Medulloblastoma n csi kiran

1. MEDULLOBLASTOMA
DR. KIRAN

2. INTRODUCTION
Most common malignant brain tumor of childhood
• 20% of all primary tumors of the central nervous system
among children less than 19 years of age
• Peak incidence : 5 - 9 years of age
• Occur exclusively in the cerebellum
Belongs to the family of small round blue cell tumours.
• 10-20% of brain tumors in pediatric age group.
• 40% of tumors of the posterior fossa.

3. PATHOLOGY
• Gross
– Soft, friable tumors
– Often with necrosis
• Microscopy
– Highly cellular tumors with abundant dark staining, round or
oval nuclei, and little cytoplasmic differentiation
– Spectrum of histopathologic appearance ranges from tumors
with extensive nodularity to those with large cell/anaplastic
features
– Mitoses are abundant
– Neuroblastic Homer wright rosettes can be found in up to 40%
of cases

4. PATHOLOGY
• Pathological subtypes
– Classical
– Desmoplastic/nodular
type
– Large-cell variant
– Anaplastic
Medulloblastoma
Molecular Subtypes
• I. WNT-activated
• II. SHH-activated, TP53
mutant
• III. SHH-activated, TP53
wild type .
• IV. non-WNT/non-SHH,
group 3
• V. non-WNT/non-SHH,
group 4

5. PATHOLOGY
Immunohistochemistry
• Neuronal markers
• Synaptophysin
• Neuron specific enolase
• Nestin, a marker of primitive neuroepithelial cells,
consistent with their presumed Origin from neuronal
progenitors in the cerebellum

6. Molecular Sub grouping(WHO 2016)
WNT Pathway-
• display classic medulloblastoma histology and nuclear localization of
CTNNB1 (β-catenin).
• Best prognosis.
• Monosomy 6 : Hallmark chromosomal aberration found in almost all cases
of WNT medulloblastoma
• SHH Pathway
• Desmoplastic (or nodular) histology is almost exclusively restricted to
SHH medulloblastomas.
• intermediate prognosis.
– deletions of chromosomes 9q and 10q.
• WNT Pathway
• SHH Pathway
• Group 3
• Group 4

7. Group 3
• Worst outcome of the four subgroups.
• More common in males.
• Frequently of the LCA subtype.
• High-level amplification of the MYC proto-oncogene is
characteristic of group 3 medulloblastomas.
Group 4
• Most common subgroup.
• 5-year survival of ~ 75%.
• Mainly of classic histology.
• MYCN amplification.
• i(17q) is found in the majority of these cases .

9. Clinical Features
• Symptoms of increased
intracranial pressure
– Nocturnal or morning
headaches
– Nausea
– Vomiting
– Altered mental status
• Tumors in the midline
– Gait ataxia
– Truncal instability
• Tumors in the lateral
cerebellar hemispheres
– Limb clumsiness
– Incoordination
• Cerebellar, brainstem, or
cranial nerve involvement
– Dizziness
– Double vision

10. Adult vs Peadiatric Medulloblastoma
• Usual age ~ 4 – 8 yrs
• Shorter clinical History (~ 3 months)
Classical type predominates
• Median cerebellar syndrome
predominates
• 72% pediatric cases are median in origin
• Biologically more aggressive – more
labeling index and less apoptotic index
• Poorer resectability – median location
• Higher surgical morbidity and
mortality
• Poorer RT tolerance Poorer
long term survival
Median age ~ 24 – 30 yrs
Longer history ( ~ 5 months)
Desmoplastic type relatively
commoner
Lateral cerebellar syndrome seen
45% are median in origin and 43%
lateral
Biologically less aggressive – less
labeling index and more apoptotic index
Greater resectability - lateral location Lower
surgical morbidity and mortality
– impact of location and age
Better RT tolerance
Better long term survival

11. Workup
• Imaging
– MRI brain (with Contrast)
• T1: hypointense to grey matter
• T1 C+ (Gd): 90% enhance,
often heterogeneously
• T2
– overall are iso to
hyperintense to grey matter
• FLAIR: hyperintense to
surrounding brain
• DWI: shows restricted diffusion
• MR spectroscopy: elevated
choline, NAA decreased, may
show a taurine peak
T1 FLAIR
T1 C+
On CT they are usually hyperdense (90%) and cysts
formation/necrosis is common (40-50%), especially in older
patients.

