who classification 2021
TRANSCRIPT
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WHO classification 2021
H.K. Ng
Chinese University of Hong Kong
Full ppt at http://www.acp.cuhk.edu.hk/hkng/
Sorry this is going to be a boring talk
45 minutes are not enough for the CNS classification asWe have many more entities than other systemsSo there is only enough time to read through the entireClassificatiionParts of the classification which do not havemany changes will not be dealt with.
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Just too many entities
WHO also includes a section on hereditary brain tumor syndromes
Some entities I have not seen myself
Sorry cannot illustrate everything
WHO Classification 2021
Imminently in print and latest June
Look out for summary in Neuro‐oncology soon
Louis DN et al.
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Disclaimer : Just don’t shoot the messenger
WHO 2021 – led by IARC
Ten neuropathologists
‐ Brat, Dan
‐ Ellison, David
‐ Figarella‐Branger, Dominique
‐ Hawkins, Cynthia
‐ Louis, David
‐ Perry, Arie
‐ Ng, H K
‐ Von Deimling, Andreas
‐ Reifenberger, Guido
‐ Wesseling, Pieter
Two clinicians
‐ Pfister, Stefan
‐ Soffietti, Riccardo
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Some general changes
• Pediatric and adult gliomas separate
• Grading changed to Arabic numerals, e.g. 1, 2,3, 4 and not I, II, III,IV
• Grading is WITHIN each tumor group
• Methylomes a desirable criteria in
• Many of the new and rare lesions diagnosable by methylation profiles
• Appreciate that some tumors are Not Elsewhere Classified (NEC)
• Integrated diagnosis as per Haarlem (2014) recommendation
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Whole genome methylation profiling
BinaryIDAT files(1 for red, 1 for green)
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Typical report from DKFZ Molecular Classifier
Capper D et al. Nature 2018
Methylation profiling listed as DESIRABLE criteria in WHO 2021for many entities
“Histological diagnosis withoutHistology”
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IDH glioma, subclass high grade astrocytoma
IDH glioma, subclass 1p/19q codeleted oligodendroglioma
IDH glioma, subclass astrocytoma
IDH mutant glioblastomas (our cohort, n=86)
glioblastoma, IDH wildtype, subclass RTK I
glioblastoma, IDH wildtype, subclass RTK II
glioblastoma, IDH wildtype, subclass mesenchymal
O_IDH
A_IDH
A_IDH_HG GBM_MES
GBM_RTK I
GBM_RTK II
The methylomesA new kind of“histology”
Figure 1. Unsupervised clustering of reference cohort samples and 85 IDH mutant glioblastomas using t-SNE dimensionality reduction. The reference cohort of the DKFZCNS tumor classifier includes 82 tumour and 9 non-tumour classes and they are shown as circles of different colors. The 85 primary IDH mutant glioblastomas of ourcohort clustered mainly to the (I) IDH mutant high grade astrocytomas; (2) glioblastoma, IDH wildtype, subclass RTK II and (3) subclass mesenchymal (green triangles).Mutations of IDH in our samples were tested and confirmed by independent PCR and sanger sequencing.
Wong, NgModern Pathology 2021
Methylomes also give you the complete cytogenetic picture of copy number variation of genes
Wong, Ng. Modern Pathology 2021
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Other information obtainable from methylomes
• MGMT
• 1p19q status
• G‐CIMP status (have to workOut yourself)
Pediatric gliomas
2.1.2: Pediatric-type diffuse low-grade gliomas2.1.2.1: Diffuse astrocytoma, MYB- or MYBL1-altered2.1.2.2: Angiocentric glioma 2.1.2.3: Diffuse low-grade glioma, MAPK-altered2.1.2.4: Polymorphous low-grade neuroepithelial tumour of the young
2.1.3: Pediatric-type diffuse high-grade gliomas2.1.3.1: Diffuse midline glioma, H3 K27M-mutant2.1.3.2: Diffuse hemispheric glioma, H3 G34-mutant2.1.3.3: Diffuse paediatric-type high-grade glioma, H3-wildtype and IDH-wildtype2.1.3.4: Diffuse midline glioma, EGFR-mutant 2.1.3.5: Infant-type hemispheric glioma, H3-wildtype
2.1.4: Circumscribed astrocytic gliomas2.1.4.1: Pilocytic astrocytoma2.1.4.2: High-grade astrocytoma with piloid features2.1.4.3: Pleomorphic xanthoastrocytoma2.1.4.6: Subependymal giant cell astrocytoma2.1.4.7: Chordoid glioma2.1.4.8: Astroblastoma-MN1
