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Primary brain tumors, including embryonal tumors, are a diverse group of diseases that together constitute the most common solid tumor of childhood. Brain tumors are classified according to histology, but tumor location and extent of spread are important factors that affect treatment and prognosis. Immunohistochemical analysis, cytogenetic and molecular genetic findings, and measures of mitotic activity are increasingly used in tumor diagnosis and classification.
The PDQ childhood brain tumor treatment summaries are organized primarily according to the World Health Organization (WHO) classification of nervous system tumors. For a full description of the classification of nervous system tumors and a link to the corresponding treatment summary for each type of brain tumor, refer to the PDQ summary on Childhood Brain and Spinal Cord Tumors Treatment Overview.
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 histologic and immunohistochemical features, such as the degree of apparent cellular transformation along identifiable cell lineages (ependymal, glial, etc.), can be used to separate these tumors to some degree. However, a convention, which has been accepted by the WHO, also separates these tumors on the basis of presumed location of origin within the central nervous system (CNS). Molecular studies have substantiated the differences between tumors arising in different areas of the brain and give partial credence to this classification approach.
As of 2016, the WHO has proposed an integrated phenotypic and genotypic classification system for CNS tumors. The term primitive neuroectodermal tumor (PNET) has been removed from the newest WHO diagnostic lexicon, although some rare entities (e.g., medulloepithelioma) have remained. A molecularly distinct entity, embryonal tumor with multilayered rosettes (ETMR), C19MC-altered, has been 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 pathologic 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 utilized for risk stratification and treatment planning.[3,4,5,6]
The most recent WHO categorization of embryonal tumors is as follows:
Pineoblastoma, which in the past was conventionally grouped with embryonal tumors, is categorized by the WHO as a pineal parenchymal tumor. Given that therapies for pineoblastomas are quite similar to those utilized for embryonal tumors, pineoblastomas are discussed in this summary. A somewhat closely aligned tumor, pineal parenchymal tumor of intermediate differentiation, has recently been identified but is not considered an embryonal tumor and primarily arises in adults.
The prognosis for embryonal tumors and pineoblastomas varies greatly depending on the following:[1,7]
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.[2,5,6,8,9,10] Overall survival rates range from 40% to 90%, depending on the molecular subtype of the medulloblastoma and possibly other factors, such as extent of dissemination at time of diagnosis and degree of resection. Children 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%; specifics are discussed within each subgroup in the summary.[11,12,13,14]
Figure 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.
Embryonal tumors comprise 20% to 25% of primary CNS tumors (malignant brain tumors 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 is the incidence of embryonal tumors in adults (refer to Table 1).[15,16]
Medulloblastomas comprise the vast majority of pediatric embryonal tumors and by definition arise in the posterior fossa (refer to 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.
The clinical features of childhood embryonal tumors depend on the location of the tumor and the age of the child at the time of presentation. Embryonal tumors tend to be fast-growing tumors and are usually diagnosed within 3 months of initial onset of symptoms.
In approximately 80% of children, medulloblastomas arise in the region of the fourth ventricle. Most of the early symptomatology is related to blockage of CSF and resultant accumulation of CSF in the brain, termed hydrocephalus. Children with medulloblastoma are usually diagnosed within 2 to 3 months of onset of symptoms and commonly present with the following:
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. At times, medulloblastomas will present explosively, with the acute onset of lethargy and unconsciousness due to hemorrhage within the tumor.
In infants, the presentation of medulloblastoma is more variable and may include the following:
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) due to loss of upgaze secondary to compression of the tectum of the midbrain.
Hereditary cancer predisposition syndromes associated with medulloblastoma
Up to 10% of medulloblastoma cases arise in the setting of hereditary cancer predisposition syndromes. Syndromes known to be associated with medulloblastoma include the following:
Sometimes medulloblastoma may be the initial manifestation of the presence of germline mutations in these predisposition genes.
Nonmedulloblastoma embryonal tumors
For nonmedulloblastoma embryonal tumors, presentation is also relatively rapid and depends on the location of the tumor in the nervous system. Pineoblastomas often result in hydrocephalus due to blockage of CSF 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 manifested by pupils that react poorly to light but better to accommodation, loss of upgaze, retraction or convergence nystagmus, and lid retraction (Parinaud syndrome). As they grow, these tumors may also cause hemiparesis and ataxia.