12. MRI

14. MANAGEMENT
Multimodality approach
Surgery
Radiation therapy
Chemotherapy

15. Pre surgical Management
• Most patients will have hydrocephalus.
• Initially managed medically:
• Moist O2 inhalation (Hypercapnia is however
considered in serious situations as an last ditch
medical measure to reduce ICP)
• Propped up position
• Oral or injectable steroids (Dexa
preferred)
• Osmotic diuretics in grave circumstances.
• VP Shunting is required in majority as they
present with hydrocephalus.
• Use of filtered shunt reduces incidence of shunt
metastasis.
• Halperin et al have also described a I125
impregnated shunt.

16. Surgery
Definitions of resection:
• 90% : Total or near total
• 51 – 90%: Subtotal resection
• 11 – 50%: Partial resection
• < 10%: Biopsy

17. Post-operative neuro-imaging and CSF
Cytology
• It is recommended that post-operative MRI of the brain be acquired
immediately (within 24-48 hours of surgical resection) to accurately
identify the extent of resection.
• If screening spinal imaging had not been done pre-operatively, the same
should be acquired post-operatively for an accurate spinal staging.
• It is recommended to wait for 2-3 weeks after surgery for acquiring the
spinal MRI to reduce the chance of erroneous interpretation consequent to
post-operative enhancement of spinal leptomeninges.
• It is recommended to test the CSF for malignant cell cytology via lumbar
puncture as a part of the post-operative staging work-up. This should be
performed at least 2-3 weeks after surgery to avoid false positivity.

18. T
stage
T1 Tumor <3 cm in diameter
T2 Tumor ≥3 cm in diameter
T3a Tumor >3 cm and with extension
into aqueduct of sylvius or
foramen of luschka
T3b Tumor >3 cm and with
unequivocal extension into
brainstem
T4 Tumor >3 cm with extension past
aqueduct of sylvius or down past
foramen magnum
M
stage
M0 No evidence of gross subarachnoid
or hematogenous metastasis
M1 Microscopic tumors cells found in
CSF
M2 Gross nodular seeding intracranially
beyond the primary site (in
cerebellar/cerebral subarachnoid
space or in third or lateral ventricle)
M3 Gross nodular seeding in spinal
subarachnoid space
M4 Metastasis outside cerebrospinal axis

19. Post OP Risk Stratification
Average Risk High Risk
Age at diagnosis > 3 years < 3 years
M stage M0 M1-M4
Extent of
residual disease
< 1.5 cc on Post
OP MRI
> 1.5 cc on Post
OP MRI
Histology Classisc or
Desmoplastic
Anaplastic

20. Adjuvant treatment

24. Standard-Risk Medulloblastoma
• Reduced-dose CSI (followed by a posterior fossa boost) with systemic
chemotherapy.
• CCG pilot study*
– CSI to a dose of 23.4 Gy in combination with weekly vincristine
followed by adjuvant systemic chemotherapy consisting of vincristine
1.5 mg/m2, CCNU 75 mg/m2, and cisplatin 75 mg/m2 for 8 cycles
– Progression-free survival : 79% at 5 years
• CCG/POG phase III randomized study (A9961)
– CCNU was replaced by cyclophosphamide.
– Event-free survival at 4 years : ~ 85% in both arms.
– weekly vincristine followed by adjuvant systemic chemotherapy
consisting of vincristine 1.5 mg/m2, Cyclophosphomide, and cisplatin
75 mg/m2 for 8 cycles
*Packer et al., JCO 1999

25. High-Risk Medulloblastoma
• Radiation Therapy with concurrent and adjuvant
chemotherapy
– CSI to a dose of 36 Gy followed by Posterior fossa
boost to total of 54-55.8 Gy
– Concurrent chemotherapy with Radiation therapy
followed by Adjuvant chemotherapy.
– weekly vincristine followed by adjuvant systemic
chemotherapy consisting of vincristine 1.5 mg/m2,
CCNU 75 mg/m2, and cisplatin 75 mg/m2 for 8
cycles.

26. Medulloblastoma in Infants
– Risks of neurocognitive decline associated with the use of
radiotherapy in infants and very young children
• Chemotherapy has been used in an attempt to either delay
or avoid radiotherapy altogether
– Infants with M0 disease who have undergone total resection
may do well with chemotherapy alone.
• German Paediatric Brain Tumor Study Group; Rutkowski S et al., NEJM 2005
• Baby Brain French Society of Paediatric Oncology, SFOP; Grill J et al. Lancet Oncol.
2005

27. Medulloblastoma in Infants
• Infants with M2/3 disease
– Intensive chemotherapy regimens
– Patients with desmoplastic/nodular histology : Better
prognosis
– Overall survival at 5 years of 52.9% in the UKCCSG/SIOP
baby study
– Prognosis for those with other subtypes : Less satisfactory
• Goal of treatment
– Still to avoid radiotherapy (especially CSI) and the decision
to use it highly individualized based on the clinical
situation and the wishes of the parents

