Medulloblastoma 

Updated: Jan 10, 2018
Author: George I Jallo, MD; Chief Editor: Amy Kao, MD 

Overview

Background

First used by Bailey and Cushing in 1925,[1] the term medulloblastoma described a series of tumors found in the cerebellum of children. Originally classified as a glioma, medulloblastoma is referred to now as a primitive neuroectodermal tumor (PNET). This tumor accounts for approximately 7-8% of all intracranial tumors and 30% of pediatric brain tumors. Medulloblastoma is the most common malignant pediatric tumor in the central nervous system (CNS), accounting for nearly 20% of all childhood brain cancers and ~40% of all childhood tumors in the posterior fossa. This set of tumors is considered the most common brain malignancy among pediatric population.[2] Medulloblastoma is a type of embryonal tumor. Embryonal tumors were described over the years as a collection of histologic entities that includes medulloblastoma and also included medulloepithelioma, CNS neuroblastoma, CNS ganglioneuroblastoma and atypical teratoid/rhabdoid tumor (ATRT) as well as primitive neuroectodermal tumors (PNET). All of that changed after the 2016 World Health Organization (WHO) reclassification.[3]

Pathophysiology

In the brain, medulloblastoma most often arises in the posterior fossa as shown in the image below. The tumor has the propensity of spreading throughout the CNS. Systemic metastases of this tumor, especially to bone, also have been recognized.

CT scan demonstrates a hyperdense lesion within th CT scan demonstrates a hyperdense lesion within the posterior fossa of an 8-year-old boy who presented with nausea and vomiting.

Epidemiology

Epidemiology data is changing ever since we have a better understanding of molecular and genetic behaviors of these tumors and especially after the new World Health Organization (WHO) classification from 2016.[3]

US statistics

Age and Sex

Incidence of medulloblastoma is 1.5-2 cases per 100,000 population, with 350 new cases in the United States each year.

Medulloblastoma accounts for 64.3% of all embryonal tumors in pediatric patients (0-19 years old), according to the Central Brain Tumor Registry of the United States (CBTRUS). Males displayed higher incidence rate relative to females (males: 0.16 vs. females: 0.12), except in patients < 1 year-old.[2] Overall ratio tend to be 1.5:1 for males. Males also tend to have poorer prognosis. Among all age group, the reports from CBTRUS citing the embryonal tumor group together, with total incidence rate of 0.25 per 100,000 per year with slight male predominance (0.29 vs. 0.2). Incidence of medulloblastoma decreases with age. Incidence was 0.55 per 100,000 population, 0.57 per 100,000 population, 0.32 per 100,000 population, and 0.16 per 100,000 population in children aged 0–4, 5–9, and 10–14 years, and adolescents aged 15–19 years, respectively. Incidence was highest in patients aged 1–4 years at diagnosis, but patients aged 10–14 years showed increased incidence from 2000 to 2013, and when looking at all age groups the total incidence peaks at ages 9 years and below. When looking at CBTRUS and SEER databases covering roughly the same period of time (2000/2001 to 2013) adult patients (20 years of age and older) are about 28% from all medulloblastoma patients. Interestingly enough, for the adult group there was a significant rise in incidence rate between 2001 and 2009 with subsequent significant decline in the rate between 2009 and 2013.[2, 4]

Race

In the United States, when looking at race for pediatric population (0-19 years), there is Caucasian and Asian/Pacific Islander predominance. In the collection of data from CBTRUS and SEER, white race was reported in the majority of cases (more than 80%).[2] Yet, when comparing black population to white population for the years 2001 to 2013, blacks displayed a non-significant increase in incidence and in mortality risk.

Mortality/Morbidity

The 5-year and 10-year survival rates among all patients are 73% and 64.7%, respectively. Patients aged 1–4 years have lower survival rates for each year post diagnosis relative to patients aged 5–9, 10–14, and 20+ years up to 5 years post diagnosis. Survival rates for males and females are similar up to 10 years post diagnosis. Black patients displayed slightly lower survival rates for each year post diagnosis compared to white patients.[2] Yet the reader needs to take into consideration that these survival numbers are from before the adjustment by molecular subtypes. When looking at the new classification (even before changing from 4 subtypes to 5), certain unsettled issues in epidemiology can become clearer. The group of infants < 1 year of age has a much poorer prognosis. In previous works it was described that the age group of children less than 4 years old are divided mainly to SHH (more than 50%) and group 3 (~40%). Whereas SHH pathway-driven tumors usually lead to a fair survival rate of 75% in 5 years for children below 3 years of age, group 3 for the same age group is having significantly worse survival rates. This accounts for the discrepancy between the old survival rates in CBTRUS of about 48% for children < 1 year old and 62% for children between 1 and 4 years of age, and the more positive picture that sometime can be seen in daily life.[5, 6]

In terms of morbidity, there are a lot of potential causes and complications for the patient diagnosed with medulloblastoma:

  • Hydrocephalus: The most common complication is hydrocephalus due to compression of the normal cerebrospinal fluid (CSF) pathways. Although this is a common complication, only 10-50% of patients with preoperative hydrocephalus will need a long-term ventricular shunt. Some children can be treated with an endoscopic third ventriculostomy.
  • Cerebellar dysfunction: Tumor infiltration of the cerebellum usually is in the midline, leading to difficulties with ambulation and truncal ataxia. This is more common than signs attributable to the cerebellar hemisphere (eg, extremity dysmetria). Cerebellar mutism syndrome occurs in approximately one quarter of patients who underwent resection of medulloblastoma in the immediate postoperative period. Brainstem invasion of the tumor was the only risk factor identified as having a positive correlation with the development of cerebellar mutism. [7]
  • Leptomeningeal dissemination: One of the most feared complications of medulloblastoma is dissemination within the CSF. Medical and, less commonly, surgical therapy must be directed at controlling dissemination to cranial nerves and spinal cord and related structures. This dissemination of disease portends to a high-risk stratification.

International statistics

Incidence of medulloblastoma worldwide seems to approximate that in the United States.