Supratentorial embryonal tumors (refer to Figure 1) will result in focal neurologic 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. Nonmedulloblastoma embryonal tumors may occur anywhere in the CNS, and presentation is variable. Usually there is significant neurologic dysfunction associated with lethargy and vomiting.
Pineoblastoma is associated with germline mutations in the retinoblastoma (RB1) gene, with the term trilateral retinoblastoma 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. Rates of pineoblastoma among children with heritable retinoblastoma who undergo current treatment programs may be lower than these historical estimates.[34,35,36] Baseline brain imaging of children with retinoblastoma may identify pineoblastoma at an early stage and increase the likelihood of successful treatment.[37,38] Germline DICER1 mutations have also been reported in patients with pineoblastoma. Among 18 patients with pineoblastoma, three patients with DICER1 germline mutations were identified, and an additional three patients known to be carriers of germline DICER1 mutations developed pineoblastoma. The DICER1 mutations in patients with pineoblastoma appear to be distinct from the mutations observed in DICER1 syndrome-related tumors such as pleuropulmonary blastoma.
Diagnostic and Staging Evaluation
Diagnosis is usually readily made by either magnetic resonance imaging (MRI) or computed tomography (CT) scan. MRI is preferable because the anatomic relationship between the tumor and surrounding brain and tumor dissemination is better visualized with this method.
After diagnosis, evaluation of embryonal tumors is quite similar, essentially independent of the histologic 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 means of 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).
After surgery, imaging of the primary tumor site is indicated to determine the extent of residual disease. In addition, lumbar CSF analysis is performed, if deemed safe. Neuroimaging and CSF evaluation are considered complementary because as many as 10% of patients will have evidence of free-floating tumor cells in the CSF without clear evidence of leptomeningeal disease on MRI scan. CSF analysis is conventionally done 10 to 21 days after surgery. If CSF is obtained within 10 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, the positivity must be confirmed by a subsequent spinal tap to be considered diagnostically significant. When obtainment of fluid by lumbar spinal tap is deemed unsafe, ventricular fluid can be obtained; however, it may not be as sensitive as lumbar fluid assessment.
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.
Additional diagnostic studies for patients with desmoplastic medulloblastoma
Patients with desmoplastic tumors with extensive nodularity should be carefully evaluated for stigmata of Gorlin syndrome. One report observed that medulloblastoma with extensive nodularity (MBEN) was associated with Gorlin syndrome in 5 of 12 cases. Gorlin syndrome, also called nevoid basal cell carcinoma syndrome, is an autosomal dominant disorder in which those affected are predisposed to the development of 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.
Various clinical and biologic parameters have been shown to be associated with the likelihood of disease control of embryonal tumors after treatment. The significance of 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 utilized to predict outcome include the following:[42,43]
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 utilizing both radiation and chemotherapy.[40,42]
Extent of CNS disease at diagnosis
Patients with disseminated CNS disease at diagnosis are at highest risk of disease relapse.[41,42,43] Ten percent to 40% of patients with medulloblastoma have CNS dissemination at diagnosis, with infants having the highest incidence and adolescents and adults having the lowest incidence.
Nonmedulloblastoma embryonal tumors and pineoblastomas may also be disseminated at the time of diagnosis, although the incidence of dissemination may be somewhat less than that of medulloblastomas, with dissemination at diagnosis being documented in approximately 10% to 20% of patients.[11,12] Patients with nonmedulloblastoma embryonal tumors and pineoblastomas who have disseminated disease at the time of diagnosis have a poor overall survival, with reported survival rates at 5 years ranging from 10% to 30%.[11,12,13,14]
Age at diagnosis
Age younger than 3 years at diagnosis (except for desmoplastic medulloblastoma/medulloblastoma with extensive nodularity) portends an unfavorable outcome for those with medulloblastoma and, possibly, other embryonal tumors.[44,45,46,47,48]
Amount of residual disease after definitive surgery
Extent of resection determined during surgery has been supplanted by postoperative MRI measurement of the amount of residual disease after definitive surgery as a predictor of outcome.
