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Embryonal Tumors
Institute of Neuropathology
Brain Tumor Reference Center
Torsten Pietsch
European Congress of Pathology, Amsterdam, September 5, 2017
Revision of the WHO classification
2007 2016
The “M&M“ future of brain tumor classification:
A smart synthesis of Morphological and Molecular informationThe future of (neuro)pathology
Smart synthesis of morphological and molecular information!
TCGA Research Network et al.
Nature Genetics 2013;45:1113
WHO‘s next ?Integration of histological and molecular information
WHO‘s next ?Integration of histological and molecular information
Louis et al., Brain Pathol, 2014
Layer 1: Integrated diagnosis (incorporating all
tissue-based information)
Layer 2: Histopathological diagnosis
Layer 3: Histopathological grade (WHO grade)
Layer 4: Molecular Information
Proposed multilayered diagnosis format:
WHO 2007 Embryonal Tumor Classification
Medulloblastoma
Medulloblastoma (classic) 9470
Desmoplastic/Nodular MB 9471
MB with extensive nodularity 9471
Anaplastic MB 9474
Large cell MB 9474
CNS-PNET
CNS PNET NOS 9473
CNS Neuroblastoma 9500
CNS Ganglioneuroblastoma 9490
Ependymoblastoma 9392
Medulloepithelioma 9501
AT/RT 9508
Embryonal Tumors
Medulloblastoma, genetically definedMedulloblastoma, WNT-activatedMedulloblastoma, SHH-activated, TP53 mutated Medulloblastoma, SHH-activated, TP53 wild-type Medulloblastoma, non-WNT/non-SHH
Medulloblastoma, Group 3 Medulloblastoma, Group 4
Medulloblastoma, histologically definedMedulloblastoma, classicMedulloblastoma, desmoplastic/nodularMedulloblastoma with extensive nodularityMedulloblastoma, large cell/anaplastic
Medulloblastoma, NOS
Embryonal tumour with multilayered rosettes, C19MC AlteredEmbryonal tumour with multilayered rosettes, NOSMedulloepitheliomaCNS NeuroblastomaCNS GanglioneuroblastomaCNS Embryonal tumour, NOS
Atypical teratoid/rhabdoid tumourCNS Embryonal tumour with rhabdoid features
WHO classification 2016
Embryonal Tumors
Medulloblastoma, genetically definedMedulloblastoma, WNT-activatedMedulloblastoma, SHH-activated, TP53 mutated Medulloblastoma, SHH-activated, TP53 wild-type Medulloblastoma, non-WNT/non-SHH
Medulloblastoma, Group 3 Medulloblastoma, Group 4
Medulloblastoma, histologically definedMedulloblastoma, classicMedulloblastoma, desmoplastic/nodularMedulloblastoma with extensive nodularityMedulloblastoma, large cell/anaplastic
Medulloblastoma, NOS
Embryonal tumour with multilayered rosettes, C19MC AlteredEmbryonal tumour with multilayered rosettes, NOSMedulloepitheliomaCNS NeuroblastomaCNS GanglioneuroblastomaCNS Embryonal tumour, NOS
Atypical teratoid/rhabdoid tumourCNS Embryonal tumour with rhabdoid features
WHO classification 2016
Deletion of the SMARCB1 locus on chromosome 22
SmarcB1
- Immunohistochemistry: loss of SMARCB1 gene product
Diagnosis: Atypical Teratoid-/Rhabdoid Tumor (WHO grade IV)
New AT/RT Classification (WHO 2016)
• Diagnosis of atypical teratoid/rhabdoid tumourrequires demonstration of inactivation of SMARCB1/INI1 or, if intact, SMARCA4/BRG1 genes by either routine immunohistochemical staining for the proteins or other appropriate means.
