Presented By:
Dr. Vandana
Deptt. of Radiotherapy
CSMMU, Lucknow
Introduction The origin of Medulloblastoma is from medulla (Latin for marrow), blastos
(Greek word for germ) and oma (Greek for tumor);
means “tumor of primitive undeveloped cells located inside the cerebellum”.
Most common malignant primary brain tumor of child age group.
First described by Harvey Cushing and Percival Bailey in 1930.
Initially described as “spongioblastoma cerebelli” - a soft, suckable tumor usually arising in the vermis of cerebellum.
In 1925, changed name to medulloblastoma - from “medulloblast” - a hypothetical multipotent cell.
OriginA highly malignant primary brain tumor that originates in the
cerebellum vermis or posterior fossa.
Arise in cerebellum and projects into 4th ventricle.
Originate from embryonal cells k/a medulloblast of cerebellar stem cells. The exact cell of origin, or “medulloblast” has yet to be identified.
It is currently thought that it arises from Germinative neuroepithelial cells in the external granular layer of cerebellum.
Anatomy
Posterior fossa contains hindbrain which consists of cerebellum, pons and medulla.
The cavity of hindbrain is fourth ventricle. This is bounded in front by pons and medulla and behind by cerebellum.
The vermis separates two lateral lobes or cerebellar hemspheres.
Because of the location of the fourth ventricle, ventral to the cerebellum, mass lesions or swelling of the cerebellum can cause obstructive hydrocepahalus.
Relevant Neuroanatomy
CSF PathwaysLateral Ventricle
Foramen of Munro
Third Ventricle
Foramen of Luschka
Foramen of Magendie
Central canal of Spinal Cord
Subarachnoid Space
CSF is produced by modified ependymal cells in choroid plexus
It circulates from lateral ventricles into the third ventricle through the foramen of munro.
It then passes into the fourth ventricle through the narrow cerebral aqueduct.
From the fourth ventricle, it passes slowly through median aperture (foramen of magendie) and lateral foramina (foramen of luschka) and enters the subarachnoid space over brain and spinal cord.
It is reabsorbed into venous sinus blood via arachnoid granulations.
Epidemiology Overall account ~ 7% all
brain tumors 10-20% of brain tumors in
pediatric age group 0.4%–1% of all adult central
nervous system tumors 40% of tumors of the
posterior fossa Peak incidence at the age of 5
–6 yrs In children and 25 yrs in adults
Approximately 20% of Medulloblastoma present in infants younger than 2 years old;.
male : female (3:2)
Figure: Distribution of pediatric central nervous system (CNS) tumors by location in the CNS and by tumor type.
Adult vs. Paediatric MedulloblastomaChild Adult
Usual age ~ 4 - 8 yrs Median age ~ 24 - 30 yrs
Shorter clinical History (~ 3 months) Longer history ( ~ 5 months)
Classical type predominates Desmoplastic type relativelycommoner
Median cerebellar syndromepredominates
Lateral cerebellar syndrome seen
Biologically more agressive Biologically less aggressivePoorer resectability - median location Greater resectability - lateral location
Higher surgical morbidity andmortality
Lower surgical morbidity and mortality - impact of location and age
Poorer RT tolerance Better RT tolerance
Poorer long term survival Better long term survival
Natural HistoryArising in the
midline cerebellar vermis (roof of the
4th ventricle)
Grows into the 4th ventricle
Fills into the 4th ventricle
Spread around the 4th ventricle
Invasion of ventricular
floor
Invasion of brain stem
Invasion of brachium
pontis
CSF Spread
Extra neural spread :Young age, males and diffuse subarachnoid disease
Mode of Spread
Contagiously- cerebellar peduncle Floor of forth ventricle Ant-brain stem Inf –cervical spine Sup- above tentorium
CSF(30%) – Intracranially Leptomeninges Spinal cord
Extraneural (5%) Most common CNS tumor to spread Hematogenous MC sites are Long Bones and Ribs(10-15%) LN(4-6%)
Pathological Features
Highly cellular tumorHigh N:C ratioCells arranged in typical Homer -
Wright rosettesMultiple histological subtypes
1. Classic medulloblastomas- 70-80%
2. Desmoplastic/nodular- 7%
3. Medulloblastoma with extensive nodularity (MBEN) - 3%
4. Anaplastic
5. Large Cell
WHO classification - 2007
large cell / anaplastic (LCA) 10% to 22%.
