.: Evaluation of age-dependent treatment strategies for children and young adults with pineoblastoma: analysis of pooled European Society for Paediatric Oncology (SIOP-E) and US Head Start data. Neuro Oncol 19 (4): 576-585, 2017. [PUBMED Abstract]
Albright AL, Wisoff JH, Zeltzer PM, et al.: Effects of medulloblastoma resections on outcome in children: a report from the Children’s Cancer Group. Neurosurgery 38 (2): 265-71, 1996. [PUBMED Abstract]
Taylor RE, Bailey CC, Robinson K, et al.: Results of a randomized study of preradiation chemotherapy versus radiotherapy alone for nonmetastatic medulloblastoma: The International Society of Paediatric Oncology/United Kingdom Children’s Cancer Study Group PNET-3 Study. J Clin Oncol 21 (8): 1581-91, 2003. [PUBMED Abstract]
Lannering B, Rutkowski S, Doz F, et al.: Hyperfractionated versus conventional radiotherapy followed by chemotherapy in standard-risk medulloblastoma: results from the randomized multicenter HIT-SIOP PNET 4 trial. J Clin Oncol 30 (26): 3187-93, 2012. [PUBMED Abstract]
Thompson EM, Hielscher T, Bouffet E, et al.: Prognostic value of medulloblastoma extent of resection after accounting for molecular subgroup: a retrospective integrated clinical and molecular analysis. Lancet Oncol 17 (4): 484-95, 2016. [PUBMED Abstract]
Keeling C, Davies S, Goddard J, et al.: The clinical significance of sub-total surgical resection in childhood medulloblastoma: a multi-cohort analysis of 1100 patients. EClinicalMedicine 69: 102469, 2024. [PUBMED Abstract]
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McManamy CS, Lamont JM, Taylor RE, et al.: Morphophenotypic variation predicts clinical behavior in childhood non-desmoplastic medulloblastomas. J Neuropathol Exp Neurol 62 (6): 627-32, 2003. [PUBMED Abstract]
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Garrè ML, Cama A, Bagnasco F, et al.: Medulloblastoma variants: age-dependent occurrence and relation to Gorlin syndrome–a new clinical perspective. Clin Cancer Res 15 (7): 2463-71, 2009. [PUBMED Abstract]
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Giangaspero F, Wellek S, Masuoka J, et al.: Stratification of medulloblastoma on the basis of histopathological grading. Acta Neuropathol 112 (1): 5-12, 2006. [PUBMED Abstract]
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Kool M, Korshunov A, Remke M, et al.: Molecular subgroups of medulloblastoma: an international meta-analysis of transcriptome, genetic aberrations, and clinical data of WNT, SHH, Group 3, and Group 4 medulloblastomas. Acta Neuropathol 123 (4): 473-84, 2012. [PUBMED Abstract]
Schwalbe EC, Williamson D, Lindsey JC, et al.: DNA methylation profiling of medulloblastoma allows robust subclassification and improved outcome prediction using formalin-fixed biopsies. Acta Neuropathol 125 (3): 359-71, 2013. [PUBMED Abstract]
Shih DJ, Northcott PA, Remke M, et al.: Cytogenetic prognostication within medulloblastoma subgroups. J Clin Oncol 32 (9): 886-96, 2014. [PUBMED Abstract]
Goschzik T, Schwalbe EC, Hicks D, et al.: Prognostic effect of whole chromosomal aberration signatures in standard-risk, non-WNT/non-SHH medulloblastoma: a retrospective, molecular analysis of the HIT-SIOP PNET 4 trial. Lancet Oncol 19 (12): 1602-1616, 2018. [PUBMED Abstract]
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Childhood Medulloblastoma
Hereditary Cancer Predisposition Syndromes Associated With Medulloblastoma
Increasingly, subsets of children with brain tumors, including medulloblastoma, have been found to have germline pathogenic or likely pathogenic variants, predisposing them to the development of medulloblastoma and other cancers.[1,2] These variants have obvious implications for the affected child, siblings, parents, and, potentially, other family members in regard to cancer surveillance, prevention, diagnosis, and management. The variants may also affect specific tumor treatment.
Medulloblastoma can arise in the setting of hereditary cancer predisposition syndromes in approximately 5% of patients.[1,2] A large study of over 1,000 patients demonstrated germline pathogenic variants in approximately 5% of all patients diagnosed with medulloblastoma. Germline pathogenic variants were identified in APC, BRCA2, PALB2, PTCH1, SUFU, and TP53.[2]
Syndromes known to be associated with medulloblastoma include the following:
Turcot syndrome (related to germline pathogenic variants in APC),[3] exclusive to the WNT-activated subtype.[2]
Rubinstein-Taybi syndrome (related to germline pathogenic variants in CREBBP).[4–6]
Gorlin syndrome (also known as basal cell nevus syndrome or nevoid basal cell carcinoma syndrome, associated with germline PTCH1 and SUFU pathogenic variants).[7–11] The risk of developing medulloblastoma in patients with Gorlin syndrome appears to be higher in those with germline SUFU variants than in those with PTCH1 pathogenic variants. In one study, 2 of 115 individuals (1.7%) with Gorlin syndrome and a PTCH1 variant developed a pathology-proven medulloblastoma, compared with 3 of 9 individuals (33%) from three families with SUFU-related Gorlin syndrome. Each of the SUFU-related patients developed medulloblastoma before age 3 years.[11]
Li-Fraumeni syndrome is related to germline pathogenic variants in TP53.[12,13] Germline TP53 pathogenic variants are restricted to the sonic hedgehog (SHH)–activated subtype.[2,14]
Fanconi anemia (related to BRCA2 variants).[15–18]
Heterozygous deleterious germline pathogenic variants in GPR161 were identified in approximately 3% of cases of SHH medulloblastoma.[19] GPR161 is an inhibitor of SHH signaling. The median age at diagnosis for patients with GPR161 variants was 1.5 years. Loss of heterozygosity (LOH) at the GPR161 locus was noted in all tumors, with tumors from five of six patients showing copy-neutral LOH of chromosome 1q (on which GPR161 resides). The risk of nonmedulloblastoma cancers in patients with deleterious GPR161 variants is not defined.
Novel germline loss-of-function pathogenic variants in the largest subunit of the evolutionarily conserved Elongator complex, ELP1, were identified in 14% of pediatric patients with SHH medulloblastoma. ELP1 was the most common medulloblastoma predisposition gene, and it increased the prevalence of genetic predisposition to 40% among pediatric patients with SHH medulloblastoma.[20]
Sometimes medulloblastoma may be the initial manifestation of germline pathogenic variants in these predisposition genes. Germline testing should be considered in the following circumstances:
APC variant testing in patients with WNT-activated medulloblastoma in the absence of a somatic CTNNB1 variant.
SUFU, PTCH1, TP53, PALB2, and BRCA2 variant testing in patients with SHH-activated medulloblastoma. Patients with desmoplastic tumors with extensive nodularity should be carefully evaluated for stigmata of Gorlin syndrome.[7] One report observed that medulloblastoma with extensive nodularity (MBEN) was associated with Gorlin syndrome in 5 of 12 cases.[7] Gorlin syndrome is an autosomal dominant disorder in which those affected are predisposed to develop basal cell carcinomas later in life, especially in skin in the radiation portal. The syndrome can be diagnosed early in life by detection of characteristic dermatological and skeletal features such as keratocysts of the jaw, bifid or fused ribs, macrocephaly, and calcifications of the falx.[7]
PALB2 and BRCA2 variant testing in patients with a family history of BRCA-associated cancers or homologous recombination repair deficiency.
Given the high frequency of underlying germline pathogenic or likely pathogenic variants associated with SHH medulloblastoma, all patients with this disease should be referred for genetic counseling.
Clinical Presentation
By definition, medulloblastomas arise in the posterior fossa.[21,22] In approximately 80% of children, medulloblastomas arise in the region of the fourth ventricle. Most of the early symptomatology is related to blockage of cerebrospinal fluid (CSF) and resultant accumulation of CSF in the brain, termed hydrocephalus. Children with medulloblastoma are usually diagnosed within 2 to 3 months of the onset of symptoms. Medulloblastoma commonly presents with the following signs and symptoms:[23]
Relatively abrupt onset of headaches, especially in the morning on waking.
Nausea and/or vomiting.
Lethargy.
Ataxia, including truncal unsteadiness.
Some degree of nystagmus.
Papilledema.
Twenty percent of patients with medulloblastoma will not have hydrocephalus at the time of diagnosis and are more likely to present initially with cerebellar deficits. For example, more laterally positioned medulloblastomas of the cerebellum may not result in hydrocephalus and, because of their location, are more likely to result in lateralizing cerebellar dysfunction (appendicular ataxia) manifested by unilateral dysmetria, unsteadiness, and weakness of the sixth and seventh nerves on the same side as the tumor. Later, as the tumor grows toward the midline and blocks CSF, the more classical symptoms associated with hydrocephalus become evident.
Cranial nerve findings are less common, except for unilateral or bilateral sixth nerve palsies, which are usually related to hydrocephalus.[23] At times, medulloblastomas will present explosively, with the acute onset of lethargy and unconsciousness resulting from hemorrhage within the tumor.
In infants, the presentation of medulloblastoma is more variable and may include the following:
Nonspecific lethargy.
Psychomotor delays.
Loss of developmental milestones.
Feeding difficulties.
Increase in head circumference.
On examination, there may be bulging of the anterior fontanel due to increased intracranial pressure and abnormal eye movements, including eyes that are deviated downward (the so-called sun setting sign) because of loss of upgaze secondary to compression of the tectum of the midbrain.
Cellular and Molecular Classification
In the 2021 World Health Organization (WHO) classification, medulloblastoma is classified based on both histological and molecular features. The tumor is classified as medulloblastoma, histologically defined if no molecular testing has been performed.[22,24]
Medulloblastoma.
Medulloblastoma, molecularly defined.
Medulloblastoma, WNT-activated.
Medulloblastoma, SHH-activated and TP53-wild type.
Medulloblastoma, SHH-activated and TP53-altered.
Medulloblastoma, non-WNT/non-SHH.
Medulloblastoma, histologically defined.
Desmoplastic nodular medulloblastoma.
Medulloblastoma with extensive nodularity.
Large cell medulloblastoma.
Anaplastic medulloblastoma.
Significant attention has been focused on medulloblastomas that display anaplastic features, including increased nuclear size, marked cytological pleomorphism, numerous mitoses, and apoptotic bodies.[25,26] Using the criteria of anaplasia is subjective because most medulloblastomas have some degree of anaplasia. Foci of anaplasia may appear in tumors with histological features of both classic and large cell medulloblastomas, and there is significant overlap between the anaplastic and large cell variants, which are frequently termed large cell/anaplastic medulloblastoma.[25,26] One convention is to consider medulloblastomas as anaplastic when anaplasia is diffuse (variably defined as anaplasia occurring in 50% to 80% of the tumor).
