medulloblastoma

Anatomy

Hind brain

The cavity of hindbrain

is fourth ventricle.

Why Anatomy

Because of the location of the fourth ventricle,

So mass lesions or swelling of the cerebellum

Ventral to the cerebellum,

Cause obstructive hydrocephalus.

CSF pathway

CSF is produced by modified ependymal cells in choroid plexus.

It is reabsorbed into venous sinus blood via arachnoid granulations

Medulloblastoma ???

Medulloblastoma (MB) is the most common malignant brain

tumour of childhood.

MB originated in the cerebellum vermis and projects into 4th

ventricle.

It is currently thought that it arises from primitive

neuroepithelial cells in the external granular layer of

cerebellum.

Medulloblastoma ???

First described by Harvey Cushing and Percival Bailey in

1930.

Initially described as “spongioblastoma cerebe”

( a soft, suckable tumour).

It is name was changed from medulloblast (a hypothetical

multi-potent cell)→to medulloblastoma.

Medulloblastoma name is from:

Medulla (Latin for marrow),

Blast (Greek word for germ)

Oma (Greek for tumor);“Tumor of primitive undeveloped cells located inside the

cerebellum”.

Incidence Medulloblastoma

It occurs in children and adults

Age

Sex

CNS

The peak is between 5-9 years.

20% of MB present in infants< 2 years old.

70 % of cases before the age of 20 years.

It is rare after 4th decade of life.


The incidence of MB varies by

Age

Sex

CNS

Male : female (3:2).


The incidence of MB varies by

Age

Sex

CNS

Overall account ~ 7 % all brain tumours.MB represents 20 % of all primary CNS tumours among children <19 years of age.0.4% –1% of all adult CNS tumours.40 % of tumours of the posterior fossa.

Pathology MB

Gross picture

WHO classification

Immunohistrochemistry

Microscopic picture

Moleculare pathogenesis

Pathology MB

Gross picture ♣ Soft, friable, extensive necrosis.

Microscopic picture

♣ Highly cellular,

♣ Dark staining round or oval nuclei & little cytoplasmic

differentiation.

♣ Extensive nodular till anaplastic features.

♣ Neuroblastic Horner Wright rosettes present in 40% of cases.

Pathology MB

Immunohistrochemistry

♣ Positive to neuronal markers (synaptophysin, NSE,

nestin).

♣ Nestin→ a marker of primitive neuroepithelial cells.

♣Nuclear B-catenin staining is present in most of WNT pathway

tumours.

♣ P53 immunostaining

Pathology MB

WHO classification

♣ Classic MB 70-80%

♣ Desmoplastic /nodular MB 7%

♣ MB with extensive nodularity (MBEN) 3%

♣ Large cell anaplastic variant 10-20%

☼ Better prognosis.☼ Associated with mutations in patched- 1 gene (PTCH1) on chromosome 9.

☼ The worst prognosis.☼ CSF dissemination☼ More aggressive course.☼ High level of MYC amplification.

Pathology MB


Genetic predisposition (syndromes)

MOLECULAR SUBGROUPS

Pathology MB


Genetic predisposition (syndromes)

Gorlin syndrome (3-5 % MB cases)TURCOT SYNDROME (<1 % MB cases)Li-fraumeni syndrome

Pathology MB


GORLIN SYNDROME

The most common syndrome associated with MB (3-5 %).

Autosomal dominant → germline mutation in patched-1(PTCH-1).

PTCH-1 → over activate SHH pathway.

SUFU mutation associated with higher risk for MB than PTCH-1.

It characterized by nevoid basal cell carcinoma & skeletal

abnormalities.

Pathology MB


TURCOT SYNDROME

Brain tumour (MB)&familial adenomatous polyposis

(FAP).

FAB caused by autosomal dominant→ inactivation

adenomatous polyposis coli (APC) gene on chromosome 5.

APC is part of protein complex in the WNT signaling

pathway→ control cell proliferation and differentiation.

Pathology MB


LI-FRAUMENI SYNDROME

Mutations in TP53 (17p13). Worse outcome.

Pathology MB


MOLECULAR SUBGROUPS

MB divided into 4 groups based on:DNA copy number, mRNA expression profiles and Somatic copy number aberrations.

1.SONIC HEDGEHOG (SHH) pathway2.WINGLESS (WNT) pathway3.Group III4.Group IV

Pathology MB


SONIC HEDEHOG (SHH) pathway

Normal

PTCH-1 interact with smoothened

(SMO)- - - transcription

pathways.SHH binds PTCH-1→ inhibit

repression of SMO

→+++ transcription pathways.