• Tumours lacking this molecular genetic confirmation should be designated as embryonal CNS tumours with rhabdoid features
Vimentin EMA
Cytokeratin Ini-1
Embryonal Tumors
Medulloblastoma, genetically definedMedulloblastoma, WNT-activatedMedulloblastoma, SHH-activated, TP53 mutated Medulloblastoma, SHH-activated, TP53 wild-type Medulloblastoma, non-WNT/non-SHH
Medulloblastoma, Group 3 Medulloblastoma, Group 4
Medulloblastoma, histologically definedMedulloblastoma, classicMedulloblastoma, desmoplastic/nodularMedulloblastoma with extensive nodularityMedulloblastoma, large cell/anaplastic
Medulloblastoma, NOS
Embryonal tumour with multilayered rosettes, C19MC AlteredEmbryonal tumour with multilayered rosettes, NOSMedulloepitheliomaCNS NeuroblastomaCNS GanglioneuroblastomaCNS Embryonal tumour, NOS
Atypical teratoid/rhabdoid tumourCNS Embryonal tumour with rhabdoid features
WHO classification 2016
ETMR
EpendymoblastomaWHO 2007
Definition:
A rare malignant, embryonal tumour manifesting in neonates and young children, histologically characterized by
distinctive multilayered rosettes
Eberhart et al., Pediatr. Dev. Pathol., 2000Gessi et al., Am. J. Surg Pathol., 2009
Embryonal tumor with abundant neuropil and true rosettes (ETANTR)
> a novel entity ??
ETANTR
Ependymoblastoma
Medulloepithelioma
Ependymoblastoma (WHO 2007)ETANTR (Embryonal Tumor with abundant neuropil and true rosettes)
ETANER (......ependymoblastic rosettes)ETMR (... multilayered rosettes)
Group 1 CNS-PNET…
Ependymoblastoma (WHO 2007)ETANTR (Embryonal Tumor with abundant neuropil and true rosettes)
ETANER (......ependymoblastic rosettes)ETMR (... multilayered rosettes)
Group 1 CNS-PNET…
Voting of theexperts:
ETMR (Embryonal Tumor with multilayered rosettes), C19MC altered
Amplification of a microRNA cluster on chromosome 19q13.42
FISH
MIP
Amplification of a microRNA cluster on chromosome 19q13.42
LIN28
WHO 2007 > WHO 2016
CNS-PNET
CNS PNET NOS 9473 CNS Embryonal tumour, NOS
CNS Neuroblastoma 9500 CNS Neuroblastoma
CNS Ganglioneuroblastoma 9490 CNS Ganglioneuroblastoma
Ependymoblastoma 9392 ETMR, C19MC Altered
ETMR, NOS
Medulloepithelioma 9501 Medulloepithelioma *
*w/o CH19MC alteration
CNS (Ganglio)neuroblastoma
Sturm et al. Cell 2016
WHO 2007 > WHO 2016
CNS-PNET CNS Embryonal tumor
CNS PNET NOS 9473 CNS Embryonal tumour, NOS
CNS Neuroblastoma 9500 CNS Neuroblastoma
CNS Ganglioneuroblastoma 9490 CNS Ganglioneuroblastoma
Ependymoblastoma 9392 ETMR, C19MC Altered
ETMR, NOS
Medulloepithelioma 9501 Medulloepithelioma *
*w/o CH19MC alteration
Most frequent malignant brain tumor
of childhood
age: 0-40 J, peak at 7 years
Localization: Cerebellum
Anamnesis: short
Symptoms: Brain pressure, cerebellar symptoms
approx. 25% c.s.f. seeding at diagnosis
Therapy: OP, chemotherapy, irradiation
Prognosis: 50-60 % long-term survivors
Medulloblastoma
WHO 2007 Embryonal Tumor Classification
Medulloblastoma
Medulloblastoma (classic) 9470
Desmoplastic/Nodular MB 9471
MB with extensive nodularity 9471
Anaplastic MB 9474
Large cell MB 9474
CNS-PNET
CNS PNET NOS 9473
CNS Neuroblastoma 9500
CNS Ganglioneuroblastoma 9490
Ependymoblastoma 9392
Medulloepithelioma 9501
AT/RT 9508
Large cell medulloblastoma Anaplastic medulloblastoma
- Mixed forms with both components occur.- Both variants are related to worse prognosis.