 

Presentation

History

The majority of medulloblastomas occur as sporadic cases, yet hereditary conditions have been associated with medulloblastoma, including (1) Gorlin syndrome (nevoid basal-cell carcinoma syndrome), (2) blue rubber-bleb nevus syndrome, (3) Turcot syndrome (i.e., glioma polyposis syndrome), and (4) Rubinstein-Taybi syndrome.

Symptoms are often progressive over weeks to months, and it is not uncommon for patients to have an extended symptomatic period prior to initial diagnosis. Metastatic disease is commonly present at diagnosis (40%), and imaging of the entire craniospinal axis is an essential part of the initial diagnostic evaluation.[8]

Symptoms usually differ by anatomic location of the tumor, presence of disseminated disease, and by the presence of hydrocephalus.

Hydrocephalus

Patients with medulloblastoma most commonly have symptoms related to increased intracranial pressure (as a consequence of hydrocephalus). Symptoms usually precede presentation by no more than 2 months.

Presenting symptoms are related to the age of the patient. The younger, nonverbal patient presents with behavioral change. Symptoms in younger children include listlessness, irritability, vomiting, and decreased social interactions. Older children and adults complain of headache, especially upon awakening in the morning.

Vomiting without nausea is more common in the morning, since being recumbent (i.e., sleeping) increases intracranial pressure. Often, symptoms of headache and vomiting prompt an extensive and lengthy workup of the gastrointestinal tract prior to consideration of the CNS.

Patients may develop double vision as the sixth cranial nerve becomes stretched from the hydrocephalus. Visual disturbances more commonly are a result of papilledema.

Cerebellar symptoms

Most commonly found in children, the tumor involves the cerebellar vermis and causes gait ataxia more readily than unilateral symptoms.

Adults more commonly harbor the histological variant of desmoplastic medulloblastoma, which arises in the cerebellar hemisphere. These patients often have symptoms of ipsilateral dysmetria.

Head tilt and neck stiffness, caused by meningeal irritation, are complications of tonsillar herniation below the foramen magnum. Alternatively, head tilt can result from trochlear nerve palsy caused by direct tumor compression.

Leptomeningeal dissemination

Presenting symptoms rarely are related to dissemination of tumor in the CSF.

Patients can complain of severe weakness from tumor compression of the spinal cord or nerve roots (eg, radiculopathy).

Physical

See the list below:

  • Physiognomy
    • Increasing head circumference often is the only presenting symptom in infants.
    • Infants may have also full anterior fontanelles with split cranial sutures.
  • Funduscopic examination
    • Visual difficulty usually is due to papilledema; however, it also may originate from cranial nerve palsy (most commonly CN IV or VI).
    • Some studies have found papilledema (the most common physical finding) to be present in as many as 90% of patients.
  • Extraocular examination
    • As a consequence of hydrocephalus, the sixth cranial nerve can be compressed at the petroclival ligament, resulting in diplopia and lateral gaze paresis.
    • Fourth cranial nerve palsy can be detected on careful extraocular examination and should be considered in any patient with a head tilt.
    • Patients with fourth cranial nerve dysfunction have greatest difficulty when eyes are rotated medially and depressed (i.e., going down stairs). The fourth cranial nerve usually is compressed by direct tumor extension into the cerebral aqueduct.
    • Examination of the extraocular muscles may detect nystagmus, which, although nonspecific, can be related to a lesion of the cerebellar vermis.
  • Cerebellar signs
    • Medulloblastoma most commonly is located midline. Therefore, unilateral dysmetria is less common than either truncal ataxia or a wide-based gait. Latter symptoms are easily observable on tandem gait.
    • As stated previously, desmoplastic medulloblastoma is more common in adults and usually arises in the cerebellar hemisphere.
    • Signs of ipsilateral cerebellar dysfunction in the arm or the leg are more common in this subtype.
  • Torticollis: Head tilt can be a manifestation of either accessory nerve (cranial nerve eleven) or trochlear nerve (cranial nerve four) palsy.

Causes

Debate exists over the cellular origin of medulloblastoma.

One hypothesis is that medulloblastoma arises from primitive multipotent cells of the external granular layer of the cerebellar velum. This is an area of germ cell origin that persists for the first year of life before involuting.

The second hypothesis is that medulloblastoma arises from multipotent cells in the subependymal-subventricular region and fetal pineal region.

Genetic and molecular biology are described elsewhere in the topic.

Complications

The cerebellum is involved in many complex aspects of human behavior and function, and when it is disrupted or insulted, this can lead to significant sequelae in patients with posterior fossa tumors. Some of the complications are more common in the pediatric population. Some of the more common complications are:

  • Hemiplegia/hemiparesis
  • Cerebrospinal fluid leak
  • Cranial nerve dysfunction – Injury to cranial nerves ranging from CN IV–XII can occur with posterior fossa surgery. Symptoms can range from visual disturbances to swallowing difficulty to motor and sensory deficits.
  • Posterior fossa syndrome (PFS) – Occurs in approximately 25% of patients who underwent resection of their posterior fossa tumor (usually medulloblastoma) [9]

Symptoms of diminished speech progressing to mutism with associated irritability, emotional lability, truncal hypotonia and ataxia usually present by postoperative day two, however, can develop later. Signs of brainstem dysfunction may also be present. These symptoms were deemed moderate to severe in more than 90% of patients with identified cerebellar mutism syndrome (CMS).[7] There is a positive correlation between brainstem involvement of the tumor and the development of CMS. Patients with cerebellar mutism often show some improvement in symptoms over time, however, a considerable number had residual symptoms at one year follow-up. The eventual recovery of speech occurs for most, but with slowly improving dysarthria over many months. In addition to speech problems, a hallmark of the syndrome is behavioral changes, including regressed personality, apathy, and poverty of spontaneous movement.[9] There are no evidence-based recommendations for the pharmacologic treatment of PFS and treatment is usually supportive. There are publications suggesting the use of a partial dopamine agonist such as aripiprazole, that may have a role in treating mental status changes after posterior fossa tumor resection.[10]

 

DDx

 

Workup

Laboratory Studies

No specific biochemical test exists for the presence of medulloblastoma, although several molecular studies have revealed that histologically identical medulloblastomas are composed of distinct subgroups with different prognosis. The expression of ErbB2 has been shown to be a negative predictor of outcome. Conversely, expression of TrkC or neurotophin-3 receptor is associated with a favorable outcome. However, these markers are not standard testing at this time.

