Clinical Picture and Treatment

Clinical symptoms and signs are generally brief, typically less than 3 months in duration, and reflect the strong predilection of this tumor to arise within the cerebellum, most often in the vermis. Symptoms may include headache, general malaise, failure to thrive, vomiting, and clumsiness, among other presentations that mimic common and benign childhood pathologies seen in primary care.

Typically, the treatment strategies for MB are threefold: maximal safe resection (which may include cerebrospinal fluid [CSF] diversion), neuraxis radiotherapy, and chemotherapy.

Location

The tumor usually arises at the midline within the vermis and exhibits growth into the fourth ventricle ( Fig. 1 ).

MB: location. ( A, B ) Contrast-enhanced MR T1 images from a 6-year-old girl presenting with MB in the midline vermis, with growth into the fourth ventricle and hydrocephalus.

Less typical locations include nonventricular superior or inferior vermian tumor, cerebellar hemispheric lesions, and extension into the foramina of Magendie and foramina of Luschka to the cerebellopontine angle (CPA).

Computed Tomography and Conventional MR Imaging

On unenhanced CT, the tumor is usually characterized as hyperdense ( Fig. 2 ), and on T2 images, as isointense to hypointense compared with gray matter ( Fig. 3 ). These imaging findings are likely secondary to high cell density and high nuclear-to-cytoplasmic ratio.

MB: CT. A 9-year old boy presenting with headache and vomiting. There is a well-circumscribed solid lesion in the midline vermis, that occupies the fourth ventricle with hydrocephalus. The lesion is hyperdense on the noncontrast CT ( A ) and enhances after contrast injection ( B ).

MB: MR imaging. Same patient as Fig. 1 . A 6-year old girl complaining of neck pain, presenting with walking difficulty and ataxia. There is a well-circumscribed lesion in the midline vermis, with growth into the fourth ventricle. Some cysts with high signal intensity on T2 ( A : coronal and B : axial) as well as some foci of low signal intensity on the gradient echo ( C ) that may be related to calcification or blood are demonstrated within the lesion. The solid portion is isointense to the cerebellar cortex on T2, due to high cell density along with high nuclear-cytoplasmic ratio, also responsible for the restricted diffusion ( D : DWI, E : ADC map) and high Cho peak ( F ) demonstrated in the lesion. There is significant enhancement ( G : axial T1 with contrast) and no elevation of the blood volume ( H : rCBV map) in the perfusion study.

The tumor typically may appear heterogeneous on imaging, with findings related to cyst formation and hemorrhage on MR, and calcification seen on CT (see Fig. 3 A–C). Intratumoral cyst or necrosis is observed in 40% to 50% of cases.

MBs typically enhance.

Atypical imaging findings, such as high signal intensity compared with the cerebellar cortex on T2, as well as no enhancement may be demonstrated ( Fig. 4 ).

MB: high signal on T2 and no enhancement. An 8-year old boy presenting with headaches and vomiting. There is a solid MB within the inferior vermis growing into the fourth ventricle, with no enhancement ( A : sagittal, B : axial T1 with contrast) presenting with high signal intensity compared with the cerebellar cortex on T2 ( C : axial T2).

Sometimes the tumor presents with an infiltrative pattern instead of a solid solitary mass ( Fig. 5 ).

MB: infiltrative pattern. A 12-year old girl presenting with ataxia, headache, and vomiting. There is a diffuse infiltrative lesion ( A–C : coronal T2), involving the right greater than left cerebellum, infiltrating into the brainstem. Most of the lesion is hyperintense on T2, with some hypointense areas ( arrows in A and B ), probably related to high cell density. The neurosurgeon suspected ADEM (acute disseminated encephalomyelitis). Pathology was consistent with classic MB. There is heterogeneous enhancement ( D : sagittal T1 with contrast) as well as evidence of high cell density and high nuclear-cytoplasmic ratio characterized by restricted diffusion ( arrow in E : ADC map) and high choline on spectra ( F ).

Evidence of leptomeningeal metastatic spread is present in 33% of all cases at the time of diagnosis and is well evaluated with contrast-enhanced MR imaging of the brain and the spine. MR imaging is more sensitive than CSF studies for the detection of CSF spread of primary brain tumors.

Metastases may be leptomeningeal, dural-based, intraventricular, adherent to the spinal roots, or even to the liver ( Fig. 6 ).

