Embryonal tumors of children

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. •
•
•
•
•
•
Medulloblastoma
Atypical Teratoid/ Rhabdoid Tumours
Embryonal Tumors with Multilayered Rosettes
Primitive Neuroectodermal Tumor
Pineoblastoma
Pituitary blastoma

4. MEDULLOBLASTOMA

5. 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.

6. 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.

7. 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.

8. 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

9. Natural History
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10. 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%)

12. Pathological Features
▪ Highly cellular tumor
▪ High N:C ratio
▪ Cells arranged in typical
Homer - Wright rosettes
▪ Multiple histological subtypes
4. Anaplastic
5. Large Cell
WHO classification -2007
1. Classic medulloblastomas- 70-80%
2. Desmoplastic/nodular- 7%
3. Medulloblastoma with extensive nodularity
(MBEN) - 3%
large cell / anaplastic
(LCA) 10% to 22%.

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

14. •
•
•
•
Classical Medulloblastoma.
M/E-
Highly cellular
sheets of anaplastic cells
with scanty cytoplasm,
• hyperchromatic nuclei,
that are often elongated &
crescent shaped or angulated.
•
•
Mitoses- abundant
Occasional
Homer-Wright rosettes
and perivascular
pseudorosettes

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

16. • Positive stains
• NSE, synaptophysin, Vimentin, Desmin, Nestin
• 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

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

18. 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-

19. • 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

20. 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

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

22. Anaplastic Medulloblastoma
•
•
•
•
M/E-
Highly anaplastic nuclei
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.

23. Molecular Pathogenesis
G E N E T I C P R E D I S P O S I T I O N
(S Y N D R O M E S )
M O L E C U L A R S U B G R O U P S

24. G E N E T I C P R E D I S P O S I T I O N
(S Y N D R O M E S )
S Y N D R O M E (3- 5 % M B
S Y N D R O M E (<1 % M B
■G O R L I N
C A S E S )
■T U R C O T
C A S E S )
■ L I - F R A U M E N I S Y N D R O M E

25. 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.

26. 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.

27. LI-FRAUMENI SYNDROME
❖ Mutations in TP53 (17p13).
❖ Worse outcome.

28. M O L E C U L A R S U B G R O U P S
❖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.

29. 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.

30. 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.

31. ❖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.

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

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

34. A combination of surgery, radiotherapy and chemotherapy
Multi modal approach

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

36. Treatment at relapse
❖Relapse occurs in 20 - 30 % following initial treatment.
❖Site of relapse:
Local→ 1/3 cases
Disseminated (brain and spine)→ 1/3 cases
Both local and disseminated (brain and spine)→ 1/3
❖Time: within 3 years (children) but late relapse in (adults).

37. Collin’s Law states :
• The period of risk for recurrence of embryonal chilhood
neoplasms = age of patient at diagnosis + 9 months.

38. Atypical teratoid / rhabdoid tumor
•
•
•
•
•
•
•
•
•
Comprise 1-2% of all CNS tumours in childhood.
M:F – 1.9:1
Biallelic mutations in the SMARCB1 gene(encodes for INI1)
Infants and young children (mean age 17 months)
Tumours of cerebellum or CP angle
Usually supratentorial (cerebral or suprasellar)
Poor prognosis- Metastatic d/s and young age
Very aggressive with mean survival 11 months post-surgery
Metastasizes throughout CSF.

