Epidemiology and classification of central nervous system tumors in children

INTRODUCTION — Central nervous system (CNS) tumors include both nonmalignant and malignant tumors of the brain and spinal cord. Primary malignant CNS tumors are the second most common childhood malignancies after hematologic malignancies and are the most common pediatric solid organ tumor (table 1) [1-3]. Although progress has been made in the treatment of childhood tumors, significant mortality and morbidity are still associated with malignant brain tumors.

The epidemiology of CNS tumors in children will be reviewed here. The clinical manifestations, diagnosis, and overview of the management of CNS tumors and outcome in children are discussed separately. (See "Clinical manifestations and diagnosis of central nervous system tumors in children" and "Overview of the management of central nervous system tumors in children".)

INCIDENCE — In the United States from 2015 to 2019, the average annual incidence of primary nonmalignant and malignant CNS tumors for children and adolescents ≤19 years of age was 6.3 cases per 100,000 population [4]. Approximately 58 percent of cases were malignant and 42 percent were nonmalignant. Somewhat lower incidence rates have been reported in other parts of the world, including Japan (estimated incidence 3.61 per 100,000 children) [5], Italy (3.46 per 100,000 children) [6], Germany (2.6 per 100,000 children) [7], Australia (3 per 100,000 children) [8], and Taiwan (1.7 per 100,000 children) [9].

In the United States, CNS tumors are the most common solid tumors in children (table 1) and a leading cause of cancer death in children 0 through 14 years [1,4,10,11]. Malignant CNS tumors account for approximately 15 to 20 percent of all childhood malignancies (table 1).

The incidence of childhood CNS tumors varies with age, sex, race, and ethnicity [12]:

●Age – The incidence of childhood CNS tumors varies with age. In a report from the Central Brain Tumor Registry of the United States (CBTRUS; 2015 to 2019), the following overall annual age-adjusted incidence rates of CNS tumors per 100,000 population were reported [4]:

•Age 0 to 4 years – 6.03 per 100,000

•Age 5 to 9 years – 5.47 per 100,000

•Age 10 to 14 years – 5.88 per 100,000

•Age 15 to 19 years – 7.40 per 100,000

●Sex – The rate is higher in males compared with females [1,4,13].

●Race and ethnicity – The incidence of CNS tumors per 100,000 population in CBTRUS is greatest in White American and Asian/Pacific Islander children [4]:

•White Americans – 6.39 per 100,000

•Black Americans – 4.89 per 100,000

•Asian/Pacific Islanders – 3.47 per 100,000

•American Indians/Alaska Natives – 3.47 per 100,000

TRENDS OVER TIME — Incidence rate increased for all age groups from 1975 to 1980 and 1987 to 1992. This change in incidence did not occur progressively from 1975 to 1994 but jumped to a higher rate after 1985. This increase has been attributed to the increased availability of magnetic resonance imaging (MRI), which likely resulted in improved diagnostic sensitivity rather than an actual increase in incidence [14].

CLASSIFICATION — Two main classification systems are used to categorize childhood CNS tumors:

●World Health Organization (WHO) classification is based on tumor histology and molecular parameters

●International Classification of Childhood Cancer (ICCC) is based on the primary tumor site and morphology

World Health Organization classification — WHO classification for CNS tumors, which has been universally adopted in grouping CNS tumors, was first published in 1979 and subsequently revised five times, most recently in 2021 [15]. The 2021 WHO classification introduces major changes that advance the role of molecular diagnostics in CNS tumor classification and emphasizes the importance of integrated diagnoses (algorithm 1 and table 2 and table 3) [16].

The classification of gliomas is discussed in greater detail separately. (See "Classification and pathologic diagnosis of gliomas, glioneuronal tumors, and neuronal tumors".)

Distribution by tumor type — The relative frequencies of different tumor types vary with age. The distribution in children differs from that in adults (figure 1 and figure 2) [12]. In children, primary CNS tumors predominate and approximately one-third to one-half are located in the posterior fossa (figure 3). By contrast, CNS tumors in adults are often metastatic lesions to the cerebral cortex. These differences translate to differences in clinical presentation between pediatric and adult malignant CNS tumors. (See "Clinical manifestations and diagnosis of central nervous system tumors in children".)

The following sections provide brief summaries of epidemiologic data on selected childhood malignant and nonmalignant CNS tumor types, each of which is discussed in greater detail separately.

●Gliomas – The 2021 WHO classification is the first to separate diffuse gliomas that primarily occur in children from those that primarily occur in adults, recognizing the clinically and biologically distinct nature of these groups [15]. Gliomas account for approximately one-half of all CNS tumors in children and adolescents [2].

