GACETA MÉDICA DE MÉXICO

BRIEF COMMUNICATION

WHO CNS5 2021 includes specific mutations in gliomas that

can be identified with MRI quantitative biomarkers
Melissa García-Lezama,1 José Damián Carrillo-Ruiz,1 Sergio Moreno-Jiménez2
and Ernesto Roldán-Valadez1*
1
Directorate of Research, Hospital General de México “Dr. Eduardo Liceaga”; 2Directorate of Surgery, Instituto Nacional de Neurología y Neurocirugía
“Manuel Velasco Suárez”. Mexico City, Mexico

Abstract

In 2021, the latest version of the World Health Organization classification of central nervous system tumors (WHO CNS5) was
published, which is considered an international standard. The first editions of this classification were based on histological
characteristics and, subsequently, aspects related to new knowledge were incorporated. In the 2016 revision, molecular char-
acteristics were implemented for the classification and staging of gliomas, such as the presence of mutations in IDH1 or IDH2.
Currently, advanced magnetic resonance imaging (MRI) techniques allow assessing for the presence of 2-HG (increased
oncometabolite that precedes IDH mutations), whereby IDH mutations can be indirectly identified, without invasive procedures
being required. Advanced MRI is a growing field, highly useful for diagnosis and management of different pathologies. This
document addresses the implications of WHO CNS5 classification in the evaluation of gliomas, as well as historical aspects,
the bases of conventional MRI, and advanced MRI sequences useful in current classification.

KEYWORDS: Biomarkers. Glioblastoma. Gliomas. Magnetic resonance imaging.

WHO CNS5 2021 incluye mutaciones específicas en gliomas que pueden ser
identificadas con biomarcadores cuantitativos de resonancia magnética
Resumen

En 2021 se publicó la última versión de la clasificación de tumores del sistema nervioso central de la Organización Mundial
de la Salud (WHO CNS5 por sus siglas en inglés), considerada un estándar internacional. Las primeras ediciones se basaron
en características histológicas y posteriormente se incorporaron aspectos relacionados con nuevos conocimientos. En la re-
visión de 2016 se implementaron características moleculares para la clasificación y estadificación de los gliomas, como la
presencia de mutaciones en IDH1 y IDH2. Actualmente, las técnicas de resonancia magnética avanzada permiten valorar la
presencia de 2-HG (oncometabolito incrementado ante mutaciones en IDH), de forma que indirectamente y sin procedimien-
tos invasivos pueden identificarse las mutaciones en IDH. La resonancia magnética avanzada es un procedimiento aún en
desarrollo, de gran utilidad para el diagnóstico y manejo de distintas patologías. En el presente documento se abordan las
implicaciones de la WHO CNS5 en la evaluación de gliomas, así como aspectos históricos, las bases de la resonancia mag-
nética convencional y secuencias de resonancia magnética avanzada útiles en la clasificación actual.

PALABRAS CLAVE: Biomarcadores. Glioblastoma. Gliomas. Resonancia magnética.

*Correspondence: Date of reception: 22-09-2022 Gac Med Mex. 2023;159:161-168

Ernesto Roldán-Valadez Date of acceptance: 30-11-2022 Contents available at PubMed
E-mail: ernest.roldan@usa.net DOI: 10.24875/GMM.M22000757 www.gacetamedicademexico.com
0016-3813/© 2022 Academia Nacional de Medicina de México, A.C.. Published by Permanyer. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

