Medulloblastoma

Medulloblastoma is the most common type of primary brain cancer in children, typically presenting between the ages of 5 and 9. It is an invasive, rapidly growing tumour originating in the cerebellum or posterior fossa, classified as infratentorial. With a five-year survival rate of 72.1%, it accounts for approximately 500 new cases annually in the United States.

Signs and Symptoms

The symptoms of medulloblastoma are primarily due to increased intracranial pressure resulting from the blockage of the fourth ventricle. Symptoms often present for 1 to 5 months before diagnosis and include:

• Headaches, especially in the morning
• Nausea and vomiting
• Tiredness
• Clumsiness and a stumbling gait
• Dizziness
• Changes in vision, such as diplopia
• Handwriting problems
• Positional vertigo and nystagmus
• Papilledema and sixth cranial nerve palsy

As the disease progresses, patients may experience truncal ataxia, facial sensory loss, motor weakness, and decerebrate attacks. Extraneural metastasis is rare but can occur during relapse.

Pathogenesis

Medulloblastomas are often found near the fourth ventricle. They originate from cerebellar stem cells blocked from normal differentiation. Historically classified as primitive neuroectodermal tumours (PNET), medulloblastomas are now recognised as distinct entities. There are four molecular subgroups: WNT, SHH, Group 3, and Group 4. WNT has an excellent prognosis, while Group 3 has a poor prognosis.

Diagnosis

An MRI typically reveals a heterogeneous mass adjacent to the fourth ventricle. Histologically, medulloblastomas are cellular, with high mitotic activity and characteristic rosette formations. DNA methylation profiling aids in robust subclassification and outcome prediction. The Chang staging system and differential diagnosis, such as ruling out atypical teratoid rhabdoid tumour, are essential for accurate diagnosis.

Treatment

Treatment involves maximal surgical resection, followed by radiation and chemotherapy to increase disease-free survival. Proton beam irradiation offers reduced side effects compared to traditional radiation. Prognosis is poorer in children under 3 years old, with incomplete resection, or with metastasis. Side effects of treatment can include cognitive impairment, psychiatric illness, bone growth retardation, hearing loss, and endocrine disruption.

Chemotherapy

Chemotherapy regimens for medulloblastoma typically include lomustine, cisplatin, carboplatin, vincristine, or cyclophosphamide. In children under 3-4 years, chemotherapy can sometimes delay or replace the need for radiotherapy. However, long-term toxicities such as physical and cognitive delays remain a concern.

Outcomes

Clinical outcomes vary by cytogenetic profiles. Patients with gain of 6q or MYC amplification have poor prognosis, while those with balanced 6q and 17q profiles fare better. Survival rates are higher in children than adults, with long-term sequelae including hormonal and intellectual deficits.

Current clinical studies divide patients into low-, standard-, and high-risk groups. Low-risk patients, often WNT-activated, have high survival rates and efforts are focused on reducing therapy intensity. Standard-risk patients have five-year survival rates around 85-87%, but relapse significantly diminishes prognosis. High-risk patients may see improved outcomes with additional chemotherapy, such as carboplatin during radiation.

Epidemiology

Medulloblastomas affect fewer than two people per million annually, with a higher incidence in males and younger children. They represent the second most frequent brain tumour in children and the most common malignant brain tumour. In adults, medulloblastomas are rare, comprising less than 2% of CNS malignancies.

Research Models

Research models using gene transfer in rats and mice have identified genes involved in tumour development, such as p53 and Cxcl3. These models provide insights into potential therapeutic targets, offering hope for improved treatment strategies in the future.

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Self-assessment MCQs (single best answer)

What is the most common type of primary brain cancer in children?

Where do medulloblastomas typically originate?

Which symptom is commonly associated with medulloblastoma?

Which molecular subgroup of medulloblastoma has the best prognosis?

What imaging technique is typically used to diagnose medulloblastoma?

What is the primary purpose of proton beam irradiation in medulloblastoma treatment?

Which age group has a poorer prognosis when diagnosed with medulloblastoma?

Which chemotherapy drug is commonly used in medulloblastoma treatment?

What is a common long-term side effect of medulloblastoma treatment?

Which cytogenetic profile in medulloblastoma is associated with a poor prognosis?