includes changes of 2016 classification

1. CNS tumors – Recent Updates
(WHO classification 2016)
Presenter Dr Dhanya AN
Moderator Dr Mamatha SV

2. Contents
• Introduction
• Recent updates of CNS tumors
• General principles and challenges
• Nomenclature
• New Classification
• Newly recognized entities, variants and
patterns
• Summary

3. Introduction
1) Supporting (non-neuronal) Cells - Glial cells provide
support and protection for neurons
• Astrocytes—star-shaped cells that play an active role
in brain function by influencing the activity of neurons
1) recycling neurotransmitters
2) secreting neurotrophic factors (e.g., neural growth
factor) that stimulate the growth and maintenance of
neurons
3) dictating the number of synapses formed on neuronal
surfaces and modulating synapses in adult brain
4) maintaining the appropriate ionic composition of
extracellular fluid surrounding neurons

4. • Oligodendrocytes— The oligodendrocyte is
the analog of the Schwann cell in the central
nervous system
– responsible for forming myelin sheaths around
brain and spinal cord axons.
• Microglia— the smallest of glial cells.
– represent the intrinsic immune effector cells of the
CNS and underlie the inflammation response that
occurs following damage to the central nervous
system and the invasion of microorganisms.

5. • Ependyma — in addition to the glial cells,
– the CNS has epithelial-like cells that line the
ventricles of the brain and the central canal of the
spinal cord.
– Cuboidal to columnar cells with cilia and microvilli
and helps in secretion of CSF
2) Neurons (nerve cells)—neurons are the
structural and functional units of the nervous
system
they are specialized to conduct electrical
signals.

8. Recent updates of CNS tumors
• For the past century, the classification of brain
tumors has been based largely on concepts of
histogenesis.
– Light microscopic features in hematoxylin and eosin
sections,
– immunohistochemical expression of proteins and
– ultrastructural characterization
• Studies over the past two decades have clarified
the genetic basis of tumorigenesis in the brain
tumor entities

9. • In 2014, a meeting held in Haarlem, the
Netherlands, under the auspices of the
International Society of Neuropathology,
• Established guidelines for incorporating
molecular findings into brain tumor diagnoses,
this lead to major revision of the 2007 CNS
WHO classification

10. • The current update (2016 CNS WHO) thus
breaks with the century-old principle of
diagnosis based entirely on microscopy by
incorporating molecular parameters into the
classification of CNS tumor entities

11. General principles and challenges
• Integrated phenotypic and genotypic
parameters for CNS tumor.
• Greater diagnostic accuracy, improved patient
management , accurate determinations of
prognosis and treatment response.
• Large group of tumors that do not fit into
narrowly defined entities they are defined as
NOS( not otherwise specified )

12. • Major example of the diagnostic refinement in
new classification is oligoastrocytoma
• Under previous classification, lot of
interobserver variability
• In New classification
• Combine genotype and phenotype.
• Astrocytoma (IDH-mutant, ATRX-mutant,
1p/19q-intact)
• Oligodendroglioma (IDH-mutant, ATRX-
wildtype and 1p/19q-codeleted)

13. • So the diagnosis of oligoastrocytoma as
designated as NOS should be done
– Only in absence of molecular study “or” if dual
tumor population is there.
– Dual population to be determined by molecular
study

14. Other issue
• Microscopic appearance vs molecular study.
• If tumor shows one appearance on histology
but give molecular indication of another
• Eg: diffuse astrocytoma on histology
• but IDH mutation and 1p/19q codeletion
• The diagnosis will be oligodendroglioma,
IDH-mutant and 1p/19q-codeleted

15. • Will genotyping take over histology?
• As of now an integrated approach is
recommend by WHO 2016.
• On going research
• Grade based on histology.

