General Information About Childhood Brain and Spinal Cord Tumors

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%.[1] Childhood and adolescent cancer survivors require close monitoring because cancer therapy side effects may persist or develop months or years after treatment. Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.

Primary brain tumors are a diverse group of diseases that together constitute the most common solid tumor of childhood. 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]

Incidence

The Central Brain Tumor Registry of the United States (CBTRUS) estimates that approximately 4,300 U.S. children are diagnosed each year.[3]

References:

1. Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014.
2. 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.
3. 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.

Classification of Central Nervous System Tumors

The classification of childhood central nervous system (CNS) tumors is based on histology and location.[1] Tumors are classically categorized as infratentorial, supratentorial, parasellar, or spinal. Immunohistochemical analysis, cytogenetic and molecular genetic findings, and measures of proliferative activity are increasingly used in tumor diagnosis and classification and will likely affect classification and nomenclature in the future.

Primary CNS spinal cord tumors comprise approximately 1% to 2% of all childhood CNS tumors. The classification of spinal cord tumors is based on histopathologic characteristics of the tumor and does not differ from that of primary brain tumors.[1]

Infratentorial (posterior fossa) tumors include the following:

1. Cerebellar astrocytomas (most commonly pilocytic, but also diffuse and, less frequently, anaplastic astrocytoma or glioblastoma).
2. Medulloblastomas (including classic, desmoplastic/nodular, extensive nodularity, anaplastic, or large cell variants).
3. Ependymomas (papillary, clear cell, tanycytic, or anaplastic).
4. Brain stem gliomas (typically diffuse midline glioma, H3 K27M-mutant, and other diffuse midline gliomas; focal, tectal, and exophytic cervicomedullary gliomas are most frequently pilocytic astrocytomas).
5. Atypical teratoid/rhabdoid tumors.
6. Choroid plexus tumors (papillomas and carcinomas).

Supratentorial tumors include the following:

1. Low-grade cerebral hemispheric astrocytomas (grade I [pilocytic] astrocytomas or grade II [diffuse] astrocytomas).
2. High-grade or malignant astrocytomas (anaplastic astrocytomas and glioblastoma).
3. Oligodendrogliomas (low-grade, anaplastic, and mixed oligoastrocytomas).
4. Neuronal and mixed neuronal glial tumors (gangliogliomas, desmoplastic infantile astrocytoma/gangliogliomas, dysembryoplastic neuroepithelial tumors, and papillary glioneuronal tumors).
5. Other low-grade gliomas (including subependymal giant cell tumors and pleomorphic xanthoastrocytoma).
6. Embryonal tumors, including embryonal tumor with multilayered rosettes (ETMR) (C19MC-altered or not otherwise specified), medulloepithelioma, CNS neuroblastoma, CNS ganglioneuroblastoma, CNS embryonal tumor, and CNS embryonal tumor with rhabdoid features.
7. Atypical teratoid/rhabdoid tumors.
8. Ependymomas (papillary, clear cell, tanycytic, RELA-fusion positive, or anaplastic).
9. Meningiomas (grades I, II, and III).
10. Choroid plexus tumors (papillomas, carcinomas, and atypical choroid plexus tumor).
11. Tumors of the pineal region (pineocytomas, pineoblastomas, pineal parenchymal tumors of intermediate differentiation, and papillary tumors of the pineal region) and germ cell tumors.
12. Metastasis (rare) from extraneural malignancies.

Parasellar tumors include the following:

1. Craniopharyngiomas.
2. Diencephalic astrocytomas (central tumors involving the chiasm, hypothalamus, and/or thalamus) that are generally low-grade (including astrocytomas, grade I [pilocytic] or grade II [diffuse]).
3. Germ cell tumors (germinomas or nongerminomatous).

Spinal cord tumors include the following:

1. Low-grade astrocytomas (grade I [pilocytic] astrocytomas or grade II [diffuse] astrocytomas).
2. High-grade or malignant astrocytomas (anaplastic astrocytomas and glioblastoma [grade III or grade IV]).
3. Gangliogliomas.
4. Ependymomas (often myxopapillary).

References:

1. 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.

General Approach to Care for Children With Brain and Spinal Cord Tumors

Important concepts that should be understood by those treating and caring for a child who has a brain tumor or spinal cord tumor include the following:

1. The cause of most childhood brain tumors remains unknown; however, germline mutations are becoming increasingly recognized as cancer-predisposing, as they are identified in up to 8% of children with cancer.[1,2]
2. Selection of an appropriate therapy can only occur if the correct diagnosis is made and the stage of the disease is accurately determined.
3. Children with primary brain or spinal cord tumors represent a major therapy challenge that, for optimal results, requires the coordinated efforts of pediatric specialists in fields such as neurosurgery, neuropathology, radiation oncology, pediatric oncology, neuro-oncology, neurology, rehabilitation, neuroradiology, endocrinology, and psychology, who have special expertise in the care of patients with these diseases.[3,4] For example, radiation therapy of pediatric brain tumors is technically demanding and should be performed in centers that have experience in this area.
4. For most childhood brain and spinal cord tumors, the optimal treatment regimen has not been determined. Children who have brain and spinal cord tumors should be considered for enrollment in a clinical trial when an appropriate study is available. Such clinical trials are being carried out by institutions and cooperative groups. Survival of childhood cancer has increased as a result of clinical trials that have attempted to improve upon the best accepted therapy available. Clinical trials in pediatrics are designed to compare new therapy with treatment 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 then comparing the results with those previously obtained from existing therapy. Information about ongoing clinical trials is available from the NCI website.
5. While more than 70% of children diagnosed with brain tumors will survive for more than 5 years after diagnosis, survival rates are wide-ranging depending on tumor type and stage. Long-term sequelae related to the initial presence of the tumor and subsequent treatment are common.[5,6,7] Debilitating effects on growth and neurologic development have frequently been observed after radiation therapy, especially in younger children. Secondary tumors have increasingly been diagnosed in long-term survivors.[8] For this reason, the role of chemotherapy in allowing a delay or reduction in the administration of radiation therapy is under study, and preliminary results suggest that chemotherapy can be used to delay, limit, and sometimes obviate, the need for radiation therapy in children with benign and malignant lesions.[9,10,11] Long-term management of these patients is complex and requires a multidisciplinary approach.

   (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information about possible long-term or late effects.)

6. Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics.[12]

References:

1. Fisher JL, Schwartzbaum JA, Wrensch M, et al.: Epidemiology of brain tumors. Neurol Clin 25 (4): 867-90, vii, 2007.
2. Zhang J, Walsh MF, Wu G, et al.: Germline Mutations in Predisposition Genes in Pediatric Cancer. N Engl J Med 373 (24): 2336-46, 2015.
3. Parsons DW, Pollack IF, Hass-Kogan DA, et al.: Gliomas, ependymomas, and other nonembryonal tumors of the central nervous system. In: Pizzo PA, Poplack DG, eds.: Principles and Practice of Pediatric Oncology. 7th ed. Philadelphia, Pa: Lippincott Williams and Wilkins, 2015, pp 628-70.
4. Pollack IF: Brain tumors in children. N Engl J Med 331 (22): 1500-7, 1994.
5. Smith MA, Seibel NL, Altekruse SF, et al.: Outcomes for children and adolescents with cancer: challenges for the twenty-first century. J Clin Oncol 28 (15): 2625-34, 2010.
6. Reimers TS, Mortensen EL, Nysom K, et al.: Health-related quality of life in long-term survivors of childhood brain tumors. Pediatr Blood Cancer 53 (6): 1086-91, 2009.
7. Iuvone L, Peruzzi L, Colosimo C, et al.: Pretreatment neuropsychological deficits in children with brain tumors. Neuro Oncol 13 (5): 517-24, 2011.
8. Armstrong GT: Long-term survivors of childhood central nervous system malignancies: the experience of the Childhood Cancer Survivor Study. Eur J Paediatr Neurol 14 (4): 298-303, 2010.
9. 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.
10. 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.
11. 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.
12. Corrigan JJ, Feig SA; American Academy of Pediatrics: Guidelines for pediatric cancer centers. Pediatrics 113 (6): 1833-5, 2004.

Treatment of Newly Diagnosed and Recurrent Childhood Brain Tumors

Presently, there is no uniformly accepted staging system for most childhood brain tumors. These tumors are classified and treated on the basis of their histology and location within the brain (refer to the Table below). With advances in molecular data, it is conceivable that genomic factors will refine classification approaches and will be used progressively more to stratify patients entered on clinical trials.

