Medulloblastoma - Brigdrpksahoo
MedulloblastomaBrig. (Prof.) Dr. P. K. Sahoo,Chief Consultant,Neuro, Spine & Radio Surgery,Apollo Hospitals, Bhubaneswar
Introduction First described by Bailey and Cushing in1925 as a glioma (Spongioblastomacerebelli) Later came to be classified as a PNET(Primitive Neuro Ectodermal Tumor), atype of embryonal tumor. WHO 2016 classification of CNS tumors hasadded bio-molecular profile to thehistological entity of the tumor.
OriginDebatableHypothesis 1Hypothesis 2It originates from theprimitivemultipotentcells of the externalgranular layer of thecerebellar velum whenit fails to involute by theage of 1.Itarisesfromthemultipotent cells in thesubependymalsubventricular regionand fetal pineal region.
Epidemiology 7-8% of all intracranial tumorsCommonest malignant pediatric tumor in CNS30% of pediatric brain tumors64.3% of embryonal tumors in pediatric patients40% of posterior fossa tumors in childrenIncidence – 1.5-2 cases/100,000 populationMean age of incidence - 9 years28% of Medulloblastoma cases are found in adultsMale : Female 1.5 : 1. Males have poorerprognosis.
Mortality/Morbidity 5-year survival – 73% 10-year survival - 64.7% Prognosis is worst for infants and progressivelygets better with age at diagnosis Significant morbidities –1. Hydrocephalus – Commonest morbidity.10-50% patients need ventricular shunt or ETV1. Cerebellar dysfunction – trunkal ataxia andcerebellar mutism2. Leptomeningial dissemination
Presentation Sporadic / syndromic - Li Fraumenisyndrome, Turcot syndrome, Gorlinsyndrome, Blue rubber-Bleb nevussyndrome, Rubinstein-Taybi syndrome. Symptoms are slowly progressive overweeks to months and often patients consultneurologists/neurosurgeons late, leading todelayed diagnosis. 40% of patients arealready metastatic at the time ofdiagnosis.
1. Hydrocephalus – symptoms of raised ICP. Non-verbal age – behavioural changes Younger children – listlessness, irritability,vomiting, and decreased social interactions. Older children – early morning headache Early morning vomiting without nausea Double vision, papilloedema2. Cerebellar symptoms – Children – Trunkal ataxia (Vermis) Adults – Unilateral dysmetria (cerebellarhemisphere) Head tilt, neck stiffness (tonsillar ulopathy
Examination Physiogmony – increasing head circumference,full anterior fontanelle and split cranial sutures. Funduscopy – Papilloedema (in 90% cases) Extraocular examination – 6th CN palsy(diplopia, lateral gaze palsy), 4th CN palsy (headtilt, apparent particularly when eyes are , nystagmus (vermian lesion) Cerebellar signs – trunkal ataxia or unilateraldysmetria Torticollis – 11th or 4th CN palsy
Differential Diagnoses Brainstem GliomasCavernous Sinus SyndromesCerebellar HemorrhageCerebral AneurysmsGlioblastoma MultiformeHydrocephalusOligodendrogliomaLow-Grade AstrocytomaPediatric CraniopharyngiomaPediatric EpendymomaTolosa-Hunt Syndrome
Imaging CTscan–Slightlyhyperdense,homogenous,contrast - enhacing mass,usually arising from vermis. Obstructive hydrocephalus Leptomeningial mets Vasogenic edema Cerebellar astrocytomas –hypodense Ependymomas – iso tohyperdense, but containcalcifications Post-RT MB may calcify
MRI Hypointense on T1 imageswithhomogenousenhancement with Gd-DTPA. Hyperintensewithperilesional edema on T2. Hydrocephalus Occasionally hge and cysts Calcification is rare andhypodenseshadowsareusually vascular flow voids. Ependymomas show lateralextension into lateral recess of4th ventricle and CP angle. DTI differentiates MB frombrain stem gliomas Look for bone and spinal mets
Histological classification1. Classic MB – HomerWright rosettes2. DesmoplasticNodular (DNMB)3. MB with extensivenodularity (MBEN)4. Large cell anaplastic(LCA) – reactive forSynaptophysinClassic MBDNMB Medullomyoblastoma Melanotic MBLCA MBMPEN
Molecular sub-groups Based on the underlying oncopathogenicpathways identified by transcriptionalprofiling studies –1. WNT2. SHH3. Group 34. Group 4
WHO 2016 classification1.2.3.4.5.WNTSHH-TP53 wild typeSHH-TP53 mutantNon-WNT / non-SHHMB-NOS
Genetics of MB
Recent research trends in genetics Subgroup-specific differential heterogeneityof cis-regulatory elements in the epigenomeholds promise as better molecular genesis of different types of MB andoffers novel therapeutic targets. Role played by clonal selection and geneticdivergence and hence identification of potentialmolecular therapeutic targets in MB recurrence.
