Medulloblastoma

Medulloblastoma is an embryonal tumor of the cerebellum and the most common malignant brain tumor of childhood. Incidence is about 0.5 in 100,000 children a year, with a peak at 3 to 8 years, a male to female ratio of about 1.5 to 1, and about 70% of cases before age 15. A second smaller peak occurs in adults aged 20 to 40.

Four molecular groups define behavior

• WNT-activated (about 10%): CTNNB1 mutation, monosomy 6, survival over 90%
• SHH-activated (about 30%): infants and adults, PTCH1, SUFU or TP53 mutation, with TP53 mutation carrying a poor outlook
• Group 3 (about 25%): MYC amplification, metastatic in about 40% at diagnosis, the worst prognosis
• Group 4 (about 35%): isochromosome 17q, often metastatic, intermediate outlook

Histology is classic, desmoplastic or nodular, extensive nodularity, or large cell and anaplastic. Hereditary syndromes are Gorlin syndrome (PTCH1), Li-Fraumeni syndrome (TP53), familial adenomatous polyposis (APC, WNT group) and germline SUFU mutation.

The tumor arises in the vermis and fourth ventricle roof and spreads through the cerebrospinal fluid, with metastases in 30 to 40% at diagnosis. Average-risk disease (age 3 or over, residual tumor under 1.5 cm2, no metastasis, no anaplasia) has a 5-year survival near 80%. High-risk disease has 60 to 70%. Complications are obstructive hydrocephalus (about 80%), posterior fossa syndrome with mutism in 10 to 25% after surgery, neurocognitive decline, endocrine deficiency, hearing loss and second tumors.

• Morning headache, vomiting, lethargy and papilledema from hydrocephalus
• Truncal ataxia, wide-based gait, dysmetria and nystagmus
• Head tilt, sixth nerve palsy and diplopia
• Infants: macrocephaly, irritability and a bulging fontanelle
• Red flags: falling consciousness, bradycardia with hypertension, sunsetting eyes, and back pain or limb weakness from spinal metastases

1. MRI brain and whole spine with gadolinium, with spine imaging before surgery: a midline posterior fossa mass, hyperdense on CT, restricted diffusion, enhancing, with nodular spinal deposits.
2. Postoperative MRI within 48 to 72 hours to measure residual tumor.
3. Lumbar puncture for cytology at least 10 to 14 days after surgery (or earlier if safe before surgery, and never with raised pressure).
4. Histology and molecular classification (methylation profile, CTNNB1, TP53, MYC and MYCN status).
5. Germline testing for SUFU, PTCH1, TP53 and APC.

Differentials: pilocytic astrocytoma, ependymoma, atypical teratoid rhabdoid tumor, brainstem glioma, hemangioblastoma, metastasis.

Presentation

• Dexamethasone 0.1 to 0.25 mg/kg IV or orally every 6 hours (maximum 4 mg a dose) with omeprazole 1 mg/kg daily (maximum 20 mg).
• Hydrocephalus: external ventricular drain or endoscopic third ventriculostomy, with a permanent shunt avoided if possible.

Surgery: maximal safe midline suboccipital resection, aiming for residual under 1.5 cm2. Complications: posterior fossa syndrome, cranial neuropathy, hemorrhage and infection.

Radiotherapy (age 3 or over, start within 4 to 6 weeks):

• Average risk: craniospinal 23.4 Gy in 13 fractions of 1.8 Gy, then a boost to a total of 54 to 55.8 Gy to the tumor bed.
• High risk or metastatic: craniospinal 36 Gy in 20 fractions, then a boost to 54 to 55.8 Gy.
• Vincristine 1.5 mg/m2 IV weekly (maximum 2 mg) during radiotherapy.

Maintenance: cisplatin 75 mg/m2 IV day 1, lomustine 75 mg/m2 orally day 1 and vincristine 1.0 to 1.5 mg/m2 IV days 1, 8 and 15, every 6 weeks for 8 cycles. Give sodium thiosulfate 20 g/m2 IV 6 hours after cisplatin in localized disease to reduce hearing loss. Check audiology, creatinine, magnesium and blood count before each cycle. Prophylaxis: trimethoprim-sulfamethoxazole (trimethoprim 150 mg/m2 a day in 2 divided doses on 3 days each week) during treatment.

Infants under 3 years: avoid craniospinal radiotherapy. Use intensive chemotherapy with high-dose thiotepa and autologous stem cell rescue.

Adults: the same strategy, with craniospinal 36 Gy.

Relapse: poor outlook. Options are re-resection, temozolomide 150 mg/m2 orally days 1 to 5 every 28 days, and vismodegib 150 mg orally daily for adults with SHH tumors (contraindicated in children with open growth plates).

Follow-up: MRI brain and spine every 3 months for 2 years, every 6 months to year 5, then annually. Endocrine, audiology, neurocognitive and second tumor surveillance for life. Counsel on fertility, and offer sperm banking before chemotherapy.