Pathology MB


SONIC HEDEHOG (SHH) pathway

Abnormalities in SHH pathway are present

in 30% of MB cases.

MB pathology usually desmoplastic.5-Y OS 75 %.

SHH up-regulate MYCN gene.

Tp53 mutations are present in 10-20 % of

SHH tumours.

Pathology MB


WINGLESS (WNT) pathway

WNT tumours are seen in children and adults.

Rarely in infants.

It associated with the most favourable prognosis 5-y OS 95%.

WNT protein binds to its receptor→ destabilizes

APC protein.

Loss chromosome 6.

Pathology MB


GROUP III

Group III are seen primarily in children.

25% sporadic MB cases.

The worst prognosis.

High level of MYCN amplification.

Large cell anaplastic histology are common.

5-Y OS 50%.

↑↑↑ metastatic recurrence.

Pathology MB


GROUP IVGroup IV are seen primarily in male adolescence (male: female 3:1).

35% sporadic MB cases.

Classic histology are common.

MYCN amplification.

Isochromosome 17q and loss of one copy of X-chromosome in ♀.

Metastasis at diagnosis present in 35-40%..

5-Y OS 75%.

MOLECULAR SUBGROUPS summary

Symptoms & signs

MB patients present with symptoms and signs of:

1. Increased intra cranial tension.

2. Cerebellar dysfunction

Weeks→ few months

Evaluation

History

Morning headache

Nausea & vomiting

Visual changes

Confusion

Unsteady walking

Symptoms

Presenting symptoms are related to the age of the patient

Irritability, anorexia, failure to thrive,

macrocephaly and sun setting sign.

Behavioural changes, vomiting and

decreased social interactions.

Symptoms

Presenting symptoms are related to the age of the patient.

Headache especially upon awakening in the morning

Nausea, vomiting & altered mental status.

Gait ataxia or truncal instability (mid-line tumour)

Limb incoordination(lateral cerebellar himispheres

tumour)

Dizness and double vision(cerebellar or brainstem or

cranial nerve involvement).

Bony pains (bone metastsis).

Decerebrate rigidity, head tilt, stiff neck→ herniation.

Signs

Mid-line tumour→ a broad-based gait or difficulty with

heel-to-toe walking.

Lateral cerebellar→ dysmetria on finger-to-nose testing,

intention tremor, difficulty with heel-to-shin testing.

Cranial nerve deficits.

Prolonged ↑ ICT→ papilledema and complete or

partial loss of vision.

Confirmation of diagnosis

NeuroRadiological examination Biopsy for histopathologic examination (usually at the time of surgical resection).

NeuroRadiological examination

♣ Usually the mass compress 4th ventricle→ hydrocephalus.

MRI CTor

MRI is the gold standard Highly sensitive.

High resolution in diagnosing posterior fossa tumour because

of high quality coronal images without artefacts, associated with

beam hardening through bone in CT.

Sagittal images can be used in RT planning.

MRI better delineates tumour induced oedema.

CT brain

A large lobulated hyperdense round tumour

Internal hypodense cavity

An ill-defined faintly hypodense band represents white matter oedema.

MRI brainThe gold standard

T1-weighted MRI image:

The solid portion of the tumour

appears mildly hypointense.

The gold standard

T2-weighted MRI image:

The solid portion of the tumour

appears mildly hyperintense.

MRI brain

The gold standard

T1-weighted MRI image folowing

intravenous gadolinium:

irregular patchy contrast

enhancement of the solid areas of

the tumour (arrow).

MRI brain

MRI SPINE♣ Most sensitive for spinal cord metastasis.♣ Frequency of spinal seeding at diagnosis is 30-35%.♣ Mostly are seen in the lumbosacral and thoracic areas and are best seen on post-contrast T1-weighted images. ♣ MRI spine should be obtained whenever possible pre-operatively or else at least 2-3 weeks post-operatively.♣ Better before CSF analysis.

Metastatic work up

♣About 1/3 of MB cases metastasize through the central nervous

system.

♣ Non specific finding→ pleocytosis & ↑ protein.

♣Time: at least 2 weeks post surgery.

♣contraindicated before surgery due to ↑ ICT.

♣ Positive cytology predicts for an ↑ rate of relapse and poor outcome.Bone scan, BMA & BMB

☼ Extraneural metastases are rare.

☼ Bone is the most common site for extra-neural disease.

☼ Bone scan & BMA, BMB are not routine.