•Circumscribed astrocytomas – Several astrocytic gliomas are relatively indolent lesions, which are more circumscribed than the diffuse gliomas. All occur primarily in children. Among these, pilocytic astrocytoma is the most common, with an incidence of approximately 1 per 100,000 population (image 1) [2]. Other astrocytic tumors in this category include high-grade astrocytoma with piloid features, pleomorphic xanthoastrocytoma, subependymal giant cell astrocytoma (SEGA), chordoid glioma, and astroblastoma, MN1-altered. (See "Uncommon brain tumors", section on 'Circumscribed astrocytic gliomas'.)

•Pediatric-type diffuse low-grade gliomas – Four pediatric-type diffuse gliomas are recognized (table 2). Three of the four are WHO grade 1 tumors that typically occur in infants or young children and can be cured by surgery alone. Molecular alterations in the mitogen-activated protein kinase (MAPK) pathway define the fourth tumor in this group, which are low-grade gliomas with diffuse astrocytic or oligodendroglial morphology. (See "Classification and pathologic diagnosis of gliomas, glioneuronal tumors, and neuronal tumors", section on 'Pediatric-type diffuse low-grade gliomas'.)

•Pediatric-type diffuse high-grade gliomas – High-grade gliomas in children are divided into diffuse midline glioma, H3 K27-altered (which includes most diffuse intrinsic pontine gliomas); diffuse hemispheric glioma, H3 G34-altered; diffuse high-grade glioma, H3- and isocitrate dehydrogenase (IDH)-wildtype; and infant-type hemispheric glioma (table 2). These highly malignant and aggressive tumors carry an extremely poor prognosis. (See "Diffuse intrinsic pontine glioma" and "Classification and pathologic diagnosis of gliomas, glioneuronal tumors, and neuronal tumors", section on 'Pediatric-type diffuse high-grade gliomas'.)

•Ependymomas – Ependymal tumors are derived from primitive glia (table 4). Ependymomas account for 10 percent of intracranial tumors and 40 to 60 percent of spinal cord tumors in children and young adults, with a reported incidence of 0.3 per 100,000 population [2,17]. In children, approximately 90 percent of ependymomas are intracranial (60 percent in the posterior fossa); the remaining tumors arise within the spinal cord. In children <3 years of age, ependymomas are typically posterior fossa tumors located about or within the fourth ventricle (image 2). (See "Intracranial ependymoma and other ependymal tumors".)

●Medulloblastoma – Medulloblastoma is one of the most common malignant brain tumors of childhood (table 3). It accounts for approximately 6 to 7 percent of all pediatric CNS tumors (malignant and nonmalignant) [2]. It occurs primarily in the cerebellum (image 3). (See "Clinical presentation, diagnosis, and risk stratification of medulloblastoma".)

●Embryonal tumors – Excluding medulloblastoma, other embryonal CNS tumors include atypical teratoid rhabdoid tumors, embryonal tumor with multilayered rosettes, forkhead box R2 (FOXR2)-activated CNS neuroblastoma, and CNS tumor with BCL6 corepressor (BCOR) internal tandem duplication (table 5). In addition, some tumors previously diagnosed as CNS primitive neuroectodermal tumor (PNET) remain in a category referred to as CNS embryonal tumor, not otherwise specified (NOS). Embryonal tumors are highly malignant brain tumors associated with a very poor prognosis. (See "Uncommon brain tumors", section on 'Embryonal tumors'.)

●Tumors of the sellar region – Tumors of the sellar region include pituitary tumors and craniopharyngiomas. These tumors are generally located in the suprasellar area and arise from remnants of Rathke pouch. Together, they account for approximately 15 percent of all pediatric CNS tumors [2]. (See "Causes, presentation, and evaluation of sellar masses" and "Craniopharyngioma".)

●Glioneuronal and neuronal tumors – Glioneuronal and neuronal tumors are characterized by a variable degree of neuronal differentiation (table 6) [2]. They include gangliomas and gangliocytomas, dysplastic gangliogliocytoma of the cerebellum (Lhermitte-Duclos disease), cerebellar liponeurocytomas, central neurocytomas, and glomus tumors (paragangliomas). They account for approximately 7 percent of all pediatric CNS tumors [2]. (See "Uncommon brain tumors", section on 'Glioneuronal and neuronal tumors'.)

●Tumors of cranial and paraspinal nerves – Tumors of cranial and paraspinal nerves include schwannomas, neurofibromas, and malignant peripheral nerve sheath tumors. They account for approximately 5 percent of all pediatric CNS tumors [2]. (See "Intradural nerve sheath tumors".)

●Germ cell tumors – Germ cell tumors include germinoma, embryonal carcinoma, yolk sac tumor (endodermal sinus tumors), choriocarcinoma, and teratoma. They account for approximately 3 to 4 percent of all pediatric CNS tumors [2]. Approximately two-thirds of these tumors occur in the pineal and suprasellar areas, and the remaining occur in the supratentorial region.