16. Nomenclature
• Histopathological name followed by genetic
features
– Diffuse astrocytoma,IDH-mutant
– Oligodendroglioma, IDH-mutant and 1p/19q-
codeleted
• Tumor lacking genetic mutation designated as
wild type.
– Glioblastoma, IDH-wildtype
• Specific genetic alteration is present or absent, the
terms “positive” can be used
– Ependymoma, RELA fusion–positive.

17. • For site lacking any access to molecular
diagnostic testing, a diagnostic designation of
NOS is permissible
• NOS : either not tested for relevant genetic
parameters or the genetic alteration does not fit
any known parameter.
• NOS designation tells we do not know enough
pathologically, genetically and clinically and
which should, therefore, be subject to future study
before additional refinements in classification can
be made
• WHO grade written in roman numerical
• Italics for specific gene mutation but not for
families

18. Classification
• Diffuse Astrocytic and Oligodendroglial
tumors
• Other Astrocytic tumors
• Ependymal tumors
• Other gliomas
• Choroid plexus tumors

19. • Neuronal and mixed neuronal-glial tumours
• Tumors of the pineal region
• Embryonal tumors
• Tumors of the cranial and paraspinal nerves
• Meningiomas

20. • Mesenchymal, non-meningothelial tumors
• Melanocytic tumors
• Lymphoma
• Histiocytic tumors
• Germ cell tumors
• Tumors of the sellar region
• Metastatic tumors

21. Newly recognized entities, variants
and patterns
• Diffuse gliomas:
• In the past all astrocytic tumors had been grouped
together,
• Now all diffusely infiltrating gliomas (whether
astrocytic or oligodendroglial) are grouped together:
• 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
• Pathological point
• Prognostic similar tumors
• And targeted therapy

24. Diffuse astrocytoma and anaplastic
astrocytoma
• Grade II and grade III astrocytoma has been
divided into IDH-mutant, IDH-wildtype and
NOS categories.
• IDH wildtype is rare diagnosis to be give with
caution
• Protoplasmic and fibrillary astrocytoma
removed.

25. • Only gemistocytic astrocytoma remains as a
distinct variant of diffuse astrocytoma, IDH
mutant
– Fibrillary and protoplasmic astrocytomas are
deleted
• Gliomatosis cerebri has also been deleted from
the 2016 CNS WHO classification as a distinct
entity rather being considered a growth pattern

26. Glioblastomas
• Glioblastoma, IDH-wildtype > 55 yrs age
• Glioblastoma, IDH-mutant secondary to diffuse
gliomas
• Glioblastoma, NOS
• Sequencing for IDH differs with age.
– in younger adults IDH sequencing is highly
recommended following negative R132H IDH1
immunohistochemistry,
– whereas > 55 yr suggests that sequencing may not be
needed in the setting of negative R132H IDH1
immunohistochemistry in such patients.

28. • Epithelioid glioblastoma has been added
• IDH-wildtype glioblastoma
– Giant cell glioblastoma
– Glisarcoma
– Epitheliod glioblastoma

29. Epithelioid glioblastomas
• Abundant eosinophilic cytoplasm,
• Vesicular chromatin
• Prominent nucleoli (often resembling
melanoma cells)
• Variably present rhabdoid cells
• Children and young adults
• BRAF mutation
• Lack EGFR amplification and chromosome 10
loss
• frequent hemizygous deletions of ODZ3

30. • show a discrete border
with adjacent brain,
often suggestive of a
metastasis

31. • Epithelioid cells with
abundant eosinophilic
cytoplasm,
• Vesicular nuclei, and large
melanoma-like nucleoli
• Sometimes, a subset of
tumor cells display
eccentric nuclei and
paranuclear inclusions
that overlap with rhabdoid
neoplasms

32. • Sometimes focal
evidence of
pleomorphic
xanthoastrocytoma,
including bizarre giant
cells

33. • GFAP expression
is often limited (e)
and may even be
lacking entirely.
• In contrast, S100
(f) protein is
strongly expressed

34. • Other glial
markers, such as
OLIG2 may also
be positive (g)
• Roughly half of
Ep-GBMs express
BRAF V600E
mutant (h)

