Issue 28 || September 2024

WHAT’S NEW

IN PATHOLOGY?

numerals (1, 2, 3, 4).

• Integrated diagnoses combining both histologic

and molecular features (e.g., astrocytoma,

IDH-mutant) are now recommended.

• Layered reporting to include integrated diagnosis,

histopathological classication, CNS WHO

grade, and relevant molecular information is

recommended.

• Grading is now done within tumor types rather

than across types:

E.g., astrocytoma, IDH-mutant is assigned a

CNS grade of either 2, 3, or 4.

Modier terms such as “anaplastic” are no longer

routinely included (e.g., the term “anaplastic

astrocytoma” is no longer recommended).

• Molecular characteristics are incorporated into the

classication and grading of more tumors than in

previous editions.

• The Human Genome Organisation (HUGO)

Gene Nomenclature Classication System is used

for gene symbols and names, the Human Genome

Variation Society recommendations for gene

variants, and the International System for

Cytogenetic Nomenclature recommendations for

copy number variants.

• “Not otherwise specied (NOS)” and “Not

elsewhere classied (NEC)” are now included as

diagnostic labels:

“Not otherwise specied (NOS)” is applied when

the molecular testing required for a specic

diagnosis cannot be performed or fails to yield

results.

“Not elsewhere classied (NEC)” is applied when

a comprehensive molecular workup is performed

and the tumor does not conform to a recognized

WHO tumor type.

• Nineteen new and three provisional tumor types

are included, described below.

ADULT-TYPE DIFFUSE GLIOMAS

• Adult-type diffuse gliomas are now classied as

one of three types based on the presence/absence of

IDH mutation and 1p/19q-codeletion and graded

within each of these types.

“Oligoastrocytoma,” previously dened as a

tumor with morphologic features of both

oligodendroglioma and astrocytoma, is no longer

recognized as a distinct entity.

The “anaplastic” modier is no longer applied to

grade 3 tumors (e.g., the term “anaplastic

WHAT’S NEW IN

NEUROPATHOLOGY 2024:

CNS WHO 5TH EDITION

UPDATES

Heather Smith, MD, PhD

Jared T. Ahrendsen, MD, PhD

Department of Pathology, Northwestern University Feinberg

School of Medicine, Chicago, IL, USA

Corresponding Author:

Jared T. Ahrendsen

Department of Pathology, Northwestern University

Feinberg School of Medicine, Chicago, IL 60611, USA

E-mail: jared.ahrendsen@nm.org

ORCID

Heather Smith

https://orcid.org/0009-0002-4224-417X

Jared T. Ahrendsen

https://orcid.org/0000-0002-9309-6544

Abstract

The fth edition of the World Health Organiza-

tion (WHO) Classication of Central Nervous

System (CNS) Tumors was released in 2021, just

ve years following the updated fourth edition.

Advanced molecular testing such as next-genera-

tion sequencing, RNA fusion analysis, and DNA

methylation proling has led to more precise

grading and classication of pre-existing tumor

types as well as the recognition of new ones.

Herein, we outline the major updates of the 2021

WHO Classication of CNS tumors, with

emphasis on the expanded molecular characteriza-

tion of CNS tumors.

GENERAL CHANGES IN

TERMINOLOGY & TAXONOMY

• The words “entity” and “variant” have been

replaced by “type” and “subtype.” For example,

glioblastoma, isocitrate dehydrogenase

(IDH)-wildtype is a type of tumor, and its many

morphologic variants are now listed as subtypes.

• CNS WHO grades, previously listed in Roman

numerals (I, II, III, IV), are now listed in Arabic

oligodendroglioma” is no longer recommended).

Because of fundamental differences in natural

history and tumor biology, IDH-mutant gliomas

are no longer called “glioblastoma” even when a

CNS WHO grade of 4 can be assigned; the term

“glioblastoma” is reserved specically for

IDH-wildtype adult-type diffuse gliomas.

• Glioblastoma, IDH-wildtype:

Absence of IDH and histone H3 mutations;

Presence of either microvascular proliferation or

tumor cell necrosis;

If lacking the above histologic features, the

presence of a TERT promoter mutation, EGFR

amplication, or concurrent gain of chromosome

7 and loss of chromosome 10 (+7/-10) are

sufcient for diagnosis.

• Astrocytoma, IDH-mutant:

Presence of mutation in IDH1 or IDH2;

Absence of 1p/19q-codeletion;

CNS WHO grade 2-4 assigned based on

histologic features (as described in previous classi-

cations), with the addition of CDKN2A/B

homozygous deletion as a molecular criterion for

grade 4 designation.

• Oligodendroglioma, IDH-mutant and

1p/19q-codeleted:

Presence of IDH1 or IDH2 mutation and

concurrent 1p/19q-codeletion required for

diagnosis;

CNS WHO grade 2-3, with same histolo-

gy-based criteria as previous classication scheme.