MB: metastasis. ( A, B ) A 26-year-old woman treated for MB at the age of 8. Now presenting with ataxia and incoordination. Enhancing leptomeningeal metastases are demonstrated surrounding the brainstem, basal cisterns, temporal lobes, and occipital lobes ( A , B : axial T1 with contrast). ( C, D ) A 20-year-old man treated for MB 2 years ago. MR imaging shows dural-based metastasis in the temporal and frontal basal regions, isointense to the cortex on T2 ( C : axial) with solid enhancement ( D : axial T1 with contrast). Metastasis also may compromise the ventricular system ( E ), the spinal roots, which may look thickened ( F ), as well as the liver ( G ).

Metastasis to the brain parenchyma may bleed, resembling cavernoma ( Fig. 7 ).

MB: parenchymal metastasis resembling cavernoma. A 7-year-old girl presenting with headaches and paresthesia on the right. A solid lesion is demonstrated in the left frontal region, which is heterogeneous, hypointense on T2 ( A : axial T2), has significant low signal on the gradient echo image ( B : axial gradient echo [GRE]) and some enhancement ( C : axial T1 with contrast). Lesion was diagnosed as cavernoma. Two months later ( D , E : axial T1 with contrast) dural-based, as well as leptomeningeal metastasis are demonstrated with final diagnosis of metastatic MB.

Diffusion-Weighted MR Imaging

Apparent diffusion coefficient (ADC) values are significantly lower in MBs than in all other posterior fossa tumors ( P <.001) related to high cell density ( Fig. 8 , see also Figs. 3 D, E and 5 E).

MB-restricted diffusion. Patient diagnosed with MB, presenting with dizziness and nausea in the previous 2 months. There is a solid lesion in the midline vermis, mostly isointense to the cerebellar cortex on T2 ( A : axial T2), presenting with restricted diffusion ( B : DWI, C : ADC map).

A study by Jaremko and colleagues confirmed that diffusion imaging is the single most useful sequence for differentiating pediatric posterior fossa tumors and that, as expected, diffusion restriction is rare in grade 1 tumors and common in grade 4 tumors. The optimal threshold for distinguishing MB and juvenile pilocytic astrocytomas (JPAs), ADC minimum = 800 × 10 ⁻⁶ mm ² /s, was lower than the threshold of 900 × 10 ⁻⁶ mm ² /s used by Rumboldt and colleagues, likely because they used ADC mean rather than ADC minimum.

Desmoplastic medulloblastoma, a histologically less aggressive subtype with better prognosis than the classic type, is expected to have less highly restricted diffusion than the classic type. Some of these tumors present with no restricted diffusion at all ( Fig. 9 ).

MB: no restricted diffusion. A 51-year-old man diagnosed with desmoplastic MB, presenting with headaches and nausea in the preceding 3 months. There is an infiltrative lesion compromising most of the cerebellar parenchyma, presenting with mild high signal intensity on T2 ( A : coronal, B : axial T2), and no restricted diffusion ( C : ADC map). The lesion does not enhance ( D : axial T1 with contrast).

Proton Magnetic Resonance Spectroscopy

Choline

On MRS, MBs usually demonstrate a significant elevation of the choline (Cho) peak related to high cell density and elevated Cho/Cr and Cho/N-acetyl-aspartate (NAA) ratios, reflecting its malignant nature ( Fig. 10 , see also Figs. 3 F and 5 F).

MB: MRS. Same patient as in Fig. 8 . There is a solid enhancing MB in the cerebellar vermis ( A : sagittal T1 with contrast), presenting with very high Cho as well as Tau peak in the spectra ( B : MRS). NAA is very low and there is elevation of Glx as well as presence of Ala and lactate.

High Cho has been previously reported as a characteristic finding of embryonal tumors.

Elevation of the Cho peak is useful in distinguishing between MB and L’Hermitte-Duclos disease (LDD), as MBs occasionally may present with a laminated appearance, and with no contrast enhancement, mimicking LDD. The Cho peak is typically elevated in patients with MB when compared with patients with LDD.

Desmoplastic MBs may present with no elevation of the choline in the spectra. In these tumors, a huge myo-inositol peak may be seen related to the desmoplastic nature (Lara A. Brandão, MD, personal communication, 2013) ( Fig. 11 ).

MB: no elevation of Cho. Patient diagnosed with desmoplastic MB. MRS ( A : voxel placement-axial T2) demonstrates no elevation of the Cho peak ( B-curve ). The most striking finding is elevation of the myo-inositol peak (mI).

Dynamic Susceptibility Contrast and Dynamic Contrast-Enhanced MR Imaging

There can be variable perfusion and permeability characteristics in MB, with some lesions showing elevated perfusion and permeability and others not ( Fig. 12 , see also Fig. 3 H).

MB: low blood volume, no significant permeability. Same patient as in Figs. 8 and 10 . There is a solid enhancing MB in the cerebellar vermis ( A : axial T1 with contrast), showing no elevation of the blood volume ( B : rCBV map), as well as no significant elevation of the permeability ( C : maximum slope of increase map).

