latest who classification of embryonal tumors

1. EMBRYONAL BRAIN
TUMORS IN CHILDREN
MODERATOR: Dr Manasa R
PRESENTER: Dr Syeda Khadija
Fatima,final yr post graduate

2. INTRODUCTION
• 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
• Embryonal tumors account for a large fraction of pediatric
brain tumors.
• The tendency for these neoplasms to disseminate through
cerebrospinal fluid (CSF) was believed to contribute to a
poor outcome
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3. EMBRYONAL TUMOURS
Medulloblastoma
• Desmoplastic/nodular
medulloblastoma
• Medulloblastoma with
extensive nodularity
• Anaplastic
medulloblastoma
• Large cell
medulloblastoma
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2007 WHO CLASSIFICATION
CNS primitive
neuroectodermal tumour
•CNS Neuroblastoma
•CNSGanglioneuroblastoma
•Embryonal tumor with
abundant neuropil and true
rosettes (ETANTR)
• Ependymoblastoma
•Medulloepithelioma
Atypical teratoid / rhabdoid
tumour

4. CHALLENGES OF STRATIFIED MEDICINE
FOR CHILDREN
• 40% of children with CNS tumors are under 5 yrs of age and
are exposed to deleterious effects of the chemotherapy and
radiotherapy (esp –long term disabilities)
• Challenge is to differentiate those children who are at low
risk and modify therapy in them sparing them of the
deleterious effects
• Risk stratification : AGE,STAGE,HISTOLOGY AND
MOLECULAR FEATURES.
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5. ‘ISN-Haarlem Guidelines 2014
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1. Diagnostic entities should be defined as narrowly as possible
to optimize interobserver reproducibility, clinicopathological
predictions and therapeutic planning (avoid waste baskets!)
2. Diagnosis should be “layered” with histologic classification,
WHO grade and molecular information as “integrated
diagnosis”
3.Entity-specific molecular testing and reporting formats should
be followed in diagnostic reports

6. 10/3/2018 6
2016 WHO CLASSIFICATION
Embryonal tumors
Medulloblastomas, genetically defined
Medulloblastoma, WNT-activated
Medulloblastoma, SHH-activated and TP53-mutant
Medulloblastoma, SHH-activated and TP53-wildtype
Medulloblastoma, non-WNT/non-SHH
Medulloblastoma, group 3
Medulloblastoma, group 4
Medulloblastomas, histologically defined
Medulloblastoma, classic
Medulloblastoma, desmoplastic/nodular
Medulloblastoma with extensive nodularity
Medulloblastoma, large cell / anaplastic
Medulloblastoma, NOS
Embryonal tumour with
multi-layered rosettes,
C19MC-altered
Embryonal tumour with multi-
layered rosettes, NOS
Medulloepithelioma
CNS neuroblastoma
CNS ganglioneuroblastoma
CNS embryonal tumour, NOS
Atypical teratoid/rhabdoid
tumour
CNS embryonal tumour with
rhabdoid features

7. • The origin of Medulloblastoma is from medulla (Latin for
marrow), blastos (Greek word for germ) and oma(Greek
for tumor)
• Most common malignant primary brain tumor of child age
group.
• First described by Harvey Cushing and Percival Bailey in
1930.
• HISTOGENESIS: Embryonal cells known as
medulloblast of cerebellar stem cells in subependymal
matrix/ Germinative neuroepithelial cells in the external
granular layer of cerebellum.
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MEDULLOBLASTOMA

8. • ~ 7% all brain tumors
• 10-20% of brain tumors in
pediatric age group
• 0.4%–1% of all adult CNS
tumors
• 40% of tumors of the
posterior fossa
• Peaks in 7 yrs In children
• Approximately 17% of
Medulloblastoma present
in infants younger than 16
years old;
• male : female (3:2)
Figure: Distribution of pediatric central
nervous system (CNS) tumors by location in
the CNS and by tumor type.
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EPIDEMIOLOGY

9. ETIOLOGY
• Germline mutation of a tumor-suppressor gene, such as in
Gorlin’s syndrome –PTCH gene , Turcot’s syndrome-APC
gene, Li-Fraumeni syndrome-Tp53 gene
• Environmental exposures to JC and SV40 viruses.
• Maternal diet deficient of folate, consumption of cured
meats and exposure to N-nitrosocompounds
• Children born before term (standardized incidence ratio
3.1)10/3/2018 9