• “Adult-type” and “pediatric-type” gliomas have

been separated due to distinct molecular charac-

teristics, biological behavior, and predilection for

certain age groups. However, adult-type tumors

can occasionally affect children, and pediatric-type

gliomas are sometimes encountered in adult

patients.

PEDIATRIC-TYPE DIFFUSE

LOW-GRADE GLIOMAS

• Each tumor type demonstrates diffuse growth

pattern without high-grade morphologic features.

• Diffuse astrocytoma, MYB- or MYBL1-altered

(new entity): bland, monomorphic cells; character-

ized by fusion events involving MYB or MYBL1

(CNS WHO grade 1).

• Angiocentric glioma: also dened by MYB

alterations; however, it displays prominent

perivascular growth and characteristically harbors

the MYB::QKI fusion (CNS WHO grade 1).

• Polymorphous low-grade neuroepithelial tumor

of the young (PLNTY, new entity): CNS WHO

grade 1 epileptogenic tumor that tends to have

oligodendrocyte-like tumor cells, strong CD34

expression, calcications (Fig. 1), and MAPK

pathway alterations (most commonly BRAF

p.V600E or fusions involving FGFR2/3).

• Diffuse low-grade glioma, MAPK pathway-al-

tered (new entity): diffuse growth and bland

low-grade histomorphology; molecularly dened

by the absence of mutations in IDH and histone

H3, absence of homozygous CDKN2A/B deletion,

and the presence of a MAPK pathway alteration

(most commonly BRAF p.V600E or internal

tandem duplication in the kinase domain of

FGFR1). Specic CNS WHO grade not currently

assigned.

PEDIATRIC-TYPE DIFFUSE

HIGH-GRADE GLIOMAS

• Each tumor type demonstrates diffusely inltra-

tive growth, high-grade morphologic features,

and variably aggressive clinical behavior.

• Diffuse midline glioma, H3 K27-altered: CNS

WHO grade 4 diffusely inltrating glioma

involving a midline structure (e.g., brainstem,

thalamus, spinal cord), loss of H3K27me3

expression, and one of the following molecular

alterations:

Mutation in one of the genes encoding histone

H3, leading to the substitution of lysine with

either methionine or isoleucine at position 27

(K27M/I);

An activating mutation or amplication of

EGFR;

EZHIP overexpression.

• Diffuse hemispheric glioma, H3 G34-mutant

(new entity): CNS WHO grade 4 diffusely

inltrating glioma involving the cerebral hemi-

spheres, often with loss of nuclear ATRX expres-

sion; dened by a mutation in the histone H3-3A

gene leading to the substitution of glycine with

either arginine or valine at position 34 (G34R/V).

• Diffuse pediatric-type high-grade glioma,

H3- and IDH-wildtype (new entity): CNS WHO

grade 4 glioma with high-grade histologic

features divided into three subtypes based on

DNA methylation proling and enrichment for

particular molecular alterations:

pHGG RTK I: frequent PDGFRA amplica-

tion, intermediate prognosis (median overall

survival of 21 months), frequently associated

with prior radiation therapy or constitutional

mismatch repair deciency;

pHGG RTK II: frequent TERT promoter

mutation and EGFR amplication (similar to

glioblastoma, IDH-wildtype), tends to have

better prognosis (median overall survival of 44

months);

pHGG MYCN: frequent MYCN amplication,

poor prognosis (median overall survival of 14

months).

• Infant-type hemispheric glioma (new entity):

diffusely inltrating glioma involving the cerebral

hemispheres that tends to occur during the rst

year of life and is driven by fusion events involving

NTRK1/2/3, ALK, MET, or ROS1. Specic CNS

WHO grade not currently assigned.

CIRCUMSCRIBED ASTROCYTIC

GLIOMAS

• High-grade astrocytoma with piloid features

(HGAP, new entity): newly recognized tumor

type and one of the rst to be dened by a specic

DNA methylation prole, rather than by

histomorphology or specic molecular alteration.

The majority have morphologic features reminis-

cent of pilocytic astrocytoma or pleomorphic

xanthoastrocytoma, molecular alterations involv-

ing the MAPK pathway, homozygous deletion of

CDKN2A/B, and mutation or lost expression of

ATRX. Specic CNS WHO grade not currently

assigned.

• Astroblastoma, MN1-altered: tumor cells

arranged in perivascular pseudorosettes with

reverse nuclear polarity and now dened genetic

alteration (usually fusion event) involving MN1.

• Chordoid glioma: chordoid morphology with

recurrent PRKCA p.D463H mutation and

characteristically located in the third ventricle

(though no longer termed “chordoid glioma of the

third ventricle”).