●Meningiomas – Tumors of the meninges arise from the arachnoidal cap cell in the arachnoid membrane and have varying degrees of malignancy. They account for approximately 2 to 3 percent of all pediatric CNS tumors [2]. (See "Epidemiology, pathology, clinical features, and diagnosis of meningioma".)

●Lymphomas – Lymphoma and hemopoietic neoplasms account for a very small proportion of CNS tumors in children (<1 percent of all pediatric CNS tumors) [2].

●Unclassified tumors – Unclassified tumors include hemangiomas and other unspecified neoplasms [2].

The data described above reflect the distribution of the different tumor types in pediatric patients in the United States. The distribution may differ in other populations. For example, in a retrospective study of 1485 cases of primary CNS tumors in children cared for at a single neurosurgical center in China between 2001 and 2005, the five most common brain tumors were [13]:

●Astrocytic tumors (31 percent)

●Craniopharyngiomas (18 percent)

●Medulloblastoma (15 percent)

●Germ cell tumors (8 percent)

●Ependymal tumors (6 percent)

In the same report, the most common spinal cord tumors were ependymal tumors (19 percent), schwannomas (17 percent), and astrocytomas (15 percent) [13].

International Classification of Childhood Cancer classification — ICCC is based upon primary tumor site and is used by the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute in their epidemiologic survey of childhood cancer in the United States.

In this classification schema, tumors are categorized by site of origin, separating brain tumors from spine and cranial nerve tumors. Tumors are then further subdivided into histologic groups: ependymoma, astrocytoma, PNET, other gliomas, and miscellaneous.

A limitation of the ICCC classification is that mortality rates for tumors based upon their underlying histology cannot be identified, because the initial categorization is based on site. As an example, astrocytomas of the spinal cord would not be categorized with brain astrocytomas.

Distribution by site — The location of the tumor may impact the clinical presentation. As an example, vision loss may occur with any tumor that is localized along the optic pathway. Infratentorial tumors may present with localizing signs of ataxia or cranial neuropathies. (See "Clinical manifestations and diagnosis of central nervous system tumors in children", section on 'Tumor location'.)

The distribution of CNS tumors by site based on Central Brain Tumor Registry of the United States (CBTRUS) data is shown in the figure (figure 3) [12].

In the previously mentioned Chinese report of 1485 primary CNS tumors, 92 percent were located in the brain and 8 percent were located in the spinal cord. Sixty-two percent of the brain tumors were supratentorial.

Because spinal cord tumors are relatively rare, it is difficult to ascertain the relative frequency of specific tumors. In one case series of 35 children with a spinal cord tumor, 11 patients had neurodevelopmental tumors (ie, dermoid and epidermoid tumors, and teratomas), followed by 10 with astrocytoma, and 5 with neuroblastoma [18]. Other causes of spinal tumors included schwannoma, meningioma, giant cell tumors, extradural cystic masses, leukemic-related masses, and masses associated with neurofibromatosis (NF).

RISK FACTORS — Although the etiology of most childhood CNS tumors remains unknown, two established risk factors for the development of a CNS tumor include:

●Exposure to ionizing radiation − Cranial irradiation results in an increased risk of developing meningiomas, gliomas, and nerve sheath tumors [19]. In particular, high-dose cranial irradiation in patients with acute lymphoblastic leukemia is associated with a 6- and 10-fold increase in the risk of glioma and meningioma, respectively. (See "Acute lymphoblastic leukemia/lymphoblastic lymphoma: Outcomes and late effects of treatment in children and adolescents", section on 'Brain tumors' and "Risk factors for brain tumors", section on 'Ionizing radiation'.)

●Genetic predisposition − Many pediatric patients with CNS tumors have a genetic predisposition. In a study that used next-generation sequencing to determine the contribution of germline predisposition mutations in 1120 children with cancer, mutations that were deemed to be pathogenic or probably pathogenic were identified in 20 of 245 patients (8 percent) with CNS tumors [20].

Genetic syndromes that confer an increased risk of developing tumors of the nervous system include the following genetic conditions, which are discussed in greater detail separately:

•Neurofibromatosis (NF) is an autosomal dominant neurocutaneous disorder, which includes NF type 1 (also known as von Recklinghausen disease) and NF type 2. Both are associated with CNS tumors. (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis" and "NF2-related schwannomatosis (formerly neurofibromatosis type 2)".)

•Tuberous sclerosis is an autosomal dominant neurocutaneous disorder that is characterized by pleomorphic features involving many organ systems, including multiple benign neoplasms of the brain, kidney, and skin. (See "Tuberous sclerosis complex: Clinical features", section on 'Brain lesions'.)

