update on cns pathology-dubai 2015

8/15/2019 Update on CNS Pathology-Dubai 2015

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Astrocytomas

Pilocytic astrocytomaPXA

SEGADiffuse astrocytoma

Anaplastic astrocytomaGBM

Glial neoplasmsEpendymomas

Oligodendroglioma Anaplastic oligodendroglioma

Oligodendrogliomas

Diffuse Gliomas

Diffuse astrocytoma Anaplastic astrocytoma

GBMOligodendroglioma

Anaplastic oligodendrogliomaDiffuse midline glioma, H3 K27M mutant

Glial neoplasms Ependymomas

Pilocytic astrocytomaPXA

SEGA

Other Astrocytomas

OLD

NEW


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• Diagnosis of oligodendroglioma and anaplastic

oligodendroglioma requires demonstration of an

IDH mutation and 1p/19q co-deletion

• Oligodendroglioma is now essentially defined by

a particular genetic phenotype


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•

3 categories:

– IDH-mutant

• Majority of grade II and III diffuse astrocytomas

–

IDH-wildtype –

NOS

• If IDH testing is not available or cannot be fully

performed

•

WHO grading remains the same, even though IDH-

mutant cases have a more favorable prognosis


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•

The diagnosis of oligoastrocytoma is strongly

discouraged.

• Designated as NOS categories—should only be

rendered in absence of diagnostic molecular

testing or in the very rare instance of a dual

genotype oligoastrocytoma


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•

43 cases of oligoastrocytoma•

In all but one case, the combination of p53 mutation and ATRX loss was

mutually exclusive with 1p/19q co-deletion

•

31/43! oligo genotype (i.e. 1p/19q co-deletion and IDH mutation)

• 11/43! astro genotype (i.e. p53 mutation, ATRX loss and IDH

mutation)•

1/43! mixed genotype (p53 mutation, ATRX loss, IDH mutation and

partial 1p/19q loss) [this pt had undergone radiotherapy prior to surgery]


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•

3 categories: – Glioblastoma, IDH-wildtype

•

~90% of cases

•

Most often corresponds to primary GBM

–

Glioblastoma, IDH-mutant•

~10% of cases

•

Most often corresponds to secondary GBM

– Glioblastoma, NOS

•

Reserved for tumors for which a full IDH evaluation cannot

be performed


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The Cancer Genome Atlas Research Network. N Engl J Med 2015;372:2481-2498


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•

202 pediatric GBMs

–

Genome-wide DNA methylation profiling –

Known candidate genes were screened for alterationsvia direct sequencing or FISH


37/82

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•

PXA or pilocytic-like methylation profiles (20%) –

Subset had BRAF V600E mutations

–

Good prognosis

• H3 K27M mutation (34%)

–

Midline location (including many diffuse intrinsic pontine gliomas) –

Very poor prognosis

• H3 G34R mutation (12%)

• IDH mutation (5%)

–

Good prognosis

• H3/IDH wildtype (29%)


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Evening view from the IU Health Pathology Laboratory


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•

New variant

• Accounts for the majority of supratentorial

ependymomas in children

•

Dismal prognosis

•

Immunohistochemical expression of L1CAM –

potential surrogate marker for this variant

• Cellular ependymoma variant deleted


41/82

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42/82

;ʼ)50$'%)8$[ a +1'%)0)A1/ U$61$*%'

Classic Desmoplastic/nodular

With extensive nodularity Large cell/anaplastic

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43/82

;ʼ)50$'%)8$[ a 8)0&/70$6 '75A6)7"'WNT SHH Group 3 Group 4

Age atpresentation

Childhood Infancy; adulthood Childhood Childhood

Pathology Classic Desmoplastic/

nodular

Large cell/

anaplastic; classic

Classic; Large cell

anaplastic

Prognosis Very good>90% long-term survival

Good tointermediate

Poor Intermediate

Genetics CTNNB1 (β-catenin)mutations;monosomy 6; APC

germline mutations (Turcotsyndrome)

PTCH gene mutation(germline PTCHmutation=Gorlin

syndrome); 9qdeletion

MYC amplification CDK6 amplification;isochromosome 17q;loss of X chromosome

Immunos Nuclearβ-cateninstaining; DKK1 positive

GAB1 positive, SFRP1positive

KCNA1

% of all medullos 7-8% 28-32% 26-27% 34-38%

Treatment ? therapy de-escalation Can treat withsmoothened (SMO)inhibitors

Modified from Taylor MD, Northcott PA, Korshunov A, et al. Molecular subgroups of medulloblastoma: thecurrent consensus. Acta Neuropathol 2012;123:465-472.

# 00 50


44/82

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• Both the histologic and molecular subgroups

have prognostic and therapeutic value

Ellison et al. Acta Neuropathol 2011

D/N

Classic

LC/A

WNTSHH

non-WNT/SHH

WNT

SHH-classic or D/N

non-WNT/SHH-classic or D/N

SHH-LC/Anon-WNT/SHH-LC/A

Outcome analyses among patients aged

3-16 years on the CNS9102/PNET3 trial.Progression-free survival curves.