In older studies, the extent of resection for medulloblastomas was found to be related to survival.[42,43,49,50] A HIrnTumor and International Society of Paediatric Oncology (HIT-SIOP) study of 340 children reported that residual disease (>1.5 cm2) connoted a poorer 5-year event-free survival. Extent of resection after surgery is still used to separate patients into risk groups, with patients having more than 1.5 cm2 residual disease stratified into high-risk groups. An international, retrospective, collaborative study included 787 medulloblastoma patients of all ages who were treated in a variety of ways and incorporated molecular subgrouping and clinical factors in the analysis. The multivariate analysis found that subtotal resection, but not near-total resection (<1.5 cm2 tumor remaining), was associated with inferior progression-free survival compared with gross-total resection. This study suggests that attempts to completely remove the tumor, especially when the likelihood of neurological morbidity is high, are not warranted, as 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 where patients with more than 1.5 cm2 of disease are considered higher-risk patients. 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. However, in a Children's Oncology Group (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.
For medulloblastomas, histopathologic features such as large cell variant, anaplasia, and desmoplasia have been shown in retrospective analyses to correlate with outcome.[45,54,55] In prospective studies, immunohistochemical and histopathologic findings have not predicted outcome in children older than 3 years at diagnosis, with the exception of the anaplasia/large cell variant, which has been associated with poorer prognosis.[10,40,56] Several studies have observed that the histologic finding of desmoplasia, seen in patients aged 3 years and younger with desmoplastic medulloblastoma, especially MBEN, connotes a significantly better prognosis compared with outcome for infants and young children with classic or large cell/anaplastic medulloblastoma.[10,24,44,45,46]; [Level of evidence: 2A]
For other embryonal tumors, histologic variations have not been associated with differing outcome.
Biological/molecular tumor cell characteristics
Genomic analyses (including RNA gene expression and DNA methylation profiles, as well as DNA sequencing to identify mutations) on both fresh-frozen and formalin-fixed, paraffin-embedded sections have identified molecular subtypes of medulloblastoma.[3,4,5,6,8,9,57,58,59,60,61,62,63,64] These subtypes include those characterized by WNT pathway activation and sonic hedgehog (SHH) pathway activation, as well as additional subgroups characterized by MYC or MYCN alterations and other genomic alterations.[3,4,5,6,8,9,57,58,59,60,61,62,63] Patients whose tumors show WNT pathway activation usually have an excellent prognosis, while patients with SHH pathway-activated tumors generally show an intermediate prognosis. Outcome for the remaining patients is less favorable than that for patients with WNT pathway activation. Mutations in medulloblastoma cases are observed in a subtype-specific manner, with CTNNB1 mutations observed in the WNT subtype and with PTCH1, SMO, and SUFU mutations observed in the SHH subtype. The prognostic significance of recurring mutations is closely aligned with that of the molecular subtype with which they are associated.[4,65] At recurrence, the subtype remains unchanged from the original molecular subtype at diagnosis.
Refer to the Biologically/molecularly defined subtypes of medulloblastoma section of this summary for more information about the subtypes of medulloblastoma.
For nonmedulloblastoma embryonal tumors, integrative genomic analysis has also identified molecular subtypes with different outcomes. (Refer to the Cellular and Molecular Classification of CNS Embryonal Tumors section of this summary for more detailed information.)
Follow-up After Treatment
Relapse in children with embryonal tumors is most likely to occur within the first 18 months of diagnosis.[51,67] Surveillance imaging of the brain and spine is usually undertaken at routine intervals during and after treatment (refer to 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.[68,69,70] Growth hormone replacement therapy has not been shown to increase the likelihood of disease relapse.
By definition, medulloblastomas must arise in the posterior fossa.[1,2] The following four histologic types of medulloblastoma are recognized by the World Health Organization (WHO) classification:
Significant attention has been focused on medulloblastomas that display anaplastic features, including increased nuclear size, marked cytological pleomorphism, numerous mitoses, and apoptotic bodies.[3,4] Using the criteria of anaplasia is subjective because most medulloblastomas have some degree of anaplasia. Foci of anaplasia may appear in tumors with histologic features of both classic and large cell medulloblastomas, and there is significant overlap between the anaplastic and large cell variant, which are frequently termed large cell/anaplastic medulloblastoma.[3,4] 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 histologic 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 histologic variant is different from MBEN; the nodular variant has an expanded lobular architecture. The MBEN subtype occurs almost exclusively in infants and carries an excellent prognosis.[5,6]
Subtypes of medulloblastoma
Multiple medulloblastoma subtypes have been identified by integrative molecular analysis.[7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22] 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 medulloblastoma. However, different regions of the same tumor are likely to have other disparate genetic mutations, adding to the complexity of devising effective molecularly targeted therapy. These subtypes remain stable across primary and metastatic components. Further subclassification within these subgroups is possible, which will provide even more prognostic information.[25,26] The 2016 World Health Organization (WHO) classification has endorsed this consensus by adding the following categories for genetically defined medulloblastoma:
The WHO molecularly defined subtypes of medulloblastoma are briefly described below:[20,21,27,28]
CTNNB1 mutations are observed in 85% to 90% of WNT medulloblastoma cases, with APC mutations detected in many of the cases that lack CTNNB1 mutations. Patients with WNT medulloblastoma whose tumors have APC mutations often have Turcot syndrome (i.e., germline APC mutations). In addition to CTNNB1 mutations, 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.