39. •Large and pleomorphic
rhabdoid cells with
abundant eosinophilic
cytoplasm, often
filamentous cytoplasmic
inclusions and vacuoles
•Eccentric round nuclei
and prominent nucleolus
•May have mucinous
background
•May have epithelioid
features with poorly
formed glands or Flexner-
Wintersteiner rosettes

42. CYTOLOGY DESCRIPTION
•Cells are large, round and plasmacytoid or rhabdoid
•Also small, round, primitive, neural type cells with high N/C
ratio
•Apoptotic bodies, mitotic figures, marked necrosis
•Variable dystrophic calcification

43. GFAP
EMA VIMENTIN
POSITIVE STAINS
Vimentin, EMA, smooth
muscle actin
Cytokeratin, neurofilament
Focal GFAP, variable
synaptophysin and
chromogranin

44. DIFFERENTIAL DIAGNOSIS
•Choroid plexus carcinoma
•Composite rhabdoid tumors (with other component,
usually INI1+)
•Ependymoma
•Occasional germ cell tumors
•PNET/medulloblastoma

45. SUPRATENTORIAL PRIMITIVE
NEUROECTODERMAL TUMOR
•Rare tumor, usually cerebral hemisphere
•Medulloblastoma like histology
•Disseminate along CSF pathway
•Usually infants and children
•Uniformly small and densely hyperchromatic cells
of entirely undiff appearance disposed in
patternless sheets
•Desmoplastic mesenchymal components, high
mitotic rates, necrosis and cystic change.

46. Small blue cell tumor
with round,
hyperchromatic cells,
abundant mitotic
figures and fibrosis

47. With abundant neuropil and true rosettes.

48. POSITIVE STAINS
CD99 (strong membrane staining)
Focal GFAP
DIFFERENTIAL DIAGNOSIS
Anaplastic glioma
Atypical teratoid/rhabdoid tumor
Central PNET/medulloblastoma
Lymphoma
Melanoma
Rhabdomyosarcoma
Small cell meningioma

49. EMBRYONAL TUMOURS WITH MULTILAYERED
ROSETTES
•Amplification of a miRNA on chromosome 9(C19MC)
and over expression of the RNA binding protein
LIN28a.
•“Embryonal tumours with abundant neurophil and true
rosettes (ETANTR)”
•Ependymomatous rosettes- Multilayered cells
surrounding a lumen, patches of dense cellularity and
areas of more differentiated tumour with abundant
neurophil.
•Poor prognosis with early progression of disease and
death.

50. Ependymomatous
rosettes-
Multilayered cells
surrounding a
lumen, patches of
dense cellularity and
areas of more
differentiated tumour
with abundant
neurophil

51. LIN28A immunohistochemistry of
ETANTR
FISH analysis the C19MC 19q13.42
probe (green signals)

52. PINEOBLASTOMA
•High Grade IV of IV
•Second most common pineal gland tumor
after germ cell tumor
•Germ line mutations in either RB gene or
DICER1
•Presents with signs related to location of the
tumour in the upper midbrain, with
Parinaud’s syndrome (failure of up-gaze,
pupils that react poorly to light but
respond to accomodation, nystagmus
and lid retraction)

53. •Hydrocephalus- main presenting complaint
•Usually < 20 years
•Frequent CNS metastases or spinal seeding - main
cause of death
•5 year survival approx. 58%
•Poor prognostic factors:
7+ mitotic figures/10 HPF
Presence of necrosis
No neurofilament staining

54. Dense small nuclei and scant cytoplasm Homer-Wright
rosettes
Sheets of cells with high grade (anaplastic /
undifferentiated) features including high N/C ratio with
minimal cytoplasm and large hyperchromatic nuclei
•Necrosis, mitotic figures
•Homer-Wright or Flexner-Wintersteiner rosettes

55. Small blue cell neuroepithelial
malignant tumor

56. Positive stains
NSE, synaptophysin, retinal S-antigen
Differential diagnosis
Glial neoplasms: GFAP+
Medulloblastoma
Pineocytoma: better differentiated cells with more
cytoplasm, smaller cells, no/rare mitotic figures

57. PITUITARY BLASTOMA
•First 2 years of life with Cushing’s syndrome with
ophthalmoplegia
•Histopathology- Combi. of epithelial structures,
small embryonal cells and secretory cells.
•Express synaptophysin and chromogranin
•High frequency of germ line DICER1 mutations

58. THANK YOU