28. Craniospinal Irradiation
Indications:
Medulloblastoma
Pineoblastoma
Supratentorial PNET
Germinoma
Anaplastic Ependymoma

29. • Positioning
• Immobilization
• Simulation
• Target volume Delineation
• Treatment Planning

30. • Prone Position:
Advantages :
• Direct visualization of the field junctions.
• Good alignment of the spine
Disadvantages :
• Uncomfortable, and larger scope for patient
movement
• Difficult anesthetic procedures.
Supine
• More comfortable.
• Better reproducibility
• Safer for general anaesthesia
Diasadvantage
• Direct visualisation of spinal field
is not possible
Head position:
Extended: Most commonly used– allows the mandible to move out of the spinal
field.
Flexed: Probably straightens the cervical spine – more homogeneous
dose distribution.

32. • Concern 1
 Divergence of the upper border of the spinal field in case of single
spinal field(and inter-divergence of spinal fields in case of 2 spinal
fields)
• Concern 2
 Divergence of both cranial fields
• Spinal field simulated first (to know the divergence of the spinal
field)
• 2 spinal fields if the length is > 36 cm
• Upper border at low neck.
• Lower border at termination of thecal sac or S2 whichever is lower.
• In case of 2 spinal fields , junction at L2/L3.

33. Target Volume
The intent of CS-RT is to deliver a cancerocidal dose to the
primary tumor and any tumor cells distributed in the CSF or
tissue elsewhere in the nervous system.
The volume of irradiation thus includes:
Entire brain and its meningeal coverings with the
CSF Spinal cord and the leptomeninges with CSF
Lower border of the thecal sac
Posterior fossa - boost

34. Target Volume: Cranium
Miss will
occur
here
The lower border for a
conventional cranial field if used
with a block will result in a miss
of the cribriform plate
This corresponds to the
anterior surface of the greater
wing of the sphenoid

35. Target Volume Spinal Field
Lateral extent to include the
the transverse processes in
their entirety.
Theory is to include the spinal
subarachnoid space.
This extends to the spinal
ganglia which are situated at
the intervertebral foramina
Traditional recommendation for
lower border of spinal field is
inferior edge of S2.

36. Field Selection:
Cranial fields: Two parallel opposing lateral fields
Spinal fields:
Conventional SSD: Two fields.
Extended SSD: One field may suffice

37. Problems in field matching
• Cranial and Spinal field divergence.
• Spinal field divergence.

38. Solution
Cranial and Spinal field divergence:
• Using half beam block technique.
• Using collimator – couch rotation technique.
• Using planned gaps.
Spinal field divergence:
• Gap is given calculated as per formula.
• Abutting fields treated with the “Double Junction” technique
(spinal shift technique).
• Gap Feathering Techhnique.

39. Collimator Couch Rotation
• 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).
• Both the rotations are performed during irradiation of the cranial
fields.
• θcoll= Collimator angle to rotate (7-100)
• θcoch= Couch angle to ratate (~60)

42. Collimator rotation Couch rotation

43. Spinal field divergence:
• Gap is given calculated as per formula.
• Abutting fields treated with the “Double Junction”
technique (spinal shift technique).
• Field gap technique: Will result in a cold spot above and a
hot spot in the deeper tissues.
• “Feathering” of the gap can smoothen out the dose gradients

44. Double Junction Technique
Method to ensure dose
homogeneity without the need for
gaps.
Described: Johnson and Kepka
(Radiology, 1982)
Principle : An overlapping
segment is treated with two
different fields on alternate days
The junction is therefore
automatically feathered on
alternate days
Receives homogeneous dose 50%
of the time
Receives junctional dose in the
remaining 50% time.
No cold spots are generated

45. Double Junction technique
Day of
Planning
Day 1: The upper
spinal field is
shortened
Day 2: The lower spinal field
is shortened
Upper Spine Lower Spine
Upper Spine
Upper
Spine
Lower Spine
Lower Spine
Junction on D
1
Junction on D
2

46. Field Gap Technique
SSD
1
SSD
2
L
2 L1
S
Hot SpotCold
Spot

47. Calculation of Field Gap
SSD
1
SSD
2
L
1
L
2
S
D
S = ½ (L1 x D / SSD1) + ½ (L2 x D / SSD2)
 Many institutes use a fixed gap
ranging from <5 mm -10 mm

48. Gap Feathering
“Feathering” refers to
movement of the junction of
the two fields.
Purpose:
Reduce overdose (due to
overlap)
Reduce underdose (due to
gap)
Allows a longer segment of
the cord to be exposed to
more homogeneous dose
Feathering also reduces
the impact of setup errors.
As the treatment progresses the
under-/over -dose gets spread over a
greater area of the spinal cord
allowing more homogeneous dose
distribution

49.  Usually shifted by 1 to 2 cm at each shift
 Done every few fractions( usually 5# to 7#).
 Either in cranially or caudal direction.
 Spinal superior collimator is advanced by the same
distance superiorly (if junction to be shifted cranially).
 Similarly, lower border of superior spinal field & superior
border of inferior spinal field are also shifted superiorly,
maintaining the calculated gap between them.