Cerebrospinal fluid cytology

Differential diagnosis

♣ Pilocytic astrocytomas: cystic with mural nodule or centrally

necrotic with thick rim of enhancing tissue.

♣ Ependymomas: usually respect ventricles and may grow to fill 4th

ventricle.

♣ ATRT: rare tumour, more likely to involve the lateral hemispheres

orcerebellopontine angle and contain intratumoral haemorrhage.

Posterior fossa mass in child (need pathology + radiological findings)

Staging

Extent of tumour

T1 Tumour < 3cm in diameter.

T2 Tumour ≥ 3cm in diameter.

T3a Tumour ≥ 3cm in diameter with extension into aqueduct of sylvis and or the foramen of luschka.

T3b Tumour ≥ 3cm in diameter with unequivocal extension into brain stem.

T4Tumour ≥ 3cm in diameter with extension up past the aqueduct of sylvis and or down past the foramen of magnum.

♣ No consideration is given to number of structures invaded or the presence of hydrocephalus.

Staging

Degree of metastasis

M0 No evidence of gross subarachnoid or hematogenous metastasis.

M1 Microscopic tumour cells found in the cerebrospinal fluid.

M2 Gross nodular seeding demonstrated in the cerebellar/cerebral subarachnoid space in the third or lateral ventricles.

M3 Gross nodular seeding in the spinal subarachnoid space.

M4 Metastasis outside the cerebrospinal axis.

Prognostic factors

1. Age at diagnosis

2. Extent of disease

3. Extent of resection

4. Histology

5. Biological markers

Prognostic factors

1. Age at diagnosis

Children < three years old have poor prognosis.

5 -Y PFS was:

32%→ Children < three Y

58%→ Children > three Y.

Increased incidence of dissemination.Difficult resection.Delayed initiation of RTH.Decreased dose of RTH.

Why

2. Extent of disease

♣ M0 → 5 -Y PFS was 70%

♣ M1 → 5 -Y PFS was 57%

♣ M2,3,4→ 5 -Y PFS was 40%

Prognostic factors

3. Extent of resection

♣ Gross total resection (GTR)

♣ Near total resection (NTR){>90 % & <1.5cm2}.

♣ Subtotal resection (STR){<90 % &

>1.5cm2}.

♣ Partial resection (PR) {<50 %}.

Prognostic factors

Avoid aggressive surgical resection

It is associated with more morbidity (↑ incidence of posterior fossa syndrome).

Why

PFS93%

93%

45%

10-15%

Posterior fossa syndrome

It occurs in 25% of cases due to injury to

cerebellar vermis or dentate nuclei.

More with vermis tumours.

It is noted after a 24 - 48 hour.

Difficulty in swallowing, truncal ataxia, mutism,

less often respiratory failure.

Often improve dramatically, sometimes over many

months after surgery.

4. Histology

♣ Patients with desmoplastic/nodular or desmoplastic

with extensive nodularity→ better OS and EFS.

♣ Poor prognosis for those with large cell or anaplastic

variants.

Prognostic factors


♣ Activation of WNT pathway→ the best prognosis.

♣ Trk-C over-expression→ favourable prognosis.

♣ Activation of SHH pathway and group IV→ intermediate

prognosis.

♣ Activation of the SHH pathway + TP53 mutations→poor

prognosis.

♣ Amplification of the MYC (group III)→ the worst prognosis.

Prognostic factors


Unfavourable prognosis Isochromosome 17q or 17p deletion (30-50%)

Trisomy 7 (10-15%)

Erb B2 expression (40%)

Cyclin dependant kinase 6 (CDK6) (20%)

C-MYC over expression (with anaplasia)

OTX2 expression (20%) (with anaplasia)

Prognostic factors

Risk stratification

M stage is a crucial staging component.

Several studies had shown that the T stage of the

Chang's system did not correlate with survival, so

replaced by the definition of the post operative residual

tumour volume concept.

Risk stratification

At diagnosis:

66.6 % of patients are standard risk

33.3% are high risk.

5-years OS:

Standard Risk: > 80%.

High Risk: 30-60%.

Risk stratification

Risk Factor Standard Risk High Risk

Age > 3 years < 3 years

Residual Tumour < 1.5 cm2 > 1.5 cm2

Metastasis M0 M1 - M4

A combination of surgery, radiotherapy and chemotherapy

Multi modal approach

Differance in treatment between child & adult

Measures to alleviate increased ICP.

Specific therapy directed against the tumour.