Classic Medulloblastoma: densely packed cells, hyperchromatic nuclei
classic medulloblastoma
medulloblastoma with extensive nodularity
Medulloblastoma with extensive nodularity – (MBEN): occurs in infants and is associated with a good prognosis.
large cell medulloblastoma
anaplastic medulloblastoma
Large cell medulloblastoma: Large nuclei, abundant cytoplasm.
These ‘large cells’ tend to mix with cells with nuclear pleomorphism and k/a ‘anaplastic’ cells.
Diffuse anaplasia is associated with poor prognosis.
Desmoplastic/nodular: nodular, reticulin-free zones or ‘pale islands’. Surrounded by densely packed mitotically active cells.
Chang Surgical classification 1969 T1 Tumour < 3 cm in diameter and limited to classic position in
vermis, roof of fourth ventricle, or cerebellar hemisphere
T2 Tumour > 3 cm in diameter and further invading one adjacent structure or partially filling the fourth ventricle
T3a Tumour further invading two adjacent structures or completely filling the fourth ventricle, with extensions into aqueduct or foramina of Magendie or Luschka with marked internal hydrocephalus
T3b Tumour arising from the floor of fourth ventricle or brain stem and filling the fourth ventricle
T4 Tumour penetrates aqueduct to involve third ventricle or midbrain or extends to cervical cord
No N Stage
M0 No metastases
M1 Microscopic evidence of tumour cells in CSF.
M2 Macroscopic metastases in cerebellar and/or cerebral subarachnoid space and/or supratentorial ventricular system
M3 Macroscopic metastases to spinal subarachnoidal space
M4 Metastases outside the central nervous system
Clinical FeaturesRaised ICT: Due to obstructive or non
communicating hydrocephalus
Pressure Syndrome: Nocturnal or morning head-ache, nausea and vomiting and papilledema.
Symptoms usually precede presentation by no more than 2 months.
Presenting symptoms are related to the age of the patient. infants with open cranial sutures, irritability, anorexia,
failure to thrive, macrocephaly and setting sun sign. The younger, nonverbal patient presents with
behavioral changes, listlessness, irritability, vomiting, and decreased social interactions.
Older children and adults complain of headache, especially upon awakening in the morning.
Decerebrate rigidity, head tilt, stiff neck s/o herniation
Cerebellar Signs: In children, tumor involve cerebellar vermis causes gait ataxia. In Adults, desmoplastic variant arises in cerebellar hemisphere
causing ipsilateral dysmetria. Worsening handwriting ,difficulty with hoping or running, slurring
speech and hypotonia.
Neighbourhood syndrome: focal deficit due to pressure effect. Brain stem : diplopia, 6th cranial nerve palsy, positional
dizziness, nystagmus, tinnitus, hearing loss, facial sensory and motor loss .
Leptomeningeal dissemination: Rarely the symptoms are present. Patients can complain of radiculopathy
Bone mets- painExtra neural site- lymph node.
Diagnostic Work up
Detailed Clinical history: Morning headaches, nausea, vomitting, confusion, visual changes, unsteady walking.
Physical examination: Gait, signs of raised ICT, double vision, stiff neck
General examination
CNS examinationo Higher mental examo Cerebeller examo Sensory examo Motor examo Cranial N. exam
Ophthalmoscopy examination for papilloedema
Resection of tumor
VP Shunting +Biopsy
High dose steroids + Neuro radiological examination
Patient stable
Medulloblastoma
Histopathological examination
Patient extremelysomnolent
Confirmation of diagnosis NeuroRadiological examination Biopsy
Neuro Radiological examination
CT finding
Hyperattenuated, well-defined vermian cerebellar mass
Surrounding vasogenic edema
Cyst formation
Evidence of hydrocephalus
Fig: A, Axial noncontrast CT image demonstrates a large lobulated hyperdense round tumor (arrow) with an internal hypodense cavity. An ill-defined faintly hypodense band surrounding the hyperdense mass represents white matter edema.
MRI features: MRI is the gold standard.