Important considerations

Radiologic-pathologic correlation

The World Health Organization (WHO) classification system 2007 uses histology to classify MBs into 4 major groups, including classic, desmoplastic, MB with extensive nodularity (MBEN), and large cell/anaplastic MB subtypes :

Classic

Classic MB represents the most common histologic subtype and is composed of sheets of densely packed small round blue cells (basophilic) with a high nuclear-to-cytoplasmic ratio, mitotic and apoptotic activity, and may occur in the midline.

Elevation of Tau is seen specifically in this histologic subtype.

Desmoplastic

This subtype is hypocellular, presents with lower Tau concentration compared with the classic subtype and carries a favorable prognosis.

This histologic subtype is often found in adult patients with MB, demonstrating a cerebellar hemispheric mass extending to the overlying meninges, with desmoplastic reaction evoked by prominent leptomeningeal involvement ( Fig. 13 ).

MB: desmoplastic type. A 64-year-old woman presenting with numbness and reduced consciousness. There is an infiltrative cerebellar lesion in the left cerebellar hemisphere, extending laterally to the cerebellopontine angle, hyperintense on T2 ( A, B : axial T2) with a laminated appearance. There is no restricted diffusion, which may be demonstrated in desmoplastic MBs ( C : ADC map). There is nonhomogeneous enhancement in the lesion, associated with thickening of the adjacent meninges due to desmoplastic reaction ( D , E : axial, F : coronal T1 with contrast).

Anaplastic

Anaplastic MBs (15%) are characterized by marked nuclear pleomorphism, nuclear molding, and cell–cell wrapping, and the large cell variant (2%–4%) displays a monomorphous population of large cells whose nuclei exhibit prominent nucleoli. Both variants are characterized by a very high proliferative activity, abundant apoptosis, and a much poorer prognosis.

This is the most aggressive subtype, characterized by presence of necrosis.

Extensively nodular

MBENs tend to develop in the vermis in children younger than 3 years in most cases and is frequently represented as a nodular enhancing appearance on CT scans or MR images. Prognosis is better than for the classic MB.

Molecular subgroups

More recently there has been the development of a classification of 4 main subgroups of MBs based on molecular profiling.

The WNT and SHH groups were named after the predominant signaling pathways thought to be affected in their pathogenesis. Less is known currently regarding the pathogenesis of groups 3 (tending to harbor MYC amplification) and 4 (tending to have isochromosome 17q) and therefore generic names were chosen until they are better understood.

The SHH group has become of increasing interest because of the availability and temporary success of small molecule inhibitors to smoothened (SMO), which is part of the SHH pathway.

For a detailed comprehensive review on the molecular subgroups of MB, see the consensus article by Taylor and colleagues.

MB is the most common malignant brain tumor in children and, as such, has been the focus of tremendous efforts to genomically characterize it.

What was once thought to be a single disease has been divided into multiple, molecularly unique subgroups through gene expression profiling. Each subgroup is not only unique in its origin and pathogenesis, but also in the prognosis and potential therapeutic options. The molecular classification system has a potential use in developing prognostic models as well as for the advancement of targeted therapeutic interventions.

MB is currently stratified into 4 molecular variants through the advances in transcriptional profiling.

They include sonic hedgehog (SHH), wingless (WNT), Group III, and Group IV.

SHH (sonic hedgehog) medulloblastomas

SHH tumors are thought to account for 28% of all medulloblastomas.

They have an intermediate prognosis between good prognosis WNT tumors and poor prognosis group 3 tumors, and may be similar in prognosis to group 4. SHH MBs show a dichotomous age distribution being more common in both infants (<4 years) and adults (>16 years).

Most tumors in this group are of the desmoplastic subtype, located in the cerebellar hemisphere more often than in the midline.

WNT (wingless) medulloblastomas (∼10%)

WNT tumors are thought to be the rarest subgroup of medulloblastoma, accounting for 11% of these tumors, but they have probably been the most studied and have a very good long-term prognosis with overall survivals reaching 90%.

WNT tumors also show a specific age distribution being almost absent in infants (aged <4 years) but predominantly affecting children with a peak incidence of 10 to 12 years.

Most (97%) WNT MBs show classic histology; however, rarely, they are phenotypically large cell/anaplastic and may remarkably retain their relatively good prognosis with this phenotype. They tend to occur in the middle cerebellar peduncle/cerebellopontine angle.

Group 3

Group 3 tumors account for 28% of all MBs.

