The document summarizes key changes in the 2016 WHO classification of central nervous system tumors compared to previous classifications. It incorporates both genetic and histologic parameters. Major changes include recognizing diffuse midline glioma based on H3K27 mutations, defining ependymoma subtypes by RELA fusion status, and reclassifying gliomas based on IDH and 1p/19q codeletion status rather than histology alone. Imaging can provide non-invasive evaluation of genetic markers like IDH mutation status but cannot determine tumor grade alone. The updated classification integrates genotype with phenotype for more precise diagnosis.

1. DR S. KIRANMAI DNB (RD)
2016 UPDATES TO THE WHO
CLASSIFICATION OF TUMORS OF
THE CNS : WHAT THE
RADIOLOGIST NEEDS TO KNOW

2. • Prior classifications based on – histology and
observed level of differentiation.
• Primary CNS tumors are now thought to arise
from genetically altered pluripotent stem cells.
• 2016 WHO integrates genotypic(molecular
parametres )and phenotypic (histologic)
parametres.

3.  Two ways to identify genetic signature of brain
tumors
• Direct interrogation of mutated DNA
• Immunohistochemistry which assess the effects
of mutated genes on proteins(inexpensive), i.e it
will detect protein products(oncometabolites) of
specific oncogenic mutations

4.  Gliomatosis cerebri
 Fibrillary astrocytoma
 Protoplasmic astrocytoma
 Primitive neuroectodermal tumor
Only gemistocytic astrocytoma remains as a variant of diffuse astrocytoma.
Gliomatosis cerebri has also been deleted from the 2016 CNS WHO
classification as a distinct entity rather being considered a growth pattern. A
pattern of exceptionally widespread tumor growth that can be displayed by
any of the infiltrating gliomas, although it is most common in anaplastic
astrocytoma

5. • Diffuse midline glioma (mutations at position
K27 in the gene for histone H3)
• Ependymoma RELA fusion positive
• Multinodular and vacuolated tumor of cerebrum
• Diffuse leptomeningeal glioneuronal tumor
• Glioblastoma with primitive neuronal
component
• Epitheloid glioblastoma

6. • Solitary fibrous tumor / Hemangiopericytoma
• These lesions are actually arising from fibroblast
and are in the spectrum of the solitary fibrous
tumors of dura
• Both entities share a similar genetic alteration:
genomic inversion of 12q13 locus resulting in the
fusion of NAB2 and STAT6 genes
• Solitary fibrous tumors of the dura are WHO I
grade one lesion, whereas hemangiopericytomas
are WHO grade II or III (anaplastic) tumors

8.  Primitive neuroectodermal tumor is no longer
included in the diagnostic lexicon.
 Tumors in this group will now be referred
individually by name.
 Genetically defined - Medulloblastoma; ATRT;
and embryonal tumor with multilayered
rosettes, C19MC altered.
 Not yet genetically defined -
Medulloepithelioma, CNS neuroblastoma, CNS
ganglioneuroblastoma, and CNS embryonal
tumor NOS.

9. Subgroup Location Prognosis Age group
WNT –activated
SHH- activated
Non WNT/Non
SHH
Group 3
Group 4
10%
25-30%
20-25%
>35%
Cerebellar
peduncle, CP
cistern,
midline
fourth
ventricle
Lateral and
rostral
cerebellar
hemisphere,
4th ventricle
Diffuse
infiltrating,
midline 4th
ventricle
best
Intermediate
Worst
Slightly better
prognosis
compared to
group 3
Children and
adults
Infants and
adults
Infants and
children
Children, rare
in infants

11. B
C D
A

12.  Meningioma - WHO grade I
 Atypical Meningioma - WHO grade II
 Malignant meningioma- WHO grade III
• Atypical and malignant meningioma are indistinguishable on imaging
• Indistinct tumor margins with no border between tumor and
underlying cortex, absent/ partially effaced CSF cleft.
• Most reliable feature is the presence of lower ADC values (reflecting
higher cellularity)
• peritumoral edema is not a predictor of atypical or anaplastic
histology
• ** Difficult to determine meningioma tumor grade on the basis of
imaging findings alone.