The incidence of medulloblastoma with the desmoplastic/nodular histological variant, which most commonly arises in a cerebellar hemisphere, is higher in infants, is less common in children, and increases again in adolescents and adults. The desmoplastic/nodular histological variant is different from MBEN. The nodular variant has an expanded lobular architecture. The MBEN subtype occurs almost exclusively in infants and generally carries an excellent prognosis.[7,27,28] However, a recent report used transcriptome sequencing to identify a subset of patients with MBENs that had a high frequency of germline pathogenic alterations in PTCH1 or SUFU. These patients had less favorable outcomes.[29]
Molecular subtypes of medulloblastoma
Multiple medulloblastoma subtypes have been identified by integrative molecular analysis.[30–53] Since 2012, the general consensus is that medulloblastoma can be molecularly separated into at least four core subtypes, including WNT-activated, sonic hedgehog (SHH)–activated, group 3, and group 4. In the 2021 World Health Organization (WHO) classification, the SHH subgroup has been divided into two groups based on TP53 status. Group 3 and group 4, which require methylation analysis for reliable separation, have been combined into medulloblastoma, non-WNT/non-SHH. Because the group 3 and group 4 terminology has been used extensively in completed studies and is still in use in ongoing and planned studies, this nomenclature will be maintained throughout the clinical discussion in this summary.[22,24]
Different regions of the same tumor are likely to have other disparate genetic variants, adding to the complexity of devising effective molecularly targeted therapy.[48] However, the major subtypes noted above remain stable across primary and metastatic components.[49,52]
Further subclassification within these subgroups is possible, which will provide even more prognostic information.[50–52]
Medulloblastoma, WNT-activated
WNT tumors are medulloblastomas with aberrations in the WNT signaling pathway and represent approximately 10% of all medulloblastomas.[50] WNT medulloblastomas show a WNT signaling gene expression signature and beta-catenin nuclear staining by immunohistochemistry.[54] They are usually histologically classified as classic medulloblastoma tumors and rarely have a large cell/anaplastic appearance. WNT medulloblastomas generally occur in older patients (median age, 10 years) and are infrequently metastasized at diagnosis. Recent studies have demonstrated the value of methylation profiling in identifying WNT-activated medulloblastomas. These studies included cases that would not be detected using other current testing methods (e.g., beta-catenin immunohistochemistry, CTNNB1 variant analysis, and evaluation for monosomy 6).[55]
CTNNB1 variants are observed in 85% to 90% of WNT medulloblastoma cases, with APC variants detected in many of the cases that lack CTNNB1 variants. Patients with WNT medulloblastoma whose tumors have APC variants often have Turcot syndrome (i.e., germline APC pathogenic variants).[51] In addition to CTNNB1 variants, WNT medulloblastoma tumors show 6q loss (monosomy 6) in 80% to 90% of cases. While monosomy 6 is observed in most medulloblastoma patients younger than 18 years at diagnosis, it appears to be much less common (approximately 25% of cases) in patients older than 18 years.[50,54]
The WNT subset is primarily observed in older children, adolescents, and adults and does not show a male predominance. The subset is believed to have brain stem origin, from the embryonal rhombic lip region.[56] WNT medulloblastomas are associated with a very good outcome in children, especially in individuals whose tumors have beta-catenin nuclear staining and proven 6q loss and/or CTNNB1 variants.[45,57–59] Retrospective studies have suggested that additional TP53 variants and OTX2 copy number gains may be associated with a worse prognosis for patients with WNT medulloblastoma.[60] These latter associations need to be verified in prospective studies.[61]
Medulloblastoma, SHH-activated and TP53-altered and medulloblastoma, SHH-activated and TP53-wild type
SHH tumors are medulloblastomas with aberrations in the SHH pathway and represent approximately 25% of medulloblastoma cases.[50] SHH medulloblastomas are characterized by chromosome 9q deletions; desmoplastic/nodular histology; and variants in SHH pathway genes, including PTCH1, PTCH2, SMO, SUFU, and GLI2.[54]
Heterozygous deleterious germline pathogenic variants in the GPR161 gene were identified in approximately 3% of cases of SHH medulloblastoma.[19] GPR161 is an inhibitor of SHH signaling. Median age at diagnosis for GPR161-altered cases was 1.5 years. Loss of heterozygosity (LOH) at the GPR161 locus was noted in all tumors, with tumors from five of six patients showing copy-neutral LOH of chromosome 1q (on which GPR161 resides).
Variants in the third nucleotide (r.3A>G) of the U1 spliceosomal small nuclear RNAs (snRNAs) are highly specific for SHH medulloblastoma.[62,63] U1 snRNA r.3A>G variants are observed in virtually all cases of SHH medulloblastoma in adults, in approximately one-third of cases in children and adolescents, and are absent in cases in infants.[63] U1 snRNA variants disrupt RNA splicing, leading to inactivation of tumor-suppressor genes (e.g., PTCH1) and activation of oncogenes (e.g., GLI2). The significance of U1 snRNA r.3A>G variants in specific SHH medulloblastoma subtypes is described below.
SHH medulloblastomas show a bimodal age distribution and are observed primarily in children younger than 3 years and in older adolescence/adulthood. The tumors are believed to emanate from the external granular layer of the cerebellum. The heterogeneity in age at presentation maps to distinctive subsets identified by further molecular characterization, as follows:
The subset of medulloblastoma most common in children aged 3 to 16 years, termed SHH-alpha (a provisional subgroup in the 2021 medulloblastoma classification), is TP53 altered and is enriched for MYCN and GLI2 amplifications.[50,52] Amplifications of PTCH1 and SUFU may occur in this subtype and are mutually exclusive with TP53 variants (often germline), while the SMO variant is rare.[14,52,64] U1 snRNA variants occur in approximately 25% of SHH-alpha medulloblastoma cases and are associated with a very poor prognosis.[63]
Two SHH subtypes that occur primarily in children younger than 3 years have been described.[50] One of these subtypes, termed SHH-1 (SHH-beta), is more commonly metastatic, with more frequent focal amplifications.[65] The second of these subtypes, termed SHH-2 (SHH-gamma), is enriched for the medulloblastoma with extensive nodularity (MBEN) histology. SHH pathway variants in children younger than 3 years with medulloblastoma include PTCH1 and SUFU variants.[52] SUFU variants are rarely observed in older children and adults, and they are commonly germline events.[64]
Reports that used DNA methylation arrays have also identified two subtypes of SHH medulloblastoma in young children.[28,65] One of the subtypes contained all of the cases with SMO variants, and it was associated with a favorable prognosis. The other subtype had most of the SUFU variants, and it was associated with a much lower progression-free survival (PFS) rate. PTCH1 variants were present in both subtypes.
A fourth SHH subtype, termed SHH-delta, includes most of the adult cases of SHH medulloblastoma.[50] Virtually all cases of SHH-delta medulloblastoma have the U1 snRNA r.A>3 variant,[63] and approximately 90% of cases have TERT promoter variants.[50] PTCH1 and SMO variants are also observed in adults with SHH medulloblastoma.
The outcome for patients with nonmetastatic SHH medulloblastoma is relatively favorable for children younger than 3 years and for adults.[50] Young children with the MBEN histology have a particularly favorable prognosis.[7,27,66–68] Patients with SHH medulloblastoma at greatest risk of treatment failure are children older than 3 years whose tumors have TP53 variants, often with co-occurring GLI2 or MYCN amplification and large cell/anaplastic histology.[50,64,69]
Patients with unfavorable molecular findings have an unfavorable prognosis, with fewer than 50% of patients surviving after conventional treatment.[46,64,69–72]
The 2021 WHO classification identifies SHH medulloblastoma with a TP53 variant as a distinctive entity (medulloblastoma, SHH-activated and TP53-altered).[22,24] Approximately 25% of SHH-activated medulloblastoma cases have TP53 variants, with a high percentage of these cases also showing a TP53 germline pathogenic variant (9 of 20 in one study). These patients are commonly between the ages of 5 years and 18 years and have a worse outcome (5-year overall survival rate, <30%).[71] The tumors often show large cell anaplastic histology.[71] A larger retrospective study has confirmed the poor prognosis of these patients.[14]
Medulloblastoma, non–WNT/non–SHH-activated
The WHO classification combines group 3 and group 4 medulloblastoma cases into a single entity, partly based on the absence of immediate clinical impact for this distinction. Group 3 represents approximately 25% of medulloblastoma cases, while group 4 represents approximately 40% of medulloblastoma cases.[50,54] Both group 3 and group 4 medulloblastoma patients are predominantly male.[39,52] Group 3 and group 4 medulloblastomas can be further subdivided based on characteristics such as gene expression and DNA methylation profiles, but the optimal approach to their subdivision is not established.[50,51]
Various genomic alterations are observed in group 3 and group 4 medulloblastomas. However, no single alteration occurs in more than 10% to 20% of cases. Genomic alterations include the following:
MYC amplification was the most common distinctive alteration reported for group 3 medulloblastoma, occurring in approximately 15% of cases.[44,51]
The most common distinctive genomic alteration described for group 4 medulloblastoma (observed in approximately 15% of cases) was activation of PRDM6 by enhancer hijacking, resulting from the tandem duplication of the adjacent SNCAIP gene.[51]
Other genomic alterations were observed in both group 3 and group 4 cases, including MYCN amplification and structural variants leading to GFI1 or GFI1B overexpression through enhancer hijacking.
Isochromosome 17q (i17q) is the most common cytogenetic abnormality and is observed in a high percentage of group 4 cases, as well as in group 3 cases, but it is rarely observed in WNT and SHH medulloblastoma.[44,51] Prognosis for group 3 and group 4 patients does not appear to be affected by the presence of i17q.[73]
Group 3 patients with MYC amplification or MYC overexpression have a poor prognosis.[52] Fewer than 50% of these patients survive 5 years after diagnosis.[50] This poor prognosis is especially true in children younger than 4 years at diagnosis.[46] However, patients with group 3 medulloblastoma without MYC amplification who are older than 3 years have a prognosis similar to that of most patients with non-WNT medulloblastoma, with a 5-year PFS rate higher than 70%.[70,73]
Group 4 medulloblastomas occur throughout infancy and childhood and into adulthood. The prognosis for group 4 medulloblastoma patients is similar to that for patients with other non-WNT medulloblastomas. Prognosis may be affected by additional factors such as the presence of metastatic disease, chromosome 11q loss, and chromosome 17p loss.[43,44,50,69] One study found that group 4 patients with either chromosome 11 loss or gain of chromosome 17 were low risk, regardless of metastases. In cases lacking both of these cytogenetic features, metastasis at presentation differentiated between high and intermediate risk.[69]
For group 3 and group 4 standard-risk patients (i.e., without MYC amplification or metastatic disease), the gain or loss of whole chromosomes appears to connote a favorable prognosis. This finding was derived from the data of 91 patients with non-WNT/non-SHH medulloblastoma enrolled in the SIOP-PNET-4 (NCT01351870) clinical trial and was confirmed in an independent group of 70 children with non-WNT/non-SHH medulloblastoma treated between 1990 and 2014.[73] Chromosomal abnormalities include the following:
The gain/loss of one or more whole chromosomes was associated with a 5-year event-free survival (EFS) rate of 93%, compared with 64% for no whole chromosome gains/losses.
The most common whole chromosomal gains/losses are gain of chromosome 7 and loss of chromosomes 8 and 11.
The optimally performing prognosis discriminator was determined to be the occurrence of two or more of the following aberrations: chromosome 7 gain, chromosome 8 loss, and chromosome 11 loss. Approximately 40% of group 3 and group 4 standard-risk patients had two or more of these chromosomal aberrations and had a 5-year EFS rate of 100%, compared with 68% for patients with fewer than two aberrations.
In an independent cohort, the prognostic significance of two or more gains/losses versus zero or one gain/loss of chromosomes 7, 8, and 11 was confirmed (5-year EFS rate, 95% for patients with two or more vs. 59% for patients with one or fewer).
The classification of medulloblastoma into the four major subtypes will likely be altered in the future.[50,51,72,74,75] Further subdivision within subgroups based on molecular characteristics is likely because each of the subgroups is further molecularly dissected, although the studies are nearing consensus as data from multiple independent studies are merged. As an example, using complementary bioinformatics approaches, concordance was analyzed among multiple large, published cohorts, and a more unified subgrouping was described. For children with group 3 and group 4 medulloblastomas, eight distinct subgroups were determined by DNA methylation clustering. Specific subgroups had different prognoses.[43,54,64,76]
It is unknown whether the classification for adults with medulloblastoma has a predictive ability similar to that for children.[44,46] In one study of adult patients with medulloblastoma, MYC oncogene amplifications were rarely observed, and tumors with 6q deletion and WNT activation (as identified by nuclear beta-catenin staining) did not share the excellent prognosis seen in pediatric medulloblastomas. However, another study did confirm an excellent prognosis for WNT-activated tumors in adults.[44,46]
Staging Evaluation
Historically, staging was based on an intraoperative evaluation of both the size and extent of the tumor, coupled with postoperative neuroimaging of the brain and spine and cytological evaluation of CSF (the Chang system). Intraoperative evaluation of the extent of the tumor has been supplanted by neuraxis imaging before diagnosis and postoperative imaging to determine the amount of primary site residual disease. The following tests and procedures are now used for staging:
Magnetic resonance imaging (MRI) of the brain and spine (often done preoperatively).