10. NATURAL HISTORY
Arising 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
10
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• Floor of fourth ventricle
• Ant- Brain Stem
• Inf –Cervical Spine
• Sup- Above Tentorium
CONTAGIOUSLY
• Intracranially
• Leptomeninges
• Spinal cord
CSF(30%)
• Hematogenous
• MC sites are Long Bones and
Ribs(10-15%)
• LN(4-6%)
EXTRANEURAL(5%)
Most common CNS
tumor to spread
MODE OF SPREAD

12. CLINICAL FEATURES AND IMAGING STUDIES
1. Truncal ataxia
2. Disturbed gait
3. Intracranial hypertension-Obstruction of CSF-flow
4. Headache and morning vomiting.
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CTMRI

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GROSS

14. HISTOLOGICAL VARIANTS OF MEDULLOBLASTOMA
1. Classic medulloblastomas- 70-80%
2. Desmoplastic/nodular- 7%
3. Medulloblastoma with extensive
nodularity (MBEN) - 3%
4. Anaplastic
5. Large Cell
large cell / anaplastic
(LCA) 10% to 22%.
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15. CLASSICAL MEDULLOBLASTOMA
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Homer-Wright rosettes (groups of tumor cells arranged in a circle around a
fibrillary center). Similar rosettes are seen in adrenal neuroblastoma.
Spongioblastic features, characterized by tumour cell nuclei arranged with
their long axes in parallel, can be encountered.

16. • Most common differentiation is neuronal.
• Glial differentiation is unusual, and takes the form of
scattered small groups of cells with an astrocytic phenotype
• Vascular hyperplasia as exemplified by the glomeruloid
neovascularization of high-grade gliomas is rare
• Areas of necrosis are quite uncommon, but when present
necrotic zones may show pseudopalisading similar to that
observed in glioblastomas
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17. 10/3/2018 17
DESMOPLASMIC/NODULAR
MEDULLOBLASTOMA

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18

19. MEDULLOBLASTOMA WITH EXTENSIVE
NODULARITY
• The medulloblastoma with extensive nodularity, which was
previously designated “cerebellar neuroblastoma”, occurs in
infants
• Expanded lobular architecture, due to the fact that the
reticulin-free zones become unusually enlarged and rich in
neuropil-like tissue
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20. 10/3/2018 20
MEDULLOBLASTOMA WITH EXTENSIVE
NODULARITY
MEDULLOBLASTOMA WITH EXTENSIVE
NODULARITY

21. ANAPLASTIC MEDULLOBLASTOMA
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22. 10/3/2018
22
IMMUNOHISTOCHEMISTRY
Medulloblastoma. A Focal expression of synaptophysin. B Focal GFAP staining
of tumour cells. C Clusters of medulloblastoma cells expressing retinal S-
antigen.
(B) anti-fast-myosin immunostaining of highly differentiated, striated myogenic cells
and (C) biphasic pattern of small undifferentiated medulloblastoma cells and large
rhabdomyoblasts immunostaining for myoglobin.

23. MOLECULAR / CYTOGENETICS
Hall mark !!
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POOR
PRONOSIS

24. MB divided into 4 groups
1.SONIC HEDGEHOG (SHH) pathway
2.WINGLESS (WNT) pathway
3. TP 53 mutations
4. MYC / MYCN amplification.
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WHO 2016-MOLECULAR SUBGROUPS

25. 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.
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26. WINGLESS (WNT) pathway
WNT tumours are seen in children and adults.
It associated with the most favourable prognosis -
CLASSIC
WNT protein binds to its receptor→ destabilizes APC
protein.
Loss chromosome 6.
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27. TP 53 MUTATIONS are present in 10-20% of WNT and
SHH MB and very rarely in the other subtypes.
MYC / MYCN and isochromosome 17q - MYCC
amplification associated with a worse prognosis.
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28. 10/3/2018 28
WNT SHH Group 3 Group 4
Age at
presentation
Childhood Infancy;
adulthood
Childhood Childhood
Pathology Classic; Desmoplastic/
Extensive
nodular
Large cell/
anaplastic
classic
Large cell/
Anaplastic
classic
Prognosis Very good
>90% long-term
survival
Good to
intermediate
Poor Intermediate
Genetics CTNNB1 (β-
catenin)
mutations;
monosomy 6; APC
germline mutations
(Turcot
syndrome)
PTCH gene
mutation
(germline
PTCH
mutation=
Gorlin
syndrome)
MYC ampl CDK6
amplification;
isochromoso
me 17q;
loss of X
chromosome