13.  Now all infiltrating gliomas fell into two categories
(astrocytoma and oligodendroglioma) .Based not
only on their growth pattern and behaviors, but
also more pointedly on the shared genetic driver
mutations in the IDH1 and IDH2 gene .
 Diagnosis of oligoastrocytoma, which carried high
interobserver variability among pathologists, is
now strongly discouraged
 Oligoastrocytoma (NOS) should be used only
when testing for IDH mutation and 1p/19q
codeletion is not possible or has failed. Only rare
tumors show both astrocytic and oligodendroglial
genotypes (a so-called dual genotype) and are
truly mixed tumors

14.  For the WHO 2016 revision, IDH mutation has
become definitional for infiltrating gliomas in
adults, with 1p/19q codeletion further
characterizing the type.
 Oligodendroglioma is an infiltrating glioma that
carries both IDH mutation and 1p/19q codeletion
(which does not occur in the absence of IDH
mutation).
 Astrocytoma is an infiltrating glioma that is
subdivided in the classification by the presence of
IDH mutation and never contains 1p/19q
codeletion.

15. Localized astrocytoma Diffuse astrocytic tumors
Pilocystic- WHO grade I
Pilomyxoid II
Subependymal gaint cell I
Pleomorphic xanthoastrocytoma II

16. Diffuse astrocytic tumors WHO grade
Diffuse astrocytoma IDH mutant
Diffuse astrocytoma IDH wild type
Anaplastic astrocytoma IDH mutant
Anaplastic astrocytoma IDH wild type
Glioblastoma IDH mutant
Glioblastoma IDH wild type
Diffuse midline glioma H3K27-mutant
II
II*
III
III*
IV
IV
IV
* Biologic behavior more like IDH wild type GBM

17. • IDH 1 & 2
• 1p / 19 q Co-deletion
• ATRX(alpha thalassemia- mental retardation x-
linked gene)
• Histone H3-mutant glioma

18.  IDH 1 and IDH 2 are homodimers –part of
citric acid cycle

 Majority of diffuse astrocytomas and WHO
grade III and IV tumors with IDH mutation
also show loss of ATRX
alpha keto
glutarate
isocitrate
2 hydroxy glutarate

19. Variable IDH mutant IDH Wild type
Size Bigger Smaller
Contour Better defined contours Ill-defined contours
Extension Tend to affect one lobe
cross the midline less
frequently
Frequently multilobar
and bilateral
involvement
Location Frontal; relative sparing
of eloquent areas
Multilobar, cross the
midline
TP53 m: Temporoinsular Involvement of eloquent
areas, brain stem, and
diencephalon
TP53 n-mut: Frontal
MGMT met: Left cerebral
hemisphere, better
prognosis
MGMT unmet: Right
cerebral hemisphere,
worse prognosis

20. Growth rate Slower growth Faster growth
Necrosis NEC area and %NEC
lower
NEC area and %NEC
higher
Enhancement Homogeneous and less
intense
Heterogeneous and
more intense
Perfusion rCBV: Normal
aTBF/rTBF: Lower
rCBV: High
aTBF/rTBF: Higher
Diffusion ADC and FA: High ADC and FA: Low
Spectroscopy 2-HG positive 2-HG negative

21. 1p/19q codeletion present 1p/19q codeletion negative
Better prognosis
Seen in oligodendrogliomas
No codeletion (intact)
Poor prognosis
ATRX is inversely related to 1p/19q.
1p/19q codeletion present then ATRX will be intact - oligodendroglioma
In contrary if 1p/19q codeletion absent there will be loss of ATRX(mutated)

22.  Oligodendroglioma – IDH mutated
 1P/19q codeleted
 ATRX intact
 IDH-mutant diffuse astrocytoma-(WHO-II)
 IDH mutated
 1p/19q intact
 ATRX loss
 IDH-mutant anaplastic astrocytoma-(WHO-III)
 IDH mutated
 1p/19q intact
 ATRX loss