They are associated with the worst prognosis of all the subgroups and are frequently metastatic. Group 3 tumors are found in infants and children but very rarely in adults. Group 3 MBs are mostly classic or large cell/anaplastic morphology. MYC amplification appears to be highly associated with group 3 tumors and is associated with a worse prognosis. The tumors in this subgroup tend to be ill-defined on imaging.

Group 4

Group 4 MBs are thought to be the most common “typical” subgroup of MB, accounting for approximately 34%, and can be thought of conceptually as being associated with isochromosome 17q. Group 4 medulloblastomas rarely affect infants (0–3 years) and mainly affect children, with a peak age of 10 years.

Although they frequently metastasize, they still have an intermediate prognosis compared with the poor prognosis of group 3.

The vast majority of group 4 MBs have a classic histology.

All histologic subtypes can present with this molecular profile, except the desmoplastic one.

These tumors tend to have minimal or no enhancement.

Molecular profiling: implications in treatment

The identification of different molecular pathways involved in the pathogenesis of MBs provides new therapeutic targets for drug development.

Medulloblastomas and associated syndromes

Basal cell nevus syndrome (Gorlin syndrome)

This is a rare autosomal dominant disorder with high incidence of neoplasms, notably MB. Ten percent of these patients will develop MBs, usually desmoplastic.

Falcine calcification in children with MB may be a marker for basal cell nevus syndrome.

Turcot syndrome

Turcot syndrome is associated with familial colonic polyposis, with high incidence of brain tumors, such as MB and glioma.

Li-Fraumeni

Germline mutations of the p-53 tumor suppressor gene predisposes to different types of cancer in patients, especially soft tissue sarcomas. Ten percent of these patients develop MB.

Imaging Findings

On unenhanced CT, the tumor is usually characterized as hyperdense ( Fig. 14 ) and on T2 images, as isointense to hypointense compared with gray matter ( Fig. 15 ). These imaging findings are likely secondary to high cell density and high nuclear-to-cytoplasmic ratio and overlap with those described for MBs.

ATRT: CT. ATRT hyperdense on noncontrast CT ( A ), with enhancement in the contrast-enhanced study ( B ).

( Courtesy of A. James Barkovich, MD, San Francisco, CA.)

ATRT: MR imaging. A 5-year-old girl with irritability and hypersexuality, sent to a psychiatrist. There is a nonhomogeneous lesion presenting with a solid component isointense to the cerebellar cortex on T2 ( A : coronal and B–D : axial). Cysts are demonstrated within and adjacent to the solid component. The lesion is located off midline and extends to the CPA on the right, which favors ATRT instead of MB. Some low signal intensity foci are demonstrated within the solid portion, which may be related to blood products ( E : axial GRE). There is heterogeneous enhancement ( F : axial T1 with contrast) and significant restricted diffusion ( G : DWI, H : ADC map).

Enhancement is demonstrated in approximately 89% of the cases (see Fig. 15 F).

Due to high cell density, as well as high nuclear-to-cytoplasmic ratio, restricted diffusion is typically seen (see Fig. 15 G, H).

MRS shows elevated Cho and reduced NAA as well as a prominent Lip peak. However, there are no reports in the literature that quantify these changes or address the presence or size of Tau peaks.

Atypical Teratoid Rhabdoid Tumors Versus Medulloblastoma

The main differential diagnosis for posterior fossa ATRT is MB. If the patient is younger than 3 years, if tumor is located off midline, extending to the CPA, and if blood products are demonstrated in the lesion, one should consider ATRT as the most likely diagnosis.

However, the precise distinction can be made only through immunohistochemistry and genetic analyses. ATRTs frequently demonstrate deletions of chromosome 22q with inactivation of the INI1/hSNF5, thought to be a tumor suppressor gene. Loss of the INI1 gene product is used to diagnose ATRT, although it is not present in all ATRT tumors.

Location

Predilection for the cerebellar hemisphere instead of the cerebellar vermis is typically demonstrated. The lesion displaces and compresses the fourth ventricle ( Fig. 16 A, B ), as opposed to what is typically demonstrated in MB that usually compromises the cerebellar vermis, filling the fourth ventricle ( Fig. 16 C, D).

PA: location and signal on T2. ( A, B ) A 9-year-old girl presenting with headaches, neck pain, ataxia, and vomiting. There is a PA in the left cerebellar hemisphere, compressing and displacing the fourth ventricle ( A : coronal and B : axial T2). The solid component is hyperintense to the cerebellar cortex on T2. ( C, D ) Children diagnosed with MB. The lesion is located in the midline vermis, filling the fourth ventricle. The solid component of MB is usually isointense to the cerebellar cortex on T2 ( C ). Some MBs may present with high signal intensity on T2 ( D ), resembling a PA.

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