Medulloblastoma - What is New ?

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MEDULLOBLASTOMAMayur Mayank04.11.2015




INTRODUCTIONEmbryonal tumors 2nd most common type of CNS tumor in the paediatric age groupMedulloblastomaSupratentorial PNETAtypical teratoid/rhabdoid tumor (AT/RT)

Differentials for Medulloblastoma

INTRODUCTIONMedulloblastomaMost common malignant brain tumor of childhood20% of all primary tumors of the central nervous system among children less than 19 years of agePeak incidence : 5 - 9 years of ageOccur exclusively in the cerebellumRare after the fourth decade of life

Belongs to the family of small round blue cell tumours


Depends on the Location of the tumourRelationship to nearby structures

Clinical FeaturesSymptoms of increased intracranial pressureNocturnal or morning headachesNauseaVomitingAltered mental status

Tumors in the midline Gait ataxiaTruncal instability

Tumors in the lateral cerebellar hemispheres Limb clumsinessIncoordination

Cerebellar, brainstem, or cranial nerve involvementDizzinessDouble vision

DIAGNOSISImagingMRI brain (with Contrast)T1:hypointense to grey matterT1 C+ (Gd):90% enhance, often heterogeneouslyT2heterogeneous due to calcification, necrosis and cyst formationoverall are iso to hyperintense to grey matterFLAIR:hyperintense to surrounding brainDWI:shows restricted diffusionMR spectroscopy:elevated choline, NAA decreased, may show a taurine peak


ImagingCT scanMedulloblastomas appear as a mass arising from the vermis, resulting in effacement of the fourth ventricle / basal cisterns and obstructive hydrocephalus. They are usually hyperdense (90%) and cysts formation/necrosis is common (40-50%), especially in older patients. Calcification is seen in 10-20% of cases.Enhancement is present in over 90% of cases and is usually prominent

Without ContrastWithContrast

ImagingCT scan is sufficient to diagnose MedulloblastomasMRI is preferredAble to delineate the fourth ventricle and subarachnoid space to a much greater degree than CT. CSF seeding is common at presentation, imaging with contrast of the whole neuraxis is recommended to identifydrop metastasesandleptomeningeal spread

DIAGNOSISCSF Cytology : MandatoryFor proper staging of the diseaseFor risk stratification

Syndromic associationsMedulloblastomas are associated with a number of syndromes:Coffin-Siris syndrome Cowden syndrome Gardner syndrome Gorlin syndrome Li-Fraumeni syndrome Rubinstein-Taybi syndromeTurcot syndrome

PATHOLOGYGrossSoft, friable tumorsOften with necrosis

MicroscopyHighly cellular tumors with abundant dark staining, round or oval nuclei, and little cytoplasmic differentiationSpectrum of histopathologic appearance ranges from tumors with extensive nodularity to those with large cell/anaplastic featuresMitoses are abundantNeuroblastic Homer wright rosettes can be found in up to 40% of cases

PATHOLOGYPathological subtypesClassicalDesmoplastic/nodular typeLarge-cell variantAnaplastic Medulloblastoma

CLASSIC MEDULLOBLASTOMASheets of small round blue cells with scant cytoplasmDESMOPLASTIC MEDULLOBLASTOMANodular areas of densely packed, reticulin-rich cellsProminent and pleomorphic nuclei with large areas of necrosis and high mitotic rateLARGE CELL ANAPLASTIC MEDULLOBLASTOMA

PATHOLOGYImmunohistochemical studies Neuronal markers Synaptophysin Neuron specific enolaseNestin, a marker of primitive neuroepithelial cells, consistent with their presumed Origin from neuronal progenitors in the cerebellumAlso express markers specific for cerebellar granule cells

T stageT1Tumor 3 cm and with extension into aqueduct of sylvius or foramen of luschkaT3bTumor >3 cm and with unequivocal extension into brainstemT4Tumor >3 cm with extension past aqueduct of sylvius or down past foramen magnum