Table. (Open Table in a new window)

Subtype

Age group

Molecular characteristics

Genetic mutations

Incidence

Prognosis (10-year overall survival)

WNT activation

Found in children and adults (not infants)

WNT pathway activation

CTNNB1


DDX3X Chromatin-remodeling genes


TP53

Least common

Favorable

72%

SHH activation

5–18 years old

SHH pathway activation

TP53

About 25% of the cases

Worse

 

All age groups

SHH pathway activation

Non TP53 (wild type):

PTCH1


SMO
(mainly adults)

SUFU
(mainly infants)

TERT promoter Chromatin-remodeling genes

If no MYCN amplification and no metastatic disease – favorable

Group 3

Infants and children (more common in boys than in girls)

Elevated expression of MYC

GABRA5

over-expression

SMARCA4 Chromatin-remodeling genes


Genes of TGF-β pathway

About 25% of the cases

If MYC amplification present – very poor prognosis

Metastatic disease – very poor prognosis

Group 4

More common in children (not infants) than in adults


Lmx1A expression

Chromatin-remodeling genes

Most common

If no metastatic disease and chromosome 11 loss – favorable

Imaging Studies

Computed tomographic (CT) scan

Because most patients present with headache, a noncontrast head CT scan usually is performed because of its availability. These tumors typically are located midline in the cerebellum and extend into and fill the fourth ventricle. Prior to administration of intravenous (IV) contrast, the tumor is hyperdense to the brain as a result of its high cellularity as shown below. Preoperatively, high density on CT scan can help distinguish medulloblastoma from the hypodense appearance of a cerebellar astrocytoma. Medulloblastoma shows marked contrast enhancement. Surrounding hypodensity is indicative of vasogenic edema. Owing to compression of the fourth ventricle and outflow of CSF, marked hydrocephalus can be present.

CT scan demonstrates a hyperdense lesion within th CT scan demonstrates a hyperdense lesion within the posterior fossa of an 8-year-old boy who presented with nausea and vomiting.

Ependymoma is another hyperdense tumor that affects the posterior fossa of children. Unlike medulloblastoma, however, it often contains calcifications that can be recognized easily on CT scan. Choroid plexus papilloma usually arises in the trigone of the lateral ventricle in children; however, in adults it is most common in the fourth ventricle. Similar to ependymoma, choroid plexus papilloma commonly contains calcifications.

Magnetic resonance imaging

MRI with the administration of gadolinium DTPA is the diagnostic test of choice for medulloblastoma. Unlike CT scan, MRI can obtain multiplanar views without significant bony artifact in the posterior fossa. Nevertheless, with any increased intracranial pressure, MRI of children must be considered carefully. Younger children usually require sedation for this study. Without careful monitoring, cerebral carbon dioxide levels may increase, further aggravating intracranial hypertension. Tumor appears hypointense on pre-gadolinium T1-weighted images, usually seen expanding the fourth ventricle from its origin in the cerebellar Vermis as depicted in the following images. Brain stem is compressed and shifted ventrally.

T1-weighted sagittal MRI of an 8-year-old boy who T1-weighted sagittal MRI of an 8-year-old boy who presented with nausea and vomiting reveals an enhancing tumor within the fourth ventricle. The child underwent a suboccipital craniotomy and resection of his medulloblastoma.
T1-weighted sagittal MRI of 4-year-old boy who pre T1-weighted sagittal MRI of 4-year-old boy who presented with gait ataxia and precocious puberty. MRI shows a heterogenous enhancing tumor located within the fourth ventricle with marked hydrocephalus.
T1-weighted axial MRI shows heterogeneous enhancem T1-weighted axial MRI shows heterogeneous enhancement of the medulloblastoma in a 4-year-old boy who presented with gait ataxia and precocious puberty.
Coronal MRI confirms the presence of the tumor wit Coronal MRI confirms the presence of the tumor within the fourth ventricle of a 4-year-old boy who presented with gait ataxia and precocious puberty.

Upon administration of gadolinium in children, homogeneous enhancement commonly occurs, whereas in adults, a more heterogeneous pattern usually is seen. Proton density and T2-weighted imaging displays a hyperintense mass with a surrounding area of edema. If the tumor extends superiorly into the cerebral aqueduct and third ventricle, or inferiorly into the aqueduct of Sylvius or cisterna magna through the foramen of Magendie, marked hydrocephalus with transependymal reabsorption of CSF may occur. Occasional areas of hemorrhage or cyst can be distinguished. Because calcifications are very rare, any area of signal loss must be considered a vascular flow void. MRI can help differentiate medulloblastoma from ependymoma: the latter extends further into the lateral recess of the fourth ventricle or even further into the cerebellopontine angle. MRI with diffusion tensor imaging provides white matter tractography and can help distinguish between medulloblastoma and exophytic brainstem glioma. Studies have suggested tumor location and enhancement patterns can serve as a surrogate for genetic testing of the different medulloblastoma subtypes.[11] Others tried to look at the enhancement pattern by subgroups. Perreault et al. summarized in 2014 that tumor location and enhancement pattern were predictive of molecular subgroups of pediatric medulloblastoma and may potentially serve as a surrogate for genomic testing.[11] Some works suggested the utility of apparent diffusion coefficient in order to differentiate medulloblastoma from other posterior fossa tumors and the different subgroups.[12, 13] Yet, we still don’t have a reliable tool to differentiate preoperatively the different subtypes of medulloblastoma. Adults, more frequently than children, can have the desmoplastic variant of medulloblastoma. This form of the tumor is situated laterally in the hemisphere with indistinct borders and small cystic or necrotic areas. Besides identifying the primary lesion, MRI is beneficial in detecting metastatic lesions. To rule out drop metastases, MRI of the neuroaxis is obligatory when medulloblastoma is either considered or diagnosed. Imaging of the spine is best performed prior to surgery in order to avoid postoperative artifacts, which may be interpreted as tumor metastasis. Metastases can occur in the basal cisterns. Both recurrent lesions and metastases show sparse enhancement.