Postoperative MRI of the brain to determine the amount of residual disease.
M2: Gross nodular seeding in cerebellar-cerebral subarachnoid space and/or lateral or third ventricle.
M3: Gross nodular seeding in spinal subarachnoid space.
M4: Extraneural metastasis.
Postoperative degree of residual disease is designated as:
Gross-total resection/near-total resection: No or minimal (≤1.5 cm2) evidence of residual disease after resection.
Subtotal resection: Residual disease after diagnosis (>1.5 cm2 of measurable residual disease).
Biopsy: No tumor resection; only a sample of tumor tissue is removed.
Since the 1990s, prospective studies have been performed using this staging system to separate patients into average-risk and high-risk medulloblastoma subgroups.[78–80]
The presence of diffuse (>50% of the pathological specimen) histological anaplasia has been added to staging systems. If diffuse anaplasia is found, patients with otherwise average-risk disease are upstaged to high-risk disease.
Risk Stratification
Risk stratification is based on neuroradiographic evaluation for disseminated disease, CSF cytological examination, postoperative neuroimaging evaluation for the amount of residual disease, and patient age. For more information, see the Staging Evaluation section. Patients older than 3 years with medulloblastoma have been stratified into the following two risk groups:
Average risk: Children older than 3 years with tumors that are totally resected or near-totally resected (≤1.5 cm2 of residual disease) and who have no metastatic disease.[78]
High risk: Children older than 3 years with metastatic disease and/or subtotal resection (>1.5 cm2 of residual disease).[78] Metastatic disease includes neuroradiographic evidence of disseminated disease, positive cytology in lumbar or ventricular CSF obtained more than 14 days after surgery, or extraneural disease.[78] Children with tumors showing diffuse anaplasia and who otherwise would be considered average risk are assigned to the high-risk group.[26,38]
For younger children (younger than 3 years in some studies and younger than 4 or 5 years in others), similar separation into average-risk (no dissemination and ≤1.5 cm2 of residual disease) or high-risk (disseminated disease and/or >1.5 cm2 of residual disease) groups has been used. Histological findings of desmoplasia have also been used to connote a more favorable risk subgrouping, especially for the MBEN subgroup.[81,82]
Assigning a risk group based on the extent of resection and disease at diagnosis may not predict treatment outcome. Molecular genetics and histological factors may be more informative, although they must be evaluated in the context of patient age, the extent of disease at the time of diagnosis, and treatment received.[43,72,83] The risk characterizations of molecular subdivisions are changing and are becoming integrated into risk stratification schema to assign treatment in North American prospective studies (e.g., NCT01878617 and NCT02724579).[74]
Treatment Option Overview for Childhood Medulloblastoma
Table 3 describes the standard treatment options for newly diagnosed and recurrent childhood medulloblastoma.
Table 3. Standard Treatment Options for Childhood Medulloblastoma
Surgery is considered a standard part of treatment for histological confirmation of tumor type and as a means to improve outcome. Total or near-total resections are considered optimal if they can be performed safely.[84,85]
Postoperatively, children may have significant neurological deficits caused by preoperative tumor-related brain injury, hydrocephalus, or surgery-related brain injury.[86][Level of evidence C1] A significant number of patients with medulloblastoma develop cerebellar mutism syndrome (also known as posterior fossa syndrome). Symptoms of cerebellar mutism syndrome, which usually appear within 1 or 2 days after surgery, include the following:
Loss of speech.
Suprabulbar palsies.
Ataxia.
Hypotonia.
Emotional lability.
The etiology of cerebellar mutism syndrome remains unclear, although cerebellar vermian damage and/or disruption of cerebellar-cortical tracts has been postulated as the possible cause of the mutism.[87,88]; [89][Level of evidence C1] In two Children’s Cancer Group studies that evaluated children with both average-risk and high-risk medulloblastoma, the syndrome was identified in nearly 25% of patients.[88–90]; [91][Level of evidence C1] A retrospective analysis of 370 patients with medulloblastoma identified younger age, larger tumor size, and midline tumor location as risk factors for developing mutism. This finding is consistent with previous observations. Investigators also observed a correlation between medulloblastoma subtype and risk of mutism. Mutism was more common in patients with group 3 and group 4 medulloblastomas (30%–35% of patients) and less frequent in children with SHH-activated tumors (7% of patients).[92] A prospective study that included longitudinal neurological examination of 178 patients with medulloblastoma identified similar risk factors for mutism (higher risk with younger age; lower risk with SHH subtype), most likely because SHH-activated tumors tend to be located in the hemispheres and not in the midline. The study also reported a higher risk of developing mutism in patients who undergo tumor resections at low-volume surgery centers.[93] Approximately 50% of patients with this syndrome manifest long-term, permanent neurological and neurocognitive sequelae.[89,91]
Radiation therapy
Radiation therapy to the primary tumor site is usually in the range of 54 Gy to 55.8 Gy.[94] In most instances, this therapy is given with a margin of 1 cm to 2 cm around the primary tumor site, preferably by conformal techniques.[94] Reducing boost volumes for the whole posterior fossa and to the tumor bed plus margins did not compromise outcomes in average-risk patients in the Children’s Oncology Group (COG) ACNS0331 (NCT00085735) study.[59][Level of evidence A1] For all medulloblastomas in children older than 3 or 4 years at diagnosis, craniospinal radiation therapy is given at doses ranging between 23.4 Gy and 36 Gy, depending on risk factors such as extent of disease at diagnosis. A prospective phase II toxicity study of proton radiation therapy [95] and a retrospective efficacy report of protons versus photons for medulloblastoma [96] demonstrated equivalent outcomes for PFS, overall survival (OS), patterns of relapse, and delayed toxic effects. A retrospective study of 84 children who received either proton (n = 38) or photon (n = 46) radiation therapy demonstrated similar rates of grade 3 and grade 4 ototoxicity despite low mean cochlear doses in children who received proton radiation therapy, suggesting that other factors (e.g. cisplatin, initial tumor location in relationship to the vestibulocochlear nerve [eighth cranial nerve]) contribute to ototoxicity.[97] The comparative outcomes of these treatment technologies are under investigation.
Chemotherapy is usually administered during and after radiation therapy.
For children younger than 3 years, efforts are made to omit or delay radiation therapy, given the profound impact of radiation at this age. Children of all ages are susceptible to the adverse effects of radiation on brain development. Debilitating effects on neurocognitive development, growth, and endocrine function have been frequently observed, especially in younger children.[98–102]
Chemotherapy
Chemotherapy, usually given during and after radiation therapy, is a standard component of treatment for older children with medulloblastoma and other embryonal tumors. Chemotherapy can be used to delay and sometimes obviate the need for radiation therapy in 20% to 40% of children younger than 3 to 4 years with nondisseminated medulloblastoma.[103,104]; [102][Level of evidence C1]
Treatment of Childhood Medulloblastoma
Treatment of younger children with medulloblastoma
The 5-year event-free survival (EFS) rates for young children with medulloblastoma, arbitrarily described in the past as aged 3 years and younger at diagnosis, have ranged between 30% and 70%. There is no consensus as to what age constitutes a younger population of children with medulloblastoma who are best treated with immediate postsurgery chemotherapy and delayed or no radiation therapy. Most studies agree that in patients aged 3 years and younger, initial chemotherapy should be strongly considered. In patients between the ages of 3 and 4 years, and possibly as old as age 5 years, some investigators have recommended that radiation therapy be delayed or omitted entirely. Such decisions are based on multiple factors, including histological subtype, molecular subtype, extent of disease at diagnosis, preexisting neurological and neurodevelopmental status, and family preferences. Most long-term survivors who have been successfully treated with chemotherapy alone have had nondisseminated completely resected tumors.[81,103,105]; [106][Level of evidence B4] Several studies that have used chemotherapy alone for younger patients have observed that the finding of desmoplasia (seen in patients with desmoplastic medulloblastoma or MBEN) and/or molecular evidence of SHH signaling suggests a significantly better prognosis than the finding of classic or large cell/anaplastic medulloblastoma.[7,27,66–68]; [82][Level of evidence B4]
The treatment of younger children with newly diagnosed medulloblastoma continues to evolve. Results have been variable, and comparison across studies has been difficult because of differences in the drug regimens used and the utilization of craniospinal and local boost radiation therapy at the end of chemotherapy or when children reached age 3 years in some studies.
Standard treatment options for younger children with newly diagnosed medulloblastoma include the following:
If feasible, complete surgical resection of the tumor is the optimal treatment. Surgical resectability is associated with histology, as patients with desmoplastic/nodular medulloblastoma or MBEN have a higher rate of complete resection than patients with classic medulloblastoma.[67,68]
Adjuvant chemotherapy
Therapies for younger children with medulloblastoma have included the use of multiagent chemotherapeutic approaches, including drugs such as cyclophosphamide, etoposide, cisplatin, and vincristine, with or without concomitant high-dose intravenous and/or intraventricular methotrexate.[68,81,103,105,107,108]; [109,110][Level of evidence B4] The efficacy of chemotherapy has varied, depending on the histology and/or molecular subtype of the tumor.
Desmoplastic/MBEN medulloblastoma and/or tumors with SHH signaling
A series of studies have demonstrated that intensive chemotherapy, including either high-dose systemic and intraventricular methotrexate or high-dose chemotherapy supported by stem cell rescue, without radiation therapy, is an effective treatment for most infants and very young children with medulloblastoma.
Evidence (chemotherapy):
In the German Hirntumor (HIT) 2000 multicenter trial, a multiagent chemotherapy regimen that included high-dose intravenous and intraventricular methotrexate was used. This drug regimen did not include high-dose chemotherapy supported by bone marrow or peripheral stem cell rescue.[81]
Nineteen patients with desmoplastic medulloblastoma or MBEN had a 5-year EFS rate of 90% (±7%) and an OS rate of 100% (±0%).
All patients were treated with postoperative chemotherapy alone, and no radiation was given before progression.
An expanded cohort of the German HIT 2000 trial included an additional 23 children with nodular desmoplasia or MBEN who were treated with the same regimen. The following results were reported:[111]
Combined results confirmed the excellent survival, with a 5-year EFS rate of greater than 90%.
In this expanded cohort, molecular characterization was performed and a subset of tumors with SHH signaling were identified. These patients with tumors demonstrating SHH signaling had a similar excellent prognosis.
Further characterization of the SHH signaling molecular subtype by chromosomal aberrations did not identify any differences in EFS or OS.
Other studies have suggested that further subdivision by chromosomal aberrations in young children with SHH-driven medulloblastoma was predictive of outcome.
A COG clinical trial (CCG-9921) also had a favorable outcome for children with desmoplastic medulloblastoma (including MBEN). In this study, patients with desmoplastic tumors did not receive radiation therapy before progression.[103]
Patients in the desmoplastic group achieved an EFS rate of 77% (±9%) and an OS rate of 85% (±8%), compared with an EFS rate of 17% (±5%) and an OS rate of 29% (±6%) for patients in the nondesmoplastic group (P < .0001 for both EFS and OS comparisons).
The COG-ACNS1221 (NCT02017964) study tested systemic chemotherapy that was identical to the chemotherapy used in the German HIT 2000 trial, except for the omission of intraventricular methotrexate.[28]
The study was closed early because of a higher-than-expected rate of relapse, with a 2-year PFS rate of 52% in the 25 patients who were studied.
