Medulloblastoma

Overview

Definition

Medulloblastoma is a highly malignant primitive neuroectodermal tumor that develops in the posterior fossa in children. It is an embryonal tumor, arising from neuronal progenitor cells, and generally has a poor prognosis.

Classification of nervous system tumors

Epidemiology

• Incidence: 
  • Approximately 2 per 100,000 population in the United States
  • Approximately 500 children are diagnosed per year in the United States.
  • Most common malignant brain tumor in children
  • Approximately 10%–20% of all primary CNS tumors in children ≤ 18 years of age
• Age:
  • Peak incidence is between 5 and 9 years of age.
  • 70%–80% of patients are diagnosed before age 20.
  • The disease is extremely rare in patients over 30.
• Sex: male-to-female ratio is approximately 1.5 to 1.
• Race: higher rates in whites than blacks (80% white)

Classification

The WHO has developed both genetic and histologic classifications for medulloblastomas.

• Medulloblastomas, genetically defined:
  • Wingless-related integration site (Wnt) activated
  • Sonic hedgehog (SHH) activated:
    • SHH activated and TP53 mutant
    • SHH activated and TP53 wild type
  • Non-Wnt/non-SHH:
    • Group 3: characterized by amplification of the oncogene MYC 
    • Group 4: characterized by amplification of oncogenes MYCN and cyclin-dependent kinase 6 (CDK6)
• Medulloblastomas, histologically defined:
  • Classic medulloblastoma
  • Desmoplastic/nodular medulloblastoma
  • Medulloblastoma with extensive nodularity
  • Large-cell/anaplastic medulloblastoma
• Medulloblastoma, not otherwise specified

Etiology and pathophysiology

• Most cases occur sporadically.
• Most cases arise in the posterior fossa.
• Metastasize through the CNS and to bone
• Genetic mutations involved in WHO classification:
  • Wnt: a family of signaling oncoproteins involved in patterning decisions during embryonic development
  • SHH: stimulates proliferation of the granule cell progenitors in the brain
  • Tumor protein 53 (p53): a tumor suppressor protein
  • MYC: an oncogene encoding a multifunctional nuclear protein involved in regulating cell growth, cell division, apoptosis, and metabolism
• Approximately 5%–6% of patients have a cancer predisposition syndrome, including:
  • Familial adenomatous polyposis (FAP): caused by inactivating mutations in the APC gene (part of a complex in the Wnt-signaling pathway)
  • Nevoid basal cell carcinoma syndrome (NBCCS): caused by germline mutations in the PTCH1 gene (involved in SHH signaling)
  • Li-Fraumeni syndrome: caused by mutations in p53
  • Other germline mutations, including:
    • BRCA2
    • PALB2
    • GPR161

Clinical Presentation

Medulloblastomas typically arise in the cerebellum, so patients typically present with cerebellar symptoms and—since the most common complication of medulloblastoma is hydrocephalus—signs of increased intracranial pressure (ICP).

• Cerebellar signs and symptoms:
  • Midline cerebellar tumors: 
    • Gait ataxia: broad-based gait and/or difficulty with heel-to-toe walking
    • Truncal instability
    • Head titubation (bobbing)
    • Nystagmus
  • Lateral cerebellar tumors: limb clumsiness or incoordination 
    • Dysmetria on finger-to-nose touching
    • Intention tremor
    • Difficulty with heel-to-shin touching
• Signs and symptoms of ↑ ICP:
  • Nocturnal or morning headaches
  • Nausea and potentially severe vomiting
  • Altered mental status 
  • Papilledema
• Brainstem involvement may lead to cranial nerve deficits:
  • Diplopia
  • Hearing loss
  • Facial weakness 
  • Head tilt
• Dizziness or double vision can be due to either cerebellar, brainstem, or cranial nerve involvement.
• Leptomeningeal dissemination can result in: 
  • Spinal cord compression → paraplegia
  • Nerve root compression → radiculopathy

Diagnosis

Imaging

Magnetic resonance imaging is the imaging test of choice. Due to the fact that 20%–25% of patients have spinal involvement at presentation, MRI of both the brain and the spinal cord should be performed. Findings include:

• Contrast-enhancing midline or paramedian cerebellar mass
• Iso- or hypointense on T1-weighted images
• Heterogenous on T2-weighted images
• Mass often compresses the 4th ventricle → may lead to hydrocephalus
• Regions of necrosis, hemorrhage, or cystic changes may be present.
• May have nodular or linear enhancement in the spinal cord: 
  • Known as leptomeningeal dissemination
  • Can reach cauda equina in a phenomenon known as drop metastasis
• A CT scan may be performed if an MRI is contraindicated, but CT scans are less sensitive.