Myelography

In the past, myelography was the standard diagnostic test for medulloblastoma metastases to the spine. Today, when MRI is contraindicated, myelography is utilized, accompanied by CT scan. Yet, if for any reason MRI is contraindicated, the surgeon usually will prepare for surgery by using CT scan with contrast without obtaining myelography.

Skeletal imaging

Metastasis to the bone must be considered in any child with medulloblastoma and bone pain. This is not a routine test. A skeletal survey helps elucidate lytic or sclerotic lesions.

Radiogenomics

This is a fairly new entity in neuroradiology, trying to diagnose specific tumors by special radiology features. Several studies have been published regarding the possible use of multiple MRI features that will lead to pre-surgical diagnosis of medulloblastoma and the different subtypes. Historically, several attempts have been made to define the different histological subtypes by their anatomical location (medial, cerebellopontine, and hemispheric lesions). However, attempts to use location criteria as biomarkers for differentiation of genetic medulloblastoma entities have yielded only inconsistent results.[14]  There were some groups trying to define certain imaging features that can assist in pre-operative diagnosis of medulloblastoma subtypes. For example, Kelli et al.[14] found that hemorrhage was related to group 4 medulloblastomas, yet other groups found hemorrhage to be related to WNT-activated medulloblastomas as well.[15]  

Other Tests

Cerebrospinal fluid

Cytology of CSF is important for the staging of medulloblastoma; however, no standardized method has been agreed upon for how and when to obtain CSF. Lumbar puncture is the most common method for obtaining CSF, however, this can precipitate cerebellar tonsillar herniation (coning) in a patient with increased intracranial pressure. Although safer, lumbar puncture performed shortly after surgery can have misleading results; the fluid may contain clinically insignificant cells that have been disturbed during surgery. This may be performed 2 weeks following surgery. If a ventricular drain is placed, it can be used to obtain CSF for cytologic testing, however, ventricular samples of CSF will contain malignant cells less commonly than a sample obtained from the thecal sac. Some authors suggest obtaining CSF at the time of surgery from the cisterna magna for cytologic analysis.

Tumor genetics

Use of cytogenetic studies has been controversial.

Some original reports found a correlation between aneuploid DNA content and a better prognosis. Interestingly, DNA content of most medulloblastoma cells is diploid, signifying a poorer outcome. More recent studies, however, have failed to reproduce this relationship between ploidy and outcome.

The most common genetic abnormality found in medulloblastoma, 17qi, is an isochromosome on the long arm of chromosome 17. Found in one third to two thirds of medulloblastomas, it is common in other tumors, including leukemias.

Accompanying the isochromosome 17qi is the loss of genetic material from the short arm of chromosome 17, where the tumor-suppressor gene p53 is located.

Studies have shown that loss or damage to the p53 site is rare in medulloblastoma. Theories now implicate another focus on the short arm of chromosome 17, which is either a tumor-suppressor gene in itself or a modulator for the function of p53.

In recent years, with the finding of the main 4 subtypes, different studies described the genetic mutations relating to each group[16] :

  • WNT activation: These tumors almost uniformly have oncogenic mutations of catenin beta-1 ( CTNNB1), the protooncogene that encodes β-catenin. Their expression shows adherence to multipotential progenitor cells of the lower rhombic lip. [17] CTNNB1 mutations are found in approximately 90% of WNT medulloblastomas, and nuclear accumulation of β-catenin is a biomarker for WNT pathway activation. Other important mutations in this group include SMARCA4, Monosomy 6, which can be found in 80–85% of WNT medulloblastomas (without harboring telomerase reverse transcriptase [TERT] mutations), DEAD-box helicase 3 (DDX3X) mutations are found in 50% of WNT tumors, TERT mutations are found in 31% of WNT tumors. [18] Although tumor suppressor protein p53 (TP53) mutations can be found in 15% of the tunors in these group, it has no relevance in terms of prognosis. [19]
  • SHH activation: This subgroup is further subdivided by presence of TP53 mutation and by age groups. For infants (0–4 years) the SUFU mutations are more common than other age groups, and 42% of the infant samples have PTCH1 alterations. For children (4–17 years), there is a higher incidence of MYCN and GLI2 amplifcations that usually predict less favorable prognosis. In this subgroup, 36% pf the patients have PTCH1 alterations. [20, 21] For the adult population, the SMO mutations are more common (which allow for possible treatment options), and 54% of the adult samples have PTCH1 alterations. As a group, as long there are no PTEN or GNAS alteration, the prognosis tend to be good. [22] For the patients that harbor TP53 mutation (13% of SHH medulloblastomas), there is a need to search for germline mutations (like Li-Fraumeni syndrome). [23, 20] The prognosis in this group (SHH TP53 mutation positive) is very poor across all age groups.  
  • Non-WNT/non-SHH ( group 3): This group is known to generally have poor prognosis. Either the presence of MYC over-expression (~17% of cases), or the presence of Isochromosome 17q are a bad prognostic factors. [24] Other genes that have mutation in this subgroup are related chromatin remodeling and appear in almost 30% of the cases. [25] An important overexpression in this group includes GABRA5, which serves now as a potential treatment aim in this group. [26, 27]
  • Non-WNT/non-SHH: group 4: This is the most common group with relatively good prognosis. The homeobox transcription factor Lmx1A has been identifed as an very important regulator transcription factor of group 4 medulloblastomas. [28] Lmx1A is important in the normal development of cells in the upper rhombic lip and cerebellum, and it is also critical for the development of midbrain dopaminergic neurons, [28, 27]  which are thought to be where group 4 tumors originate. [16] The most common chromosomal aberration found in this sub-group of medulloblastoma is isochromosome 17q. Bad prognostic factors, such as chromosome 11 loss and chromosome 17 gain can be also found in this subgroup. [24] In addition, copy number changes in target genes that are important in the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κβ) signaling pathway are found in this subgroup. [16]  

Procedures

Lumbar puncture

To obtain CSF, a lumbar puncture may be necessary. Consider this very carefully since obstructive hydrocephalus, common in medulloblastoma, is an absolute contraindication.