Another treatment option for children younger than 3 years at diagnosis is high-dose chemotherapy. Results of trials using higher-dose, marrow-ablative chemotherapeutic regimens supported by stem cell rescue have also demonstrated that a subgroup of patients with medulloblastoma who are younger than 3 years and, in some studies, younger than 5 years at the time of diagnosis can be successfully treated with chemotherapy alone.[104,106,112][Level of evidence B4]; [113]
The best survival rates using this higher-dose chemotherapy approach have been seen in patients with desmoplastic medulloblastoma and MBEN.[113]
After treatment with chemotherapy without concomitant radiation therapy, patients with nondisseminated disease have achieved survival rates of nearly 90%, and patients with disseminated disease have achieved survival rates of 80%.
One study reported the outcomes of infants and young children with relapsed medulloblastoma who were initially treated without craniospinal irradiation (CSI).[114]
A substantial portion of these children were treated with CSI-based regimens and their disease was successfully salvaged.
The 3-year postrelapse survival rate was 52.4% for patients treated with curative intent.
The report found that older age at diagnosis, local relapse, and the SHH infant medulloblastoma subtype were associated with better postrelapse survival.
The addition of chemotherapy to CSI did not improve outcomes.
Nondesmoplastic, non-MBEN, and non-SHH signaling–driven medulloblastoma
Compared with children with desmoplastic medulloblastoma or MBEN treated with current intensive chemotherapy regimens, children with other histological and/or molecular subtypes fare less well. One study suggested that patients with molecularly identified group 4 tumors did well with chemotherapy alone.[111]
Evidence (chemotherapy):
In children with nondesmoplastic, non-MBEN, and/or non-SHH–signaling tumors, the EFS rates are less than 40% despite the use of intensive chemotherapy supplemented with methotrexate (intravenous and intraventricular) or the use of high-dose chemotherapy regimens supported with stem cell rescue.[68,103,111,113,115]
Outcome is particularly poor when these patients have disseminated disease.
In some studies, radiation therapy to the primary tumor site and/or craniospinal axis has been added after chemotherapy, which makes the assessment of the efficacy of chemotherapy more difficult.[111,113,115]
There is no consensus on how much radiation therapy (dose and extent) should be given and at what age radiation therapy should be instituted in young patients with localized or disseminated disease.
In the expanded HIT 2000 study, the addition of focal radiation therapy to the primary tumor site in patients with localized disease after chemotherapy did not improve EFS or OS.[111]
In the St. Jude Children’s Research Hospital (SJCRH) SJYC07 (NCT00602667) study, focal radiation therapy also did not improve EFS in infants with medulloblastoma denoted as intermediate risk (5-year EFS rate, 25% ± 12%).[65]
The COG P9934 (NCT00006461) study, which also employed focal radiation therapy, had a similar EFS (4-year EFS rate, 23% ± 12%) for patients with nondesmoplastic medulloblastoma.[116]
In the SJCRH SJYC07 study, 29 of the 54 infants with medulloblastoma whose disease progressed received CSI (median dose, 36 Gy). Of the 29 patients, 18 (62%) survived, compared with 6 of 25 patients (24%) who did not receive CSI.[65]
Treatment of children older than 3 years with average-risk medulloblastoma
Standard treatment options for children older than 3 years with newly diagnosed average-risk medulloblastoma include the following:
If feasible, total or near-total removal of the tumor is considered optimal.[84]
Adjuvant radiation therapy
Radiation therapy is usually initiated after surgery with or without concurrent chemotherapy.[117–119] The best survival results for children with medulloblastoma have been obtained when radiation therapy is initiated within 4 to 6 weeks postsurgery.[118–120]; [94,121][Level of evidence A1] A pilot study in children with WNT-activated medulloblastoma attempted to omit craniospinal radiation therapy (and treat patients with postsurgical chemotherapy alone). The study was aborted after the first two patients had early tumor recurrences.[122]
The radiation dose for patients with average-risk medulloblastoma is 54 Gy to the posterior fossa or local tumor bed and 23.4 Gy to the entire neuraxis (i.e., the whole brain and spine), termed CSI.[117–119,123]
Evidence (adjuvant radiation therapy):
With radiation therapy alone, using a craniospinal radiation dose of 35 Gy with a boost to the posterior fossa of 55 Gy, 5-year EFS rates range between 50% and 65% in patients with nondisseminated disease.[80,118]
The minimal dose of craniospinal radiation needed for disease control is unknown. Attempts to lower the dose of craniospinal radiation therapy to 23.4 Gy without chemotherapy have resulted in an increased incidence of isolated leptomeningeal relapse.[123] One series attempted to treat children with WNT-activated tumors using focal radiation therapy alone, without CSI. The study showed an unacceptable incidence of neuroaxial failure with the omission of up-front CSI.[124]
Lower doses and boost volume of craniospinal radiation were evaluated in a COG study (NCT00085735). Children aged 3 to 7 years were randomly assigned to receive a craniospinal radiation dose of either 18 Gy or 23.4 Gy, as well as whole posterior fossa versus limited target volume boost to the tumor bed.[59][Level of evidence A1]
Results revealed that 18 Gy of CSI was inferior to 23.4 Gy of CSI (5-year EFS rate of 82.6% ± 4.2% and OS rate of 85.8% for patients who received 23.4 Gy vs. EFS rate of 71.9% ± 4.9% and OS rate of 77.9% ± 4.9% for patients who received 18 Gy).
The 5-year EFS rate was 82.5% for patients who received radiation therapy targeting the tumor bed, compared with 80.5% for patients who received posterior fossa radiation therapy. Therefore, radiation therapy targeting the tumor bed was not inferior to posterior fossa radiation therapy (hazard ratio, 0.97; 94% upper confidence interval, 1.32).
Analysis according to molecular subgroups demonstrated that children with group 4 medulloblastoma who received 18 Gy of craniospinal radiation therapy had poorer EFS than those who received 23.4 Gy. This was not demonstrated in the other molecular subgroups, although the study was not sized for molecular subgroup analysis.[59] Craniospinal radiation dose reduction to 18 Gy is currently being investigated in WNT medulloblastoma patients (NCT02724579), the molecular subgroup with the best prognosis.
The SIOP-PNET-4 (NCT01351870) study compared daily radiation therapy (1.8 Gy fractions with 23.4 Gy to the neuraxis and a 30 Gy boost to the posterior fossa) with twice-per-day radiation (1 Gy fractions with 36 Gy and a 24-Gy boost to the posterior fossa).[125]
With a median follow-up of 7.8 years, the 10-year OS was not significantly different between the two radiation groups.
Long-term side effects were not reported in this study.
If chemotherapy is added after radiation therapy, 23.4 Gy of craniospinal radiation therapy has been shown to be an effective dose.[94,125–127] Lower doses are being evaluated.
Although the standard boost in medulloblastoma is to the entire posterior fossa, failure data patterns reveal that radiation therapy to the tumor bed instead of the entire posterior fossa is equally effective and may be associated with reduced toxicity.[128,129]; [59][Level of evidence A1]
Adjuvant chemotherapy
Chemotherapy is now a standard component of the treatment of children with average-risk medulloblastoma.
Evidence (adjuvant chemotherapy):
Prospective randomized trials and single-arm trials suggest that adjuvant chemotherapy given during and after radiation therapy improves OS for children with average-risk medulloblastoma.[91,117–121]
Radiation therapy and chemotherapy given during and after surgery has demonstrated 5-year EFS rates of 70% to 85%.[117–119]; [130][Level of evidence B4]
A lower radiation dose of 23.4 Gy to the neuraxis when coupled with chemotherapy has been shown to result in disease control in up to 85% of patients and may decrease the severity of long-term neurocognitive sequelae.[94,126,127,131]
A variety of chemotherapeutic regimens have been successfully used, including the combination of cisplatin, lomustine, and vincristine or the combination of cisplatin, cyclophosphamide, and vincristine.[117,118,131,132]
These therapies have increased 5-year and 10-year EFS and OS rates and have likely decreased the incidence of late relapse.
However, long-term survivors treated with multimodality therapy are at a high risk of late effects such as hearing loss, cardiac complications, and secondary neoplasms.[133]
In addition, postradiation high-dose cyclophosphamide supported by peripheral stem cell rescue, but with reduced cumulative doses of vincristine and cisplatin, has resulted in similar survival rates.[58]
Although medulloblastoma is often sensitive to chemotherapy, preradiation chemotherapy has not been shown to improve survival in patients with average-risk medulloblastoma, compared with radiation therapy and subsequent chemotherapy. In some prospective studies, preradiation chemotherapy has been related to a poorer rate of survival.[118–121]
Treatment of children older than 3 years with high-risk medulloblastoma
Standard treatment options for children older than 3 years who are newly diagnosed with medulloblastoma and have metastatic disease or have had a subtotal resection include the following:
In high-risk patients, numerous studies have demonstrated that multimodality therapy improves the duration of disease control and overall disease-free survival.[58,134] Studies show that 50% to 70% of patients with high-risk disease, including those with metastatic disease, will experience long-term disease control.[58,117,134–138]; [139,140][Level of evidence A1]; [141][Level of evidence B4] A completed COG study demonstrated that children with group 3 MYC-amplified tumors who were randomly assigned to receive carboplatin during radiation therapy had improved 5-year EFS and OS rates, compared with those who did not receive carboplatin concurrently with radiation therapy.[135] The optimal treatment for children with SHH-activated, TP53-altered medulloblastoma has not been determined, as less than 30% of patients are expected to survive 5 years from diagnosis after treatment with current therapy.[14]
Surgery
Treatment of high-risk patients is the same as for average-risk patients. An attempt at gross-total resection is considered optimal, if feasible.[80,84]
Adjuvant radiation therapy
In contrast to standard-risk treatment, the craniospinal radiation dose is generally 36 Gy.
Adjuvant chemotherapy
Evidence (adjuvant chemotherapy):
The drugs that are useful in children with average-risk disease are the same drugs that have been used extensively in children with high-risk disease, including cisplatin, lomustine, cyclophosphamide, etoposide, and vincristine.[139]
These therapies have increased 5-year and 10-year EFS and OS rates and have likely decreased the incidence of late relapse.
However, long-term survivors treated with multimodality therapy are at a high risk of late effects such as hearing loss, cardiac complications, and secondary neoplasms.[133]
Postradiation high-dose nonmyeloablative chemotherapy supported by peripheral stem cell rescue, but with reduced cumulative doses of vincristine and cisplatin, has also been used and has resulted in 5-year PFS rates of approximately 60%.[58]
The COG ACNS0332 (NCT00392327) study randomly assigned patients to receive daily carboplatin compared with weekly vincristine during radiation therapy (36 Gy craniospinal plus a posterior fossa boost) followed by six cycles of adjuvant treatment with cisplatin, cyclophosphamide, and vincristine.[135]
Of the 261 evaluable patients, the 5-year EFS rate was 62.9%, and the OS rate was 73.4%.
For the entire cohort, there was no difference in EFS rate between patients who were treated with carboplatin (66.4%) and patients who were not treated with carboplatin (59.2%).
In a subset analysis based on molecular subgrouping, patients with group 3 medulloblastoma appeared to benefit from the use of daily carboplatin during radiation therapy, with a 5-year EFS rate of 73.2% for patients who received carboplatin, compared with 53.7% for those who did not.
A second randomization testing the utility of isotretinoin maintenance therapy was closed at the time of a planned interim analysis for futility.
In a trial of 51 patients with newly diagnosed high-risk disease, patients were treated with postoperative induction chemotherapy (etoposide and carboplatin), followed by two high-dose thiotepa courses with peripheral stem cell rescue and risk-adapted craniospinal radiation therapy.[136]
The 5-year PFS and OS rates were 76%.
Treatment options under clinical evaluation for childhood medulloblastoma
Early-phase therapeutic trials may be available for selected patients. These trials may be available via the COG, the Pediatric Brain Tumor Consortium, or other entities. Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.