161
 Gaceta Médica de México. 2023;159
Background
The World Health Organization published the fifth
edition of the Classification of Tumors of the Central
Nervous System (WHO CNS5) in 2021. Previous four
editions corresponded to the years 1979, 1993, 2000,
and 2007, and there was a subsequent revision in
2016.1,2 In the WHO CNS5 classification, 22 new
types of tumors are recognized; in addition, the no-
menclature for some tumors was revised in 2016
based on recent findings in genetic-molecular diag-
nosis.1 The fifth edition emphasizes the importance
of integrated diagnoses, some based on novel diag-
nostic technologies, such as DNA methylome
profiling. 2
To stage severity and for the management of tu-
mors, the new classification emphasizes identifica-
tion of specific mutations (among the most relevant,
in isocitrate dehydrogenase [IDH] genes) and dom-
inance of genetic patterns, rather than histological
characteristics. As a consequence of this new clas-
sification, the American Society for Radiation Oncol-
ogy has recently published updated clinical practice
guidelines for diffuse glioma with IDH mutations,
which were published in May 2022. 3 During the sec-
ond half of 2021 and in 2022, some indexed and
official journals of medical specialties in the United
States that treat brain tumors published articles
commenting on the subject. 2,4-6 Most these articles
are directed at medical specialists (radiologists, on-
cologists, neurosurgeons, etc.) and address ad-
vanced magnetic resonance imaging (MRI)
techniques that allow, in a non-invasive way, brain
tumors in vivo characterization; in addition to quali-
tative morphological aspects, these techniques
make quantification of metabolites related to muta-
tions in the central nervous system (CNS) possible,
which is an essential part of diagnosis. These pos-
sibilities with MRI, which until a few years ago ap-
peared to be science fiction, have become a reality
in tertiary care hospitals that have the necessary
technology.
Given that the subject is one of our lines of re-
search, we have prepared this document addressed
to physicians who treat brain tumors (pediatricians,
neurologists, oncologists, radiologists, neurosur-
geons, etc.), in which we comment about the changes
in WHO CNS5 classification of gliomas that can be
typified by means of advanced MRI, in order to iden-
tify genetic mutations indicative of an aggressive
162
tumor and that it is necessary for the treatment plan
to be changed. A historical description of WHO CNS5
classification is included, as well as a summary of the
most relevant changes in the classification, current
concepts in conventional MRI diagnosis for glioblas-
toma, and a brief description of advanced MRI tech-
niques that identify the aforementioned mutations.
Historical aspects
WHO CNS classification first edition was presented
in 1979 by Zülch et al. This system has become the
international standard for CNS tumors diagnosis, with
periodic revisions and updated editions.6 The first edi-
tion was mainly based on clinical and histological
data, such as those obtained by hematoxylin-eosin
staining; subsequent editions integrated knowledge
on immunohistochemistry, as well as molecular
biomarkers.1,2,6
Traditionally, CNS tumors grading has been based
on histological aspects, but certain molecular markers
can provide important prognostic information. For this
reason, molecular parameters have been included as
biomarkers for tumor grading and subsequent prog-
nostic estimation. 2
Changes in WHO CNS5 classification
This edition introduces numerous relevant changes,
from the nomenclature and grading of certain tumors,
to the addition of new types of brain tumors. In the
fourth edition, gliomas were distributed in different
classification groups; in the fifth edition, they were
included in a single group called “Gliomas, glioneuro-
nal, and neuronal tumors”. An important aspect is the
division of diffuse gliomas according to their frequen-
cy in children or adults. 2
A specific change for the category of diffuse glio-
mas consists of new criteria for establishing
IDH-wildtype glioblastoma diagnosis: tumors classi-
fied due to their histopathological characteristics as
grade 2 or 3 IDH-wildtype astrocytoma were observed
to frequently have an aggressive behavior, compara-
ble to that of glioblastomas, which is why genetic al-
terations that could predict aggressive behavior were
evaluated. The result was EGFR amplification, muta-
tions in TERTp, gain of chromosome 7 or loss of chro-
mosome 10. Currently, an IDH-wildtype astrocytoma
with any of these alterations allows a glioblastoma
diagnosis, even if it does not exhibit typical histo-
pathological characteristics.6 The changes in WHO
 García-Lezama M et al. WHO CNS5 mutations in gliomas and biomarkers

Table 1. Differences between WHO CNS 2016 and 2021 editions

WHO CNS

Fourth edition (2016) Fifth edition (2021)