CSF diversion

If the patient is symptomatic from obstructive hydrocephalus, placement of an external ventricular drain may be a lifesaving procedure. Some centers also advocate an endoscopic third ventriculostomy (ETV) with or without choroid plexus cauterization to bypass the obstruction. This may also obviate the need for a shunt in the future following surgical removal of the tumor. Yet, the incidence of urgent CSF diversion is not high. Schneider et al., published in 2015 that the overall rate of CSF diversion surgery for SHH, Group 3, and Group 4 medulloblastomas was around 30% in their series, but no patients with a WNT medulloblastoma required shunting. The low incidence of hydrocephalus in patients with WNT medulloblastoma likely reflects both host factors (age) and disease factors (lack of metastases). They speculated that the absence of hydrocephalus in patients with WNT medulloblastomas likely contributes to their excellent rate of survival and may also contribute to a higher quality of life than for patients in other subgroups.[29] Most neurosurgeons try not to do a definite CSF diversion (i.e., ETV or VP shunt), and advocate temporary diversion like external drain if needed and resection of the tumor that will alleviate the obstruction.

Histologic Findings

Upon gross pathology, medulloblastoma appears as a poorly demarcated pink-purple-gray friable mass usually arising from the cerebellar vermis in children. Areas of necrosis may be seen, however, cysts or calcifications are rare.

Desmoplastic variants may be more firm. On microscopic examination, cells are small and poorly differentiated, with scant cytoplasm and little stroma (see the image below). A high mitotic index is common. Classic Homer-Wright rosettes can be seen in one fifth of cases. Elongated cells surrounding eosinophilic circular zones devoid of lamina and blood vessels form these pseudorosettes. Differentiation can be seen along astrocytic, neuronal, ependymal, or even mesenchymal lines.

High-power magnification hematoxylin and eosin (H& High-power magnification hematoxylin and eosin (H&E) section of a typical medulloblastoma

Rorke classified this tumor with other primitive neuroectodermal tumors, which include pineoblastoma, ependymoblastoma, retinoblastoma, central neuroblastoma, and peripheral neuroblastoma[30] . This classification system is not accepted universally.

Desmoplastic medulloblastoma is a variant more often seen in adults and more common in the cerebellar hemisphere. In addition to containing all microscopic characteristics of childhood medulloblastoma, the desmoplastic type contains a dense reticulin network; cells are arranged in a biphasic pattern with areas of high and low cellularity. Cells in this variant may assemble along reticulin fibers.

Histologic subtypes

Three other histologic subtypes exist: Medullomyoblastoma, melanotic medulloblastoma, and large cell medulloblastoma.

  • Medullomyoblastoma:Striated and smooth muscle cells are the hallmark of medullomyoblastoma. The tumor can contain cells that show elements of neuronal and glial differentiation. If the presumptive medullomyoblastoma contains elements of ectodermal, mesodermal, and endodermal differentiation, the tumor must be considered a teratoma. 

  • Melanotic medulloblastoma: Small, undifferentiated cells containing melanin are characteristic of this very rare melanotic medulloblastoma.

  • Large-cell medulloblastoma: This subtype has large vesicular nuclei with prominent nucleoli. Cells of the large-cell medulloblastoma are remarkable in their immunoreactivity for synaptophysin. This particular tumor is associated with a poorer clinical outcome. Although large-cell medulloblastoma is associated with a more aggressive course, medullomyoblastoma has a clinical course similar to that of ordinary medulloblastoma. However, the desmoplastic variant has a more favorable outcome. 

Aside from these findings, associating histologic findings with outcome has been very difficult. As in other tumors, vascularity and endothelial hyperplasia do not seem to influence recurrence rates. In some studies, however, the presence of necrosis (or a high mitotic index) has been associated with a shorter relapse-free interval. 

 

Treatment

Approach Considerations

For the patient with few neurological signs and no hydrocephalus, the entire presurgical workup can be facilitated on an outpatient basis. Admit patients with significant neurological symptoms (especially those with either change in mental status or imaging evidence of considerable hydrocephalus such as transependymal flow) to the hospital in a monitored setting.[31]

The cranium initially can accommodate a small increase of CSF volume with little change in intracranial pressure. However, since the skull is a rigid container with a finite volume (threshold), further increases in ventricular size lead to dramatic increases of intracranial pressure (Monroe-Kellie Doctrine). Decreased mental status is an indication that the ventricular volume is approaching that threshold; enlargement of ventricles beyond the threshold is accompanied by potentially disastrous consequences.

Frequent neurologic assessment by the nursing staff is extremely important. Any further decline in mental status is indication for administration of hypertonic saline and emergent neurosurgical consultation for placement of an external ventricular drain.

Staging

Postoperatively, medical care revolves around staging, chemotherapy, and irradiation. Within 48 hours of surgery, a follow-up gadolinium-enhanced MRI is necessary to assess residual tumor size prior to the onset of enhancing reactive gliosis, which may be interpreted as tumor.

Staging is dependent upon extent of resection, radiographic evidence of tumor spread, and CSF cytology. Recently, a move away from the Chang TNM staging system[32] to a simplified high-risk/low-risk categorization has occurred. Those patients, who undergo gross total resection, with no radiographic evidence of spread and no malignant cells on CSF cytology, are considered in a low-risk category; however, presence of any of the 3 would place the patient into the high-risk group. For years, since 1999 when a consensus regarding risk stratification was published, neurosurgeons have used a risk management tool looking at residual tumor (more or les than 1.5 cm2, metastases, etc.). Extent of resection is still identified as a high-risk marker. Specifically, most protocols identify a residual tumor of 1.5 cm2 as being high risk warranting intensification of craniospinal irradiation to 36 Gy.[33] However, this is predominantly based on the CCG-921 trial, which was conducted in the pre-MRI era, and was based on the limit of detection by CT scanning.[34] Moreover, the question of near-total resections (0–1.5 cm2) has not been discussed for the past 25 years. Thompson and colleagues showed in 2016 that near-total resection poses no additional survival risk to gross total resection, and that the prognostic benefit of a subtotal resection is attenuated after accounting for molecular subgroup affiliation.

