WHO 2021 CLASSIFICATION

OF BRAIN TUMOURS
What is new? What is gone?

MB Bch BAO BA, Dr Rad (UKM)

Ampang Hospital
Selangor, Malaysia

MBBS

University Malaya Medical

Center (UMMC)
Selangor, Malaysia
 Apply &
1 Recall 2 Understand 3
Analyse
Brief overview "Must-know" topics Approach to
new changes of for radiologist selected brain
fifth edition 2021 including key tumours cases
WHO molecular according to this
classification of alterations of new WHO
brain tumours gliomas. classification
Overview 2021 WHO Classification of Tumours of Central Nervous System

Publication of (4+ edition) 2016 WHO classification of

tumours of the CNS causes paradigm shift in diagnosis of CNS
neoplasm.

Both histologic features and genetic alterations were

incorporated into the diagnostic framework, classifying and
grading of brain tumours.

Imaging or histologic features alone are not reliable to

classify or grading a tumour. Molecular markers are crucial.

Taxonomy changes
o Grouping

BRIEF Nomenclature changes

NEW o Simplification
CHANGES o Location dropped

Grading changes
o Arabic numerals
Layered pathological report
Integrated diagnosis
1 Diffuse low-grade glioma, MAPK pathway altered Not otherwise specified
(NOS) -> tumours where
complete molecular
Histological diagnosis
2 Oligodendroglioma
classification is not available
Not elsewhere classified
(NEC) -> tumours that have
3 WHO CNS5 Grade
Not assigned
been fully characterised but
that do not fit within the
established classification
system
4 Molecular information
Duplication of the FGRF1 tyrosine kinase domain

What if an integrated WHO CNS5 diagnosis cannot be obtained?

The final diagnosis will be a combination of histological diagnosis and the additional
data available, followed by NOS or NEC.
Taxonomy
Molecular changes incorporated.
This is not UNIVERSAL. Some types are rarely diagnosed with molecular
approach.
Some types grouped by markers, ie: IDH or H3.
This is likely intermediary hybrid.

"Types" and "Subtypes" to replace "entities" and "variants".

For example, meningioma represents one "type" with many "variants" like
clear cell, chordoid.
Nomenclature
Locational names modifier has been dropped unless of clinical utility.

1. Third ventricle has been dropped from choroid glioma.

2. Medulloblastoma, as it occurs in 1 location; Location modifier is not necessary.

Modifiers such as "anaplastic" have been removed.

What was previously known as an "anaplastic astrocytoma" is now referred to as

an "astrocytoma, IDH-mutant, CNS WHO grade 3"

Glioblastoma IDH mutant was replaced by Astrocytoma, IDH mutant, grade 4

Glioblastoma term is reserved only for IDH-wildtype disease.

Grading
Roman numerals are OUT! Arabic numerals provide for less chance of error.

Previously the Roman numerals I, II, III and IV replaced by the Arabic
numerals 1, 2, 3 and 4

Grading within tumour types

- IDH-mutant astrocytoma Grades 2 to 4 (no grade 1 astrocytoma)

- Meningiomas Grades 1 to 3 (no grade 4 meningioma)
- Glioblastoma, IDH-wildtype can only ever be a Grade 4 tumour

The IDH mutation status assumes the leading

role in the classification of adult gliomas.
Grading
WHO grade no longer restricted to histological grade
Molecular grading may supersede histological features

IDH-wildtype astrocytoma with low-grade histologic features can be

considered Grade 4 (glioblastoma) in the presence of
EGFR amplification
TERT promoter mutation
the combined gain of chromosome 7 and loss of chromosome 10
 Molecular alterations to know
Important in
Necessary for the Astrocytoma, IDH mutant
diagnosis of
oliodendroglioma Upstages the tumour to
WHO grade 4 regardless
of histology