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Childhood Nonmedulloblastoma Embryonal Tumors
The 2021 World Health Organization (WHO) Classification of Tumors of the Central Nervous System (CNS) is listed below in the Cellular and Molecular Classification section. All nonmedulloblastoma tumors of neuroectodermal origin that lack the specific histopathological features or molecular alterations that define other CNS tumors are classified as CNS embryonal tumors.[1,2] These tumors will be discussed in this section, with the exception of atypical teratoid/rhabdoid tumors (AT/RTs). For more information, see Childhood Central Nervous System Atypical Teratoid/Rhabdoid Tumor Treatment. Pineoblastoma will also be discussed in this summary because it shares histological features with the embryonal tumors and is conventionally treated in the same fashion. For more information, see the Childhood Pineoblastoma section.
Clinical Presentation
For nonmedulloblastoma embryonal tumors, presentation is also relatively rapid and depends on the location of the tumor in the nervous system. Embryonal tumors tend to grow fast and are usually diagnosed within 3 months of initial onset of symptoms.
Nonmedulloblastoma embryonal tumors may occur anywhere in the CNS, and presentation is variable. Usually there is significant neurological dysfunction associated with lethargy and vomiting. Supratentorial embryonal tumors (see Figure 1) result in focal neurological deficits such as hemiparesis and visual field loss, depending on which portion of the cerebral cortex is involved. They may also result in seizures and obtundation.
Cellular and Molecular Classification
The 2021 WHO Classification of Tumors of the CNS organizes nonmedulloblastoma embryonal tumors primarily by histological and immunohistological features and, in some cases, by molecular findings. The classification includes the following:[1,2]
Atypical teratoid/rhabdoid tumor (AT/RT).
Cribriform neuroepithelial tumor.
Embryonal tumor with multilayered rosettes (ETMR).
CNS neuroblastoma, FOXR2-activated.
CNS tumor with BCOR internal tandem duplication.
CNS embryonal tumor, not elsewhere classified (NEC)/not otherwise specified (NOS).
NEC is defined as a tumor not elsewhere classified. The NOS nomenclature is used for tumors that cannot be further classified. For many lesions, there are overlapping histological features, and methylation-based clustering is critical for specific diagnosis.[1,2] The contribution of DNA methylation profiling to correctly diagnose supratentorial embryonal tumors was demonstrated in a clinical trial of patients with supratentorial primitive neuroectodermal tumors of the CNS (CNS-PNET) and pineoblastoma.[3] For the pineoblastoma cases, there was high concordance between the diagnosis made by methylation profiling and the diagnosis made by central pathology review diagnosis (26 of 29). However, for the remaining 31 patients without pineoblastoma in the study, the diagnosis made by methylation profiling was high-grade glioma in 18 patients, AT/RT in 2 patients, and RELA fusion–positive ependymoma in 2 patients. Adjudication of discrepancies between the diagnosis made by central review pathology and the diagnosis made by methylation profiling was in favor of methylation profiling in the ten cases that were re-examined.
Subtypes of nonmedulloblastoma embryonal tumors
Molecular subtypes of nonmedulloblastoma embryonal tumors
Studies applying unsupervised clustering of DNA methylation patterns for nonmedulloblastoma embryonal tumors found that approximately one-half of these tumors diagnosed as nonmedulloblastoma embryonal tumors showed molecular profiles characteristic of other known pediatric brain tumors (e.g., high-grade gliomas).[4,5] These observations highlight the utility of molecular characterization to assign this class of tumors to their appropriate biology-based diagnosis.
Among the tumors diagnosed as nonmedulloblastoma embryonal tumors, molecular characterization identified genomically and biologically distinctive subtypes, including the following:
Cribriform neuroepithelial tumor: Representing less than 50% of nonmedulloblastoma embryonal tumors, this subtype is a nonrhabdoid tumor that arises in the vicinity of the third, fourth, or lateral ventricles. This tumor is characterized by cribriform strands and ribbons and demonstrates loss of nuclear SMARCB1 expression. The median age at diagnosis is 20 months. This tumor occurs more often in males, with a male-to-female ratio of 1.5 to 1.[6]
Genomic characterization of ten cases of cribriform neuroepithelial tumors showed large heterozygous 22q deletions in nine of ten cases with SMARCB1 variants on the alternative allele.[6] Cribriform neuroepithelial tumor showed DNA methylation profiles that matched those of the TYR subtype of atypical teratoid/rhabdoid tumor (AT/RT), a tumor that also arises in young children and shows loss of SMARCB1 expression. Patients with cribriform neuroepithelial tumors appear to have relatively favorable outcomes, in contrast to those of patients with AT/RT-TYR.[6]
Embryonal tumor with multilayered rosettes (ETMR): Representing up to 20% of nonmedulloblastoma embryonal tumors, this subtype combines embryonal, rosette-forming, neuroepithelial brain tumors that were previously categorized as either embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma, or medulloepithelioma.[4,7] ETMRs arise most commonly in young children (median age at diagnosis, 2–3 years) but may occur in older children.[5,7–11]
ETMRs are defined at the molecular level by high-level amplification of the microRNA cluster C19MC and by a gene fusion between TTYH1 and C19MC.[7,12,13] This gene fusion puts expression of C19MC under control of the TTYH1 promoter, leading to high-level aberrant expression of the microRNAs within the cluster. The World Health Organization (WHO) allows histologically similar tumors without C19MC alteration to be classified as ETMR, not otherwise specified (NOS). This subclass of tumors without C19MC alterations may harbor biallelic DICER1 variants.
Central nervous system (CNS) neuroblastoma with FOXR2 activation (CNS NB-FOXR2): Representing 10% to 15% of nonmedulloblastoma embryonal tumors, this tumor may occur in children younger than 3 years, but it more frequently occurs in older children. This subtype is characterized by genomic alterations that lead to increased expression of the transcription factor FOXR2.[4] CNS NB-FOXR2 is primarily observed in children younger than 10 years, and the histology of these tumors is typically that of CNS neuroblastoma or CNS ganglioneuroblastoma.[4,14] There is no single genomic alteration among CNS NB-FOXR2 tumors leading to FOXR2 overexpression, with gene fusions involving multiple FOXR2 partners identified.[4] Protein expression of SOX10 and ANKRD55 detected by immunohistochemistry has been proposed as a potential biomarker to differentiate CNS NB-FOXR2 tumors from related tumor types.[14]
CNS high-grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR): Representing up to 3% of nonmedulloblastoma embryonal tumors, this subtype is characterized by internal tandem duplications of BCOR,[4] a genomic alteration that is also found in clear cell sarcoma of the kidney.[15,16] While the median age at diagnosis is younger than 10 years, cases arising in the second decade of life and beyond do occur.[4]
Although not listed as separate entities in the 2021 WHO Classification of Tumors of the CNS, other nonmedulloblastoma embryonal tumors have also been described as separate entities, including the following:
CNS Ewing sarcoma family tumor with CIC alteration (CNS EFT-CIC): Representing 2% to 4% of nonmedulloblastoma embryonal tumors, this subtype is characterized by genomic alterations affecting CIC (located on chromosome 19q13.2), with fusion to NUTM1 being identified in several cases tested.[4,5] CIC gene fusions are also identified in extra-CNS Ewing-like sarcomas, and the gene expression signature of CNS EFT-CIC tumors is similar to that of these sarcomas.[4] CNS EFT-CIC tumors generally occur in children younger than 10 years and are characterized by a small cell phenotype but with variable histology.[4]
CNS high-grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1): Representing 1% to 3% of nonmedulloblastoma embryonal tumors, this subtype is characterized by gene fusions involving MN1 (located on chromosome 22q12.3), with fusion partners including BEND2 and CXXC5.[4,5] The CNS HGNET-MN1 subtype shows a striking female predominance, and it tends to occur in the second decade of life.[4] This subtype contained most cases carrying a diagnosis of astroblastoma per the 2007 WHO classification scheme.[4] This subtype has not been added to the WHO diagnostic lexicon. Two other reports that together examined 35 cases of histologically defined astroblastoma found that 14 showed methylation profiles consistent with CNS HGNET-MN1 and/or MN1 alterations by fluorescence in situ hybridization.[17,18]
Medulloepithelioma: Medulloepithelioma with the classic C19MC amplification is considered an ETMR, C19MC-altered (see the ETMR information above). However, when a tumor has the histological features of medulloepithelioma, but without a C19MC amplification, it is still identified as an ETMR.[19,20] Medulloepithelioma tumors are rare and tend to arise most commonly in infants and young children. Medulloepitheliomas, which histologically recapitulate the embryonal neural tube, tend to arise supratentorially, primarily intraventricularly, but may arise infratentorially, in the cauda, and even extraneurally, along nerve roots.[19,20] Intraocular medulloepithelioma is biologically distinct from intra-axial medulloepithelioma.[21,22]
CNS embryonal tumor with PLAGL amplification: A retrospective analysis of more than 90,000 pediatric and adult brain tumors identified a small subset of embryonal tumors (n = 31) with distinct methylation profiles and high-level amplification and overexpression of either PLAGL1 or PLAGL2.[23] Additional recurrent genetic alterations observed in other pediatric CNS tumor types were not observed in these cases. These tumors occurred throughout the brain and were most commonly composed of primitive embryonal-like cells without markers of glial or neuronal differentiation. In this small cohort, differences in age at diagnosis and 10-year overall survival (OS) rates were reported between patients with PLAGL1 amplification (median age, 10.5 years; OS rate, 66%) and patients with PLAGL2 amplification (median age, 2 years; OS rate, 25%).
Staging Evaluation
Patients with nonmedulloblastoma embryonal tumors are staged in a fashion similar to that used for children with medulloblastoma. However, these patients are not assigned to average-risk and high-risk subgroups for treatment purposes because all patients are considered high risk. For more information, see the medulloblastoma Staging Evaluation section.
Treatment of Childhood Nonmedulloblastoma Embryonal Tumors
The optimal treatment of childhood nonmedulloblastoma embryonal tumors remains unclear and under study. Retrospective studies of fairly large numbers of patients have suggested management approaches for the more common subgroups, including AT/RTs, ETMRs, and FOXR2-activated tumors. For more information about the treatment of AT/RTs, see Childhood Central Nervous System Atypical Teratoid/Rhabdoid Tumor Treatment.
Standard treatment options for children aged 3 years and younger with newly diagnosed nonmedulloblastoma embryonal tumors, excluding AT/RTs, ETMRs, and FOXR2-activated tumors, include the following:
Surgery.
Adjuvant chemotherapy.
Treatment of children aged 3 years and younger with embryonal tumors is similar to that outlined for children aged 3 years and younger with medulloblastoma. Aggressive surgical resection is reasonable, given the improved rate of survival for medulloblastomas and other ETMRs after total or near-total resection.[11] For more information, see the Treatment of younger children with medulloblastoma section.
With the use of chemotherapy alone, outcome has been variable, with survival rates at 5 years ranging between 0% and 50%.[24–26]; [27][Level of evidence B4] The addition of craniospinal irradiation to chemotherapy-based regimens may successfully treat some children but with anticipated neurodevelopmental decline.[28][Level of evidence B4] Localized radiation therapy to the tumor site, either before or after chemotherapy, has been given, although data supporting its efficacy are unclear.
Treatment of children older than 3 years
Standard treatment options for children older than 3 years with newly diagnosed nonmedulloblastoma embryonal tumors, excluding AT/RTs, ETMRs, and FOXR2-activated tumors, include the following:
Nonmedulloblastoma embryonal tumors are often amenable to resection. In reported case series, 50% to 75% of tumors in patients were totally or near-totally resected.[29,30]; [3][Level of evidence A1]
Attempting aggressive surgical resection is the first step in the management of newly diagnosed nonmedulloblastoma embryonal tumors. Although previous studies did not demonstrate that the extent of resection is predictive of outcome,[29–31] one study demonstrated improved survival when the tumor was completely resected.[32][Level of evidence B4] A published study (COG-ACNS0332 [NCT00392327]) of molecularly classified nonmedulloblastoma embryonal tumors revealed improved overall survival (OS) for patients who had less than 1.5 cm2 of residual disease, compared with patients who had more than 1.5 cm2 of residual disease.[3][Level of evidence A1]
Adjuvant radiation therapy
After surgery, children with nonmedulloblastoma embryonal tumors usually receive treatment similar to that received by children with high-risk medulloblastoma.