Medical Care

Irradiation

Radiation therapy for medulloblastoma is aimed at destroying cells along the entire neuraxis. Local recurrence has been associated with a lower radiation dose at the primary site. Patients receiving less than 5000 centigray (cGy) have over twice the local recurrence rate as those receiving at least this dose.

Rieken et al[35, 36]  found that craniospinal irradiation following complete resection of medulloblastoma yielded overall survival and local and distant progression-free survival rates of 73%, 62%, and 77% at 60 months in children and adults.[35]  The authors delivered a median craniospinal dose of 35.5 Gy and administered additional boosts to the posterior fossa up to 54.0 Gy. Initiating treatment within 28 days, macroscopic complete tumor resection, and desmoplastic histology were associated with improved outcome.

In addition, clinical trials have documented that radiation therapy to only the cranium results in metastasis to the spine (even in the absence of positive cytology or radiographic evidence of spread). Most standard therapy for low-stage disease includes 36 cGy to both the brain and spinal cord with a boost of 18-20 cGy to the primary tumor site. Some institutions use different regimens including higher doses in several fractions. Others recommend proton beam therapy, which has been shown in one study to have the same efficacy with potential decrease in adverse effects of radiation.[37]

Unfortunately, radiation can have a destructive influence on the developing nervous system. Complications of radiotherapy can include lowered intelligence quotient (IQ) score, small stature, endocrine dysfunction, behavioral abnormalities, and secondary neoplasms (experienced by those fortunate to have prolonged survival).

A small study by Gupta et al reported a good overall survival rate for standard-risk children treated with hyperfractionated therapy (two daily fractions) with a total tumor bed dose of 68 Gy for 6-7 weeks. This treatment approach may be reasonable in centers without access to chemotherapy, but caution must be undertaken as the median follow-up was only 33 months. The authors found preserved cognitive function at 2 years posttreatment but long-term results were not available. In addition, secondary malignancies were not reported.[38]

White matter necrosis, which can enlarge and produce significant mass effect and vascular disorders,[39]  is another feared long-term complication of radiation. Reduction in IQ and neurobehavioral function is related directly to the age at which radiation is administered. Radiotherapy, however, remains the most effective adjunct for medulloblastoma and is used in children despite its consequences.

Chemotherapy

Chemotherapy has evolved from use for advanced recurrent disease to use as a common tool in the modern armamentarium against medulloblastoma. However, despite the common use of chemotherapy today, exact benefits remain unclear.

To reduce radiation dose or postpone irradiation until it can be better tolerated, chemotherapy utilization is focusing on young children, especially infants. Among the several regimens now being used, one of the most aggressive is the “8 drugs in 1 day” protocol, which employs vincristine, carmustine, procarbazine, hydroxyurea, cisplatin, cytarabine, prednisone, and cyclophosphamide.

Children’s Cancer Group reported better results with a vincristine, lomustine, and prednisone (VCP) protocol. The study reported a 63% 5-year progression-free survival rate for VCP as opposed to 45% in the same group for the “8 in 1 day” regimen.

Pediatric Oncology Group showed similar survival results in the same age group when chemotherapy was followed by radiation. That study protocol utilized vincristine, cyclophosphamide, etoposide, and cisplatin. Thus far, the greatest benefit from the addition of chemotherapy has been seen in those patients with more advanced disease.

New studies are looking at sensitizing the tumor to irradiation with the concomitant use of chemotherapy. Also, the use of presurgical chemotherapy to treat patients in extremis prior to surgery has been reported.

Like radiation, chemotherapy involves toxic effects. Adverse effects include renal toxicity, ototoxicity, hepatotoxicity, pulmonary fibrosis, and gastrointestinal disturbances. Most of these effects are transient and reverse with the withdrawal of the drug. However, when methotrexate is used in combination with irradiation, irreversible necrotizing leukoencephalopathy can occur.

In children with metastatic MB, tandem HDCT (high-dose chemotherapy) with ASCT (autologous stem cell therapy) followed by conventional craniospinal RT proved its feasibility without jeopardizing survival.

Other data suggest that oncolytic measles viruses encoding anti-angiogenic proteins may have therapeutic benefit against medulloblastoma and support ongoing efforts to target angiogenesis in medulloblastoma. Another important advance in adjuvant therapy is the use of vismodegib (SMO inhibitor) against some SHH subtype medulloblastomas, which showed very promising results in adults as well as the pediatric population.[40]  Yet, research is still ongoing in that perspective.

Surgical Care

Surgery is still the mainstay initial therapy for medulloblastoma, as both a tool for diagnosis and as a risk-stratification factor. The recommendation is still to go for the safest resection possible, and if a second surgery is needed it is better to do it before starting the adjuvant treatment. This strategy might change in the near future, with better understanding of the specific subgroups biology and with the advance in new treatment agents. As for today, patients in whom gross total resection is possible are found to have longer recurrence-free intervals than patients who have residual tumor at the end of surgery.[41, 42]

Surgery also has the added benefit of restoring the natural CSF pathways in the brain. A majority of patients will have resolution of their hydrocephalus after surgery. Several important points in regard to surgery:

  • At the time of surgery, the extent of subarachnoid spread of the tumor can be assessed. When involved with tumor, the surrounding subarachnoid space is opaque, with a granular appearance often referred to as "sugar coating." This condition is associated with early subarachnoid seeding along the entire neuraxis and early recurrence.
  •  In one third of cases, the tumor adheres to the floor of the fourth ventricle with or without brainstem invasion precluding gross total resection.
  • The purpose of postoperative MRI within 48 hours after surgery is twofold. Aside from staging, the MRI delineates any residual tumor; if the surgeon believes the residual tumor is removable, re-exploration of the patient during the same hospitalization for additional tumor removal is a reasonable possibility. The patient spends the first postoperative night in ICU.
  • If the surgery entails significant manipulation or invasion of the brainstem, the patient should remain intubated for the first postoperative night and be extubated carefully once lower cranial nerve function has been assessed. However, if the surgeon believes that involvement of the floor of the fourth ventricle was minimal, the patient may be extubated in the operating room.
  • If the patient has not had an external ventricular drain placed preoperatively, one might be placed at the time of surgery.
  • Postoperative drainage is maintained for a variable duration depending on the appearance of the CSF, amount of output and intracranial pressure (ICP) readings. When deemed appropriate by the surgeon, the drain is clamped and the ICP is monitored. If the patient tolerates 24 hours of having the drain clamped, the ventriculostomy is removed.
  • Decrease in mental status, sustained elevated ICP, or uncontrolled headache are indications for opening the ventriculostomy and continuing drainage. Continued drainage will allow blood and postoperative cellular debris to clear; clamping can be reattempted after CSF clears.
  • If repeated drainage fails to relieve symptoms, a ventriculoperitoneal shunt must be placed for long-term control of hydrocephalus; however, this is necessary in only approximately 15% of patients. The alternative to shunting is a third ventriculostomy. This can reestablish CSF flow without the potential for peritoneal seeding of tumor. 

Molecular and Genetic Alteration

WNT activation

Patients with WNT-activated medulloblastoma are ideal candidates for therapy reduction to minimize the long-term effects of current therapy (reduce not only their cranio-spinal radiation dose but also their chemotherapy). These patients tend to have the most favorable outcomes (the tumor tends to be very vascular so even drugs that usually will not cross the blood-brain barrier will have good effect in this subgroup[15] ); hence, current treatment protocols for this subgroup tumors are designed to minimize radiation and standard chemotherapy and seek new treatments that target oncogenic mechanisms.  

SHH pathway

This subgroup is much more complex for treatment than the WNT group, especially since tumors are much less vascular making it harder to get to a desirable level of drug activity when treating these patients with chemotherapy. There are 2 main components to identify these patients: age and the presence of TP53.

Infants and toddlers (0–4 years old) tend to have a more unfavorable gene mutation that will lead to poorer outcome. In older patients, there is a higher likelihood of PTCH1 and SMO mutations that in some cases can be treated with SMO inhibitors that can lead to better prognosis.

As a group, TP53 must be checked, with advisable genetic family consult when positive.[33] These mutations are highly enriched in children aged 3–17 years. When this mutation is present in SHH, prognosis is very poor regardless of age. Patients with SHH medulloblastoma and positive TP53 should be selected for more intensive therapies. For these patients, protocols include removing DNA alkylating chemotherapy and minimizing radiation therapy and relying instead on antimetabolite, microtubule-disrupting, or other types of chemotherapy. Agents like, PI3K, mTOR, arsenic trioxide, and AKT inhibitors are potentially valuable in controlling specific targets in the SHH pathway and its interaction and links with the PI3K, mTOR, and AKT pathways.[16, 43] In this subgroup (SHH with TP53 positive), the real treatment for residual tumor or recurrent disease is surgery. The overall outcome is intermediate depending on the age group.[33]  Young children have a more favorable outcome, while patients with TP53-mutated SHH medulloblastoma do poorly.[44, 20] Compared to the other subgroups, SHH tumors more frequently recur locally in the original resection cavity.[33]

Non-WNT/non-SHH: Group 3

Patients within this group have a poor prognosis. Their classic fingerprint is the MYC amplification. More than 50% of cases are metastatic at the time of diagnosis, which serves as a poor prognostic factor. Older children in group 3 have a 50% survival in 5 years if they have risk-adapted therapy. These tumors are more common in males and infants (which tend to have poorer prognosis). 17q is a predictor of poor outcome in group 3 medulloblastomas. There are few gene mutations already known that are with potential therapy implication: MYC over-expression, GABRA5 overexpression, transforming growth factor beta (TGF-β) signaling pathway mutations. Cytotoxic drugs, like pemetrexed and gemcitabine or MYC-inhibitors as well as others are under trials that are open across the United States. For example, The SJMB12 study (for all medulloblastoma subgroups, mentioned in the previous section) is also prospectively evaluating the use of pemetrexed, gemcitabine, vincristine, cisplatin, and cyclophosphamide in the high-risk medulloblastoma cases, and this study is currently open.[16]  Unless under research protocol, the real treatment for residual tumor or recurrent disease is surgery. Group 3 patients recur most frequently with metastatic dissemination and a tumor bed devoid of disease.

Non-WNT/non-SHH: Group 4

This group is also known as the glutamatergic subgroup, and it is the most common molecular subgroup and much more common among males. The average-risk patients in this subgroup have excellent survival with the current standard-of-care treatment options. Presence of metastatic disease at diagnosis or chromosome 11 loss and chromosome 17 gain appear to dictate the prognosis in this subgroup of medulloblastoma patients. As mentioned, this group tends to have more vascular tumors, which might explain their good response to regular treatment. Yet, approximately 30% are metastatic at diagnosis,[27] which makes surgery less effective as a treatment tool. Irradiated Group 4 patients recur most frequently with metastatic dissemination and a tumor bed typically devoid of disease.[42, 16]  

Consultations

Consultations with an oncologist, neurosurgeon and/or a radiation oncologist may prove helpful.

Diet

No special diet is beneficial.

Activity

No activity restrictions are necessary.

 

Medication

Medication Summary

Medulloblastoma is treated primarily with surgical excision followed by radiation therapy and chemotherapy. Few drugs are of benefit in this disease. Exceptions are glucocorticoids, which can aid in decreasing vasogenic edema. Mannitol or hypertonic saline is utilized in the acute setting when the physician is faced with a herniating patient. Chemotherapy is used as adjuvant therapy in some patients. Administration of toxic compounds that affect multiple organ systems is in the realm of the experienced oncologist.