35. • Glioblastoma with primitive neuronal
component was added as a pattern
• Known as glioblastoma with PNET-like
component
• Comprised of diffuse astrocytoma(any grade)
or rarely oligodenroglioma
• With well demarcated nodules containing
primitive cells with neuronal differentiation.
– Homer Wright rosettes, synaptophysin positivity
and loss of GFAP expression
• MYC or MYCN amplification

36. • These tumors have a tendency for craniospinal
fluid dissemination
• So on diagnosis warrants a search for
craniospinal seeding clinically.
• Small cell glioblastoma/astrocytoma
• granular cell glioblastoma/astrocytoma remain
the same as growth pattern
• Both have poor glioblastoma-like prognosis

37. • astrocytic component on
the left and the primitive
neuronal component on
the right
• The primitive neuronal
component is evident as
a highly cellular nodule
within an classic
diffuse astrocytoma

38. • Well-formed Homer
Wright rosettes (c)
• (d) Large
cell/anaplastic
• increased cell size,
• vesicular chromatin,
• macronucleoli,
• cell–cell wrapping
(arrows)

39. • The primitive
component typically
shows loss of glial
marker expression,
including GFAP and
OLIG2 (e)
• (f) gain of neuronal
features, such as
• synaptophysin
positivity

40. • A subset of cases
demonstrates
features of secondary
glioblastoma, by
showing IDH1
R132H mutant
protein expression
(g).
• (h) FISH revealed
MYCN gene
amplification

41. Oligodendrogliomas
• Requires both IDH gene family mutation and
combined whole-arm losses of 1p and 19q
(1p/19q codeletion).
• In absence of genetic testing -“NOS “ can be
given

42. • Childhood tumors that histologically resemble
oligodendroglioma often do not demonstrate
IDH gene family mutation and 1p/19q
Codeletion
• Until such tumors are better understood at a
molecular level
• Should be included in the oligodendroglioma,
NOS category

43. Oligoastrocytomas
• This diagnosis strongly discouraged
• With proper genetic testing can be grouped under
astrocytoma or oligodendroglioma
• But can be reported with suffix “NOS “ In
absence of genetic testing
• Rare cases of true oligoastrocytoma (genetically,
phenotypically) have been reported
• Until further reports confirming such tumors are
available for evaluation as part of the next WHO
classification, they should be included under the
provisional entities of oligoastrocytoma, NOS

44. Pediatric diffuse gliomas
• Pediatric diffuse gliomas were grouped with
their adult counterparts
• Information on the distinct underlying genetic
abnormalities is emerging
• K27M mutations in the histone H3 gene
H3F3A and some times HIST1H3B gene
• This newly defined entity is termed diffuse
midline glioma, H3 K27M–mutant - includes
tumors previously referred to as diffuse
intrinsic pontine glioma (DIPG)

45. • These tumors involve
the brain stem
(especially pons), spinal
cord, thalamus
• Minimal
hypercellularity and
cytologic atypia

46. • tumor cells strongly
expressed the H3
K27M–mutant protein
(c)
• (d) showed loss of
ATRX expression

47. • In thalamic mass classic
features of glioblastoma
with prominent
multinucleated giant cell
are seen

48. • In addition to H3
K27M–mutant
protein expression
(g)
• (h) strong p53
staining

49. Other astrocytomas
• Anaplastic pleomorphic xanthoastrocytoma,
WHO grade III has been added.
• Previously Pleomorphic xanthoastrocytoma
with anaplastic features.
• 5 or more mitoses per 10 high-power fields
• Necrosis may be present
• Bad prognosis

50. • Grading of pilomyxoid astrocytoma has also been
changed(earlier grade II)
• Significant similarities between pilocytic and
pilomixoid genetic features.
• Further studied needed to clarify behavior
• Till then suppress the grade