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. 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 mutations.[22,29]
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 outcome of patients with nonmetastatic SHH medulloblastoma is relatively favorable for children younger than 3 years and for adults. Young children with the MBEN histology have a particularly favorable prognosis.[5,6,31,32,33] Patients with SHH medulloblastoma at greatest risk of treatment failure are children older than 3 years whose tumors have TP53 mutations, often with co-occurring GLI2 or MYCN amplification and large cell/anaplastic histology.[25,30,34]
Patients with unfavorable molecular findings have an unfavorable prognosis, with fewer than 50% of patients surviving after conventional treatment.[27,30,34,35,36]
The 2016 WHO classification identifies SHH medulloblastoma with a TP53 mutation as a distinctive entity (medulloblastoma, SHH-activated and TP53-mutant). Approximately 25% of SHH-activated medulloblastoma cases have TP53 mutations, with a high percentage of these cases also showing a TP53 germline mutation (9 of 20 in one study). These patients are commonly between the ages of 5 years and 18 years and have a worse outcome (overall survival at 5 years, <50%). The tumors often show large cell anaplastic histology.
Various genomic alterations are observed in group 3 and group 4 medulloblastoma; however, no single alteration occurs in more than 10% to 20% of cases.
Group 3 patients with MYC amplification or MYC overexpression have a poor prognosis, with fewer than 50% of these patients surviving 5 years after diagnosis. This poor prognosis is especially true in children younger than 4 years at diagnosis. 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 progression-free survival (PFS) rate higher than 70%.
Group 4 medulloblastomas occur throughout infancy and childhood and into adulthood. They also predominate in males. The prognosis for group 4 medulloblastoma patients is similar to that for patients with other non-WNT medulloblastoma and may be affected by additional factors such as the presence of metastatic disease and chromosome 17p loss.[20,21,25]
The classification of medulloblastoma into the four major subtypes will likely be altered in the future.[25,26,37,38] Further subdivision within subgroups based on molecular characteristics is likely as each of the subgroups is further molecularly dissected, although there is no consensus regarding an alternative classification.[20,30,39]
Whether the classification for adults with medulloblastoma has a predictive ability similar to that for children is unknown.[21,27] In one study of adult 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, although another study did confirm an excellent prognosis for WNT-activated tumors in adults.[21,27]
Nonmedulloblastoma Embryonal Tumors
The WHO Classification of Tumors of the Central Nervous System (CNS) classifies nonmedulloblastoma embryonal tumors primarily by histologic and immunohistologic features, with the exception of embryonal tumor with multilayered rosettes (ETMR) and atypical teratoid tumor with rhabdoid features. By definition, these tumors arise in the cerebral hemisphere, brain stem, or spinal cord and are composed of undifferentiated or poorly differentiated neuroepithelial cells that may display divergent differentiation. This classification, based on the histopathological characteristics and location of the tumor, is as follows:
CNS embryonal tumors that demonstrate distinct areas of neuronal differentiation are termed cerebral neuroblastomas and, if ganglion cells are present, ganglioneuroblastomas. Likewise, medulloepitheliomas have a specific histologic pattern and remain a separate entity.[2,40]
Pineoblastoma is histologically similar to medulloblastoma and shares histologic features with embryonal tumors; however, because of the WHO classification, its histogenesis is linked to the pineocyte (a type of pineal cell) and is classified separately. This classification does not take into account the molecular genetic makeup of these tumors.