> WHO 2016: simplified category: Large cell/anaplastic MB
Progenitor cells
classic MB MB with extensive nodularity
Desmoplastic/nodular MB
WNT activation
Mutation CTNNB1
Monosomy 6
Hedgehog activation
Mutation PTCH1, SUFU, SMO
LOH 9q, LOH 10q
Loss 17p
Gain 17q
others
myc amplification
others
EGLventricular
matrix
large cell MB / anaplastic MB
cpa /midline
tumorshemispheric or
midline tumors
lower rhombic lip
MycN-GLI2 amplif.
loss TP53
classic MB
“Medulloblastoma“ represents five different diseases
midline
tumors
Medulloblastoma, histologically defined
Medulloblastoma, classicMedulloblastoma, desmoplastic/nodularMedulloblastoma with extensive nodularityMedulloblastoma, large cell/anaplastic
Medulloblastoma, genetically defined
Medulloblastoma, WNT-activatedMedulloblastoma, SHH-activated, TP53 mutated Medulloblastoma, SHH-activated, TP53 wild-type Medulloblastoma, non-WNT/non-SHH
Medulloblastoma, Group 3*Medulloblastoma, Group 4*
Medulloblastoma, NOS
* provisional variants
WHO Classification 2016
ß-catenin in the wnt signaling pathway
20-1571 (mutated) 60-221 (wt control)
-catenin nuclear accumulation
PNET 3 trial:
27 out of 109 non-nodular/desmopl. MBs (25%)show nuclear ß-catenin staining
5y OS 92.3 % vs. 65.3 % (p= .0015)
Standard Risk:Standard Therapy
Low Risk:Reduced Therapy
High Risk: Maximal /
novel Therapies
SURGERY
Histology
+
MolecularPhenotype
+
ClinicalFactors
PNET5 Medulloblastoma Stratification
3 weeks
WNT medulloblastomas frequently show monosomy 6
Integrated diagnosis
Integrated Diagnosis
Histological Classification Classic medulloblastoma
WHO Grade IV
Molecular Information pending
Integrated diagnosis
Integrated Diagnosis Classic medulloblastoma, WNT activated, WHO grade IV
Histological Classification
Classic medulloblastoma
WHO Grade IV
Molecular Information CTNNB1 exon 3 mutated, monosomy 6
Pietsch et al., Acta NP 2014
Smoh
MycN
PTCH
GLI1
Ptch
Hh
Costal-2
Su(Fu) Fused
Gli
Activation of Shh Signalling by Mutations in Medulloblastomas
Progression-free Survival among 23 Children with Classic and 20 Children with Desmoplastic Medulloblastoma.
Rutkowski S et al. N Engl J Med 2005;352:978-986.
Kinases
TrkA TrkB TrkC
NGF BDNF NT3
p75NTR
Death domain
NTs
Neuronal death (Apoptosis) Neuronal survival
p75-NTR is a SHH target and expressed in cerebellar progenitor cells and desmoplastic type medulloblastomas
Bühren et al., JNEN 2000, Küchler et al., IJC 2011
Immunohistochemistry for absence and presence of Shh and Wnt activation
• anti- ß-catenin (nuclei positive in Wnt MBs)• anti- YAP1 (nuclei positive in Wnt and Shh MBs)• anti- p75 NGFR / GAB1 (positive in Shh MBs)
Classification of medulloblastomas using immunohistochemistry
anti-ß-Catenin anti-Yap1 anti-p75 NGFR anti-Otx2
+ + +
+ + -
--
-
-
- +
Can the “4 biological subgroup“ model used for clinical decision making ?
Taylor et al., Acta NP, 2012
Progenitor cells
classic MB MB with extensive nodularity
Desmoplastic/nodular MB
WNT activation
Mutation CTNNB1
Monosomy 6
Hedgehog activation
Mutation PTCH1, SUFU, SMO
LOH 9q, LOH 10q
Loss 17p
Gain 17q
others
myc amplification
others
EGLventricular
matrix
large cell MB / anaplastic MB
cpa /midline
tumorshemispheric or
midline tumors
lower rhombic lip
MycN-GLI2 amplif.
loss TP53
classic MB
“Medulloblastoma“ represents five different diseases
midline
tumors
Anaplastic medulloblastoma with p53 accumulation:
Indication of possible Li-Fraumeni syndrome
p53
Chromotripsis of chromosome 13
SHH-p53 genomic instability
Histological features: focal/diffuse anaplasia, desmoplasia, p53 accumulation
Medulloblastoma, histologically defined
Medulloblastoma, classicMedulloblastoma, desmoplastic/nodularMedulloblastoma with extensive nodularityMedulloblastoma, large cell/anaplastic
Medulloblastoma, genetically defined
Medulloblastoma, WNT-activatedMedulloblastoma, SHH-activated, TP53 mutated Medulloblastoma, SHH-activated, TP53 wild-typeMedulloblastoma, non-WNT/non-SHH
Medulloblastoma, Group 3 Medulloblastoma, Group 4
Medulloblastoma, NOS
WHO Classification 2016
Do methylation / expression groups represent disease entities ?