Important in adult-
type glioma, IDH
Determines prognosis wildtype
in Pediatric-type
gliomas Upstages the
tumour to
glioblastoma WHO
grade 4 regardless
of the histological
findings
Newly
recognized
Tumour
Types in 2021
WHO
classification
CNS tumours
Case 1: 45-year-old man with seizure
Case: Bruno Di Muzio rID: 39124

T2 FLAIR ADC T1 Gad

A relatively well circumscribed intra-axial mass with Family Options:

epicenter at the white matter of right temporal lobe.
It is associated with minimal amount of vasogenic
oedema. A small cystic component at the anterior
aspect of mass. No restricted diffusion (bright on
ADC map). Minimal enhancement post contrast.
Adult-type diffuse glioma
Pediatric-type diffuse low grade glioma
Pediatric-type diffuse high grade glioma
Circumscribed astrocytic glioma
Glioneural and neuronal tumour
Ependymoma
Case 1: 45-year-old man with seizure
Family options:
Case: Bruno Di Muzio rID: 39124
Adult-type diffuse glioma
o Astrocytoma, IDH-mutant
o Oligodendroglioma, IDH-mutant, 1p19q codeleted
o Glioblastoma, IDH-wildtype

In view of lack of significant enhancement, large degree of

vasogenic oedema, infiltrative margin and restricted
diffusion, the diagnosis of astrocytoma (IDH-mutant) is
favoured rather than glioblastoma.
Formerly, we would name it as anasplatic astrocytoma.
T2
New 2021 WHO classification, the
diagnosis of this tumour would be IDH-
mutant, astrocytoma, CNS WHO Grade 3.
Case 2: 20-year-old lady with seizure and headache
Case: Rutuparna S rID: 74287

T2 FLAIR T1 SWI

A large well-defined intra-axial supratentorial mass Family Options:

centered in left parietal lobe with solid and cystic Adult-type diffuse glioma
component. A large area of heterogeneously Pediatric-type diffuse low grade glioma
hyperintense on T2W/FLAIR and T1W with Pediatric-type diffuse high grade glioma
corresponding susceptibility artefacts on SWI, Circumscribed astrocytic glioma
corresponding with haemorrhage. Minimal Glioneural and neuronal tumour
perilesional oedema. Ependymoma
Case 2: 20-year-old lady with seizure and headache
Family options:
Circumscribed astrocytic glioma
o Pilocytic astrocytoma
o High grade astrocytoma w/ piloid features
o Pleomorphic xanthoastrocytoma
o SEGA
o Choroid glioma
o Astroblastoma, MN1-altered

New 2021 WHO classification, the diagnosis of this tumour is

Astroblastoma, MN1-altered.

Rare glial tumours

PEARLS

Found in cerebral hemispheres of young adult/child T2

MN1 alteration is used to define this lesion.
Have not been given WHO grade with range of behaviour.
Case: Rutuparna S rID: 74287
Areas of cystic degeneration-> Bubbly appearance
Calcification is very common.
Solid components to be isointense to grey matter.
Heterogeneous enhancement post gadolinium.
Case 3: 7-year-old girl with headache and 6th nerve palsy
Case: Jeremy Jones rID: 68487

T2 T1 Gad Sagittal T1 Gad

Large expansile brainstem lesion centred on the Family Options:

pons. The lesion encases the basilar artery but
preserved flow void. Heterogeneous signal
intensities with cystic components. Small focal
areas of contrast enhancement posteriorly.
Fourth ventricle is slightly effaced.
Adult-type diffuse glioma
Pediatric-type diffuse low grade glioma
Pediatric-type diffuse high grade glioma
Circumscribed astrocytic glioma
Glioneural and neuronal tumour
Ependymoma
Case 3: 7-year-old girl with headache and 6th nerve palsy
Family options:
Pediatric-type diffuse high grade glioma
Case: Jeremy Jones rID: 68487
o Diffuse midline glioma, H3 K27 altered
o Diffuse hemispheric glioma, H3 G34-mutant
o Diffuse pediatric-type high-grade glioma, H3 wildtype and IDH-
wildtype
o Infant-type hemispheric glioma

New 2021 WHO classification, the diagnosis of this tumour is

diffuse midline glioma, H3 K27 altered, CNS WHO grade 4.