Newly Diagnosed or Recurrent Tumor Type and Its Related PDQ Treatment Summary

Tumor Type	Pathologic Subtype	Related PDQ Treatment Summary
CNS = central nervous system; NOS = not otherwise specified; WHO = World Health Organization.
a Grade uncertain.
Astrocytomas and Other Tumors of Glial Origin
–Low-Grade Astrocytomas	Diffuse astrocytoma,IDH-mutant,IDH-wild type, or NOS	Childhood Astrocytomas Treatment
	Pilocytic astrocytoma
	Pleomorphic xanthoastrocytoma
	Subependymal giant cell astrocytoma
–High-Grade Astrocytomas	Anaplastic astrocytoma,IDH-mutant orIDH-wild type	Childhood Astrocytomas Treatment
	Anaplastic pleomorphic xanthoastrocytoma
	Diffuse midline glioma,H3 K27M-mutant
	Glioblastoma,IDH-mutant
	Glioblastoma,IDH-wildtype
–Other Astrocytomas or Gliomas	Angiocentric glioma	Childhood Astrocytomas Treatment
	Astroblastomaa
	Choroid glioma of the third ventricle
	Pilomyxoid astrocytomaa
Brain Stem Glioma
	Diffuse intrinsic pontine glioma,H3 K27M-mutant	Childhood Brain Stem Glioma Treatment
	Focal or low-grade brain stem glioma
CNS Embryonal Tumors
–Medulloblastomas	Medulloblastoma, WNT-activated	Childhood CNS Embryonal Tumors Treatment
	Medulloblastoma, SHH-activated andTP53-mutant
	Medulloblastoma, SHH-activated andTP53-wildtype
	Medulloblastoma, non-WNT/non-SHH
–Nonmedulloblastomas	CNS ganglioneuroblastoma
	CNS neuroblastoma
	Embryonal tumor with multilayered rosettes (ETMR),C19MC-altered or NOS
	Medulloepithelioma
–CNS Atypical Teratoid/Rhabdoid Tumor	Childhood CNS Atypical Teratoid/Rhabdoid Tumor Treatment
Pineal Parenchymal Tumors	Pineoblastoma	Childhood CNS Embryonal Tumors Treatment
CNS Germ Cell Tumors
–Germinomas	Childhood CNS Germ Cell Tumors Treatment
–Teratomas		Immature teratoma
		Mature teratoma
		Teratoma with malignant transformation
–Non-Germinomatous Germ Cell Tumors		Choriocarcinoma
		Embryonal carcinoma
		Mixed germ cell tumor
		Yolk sac tumor
Craniopharyngioma	Childhood Craniopharyngioma Treatment
Ependymoma
	Subependymoma (WHO grade I)	Childhood Ependymoma Treatment
	Myxopapillary ependymoma (WHO grade I)
	Ependymoma (WHO grade II)
	Ependymoma,RELAfusion–positive (WHO grade II or grade III)
	Anaplastic ependymoma (WHO grade III)
Tumors of the Choroid Plexus

Recurrence is not uncommon in both low-grade and malignant childhood brain tumors and may occur many years after initial treatment. Disease may occur at the primary tumor site or, especially in malignant tumors, at noncontiguous central nervous system (CNS) sites. Systemic relapse is rare but may occur. At time of recurrence, a complete evaluation for extent of relapse is indicated for all malignant tumors and, at times, for lower-grade lesions. Biopsy or surgical re-resection may be necessary for confirmation of relapse and/or tumor transformation over time, including change in grade and molecular makeup.[1,2] Other entities, such as secondary tumor and treatment-related brain necrosis, may be clinically indistinguishable from tumor recurrence.[3] The determination of the need for surgical intervention must be individualized on the basis of the initial tumor type, the length of time between initial treatment and the reappearance of the lesion, and other clinical parameters.

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

References:

1. Morrissy AS, Garzia L, Shih DJ, et al.: Divergent clonal selection dominates medulloblastoma at recurrence. Nature 529 (7586): 351-7, 2016.
2. Mistry M, Zhukova N, Merico D, et al.: BRAF mutation and CDKN2A deletion define a clinically distinct subgroup of childhood secondary high-grade glioma. J Clin Oncol 33 (9): 1015-22, 2015.
3. Packer RJ, Zhou T, Holmes E, et al.: Survival and secondary tumors in children with medulloblastoma receiving radiotherapy and adjuvant chemotherapy: results of Children’s Oncology Group trial A9961. Neuro Oncol 15 (1): 97-103, 2013.

Treatment of Newly Diagnosed and Recurrent Childhood Spinal Cord Tumors

There is no uniformly accepted staging system for childhood primary spinal cord tumors. These tumors are classified and treated based on their location within the spinal cord, tumor extent at diagnosis, and histology. Refer to the following PDQ summaries for more information on the staging and treatment of newly diagnosed and recurrent childhood spinal cord tumors:

• Childhood Astrocytomas Treatment.
• Childhood Central Nervous System Embryonal Tumors Treatment.
• Childhood Ependymoma Treatment.

Changes to This Summary (08 / 02 / 2017)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

This summary was comprehensively reviewed.

General Information About Childhood Brain and Spinal Cord Tumors

Added Louis et al. as reference 2.

Classification of Central Nervous System Tumors

This section was extensively revised.

General Approach to Care for Children with Brain and Spinal Cord Tumors

Revised text to state that the cause of most childhood brain tumors remains unknown; however, germline mutations are becoming increasingly recognized as cancer-predisposing, as they are identified in up to 8% of children with cancer (cited Zhang et al. as reference 2).

Treatment of Newly Diagnosed and Recurrent Childhood Brain Tumors

Revised text to state that with advances in molecular data, it is conceivable that genomic factors will refine classification approaches and will be used progressively more to stratify patients entered on clinical trials.

Revised the Table to reflect the recent changes to the World Health Organization classification of central nervous system tumors.

Revised text to state that biopsy or surgical re-resection may be necessary for confirmation of relapse and/or tumor transformation over time, including change in grade and molecular makeup (cited Morrissy et al. and Mistry et al. as references 1 and 2, respectively). Also added Packer et al. as reference 3.

This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® – NCI’s Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood brain and spinal cord tumors. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

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

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Childhood Brain and Spinal Cord Tumors Treatment Overview 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 Health System)
• Malcolm A. Smith, MD, PhD (National Cancer Institute)

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

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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The preferred citation for this PDQ summary is:

PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Brain and Spinal Cord Tumors Treatment Overview. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/brain/hp/child-brain-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389453]

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Last Revised: 2017-08-02