Recent Advances

1. EMBRYONAL BRAIN TUMORS IN
CHILDREN
Dr. Evith Pereira
Dr. Amruta Padhye
Moderator – Dr. D.B.Borkar

2. • Cancer in childhood is rare with only 1:600 children developing
malignancy by the age of 15 years.
• 20 -25% of childhood tumors are of CNS origin
• This equates to 2.4 cases / 100,000 children per year

3. 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.

4. Origin
• A 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.

5. 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.

6. Adult vs. Paediatric Medulloblastoma
Child 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 relatively
commoner
Median cerebellar syndrome
predominates
Lateral cerebellar syndrome seen
Biologically more agressive Biologically less aggressive
Poorer resectability - median location Greater resectability - lateral location
Higher surgical morbidity and
mortality
Lower surgical morbidity and mortality -
impact of location and age
Poorer RT tolerance Better RT tolerance
Poorer long term survival Better long term survival

7. Natural History
Arising in the midline
cerebellar vermis (roof
of the 4th
ventricle)
Arising in the midline
cerebellar vermis (roof
of the 4th
ventricle)
Grows into the 4th
ventricle
Grows into the 4th
ventricle
Fills into the 4th
ventricle
Fills into the 4th
ventricle
Spread around the
4th
ventricle
Spread around the
4th
ventricle
Invasion of
ventricular floor
Invasion of
ventricular floor
Invasion of brain
stem
Invasion of brain
stem
Invasion of
brachium pontis
Invasion of
brachium pontis
CSF SpreadCSF Spread
Extra neural spread :Young age, males and diffuse subarachnoid diseaseExtra neural spread :Young age, males and diffuse subarachnoid disease

8. 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%)

10. Pathological Features
Highly cellular tumor
High N:C ratio
Cells arranged in typical
Homer - Wright rosettes
Multiple 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%.

11. • Gross
• Well circumscribed, gray-pink, soft/friable.
well-circumscribed
soft, fleshy tumor with
areas of softening & necrosis
in the center.

12. • M/E-
• Highly cellular
• sheets of anaplastic cells with scanty cytoplasm,
• hyperchromatic nuclei,
that are often elongated &
cresent shaped
• Mitoses- abundant
• Occasional
Homer-Wright rosettes

13. • Homer-Wright rosettes (groups of tumor cells arranged in a circle around a fibrillary
center). Similar rosettes are seen in adrenal neuroblastoma.

14. • Positive stains
• NSE, synaptophysin
• Focal GFAP
• Molecular / cytogenetics description
• Isochromosome (17q) or 17p-
• 5-30% overexpress c-myc or N-myc;
• C-myc overexpression is associated with poor prognosis

15. • Differential diagnosis
• Lymphoma: diffusely infiltrates CNS until it mixes with normal and reactive
fibrillar cells
• PNET
• Ependymoma

16. • Desmoplasmic/nodular medulloblastoma
• nodular b/c of its architecture
• desmoplastic because it is permeated by (reticulin) fibers that give it a firm
consistency
• M/E-

17. • Round pale nodules of tumor separated by zones of darker tumor cells.
• Paler tumor nodules showing a population of uniform round to oval cells on
a pale pink fibrillary background.
• The cells have a more mature neuronal appearance and are less active
mitotically.
• The surrounding darker tumor cells are more primitive appearing with brisk
mitotic activity.
•
• Desmoplastic medulloblastoma has a better prognosis than the classic form

18. • Medulloblastoma with extensive nodularity
• M/E-
• Low power view  numerous pale islands
• The nodules are composed of a uniform population of tumor cells. The background
is reticulin-free & rich in neuropil-like tissue. Mitosis is not significantly increased.
The cells often show streaming in parallel rows

19. • Special stain-
• Reticulin-rich areas of high cellularity

20. • Anaplastic Medulloblastoma
• M/E-
• Highly anaplasticnuclei
• with high rate of mitosis &
apoptosis.
• Primitive looking cells
with nuclear molding.
• Some are
composed of large cells
with rounded vesicular nuclei
(i.e. no nuclear molding).
• Poor prognosis.

21. Molecular Pathogenesis
Genetic predisposition
(syndromes)
MOLECULAR SUBGROUPS

22. Genetic predisposition
(syndromes)
Gorlin syndrome (3-5 % MB
cases)
TURCOT SYNDROME (<1 % MB
cases)
Li-fraumeni syndrome

23. 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.
 characterized by nevoid basal cell carcinoma & skeletal
abnormalities.

24. 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.

25. LI-FRAUMENI SYNDROME
 Mutations in TP53 (17p13).
 Worse outcome.

26. MOLECULAR SUBGROUPS
MB divided into 4 groups based on:
DNA copy number,
mRNA expression profiles and
Somatic copy number aberrations.
1.SONIC HEDGEHOG (SHH) pathway
2.WINGLESS (WNT) pathway
3. TP 53 mutations
4. MYC / MYCN amplification.

27. SONIC HEDEHOG (SHH) pathway

Abnormalities in SHH pathway are present
in 30% of MB cases.
MB pathology usually desmoplastic.
SHH up-regulate MYCN gene.
Tp53 mutations are present in 10-20 % of
SHH tumours.

28. 
WINGLESS (WNT) pathway
WNT tumours are seen in children and adults.
 Rarely in infants.
It associated with the most favourable
prognosis
WNT protein binds to its receptor→
destabilizes APC protein.
Loss chromosome 6.

29. TP 53 MUTATIONS are present in 10-20% of
WNT and SHH MB and very rarely in the other
subtypes.
MYC / MYCN - amplification of MYC group
genes is associated with a worse prognosis.

30. Symptoms & signs
MB patients present with symptoms and signs of:
1. Increased intra cranial tension.
2. Cerebellar dysfunction
Weeks→ few months

31. Evaluation
History
Morning headache
Nausea & vomiting
Visual changes
Confusion
Unsteady walking

32. A combination of surgery, radiotherapy and chemotherapy
Multi modal approach
 Difference in treatment between child & adult
 Measures to alleviate increased ICP.
 Specific therapy directed against the tumour.
 Complications
 Follow up
 Treatment at relapse

33. Child Adult
Usual age ~ 4 - 8 yrs Median age ~ 24 - 30 yrs
Shorter History (~ 3 months) Longer history ( ~ 5 months)
Classical type predominates Desmoplastic type relatively
commoner
Median cerebellar syndrome
predominates
Lateral cerebellar syndrome seen
Biologically more aggressive Biologically less aggressive
Poorer resectability
(median location)
Greater resectability
(lateral location)
Higher surgical morbidity and
mortality
Lower surgical morbidity and
mortality
Poorer RT tolerance Better RT tolerance
Poorer long term survival Better long term survival
Difference in treatment between child & adult

34. 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).