Terms for classification Entities and variants Types and subtypes

Numeration Roman numbers Arabic numbers

Taxonomy: tumor groups Divided into 17 groups: oligodendroglial and diffuse
astrocytic tumors, other astrocytic tumors, ependymal
tumors, other gliomas, choroid plexus tumors, neuronal
tumors and mixed neuronal-glial tumors, pineal
region tumors, embryonal tumors, cranial nerve and
paraspinal tumors, meningiomas, mesenchymal tumors
and non-meningothelial tumors, melanocytic tumors,
lymphomas, histiocytic tumors, germ cell tumors,
tumors of the sellar region and metastatic tumors
Divided into 13 groups: gliomas, glioneuronal and
neuronal tumors, choroid plexus tumors, embryonal
tumors, pineal tumors, cranial and paraspinal nerve
tumors, meningiomas, mesenchymal and non-
meningothelial tumors involving the CNS, melanocytic
tumors, hematolymphoid tumors involving the
CNS, germ cell tumors, tumors of the sellar region,
metastases to the CNS, and genetic tumor syndromes
involving the CNS

Staging Through different tumor entities Between the same type

Newly-recognized tumor 22
types

Specific changes: Gliomas, glioneuronal and neuronal tumors

Diffuse gliomas They were classified in the group of diffuse They are classified in the group of gliomas, glioneuronal
oligodendroglial and astrocytic tumors. There was no and neuronal tumors, divided in two subgroups
distinction by age according to involvement frequency in children or
adults.

Newly-recognized tumor 14
types

Classification Common diffuse gliomas were divided into 15 different Common diffuse gliomas are divided into 3 types
simplification entities

IDH-mutant diffuse astrocytic tumors; corresponded IDH-mutant diffuse astrocytic tumors; only IDH-mutant
to three different tumor types according to histological astrocytomas are considered and subsequently receive
parameters WHO grade 2, 3, or 4

Tumor grading Based on histological characteristics Genetic alterations can change tumor grade, even
without the corresponding histological features being
present, such as a homozygous CDKN2A/B deletion,
which results in grade 4 in IDH-mutant astrocytomas.
Similarly, IDH-wildtype glioblastoma diagnosis can
be established in the context of an IDH-wildtype
diffuse astrocytic glioma if it exhibits any of the
following mutations: mutation in TERT promoter, EGFR
amplification, gain of one chromosome 7, or loss of one
chromosome 10
CDKN2A: cyclin-dependent kinase inhibitor 2A; CNS: central nervous system; EGFR: epidermal growth factor receptor; IDH: isocitrate dehydrogenase; TERT: telomerase reverse
transcriptase; WHO CNS: World Health Organization Classification of Tumors of the Central Nervous System.

CNS5 classification, compared to previous edition, are
summarized in table 1. Figure 1, using an algorithm,
describes how the diagnosis of diffuse gliomas is car-
ried out according to the new classification.
WHO CNS5 also emphasizes the use of molecular
biomarkers for the diagnosis of gliomas, implemented
since fourth edition revision in 2016, i.e., according to
mutations in the gene that encodes IDH1 or IDH2.
These mutations are considered an early event in the
genesis of gliomas and are commonly found in
low-grade gliomas. The prognosis of patients with
diffuse gliomas with IDH1 or IDH2 mutations is better
than in those with IDH-wildtype gliomas.7 These mu-
tations have been associated with 2-hydroxyglutara-
mate (2-HG) accumulation in the tumor.8
Conventional MRI for diagnosis
Gliomas are CNS primary tumors that arise from
glial cells different lineages.9 Glioblastoma is an
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 Gaceta Médica de México. 2023;159

Diffuse glioma

IDH-Mutant IDH-Wildtype

Retained ATRX Mutant ATRX

One or more of the
following: Necrosis,
1p/19q codeletion 1p/19q intact, TP53 mutation microvascular
proliferation, TERT
mutation, EGFR
amplification, +7/-10
CDKN2A/B CDKN2A/B
Wildtype Homozygous deletion

Necrosis and/or
microvascular proliferation

IDH-Mutant,
1p/19-codeleted IDH-mutant IDH-mutant IDH-Wildtype
oligodendroglioma, astrocytoma astrocytoma glioblastoma
WHO grade 2/3 WHO grade 2/3 WHO grade 4 WHO grade 4