29. 10/3/2018 29
Immunostaining Nuclear β-
catenin
staining;
DKK1
positive
GAB1
positive,
SFRP1
positive
KCNA1
% of all
medulloblastoma
7-8% 28-32% 26-27% 34-38%
Treatment ? therapy
de-
escalation
Can treat
with
SMO
inhibitors

30. 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 multiple basal cell carcinoma of skin
,odontogenic keratocysts, skeletal abnormalities and
medulloblastoma
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GENETIC PREDISPOSITION (SYNDROMES)

31. TURCOT SYNDROME TYPE 2
Brain tumour (MB) & familial adenomatous polyposis
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
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LI-FRAUMENI SYNDROME
 Mutations in TP53 (17p13).
 Worse outcome.

32. 1. Lymphoma :perivascular infiltration,no rossettes or
nodules,LCA +
2. Atypical teratoid / Rhabdoid tumor-IHC INI 1 neg
3. PNET-EWS-FL11 fusion gene FISH
4. Ependymoma-perivascular pseudo
rosettes,Synaptophysin neg
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DIFFERENTIAL DIAGNOSIS

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
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
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34. TREATMENT AT RELAPSE
Collin’s Law states :
The period of risk for recurrence of embryonal chilhood
neoplasms = age of patient at diagnosis + 9 months.
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
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35. •Rare tumor, WHO grade IV. usually cerebral hemisphere
•WHO 2007
CNS PNET
CNS neuroblastoma
CNS ganglioneuroblastoma
ETANTR
Medulloepithelioma
Ependymoblastoma
• RE-CLASSIFIED:WHO 2016- EMBRYONAL TUMOR WITH
MULTILAYERED ROSETTES
SUPRATENTORIAL PRIMITIVE
NEUROECTODERMAL TUMOR
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36. CLINICAL FEATURES AND IMAGING STUDIES
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• Cerebrum -seizures,
disturbances of
consciousness,increased
intracranial pressure or motor
deficit.
• Suprasellar-visual and/or
endocrine problems.

37. • Amplification of a miRNA on chromosome 9(C19MC) and
over expression of the RNA binding protein LIN28a.
• Includes Embryonal tumours with abundant neuropil and
true rosettes (ETANTR)”/ EPENDYMOBLASTOMA /
MEDULLOEPITHELIOMA.
•Poor prognosis with early progression of disease and death.
EMBRYONAL TUMOURS WITH
MULTILAYERED ROSETTES
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In the absence of C19MC amplification- ETANTR/ ETMR
should be diagnosed as embryonal tumor with
multilayered rosettes, NOS

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

39. 10/3/2018 39
CENTRAL NEUROBLASTOMACENTRAL GANGLIONEUROBLASTOMAEPENDYMOBLASTOMA
MEDULLOEPITHELIOMA
NESTIN EXPRESSION IN MEDULLOEPITHELIOMA

40. Cytoplasmic expression of
LIN28A immunohistochemistry of
ETANTR
Amplification of C19MC
19q13.42 locus by FISH
probe (green signals)
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41. 1. Central neurocytoma-lacks multilayered rosettes
2. Anaplastic Ependymoma-less cellular, No C19MC
ampl, pseudovascular rosettes
3. Peripheral PNET – CD99 +, EWS-FL11 Fusion gene
on FISH
4. Lymphoma-No rosettes,LCA+
5. Small cell Melanoma-HMB45+
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DIFFERENTIAL DIAGNOSIS

42. ATYPICAL TERATOID / RHABDOID TUMOR
• Comprise 1-2% of all CNS tumours in childhood.20%<3 yrs
M:F – 1.6-2:1
• Biallelic mutations in the SMARCB1 gene(encodes for INI1)
• Infratentorially- Most common,Young children-cerebellar
hemispheres, cerebellopontine angle and brain stem
• Supratentorially-cerebral hemispheres mostly
• HISTOGENESIS:Pleuripotent fetal cells/neural crest cells
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43. CLINICAL FEATURES AND IMAGING STUDIES
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 Infants-lethargy, vomiting or
failure to thrive, Head tilt and
cranial nerve palsy(6,7)
 Children older than three years-
Headache and hemiplegia.
 Infants and young children
(mean-17 months) and
metastatic disease–Poor
prognosis