Treatment Surgery is the mainstay initial therapy for MB, both as atool for diagnosis and as a risk-stratification factor. Intra-operative EVD, if not done pre-operatively. It givesadded benefit of ICP monitoring. Its duration dependsupon CSF color, EVD output and ICP. It should beremoved if the patient can tolerate clamping for 24 hrs(no decrease in mental status, no elevation of ICP, noheadache) A contrast-enhanced MRI should be done 48 hrs aftersurgery to look for residual tumor and stratify the riskand stage of the tumor. Delayed MRI can makedifferentiating between residual tumor and postradiation necrosis difficult. If a re-do surgery is required, it should be done beforeadjuvant therapy.
Surgery for MedulloblastomaProne position withhead flexed and fixedon a pin-type orhorseshoe-type headholder.Operativeadjunctslikeframeless stereotaxy,USG,evokedpotential and cranialnervemonitoringmay be used, ifavailable.
A standard midlineposteriorfossaexposureisperformed, with theincisionextendingfrom slightly rostralto the inion down tothemidcervicalregion.
Thecervicalmusculatureismobilized laterally offthe occiput and theposterior arches of C1and upper half of C2 inthe midline avascularplane(ligamentumnuchae)
from just below theestimated location oftransverse sinus to theepisthion. If tumor isknown to extend into thecervical spinal canal,posterior arch of C1 mayneed to be removed.
The dura is thenopened in a Yfashion, with caretaken to achievehemostasis of theoccipital and circulardural sinuses, whicharecommonlyencountered.
Cotton pads are placedalong the floor of thefourth ventricle andthe normal cerebellumto develop a planebetween them and thetumor, before tumorremoval is begun
Tumor is removedwithUltrasonicaspiratororbipolar coagulationand suction
For adequate exposureover the perimeter ofthe tumor, the distalportion of the vermisoften needs to bedivided. Resection ofthe tumor begins fromits dorsal aspect andcarriedventrallytowards the floor of the4th ventricle.
Invasion of the tumor in sub-arachnoidspaces (sugar coating), brain stem andcerebellar peduncles must be identified andresection stopped to avoid post-opneurological deficits. At the end of the procedure, the aqueduct ofSylvius, the lateral foramina of Luschka, andthe obex are inspected to ensure completeremoval of tumor.
An alternative approach is Inferior y for tumors extending intolateral cisterns. It provides access to tumorin the 4th ventricle without the need for aVermian incision. A cerebellar hemispheric MB is typicallyapproached with a horizontal or verticalincision through the cerebellar cortex that isthe shortest distance from the tumor.
Watertightduralclosure, followed byreplacement of theboneflapandmultilayer closure ofthe superficial tissues.
Chang staging system
High/average risk staging system Based on CCG-921 trial (1991)Average riskHigh riskGross total resection (GTR),Any 1 of the 3 absentno radiographic evidence ofspreadno malignant cells on CSFcytology Residual tumor less than 1.5 cm3 was associatedwith improvement in 5-year PFS of greater than20% in patients with M0 disease and an 11%difference for all patients irrespective of age, Mstage, or any other measured factors. Albright et al,NeuroSurgery, 1996.
GTRNo residualtumor onradiographSTR 1.5 cm³ ofresidualtumorNTR 1.5 cm³ ofresidualtumor NTR and GTR have similar survival rates, if submolecular profiling is taken into account –Thompson et al. Lancet Oncology, 2016. If brainstem is involved, aggressive resection ofthe disease is not recommended, due to highpotential for morbidity and the high sensitivityof the tumor to radiation and chemotherapy.
Management of Hydrocephalus Following resection, 10 - 40% of the patientshave hydrocephalus requiring CSF diversion(VP shunt or ETV). Riva-Cambrin et al. in 2015 developed theCanadian Preoperative Prediction Rule forHydrocephalus (CPPRH) for use in thepreoperative prediction of shunt dependence,which can aid in surgical planning and patientcounseling.
Complications Hemiplegia/hemiparesis CSF leak Hydrocephalus (10-50% cases may needpermanent CSF diversion procedures) Brain stem dysfunction Cranial nerve dysfunction (4th to 12th CN) Cerebellar mutism syndrome Posterior fossa syndrome (about 25% of cases)
Radiotherapy Not indicated in age 3 years due to extremelypoor neurocognitive outcome. Above 3 years –1. High risk pts posterior fossa or surgical bedradiation (54–55.8 Gy) with high-dose CSI (36.0Gy) followed by adjuvant chemotherapy2. Low risk pts posterior fossa or surgical bedradiation (54–55.8 Gy) with reduced-dose CSI(23.4 Gy) followed by adjuvant chemotherapy 68 Gy for 6-7 weeks in hyperfractionated doseshas overall increased survival, but long-termresults are awaited – Gupta et al
Risk stratification for RT in molecular eraRisk categoryLow riskAverage riskHigh riskVery high riskSurvival 90 %75-90%50-75% 50%patients withmetastaticSHH or Group4 tumors,or MYCN amplified SHHmedulloblastomas.Group 3 withmetastases orSHHwith TP53 mutation.MolecularsubtypesWNT subgroup All other typesand nonmetastaticGroup 4tumors withwholechromosome11 loss orwholechromosome17 gainRamaswamy et al - Acta neuropathologica 2016.