Complication Follow up Treatment at relapse

Child AdultUsual age ~ 4 - 8 yrs Median age ~ 24 - 30 yrs

Shorter History (~ 3 months) Longer history ( ~ 5 months)Classical type predominates Desmoplastic type relatively

commonerMedian cerebellar syndrome

predominatesLateral cerebellar syndrome seen

Biologically more aggressive Biologically less aggressivePoorer resectability

(median location)Greater resectability

(lateral location)Higher surgical morbidity and

mortalityLower surgical morbidity and

mortality Poorer RT tolerance Better RT tolerance

Poorer long term survival Better long term survival

Differance in treatment between child & adult Treatment






Complications Follow up Treatment at relapse

TreatmentMeasures to alleviate increased ICP

Increased intra-cranial pressure Aetiology: obstructive hydrocephalus.

Symptoms: Headache is the earliest symptom (pain fibres of cranial nerve V).VomitingDepressed global consciousness (due to local pressure of mass or pressure on mid-brain reticular formation).

Normal ICP= 20 mmHg

Nocturnal awakeningWorsening by cough, urination, or defecation.Recurrent and localized.Progressive increase in frequency or severity.

Treatment

Increased intra-cranial pressure Signs:

Papilledema

Retinal hemorrhage

Macrocephaly:split sutures or bulging fontanel, sun setting eyes

(infants).

3rd nerve palsy (the most common).

Consciousness ranged from irritability till coma.

Cushing triad→ late sign (↑ABP, ↓HR, respiratory depression).

Herniation (headache, altered level of consciosness, followed by

pupillary changes).

Measures to alleviate increased ICP

Treatment

Increased intra-cranial pressure Signs:


Treatment

Increased intra-cranial pressure Management:

Initial stabilization, Evaluation, General measures &Specific measures

Maintain adequate ventilation & normal PaCO2

→ to prevent vasodilation.

Maintain adequate blood pressure

→ to prevent cerebral ischemia.


Treatment



Once patient is stabilized CT brain (without contrast) should be done.

Lumbar puncture→ if necessary should be done after CT brain.


Treatment



Elevate head 15-30 degree.

Maintain adequate blood pressure (isotonic fluids 0.9% saline).

Control of fever as hyperpyrexia increase cerebral metabolism.

Prophylactic anticonvulsants (pheytoin, levetiracetam) for high

risk developing seizures.


Treatment



Mannitol

↑osmotic pressure of glomerular filterate.

Inhibits tubular reabsorption of water and electrolytes.

Osmotic diuresis→ osmotic gradient between plasma and parenchymal

tissue→ reduction of brain water content.

Dose: 0.25-1 gram/kg iv bolus every/8 hours.

Side effects: electrolyte imbalance, hypovolemia, acute renal failure.


Corticosteroids (dexamethasone) Anti-inflammatory and membrane stabilization.Dose: 0.25-0.5 mg/kg/6H MAX 16mg/d

HyperventilationIt is reserved for acute brain herniation or ↑ICT that fail to respond to previous therapies.

Expermental measures Hypothermia: ↓ cerebral metabolism.Indomethacin: cerebral vasoconstriction.






Complications Follow up Treatment at relapse

TreatmentSpecific therapy directed against the tumour.

TreatmentVentriculoperitoneal shunt

Complication

Blood clot or bleeding in the brain

Brain swelling

Seizures

Damage to brain tissue

Infection in the brain

The shunt may become infected.

The shunt may stop working and fluid

will begin to build up in the brain again.

Through VP shunt, tumour can spread

TreatmentSurgery

Maximal safe resection.

Benefits: Confirm diagnosis,

Relives ↑ ICT (shunting),

↑ survival.

GTR & STR (OS 70-80%) is better than biopsy (OS 40%).

Pre-operative: do MRI brain & spine + give high dose steroid.

Post-operative: MRI brain (24-72 hours), MRI spine (2 weeks).

The mainstay of treatment

TreatmentSurgery

Complications:

Edema in the brain

Hematoma

Aseptic meningitis

Posterior fossa syndrome (cerebellar mutism)

Cervical instability

The mainstay of treatment

TreatmentRadiotherapyCentral role in treatment

Aim:Control any residual in posterior fossa

Treat any spread along CS axis.

Starting time: within 28 days following surgery.

Duration of treatment: 45 to 47 days.

Position:Prone (preferred)

Supine: More patient comfort - In anaesthetic patient.


Target Volume:Entire brain and its meningeal coverings with the CSF

Spinal cord and the leptomeninges with CSF

Posterior fossa – boostDose:

CSI (Phase I)

36 Gy (HR) or 23.4 Gy (SR) over 4 weeks @ 1.5-1.8 Gy per #.

Posterior fossa boost/tumour bed (Phase II)

18 Gy (HR)to 32.4 Gy (SR) in 10-11# over 2 weeks.

Commitment weekly vincristine.