Iso- to- hypointense relative to adjacent cerebellar vermis (T1
images)
Iso intense to slightly Hyperintense on T2 weighted images
Homogeneous enhancement (but may be irregular and patchy)
following contrast
MRI with contrast enhancement is very sensitive for detection of
tumor spread, metastatic seeding in the cranial and spinal
subarachnoid spaces.
Fig: (B,) non-contrast axial T1-weighted (C,) T2-weighted MR images; the solid portion of the tumor appears mildly hypointense on T1-weighting and mildly hyperintense on T2-weighting (arrow). Following intravenous gadolinium, an axial T1-weighted image (D,) demonstrates irregular patchy contrast enhancement of the solid areas of the tumor (arrow).
Adult Medulloblastoma Poorly defined masses
located in the cerebellar hemisphere.
Cyst like regions are morecommonly seen
Fig: (A,) Axial T2-weighted MR image demonstrates a poorly circumscribed mass with a heterogeneous signal pattern in the anteroinferior portion of the right cerebellar hemisphere. (B,) After intravenous administration of gadolinium, the tumor demonstrates homogeneous contrast enhancement with well-circumscribed margins (arrow). Punctate intratumoral hypointensities represent enlarged vascular channels and/or focal calcifications.
Spinal MRI
Fig: Sagittal and axial MRI, T1 weighted Gadolinium contrast enhancement – Medulloblastoma with metastatic spread to the meninges within the posterior fossa and with a large intramedullary deposit.
Most sensitive for spinal cord mets
Frequency of spinal seeding
at diagnosis is 30-35%.
M.C.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.
Advantage of MRI over CT
Highly sensitiveHigh resolution in diagnosing posterior
fossa tumor because of high quality coronal images without artifacts, associated with beam hardening through bone in CT.
Sagittal images can be used in RT planning.MRI better delineates tumor induced
edema.
CSF examination: Important for stagingLumber puncture: most common method for obtaining
CSF.can’t be obtained pre-operatively because of raised ICT.
More commonly obtained at 3 weeks post operatively. To avoid risk of misinterpretation due to post operative changes.
Routine Investigations: Hemogram, KFT, LFT, Serum electrolyte, Chest X-ray, USG abdomen (Not mandatory)
Skeleton imaging: In case of Bone mets.
Risk Factor
• At diagnosis, 2/3rd of patients are standard risk and 1/3 are high risk.
• Standard Risk: 5yr. Survival is more than 80%• High Risk: 5 yr survival is 30-60%
• 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 tumor volume concept.
Risk Factor Standard Risk High Risk
Age > 3 yrs. < 3 yrs
Residual Tumor < 1.5 cm2 (Complete or near total resection)
> 1.5 cm2 (subtotal or biopsy)
Mets M0 M1 - M4
Treatment Medulloblastoma is well managed by multimodal approach.
Surgery“Surgery is usually the first step and mainstay of treatment.”
Objective: Remove or Reduce as much of the tumor's bulk as possible. Relieve ICT & local pressure effect ,i.e. Shunting. Tissue Diagnosis and staging – Biopsy.
Suboccipital Craniotomy
Surgery is classified as: No evidence of residual tumor at surgery and negative postoperative
imaging : Gross total resection
> 90% : Total or near total 51 - 90% : Subtotal resection 11 - 50% : Partial resection < 10% : Biopsy
ComplicationEdema in the brainHematomaAseptic meningitis Cervical instabilityPosterior fossa syndrome/ cerebellar mutism syndrome:
15% of children Difficulty in swallowing, truncal ataxia, mutism, and, less
often, respiratory failure noted after a 12 to 24 hour often improve dramatically, sometimes over many months
after surgery.
Advantage: Longer recurrence-free interval (Gross total resection).
“Exception is Brainstem involvement”. restores natural CSF pathways.
Ventriculoperitoneal ShuntVP shunting done for hydrocephalous
reduction if repeated drainage fails to release symptoms.
Complication:Blood clot or bleeding in the brainBrain swellingThe shunt may stop working and
fluid will begin to build up in the brain again.
The shunt may become infected. Infection in the brainDamage to brain tissueSeizuresThrough VP shunt, tumor can spread.