M stageM0No evidence of gross subarachnoid or hematogenous metastasisM1Microscopic tumors cells found in CSFM2Gross nodular seeding intracranially beyond the primary site (in cerebellar/cerebral subarachnoid space or in third or lateral ventricle)M3Gross nodular seeding in spinal subarachnoid spaceM4Metastasis outside cerebrospinal axis

MANAGEMENTMultimodality approach

SurgeryForms the mainstay of managementMajor goals of surgery To achieve an oncologic resection To restore normal flow of CSF

Complete resection (GTR/R0) results in significantly better prognosisInsufficient as single modality : High rates of recurrence if used alone

Risk StratificationExtent of diseaseAge at Diagnosis

Post OP Risk StratificationAverage RiskHigh RiskAge at diagnosis> 3 years< 3 yearsM stageM0M1-M4Extent of residual disease< 1.5 cc on Post OP MRI> 1.5 cc on Post OP MRI

Extent of DiseaseLocalized disease has a good prognosis

Dissemination of disease confers poor prognosis

Age at diagnosisRelationship between age and outcome in medulloblastoma is nonlinear

Patients at the extremes of the age distribution (ie, infants/young children and adults) are worse than those in the middle

Young age at diagnosis has a negative impact on both long-term survival and quality of life in survivors

Children younger than age five years with medulloblastoma, and particularly those younger than three, have a significantly poorer prognosis

Other Prognostic MarkersHistologyMolecular and cytogenetic markers

HistologyImportant prognostic factorBest PrognosisWorst Prognosis

Molecular and cytogenetic markersGood PrognosisHigh expression of Trk CPoor PrognosisOverexpression of erbB2 (Her 2)Amplification of c-myc/n-mycOverexpression of c-myc mRNAIsolated 17p loss (Isochromosome 17q)

Radiotherapy for Medulloblastoma

Radiotherapy for MedulloblastomaCraniospinal Irradiation (CSI) : Standard of care

Target volume Meninges overlying the brain and spine including extensions along nerve roots

Radiotherapy for MedulloblastomaCSI is followed by a boost to the posterior fossa. Entire posterior fossa : Treated to a total dose of 54 to 55.8 Gy. Conformal treatment techniquesReduce the dose to the inner earLittle sparing of other structures such as, and most especially, supratentorial brain

Better sparing of the cochlea, pituitary and hypothalamus, and the temporal lobes can be achieved using a reduced target volume for the boost

Radiotherapy for MedulloblastomaFukunaga-Johnson et al. Low risk of isolated failure outside the tumor bed in the posterior fossa in a cohort of 114 patients

Optimal CTV for a reduced-volume posterior fossa boostExpansion of 1.5 cm around the GTV (any macroscopic residual tumor and the surgical bed) seems to be reasonable Under investigation in the current COG study for standard-risk disease

Patterns of RelapseStudySFOP M-750% of relapses correlated with targeting deviationsMSFOP-93 and MSFOP-98Relapse rate 17% in patients who had inadequate coverage of only one part of the CTV (eg: cribriform plate)28% for patients who had inadequate coverage at two sites67% for patients who had inadequate coverage at three or more sitesSFOP pilot studyOverall survival at 5 years significantly worse for patients with inadequate coverage at two or more sites as compared with no or only one major deviation (54.4% vs. 79.3%)SIOP PNET-3PF recurrence occurred in 11 (34.4%) of 32 with a PF targeting deviation compared with 13 (16.3%) of 80 without (p 0.043)

Radiotherapy for MedulloblastomaIdeal time to start Radiation therapy :CSI should ideally start within 28 to 30 days following surgeryDelay to radiotherapy has be associated with poorer outcomes

Radiotherapy for MedulloblastomaWhen CSI has to be interrupted,Hematologic toxicity - treatment should continue to the posterior fossa boost volume while waiting for the blood counts to recover. G-CSF may be used to hasten recovery of the counts

Adjuvant Treatment of MedulloblastomaBased on risk stratificationStandard RiskHigh RiskTreatment of children 95% of these patients will survive their diseaseEqually distributed between males and femalesLeast common of the four subgroupsAssociated with Turcots Syndrome