GLIONEURONAL AND

NEURONAL TUMORS

• Two new and one provisional tumor types, includ-

ing:

Diffuse glioneuronal tumor with oligodendrogli-

oma-like features and nuclear clusters (DGONC,

provisional entity): variably differentiated cells

with oligodendroglioma-like perinuclear halos,

scattered multinucleated cells, and nuclear

clusters. Molecular ndings include monosomy

Fig. 1. Polymorphous low-grade neuroepithelial tumor of the young (PLNTY). Low-grade neoplasm demonstrat-

ing diffuse growth pattern and microcalciﬁcations (top panel). Strong, regional CD34 expression by tumor cells

(bottom panel).

14 and a distinct DNA methylation prole.

Specic CNS WHO grade not currently

assigned.

Myxoid glioneuronal tumor (new entity): CNS

WHO grade 1 neoplasm composed of oligoden-

drocyte-like cells in a myxoid stroma (Fig. 2),

often with oating neurons and neurocytic

rosettes. Typically arises in the septal nuclei,

periventricular white matter, or corpus callosum.

Recurrent PDGFRA p.K385L/I mutation.

Multinodular and vacuolating neuronal tumor

(new entity): monomorphic neuronal elements

arranged in clusters with vacuolated cells and

matrix (CNS WHO grade 1). These tend to have

MAPK pathway activating mutations, most

commonly in MAP2K1 or BRAF (not p.

V600E).

EPENDYMAL TUMORS

• Ependymal tumors are now classied by a

combination of tumor location, histopathology,

and molecular features. Ependymoma tumor

types form distinct molecular-anatomic clusters

that can be identied by DNA methylome

analysis.

• “Anaplastic ependymoma” is no longer a listed

entity.

• Supratentorial, posterior fossa, and spinal ependy-

momas can be assigned a CNS WHO grade of 2

or 3 based on the presence of microvascular

proliferation, brisk mitotic activity, and necrosis

(similar to prior classication schemes).

• Supratentorial ependymomas:

Supratentorial ependymoma, ZFTA fusion-posi-

tive: The majority have fusions involving ZFTA

(formerly C11orf95) with RELA.

Supratentorial ependymoma, YAP1 fusion-posi-

tive (new entity): The most common fusion

partner is MAMLD1.

• Posterior fossa ependymomas are divided into two

methylation classes:

Posterior fossa group A (PFA, new entity):

dened by loss of H3K27me3 expression. These

occur primarily in children and are locally aggres-

sive.

Posterior fossa group B (PFB, new entity):

dened by retained H3K27me3 expression.

These are more common in adults and show

more indolent behavior.

• Spinal ependymomas have their own methylation

cluster and tend to show 22q loss and NF2

mutations.

Spinal ependymoma, MYCN amplied (new

entity): high-grade features are common,

including anaplasia, elevated mitotic activity,

microvascular proliferation, and necrosis. These

are clinically more aggressive than conventional

spinal ependymomas.

• Myxopapillary ependymomas are now assigned a

CNS WHO grade of 2 instead of 1 due to their

tendency to recur and disseminate.

EMBRYONAL TUMORS

• Medulloblastomas are now classied by a combi-

nation of molecular and histologic parameters.

Two new and one provisional embryonal tumor

types are also now described.

• Medulloblastomas are still divided into four

molecular groups, and all are assigned a CNS

WHO grade 4:

Medulloblastoma, WNT-activated;

Medulloblastoma, SHH-activated and TP53-mu-

tant;

Medulloblastoma, SHH-activated and

TP53-wildtype;

Medulloblastoma, non-WNT/non-SHH.

• Histopathologic classication of medulloblastoma

(classic, desmoplastic/nodular, medulloblastoma

with extensive nodularity, and large cell/anaplas-

tic) are now considered morphologic patterns and

summarized in one section.

• Embryonal tumor with multilayered rosettes

(ETMR): dened as having either a C19MC

alteration or DICER1 mutation and includes the

previously described embryonal tumor with abun-

dant neuropil and true rosettes (ETANTR),

medulloepithelioma, and ependymoblastoma.

• Atypical teratoid/rhabdoid tumor (AT/RT) is now

required to have SMARCB1 or SMARCA4 loss (or

DNA methylation prole aligned with AT/RT).

• Two new and one provisional tumor types:

Cribriform neuroepithelial tumor (provisional

entity): neuroepithelial tumor with cribriform

architecture, periventricular location, and

SMARCB1 loss.

CNS neuroblastoma, FOXR2-activated (new

entity): dened by FOXR2 rearrangements.

These show varying amounts of neuroblastic and

neuronal differentiation, and their cell of origin

remains unknown. Assigned CNS WHO grade

CNS tumor with BCOR internal tandem

duplication (new entity): CNS embryonal tumor

(CNS WHO grade 4) dened by an internal

duplication in exon 15 of BCOR.