52. Ependymomas
• More prognostic and reproducible classification
and grading scheme is yet to be published
• Ependymoma, RELA fusion–positive, This variant
accounts for the majority of supratentorial tumors
in children
• Cellular ependymoma, has been deleted
• More studies needed

55. Neuronal and mixed neuronal-glial
tumours
• Newly recognized entity diffuse
leptomeningeal glioneuronal tumor
• Present with diffuse leptomeningeal disease
• With or without a recognizable parenchymal
component
• Commonly in spinal cord.
• Children and adolescents

58. Diffuse leptomeningeal glioneuronal
tumor
• Monomorphic clear cell glial morphology,
reminiscent of oligodendroglioma
• BRAF fusions ,deletions of chromosome arm
1p, either alone or occasionally combined with
19q
• IDH mutations are absent.
• Nosological position unclear whether to place
under gliomas or glioneural tumors
• Prognosis variable

59. this DLGNT patient had widespread expansion and fibrosis
of spinal (a) and cerebral (b), along with intraventricular
masses and variably cystic, mucoid intraparenchymal
extensions

60. The DLGNT biopsy specimen showed a leptomeningeal infiltrate (c) with
oligodendroglioma-like cytologic features (d).

61. OLIG2-positive (e), variable synaptophysin immunoreactivity(f)

62. FISH showing chromosome 1p deletion (g; tumor cells
showing red as 1p, green as 1q signals)
BRAF fusion/duplication (h; increased red BRAF and green KIAA1549
copy numbers, in addition to yellow fusion signals)

63. • Newly recognized architectural related to
ganglion cell tumors is found, multinodular
and vacuolated pattern
• Reported as multinodular and vacuolated
tumor of the cerebrum
• Multiple nodules of tumor with a conspicuous
vacuolation. The tumor cells show glial and/or
neuronal differentiation

65. Medulloblastomas
• There are long-established histological variants of
medulloblastoma
– desmoplastic/nodular,
– medulloblastoma with extensive nodularity,
– large cell, and
– Anaplastic , have clinical utility
• widely accepted four genetic (molecular) groups of
medulloblastoma
– WNT activated,
– SHH-activated,
– “group 3”
– “group 4”
• “Genetically defined” and “Histologically defined”
variants

66. • Wingless (Wnt) -family of growth factor
receptors involved in embryogenesis and cell–
proliferation control mechanisms
• SHH – Sonic Hedgehog
• Group 3 – MYC amplification
• Group 4 - Isochromosome 17q
• Integrated diagnosis that includes both the
molecular group and histological phenotype

70. Other embryonal tumors
• Substantial changes
• Removal of the term primitive
neuroectodermal tumor or PNET from the
diagnostic lexicon
• Reclassification based on amplification of the
C19MC region on chromosome 19

71. • Amplification of the C19MC seen in
– Embryonal tumors with multilayered rosettes,
– Some cases, medulloepithelioma
• Presence of C19MC amplification results in a
diagnosis of embryonal tumor with multilayered
rosettes (ETMR), C19MC-altered.
• In the absence of C19MC amplification, a tumor
with histological features conforming to
ETANTR/ ETMR should be diagnosed as
embryonal tumor with multilayered rosettes, NOS

73. • Atypical teratoid/rhabdoid tumor (AT/RT) is
now defined by alterations of either INI1 or,
very rarely, BRG1
• Histological features of AT/RT but no genetic
features then descriptive diagnosis of CNS
embryonal tumour with rhabdoid features
• CNS embryonal tumor, NOS that includes
tumors previously designated as CNS PNET.