Cerebrospinal fluid analysis

Cerebrospinal fluid analysis is important in the evaluation for metastasis since approximately ⅓ of medulloblastomas metastasize through the CSF. These medulloblastomas show:

• Neoplastic cells on cytopathologic examination
• Elevated protein and mild pleocytosis (nonspecific findings)
• ↑ Risk of relapse and poorer prognosis
• Note: Most patients present with ↑ ICP and/or hydrocephalus, requiring lumbar puncture to be delayed until after surgical resection to prevent brain herniation.

Histopathology

Diagnosis requires confirmation by histopathologic examination at the time of surgical resection.

• Gross characteristics: 
  • Well-circumscribed, gray, soft, friable tumors 
  • Usually have associated necrosis
• Microscopic characteristics:
  • Highly cellular tumors with abundant dark staining
  • Small cells with little cytoplasm
  • Oval or round, hyperchromatic nuclei that are elongated or crescent shaped.
  • Often have abundant mitosis
  • Homer Wright rosettes found in up to 40% of patients.
• Markers expressed in histopathological studies:
  • Synaptophysin
  • Neuron-specific enolase
  • Nestin (a marker of primitive neuroepithelial cells)
  • Nuclear β-catenin staining: present in Wnt pathway tumors
  • P53 mutations

Management and Prognosis

Management

The standard of care for management of medulloblastoma is combined modality therapy, including surgery, chemotherapy, and radiation.

• Goals of therapy:
  • Remove the tumor
  • Alleviate ↑ ICP
  • Prevent recurrence
• Surgery with maximal safe resection of the tumor
• Systemic chemotherapy
• Craniospinal radiation therapy (RT):
  • Higher doses are associated with better tumor control.
  • Craniospinal RT in children can cause: 
    • Significant neurocognitive impairment
    • Hearing loss
    • Growth abnormalities
    • Hypothyroidism
    • Adrenal insufficiency
    • Hypogonadism and infertility
  • RT may be avoided or given in lower doses in infants and very young children.
• For high-risk disease (metastatic, unresectable, or recurrent disease):
  • Optimal therapy is unknown.
  • Patients should be included in a clinical study if possible.

Prognosis

• Survival in children:
  • With modern combined modality therapy, approximately 75% of children who are diagnosed with medulloblastoma survive into adulthood.
  • 5-year survival: 
    • Children diagnosed before age 3: 40%–50%
    • If the disease is disseminated at the time of diagnosis: 15%–30% 
• Survival in adults:
  • 5-year survival rate: 65%
  • 10-year survival rate: 52%
• Wnt tumors are associated with an excellent prognosis.
• Factors associated with poor prognosis:
  • Young age (< 3 years old)
  • Disseminated or metastatic disease at diagnosis
  • Residual tumor post-resection
  • Large cell or anaplastic histology
  • Non-Wnt/non-SHH group 3 and 4 tumors
• In 80% of survivors, there are treatment-related morbidities, especially those caused by the craniospinal radiation therapy listed above.

Differential Diagnosis

The following posterior fossa tumors are differential diagnoses for medulloblastoma:

• Pilocytic astrocytoma: 2nd most common brain tumor in children. Magnetic resonance imaging can help distinguish this tumor from others. For example, pilocytic astrocytomas are usually solitary cystic lesions with a mural nodule, or they have central necrosis with a thick rim of enhancing tissue. In contrast, medulloblastomas tend to have multiple smaller cysts, if cysts are present at all. 
• Ependymoma: a tumor that arises from the ependymal lining of the ventricular system, typically at the base of the 4th ventricle. Tumors are usually intracranial in children and in the spinal cord in adults. Ependymomas more commonly extend through the foramen of Magendie (inferiorly) or Luschka (laterally), while this type of extension is rare in medulloblastoma. Magnetic resonance imaging is the standard imaging technique, but histologic confirmation is required for diagnosis. Treatment involves surgical resection and adjuvant radiation and/or chemotherapy (based on age). 
• Atypical teratoid/rhabdoid tumors (AT/RT): a rare, aggressive primary CNS tumor arising from embryonal cells that can appear similar to a medulloblastoma on MRI. Atypical teratoid/rhabdoid tumors can form anywhere in the CNS but typically develop in the cerebellum, most commonly in children < 3 years old. These tumors contain neuroepithelial, rhabdoid, epithelial, and mesenchymal cells. Compared with medulloblastomas, AT/RTs are more likely to involve the lateral hemispheres or cerebellopontine angle and contain hemorrhage within the tumor.