Overallsurvival73%Local PFSRDistantPFSRnb62%77%Side effects of radiotherapy –1.Lowered intelligence quotient (IQ) score2.Small stature3.Endocrine dysfunction4.Behavioral abnormalities5.Secondary neoplasms (if survival is prolonged)6.White matter necrosis
Chemotherapy Use started for recurrent disease. Use extended for initial therapy (unresectable tumor)and maintenance therapy. Sole adjuvant therapy in age 3 years Reduces the dosage of radiotherapy or delays itsinstitution Cisplatin-based therapy for 4-9 cycles “8 drugs in 1 day” protocol - Vincristine, Carmustine,Procarbazine, Hydroxyurea, Cisplatin, Cytarabine,Prednisone, Cyclophosphamide (45% 5-year PFSR) Vincristine, Lomustine, Prednisone (VCP) protocol(63% 5-year PFSR) Vincristine, Cyclophosphamide, Etoposide, Cisplatin.
Recent advances Specific targeted therapy for each of the 4molecular sub-groups are in pre-clinical orclinical stage. Vismodigib - Smoothened (SMO) receptorantagonists Thiostrepton, an antagonist of FOXM1sensitizes MB cells to Cisplatin. In metastatic diseases – tandem chemotherapy,ASCT (Autologous stem cell treatment) & CSI(cranio-spinal irradiation) Oncolytic measles viruses encoding antiangiogenic proteins
Recurrent diseases Options for recurrent disease are limited. Ifosfamide, Cisplatin, and Etoposide - severemyelosuppression. Bevacizumab and Irinotecan with orwithout Temozolomide. Research for molecular targeted therapy isunderway.
Adverse effects Renal toxicityOtotoxicityHepatotoxicityPulmonary fibrosisGastrointestinal disturbances.Methotrexate used in combination withirradiation,may causeirreversiblenecrotizing leukoencephalopathy
Follow up MRI should be repeated and mental status,cerebellar and cranial nerve signs must beexamined for recurrence every 3 months thefirst year; every 4-6 months the second year;and yearly thereafter. Radiation therapy is an outpatient proceduretypically performed at least 2 weeks followingoperative intervention in order to allowadequate surgical incision healing.
Thank you all
Calcification is rare and hypodense shadows are usually vascular flow voids. Ependymomas show lateral extension into lateral recess of . plane (ligamentum nuchae) A posterior fossa craniotomy is then performed, extending from just below the estimated location of transverse sinus to the episthion. If tumor is
A study of the molecular biology was done in collaboration with the Department of Bioengineering, Gauhati University. Histological Examination: The different histopatholog-ical variants of medulloblastoma were differentiated using standard histological preparations (hematoxylin and eosin), which were used to assess general architectural and .
the Sonic Hedgehog subgroup of medulloblastoma. Haotian Zhao The Keynote presentation was delivered by Craig Thompson, President and Chief . conference, while Maciej Mrugala will extend his neuro-oncology review course to a full day program. Three final comments on the annual meeting. Fir
North West General Hospital Peshawar: Dr Tariq Khan, Dr Atif Munawar. Pakistan Institute of Medical Sciences, Islamabad: Dr Nuzhat Yasmeen. Pakistan Institute of Neurosciences.Lahore: Prof Dr Khalid Mehmood , Dr Adeeb ul Hassan. Patel Hospital: Dr Yaseen Rauf Mushtaq. Shaukat Khanum Cancer Memorial Hospital:
Aim: Comparison of the integral dose (ID) delivered to organs at risk (OAR), non-target body and target body by using different techniques of craniospinal irradiation (CSI). )alreadyplannedandtreatedeither with linear accelerator three-dimensional conformal radiation therapy (Linac-3DCRT)
transformed progenitor cells that have acquired self-renewal capabilities (Hart and El-Deiry, 2008; Takebe and Ivy, 2010). It was shown that lineage-restricted granule cell progenitors, and not neural stem cells, can give rise to Hedgehog-induced medulloblastoma which points to the latter concept (Schuller et al., 2008).
FM.14.014 as used for Lisa Norris's treatment plan 57 Annex 3: BOC quality system document number WI 13.26.06, written procedures for 'Medulloblastoma Calculations' 59 Annex 4: A copy of the Inspector's note of the incident investigation meeting held on 10th February 2006 65 Annex 5: Staff interviews 77
governing America’s indigent defense services has made people of color second class citizens in the American criminal justice system, and constitutes a violation of the U.S. Government's obligation under Article 2 and Article 5 of the Convention to guarantee “equal treatment” before the courts. 8. Lastly, mandatory minimum sentencing .
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