Previously known as diffuse intrinsic pontine gliomas (no

PEARLS

longer in use)
WHO grade 4 tumours regardless of histological features
Glioblastoma no longer applied to pediatric brain tumours.
T1 Gad Sagittal
Can be found throughout the midline structures (thalamus,
brainstem and spinal cord)
MRI: T2 heterogeneous. Minimal enhancement post Gad.
Poor prognosis, 2-year survival <10%.
Case 4: Adult patient with skull mass Case: Frank Gaillard rID: 4326

T2 T1 Gad T1 Gad Coronal

Family Options:
A very large extra-axial mass eroding Meningiomas
through the left fronto-parietal bone. It Mesenchymal, non-meningothelial tumours
vividly enhances. There is no evidence of Hematolymphoid tumours
invasion into the brain. Minimal right Histocytic tumours
subfalcine herniation and hydrocephalus. Germ cell tumours
Metastases to the CNS
Case 4: Adult patient with skull mass
Family options:
Mesenchymal, non-meningothelial tumours
o Solitary fibrous tumour Case: Frank Gaillard rID: 4326
o Hemangiomas and vascular malformations
o Hemangioblastoma
o Rhabdomyosacroma
o Ewing sarcoma
o Primary intracranial sarcoma, DICER1-mutant
c CIC-rearranged sarcoma
o Intracranial mesenchymal tumour, FET-CREB fusion positive

New 2021 WHO classification, the diagnosis of this tumour is

solitary fibrous tumour.
PEARLS

Hemangiopericytoma no longer occurs in WHO classification

May be WHO CNS grade 1 to 3
Almost always solitary supratentorial extra-axial mass. T1 Gad
Tendency to erode adjacent bone.
Major differential diagnosis is meningioma (more common).
Case 5: 30-year-old man with bitemporal hemianopia
Case: Matheus Costa Cabral rID: 98202

T1 Sag T1 Gad Sag FLAIR T2

A large suprasellar solid-cystic mass, with Family Options: Tumours of the sellar region
enhancing solid component. Intrinsic bright on Adamntinomatous craniopharyngioma
T1 in supero-anterior aspect may represent Papillary craniopharyngioma
haemorrhagic or proteinaceous content. Pituicytoma
Significant compression onto optic chiasm. Pituitary adenoma
Normal enhancing pituitary gland denotes the Pituitary blastoma
origin of mass is from suprasellar region. Rathke's cleft cyst
Case 5: 30-year-old man with bitemporal hemianopia
Adamantinomatous craniopharyngioma
Bimodal age distribution
Case: Matheus Costa Cabral rID: 98202
Presence of proteinaceous cysts
Craniopharyngioma Multilobular, irregular

Considered two
separate Papillary craniopharyngioma
diagnoses Usually middle-aged adults
Usually smooth borders
Often solid or cysts of simple fluid

New 2021 WHO classification, the diagnosis of this tumour is

Adamantinomatous craniopharyngioma.

Primarily suprasellar tumour

PEARLS

Small intrasellar component in 20 - 25%

T1 Gad Sag
T1 hyperintense due to high protein content "motor oil cyst"
Vivid enhancement of solid component
90% has calcification.
cf Rathke cleft cyst (no enhancement or solid component,
calcification is rare, most completely intrasellar)
Case 6: 55-year-old man incidental finding on MRI brain

T2 FLAIR T1 Gad Perfusion

CBV

Case: Frank Gaillard rID: 154110

Multilobulated subcortical non-enhancing non-

expansile left precentral gyrus T2
hyperintensity (bubbly appearance) does not
suppress on FLAIR. The lesion has slightly
facilitated diffusion and perfusion
characteristics similar to the surrounding brain.
DWI ADC
Case 6: 55-year-old man incidental finding on MRI brain
Family options:
Glioneuronal and neuronal tumours (in view of cortical/subcortical Case: Frank Gaillard rID: 154110
location)
o All neuronal component tumours remain grouped
o Well-circumscribed cortical and subcortical T2 hyperintensities.
o No enhancement or restricted diffusion on DWI

New 2021 WHO classification, the diagnosis of this tumour is

Multinodular and vacuolating neuronal tumour (MVNT), WHO
CNS Grade 1.