Conventionally, patients are treated with radiation to the entire neuraxis with local boost radiation therapy, as given for medulloblastoma.[31] Local boost radiation therapy may be problematic because of the size of the tumor and its location in the cerebral cortex. Also, there is no definitive evidence that craniospinal radiation therapy is superior to radiation to the primary tumor site alone in children with nondisseminated lesions.[29–31]
Adjuvant chemotherapy
The chemotherapeutic approaches during and after radiation therapy are similar to those used for children with high-risk medulloblastoma. The 3-year to 5-year OS rates range from 25% to 50%.[29–31]; [32,33][Level of evidence B4]; [34][Level of evidence C1]
In a published study of nonpineal tumors that were diagnosed as CNS primitive neuroectodermal tumors (PNETs) by traditional pathology, 71% of cases were revealed to be glioblastoma or another diagnosis by DNA methylation studies. Patients with nonmedulloblastoma embryonal tumors (n = 36) (including pineoblastomas, n = 26) had a 5-year OS rate of 78.5% (95% confidence interval [CI], 62.2%–94.8%). In contrast, the patients with glioblastoma had a 5-year OS rate of 12% (95% CI, 0%–24.7%). The study showed no benefit for children who received carboplatin or isotretinoin.[3][Level of evidence A1] This study highlights the importance of molecular classification of tumors traditionally termed CNS-PNET.[4]
Treatment of Childhood Embryonal Tumors With Multilayered Rosettes or Medulloepithelioma
A registry-based review of 159 patients with a confirmed molecular diagnosis of ETMR reported survival results for different treatments.[11]
The 2-year event-free survival (EFS) and OS rates were 0% for patients treated with conventional chemotherapy without radiation therapy, regardless of the degree of surgical resection.
The 2-year EFS rate was 21% and the OS rate was 30% for patients who had a gross-total resection and were treated with high-dose chemotherapy without radiation therapy.
The 2-year EFS rate was 44% for children treated with high-dose chemotherapy and radiation therapy after a subtotal resection and 66% for patients treated with high-dose chemotherapy and radiation therapy after a gross-total resection.
The relative roles of focal radiation therapy versus craniospinal radiation therapy could not be assessed in this review.
In a separate, but possibly overlapping, international retrospective review, 49 patients with histologically confirmed (by the treating institution) ETMRs were treated between 1988 to 2017 in a variety of ways.[35] The 5-year progression-free survival rate was 18% (± 6%), and the OS rate was 24% (± 6%). Most survivors received radiation therapy, including both local and craniospinal treatment, and there was no clear difference in outcomes between the types and extent of radiation therapy. The relative benefits of conventional chemotherapy compared with high-dose chemotherapy could not be assessed.[5]
In a subsequent publication, likely including some of the patients from the retrospective study, treatment was limited to only those who received chemotherapy and radiation therapy on the prospective P-HIT study or per the study protocol. The P-HIT study included postsurgery chemotherapy, high-dose chemotherapy, and radiation for some patients. In 35 patients with ETMRs, 8 long-term survivors were identified, 6 of whom had received either craniospinal or local radiation therapy, in addition to induction and high-dose chemotherapy. None of the patients who presented with brain stem disease survived. The 5-year survival was best for patients with localized disease, possibly for those treated with both induction and high-dose chemotherapy. The role of radiation therapy or the optimal volume of radiation therapy (local versus craniospinal) could not be determined.[10]
These studies suggest that the outcome for children with ETMRs may not be as dire as suggested by initial studies, which found a 5-year survival rate of 25% or lower. Outcome is more favorable in children with localized disease at the time of diagnosis and those who were treated with aggressive postsurgical chemotherapy, including induction and high-dose consolidation treatment. The role of radiation therapy is still unproven, and there is no evidence that craniospinal radiation in patients with localized disease is superior to focal radiation therapy.[5,10,11]
Treatment of CNS Neuroblastoma, FOXR2-Activated
The optimal treatment of patients with CNS neuroblastoma, FOXR2-activated tumors has not been confirmed by prospective studies. In a retrospective review of patients diagnosed between 1988 and 2007, the highest rates of survival were seen after complete or near-complete resections in patients with nonmetastatic tumors who also received craniospinal radiation therapy and possibly chemotherapy. With this type of approach, up to 75% of children (35 of 42) were alive 5 years after diagnosis and treatment. This tumor tends to occur in a somewhat older population than some of the other nonmedulloblastoma embryonal tumors.[5]
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Hwang EI, Kool M, Burger PC, et al.: Extensive Molecular and Clinical Heterogeneity in Patients With Histologically Diagnosed CNS-PNET Treated as a Single Entity: A Report From the Children’s Oncology Group Randomized ACNS0332 Trial. J Clin Oncol : JCO2017764720, 2018. [PUBMED Abstract]
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]
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Korshunov A, Sturm D, Ryzhova M, et al.: Embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma, and medulloepithelioma share molecular similarity and comprise a single clinicopathological entity. Acta Neuropathol 128 (2): 279-89, 2014. [PUBMED Abstract]
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Juhnke BO, Gessi M, Gerber NU, et al.: Treatment of embryonal tumors with multilayered rosettes with carboplatin/etoposide induction and high-dose chemotherapy within the prospective P-HIT trial. Neuro Oncol 24 (1): 127-137, 2022. [PUBMED Abstract]
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Timmermann B, Kortmann RD, Kühl J, et al.: Role of radiotherapy in the treatment of supratentorial primitive neuroectodermal tumors in childhood: results of the prospective German brain tumor trials HIT 88/89 and 91. J Clin Oncol 20 (3): 842-9, 2002. [PUBMED Abstract]
Jakacki RI, Burger PC, Kocak M, et al.: Outcome and prognostic factors for children with supratentorial primitive neuroectodermal tumors treated with carboplatin during radiotherapy: a report from the Children’s Oncology Group. Pediatr Blood Cancer 62 (5): 776-83, 2015. [PUBMED Abstract]
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Liu APY, Dhanda SK, Lin T, et al.: Molecular classification and outcome of children with rare CNS embryonal tumors: results from St. Jude Children’s Research Hospital including the multi-center SJYC07 and SJMB03 clinical trials. Acta Neuropathol 144 (4): 733-746, 2022. [PUBMED Abstract]
Childhood Pineoblastoma
The World Health Organization classifies pineoblastomas in the tumors of the pineal region group. However, they are discussed in this summary because they share histological features with other embryonal tumors and are conventionally treated like other embryonal tumors.[1–3]
Clinical Presentation
Pineoblastoma often results in hydrocephalus due to blockage of cerebrospinal fluid at the third ventricular level and other symptoms related to pressure on the back of the brain stem in the tectal region. Symptoms may include a constellation of abnormalities in eye movements (Parinaud syndrome), manifested by pupils that react poorly to light but better to accommodation, loss of upgaze, retraction or convergence nystagmus, and lid retraction. As they grow, these tumors may also cause hemiparesis and ataxia.[4]
Cellular and Molecular Classification
Pineoblastoma is histologically similar to medulloblastoma and shares histological features with embryonal tumors. It is classified as a subgroup of pineal parenchymal tumors.[5,6]
Pineoblastoma can be classified into four distinctive subtypes with unique clinical and molecular characteristics:[7]
The microRNA (miRNA) processing–altered 1 (PB-miRNA1) and miRNA processing–altered 2 (PB-miRNA2) subtypes are characterized by somatic or germline variants involving microRNA biogenesis genes (DICER1, DROSHA, and DGCR8). They are distinguished from each other by their DNA methylation profiles.
The PB-MYC/FOXR2 subtype shows MYC activation and FOXR2 overexpression.
The PB-RB1 subtype has RB1 alterations, and a minority of cases have a clinical diagnosis of trilateral retinoblastoma.
Additional information about each of the subtypes is provided below.
Genomics of Pineoblastoma
Pineoblastoma, which was previously conventionally grouped with embryonal tumors, is now categorized by the World Health Organization as a pineal parenchymal tumor. Given that therapies for pineoblastoma are quite similar to those used for embryonal tumors, the previous convention of including pineoblastoma with the central nervous system embryonal tumors is followed here. Pineoblastoma is associated with germline pathogenic variants in both the RB1 gene and the DICER1 gene, as described below:
Pineoblastoma is associated with germline pathogenic variants in RB1. The term trilateral retinoblastoma is used to refer to ocular retinoblastoma in combination with a histologically similar brain tumor generally arising in the pineal gland or other midline structures. Historically, intracranial tumors have been reported in 5% to 15% of children with heritable retinoblastoma.[8] Rates of pineoblastoma among children with heritable retinoblastoma who undergo current treatment programs may be lower than these historical estimates.[9–11] In a study of patients with molecularly classified pineal parenchymal tumors, 6 of 221 cases (3%) had a clinical diagnosis of trilateral retinoblastoma.[7]
Germline DICER1 pathogenic variants occur in some patients with pineoblastoma.[12] In one study, among 18 patients with pineoblastoma, 3 patients with DICER1 germline pathogenic variants were identified, and an additional 3 patients known to be carriers of germline DICER1 pathogenic variants developed pineoblastoma.[12] The DICER1 variants in patients with pineoblastoma are loss-of-function variants that appear to be distinct from the variants observed in DICER1 syndrome–related tumors such as pleuropulmonary blastoma.[12]
Genomic methods have been applied to pineoblastoma in an attempt to learn more about the tumor biology and guide future molecular classification. A retrospective, international meta-analysis included 221 children and adults diagnosed with pineoblastoma (n = 178) and pineal parenchymal tumors of intermediate differentiation (PPTID) (n = 43).[7] The evaluation identified four molecular groups of pineoblastoma based on DNA methylation, transcriptome profiling, and gene sequencing, as described below.
The microRNA (miRNA) processing–altered 1 (PB-miRNA1) and miRNA processing–altered 2 (PB-miRNA2) subtypes are characterized by somatic or germline variants involving miRNA biogenesis genes (DICER1, DROSHA, and DGCR8).
PB-miRNA1 represented approximately 50% of molecularly classified pineoblastoma cases, while PB-miRNA2 represented approximately 15% of the cases.
The median age at presentation of PB-miRNA1 was approximately 8 years, and the median age at presentation of PB-miRNA2 was 12 years.
The 5-year survival rate for patients with PB-miRNA2 (100%) exceeded that for patients with PB-miRNA1 (70%).
The PB-MYC/FOXR2 subtype shows MYC activation (sometimes with MYC copy number gain and occasionally with MYC amplification) and FOXR2 overexpression.
PB-MYC/FOXR2 represented approximately 20% of molecularly classified pineoblastoma cases.
PB-MYC/FOXR2 cases presented at a young age (median, 1.4 years).
Approximately 40% of patients with PB-MYC/FOXR2 presented with metastatic disease.
The 5-year survival rate for patients with PB-MYC/FOXR2 was approximately 20%.
The PB-RB1 subtype has RB1 alterations. In one study, 6 of 25 patients with the PB-RB1 subtype had a clinical diagnosis of trilateral retinoblastoma.
The PB-RB1 subtype represented approximately 10% of molecularly classified pineoblastoma cases.
Approximately 70% of PB-RB1 cases presented with metastatic disease.
The 5-year survival rate for patients with PB-RB1 was approximately 30%.
Cases with DNA methylation profiles indicating PPTID sometimes had a histological diagnosis of pineoblastoma, but the clinical and biological characteristics of these cases were distinctive from those of the pineoblastoma subtypes described above.