44. RHABDOID TUMOUR PREDISPOSITION
SYNDROME
• Constitutional loss or inactivation of one allele of the INI1
gene.
• A disorder characterized by a markedly increased risk to
develop malignant rhabdoid tumours (MRTs)
• Other CNS tumours that have been reported to be
associated with the RTPS include choroid plexus
carcinoma, medulloblastoma, and supratentorial primitive
neuroectodermal tumour
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45. GROSS
• Soft, pinkish-red
• and bulky, and often
appear to be
• demarcated from
adjacent parenchyma.
• They typically contain
necrotic foci and
• may be haemorrhagic.
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46. 10/3/2018 46
HISTOPATHOLOGY

47. CYTOLOGY
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48. 10/3/2018 48
IMMUNOHISTOCHEMISTRY

49. 1. Choroid plexus carcinoma-CK+, EMA-
2. Composite rhabdoid tumors (with other component,
usually INI1+)
DIFFERENTIAL DIAGNOSIS
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If a tumor has histological features of AT/RT but NO
diagnostic genetic alterations, then diagnose it as CNS
embryonal tumour with rhabdoid features (WHO-2016)

50. •A highly malignant primitive embryonal tumour (WHO grade
IV) 40% of pineal parenchymal tumors
•2nd most common pineal gland tumor after germ cell tumor
•Germ line mutations in either RB gene or DICER1
•HISTOGENESIS: arise from cells of developing human
pineal gland and retina
•Express synaptophysin and chromogranin
PINEOBLASTOMA
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51. CLINICAL FEATURES AND IMAGING STUDIES
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• Usually < 20 years
• Hydrocephalus- main presenting
complaint
• Perinauds syndrome
• Frequent CNS metastases or
spinal seeding - main cause of
death
• 5 year survival approx. 58%

52. GROSS
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Soft ,
friable,poorly
demarcated
with areas of
necrosis and
heamorrhages

53. 10/3/2018 53
HISTOPATHOLOGY

54. Dense small nuclei and scant cytoplasm
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CYTOLOGY

55. •Poor prognostic factors:
7+ mitotic figures/10
HPF
Presence of necrosis
No neurofilament
staining
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56. POSITIVE STAINS
NSE, synaptophysin, retinal S-antigen
DIFFERENTIAL DIAGNOSIS
1. Glial neoplasms: GFAP+
2. Medulloblastoma
3. Pineocytoma: better differentiated cells with more
cytoplasm, smaller cells, no/rare mitotic figures
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57. SUMMARY
• Brain tumors are the most common malignancy related
cause of death in children.
• Molecular and pathological stratification is critical in
determining the type and intensity of treatment.
• Medulloblastoma, can be stratified on the basis of
histological and molecular subtyping, in to high risk
(anaplastic/large cell,MYC/MYCN amplified) and low
risk(WNT)
• Classification of other embryonal tumor types by molecular
approach is defining new subtypes with distinct clinical
outcomes.
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58. REFERENCES
1. Juan Rosai ,Rosai and Ackerman’s Surgical pathology ,10th
ed,Vol2,©2004 ; Elsevier’s Inc. Ch 28 Central Nervous system :
pg 2377-2384.
2. Ivan Damjanov,James Lindar, Anderson’s pathology,10th ed,Vol-
4,©2004 ; Mosby Publishers. Ch 77 Central Nervous system : pg
2755-2758.
3. WHO Classification of Tumours of the Central Nervous System
,© International Agency for Research on Cancer, 2007 ;Chapter
8-Embryonal tumors:pg132-149.
4. David N. Louis et al , The 2016 World Health Organization
Classification of Tumors of the Central Nervous System: a
summary, Acta Neuropathol ,2016;131:803–820.
5. Roger E. McLendon et al,Embryonal Central Nervous System
Neoplasms Arising in Infants and Young Children A Pediatric
Brain Tumor Consortium Study , Arch Pathol Lab Med ,
2011;135:984–993.10/3/2018 58