What clinicians need to know about the WHO classification 2021
H.K. Ng, Department of Pathology
Chinese University of Hong Kong
Full ppt at http://www.acp.cuhk.edu.hk/hkng/
Disclaimers
WHO is slow…….. We are probably already out of date
Not happy faces !!
A few not fully alert
Consensus meetings of the Twelve, August 2020 – so we are definitely out of date already
Some general changes
Adult diffuse gliomas
Should the diagnosis of
glioblastoma just be
HISTOLOGICAL ?
Endothelial proliferation
necrosis
TERT promoter mutations
From Wesseling and Verhaak
Life history of a glioblastoma
TERT is a common end point
CDKN2A/B homozygous deletion (FISH or methylation) : major prognosticator in IDH mutant astrocytomas
Criteria for molecular Astrocytoma Grade IV
Key references : Shirahata, von Deimling, ANP 2019; Yang R, Ng HK. Brain Pathology 2020
CIMPACT-NOW Brat et al. 2020
Li, Ng.
NOA 2019
Adult diffuse gliomas – WHO 2021
(Grades 2-4, “IDH mut glioblastoma” discarded;
homozygous deletion of CDKN2A/B as Grade 4 criteria for cases not
fulfilling histology criteria)
(EGFR, TERT, +7/-10 for cases not fulfilling histology criteria)
But that does NOT mean :
So don’t order molecular tests just by ticking the boxes
Not all molecular tests are necessary for diagnosis. Check
with your pathologist
Not all glioblastomas fulfill the listed molecular criteria as
of now
We are talking about diagnosis, and not about search for
potential targets etc.
In a cohort of adult IDH mutant glioblastomas, only 55% showed CDKN2A/B deletion. Wong, Ng. Modern Pathology 2021
In another cohort of IDHwt TERTwt glioblastomas, 65% do not exhibit EGFR amplification or +7/-10. Liu, Ng, unpublished data
Other information obtainable from methylomes
Out yourself)
Methodology
Low grade adult IDHwt astrocytoma ?
If not fulfilling criteria, regarded as NEC
(Not Elsewhere Classified)
Are all histologically lower grade IDHwt gliomas just
Glioblastomas ?
Are molecular glioblastomas (IDHwt or IDH mut) really
have the same prognosis as histologically defined
glioblastoma ?
Shirahata, von Deimling et al.
Acta Neuropathologica 2018
Showed a worsened survival
for IDH mutant Grade III
gliomas with homozygous deletion
of CDKN2A/B and when compared
with IDH mutant glioblastoma
IDH mutant LGG – Yang, Ng. Brain Pathology 2020
Survival Analysis of IDH-mutant lower-grade astrocytomas – combinations of CDKN2A, CDK4 and PDGFRA
Low risk group: Non-alterations
Intermediate risk group: CDKN2A deletion and CDK4 amplification
High risk group: PDGFRA amplification
Low
(n=73)
High
(n=27)
p<0.001
A
Intermediate
(n=49)
Probability
100
80
60
40
20
0
60
0
100
80
40
20
Progression-free survival (months)
Low
(n=74)
High
(n=30)
p<0.0001
B
Intermediate
(n=51)
Probability
Overall survival (months)
100
80
60
40
20
0
60
0
100
80
40
20
Yang, Ng. Brain Pathology 2020
OS (years)
Survival %
Molecularly lower-grade (n=68)
Molecularly high grade (n=51)
p <0.001
IDH wild-type lower-grade gliomas have good or bad survivals depending on molecular features
Aibaidula, Ng. Neuro-oncology 2017
The triple negative lower grade gliomas
(IDH, TERT, 1p19q) do not
behave like glioblastomas in spite of being
IDHwt
Among Low Grade Gliomas which are IDH-, 1p19q non-deleted, TERT- (n=80)
Chan, Ng. New England Journal of Medicine 2016
26
27
Aoki, Natsume
Neuro-oncology 2018
Similar message : some IDHwt LGG have better and some have worse prognosis depending on molecular
features – not all are IDHwt glioblastomas
Berzero, Sanson. NO 2021
- Grading is still important
In IDHwt LGG
-TERTmut only IDHwt LGG has
better prognosis
WHO 2021 – separate out the pediatric-type gliomas