Figure 1. Representative diagram of diffuse gliomas diagnosis according to WHO CNS5 new classification. ATRX: ATP-dependent helicase;
CDKN2A: cyclin-dependent kinase inhibitor 2A; EGFR: epidermal growth factor receptor; IDH: isocitrate dehydrogenase; TERT: telomerase
reverse transcriptase; TP53: tumor protein 53; WHO: World Health Organization.

extremely heterogeneous subtype of diffuse high-
grade gliomas, the most common in adults, the most
lethal,9,10 and is stratified as grade 4 according to the
World Health Organization classification.2,10 This tumor
is characterized by marked neovascularity, increased
mitosis, high cellularity, nuclear pleomorphism, and
microscopic evidence of necrosis. Since previous de-
cades, imaging findings describe a highly heteroge-
neous appearance, typically with central areas of
necrosis or hemorrhage, irregular borders, and perile-
sional edema.11
Gadolinium-enhanced MRI is the gold standard
for brain tumors evaluation. Conventional MRI mo-
dalities include T1 without contrast, T1 with contrast
(frequently gadolinium), FLAIR, and T2.10,12,13 Fig-
ure 2 shows the classic appearance of a glioblas-
toma using conventional imaging techniques.
Imaging features suggestive of a grade 2 or 3 dif-
fuse glioma include a circumscribed and supraten-
torial, homogeneous and hyperintense mass on T2,
typically located in the frontal or temporal lobes,
without calcifications or contrast enhancement.
With FLAIR, it is typical to find a homogeneous
164
mass, relatively hypointense in all its extension if
compared with the T2 sequence, except for a hy-
perintense peripheral halo. Grade 3 astrocytomas
may show higher heterogeneity on T2 and contrast
enhancement. 5
Advanced MRI sequences for diagnosis
Since 2006, studies have been published on the
use of advanced MRI techniques whereby it is pos-
sible to quantitatively analyze images. With advanced
MRI techniques implementation, non-invasively
studying the tumor and peritumoral characteristics
useful for prognosis and treatment assessment was
made possible.14-16 Advanced MRI techniques contin-
ue to be developed, and physicians who are not
specialists in the subject may ignore them; generally,
there is the notion that images only show qualitative
aspects. As more knowledge on advanced imaging
has been acquired, clinicians have learned that con-
ventional MRI is just the tip of the iceberg. Advanced
MRI techniques are divided into four types: diffusion,
 García-Lezama M et al. WHO CNS5 mutations in gliomas and biomarkers

A B C D
D

Figure 2. Conventional magnetic resonance imaging techniques used in the evaluation of brain tumors (in this case a glioblastoma). A: T1
without contrast; B: T1 with contrast; C: FLAIR; D: T2.

Figure 3. Conventional qualitative techniques (above the gray line) compared with advanced magnetic resonance imaging techniques (below
the gray line). AD: axial diffusivity; ASL: arterial spin labeling; Cho: choline; CL: linear tensor; CP: flat tensor; CS: spherical tensor; DCE: dynamic
contrast-enhanced; DSC: dynamic susceptibility contrast; FA: fractional anisotropy; mI/Cr: myo-inositol/creatine; L: diffusion tensor total mag-
nitude; NAA: N-acetyl-aspartate; P: pure isotropic diffusion; Q: pure anisotropic diffusion; RA: relative anisotropy; rCBF: relative cerebral blood
flow; rCBV: relative cerebral blood volume; RD: radial diffusivity.

perfusion, spectroscopy, and diffusion tensor. In re- modalities.12,13,17-20 Figure 3 represents the MRI tech-
cent years, we have published articles on how glio- niques; conventional modalities involve a smaller
blastoma is observed using these four imaging percentage of current imaging.
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 Gaceta Médica de México. 2023;159

Figure 4. MRS of a patient with a tumor positive for IDH mutation. A: chart of metabolites detected in the white box (healthy tissue zone);
B: chart of metabolites detected in the black box (tumor lesion zone). Presence of the 2-HG oncometabolite stands out in chart B (tumor), com-
pletely absent in chart A (healthy tissue). MRS: magnetic resonance spectroscopy; Cho: choline; Naa: N-acetyl-aspartate; Lac: lactate; 2-HG:
2-hydroxyglutarate; M-ins: myo-inositol.