23.  IDH- Wild diffuse astrocytoma-(WHO –II*)
 IDH Intact
 1p/19q intact
 ATRX loss
 behave like GBM
 IDH – Wild anaplastic astrocytoma-(WHO-III*)
 IDH Intact
 1p/19q intact
 ATRX loss
 Exhibit wide spread infiltrative pattern(previously
gliomatosis cerebri)

24.  IDH mutant GBM- (WHO-IV)
 IDH mutated
 1p/19q intact
 ATRX loss
 secondary GBM(degenerated from low
grade astrocytoma).
 IDH wild GBM- (WHO-IV)
 IDH intact
 1p/19q intact
 ATRX loss
 Primary GBM

26. Mismatch sign on
T2 and FLAIR
images, high
signal on ADC , no
enhancement,low
rCBVmax values,
Increased Cho/Cr
ratio .The high-
resolution MR
spectroscopy by
69 ms of echo time
reveals the 2-HG
peak causing a
triplet within the
glutamine-
glutamate complex
(Glu-Gln), which is
consistent with the
existence of IDH1
mutation

27. IDH mutant
gliomas(A,B,C) tend to
have more defined borders
compared with their wild-
type counterpart. IDH wild-
type tumors usually have
lower ADC values
(arrowheads in D)
compared with IDH mutant
(arrowheads in A), on the
other hand, gliomas IDH
mutant show less intense
enhancement (arrows in C)
than IDH wild-type (arrows
in F ). More extensive
corpus callosum
involvement related to IDH
wild-type glioblastomas

28. MR spectroscopy reveals the 2-HG peak causing a triplet within the
glutamine-glutamate complex (Glu-Gln) at 2.25ppm , which is consistent
with the existence of IDH1 mutation

29. Gliomatosis cerebri pattern of tumor growth, frontal disease that is
greater on the right than on the left, with bilateral medial thalamic
involvement.

30. As a majority of DIPGs seen in pediatric age group harbor mutations at
position K27 in the gene for histone H3, this subset has now been formally
recognized as a specific tumor entity .The term diffuse midline glioma indicates
that these tumors do not exclusively occur in the pons and also may be found
in the thalami, cerebellum, spinal cord, and other midline structures,
including the third ventricle, hypothalamus, and pineal region

33.  Found in approximately 70% of all childhood
supratentorial tumors and is absent in posterior
fossa or spinal cord ependymomas .
 WHO has now defined a type of supratentorial
ependymoma based on the presence of this
fusion of C11orf95 with RELA.
 At imaging, supratentorial tumors tend to
manifest as large hemispheric solid and cystic
masses in both children and adults. Solid
components show diffusion restriction and
perfusion compatible with a high-grade tumor.

34. Layered
diagnosis of
CNS tumors.
Integrated
diagnosis comes
last, only after
layers 2–4 are
defined.

35. Deletions Additions Changes
• Gliomatosis cerebri
• Fibrillary astrocytoma
• Protoplasmic
astrocytoma
• PNET
• Hemangiopericytoma
/solitary fibrous
tumor
• Brain invasion of
meningioma
• Medulloblastoma(gen
etic subtypes)
• Diffuse astrocytoma
• Embryonal tumors
• Diffuse midline
glioma(mutations
at position K27 in
the gene for histone
H3)
• Ependymoma
RELA fusion
positive(fusion of
the C11orf95 and
RELA genes)
• Multinodular and
vacuolated tumor
of cerebrum
• Diffuse
leptomeningeal
glioneuronal tumor
• Glioblastoma with
primitive neuronal
component

36.  2016 updates to the WHO brain tumor
classification system : Derek R. Johnson, Julie B.
Guerin, Caterina Giannini, Jonathan M.
Morris, Lawrence J. Eckel, and Timothy J.
Kaufmann RadioGraphics 2017 37:7, 2164-2180
 The 2016 World Health Organization
Classification of Tumors of the Central
Nervous System: A Practical Approach for
Gliomas, Part 2. Isocitrate Dehydrogenase
Status—Imaging Correlation