2.1.2: Pediatric-type diffuse low-grade gliomas� 2.1.2.1: Diffuse astrocytoma, MYB- or MYBL1-altered� 2.1.2.2: Angiocentric glioma � 2.1.2.3: Diffuse low-grade glioma, MAPK-altered� 2.1.2.4: Polymorphous low-grade neuroepithelial tumour of the young� �2.1.3: Pediatric-type diffuse high-grade gliomas� 2.1.3.1: Diffuse midline glioma, H3 K27M-mutant� 2.1.3.2: Diffuse hemispheric glioma, H3 G34-mutant� 2.1.3.3: Diffuse paediatric-type high-grade glioma, H3-wildtype and IDH-wildtype� 2.1.3.4: Infant-type hemispheric glioma, H3-wildtype�2.1.4: Circumscribed astrocytic gliomas� 2.1.4.1: Pilocytic astrocytoma� 2.1.4.2: High-grade astrocytoma with piloid features� 2.1.4.3: Pleomorphic xanthoastrocytoma� 2.1.4.6: Subependymal giant cell astrocytoma� 2.1.4.7: Chordoid glioma� 2.1.4.8: Astroblastoma-MN1�2.1.5: Glioneuronal and neuronal tumours � 2.1.5.1: Ganglioglioma� 2.1.5.2: Desmoplastic infantile astrocytoma / ganglioglioma � 2.1.5.3: Dysembryoplastic neuroepithelial tumour � 2.1.5.4: Diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters � 2.1.5.5: Papillary glioneuronal tumour
Many others………………………………
Bandopadhayay P Pediatric Blood & Cancer 2014
N=4,400
Grades 1 and 2 gliomas in children have similar prognosis
Grades 3 and 4 gliomas in children have similar prognosis in children
Whole genome methylation profiling – more useful in pediatric tumors
Binary
IDAT files
(1 for red,
1 for green)
Typical report from DKFZ Molecular Classifier
Capper D et al. Nature 2018
Methylation profiling listed as
DESIRABLE criteria in WHO 2021
for many entities
“Histological diagnosis without
Histology”
WHO 2021 – separate out the pediatric-type gliomas
2.1.2: Pediatric-type diffuse low-grade gliomas� 2.1.2.1: Diffuse astrocytoma, MYB- or MYBL1-altered� 2.1.2.2: Angiocentric glioma � 2.1.2.3: Diffuse low-grade glioma, MAPK-altered� 2.1.2.4: Polymorphous low-grade neuroepithelial tumour of the young� �2.1.3: Pediatric-type diffuse high-grade gliomas� 2.1.3.1: Diffuse midline glioma, H3 K27M-mutant� 2.1.3.2: Diffuse hemispheric glioma, H3 G34-mutant� 2.1.3.3: Diffuse paediatric-type high-grade glioma, H3-wildtype and IDH-wildtype� 2.1.3.4: Infant-type hemispheric glioma, H3-wildtype�2.1.4: Circumscribed astrocytic gliomas� 2.1.4.1: Pilocytic astrocytoma� 2.1.4.2: High-grade astrocytoma with piloid features� 2.1.4.3: Pleomorphic xanthoastrocytoma� 2.1.4.6: Subependymal giant cell astrocytoma� 2.1.4.7: Chordoid glioma� 2.1.4.8: Astroblastoma-MN1�2.1.5: Glioneuronal and neuronal tumours � 2.1.5.1: Ganglioglioma� 2.1.5.2: Desmoplastic infantile astrocytoma / ganglioglioma � 2.1.5.3: Dysembryoplastic neuroepithelial tumour � 2.1.5.4: Diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters � 2.1.5.5: Papillary glioneuronal tumour
Many others………………………………
H3K27M
6 years old female
Thalamic GBM
K27M-H3.3 mutations
(AAG → ATG, lysine → methionine)
“DIPG” – H3K27M mutant mid-line glioma
Cynthia Hawkins, AANP
Cynthia Hawkins, AANP web
Pediatric high grade gliomas IDHwt, H3wt are still poorly characterized
2019
Infant high grade gliomas comprise multiple subgroups
Characterised by novel target fusions and better survivals
Clarke M, Mackay A…….Ng HK……Jones C
Cancer Discovery 2020
Infantile gliomas are a separate group in WHO 2021
Note : NTRK inhibitors in clinical trials
2.1.4: Circumscribed astrocytic gliomas� 2.1.4.1: Pilocytic astrocytoma� 2.1.4.2: High-grade astrocytoma with piloid features� 2.1.4.3: Pleomorphic xanthoastrocytoma� 2.1.4.6: Subependymal giant cell astrocytoma� 2.1.4.7: Chordoid glioma� 2.1.4.8: Astroblastoma-MN1
pilocytic
Prototype circumscribed glioma : pilocytic astrocytoma
BRAF Gene Rearrangement (Fusion) - a key test that your lab should have – adult patients too
Two normal signals (orange) plus a smaller third signal near one of the large signals
Other methodology : Nanostring, RNAseq, NGS
Ependymoma
Medulloblastoma
`
Medulloblastoma
Medulloblastoma, molecularly defined
McLendon, Miller, Ng.
Hematology Oncology
Clinics 2021
As per WHO 2021
M/5. Anaplastic medulloblastoma with drop metastasis and MYC amplification
Molecular grouping of medulloblastoma
Robin O
Barnard
Peter Burger
F Stephen Vogel