CNS tumors in children.Comprehensively discussed for Radiotherapy Aspects.

1. Central Nervous System Tumors in
Children
Dr Sasikumar Sambasivam
DNB Resident
Radiation Oncology

2. Introduction
• 20% to 25% of all malignancies that occur in childhood
• etiology remains largely unknown
• Only 2% to 5% can be ascribed to a genetic predisposition with
– neurofibromatosis types 1 and 2,
– tuberous sclerosis,
– nevoid basal cell (Gorlin's) syndrome,
– the adenomatous polyposis syndromes, and Li-Fraumeni
syndrome.
– ionizing radiation used for diagnostic or therapeutic
purposes

5. CNS tumors in children

6. Astrocytic Tumors
• Diffusely infiltrating astrocytomas,
– Diffuse astrocytomas (WHO grade II),(or fibrillary)
– Anaplastic astrocytoma (WHO grade III),
– Glioblastoma multiforme (WHO grade IV) and
variants,
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Pilocytic astrocytoma (WHO grade I),(MC)
Pleomorphic xanthoastrocytoma,
Desmoplastic cerebral astrocytoma of infancy,
Subependymal giant cell astrocytoma.

7. Low-Grade Astrocytomas (WHO Grades I and II)
Astrocytic
Tumors
• Cerebellar astrocytomas (15% to 20% of all CNS
tumors),
• Hemispheric astrocytomas (10% to 15%),
• Midline supratentorial tumors, including the corpus
callosum, lateral and third ventricles, and the
hypothalamus and thalamus (10% to 15%),
• Optic pathway tumors (app 5% )
• Brainstem LGA (10% to 15% of all; 20% to 30% of these
are LGA),
• LGA of the spinal cord (3% to 6% of all; approximately
60% of these are LGA).

8. • Pilocytic astrocytomas :
• MC of all primary CNS tumors
• the anterior optic pathway, the
cerebellum
• well circumscribed and frequently
have an associated cystic
component
• histologically --a biphasic pattern :
compacted bipolar cells with
Rosenthal fibers and loose-textured
multipolar cells with microcysts and
granular bodies.
Astrocytic
Tumors

9. Management of LGA
• Surgery is the mainstay of treatment.
Astrocytic
Tumors
• Complete resection –likely-- in smaller,wellcircumscribed and those in noneloquent parts.
• Role of postop RT following lesser degrees of tumor
resection remains unclear
• IF adj RT – avoided in infants and 2-3 yrs of age, by
starting on CT.
• CT for Children with NF-1

10. Astrocytic
• Regarding Radiotherapy in LGA:
Tumors
– Not indicated after complete resection.
– Indicated in incomplete resection in situations when tumor
progression would compromise neurologic function .
 The clearest indication for radiotherapy is in patients with
progressive and/or symptomatic disease that is unresectable
GTV : Preop volumes
CTV :
for a well circumscribed tumor margin of 1 cm or even
GTV= CTV , around the GTV as seen on T1 W CEMRI.
If infiltrative, margins of 1 to 1.5 cm as seen on T2 W FLAIR

11. Astrocytic
Tumors—
LGA
• Dose: 50 to 54 Gy as std of care
• Technique:
– EBRT –conventional fractionation
– Radiosurgery
– Brachytherapy
• Follow up: Imaging studies
• OAS at 10 and 15 years : 80 to 100 %

12. High-Grade Astrocytomas (WHO Grades III and IV)
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Astrocytic
Tumors
5% of all CNS tumors in children
Adolescents
GBM –MC
Site: Cerebrum
Surgery --std of care
Post op RT always indicated dose ranging from
50- 54 Gy if feasible upto 60 Gy
• Role of chemo as for adults – yet to be
established
• Poor Prognosis

13. Brainstem Gliomas
Astrocytic
Tumors
Low grade, favorable, tumors:
Focal (solid/cystic) intrinsic tumors
Dorsal exophytic tumors
Cervicomedullary tumors
Unfavorable tumors:
Diffuse intrinsic (pontine)tumors(DIPG)(70-80% )
Primitive neuroectodermal tumors
Atypical teratoid/rhabdoid tumors

14. DIPG
• Brain stem enlargement
• Extn to Mid brain and medulla in 2/3 rds
• Mostly fibrillary astrocytomas with a propensity
for malignant change
• Multiple cranial N palsies,ataxia
• MRI if shows ring enhancement – high grade
• Biopsy not preferred
• Poor prognosis
• Surgery no role.
• Chemo no role
• RT as a direct intervention
• Hypo/hyperfractionation vs Conventional: No diff
Astrocytic Tumors

15. Astrocytic Tumors
Management of Brainstem Tumors

16. Ependymal Tumors
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5% to 10% of all Paediatric CNS Tumors
Infants and children younger than age 5 years
Supra and infratentorial
Signs of raised intracranial pressure
Well circumscribed, with displacement rather than
invasion
Completeness of the surgical resection – is a matter of
outcome
If residual– second look Sx
Post op Local RT- Std of Care
The role of chemotherapy--?

