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 (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 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