Approximately 75% of cases with a molecular classification of PPTID had tumors with variants in KBTBD4, a gene that is also altered in group 3 and 4 medulloblastomas.
Most PPTID cases occurred in adults, with a median age exceeding 30 years.
The 5-year survival rate for patients with PPTID was 85%.
Staging Evaluation
Dissemination at the time of diagnosis occurs in 10% to 30% of patients with pineoblastoma.[13] Because of the location of the tumor, total resections are uncommon, and most patients have only a biopsy or a subtotal resection before postsurgical treatment.[13,14] Staging for children with pineoblastomas is the same as for children with medulloblastoma. However, the patients are not assigned to average-risk and high-risk subgroups for treatment purposes.[13] For more information, see the medulloblastoma Staging Evaluation section.
Treatment Option Overview for Childhood Pineoblastoma
Table 4 describes the treatment options for newly diagnosed and recurrent childhood pineoblastoma.
Table 4. Treatment Options for Childhood Pineoblastoma
Treatment Group
Treatment Options
Newly diagnosed childhood pineoblastoma
Children aged 3 years and younger
Biopsy (for diagnosis) and total resection, if possible
No standard treatment options currently exist for children aged 3 years and younger with pineoblastoma.[15] The following treatment approaches are available:
Biopsy and, if possible, total resection, is usually performed to diagnose pineoblastoma.
Adjuvant chemotherapy
Children aged 3 years and younger with pineoblastoma are usually treated initially with chemotherapy in the hope of delaying, if not obviating, the need for radiation therapy.[16] Overall prognosis for this group remains very poor.[17–19] In two sequential, multicenter, prospective clinical trials, all five children younger than 3 years who were treated with chemotherapy died.[20][Level of evidence B4] In children responding to chemotherapy, the timing and amount of radiation therapy required after chemotherapy is unclear. The addition of craniospinal irradiation to chemotherapy-based regimens may successfully treat some children but with anticipated neurodevelopmental decline.[21][Level of evidence B4] Two large pooled analyses both revealed dismal survival for children younger than 3 or 4 years with pineoblastoma.[18,19]
High-dose, marrow-ablative chemotherapy with autologous bone marrow rescue or peripheral stem cell rescue
High-dose, marrow-ablative chemotherapy with autologous bone marrow rescue or peripheral stem cell rescue has been used with some success in young children.[22][Level of evidence B4] Two pooled analyses also revealed this modality may have some efficacy.[18,19]
Treatment of children older than 3 years
Standard treatment options for children older than 3 years with newly diagnosed pineoblastoma include the following:
Surgery is usually the initial treatment for patients with pineoblastoma to diagnose the tumor.[23] Total resections have been associated with better outcomes.
Adjuvant radiation therapy
The usual postsurgical treatment for patients with pineoblastoma begins with radiation therapy, although some trials have used preradiation chemotherapy. The total dose of radiation therapy to the tumor site is 54 Gy to 55.8 Gy using conventional fractionation.[13,14]
Craniospinal irradiation with doses of 23.4 Gy to 36 Gy are also recommended because of the propensity of this tumor to disseminate throughout the subarachnoid space.[13,14,17]
The 5-year disease-free survival rate exceeds 50% in children with localized disease at diagnosis who undergo aggressive resection.[13,14,24,25][Level of evidence A1] The Children’s Oncology Group (COG) COG-ACNS0332 (NCT00392327) study of 36 patients with nonmedulloblastoma embryonal tumors (which included 26 pineoblastomas) reported a 5-year overall survival (OS) rate of 78.5% (95% confidence interval, 62.2%–94.8%).[25][Level of evidence A1]
For patients with disseminated disease at the time of diagnosis, survival is considerably poorer.[13,14] In the COG-ACNS0332 (NCT00392327) study, there was no significant difference in event-free survival or OS according to metastatic status.
Treatment options under clinical evaluation for childhood pineoblastoma
For patients with pineoblastoma, a variety of different treatment approaches are under evaluation, including the use of higher doses of chemotherapy after radiation therapy supported by peripheral stem cell rescue and the use of chemotherapy during radiation therapy.
Early-phase therapeutic trials may be available for selected patients. These trials may be available via the COG, the Pediatric Brain Tumor Consortium, or other entities. Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.
References
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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]
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Chintagumpala MM, Paulino A, Panigrahy A, et al.: Embryonal and pineal region tumors. In: Pizzo PA, Poplack DG, eds.: Principles and Practice of Pediatric Oncology. 7th ed. Lippincott Williams and Wilkins, 2015, pp 671-99.
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de Jong MC, Kors WA, de Graaf P, et al.: Trilateral retinoblastoma: a systematic review and meta-analysis. Lancet Oncol 15 (10): 1157-67, 2014. [PUBMED Abstract]
Ramasubramanian A, Kytasty C, Meadows AT, et al.: Incidence of pineal gland cyst and pineoblastoma in children with retinoblastoma during the chemoreduction era. Am J Ophthalmol 156 (4): 825-9, 2013. [PUBMED Abstract]
Abramson DH, Dunkel IJ, Marr BP, et al.: Incidence of pineal gland cyst and pineoblastoma in children with retinoblastoma during the chemoreduction era. Am J Ophthalmol 156 (6): 1319-20, 2013. [PUBMED Abstract]
Turaka K, Shields CL, Meadows AT, et al.: Second malignant neoplasms following chemoreduction with carboplatin, etoposide, and vincristine in 245 patients with intraocular retinoblastoma. Pediatr Blood Cancer 59 (1): 121-5, 2012. [PUBMED Abstract]
de Kock L, Sabbaghian N, Druker H, et al.: Germ-line and somatic DICER1 mutations in pineoblastoma. Acta Neuropathol 128 (4): 583-95, 2014. [PUBMED Abstract]
Jakacki RI, Zeltzer PM, Boyett JM, et al.: Survival and prognostic factors following radiation and/or chemotherapy for primitive neuroectodermal tumors of the pineal region in infants and children: a report of the Childrens Cancer Group. J Clin Oncol 13 (6): 1377-83, 1995. [PUBMED Abstract]
Timmermann B, Kortmann RD, Kühl J, et al.: Role of radiotherapy in the treatment of supratentorial primitive neuroectodermal tumors in childhood: results of the prospective German brain tumor trials HIT 88/89 and 91. J Clin Oncol 20 (3): 842-9, 2002. [PUBMED Abstract]
Liu APY, Li BK, Vasiljevic A, et al.: SNO-EANO-EURACAN consensus on management of pineal parenchymal tumors. Neuro Oncol 26 (12): 2159-2173, 2024. [PUBMED Abstract]
Mason WP, Grovas A, Halpern S, et al.: Intensive chemotherapy and bone marrow rescue for young children with newly diagnosed malignant brain tumors. J Clin Oncol 16 (1): 210-21, 1998. [PUBMED Abstract]
Liu APY, Gudenas B, Lin T, et al.: Risk-adapted therapy and biological heterogeneity in pineoblastoma: integrated clinico-pathological analysis from the prospective, multi-center SJMB03 and SJYC07 trials. Acta Neuropathol 139 (2): 259-271, 2020. [PUBMED Abstract]
Hansford JR, Huang J, Endersby R, et al.: Pediatric pineoblastoma: A pooled outcome study of North American and Australian therapeutic data. Neurooncol Adv 4 (1): vdac056, 2022. [PUBMED Abstract]
Mynarek M, Pizer B, Dufour C, et al.: Evaluation of age-dependent treatment strategies for children and young adults with pineoblastoma: analysis of pooled European Society for Paediatric Oncology (SIOP-E) and US Head Start data. Neuro Oncol 19 (4): 576-585, 2017. [PUBMED Abstract]
Hinkes BG, von Hoff K, Deinlein F, et al.: Childhood pineoblastoma: experiences from the prospective multicenter trials HIT-SKK87, HIT-SKK92 and HIT91. J Neurooncol 81 (2): 217-23, 2007. [PUBMED Abstract]
Friedrich C, von Bueren AO, von Hoff K, et al.: Treatment of young children with CNS-primitive neuroectodermal tumors/pineoblastomas in the prospective multicenter trial HIT 2000 using different chemotherapy regimens and radiotherapy. Neuro Oncol 15 (2): 224-34, 2013. [PUBMED Abstract]
Fangusaro J, Finlay J, Sposto R, et al.: Intensive chemotherapy followed by consolidative myeloablative chemotherapy with autologous hematopoietic cell rescue (AuHCR) in young children with newly diagnosed supratentorial primitive neuroectodermal tumors (sPNETs): report of the Head Start I and II experience. Pediatr Blood Cancer 50 (2): 312-8, 2008. [PUBMED Abstract]
Jakacki RI, Burger PC, Kocak M, et al.: Outcome and prognostic factors for children with supratentorial primitive neuroectodermal tumors treated with carboplatin during radiotherapy: a report from the Children’s Oncology Group. Pediatr Blood Cancer 62 (5): 776-83, 2015. [PUBMED Abstract]
Gururangan S, McLaughlin C, Quinn J, et al.: High-dose chemotherapy with autologous stem-cell rescue in children and adults with newly diagnosed pineoblastomas. J Clin Oncol 21 (11): 2187-91, 2003. [PUBMED Abstract]
Hwang EI, Kool M, Burger PC, et al.: Extensive Molecular and Clinical Heterogeneity in Patients With Histologically Diagnosed CNS-PNET Treated as a Single Entity: A Report From the Children’s Oncology Group Randomized ACNS0332 Trial. J Clin Oncol : JCO2017764720, 2018. [PUBMED Abstract]
Treatment of Recurrent Childhood Medulloblastoma and Other CNS Embryonal Tumors
Recurrence of all forms of central nervous system (CNS) embryonal tumors is not uncommon and usually occurs within 36 months of treatment. However, recurrent tumors may also develop many years after initial treatment.[1–3] In such late relapses, especially those occurring 5 or more years after diagnosis, differentiation from secondary tumors such as high-grade gliomas can be difficult. Histological confirmation is recommended and usually required. In a 2021 report, a paired molecular cohort was assembled, consisting of 127 patients with tissue specimens available from both their primary medulloblastomas and subsequent tumors associated with relapse. Comparative molecular analyses were performed using the patient-matched tumor specimens. DNA methylation-based classification identified nine relapse cases (7%) as histologies other than medulloblastoma.[4] Disease may recur at the primary site or may be disseminated at the time of relapse. Sites of noncontiguous relapse may include the spinal leptomeninges, intracranial sites, and cerebrospinal fluid, in isolation or in any combination, and may be associated with primary tumor relapse.[1,2,5] Extraneural disease relapse is rare and is seen primarily in patients who were treated with radiation therapy alone.[6][Level of evidence C1]
Studies have found that even in patients with nondisseminated disease at diagnosis, and independent of the dose of radiation therapy or the type of chemotherapy, approximately one-third of patients will experience a relapse at the primary tumor site alone, one-third at the primary tumor site plus distant sites, and one-third at distant sites without relapse at the primary site.[1,2,5]
For most children, treatment is palliative, and disease control is transient in patients previously treated with radiation therapy and chemotherapy, with more than 80% of patients progressing within 2 years.[3]; [7][Level of evidence C1] The temporal and spatial patterns of relapse differ between molecular subgroups. Patients with group 4 medulloblastomas present with delayed relapse compared with patients in other subgroups. In children who develop relapsed disease after radiation-sparing strategies, patients with group 4 and SHH medulloblastomas have higher rates of local relapse (42% and 39%, respectively), compared with patients with group 3 disease (17%).[8] For young children, predominantly those younger than 3 years at diagnosis who were never treated with radiation therapy, longer-term control with reoperation, radiation therapy, and chemotherapy is possible.[5,8–12]
At the time of relapse, a complete evaluation for extent of recurrence is indicated for all embryonal tumors. Biopsy or surgical resection may be necessary for confirmation of relapse because other entities, such as secondary tumors and treatment-related brain necrosis, may be clinically indistinguishable from tumor recurrence. The need for surgical intervention must be individualized based on the initial tumor type, the length of time between initial treatment and the reappearance of the lesion, and clinical symptoms.