17. Choroid Plexus Tumors
• Choroid plexus papilloma (WHO grade I) and choroid
plexus carcinoma (WHO grade III).
• 2% to 4% in paediatric CNS Tumors(<3 Y)
• MC--lateral ventricles causing obstruction to CSF flow
• Surgery is the treatment of choice-both for the primary
lesion and for macroscopic metastatic deposits
• RT benefits +; But CT preferred d/t age.

18. Embryonal Tumors
• 2nd MCtype of CNS tumor in the pediatric age
• Most are PNETs ---undifferentiated round cell tumors with
divergent patterns of differentiation as follows:
– Ependymoblastoma,
– Medulloblastoma,
• Desmoplastic medulloblastoma
• Large cell medulloblastoma
– Supratentorial PNET.
• Two tumor types with distinctly different histologies that appear
to evolve by different genetic pathways also are included in the
category of embryonal tumors:
– Medulloepithelioma,
– Atypical teratoid/rhabdoid tumor.

19. •
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Medulloblastoma
Embryonal Tumors
15% to 20% of all paediatric CNST
Median age 6 years
MC site-cerebellar vermis and projects into the fourth ventricle
Types:
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Desmoplastic/nodular
With Extensive nodularity
Anaplastic
Large cell
• Frequency of spinal seeding at diagnosis -30-40%
• CEMRI of the Craniospinal axis (Solid masses with uniform
enhancement)
• CSF cytology– IOC primarily (to be obtained preoperatively or 2-3 wks
postop)
• Rarely spread outside the CNS -to lymph nodes and bone

20. Medulloblastoma
• CT and MRI –
• appear as solid masses
• that enhance usually fairly homogeneously with
contrast material

21. Medulloblastoma
Chang Staging System for Metastases in Patients with Medulloblastoma
M0
No metastases
M1
Tumor cells found in cerebrospinal fluid
M2
Gross nodular seeding in the cerebellar,
cerebral subarachnoid space, or in the third or
lateral ventricles
M3
Gross nodular seeding in the spinal
subarachnoid space
M4
Metastases outside the central nervous
system

22. Medulloblastoma
• Outcome:
– Age,
– Presence of leptomeningeal spread at presentation
and
– completeness of surgical resection
• Risk categories: standard and high risk.
– Std Risk: complete or subtotal resection with <1.5
cm2 of residual tumor and no evidence of CSF
dissemination (M0)
– High risk : larger volume(>1.5 cm2) residual tumor
and those with evidence of CSF dissemination at
diagnosis.

23. Management of Standard-Risk Medulloblastoma
• >3 years- post op RT-craniospinal axis to a dose of 35 to 36 Gy
followed by a boost to the whole posterior fossa to a total dose of
54 to 55.8 Gy, traditionally. (others: reduced post fossa boost)
• An alternative strategy consists of reduced-dose CSI followed by a
boost to the posterior fossa to a total dose of 55.8 Gy in
combination with systemic chemotherapy(Vincristine and
Cisplatin)
– CCG Pilot study: 23.4 GyCSI f/b adj V,CCNU,P ;PFS: 79% at 5 Y
– CCG /POG Phase III RCT – Vincristine /Cyclo/Cisplatin—EFS 85%
at 4 yrs
– Current CCG study -18Gy in children 3-8 yrs--- Pending results

24. Management of High-Risk Medulloblastoma
• M0-- it would be logical to consider using a
radiotherapy dose to residual disease in the
posterior fossa higher than the standard 55.8
Gy
• M1 disease – controversial and may be
treated like M2/3
– Chemotherapy
– COG pilot study with Carboplatin (M2/3)
– New studies -HART with Pre and Post RT -CT

25. Management of Medulloblastoma in Infants
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20% to 40% of all CNS tumors in infants
Desmoplastic /nodular/extensive nodularity –Common
But worser than the older children
The rate of complete resection is lower in this age group
• The frequency of leptomeningeal seeding at diagnosis is
higher (as much as 50%)
• Chemotherapy has been used in an attempt to either
delay or avoid radiotherapy altogether due to effects on
cognition by RT