•Von Hippel-Lindau disease is an autosomal dominant disorder associated with hemangioblastomas, pancreatic cysts, neuroendocrine tumors, renal tumors, and pheochromocytomas. (See "Clinical features, diagnosis, and management of von Hippel-Lindau disease" and "Molecular biology and pathogenesis of von Hippel-Lindau disease".)

•Basal cell nevus syndrome, also referred to as Gorlin syndrome or nevoid basal cell cancer syndrome, is caused by germline mutations of the patched 1 (PTCH) gene, a tumor suppressor gene. It is associated with an increased risk of medulloblastoma. (See "Nevoid basal cell carcinoma syndrome (Gorlin syndrome)".)

•Li-Fraumeni syndrome is an autosomal dominant disorder characterized by soft tissue and bone sarcomas, breast cancers, and other malignancies, including brain tumors, leukemia, and adrenocortical cancer. (See "Li-Fraumeni syndrome".)

•Turcot syndrome is a disorder that includes brain tumors (primarily medulloblastomas and gliomas) and one of two forms of colonic polyposis. (See "Clinical manifestations and diagnosis of familial adenomatous polyposis", section on 'Extracolonic manifestations'.)

Maternal exposure to drugs during pregnancy is of interest as a risk factor for childhood brain tumors and other cancers, but existing data are limited and inconclusive [21]. In a case-control study of 280 childhood brain tumor cases and over 900 matched controls that used maternal interviews to assess fetal exposure to a variety of medication classes, maternal use of immunosuppressant medications was associated with increased risk of glial tumors (odds ratio 2.73, 95% CI 1.17-6.39) [22]. This finding warrants further study, as maternal blood and immune disorders have been identified as a potential risk factor in at least one other epidemiologic study [23].

SURVIVAL RATES — Survival after diagnosis with a primary brain or other CNS tumor varies considerably, depending on the age of the child and the type of tumor. Based on data from the Central Brain Tumor Registry of the United States (CBTRUS; 2015 to 2019), pituitary and nerve sheath tumors were the histologic groups with the highest survival rates after diagnosis, whereas embryonal tumors and malignant gliomas had the lowest survival rates after diagnosis [4].

The prognosis of the following specific CNS tumors that occur in children are discussed separately:

●Pilocytic astrocytoma (see "Uncommon brain tumors", section on 'Pilocytic astrocytoma')

●Malignant gliomas (see "Diffuse intrinsic pontine glioma")

●Medulloblastoma (see "Treatment and prognosis of medulloblastoma", section on 'Prognosis and genetic risk')

●Craniopharyngioma (see "Craniopharyngioma", section on 'Prognosis')

●Ependymoma (see "Intracranial ependymoma and other ependymal tumors", section on 'Prognosis')

●Focal brainstem glioma (see "Focal brainstem glioma", section on 'Prognosis')

●Germ cell tumors (see "Intracranial germ cell tumors")

●Intradural nerve sheath tumors, such as schwannomas, neurofibromas, and malignant peripheral nerve sheath tumors (see "Intradural nerve sheath tumors", section on 'Prognosis')

●Meningioma (see "Management of known or presumed benign (WHO grade 1) meningioma", section on 'Outcomes and prognosis' and "Management of atypical and malignant (WHO grade 2 and 3) meningioma", section on 'Prognosis')

●Spinal cord tumors (see "Spinal cord tumors")

●Tuberous sclerosis (see "Tuberous sclerosis complex: Clinical features", section on 'Presentation')

●Other uncommon brain tumors (see "Uncommon brain tumors")

SUMMARY

●Epidemiology – In the United States, the estimated incidence of childhood primary nonmalignant and malignant central nervous system (CNS) tumors is approximately 6 cases per 100,000 population. Somewhat lower incidence rates are reported in other parts of the world.

In the United States, primary malignant CNS tumors are the second most common childhood malignancies after hematologic malignancies and are the most common pediatric solid organ tumor (table 1). CNS tumors are a leading cause of cancer death in children 0 through 14 years. (See 'Incidence' above.)

●Classification – CNS tumors are classified according to histology and molecular parameters. The most common tumor types in children include gliomas (particularly pilocytic astrocytomas) and medulloblastomas (figure 1). The distribution varies with age (figure 2). (See 'World Health Organization classification' above.)

●Distribution – The location of the tumor impacts the clinical presentation. Brain tumors account for approximately 90 percent of all CNS tumors, and the remaining CNS tumors are found in the spinal cord and cranial nerves. Approximately one-third to one-half of CNS tumors in children are located in the posterior fossa (figure 3). (See 'Distribution by site' above.)

●Risk factors – Although the etiology of most childhood CNS tumors remains unknown, two established risk factors for the development of a CNS tumor in children include exposure to ionizing radiation and genetic predisposition. (See 'Risk factors' above.)

●Prognosis – Survival time after diagnosis with primary brain or other CNS tumor varies considerably, depending on the age of the child and the tumor type. (See 'Survival rates' above.)