RADIOTHERAPY Highly radio-sensitive. RT plays a central role.
Objective: To treat microscopic cancer cells / residual tumor with
the goal of reducing its size or stopping its progression.
Prevent or treat spread through CSF. Covering the entire subarachnoid space is an essential component in the management of medulloblastoma. So We do Craniospinal irradiation (CSI).
Cont…CSI is a very complex techniqueGoal is to achieve uniform dosage throughout the
subarachnoid space, encompassing the entire intracranial vault and spinal canal.
Fundamental is the use of opposed lateral fields including the cranium
and upper cervical spinal canal, matching a posterior spinal field including the full spinal
subarachnoid space with cranial field in larger children, the upper posterior spinal field
matching with a separate lower posterior spinal field
Target Volume:Entire brain and its meningeal coverings with the CSF
Spinal cord and the leptomeninges with CSFPosterior fossa – boost
Energy4-6 MV linac or Co60
PortalsWhole Brain: Two parallel opposed lateral field.Spine: Direct Posterior field
Scheduling of radiotherapy:Starting time : within 28 days following surgeryDuration of treatment : 45 to 47 days
Dose CSI (Phase I)
30- 36 Gy in 18 - 21 # over 4 weeks to the cranium @ 1.5-1.8 Gy per #
30-36 Gy in 18-21 # over 4 weeks to the spine @ 1.5-1.8 Gy per #
Posterior fossa boost (Phase II)18-20 Gy in 10-11# over 2 weeks to the posterior fossa
PLANNING STEPS Positioning Immobilization Simulation Field arrangement Matching of CSI Aligning of spinal field Implementation of plan
Patient position Prone (preferred): Supine:
More patient comfort. In-anaesthetic patient
Head position Slightly extended and the
shoulders pulled down to avoid beam divergence
into the mandibule & dentition.
Facilitates the use of a moving junction between the cephalad border of post. Spine field and the lower borders of cranial fields.
Lumbar and Thoracic spine ll to couch.
Immobilization method1.Orfit cast for immobilization of
the head, cervical spine & shoulder
2.Small children –inverted full body plaster cast with facial area open for access for anesthesia
3.Alpha cradle4.Vacuum devices
Different RT techniques for CSI Initially entire CNS is irradiated at one
stretch with a single field. Pt. is prone below a shielded screen on top of RT table. It is known as Patterson FARR technique. Co60 source exposes the entire craniospinal axis at a focus distance of 125 c.m.
Moving Field technique: Table and pt. moves longitudinally in relation to a perpendicular Co60 beam which is stationary at 50 cm focal skin distance.
Hockey Stick technique: Pt. prone with head turned to one side. Field at base of brain is defined by cribriform
plate and is above both orbital cavities. Include middle cranial fossa and to exclude
orbit and lens. Each side of head is treated on alternate
days.
German Helmet Technique
German Helmet Technique: Field set so that beam flashes over entire head in ant , post, & sup directions and only the
caudal margin is defined by collimator by RT machine .
Caudal margin is set up so that it follows a line drawn from Eyebrow through the ext. auditory canal to the post aspect of the skull At C2-C3 jt.
Here we shield extra-Cranial structure in the subfrontal region,facial structures, teeth and lens.
Field ArrangementsWhole brain
o In the simulator, opposing lateral fields are applied to the whole brain with a collimator rotation of 7-11o to match the divergence of the direct posterior spinal field.
SFOP guidelines- The recommended placement of block is:o 0.5 cm below the orbital roof .o 1 cm below and 1 cm in front
of the lower most portion of the temporal fossa .
o 1 cm away from the extreme edges of the calvaria.
In Medulloblastoma nearly 15-20% of recurrences occur at cribriform plate site which is attributed to overzealous shielding ,because of its proximity to ocular structure it often get shielded.
SPINAL FIELD Laterally - 1 cm margin
beyond the pedicles, to cover the spinal cord and meninges along the nerve roots upto the spinal ganglia
Caudal-1 cm below the termination of the thecal sac i.e. L5 –S3.
2 spinal fields are used if the length is > 36 cm.
In Dorsal Region, block lat. Field to cover heart and lungs.
In Lumber Region, reduce field to spare BM and Gonads.