Genomic molecular characterizations of embryonal tumors and pineoblastomas have demonstrated substantial heterogeneity among these tumors. These tumors are also molecularly different from medulloblastomas.
Although the WHO classification system does not yet use molecular findings to classify nonmedulloblastoma embryonal tumors, future classification will most likely be based on both histological and molecular findings and, possibly, site of origin in the nervous system.
Subtypes of nonmedulloblastoma embryonal tumors
A study applying unsupervised clustering of DNA methylation patterns for 323 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 glioma, atypical teratoid/rhabdoid tumor). This observation highlights the utility of molecular characterization to assign this class of tumors to their appropriate biology-based diagnosis.
Among the same collection of 323 tumors diagnosed as nonmedulloblastoma embryonal tumors, molecular characterization identified genomically and biologically distinctive subtypes, including the following:
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.[42,43,44] 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.
Medulloepithelioma is identified as a histologically discrete tumor within the WHO classification system.[47,48] 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.[47,48] Medulloepithelioma with the classic molecular change is considered an ETMR.
Pineoblastoma, which was previously conventionally grouped with embryonal tumors, is now categorized by the WHO as a pineal parenchymal tumor. Given that therapies for pineoblastoma are quite similar to those utilized for embryonal tumors, the previous convention of including pineoblastoma with the CNS embryonal tumors is followed here. Pineoblastoma is associated with germline mutations in both the retinoblastoma (RB1) gene and in DICER1, as described below:
Staging of Medulloblastoma
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 cerebrospinal fluid (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 amount of primary site residual disease. The following tests and procedures are now used for staging:
The tumor extent is defined as:
Postoperative degree of residual disease is designated as:
Since the 1990s, prospective studies have been performed using this staging system to separate patients into average-risk and high-risk medulloblastoma subgroups.[2,3,4]
The presence of diffuse (>50% of the pathologic specimen) histologic anaplasia has been incorporated as an addition to staging systems. If diffuse anaplasia is found, patients with otherwise average-risk disease are upstaged to high-risk disease.
Staging of Nonmedulloblastoma Embryonal Tumors
Patients with nonmedulloblastoma, nonmedulloepithelioma embryonal tumors are staged in a fashion similar to that used for children with medulloblastoma; however, the patients are not assigned to average-risk and high-risk subgroups for treatment purposes (refer to the Staging of Medulloblastoma section of this summary for more information).
Medulloepitheliomas frequently disseminate to the neuraxis. Medulloepithelioma is staged in the same way as medulloblastoma; however, the patients are not assigned to average-risk and high-risk subgroups for treatment purposes (refer to the Staging of Medulloblastoma section of this summary for more information).
Staging of Pineoblastoma
Dissemination at the time of diagnosis occurs in 10% to 30% of patients. 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.[6,7] Staging for children with pineoblastomas is the same as that performed for children with medulloblastoma; however, the patients are not assigned to average-risk and high-risk subgroups for treatment purposes (refer to the Staging of Medulloblastoma section of this summary for more information).
Risk Stratification for Medulloblastoma
Risk stratification is based on neuroradiographic evaluation for disseminated disease, cerebrospinal fluid (CSF) cytological examination, postoperative neuroimaging evaluation for the amount of residual disease, and patient age. Patients older than 3 years with medulloblastoma have been stratified into the following two risk groups:
For younger children, in some studies for those younger than 3 years and for others younger than 4 or 5 years, 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 employed. Histologic findings of desmoplasia have also been used to connote a more favorable risk subgrouping, especially for the medulloblastoma with extensive nodularity subgroup.[4,5]
Assigning a risk group based on extent of resection and disease at diagnosis may not predict treatment outcome. Molecular genetics and histologic factors may be more informative, although they must be evaluated in the context of the age of the patient, extent of disease at time of diagnosis, and treatment received.[6,7] Although molecular subdivisions will likely change risk characterization in the future, they are not routinely used to assign treatment in North American prospective studies (e.g., NCT01878617).
Table 3 describes the standard treatment options for newly diagnosed and recurrent childhood CNS embryonal tumors.
(Refer to the PDQ summary on Childhood Central Nervous System Atypical Teratoid/Rhabdoid Tumor Treatment for more information about the treatment of CNS atypical teratoid/rhabdoid 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%. 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.)
