Pediatric Neuro-oncology: Medulloblastoma

Molecular subgroups and risk stratification: 1) WNT-activated (10-15%) - older children/adolescents, beta-catenin/CTNNB1 mutations, classic histology, lateral cerebellum location, excellent prognosis (5-year survival >90%); reduced therapy trials underway; 2) SHH-activated (25-30%) - bimodal age (infant <3, adolescent), Patched1 (PTCH1)/Smoothened (SMO)/SUFU/MYCN mutations, hemispheric location, desmoplastic histology in infants; prognosis variable - infant SHH excellent (90%), TP53-mutant SHH poor (30-40%), adolescent good (60-80%); 3) Group 3 (25-30%) - infants and young children, MYC amplification, large cell anaplastic histology often, photoreceptor signaling, worst prognosis (5-year survival 30-60%) due to MYC-driven metastases; 4) Group 4 (35-40%) - most common in older children/adolescents, MYCN amplification subset, isochromosome 17q frequent, classic histology often, intermediate-poor prognosis (5-year survival 50-75%); 5) Risk stratification - average risk: GTR or near-total resection (<1.5 cm² residual), no metastases (M0), age >3 years, WNT or favorable Group 4; 5-year survival 70-90%; 6) High risk - subtotal resection (>1.5 cm² residual), metastases (M1-M4), age <3 years, MYC/MYCN amplification, TP53-mutant SHH, large cell anaplastic histology, Group 3 with metastases; 5-year survival 40-70%.

Diagnosis and surgical management: 1) Clinical presentation - increased intracranial pressure (headache, vomiting, papilledema), cerebellar dysfunction (ataxia, dysmetria, dysarthria), cranial nerve deficits, behavioral changes, hydrocephalus often present at diagnosis (50-70%); 2) Imaging - MRI brain and spine with contrast (gold standard); typically homogeneously enhancing midline cerebellar mass; spine MRI mandatory for staging (M3 metastases drop on staging); CT for emergency hydrocephalus assessment; 3) Lumbar puncture - CSF cytology after stabilization (tumor cells M1+); often deferred until after resection (avoid herniation); 4) Surgical management - maximal safe resection by experienced pediatric neurosurgeon; goal gross total resection (GTR) or near-total (>95%); intraoperative ultrasonography, neuronavigation, intraoperative MRI; CSF diversion for hydrocephalus (often shunt); risk of posterior fossa syndrome (transient mutism, ataxia, behavioral) 25-40%; 5) Histology and molecular workup - WHO classification combining histology (classic, desmoplastic, large cell anaplastic, MBEN) and molecular subgroup (WNT, SHH, Group 3, Group 4); methylation profiling, fluorescence in situ hybridization, immunohistochemistry; pathology review at experienced center; 6) Postoperative - imaging within 72 hours to assess resection extent and detect new metastases.

Treatment and outcomes: 1) Average-risk treatment (>3 years, M0, GTR/near-GTR) - craniospinal radiation 23.4 Gy with posterior fossa or tumor bed boost to 54-55.8 Gy; concurrent vincristine; followed by 8 cycles of chemotherapy (cisplatin, lomustine/CCNU, vincristine, cyclophosphamide); 2) High-risk treatment - higher-dose CSI 36 Gy with boost; intensive chemotherapy with cisplatin, vincristine, etoposide, cyclophosphamide; 3) Infant treatment - radiation deferred or replaced by intensive chemotherapy ± high-dose chemotherapy with autologous stem cell rescue (HDC/ASCR); 'Head Start' protocols, conventional Pediatric Oncology Group regimens; benefit of preserving neurodevelopment but lower cure rate; 4) Specific subgroup considerations - WNT trials reducing CSI to 15-18 Gy and lower chemotherapy intensity; SHH-TP53 mutant requires intensive therapy and germline TP53 testing; Group 3 highest unmet need, novel therapies in trials (HDAC inhibitors, MYC-targeted); Group 4 newer biomarkers being studied; 5) Targeted therapy and trials - SHH pathway inhibitors (vismodegib for adult SHH MB), MYC-targeted, BET inhibitors, CDK inhibitors in trials; 6) Outcomes - 5-year overall survival: WNT 95%, SHH 60-85% (worse with TP53 mutation), Group 3 60-70% with current therapy, Group 4 75-85%; recurrence treatment limited - re-resection, focal radiation, retreatment chemotherapy, palliative care; 7) Late effects - neurocognitive impairment (especially with younger age, full CSI dose), endocrine (growth hormone, thyroid, gonadal), hearing loss (cisplatin, fields including cochlea), secondary malignancies (5-15%), psychosocial impact; 8) Survivorship - lifelong followup with imaging schedule (every 3-6 months first 2 years, then 6-12 months, then annually), endocrine assessment, neurocognitive monitoring, secondary cancer surveillance, hearing tests, transition to adult care; 9) Multidisciplinary care - pediatric oncology, neurosurgery, radiation oncology, pathology, endocrinology, neurology, neuropsychology, child life, school liaison; 10) Future directions - molecularly-stratified therapy, immunotherapy approaches (CAR-T, checkpoint inhibitors), liquid biopsy for monitoring, novel targeted therapies, late effect reduction strategies.