51. Borders
 Anterior: Posterior clinoid process.
 Posterior: Internal occipital
protuberance.
 Inferior: C2-C3 interspace.
 Superior: Midpoint of foramen magnum
& vertex or 1 cm above the tentorium
(as seen on MRI).
Field arrangement
Two lateral opposing fields.

52. • GTV- Tumor bed on MRI
• CTV = GTV + 15 mm.
• PTV = CTV + 3-5 mm, modified only at sella.
• Immobilization accuracy +/- 3-5 mm.
• 95% of isodose covers 100% of CTV & 95% Of PTV.
• Constraints:
• < 70% Supratentorial brain to receive > 50% boost dose.
• < 80% Left & right cochlea to receive > 80% ofboost dose.
• < 50% Pituitary to receive > 30% of boost dose.
• < 10% Left & right optic nerve & chiasma to receive>
50.4 Gy each.

54.  IMRT plans provided better healthy tissue sparing than
either the 2D or the 3D plans.
 IMRT results in better sparing of OARs without asignificant
increase in integral dose.

56.  The plan used three field sets, each with a unique
isocenter.
 One field set with seven fields treated the cranium.
 Two field sets treated the spine, each set using three fields.
 Fields from adjacent sets were overlapped, and the
optimization process smoothly integrated the dose inside the
overlapped junction.
•one IMRT plan is required for
the entire target volume.

57. Sagittal view shows the dose distribution for one of the patient’s jagged-
junction IMRT plan (i) and the conventional plan (ii) for the same patient.
Regions A and B show the dose distribution in the cranial-spinal and superior-
inferior junctions.

58. •A reduction of late sequelae and thus improved quality of life may
be achieved by the use of VMAT.
•A VMAT planning solution for different lengths of craniospinal axis
has been developed, with significant reductions in dose to the OAR
around the brain, neck, and thoracic regions.
•HOWEVER there may be a risk of second malignancy due to
increase of integral dose.

59.  It is a rotational IMRT- no need for junction.
 Helical TomoTherapy delivers continuous arc–based
intensity-modulated radiotherapy that gives high
conformality and excellent dose homogeneity for the target
volumes.
 Helical TomoTherapy allows for differential dosing of
multiple targets, resulting in very good dose distributions.
 The use of pretreatment MVCT imaging with Helical
Tomotherapy allows for increased precision with respect to
patient positioning and use of a reduced PTV margin.

60. Proton therapy
- Uniform dose distributuon to the posterior fossa and spinal cord with in the
thecal sac.
-Near complete organ sparing, lower probability of developing secondary
hearing, hormonal defects.
-Long term effect of neutron spill- not quantified.

61. • Proton CSI is superior to other CSI modalities in terms of OAR doses
and toxicities.
•There is a decreased risk of radiocarcinogenesis with proton CSI than with
conventional radiation therapy.
•The reduction in risk of toxicity and radiocarcinogenesis offered by
proton craniospinal irradiation appear to outweigh the increased costs.

62.  • Pituitary
 • Eyes / Lens
 • Cochlea / Inner ear
 • Parotid
 • Oral cavity
 • Mandible
 • Thyroid
 • Larynx
• Heart
• Lungs
• Oesophagus
• Liver
• Kidneys
• Gonads (Testes / Ovaries)
• Breasts
• Whole Pelvis( marrow)

63. Complications of Treatment
• Posterior fossa syndrome
• Neurocognitive impairment
• Hearing loss
• Short stature
• Endocrine abnormalities
– GH deficiency
– Hypothyroidism
– ACTH deficiency
• Second malignancies

64. CONCLUSIONS
• In Standard risk- Reduced dose CSI with Concurrent and adjuvant
Chemotherapy.
• In High risk Standard dose CSI with Concurrent and adjuvant
Chemotherapy.
• New molecular subgrouping Of Medulloblastoma has given a new
insight on the causation of the disease.
• It is presently of prognostic importance only.
• Newer treatment strategies targeting the molecular pathways are
under trial.

65. • Thank You.