Surgery is considered a standard part of treatment for histologic 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.[1,2]
Postoperatively, children may have significant neurologic deficits caused by preoperative tumor-related brain injury, hydrocephalus, or surgery-related brain injury.[Level of evidence: 3iC] A significant number of patients with medulloblastoma will develop cerebellar mutism syndrome (also known as posterior fossa syndrome). Symptoms of cerebellar mutism syndrome include the following:
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 for the mutism.[4,5]; [Level of evidence: 3iC] In two Children's Cancer Group studies evaluating children with both average-risk and high-risk medulloblastoma, the syndrome has been identified in nearly 25% of patients.[5,6,7]; [Level of evidence: 3iiiC] Approximately 50% of patients with this syndrome manifest long-term, permanent neurologic and neurocognitive sequelae.[6,8]
Radiation therapy to the primary tumor site is usually in the range of 54 Gy to 55.8 Gy. In most instances, this is given with a margin of 1 cm to 2 cm around the primary tumor site, preferably by conformal techniques. 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  and a retrospective efficacy report of protons versus photons for medulloblastoma  demonstrated equivalent outcomes for progression-free survival (PFS), overall survival (OS), patterns of relapse, and delayed toxic effects. Comparative outcomes for these treatment technologies are under investigation. Chemotherapy is routinely administered during and after radiation therapy.
For children younger than 3 years, efforts are made to omit or delay radiation, 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 neurologic/cognitive development, growth, and endocrine function have been frequently observed, especially in younger children.[11,12,13,14,15]
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.[16,17]; [Level of evidence: 3iiiC]
Children Older Than 3 Years with Average-Risk Medulloblastoma
Standard treatment options
Standard treatment options for children older than 3 years with newly diagnosed average-risk medulloblastoma include the following:
If deemed feasible, total or near-total removal of the tumor is considered optimal.
Radiation therapy is usually initiated after surgery with or without concurrent chemotherapy.[18,19,20]
Adjuvant radiation therapy
Chemotherapy is now a standard component of the treatment of children with average-risk medulloblastoma.
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:
As for those with average-risk disease, attempt at gross-total resection is considered optimal, if deemed feasible.[1,25]
In high-risk patients, numerous studies have demonstrated that multimodality therapy improves the duration of disease control and overall disease-free survival (DFS).[33,34] Studies show that approximately 50% to 70% of patients with high-risk disease will experience long-term disease control, including those with metastatic disease.[18,33,34,35,36]; [Level of evidence: 1iiA]; [Level of evidence: 2A]
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, refer to the ClinicalTrials.gov website.
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
Children Aged 3 Years and Younger
Five-year DFS rates for young children with medulloblastoma have ranged between 30% and 70%, with most long-term survivors successfully treated with chemotherapy alone, having nondisseminated, totally resected tumors and histologic evidence of desmoplasia.[16,39,40]; [Level of evidence: 2A]
The treatment of children younger than 3 to 4 years with newly diagnosed medulloblastoma continues to evolve. Therapeutic approaches have attempted to delay and, in some cases, avoid the use of craniospinal radiation therapy because of its deleterious effects on the immature nervous system. Results have been variable, and comparison across studies has been difficult because of differences in 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 children aged 3 years and younger with newly diagnosed medulloblastoma include the following:
If deemed feasible, complete surgical resection of the tumor is the optimal treatment. Surgical resectability is associated with histology, as patients with desmoplastic/nodular medulloblastoma or medulloblastoma with extensive nodularity (MBEN) have a higher rate of complete resection than do patients with classic medulloblastoma.[42,43]
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.
(Refer to the PDQ summary on Childhood Central Nervous System Atypical Teratoid/Rhabdoid Tumor Treatment for more information about the treatment of central nervous system [CNS] atypical teratoid/rhabdoid tumors.)
(Refer to the Treatment of Newly Diagnosed Medulloepithelioma section of this summary for information about the treatment of medulloepithelioma.)
Children Older Than 3 Years
Standard treatment options for children older than 3 years with newly diagnosed nonmedulloblastoma, nonmedulloepithelioma embryonal tumors include the following:
After surgery, children with nonmedulloblastoma embryonal tumors usually receive treatment similar to that received by children with high-risk medulloblastoma.
Adjuvant radiation therapy and chemotherapy
Treatment of children aged 3 years and younger with nonmedulloblastoma, nonmedulloepithelioma embryonal tumors is similar to that outlined for children aged 3 years and younger with medulloblastoma. (Refer to the medulloblastoma Children Aged 3 Years and Younger section of this summary for more information).