26. Medulloblastoma
• POG study in Infants: Chemotherapy alone: 5
Y OAS :69%
• RT still an important component
– Most recurrences as early as 6 to 12 months
– North American study –RT limited to a volume of
tumor bed plus CTV of 1 cm margin for children
without Lepto meningeal seeding

27. Medulloblastoma
Cranio Spinal Irradiation
• CSI –Std of Care
• Coverage of entire target volume that includes the
meninges overlying the brain and spine including the
extensions along the nerve roots is critical

28. Treatment Techniques-CSI
Medulloblastoma
• The CTV for CSI has an irregular shape that consists
of the whole of the brain and spinal cord and
overlying meninges
• Some use the lower borders of lateral whole-brain
fields are matched to the cephalad border of a
posterior spine field
• Some use a moving junction between the brain
and spine fields to minimize the risk of underdose
or overdose in the cervical spinal cord

29. Medulloblastoma
Patient Positioning and Immobilization
• Prone/ Supine*
• full-body immobilization
• using neck extension together with careful
selection of the level for the junction of the
brain and spine fields –
– it is possible to avoid including the dentition in the
exit from the superior aspect of the spinal field, and
thus any damage to developing teeth that may
result in stunted tooth growth, impaction,
incomplete calcification, delayed development, and
caries.

30. Technical Considerations for Craniospinal Irradiation
Problem
Target volume definition may be difficult using
conventional simulation
Prone position uncomfortable, difficult to
monitor airway
Field matching over cervical spine, risk of overor underdosage
Choice of extended SSD or second field for
treatment of spinal axis
Inhomogeneity along spinal axis
Medulloblastoma
Possible Solutions
Use CT simulation with CT-MRI co registration
Supine position preferred
Angle brain fields
Use half beam block for brain fields
Use couch rotation or match line wedge
Two fields preferred
Use compensator, MLC
Irradiation of normal tissues:
Mandible/teeth
Thyroid
Heart
Neck extension
Care with level of junction
Use lower junction
GI tract
Care with width of spine field
Use electrons, IMRT, protons
Use electrons, IMRT, protons
Gonads
Care with lower limit and width of spine field
GI, gastrointestinal; IMRT, intensity-modulated radiation therapy; MLC, multileaf collimator; SSD,
source-skin distance.

31. Target Volume Definition
Medulloblastoma
• CT simulation is
– necessary to ensure adequate coverage of CTV in subfrontal
region:Cribriform plate
– invaluable in identifying the lateral aspect of CTV for the
spine field that includes the extensions of the meninges
along the nerve roots to the lateral aspects of the spinal
ganglia.
• The field, which must be wide enough to encompass
the intervertebral foramina in the lumbar region, can
be blocked laterally in the dorsal region to avoid
unnecessary irradiation of the heart and lungs

32. Medulloblastoma
• In the lumbar region, it is important to avoid an
excessively wide field that will result in unnecessary
irradiation of the bone marrow and gonads.
• MRI is required to determine the lower limit of CTV for
the spine field.
• Traditionally the lower border of the spine field was
placed at the lower border of the second sacral vertebra,
but it is well documented that the lower border of the
thecal sac can be as high as L5 or as low as S3.
• It is below S2 in 7% of children ; MRI is helpful.

33. Medulloblastoma
• CT simulation with CT-MRI co registration ---required
for accurate determination of the target volume for the
posterior fossa boost, both for definition of the target
volume and for contouring of critical normal structures
such as the cochlea, pituitary/hypothalamus, and brain
that will allow accurate estimation of the dose to these
structures.
• CSI is followed by a boost to posterior fossa
• Traditionally entire post fossa received 54 to 55.8 Gy
• Sparing of at risk organs – a consideration

34. Medulloblastoma
• Another option in Std Risk: reduced target volume
for the boost
• Fukunaga –Johnson et.al found a low risk of isolated
failure outside tumor bed in posterior fossa and SFOP
studies support this approach.
• Optimal CTV for a reduced volume post fossa boost
remains to be defined
• But anatomically confined expansion of 1.5cm around
GTV – reasonable (Current COG study)

35. Medulloblastoma
Whole post fossa Vs Reduced Volume Boost

36. Medulloblastoma

37. Medulloblastoma
Treatment Planning and Delivery
• In general, photons in the 6 to 10 MV range provide
satisfactory coverage of the PTV.
• A variation of dose along the spinal axis of >10% will require
the use of dose compensation that can be achieved using
dynamic MLCs
• To cover the clinical target volume for craniospinal irradiation,
lateral opposed fields are used to treat the brain and a direct
posterior field is used to cover the spinal axis.
• Electrons are also used to treat spinal axis.