MENINGIOMAS

• Now considered one tumor type with multiple

morphologic subtypes

• Terms “atypical meningioma” and “anaplastic

meningioma” are retained, unlike other tumor

types described above.

• Morphologic assignment of CNS WHO grades

1-3 is generally unchanged from prior edition.

• New molecular criteria for meningioma grading:

the presence of TERT promoter mutation or

homozygous CDKN2A/B deletion now warrants

designation as CNS WHO grade 3.

MESENCHYMAL AND PERIPHERAL

NERVE SHEATH TUMORS

• Nomenclature changes include the following:

Hemangiopericytoma is now called solitary

brous tumor, similar to the nomenclature

change in the WHO Classication of Bone &

Soft tissues, though grading criteria differ

between CNS and extra-CNS tumors;

Melanotic schwannoma is now called malignant

melanotic nerve sheath tumor;

Mesenchymal chondrosarcoma is now listed as a

distinct tumor type;

Paraganglioma is now referred to as cauda equina

neuroendocrine tumor.

• New and provisional tumor types include the

following:

Intracranial mesenchymal tumor, FET::CREB

fusion-positive (provisional entity): mesenchymal

tumor with widely variable architecture ranging

from sheet-like to cord-like but generally has a

collagenous or myxoid stroma, relatively low

mitotic activity, and hemangioma-like collections

of dilated, thin-walled vessels. Dened by a

fusion involving a member of the FET

RNA-binding protein family (most commonly

Fig. 2. Myxoid glioneuronal tumor. Small, monomorphic “oligo-like” tumor cells embedded in a prominent myxoid

matrix. Molecular characterization of this case revealed a PDGFRA p.K385L mutation.

Dr. Heather Smith is new to

PathologyOutlines.com, starting in 2024.

She completed her pathology residency at the

University of Chicago and is currently a neuro-

pathology fellow at Northwestern University

Feinberg School of Medicine in Chicago, IL.

Her clinical and research interests include

surgical neuropathology, molecular classica-

tion of brain tumors, and bone/soft tissue

pathology.

Dr. Jared T. Ahrendsen joined the Department

of Pathology as an Assistant Professor of

Pathology at Northwestern University

Feinberg School of Medicine in 2022, where

he specializes in neuropathology and autopsy

pathology. Dr. Ahrendsen is also a trained

forensic pathologist and does forensic neuropa-

thology consultations. He has been writing for

PathologyOutlines.com since 2021 and joined

the neuropathology editorial board in 2023.

He received the PathologyOutlines.com Best

Author Award in 2022 and 2023. Dr. Ahrend-

sen’s research interests include molecular

classication of brain tumors and the utiliza-

tion of post-mortem brain tissue to better

understand human neurologic disease and

injury.

Meet the Authors

EWSR1) with a member of the CREB family of

transcription factors (CREB1, ATF1, or CREM).

CIC-rearranged sarcoma (new entity): high-

grade, poorly differentiated sarcoma (similar to

those arising outside of the CNS) and dened by

a fusion involving CIC (most often NUTM1).

Primary intracranial sarcoma, DICER1-mutant

(new entity): dened by mutations in DICER1

(somatic or germline) and usually consists of

spindled to pleomorphic cells, characteristic cyto-

plasmic eosinophilic globules, and abundant

mitotic activity (Fig. 3).

PITUITARY AND PINEAL TUMORS

• The following are changes in pituitary tumor

nomenclature:

Adamantinomatous craniopharyngioma and

papillary craniopharyngioma, which have distinct

morphology and molecular drivers, are now

considered distinct tumor types.

Pituitary adenoma is now called pituitary

neuroendocrine tumor (PitNET).

• New tumor types include the following:

Pituitary blastoma (new entity): usually driven

by alterations in DICER1 and composed of large

anterior pituitary neuroendocrine cells, cuboidal

or columnar primitive Rathke pouch epithelium,

and small undifferentiated blastemal cells.

Desmoplastic myxoid tumor of the pineal region,

SMARCB1-mutant (new entity): extremely rare

tumor with relatively bland spindled to epithelial

cells arranged in cords within myxoid and

heavily collagenized stroma. These are driven by

alterations in SMARCB1 (Fig. 4).

Fig. 3. Primary intracranial sarcoma, DICER1-mutant. Malignant spindle cells arranged in fascicles. Tumor cells in

the center with characteristic eosinophilic cytoplasmic globules.

Fig. 4. Desmoplastic myxoid tumor of the pineal region, SMARCB1-mutant. Histology (top panel) reveals cords of

epithelioid tumor cells embedded in a variably myxoid (shown) and desmoplastic (not shown) stroma. Immunohis

tochemistry demonstrates loss of nuclear SMARCB1 (INI1) expression in tumor cells (bottom panel).