Glucocorticoids

Class Summary

Reduction of vasogenic edema is the role of glucocorticoids in malignant brain tumors. They can be very effective in medulloblastoma and can even alleviate hydrocephalus by reopening CSF pathways in the posterior fossa. Although any of several glucocorticoids can be used, dexamethasone is used most often. Equivalent doses of various glucocorticoids are 0.75 mg for dexamethasone, 4 mg for methylprednisolone and triamcinolone, 5 mg for prednisolone and prednisone, 20 mg for hydrocortisone, and 25 mg for cortisone.

Dexamethasone (DoubleDex, DexPak, Zodex)

Most commonly used drug to treat vasogenic edema secondary to medulloblastoma. Promotes reduction of edema after craniotomy.

Methylprednisolone (Solu-Medrol, Depo-Medrol, Medrol)

Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability.

Prednisolone (Millipred, Veripred 20, Orapred ODT)

Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reducing capillary permeability.

Prednisone (Rayos, Deltasone)

May decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear cell activity.

Hydrocortisone (Solu-Cortef, Cortef)

Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability.

Cortisone

Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability.

Osmotic diuretics

Class Summary

These agents are used in the acute setting to prevent further increases of intracranial pressure. In addition to mannitol, hypertonic saline (3% or 5%) also creates an osmotic gradient that shifts fluid from the intracellular to the interstitial and intravascular space. Improves mean arterial pressure and increases total intravascular volume avoiding hypotension as seen commonly with the administration of mannitol.

Mannitol (Osmitrol)

A diuretic agent used to create an osmotic gradient between CSF in arachnoid space and plasma. Used in the acute setting to prevent further increases of intracranial pressure, however can precipitate hypotension given mechanism.

 

Follow-up

Further Outpatient Care

Imaging is the primary mode of monitoring residual disease, efficacy of continuing medical treatment, and recurrence or metastasis. Because medulloblastoma is aggressive, frequent monitoring is essential. MRI should be repeated every 3 months the first year; every 4-6 months the second year; and yearly thereafter.

Radiation therapy is an outpatient procedure typically performed at least 2 weeks following operative intervention in order to allow adequate surgical incision healing.

Any signs of change in mental status are indications for outpatient visits, as they may herald hydrocephalus and possible recurrence.

Lower cranial nerve or cerebellar signs also may signal recurrence.

Steroids are typically tapered to off, however some patients may require low dose steroid therapy depending on the extent of disease. Adverse effects of steroids must be monitored.

Further Inpatient Care

Admit patients in whom further surgical intervention is being contemplated.

Chemotherapy usually is administered on an inpatient basis.

Inpatient and Outpatient Medications

Taper steroid use. However, chemotherapy and radiation therapy may exacerbate edema and necessitate low-dose corticosteroids for a short period of time.

Antiepileptic medication usually is not necessary when the tumor is located in the posterior fossa.

Spread of disease to the supratentorial compartment may cause seizures and indicate antiseizure medication.

Transfer

Transfer may be necessary for treatment at a center familiar with pediatric neurosurgery, pediatric oncology, or pediatric radiotherapy.

Deterrence/Prevention

No known precautions currently exist to prevent the disease or its recurrence.

Complications

Hydrocephalus (the most common complication of medulloblastoma) can cause secondary visual problems. Cerebellar dysfunction (the second most common complication of the disease) may lead to problems with coordination and gait. Cranial nerve palsy from brainstem involvement can lead to difficulties with vision, speech, and swallowing. With subarachnoid spread to the spinal cord, the unfortunate complications are radiculopathy and weakness.

Complications accompany the treatment of medulloblastoma. Fortunately, most of these complications are transient. The most common complication after surgery is a temporary worsening of ataxia accompanied by nystagmus. One of the most commonly cited complications is cerebellar mutism. The anatomic site of origin is thought to be the deep cerebellar nuclei. The constellation of symptoms includes apathy, minimal-to-absent speech, emotional lability, and refusal to initiate movement. Hemiparesis can accompany mutism. Lower cranial nerves are intact, but the syndrome is accompanied by a swallowing apraxia. Other complications include a temporary Parinaud syndrome and pneumocephalus. A common complication of any surgery in the posterior fossa is aseptic meningitis. This can be alleviated with a short course of corticosteroids.

Complications of radiation therapy have been discussed previously and include lowered IQ, small stature, endocrine dysfunction, behavioral abnormalities, secondary neoplasms, and radiation necrosis of the white matter.

Chemotherapy also has numerous adverse effects on multiple organ systems including renal toxicity, ototoxicity, hepatotoxicity, pulmonary fibrosis, and gastrointestinal disturbance. Methotrexate, when used in combination with irradiation, can cause permanent necrotizing leukoencephalopathy.

Prognosis

Medulloblastoma is a very aggressive tumor. Even after a good response to surgery and radiation, recurrence is common; most recurrences occur within 2 years after treatment.

The most common location of recurrence is at the primary tumor site in the posterior fossa.

With the use of adjuvant chemotherapy, incidence of recurrence in the spinal canal and the supratentorial region seems to decrease.

Systemic metastases, in the absence of a CSF shunting system, are also a recognized problem in 10-20% of patients. Bone is the most common site of systemic metastasis; regional lymph node sites follow.

The Collin law was first hypothesized for Wilms tumor and has been expanded since to cover many pediatric tumors thought to be congenital in origin.

The Collin law states that if a tumor has not recurred in a period of time equal to age of the patient plus 9 months, that patient can be considered to be cured.

The Collin law generally holds for medulloblastoma, however, several late recurrences (longer than 10 years after diagnosis) have been reported. The 5-year progression-free survival rate in that group is 70–80% for patients at low risk and 60–70% for patients at high risk.

Greater age at diagnosis has been associated with a better prognosis, most likely because adults more often harbor the less aggressive desmoplastic variant of medulloblastoma.

Why females have a longer recurrence-free interval is not understood.

For discussion of prognosis by subtypes, see Approach Considerations.

Patient Education

Teach patients and families about early signs of hydrocephalus, especially if the patient has a ventricular shunt in place.