38. • The field junction, which is over the cervical cord at a level
that avoids the inclusion of the teeth in the exit of the spinal
field, usually is moved weekly to avoid over- or underdosage

39. Supratentorial PNET
Embryonal Tumors
• <5% of all CNS tumors in the pediatric age group
• The median age at presentation is 3 years
• Tumors arising in the cerebral hemispheres in particular are often
very large at diagnosis
• On imaging they are often quite heterogeneous with cystic or
necrotic areas and areas of hemorrhage.
•
Leptomeningeal seeding—40%
• MRI of the spinal axis and CSF cytology are mandatory prior to
treatment.

40. Supratentorial PNET
• The standard of care --– >3 years with S-PNETs without leptomeningeal
spread consists of ---maximal surgical resection
followed by postoperative radiotherapy
– (CSI plus a boost to doses similar to those used for high-risk
medulloblastoma) followed by chemotherapy

41. Atypical Teratoid/Rhabdoid Tumor
• Uncommon, highly malignant embryonal tumor
unique to childhood
• Peak– birth to 2 yrs
• Composed of rhabdoid cells with or without fields
resembling a classical PNET
• Diagnosed on the basis of the characteristic
molecular findings, namely deletion and/or
mutation of INI1 locus on Chromosome 22
• Most commonly arises in the posterior fossa
• Leptomeningeal seeding in 1/3 at presentation

42. Diagnosis
ATRT
• MRI Magnetic resonance imaging of the brain and spine
• Lumbar puncture to look for M1 disease
• CT of chest and abdomen to check for a tumor
• Bone Marrow Aspiration and Bone marrow biopsy
• Bone scan.
• It is difficult to diagnosis AT/RT only from radiographic
study; HPR is essential with IHC and Cytogenetic study

43. ATRT
• Sx-induction chemotherapy early RT(CSI)-
Consolidation Chemo
• DOSE• < 3 yr, up to 24 Gy to whole brain and spinal cord,
and boost local site up to 54 to 56 Gy.
• > 3 yr up to 36 Gy to whole brain and spinal cord, and
boost local site up to 56 Gy.

44. Germ Cell Tumors
• GCT of CNS-morphologic homologues of
germinal neoplasms arising in the gonads and at
other extragonadal sites.
– Germinoma,
– Embryonal carcinoma,
– Yolk sac tumor (endodermal sinus tumor),
– Choriocarcinoma,
– Mature teratoma,
– Immature teratoma,
– Teratoma with malignant transformation,
– Mixed germ cell tumors

45. GCTs
• Asia---account for as many as 15% to 18% of all CNS
tumors occurring in childhood
• 10 to 12 years. Boys more frequently than girls, with a
ratio of approximately 3:1
• CNS germ cell tumors arise from primordial germ cells
in structures about the third ventricle, with the region
of the pineal gland being the most common site of
origin, followed by the suprasellar region.
– Nongerminomatous germ cell tumors are the most common
tumor type in the former area, and germinomas in the latter

46. Bi- or multifocal disease around the third ventricle is seen in
approximately 10%
GCTs
•CE MRI of the spinal axis is an essential part of the work-up
to exclude leptomeningeal dissemination, which is found at
diagnosis in <10% of patients with germinomas and 10% to
15% of patients with NGGCT.
•Serum and CSF tumor markers
– Elevated--beta HCG (<100 IU/mL) may be seen with pure
germinomas that often contain syncytiotrophoblastic cells.
– Higher levels ofbeta hCGare more suggestive of a
choriocarcinoma.
– An elevated AFP is diagnostic of a yolk sac tumor.

47. Germinoma
• Unifocal disease and without leptomeningeal spread -radiotherapy (CSI and boost)
• A combined approach using platinum-based
chemotherapy followed by reduced-volume, reduceddose radiotherapy is a very attractive option that is
being investigated by many groups, with disease-free
survival rates in the 90% to 96% range.
• Hence options:
– craniospinal radiotherapy,
– limited volume (whole-ventricle)
radiotherapy alone, and
– chemotherapy followed
by whole ventricle or local radiotherapy

48. Non germinomatous GCT
• A multimodality approach that includes both
chemotherapy and radiotherapy appears to be
associated with the best outcome
• Favourable--- Whole Ventricle RT
• Unfavourable --- CSI and Boost
• A dose of 36 Gy is used, followed by a boost to
the primary site to a total dose of 54 Gy.