2.1.5: Glioneuronal and neuronal tumours2.1.5.1: Ganglioglioma2.1.5.2: Desmoplastic infantile astrocytoma / ganglioglioma2.1.5.3: Dysembryoplastic neuroepithelial tumour2.1.5.4: Diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters 2.1.5.5: Papillary glioneuronal tumour2.1.3.13 Diffuse leptomeningeal glioneuronal tumor
Many others………………………………
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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
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H3K27M
• Midline H3K27M mutant gliomas (DIPG)
• Pitfalls : may occur outside midline; usually poor prognosis
6 years old female
Thalamic GBM
K27M-H3.3 mutations
(AAG → ATG, lysine → methionine)
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“DIPG” – H3K27M mutant mid‐line glioma
Cynthia Hawkins, AANP
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Cynthia Hawkins, AANP
Cynthia Hawkins, AANP web
Pediatric high grade gliomas IDHwt, H3wt are still poorly characterized
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Diffuse midline glioma, EGFR mutant
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2019
Infant high grade gliomas comprise multiple subgroupsCharacterised by novel target fusions and better survivalsClarke M, Mackay A…….Ng HK……Jones CCancer Discovery 2020
Infantile gliomas are a separate group in WHO 2021
Note : NTRK inhibitors in clinical trials
Polymorphous low grade neurepithelial tumor of the youngFrom WHO 2021
About 50% BRAF mutated or have other MAPK aberrations,usually FGFR2 or FGFR3
CD34WHO 2021
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？ A form of PLNTY or pediatric low gradeGlioma with MAPK activationYang, Ng. Brain Pathology 2020
8/M
BRAF
Angiocentric glioma – MYB‐QKI fusionA Grade 1 pediatric diffuse glioma characterized by chronic intractable seizure
WHO 2021
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Diffuse astrocytoma, MYB or MYBL1 alteredIs a grade 1 pediatric diffusely infiltrative glioma
Previously called isomorphic glioma
Lassaletta…Ng....TarboriJournal of Clinical Oncology2017
BRAF V600E is a poor prognosticator for p‐LGG
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Pro
gres
sion
fre
e su
rviv
alO
vera
ll s
urvi
val
Time (months)
Time (months)
Intermediate risk; n=111
Low risk; n=86
High risk; n=21
Risk stratification of pLGG into low, intermediate and high groups
p<0.0001
High risk (H3F3A or TERT promoter mutation)
Low risk(BRAF fusion or MYB amplification
Intermediate risk (BRAFV600E or without H3F3A/TERT/BRAF/MYB alterations)
p<0.0001
p-=0.0002
Intermediate risk; n=111
Low risk; n=86
High risk; n=21 p<0.0001
p<0.0001
p-=0.0023
Yang, Ng. Acta Neuropathologica 2018
Ryall, HawkinsCancer Cell 2020
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WHO2021 defines DNET as a cortical, circumscribedGlioneuronal tumor with alterations of FGFR1
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Desmoplastic infantileAstrocytoma / Ganglioglioma
Glioneuronal tumor
Myxoid glioneuronal tumor
A tumor at septum pellucidum or periventricularregion with characteristic dinucleotide putationof PDGFRA. Slow growing. Grade 1.
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Diffuse leptomeningeal gliomaNg, Poon. Pathology 1999
May exhibit 1p loss or BRAF fusion
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Papillary glioneuronal tumor is defined by PRKCA‐fusions
WHO 2021
2.1.4: Circumscribed astrocytic gliomas2.1.4.1: Pilocytic astrocytoma2.1.4.2: High-grade astrocytoma with piloid features2.1.4.3: Pleomorphic xanthoastrocytoma2.1.4.6: Subependymal giant cell astrocytoma
2.1.4.7: Chordoid glioma2.1.4.8: Astroblastoma-MN1
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Astroblastoma is defined now by MN1‐alterations
WHO 2021
pilocytic
Prototype circumscribed glioma : pilocytic astrocytoma
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BRAF Gene Rearrangement (Fusion)
Two normal signals (orange) plus a smaller third signal near one of the large signals
PXA is characterized by BRAF mutation and CDKN2A deletion
BRAF V600E
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Adult diffuse gliomas
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Should the diagnosis of glioblastoma just be HISTOLOGICAL ?