74. Nerve sheath tumors
• Similar to that of the 2007 CNS WHO
• Few changes
• Melanotic schwannoma classified as a distinct
entity rather than variant
• Clinically , malignant behavior in a significant
subset and genetically, associations with
Carney Complex and the PRKAR1A gene
distinct from conventional schwannoma

75. • Hybrid nerve sheath tumors have been
included in the 2016 CNS WHO, recognized in
a variety of combinations.
• Two subtypes of Malignant peripheral nerve
sheath tumor (MPNST):
– Epithelioid MPNST and
– MPNST with perineurial differentiation

78. Meningiomas
• Classification and grading of meningiomas did
not undergo major revisions.
• Introduction for brain invasion as a criteria for
atypical meningioma (grade II)
• Previously only considered as staging criteria
• Brain invasion joins a mitotic count of 4 or
more as a histological criterion that can suffice
for diagnosing an atypical meningioma, WHO
grade II.

79. • Atypical meningioma can also be diagnosed on
the basis of the Additive criteria of 3 of the
other 5 histological features:
– Spontaneous necrosis,
– Sheeting (loss of whorling or fascicular
architecture),
– Prominent nucleoli,
– High cellularity
– Small cells (tumor clusters with high
nuclear:cytoplasmic ratio).

82. Solitary fibrous tumor /
hemangiopericytoma
• Both solitary fibrous tumors and
hemangiopericytomas occur in the neuraxis,
share inversions 12q13, fusing the NAB2 and
STAT6 genes
• Overlapping features if not identical entities
• WHO 2016 combined term solitary fibrous
tumor / hemangiopericytoma

83. Three grades
• Grade I
• Grade II
• Grade III

84. • Grade I
• Highly collagenous,
• relatively low
cellularity,
• spindle cell lesion
previously diagnosed as
solitary fibrous tumor;

85. • Grade II
• More cellular,
• less collagen with
plump cells
• “staghorn” vasculature
that was previously
diagnosed in the CNS as
hemangiopericytoma;

86. • Grade III
• termed anaplastic
hemangiopericytoma
• Diagnosed on the basis
of 5 or more mitoses per
10 high-power fields.

87. • Some tumors with a histological appearance
more similar to traditional solitary fibrous
tumor can also display malignant features
• WHO grade III, using the cutoff of 5 or more
mitoses per 10 high-power fields.
• Additional Studies will, therefore, be required
To fine-tune this grading system.

92. Report format

93. Report format

95. Summary
• Formulating concept of how CNS tumor
diagnoses are structured in the molecular era
• Major restructuring of diffuse gliomas, with
incorporation of genetically defined entities
• Major restructuring of medulloblastomas, with
incorporation of genetically defined entities

96. • Major restructuring of other embryonal tumors,
with incorporation of genetically defined entities
• Removal of the term “primitive neuroectodermal
tumor”
• Incorporation of a genetically defined
ependymoma variant
• Novel approach distinguishing pediatric look-
alikes, including designation of novel, genetically
defined entity

97. Addition of newly recognized entities, variants and
patterns
• IDH-wildtype and IDH-mutant glioblastoma
(entities)
• Diffuse midline glioma, H3 K27M–mutant
(entity)
• Embryonal tumour with multilayered rosettes,
C19MC-altered (entity)
• Ependymoma, RELA fusion–positive (entity)

98. • Diffuse leptomeningeal glioneuronal tumor
(entity)
• Anaplastic PXA (entity)
• Epithelioid glioblastoma (variant)
• Glioblastoma with primitive neuronal
component (pattern)
• Multinodular and vacuolated pattern of
ganglion cell tumor (pattern)

99. • Deletion of former entities, variants and terms
– Gliomatosis cerebri
– Protoplasmic and fibrillary astrocytoma variants
– Cellular ependymoma variant
– Cellular schwannoma variant
– “Primitive neuroectodermal tumour” terminology
• Addition of brain invasion as a criterion for
atypical meningioma
• Restructuring of SFT/HPC as one entity and
adapting a grading system

100. References
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International Agency for Research on Cancer,
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Idema AJ, Rivera AL, et al. Significance of
complete 1p/19q co-deletion, IDH1 mutation and
MGMT promoter methylation in gliomas: use
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102. • Lang SS, Zager EL, Coyne TM, Nangunoori R,
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