Radiation Oncology/Medulloblastoma/Overview

Medulloblastoma Overview

Epidemiology

 * Most common malignant brain tumor of childhood (20% of CNS tumors in children <19 years old; glioma #1). 550 cases in the US
 * Median age of presentation is 5-7 years old. 75% medulloblastomas occur in children <15 years old.
 * Slight male predominance.
 * Highest risk of CSF+ at presentation (30-35%)

Clinical Presentation

 * Increased intracranial pressure: Headaches, nausea, vomiting
 * Cranial nerve deficits
 * Ataxic gait
 * In infants: loss of milestones, increased head circumference, head tilt due to CN IV palsy
 * Clinical exam: papilledema, nystagmus, CN abnormalities (VI most common -> "setting sun" sign with downward gaze)
 * 50-75% have <3 months of symptoms; prolonged symptoms duration multiplies probability of favourable treatment outcome of basic disease

Radiographic

 * Plain films: often invisible
 * CT: hyperdense on unenhanced study, enhances with contrast, can appear homogenous
 * MRI: hyperintense on T1, heterogenous on T2, often compresses 4th ventricle
 * Get imaging before starting steroids
 * Pre-op MRI brain and spinal cord (post-op spine can give false positives)
 * Post-op MRI brain within 48 hours
 * Pre-op CSF before surgery if safe (no increased ICP), else 10-14 days after surgery to avoid false-positive findings from surgical debris
 * If advanced, metastatic work-up

Histology

 * "Small round blue cell"; classified as primitive neuroectodermal tumor (PNET)
 * Medulloblasts are derived from cerebellar granule cells (account for almost half of all neurons in CNS), through activation of Sonic Hedgehog Pathway, likely from external granular layer of the cerebellum
 * Genetics: Loss of 17p, 10q, 16q, chromosome 11; excess of 17q, chromosome 7

Prognostic Factors

 * Molecular profiling risk stratification (PMID 21357776)
 * Excellent prognosis: Wnt pathway
 * Good prognosis: Hh pathway (Hedgehog)
 * Fair prognosis: all others
 * Poor prognosis: c-MYC amplification
 * Histological risk stratification
 * Histologically poor prognosis: Large-cell anaplastic (LCA) variant, diploid DNA, LOH 17p, p53 mutation and expression, low TrkC (tyrosine kinase that mediates neuronal differentiation; 4.8x risk of death), MYC mRNA (c-myc/MYCC) expression, HER2-neu positive (ErbB2+), HER2+/HER4+ coexpression
 * Histologically better prognosis: Desmoplastic variant, high TrkC expression, ErbB2-, β-catenin (beta-catenin) nucleopositivity
 * Historical risk stratification:
 * Clinically poor prognosis: Age <3 years, M2-4 disease, unresectable or subtotal resection (>1.5 cm2)
 * Clinically better prognosis: Age >5-7 years, M0 disease (no metastasis), tumor is not visible on the postoperative image

Anatomy

 * Posterior Fossa borders
 * Anterior: clivus and posterior clinoid
 * Posterior: calvarium
 * Superior: tentorium
 * Inferior: occipital bone
 * Lateral: portions of temporal, occipital, parietal bones

Natural History

 * Dissemination: CSF seeding, intracranial, subarachnoid space, mets outside CNS <5%
 * Most recurrences within two years, at the site of primary tumor (50%)
 * Medulloblastoma tends to follow Collins' law (see PMID 9213055), which defines the period of risk for recurrence as the patient's age at diagnosis + 9 months of gestation. According to Collin's law, if a patient has no evidence of recurrence within this time period, he is considered cured (e.g. a 3 year old with medulloblastoma is cured when his disease free interval reaches 3 years + 9 months). The premise is that if this tumor was present in utero, then gestation+age determines rate of growth for it to become clinically evident. Therefore, if there is residual disease after treatment, it should become clinically evident again within the same time-frame
 * 10-year survival for all stages: 40-50%
 * For today considerable part of survivors is living 20-25 years and more from the moment of primary treatment

Other Resources

 * ASTRO/ARRO Journal Club Webinar 2011 - "Survival and Prognostic Factors of Early Childhood Medulloblastoma: An International Meta-Analysis" with Larry Kun, MD, FASTRO