SSD techniqueGantry Angle = 0 degree
IMP point is length and depth of spinal fields.
Field of approx.4–6 cm wide box over the spinal cord/vertebral bodies extends from C2 –S2 .
Post fossa boostVolume includes entire
Infratentorial compartment.Field arrangement :
Two lat opposing fields .
SFOP Guidelines : Ant -0.5 cm in front of clivus Upper -1 cm above midpoint
b/w line joining foramen magnum and the skull.
Post- ll to ant margin in air . Lower – 1 cm below occipital
foramen.
TECHNIQUES OF MATCHING CS FIELDS
Collimator/Couch rotation
Half beam block Asymetric jaws Moving Junction
technique
Collimator Couch rotation Classically described technique.
Divergence of the spinal field
into the cranial field is overcome
with collimator rotation
Divergence of the cranial fields
into the spinal fields is
overcome with couch rotation
(rotated so that the foot end
moves towards the gantry).
Collimator rotation allowscranial field to match
spinal field divergence
Coll θ = arc tan (L1 /2 x SSD)For Co60 SSD = 80
Zone of overlap of spinal field if collimator rotation isnot applied in cranial field
SSD
L1
Collimator rotation : While treating cranial field rotate Collimator of lateral field so that its inferior border is parallel to divergence of sup. Aspect of spinal field .
θ
In order to avoid the overlap resulting from inf. Divergence of cranial field, rotate the couch towards the collimator so that fields margins of two fields become parallel.
Degree of couch rotation depends upon the length of lateral cranial fields and SAD
Θ couch = arc tan (1/2 x L2 /SAD)L2 = Cranial field length
COUCH ROTATION
Fig: Rotation of the couch toward the gantry is necessary to match the caudal margin of the lateral cranial fields with the cephalad margin of the posterior spinal field.
COUCH ROTATION
Couch θ = arc tan (L2/2 x SAD)For Co60 SAD = 80
L2 ( Length of cranial field)
Cranial field
SAD
Zone ofoverlap
Spinal field
Couch rotationduringtreatment ofcranial field
θ
Disadvantage of Couch Collimator rotation
The lesser separation at the neck can increase the dose to the spinal cord.
Due to the couch rotation the cranial portions of the skull can move away and get treated a greater SSD (resulting in under dosage)
Conversely in case of
the spinal cord the
lower SSD will result
in an increased
dose.
Areas of the opposite
lower temporal lobe
can get lower dose if
customized blocks
are used - lower
border of the cranial
fields need to be
more generous.
Figure: This figure illustrates a potential complication of the craniospinal setup. A couch angle on the lateral cranial fields can cause the contralateral temporal lobe to be underdosed
Half Beam Blocking
Actual Field LengthSpinal field
Moving junction in CSI
Feathering after every 5-7 fraction smoothes out any over or underdose over a longer segment of cord .
Usually shifted by 1-2cm at each shift .
Either in cranial or caudal direction.
Lower border of sup. Spinal field & sup. Border of inf. Spinal field are also shifted superiorly , maintaining the calculated gap b/w them.
“Feathering” refers to movement of the junction of the two fields across the treatment length.
Aligning Spinal field Abutting fields : will result in
heterogenous dose to the spinal cord . To overcome this various techniques are
available o Gap technique o Double junction technique o Moving junction technique
Fixed or calculated gap spinal fields
Gap calculation formulaS= ½ x L1(d/SSD1)+1/2xL2(d/SSD2)
Cold Spot Hot Spot
SSD 2 SSD 1
L2 S L1
Double junction techniques
The post field divided into two halves.
An overlapping segment is treated with two diff. fields on alternate days.