Taylor et al., Acta NP, 2012
Pietsch et al., Acta NP 2014
Group 3 / Group 4 subgroups are overlapping and confluent variantsof non-WNT/non-SHH medulloblastomas
Northcott et al., Nature 2017
Medulloblastoma, histologically defined
Medulloblastoma, classicMedulloblastoma, desmoplastic/nodularMedulloblastoma with extensive nodularityMedulloblastoma, large cell/anaplastic
Medulloblastoma, genetically defined
Medulloblastoma, WNT-activatedMedulloblastoma, SHH-activated, TP53 mutated Medulloblastoma, SHH-activated, TP53 wild-type Medulloblastoma, non-WNT/non-SHH
Medulloblastoma, Group 3*Medulloblastoma, Group 4*
Medulloblastoma, NOS* provisional variants
WHO Classification 2016
Survival analysis – expression/methylation groupsRNA sequencing – HIT series
Survival Analysis - Expression Groups
Years
0 2 4 6 8 10 12
Overa
ll S
urv
ival
0,0
0,2
0,4
0,6
0,8
1,0 WNT
SHH
Grp4
Grp3
Survival analysis – expression/methylation groups
Survival Analysis - Expression Groups
Years
0 2 4 6 8 10 12
Overa
ll S
urv
ival
0,0
0,2
0,4
0,6
0,8
1,0
Survival Analysis - Expression groups / MYC amplification
Years
0 2 4 6 8 10 12
Ove
rall
Su
rviv
al
0,0
0,2
0,4
0,6
0,8
1,0
c-MYC amplified
Biomarkers
- diagnostic
- prognostic
- predictive
Taylor et al., Acta NP, 2012
Consensus expression / methylation subgrouping 2012
Progenitor cells
classic MB MB with extensive nodularity
Desmoplastic/nodular MB
WNT activation
Mutation CTNNB1
Monosomy 6
Hedgehog activation
Mutation PTCH1, SUFU, SMO
LOH 9q, LOH 10q
Loss 17p
Gain 17q
others
myc amplification
others
EGLventricular
matrix
large cell MB / anaplastic MB
midline
tumorshemispheric or
midline tumors
lower rhombic lip
MycN-GLI2 amplif.
loss TP53
cerebello-
pontine
angle
classic MB
Medulloblastoma entities – WHO 2016
Medulloblastoma, histologically defined
Medulloblastoma, classicMedulloblastoma, desmoplastic/nodularMedulloblastoma with extensive nodularityMedulloblastoma, large cell/anaplastic
Medulloblastoma, genetically defined
Medulloblastoma, WNT-activatedMedulloblastoma, SHH-activated, TP53 mutated Medulloblastoma, SHH-activated, TP53 wild-type Medulloblastoma, non-WNT/non-SHH
Medulloblastoma, Group 3 Medulloblastoma, Group 4
Medulloblastoma, NOS
>>> Integrated diagnosis !!
WHO Classification 2016
Medulloblastoma, histologically defined
Medulloblastoma, classicMedulloblastoma, desmoplastic/nodularMedulloblastoma with extensive nodularityMedulloblastoma, large cell/anaplastic
Medulloblastoma, genetically defined
Medulloblastoma, WNT-activatedMedulloblastoma, SHH-activated, TP53 mutated Medulloblastoma, SHH-activated, TP53 wild-type Medulloblastoma, non-WNT/non-SHH
Medulloblastoma, Group 3 Medulloblastoma, Group 4
WHO Classification 2016
>> To diagnose medulloblastoma according to WHO-Classifikation 2016,
1) WNT- and SHH-activated tumors have to be identified,
2) in SHH-activated tumors, TP53 mutational status must be determined.
Thank you !