With the use of chemotherapy alone, outcome has been variable, with survival rates at 5 years ranging between 0% and 50%.[7,8,9]; [Level of evidence: 2Di] The addition of craniospinal irradiation to chemotherapy-based regimens may successfully treat some children but with anticipated neurodevelopmental decline.[Level of evidence: 2A]
There are few data on which to base treatment of newly diagnosed medulloepithelioma and embryonal tumor with multilayered rosettes (ETMR). Treatment considerations are usually the same as those for children with high-risk medulloblastoma and for children aged 3 years and younger at diagnosis with other embryonal tumors. (Refer to the Children Older Than 3 Years with High-Risk Medulloblastoma and the Children Aged 3 Years and Younger sections of this summary for more information.)
Prognosis is poor, with 5-year survival rates ranging between 0% and 30%.[1,2,3] 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.[Level of evidence: 3iA]
Standard treatment options for children older than 3 years with newly diagnosed pineoblastoma include the following:
Surgery is usually the initial treatment for pineoblastoma for diagnosis. Total and near-total resection is infrequently obtained in pineoblastomas, and the impact of the degree of resection on outcome is unknown.[2,3]
The usual postsurgical treatment for pineoblastomas begins with radiation therapy, although some trials have utilized preradiation chemotherapy. The total dose of radiation therapy to the tumor site is 54 Gy to 55.8 Gy using conventional fractionation.[2,3]
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.
Biopsy is usually performed to diagnose pineoblastoma.
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. Overall prognosis for this group of children remains very poor. All five children younger than 3 years who were treated with chemotherapy on two sequential multicenter prospective clinical trials died.[Level of evidence: 2A] 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.[Level of evidence: 2A]
High-dose, marrow-ablative chemotherapy with autologous bone marrow rescue or peripheral stem cell rescue has been used with some success in young children.[Level of evidence: 2Di]
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 develop many years after initial treatment.[1,2] 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.[1,2,3] Extraneural disease relapse may occur but is rare and is seen primarily in patients treated with radiation therapy alone.[Level of evidence: 3iiiA]
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 relapse at the primary tumor site alone; one-third will relapse at the primary tumor site plus distant sites; and one-third will relapse at distant sites without relapse at the primary site.[1,2,3]
There are no standard treatment options for recurrent childhood CNS embryonal tumors. (Refer to the Treatment for Recurrent Childhood CNS Atypical Teratoid/Rhabdoid Tumor section in the PDQ summary on Childhood Central Nervous System Atypical Teratoid/Rhabdoid Tumor Treatment for more information.)
For most children, treatment is palliative and disease control is transient in patients previously treated with radiation therapy and chemotherapy, with more than 90% progressing within 12 to 18 months. 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.[3,5,6,7]
Treatment approaches may include the following:
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 on the basis of the initial tumor type, the length of time between initial treatment and the reappearance of the lesion, and clinical symptomatology.
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, including reirradiation at the primary tumor site, focal areas of radiation therapy to sites of disseminated disease and, rarely, craniospinal radiation therapy. In most cases, such therapy is palliative. Stereotactic radiation therapy and/or salvage chemotherapy can also be used (see below).
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.[6,7,23,24,25,26][Level of evidence: 2A]; [Level of evidence: 3iiB]; [28,29][Level of evidence: 3iiiA]
Molecularly targeted therapy
With the 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 sonic hedgehog (SHH) subgroup medulloblastomas, the SHH PTCH1 inhibitor vismodegib demonstrated radiographic responses in 3 of 12 pediatric-aged patients, with two responses being sustained for less than 2 months and one response for more than 6 months. Only patients with upstream mutations of the SHH pathway, at the level of PTCH1 or SMO, responded.
Treatment Options Under Clinical Evaluation
Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the ClinicalTrials.gov website for APEC1621 (NCT03155620).
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.
Cellular and Molecular Classification of CNS Embryonal Tumors
The Subtypes of medulloblastoma subsection was extensively revised.
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.
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 embryonal 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:
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 Embryonal Tumors Treatment are:
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
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The preferred citation for this PDQ summary is:
PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Central Nervous System Embryonal Tumors Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/brain/hp/child-cns-embryonal-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389418]
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Last Revised: 2017-09-20
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