49. Classification of Nongerminomatous Germ Cell Tumors
Good prognosis
Mature teratoma
Poor prognosis
Teratoma with malignant transformation
Embryonal carcinoma
Yolk sac tumor
Intermediate prognosis
Choriocarcinoma
Immature teratoma
Mixed germ cell tumors including a
Mixed germ cell tumors consisting of
component of embryonal carcinoma, yolk
germinoma with either mature or immature sac tumor, choriocarcinoma, or teratoma
teratoma
with malignant transformation

50. Tumors of the Sellar Region
• Craniopharyngioma,
– Adamantinomatous craniopharyngioma
– Papillary craniopharyngioma
• Xanthogranuloma,
• Pituitary adenomas.

51. Craniopharyngioma
• Benign partly cystic epithelial tumors that arise
in the sellar region from remnants of Rathke's
pouch
• MC in Children- adamantinomatous
• 5% of intracranial tumors in children
• 5 and 14 years.
• have both suprasellar and intrasellar
components

52. Craniopharyngioma
• Children typically present with neuroendocrine deficits,
especially diabetes insipidus and growth failure.
• Visual-field deficits bitemporal hemianopia often go unnoticed
initially.
• Compression of the third ventricle may lead to hydrocephalus
and symptoms and signs of raised intracranial pressure.

53. Craniopharyngioma
• On neuroimaging:
– with solid and cystic
areas in varying
proportions;
– calcification is seen
in the majority of
cases.
– The solid portions
and the cyst capsule
usually enhance with
the use of contrast
material.

54. Craniopharyngioma
• Complete surgical resection(Transsphenoidal
approach), as confirmed on postoperative imaging, is
associated with long-term tumor control in 85% to
100% of patients
• Patients with
– tumors that are smaller and/or subdiaphragmatic in location
and without hypothalamic symptoms would be managed
surgically,
– while other patients at higher risk for complications
secondary to surgery would be managed with biopsy, cyst
decompression, if necessary, and radiotherapy

55. Craniopharyngioma
• Role of RT as sole therapy:
– After biopsy
– After incomplete surgery
– At progression
– Recurrence
• Other options
– Injection of radioactive colloid P32 and Y90--- if the
lesion has a small solid comp. and a simple cyst
– May be combined with Stereotactic RT to solid
comp.

56. Craniopharyngioma
• EBRT
– Target Volume: entire lesion with preop MRI
– 0.5 cm margin or even 0 cm can be justified for a
CTV (Studies show excellent results)
– Dose: 54-55 Gy over 30 fractions
• During even after RT--Cyst may enlarge
• Emergency cyst decompression may avoid further
neuro complications

57. Radiation Dose Fractionation in Children
• Conventionally 1.8 Gy / Fr
• Avg dose: 54.5- 55.8 Gy
• If it is a primary tumor of spinal cord: 50.4 Gy
• In case of Germinomas: even doses of 1.5 Gy /fr and
lower doses of 30 to 45 Gy
• HFRT may be a useful strategy in situations where dose
escalation cannot be obtained by conventional
fractionation

58. Issues regarding RT in children
• Neurocognitive sequelae
• Myelinization and functional maturation of the CNS
continue until well into adolescence and even into
young adulthood.
• Failure to acquire new knowledge and skills at an ageappropriate rate and show a progressive decline in IQ
over time
• Endocrine deficits

59. To Minimize the long-term effects
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Avoidance of radiotherapy altogether
Delay to radiotherapy for young children
Use of focal rather than extended-field
Use of daily anesthesia and improved immobilization
techniques
Use of image-based treatment planning
New radiation modalities
Reduction of the dose of radiotherapy
Use of smaller fraction sizes where appropriate
Use of hyperfractionated radiotherapy (HFRT)

60. Follow up
• During treatment:
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For vomitting ,headache
ICT
Fatigue
Usually recover quickly after treatment
• After treatment: (apart from imaging)
• For hormonal deficits (esp. Primary hypothyroidism in CSI
by photons and GH deficit secondary to incln. Of
hypothalamo pituitary axis)
• Ophthalmology and audiology f/u
• Access to neuropsychologist in case of special needs
,vocational assessment sos.

61. Thank you.