MR spectroscopy to identify IDH mutations
In gliomas, hydrogen magnetic resonance spectros-
copy (MRS) shows a typical image characterized by
increases in lactic acid and choline in the 0.9 to 1.3
parts per million (ppm) regions, as well a decrease in
N-acetyl-aspartate in the 2.0 ppm region. 21
MRS has a role in the evaluation of IDH1 and IDH2
mutations (although, by themselves, they do not show
clear radiological evidence; 2-HG, an increased me-
tabolite in the presence of these mutations, can be
detected by MRS); its sensitivity and specificity is 100
and 81.3%, respectively, with these values favoring its
diagnostic scope. 22,23
Initially, it was thought that the 2-HG metabolite
could be detected in the region between 1.91 and
2.24 ppm, but the peak of that metabolite overlapped
with glutamate, glutamine, and gamma-aminobutyric
acid. For this reason, the region between 4.0 and
166
3.5 ppm is used to identify gliomas with IDH1 and
IDH2 mutations, in which differences between
IDH-wildtype mutations and those previously classi-
fied as “IDH-mutant” are observed. 21 Figure 4 shows
an example of the presence of 2-HG in MRS-detected
tumor tissue.
In addition, IDH1 and IDH2 enzymes status typing
using diffusion tensor imaging has shown favorable
results when artificial intelligence techniques such as
machine learning are combined. 24 In 2020, Flores Al-
vares et al. indicated that MRS and diffusion tensor
imaging would be implemented in the World Health
Organization classification of brain tumors.12
Future directions
The study of glioblastoma and other gliomas is
not over yet; integration of new advanced imag-
ing techniques provides better non-invasive in vivo
 García-Lezama M et al. WHO CNS5 mutations in gliomas and biomarkers
characterization of tumors.25 The use of these tech-
niques at tertiary care hospitals will allow new informa-
tion to be obtained that may help identify the
microstructure and heterogeneity of gliomas, as well as
tumor infiltration, among other aspects, which will allow
better risk stratification and treatment planning.25-27
MRI plays a key role in the evaluation of brain tu-
mors, although conventional techniques remain the
standard for diagnosing and assessing evolution.10 In
the latest update of the American Society for Radia-
tion Oncology guidelines, surveillance with MRI every
six months is recommended in patients with oligoden-
drogliomas with good prognosis.3
The possibility to identify the presence of IDH mu-
tation using MRS and diffusion tensor has great im-
pact on tumor evaluation and prognosis establishment,
which is why, since 2020, it became clear that it could
be incorporated to the World Health Organization
SNC tumors classification.12
MRS has great potential in 2-HG routine analysis,
especially in sensitive areas of the brain where surgi-
cal risk is high, as well as in the monitoring of metab-
olites associated with IDH mutation during treatment
with specific therapies.
In conclusion, advanced imaging implementation con-
stitutes a challenge for the different specialties related
to the management of brain tumors. However, the diffi-
culty for gaining access to these technologies (which
are not available at all institutions) and the longer image
processing time (which must be carried out by trained
personnel) constitute important limitations. Despite the
above, the future of neuroradiology daily practice will
include advanced imaging techniques, which will pro-
vide further knowledge about tumor biology and stag-
ing, in addition to the follow-up of new treatments.
Funding
The authors declare that they have not received any
funding for this study.
Conflicts of interest
The authors declare that they have no conflicts of
interest.
Ethical disclosures
Protection of human and animal subjects. The
authors declare that no experiments were performed
on humans or animals for this research.
Confidentiality of data. The authors declare that
no patient data appear in this article.
Right to privacy and informed consent. The au-
thors declare that no patient data appear in this
article.
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