Endothelial proliferationnecrosis
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TERT promoter mutations
From Wesseling and Verhaak
Life history of a glioblastoma
TERT is a common end point
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CDKN2A/B homozygous deletion (FISH or methylation) : major prognosticator in IDH mutant astrocytomasCriteria for molecular Astrocytoma Grade IV
Also 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
• Astrocytoma, IDH mutant
(Grades 2‐4, “IDH mut glioblastoma” discarded;
homozygous deletion of CDKN2A/B as Grade 4 criteria for cases not
fulfilling histology criteria)
• Oligodendroglioma, IDH mutant and 1p19q codeleted
• Glioblastoma, IDH wild type
(EGFR, TERT, 7+/10‐ for cases not fulfilling histology criteria)
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But that does not mean :
• You need to do CDKN2A/B to diagnose an obvious glioblastoma which is IDH mutant (Wong, Ng. Modern Pathology 2021)
• You need to do EGFR or TERT or 7+/10‐ for an obvious glioblastoma which is IDHwt
• These are criteria for molecular glioblastoma or Grade 4 for the Grade 2‐3 lesions which do not fulfil the histological criteria
Giant cell glioblastoma is a variant enriched for p53 mutatipn (Shi, Ng. Brain Pathology 2019)
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Epitheloid glioblastoma typically has BRAF mutation
BRAFWHO 2021
Ependymoma
• Supratentorial ependymoma• Supratentorial ependymoma ZFTA (RELA) fusion‐positive• Supratentorial ependymoma YAP1 fusion‐positive• Posterior fossa ependymoma• Posterior fossa ependymoma Group PFA• Posterior fossa ependymoma Group PFB• Spinal ependymoma• Spinal ependymoma, MYCN‐amplified• Myxopapillary ependymoma• Subependymoma
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Posterior fossa ependymoma is the commonestclinical scenario for ependymomas
Witt & Pfister Cancer Cell 2011
PFA younger age and majority
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M/3 L frontal lobe tumor
RELA
LICAM
Or p65/RELA
Most supratentorial ependymomas are ZFTA (RELA) fusion positiveand clinically aggressive
RELA‐positive ependymoma
M/15, ST. T and QMH, 2007‐2019
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Spinal cord ependymomas are mostly low grade
From :Ng in Russell and Rubinstein2006
Spinal ependymoma
• Without MYCN : good prognosis
• With MYCN : poor prognosis
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Medulloblastoma
`
Medulloblastoma
Medulloblastoma, molecularly defined
• Medulloblastoma, Wnt activated
• Medulloblastoma, SHH activated and p53 wt
• Medulloblastoma, SHH activated and p53 mt
• Medulloblastoma, non‐Wnt, non‐SHH
• Medulloblastoma, histologically defined
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McLendon, Ng.Hematology /OncologyClinics 2021
Wnt MB ‐ Beta‐catenin
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SHH medulloblastoma
Filamin
Yap1
M/5. Anaplastic medulloblastoma with drop metastasis and MYC amplification
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Molecular grouping of medulloblastoma
• IHC (cannot distinguish Group 3 and Group 4)
• Nanostring transcriptomes
• Methylation profiling
• In addition
• FISH for example for MYC or MYCN or other cytogenetics required by your clinicians if not doing methylation profiling
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Other CNS embryonal tumors
• Atypical teratoid rhabdoid tumor (AT/RT)
• Cribriform neuroepithelial tumor
• Embryonal tumor with multi‐layered rosettes (ETMR)
• CNS neuroblastoma FOXR2 activated
• CNS tumor with BCOR internal tandem duplication
SMARCB1 (INI1) loss
• Lost in ATRT
• But also in poorly differentiated chordomas
• CRINET
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Figure 2a. AT/RTM/6 months, cerebellar tumor.This area represents the area of the tumor with rhabdoid‐like cells
Heterozygous mutationNM_003073.4:c.367C>TNP_003064:p.Q123*
Germline mutation of SMARCB1exon 4
AT/RT, negative INI1‐staining
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CRINET is a ventricular tumor characterized by histology and SMARCB1 mutation and INI1‐lossBehavior is still not very certain at this stage
WHO 2021
ETMR(embryonal tumor with multi‐Layered rosettes)F/1, frontal lobe tumor.
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ETMR – Lin28A positive and C19MC amplifictaion
All types of meningiomasas a single tumor entity with Different grades
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Mesenchymal non‐meningeal tumors ‐selected• Solitary fibrous tumor
• Rhabdomyosarcoma
• Intracranial mesenchymal tumor, FET‐CREB fusion positive
• CIC‐rearranged sarcoma
• Primary intracranial sarcoma, DICER‐mutant
• Ewing sarcoma
Pineal tumors
• Pineocytoma
• Pineal parenchymal tumor of intermediate differentiation
• Pineoblastoma
• Papillary tumor of the pineal gland
• Desmoplastic myxoid tumor of the pineal region, SMARCB1 mutant
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Tumors of the sellar region
• Adamantinomatous craniopharyngioma
• Papillary craniopharyngioma
• Pituicytoma, granular cell tumor and spindle cell oncocytoma
• Pituitary adenoma of PitNET
• Pituitary blastoma
Robin OBarnard
Peter BurgerF Stephen Vogel
S K Yee Foundation