The junction is therefore automatically feathered onalternate days
Upper Spine Lower Spine
Day of Planning
Upper Spine Lower Spine
Day 1: The upper spinalfield is shortened
Upper Spine Lower Spine
Day 2: The lower spinal field isshortened
Junction on D 1 Junction on D 2
RADIATION TOXICITY ACUTE TOXICITY
Nausea, vomitingneutropenia,
thrombocytopeniaFatigue, headache,
drowsiness Alopecia, mild
dermitis Serous otitis mediamucositis,
oesophagitis (exit dose from spinal cord)
Spinal cord Chronic progressive myelitis
Brain Radiation necrosis
Intellectual deficit
Lens of eye Cataract formation
Retina Radiation retinopathy
Optic nerve Optic neuritis
Inner ear Sensorineural hearing loss
Hypothalamic-pituitary axis
Endocrinopathies ( hypothyroidism and decreased growth hormone secretion)
Secondary Malignancy
LATE TOXICITY
CHEMOTHERAPY chemo-sensitive Indication for CT :
1. As Adjuvant with Surgery in child <3 yrs to delay/avoid RT.
2. In Recurrent /Progressive disease .3. In patients with Extra cranial mets .4. High risk Pt. to improve cure rates5. In avg. risk group to allow reduced RT dose.
Chemotherapy regimenSingle agent CCNU
Lomustine 100-130 mg/m2 x 6 wks
PCV Procarbazine 60-75 mg/m2 PO D18-21 CCNU 110-130 mg/m2 PO D1 Vincristine 1.4mg/m2 IV D8 &D29
Cisplatin & Etoposide Cisplatin 30mg/m2 IV D1-D3 Etoposide 100 mg/m2 IV D1-D3
PCV (Most commonly used) CCNU 75 mg/m2 Cisplatin 75 mg/ m2 Vincristine 1.5 mg/m2
8 in 1 Regimen: MethylPDN 300 mg/m2 Vincristine 1.5 mg/m2 CCNU 75 mg/m2 Procarbazine 75 mg/m2 Hydroxyurea 1500 mg/m2 Cisplatin 60 mg/m2 Cytarabine 300 mg/m2 Endoxan 300 mg / m2
CVP x 6 weekly CCNU 75 mg/m2 D1 Vincristine 1.5 mg/m2 wklyx 3wks Prednisolone 40 mg / m2 x 14 days
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 yrs.
In high-risk :
brain and spinal MRI - every 3 months for the first 2 years then every 6 months.
RecurrenceRelapses occur in nearly 75% of paediatric cases within 2 years.Predicted by collins rule of recurrence=age at diagnosis +9monthSites
• Post. Fossa • supratentorial region including cribriform plate • spinal cord • ventricular walls
Diagnosed by neuroimaging; occasionally, clinical progression precedes neuroimaging
findings.Treatment at relapse: Localized brain recurrence: Surgery“radiation therapy
combined with various chemotherapy schedules.”Disseminated disease: Chemotherapy or best supportive
care including radiation.
RECENT ADVANCESCSI followed by chemotherapy is the standard of care for
both average and high-risk children ages 3 and olderCurrent standard approach:Standard risk: Surgical
resection CSI 23.4 Gy at 1.8-Gy/fx with PF boost to 54 Gy with concurrent vincristine PCV chemo. DFS ~80%
High risk: Surgical resection post-op CSI 36–39 Gy at 1.8-Gy/fx, with entire PF and mets >1 cm boosted to 54 Gy with concurrent vincristine PCV chemo. DFS ~60%
Infants<3-year old: Surgery intensive chemo. Reserve RT for salvage
Contemporary CSI treatment & planning approach uses MRI and CT simulations (3D RTP).
Posterior boost also benefits from 3D-RTP and the use of highly-conformal 3D-CRT or IMRT techniques.
Ongoing Trials
In average-risk disease, lowering of the craniospinal dosage to 18 Gy, conformal posterior fossa radiotherapy to the tumor volume and intensification of chemotherapy with autologous peripheral blood stem cell support.
Use of Proton in treatment to reduce exit dose.The current SIOP (PNET 4) and UK-CCSG (CNS 2001) are
addressing hyperfractionated and accelerated hyperfractionated delivery, respectively, in standard-risk
SummaryMedulloblastoma is pediatric age group tumor.Raised ICT is the most common presentation.CT, MRI have important role in diagnosis and
treatment.Surgery is the primary modality of treatment .RT has central role in treatment.Standard risk:
surgery CranioSpinal Radiation or concurrent chemo RT followed by post radiation
chemotherapy.High risk: CranioSpinal radiation and post RT
chemotherapy.Infants pt treated with intent to avoid or delay the RT.Long term neurological sequalae seen in CSI.
THANK YOU