Benign tumour with long term stability T2

Associated with seizures
PEARLS

Often in temporal lobe. MVNT-like lesions have been reported

in posterior fossa.
Now recognized as distinct diagnosis (previously discussed as
gangliocytoma)
MRI: cluster of T2-FLAIR hyperintense nodules 'bubbles' along
undersurface of cerebral cortex and subcortical white matter.
If asymptomatic, should be followed by imaging alone.
Case 7: 40-year-old man with seizure Case: Frank Gaillard rID: 53901

MRS

T2 FLAIR T1 Gad

A high T2 signal mass in the posterior part of the left Family Options:
superior frontal gyrus, has high T2 signal and
Adult-type diffuse glioma
incomplete FLAIR suppression with peripheral rim of
Pediatric-type diffuse low grade glioma
Pediatric-type diffuse high grade glioma
hyperintensity (T2/FLAIR mismatch sign). No
Circumscribed astrocytic glioma
enhancement. Spectroscopy demonstrates elevated
Glioneural and neuronal tumour
choline and reduced NAA.
Ependymoma
Case 7: 40-year-old man with seizure
Family options:
Adult-type diffuse glioma
Case: Frank Gaillard rID: 53901
o Astrocytoma, IDH-mutant
o Oligodendroglioma, IDH-mutant, 1p19q codeleted
o Glioblastoma, IDH-wildtype

New 2021 WHO classification, the diagnosis of this tumour

would be Astrocytoma , IDH-mutant, CNS WHO Grade 3.

Previously known as protoplasmic astrocytoma, no longer

recognised as a distinct entity.
PEARLS

T2-FLAIR mismatch sign- highly specific radiogenomic signature

for astrocytomas (IDH-mutant, 1p19q non-codeleted)
- High specificity (100%), Low sensitivity(42%).
Helpful in distinguishing an astrocytoma from an
FLAIR
oligodendroglioma.
Oligodendroglioma must have IDH mutation and 1p19q
codeletion (either grade 2 or 3), frontal lobe location,
heterogeneity, calcification with variable enhancement.
Take Home Points
Diagnosis and tumour grading is no longer exclusive dependence on
histology, but a combination of phenotype and molecular profiling.
This new paradigm is reflected in proposed layered pathological report.
Main molecular drive in adult-type diffuse gliomas is IDH mutation status.
Most important molecular abnormality in high-grade paediatric-type diffuse
gliomas are alterations of Histone 3 gene (H3).
T2/FLAIR mismatch sign has a 100% specificity for Astrocytoma, IDH
mutant.
No other imaging findings are specific for any molecular abnormality.
However, based on patient’s age, tumour location and imaging appearance,
radiologist is capable of narrowing down the differential diagnoses to a few
entities.
References

1. Louis D, Perry A, Wesseling P et al. The 2021 WHO Classification of Tumors of the
Central Nervous System: A Summary. Neuro-Oncology. 2021;23(8):1231-51.
2. Louis D, Wesseling P, Paulus W et al. CIMPACT-NOW Update 1: Not Otherwise
Specified (NOS) and Not Elsewhere Classified (NEC). Acta Neuropathol.
2018;135(3):481-4.
3. Weller M, van den Bent M, Preusser M et al. EANO Guidelines on the Diagnosis and
Treatment of Diffuse Gliomas of Adulthood. Nat Rev Clin Oncol. 2020;18(3):170-
86.