Radiation therapy
Patients with recurrent embryonal tumors who have already received radiation therapy and chemotherapy may be candidates for further radiation therapy depending on the site and dose of previous radiation. Treatment may include reirradiation at the primary tumor site, focal areas of radiation therapy to sites of disseminated disease, and craniospinal irradiation (CSI).[13,14] However, long-term survival has been observed in a subset of patients who received chemotherapy alone at the time of diagnosis and had local relapse. This finding was primarily noted in young children with SHH-activated disease.[8,15] In most cases, such therapy is palliative. Stereotactic radiation therapy and/or salvage chemotherapy can also be used.[16] For more information, see the Chemotherapy section.
One retrospective study reported the outcomes of infants and young children with relapsed medulloblastoma who were initially treated in a variety of different chemotherapy clinical trials without CSI.[8]
At the time of relapse, 73% of these children were treated with CSI-based regimens.
The 3-year postrelapse survival rate was 52.4% for patients treated with curative intent.
The 3-year postrelapse survival rates for children with SHH, group 3, and group 4 medulloblastoma who received salvage radiation therapy were 61%, 40%, and 79%, respectively. Patients with SHH disease were less likely to receive salvage radiation therapy.
Older age at diagnosis, local relapse, and the SHH infant subtype were associated with better postrelapse survival.
Chemotherapy
Recurrent CNS embryonal tumors can respond to chemotherapeutic agents used singularly or in combination, including cyclophosphamide, cisplatin, carboplatin, lomustine, etoposide, topotecan, temozolomide, the combination of irinotecan and temozolomide with or without bevacizumab, and antiangiogenic metronomic therapy.[9,17–27]; [28–30][Level of evidence B4] Approximately 30% to 50% of these patients have objective responses to conventional chemotherapy, but long-term disease control is rare.
For select patients with recurrent medulloblastoma—primarily infants and young children who were treated at the time of diagnosis with chemotherapy alone and who developed local recurrence—long-term disease control may be obtained after further treatment with chemotherapy plus local radiation therapy. This potential may be greatest in patients who are able to undergo complete resection of the recurrent disease.[31][Level of evidence B4]; [32][Level of evidence C1]
In a St. Jude Children’s Research Hospital study (SJYC07 [NCT00602667]), 29 patients with progressive disease received CSI (median dose, 36 Gy; interquartile range, 36–36). Of these 29 patients, 18 (62%) were alive at the time of publication, compared with 6 of 25 patients (24%) who did not receive CSI.[12][Level of evidence B4]
High-dose chemotherapy with stem cell rescue
For patients who have previously received radiation therapy, higher-dose chemotherapeutic regimens, supported with autologous bone marrow rescue or peripheral stem cell support, have been used with variable results.[10,11,33–36][Level of evidence B4]; [37–39][Level of evidence C1]
With such regimens, objective response is frequent, occurring in 50% to 75% of patients. However, long-term disease control is obtained in fewer than 30% of patients and is seen primarily in patients in first relapse and those with only localized disease at the time of relapse.[11]; [36][Level of evidence B4]; [37][Level of evidence C1]
Additionally, results from national trials for relapsed medulloblastoma that specified intent to transplant as part of their treatment plan showed that only approximately 5% of patients initiating retrieval therapy achieved long-term disease-free survival with this strategy.[36,40] Thus, studies that report from the time of transplant overestimate the benefit of transplant-based approaches for the total population of patients who have a relapse.
Long-term disease control for patients with disseminated disease is infrequent.[41][Level of evidence C1]
Molecularly targeted therapy
With increased knowledge of the molecular and genetic changes associated with different subtypes of medulloblastoma, molecularly targeted therapy, also called precision therapy, is being actively explored in children with recurrent disease.
In patients with recurrent SHH-activated medulloblastomas, the SHH PTCH1 inhibitor vismodegib demonstrated radiographic responses in 3 of 12 pediatric patients. Two of the responses were sustained for less than 2 months, and one response was sustained for more than 6 months. Response was only seen in patients with upstream variants of the SHH pathway, at the level of PTCH1 or SMO.[42] However, because of the development of irreversible growth plate fusions, the use of vismodegib is limited to skeletally mature children.[43]
Treatment Options Under Clinical Evaluation for Recurrent Childhood Medulloblastoma and Other CNS Embryonal Tumors
Early-phase therapeutic trials may be available for selected patients. These trials may be available via the Children’s Oncology Group (COG), the Pediatric Brain Tumor Consortium, or other entities. Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
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Butturini AM, Jacob M, Aguajo J, et al.: High-dose chemotherapy and autologous hematopoietic progenitor cell rescue in children with recurrent medulloblastoma and supratentorial primitive neuroectodermal tumors: the impact of prior radiotherapy on outcome. Cancer 115 (13): 2956-63, 2009. [PUBMED Abstract]
Robinson GW, Rudneva VA, Buchhalter I, et al.: Risk-adapted therapy for young children with medulloblastoma (SJYC07): therapeutic and molecular outcomes from a multicentre, phase 2 trial. Lancet Oncol 19 (6): 768-784, 2018. [PUBMED Abstract]
Wetmore C, Herington D, Lin T, et al.: Reirradiation of recurrent medulloblastoma: does clinical benefit outweigh risk for toxicity? Cancer 120 (23): 3731-7, 2014. [PUBMED Abstract]
Baroni LV, Freytes C, Fernández Ponce N, et al.: Craniospinal irradiation as part of re-irradiation for children with recurrent medulloblastoma. J Neurooncol 155 (1): 53-61, 2021. [PUBMED Abstract]
Hill RM, Richardson S, Schwalbe EC, et al.: Time, pattern, and outcome of medulloblastoma relapse and their association with tumour biology at diagnosis and therapy: a multicentre cohort study. Lancet Child Adolesc Health 4 (12): 865-874, 2020. [PUBMED Abstract]
Abe M, Tokumaru S, Tabuchi K, et al.: Stereotactic radiation therapy with chemotherapy in the management of recurrent medulloblastomas. Pediatr Neurosurg 42 (2): 81-8, 2006. [PUBMED Abstract]
Friedman HS, Oakes WJ: The chemotherapy of posterior fossa tumors in childhood. J Neurooncol 5 (3): 217-29, 1987. [PUBMED Abstract]
Needle MN, Molloy PT, Geyer JR, et al.: Phase II study of daily oral etoposide in children with recurrent brain tumors and other solid tumors. Med Pediatr Oncol 29 (1): 28-32, 1997. [PUBMED Abstract]
Gaynon PS, Ettinger LJ, Baum ES, et al.: Carboplatin in childhood brain tumors. A Children’s Cancer Study Group Phase II trial. Cancer 66 (12): 2465-9, 1990. [PUBMED Abstract]
Allen JC, Walker R, Luks E, et al.: Carboplatin and recurrent childhood brain tumors. J Clin Oncol 5 (3): 459-63, 1987. [PUBMED Abstract]
Ashley DM, Longee D, Tien R, et al.: Treatment of patients with pineoblastoma with high dose cyclophosphamide. Med Pediatr Oncol 26 (6): 387-92, 1996. [PUBMED Abstract]
Lefkowitz IB, Packer RJ, Siegel KR, et al.: Results of treatment of children with recurrent medulloblastoma/primitive neuroectodermal tumors with lomustine, cisplatin, and vincristine. Cancer 65 (3): 412-7, 1990. [PUBMED Abstract]
Friedman HS, Mahaley MS, Schold SC, et al.: Efficacy of vincristine and cyclophosphamide in the therapy of recurrent medulloblastoma. Neurosurgery 18 (3): 335-40, 1986. [PUBMED Abstract]
Castello MA, Clerico A, Deb G, et al.: High-dose carboplatin in combination with etoposide (JET regimen) for childhood brain tumors. Am J Pediatr Hematol Oncol 12 (3): 297-300, 1990. [PUBMED Abstract]
Cefalo G, Massimino M, Ruggiero A, et al.: Temozolomide is an active agent in children with recurrent medulloblastoma/primitive neuroectodermal tumor: an Italian multi-institutional phase II trial. Neuro Oncol 16 (5): 748-53, 2014. [PUBMED Abstract]
Le Teuff G, Castaneda-Heredia A, Dufour C, et al.: Phase II study of temozolomide and topotecan (TOTEM) in children with relapsed or refractory extracranial and central nervous system tumors including medulloblastoma with post hoc Bayesian analysis: A European ITCC study. Pediatr Blood Cancer 67 (1): e28032, 2020. [PUBMED Abstract]
Levy AS, Krailo M, Chi S, et al.: Temozolomide with irinotecan versus temozolomide, irinotecan plus bevacizumab for recurrent medulloblastoma of childhood: Report of a COG randomized Phase II screening trial. Pediatr Blood Cancer 68 (8): e29031, 2021. [PUBMED Abstract]
Minturn JE, Janss AJ, Fisher PG, et al.: A phase II study of metronomic oral topotecan for recurrent childhood brain tumors. Pediatr Blood Cancer 56 (1): 39-44, 2011. [PUBMED Abstract]
Peyrl A, Chocholous M, Kieran MW, et al.: Antiangiogenic metronomic therapy for children with recurrent embryonal brain tumors. Pediatr Blood Cancer 59 (3): 511-7, 2012. [PUBMED Abstract]
Peyrl A, Chocholous M, Sabel M, et al.: Sustained Survival Benefit in Recurrent Medulloblastoma by a Metronomic Antiangiogenic Regimen: A Nonrandomized Controlled Trial. JAMA Oncol 9 (12): 1688-1695, 2023. [PUBMED Abstract]
Ridola V, Grill J, Doz F, et al.: High-dose chemotherapy with autologous stem cell rescue followed by posterior fossa irradiation for local medulloblastoma recurrence or progression after conventional chemotherapy. Cancer 110 (1): 156-63, 2007. [PUBMED Abstract]
Bakst RL, Dunkel IJ, Gilheeney S, et al.: Reirradiation for recurrent medulloblastoma. Cancer 117 (21): 4977-82, 2011. [PUBMED Abstract]
Dunkel IJ, Boyett JM, Yates A, et al.: High-dose carboplatin, thiotepa, and etoposide with autologous stem-cell rescue for patients with recurrent medulloblastoma. Children’s Cancer Group. J Clin Oncol 16 (1): 222-8, 1998. [PUBMED Abstract]
Park JE, Kang J, Yoo KH, et al.: Efficacy of high-dose chemotherapy and autologous stem cell transplantation in patients with relapsed medulloblastoma: a report on the Korean Society for Pediatric Neuro-Oncology (KSPNO)-S-053 study. J Korean Med Sci 25 (8): 1160-6, 2010. [PUBMED Abstract]
Gilman AL, Jacobsen C, Bunin N, et al.: Phase I study of tandem high-dose chemotherapy with autologous peripheral blood stem cell rescue for children with recurrent brain tumors: a Pediatric Blood and MarrowTransplant Consortium study. Pediatr Blood Cancer 57 (3): 506-13, 2011. [PUBMED Abstract]
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Latest Updates to This Summary (04/11/2025)
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
This summary was comprehensively reviewed.
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.
About This PDQ Summary
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood medulloblastoma and other central nervous system embryonal tumors. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
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Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Childhood Medulloblastoma and Other Central Nervous System Embryonal Tumors Treatment are:
Kenneth J. Cohen, MD, MBA (Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital)
Louis S. Constine, MD (James P. Wilmot Cancer Center at University of Rochester Medical Center)
Roger J. Packer, MD (Children’s National Hospital)
Malcolm A. Smith, MD, PhD (National Cancer Institute)
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Levels of Evidence
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PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Medulloblastoma and Other Central Nervous System Embryonal Tumors Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/brain/hp/child-cns-embryonal-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389418]
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