Acute ComplicationNausea, vomiting

Neutropenia, thrombocytopenia

Fatigue, headache, drowsiness

Alopecia, mild dermitis

Serous otitis media

Mucositis, oesophagitis (exit dose from spinal cord)


Chronic Complication: (↑↑↑ with young age)Spinal cord Chronic progressive myelitis.Brain Radiation necrosis - Intellectual deficit.Lens of eye Cataract formationRetina Radiation retinopathyOptic nerve Optic neuritisEar Sensorineural hearing loss Endocrinopathies (hypothyroidism and decreased growth hormone secretion)Secondary Malignancy

How to avoid Complication↓↓ dose COG trial in SR & 3-7 years→ CSI 18 versus 23.4 Gy.

↓↓ field tumour bed (±1-2cm) versus posterior fossa.

Technique 3D conformal - IMRT - proton beam therapy - spare

cochlea and hypo-thalamus.

TreatmentChemotherapy

Chemo-sensitive tumour

Aim: SR→ ↓↓ dose of RTH & ↓↓ incidence of relapse.

Infant→ delay RTH to developing brain & spinal

cord.

Type of chemotherapy Regimen: Standard Risk Disease

High Risk Disease

Infant & young children (<3 years old)



SRType:

Weekly VCR during radiotherapy then 8 cycles of VCR, Cisplatin, CCNU or CTX.

Outcome: 10-Y OS→ 81% & 10-Y EFS→76%.

No difference between two arms.

Electrolyte abnormalities more with CCNU.

Infectious complication more with CTX.



HRType:

Weekly VCR during radiotherapy then

6 cycles of VCR, Cisplatin, CTX.

Outcome: 5-Y OS→ 36%.

Prospective studies:Auto BMT post RTH and 4 cycles of high-dose

chemotherapy→ 5-Y EFS→70%.

Using carboplatin during radiotherapy.



Infants and young children (<3 years)

I. Induction multi-agents chemotherapy Benifits→ delay or eliminate need to RTH→ this will allow

nervous system a chance to develop.

Drawbacks: Intensive chemotherapy in young children carries

higher risk of 2nd malignancy.

II. ± second look surgery


Infants and young children (<3 years)Type:

Systemic chemotherapy + HD chemotherapy.

More intensive 5 drug Systemic chemotherapy + intra-ventricular

chemotherapy (methotrexate)

5 Y OS→66 % & 5 Y PFS→ 58 %.

CCHE→ Induction Systemic chemotherapy (4 cycles) ± 2nd look

surgery→ local conformal RTH→ Maintaince chemotherapy (8

cycles).

Outcome: 5 years OS 40-50%.

TreatmentComplication

Posterior fossa syndrome

Neurocognitive impairment

Risk factors: young age, HR disease, high radiation dose.

Progressive ↓IQ, impairment of reading skills, attention,

working memory.

Hearing loss: Sensorieural hearing loss and ataxia.

Short stature: CSI→ decreased skeletal growth.

Endocrine abnormalities: very common following RTH of the

pituitary hypothalamic axis & thyroid→↓GH, ACTH, TSH.

Secondary cancers: cumulative 10-years incidence rate 4.2%.

TreatmentFollow up

Follow up for disease recurrence and treatment complications.An isolated spine recurrence was detected in rate 7/1000 MRI

during follow up.

In standard risk:

Brain MRI - every 3 months, for the first 2 years

Spinal MRI - every 6 months, for the first 2 years;

Then Brain MRI every 6 months up to 3 years and

Spinal MRI every year for 3 years.

In high-risk:

Brain and spinal MRI - every 3 months for the first 2 years

Then every 6 months.

Treatment

Treatment at relapse

Relapse occurs in 20 - 30 % following initial treatment.

Site of relapse:

Local→ 1/3

Disseminated (brain and spine)→ 1/3

Both local and disseminated (brain and spine)→ 1/3

Time: within 3 years (children) but late relapse in (adults).

Treatment

Treatment at relapse

Surgery→ to achieve 2nd GTR.

High dose chemotherapy with auto BMT.

CSI after salvage therapy for infant and young children who

relapsed following surgery and chemotherapy only.

Emerging therapies:

Vismodegib: is a selective Hedgehog pathway inhibitor (phase II trial).

Mab against ErbB2

THANL YOU

medulloblastoma

Education