45/82

• p53 mutations are enriched in WNT (16%) and SHH (21%) subgroups, but not in

groups 3 and 4

• WNT!p53 mutation has no prognostic implication (5 yr OS 90% and 97% for p53

mutant and wild type, respectively [p=.21])

• SHH!

– p53 mutation: older children, poor prognosis (5 yr OS 41%)

– p53 wild type: infants & adults, better prognosis (5 yr OS 81%) [p


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•

2007 WHO: PNET is an umbrella term, underwhich fall multiple histologic variants

–

Cerebral neuroblastoma/gangioneuroblastoma

–

Embryonal tumor with abundant neuropil and true

rosettes (ETANTR) –

Ependymoblastoma

–

Medulloepithelioma

•

2016 WHO: The term “primitive neuroectodermal

tumor (PNET)” has been completely removed from

the diagnostic lexicon


50/82

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•

2007 WHO: PNET is an umbrella term, underwhich fall multiple histologic variants

–

Cerebral neuroblastoma/gangioneuroblastoma

–

Embryonal tumor with abundant neuropil and true

rosettes (ETANTR) –

Ependymoblastoma

–

Medulloepithelioma

•

2016 WHO: The term “primitive neuroectodermal

tumor (PNET)” has been completely removed from

the diagnostic lexicon

=

Embryonal

tumor with

multilayeredrosettes,

C19MC altered


51/82

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•

Clinical: usually patients less than 4 years of age; highlyaggressive with avg survival of 12 months

•

Immunostain for LIN28A

•

FISH analysis for 19q13.42

(C19MC amplification)

ETANTR LIN28A


52/82

Ependymoblastoma

Medulloepithelioma

LIN28A

LIN28A


53/82

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•

2016 WHO

– Atypical teratoid/rhabdoid tumor (AT/RT) is

defined by alterations in INI1 (i.e. SMARCB1)

or very rarely BRG1


54/82

]\Ti\ 8)6"+)0)A: $*# F-F` 0)'%

Integrated diagnosis Atypical teratoid/rhabdoid

tumor, WHO grade IV

Histological classification Embryonal tumor with

rhabdoid features

WHO grade IV

Molecular information INI1 loss of protein

expression/mutation or BRG1

loss of protein expression/

mutation


55/82

]\Ti\ 8)6"+)0)A: 57% F-F` 6&%$1*

Integrated diagnosis Embryonal tumor withrhabdoid features, WHO

grade IV

Histological classification Embryonal tumor with

rhabdoid features

WHO grade IV

Molecular information INI1 and BRG1 expression

retained/not mutated or

molecular/IHC testing notperformed


56/82

Indianapolis

Central Library


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!*6&')0U 1''7&'T/+$00&*A&'• WHO grading

–

Determinations are still made on the basis of histologic criteria

–

WHO grade (natural progression) vs “therapy” grade (based on

response to adjuvant therapy)

–

Should grade be altered based on molecular findings?

• Testing:

–

What about centers that don’t have access to moleculartechniques or surrogate immunostains? (NOS)

–

How much testing?

• Reporting: format and timing

•

Wastebaskets (NOS designations)—these groups oftumors should be the subject of future studies to further

improve classification

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• Molecular alterations are helping to further refine the

diagnosis and classification of CNS tumors• Updated 2016 WHO will feature an integrated diagnosis

concept, including histology, grade and molecularfeatures

•

Diffuse gliomas: 3 molecular groups –

IDH mut, 1p/19 co-deleted! good prognosis

–

IDH mut, 1p/19q intact! intermediate prognosis

–

IDH wt! poor prognosis

•

Medulloblastoma: combination of both molecular andhistologic subgroups have prognostic and therapeutic

significance


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Thank you

i&4&6&*/&'


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i&4&6&*/&'1. Brat DJ, Verhaak RGW, Aldape KD, et al. Comprehensive, integrative genomic analysis of

diffuse lower grade gliomas. New England Journal of Medicine 2015;372(26):2481-98.

2. Ellison DW, Dalton J, Kocak M, et al. Medulloblastoma: clinicopathologic correlates of SHH,

WNT, and non-SHH/WNT molecular subgroups. Acta Neuropathol 2011;121(3):381-396.3.

Korshunov A, Ryzhova M, Hovestadt V, et al. Integrated analysis of pediatric glioblastoma

reveals a subset of biologically favorable tumors with associated molecular prognostic markers.

Acta Neuropathol 2015;129:669-678.

4. Louis DN, Perry A, Burger P, et al. International society of neuropathology – Haarlem

consensus guidelines for nervous system tumor classification and grading. Brain Pathology

2014;24:429-435.

5.

Pajtler KW, Witt H, Sill M, et al. Molecular classification of ependymal tumors across all CNScompartments, histopathological grades, and age groups. Cancer Cell 2015;27:728-743.

6. Sahm F, Reuss D, Koelsche C, et al. Farewell to oligoastrocytoma: in situ molecular genetics

favor classification as either oligodendroglioma or astrocytoma. Acta Neuropathol

2014;128:551-559.

7. Scheithauer BW. Development of the WHO classification of tumors of the central nervous

system: a historical perspective. Brain Pathology 2009;19:551-564.

8.

Taylor MD, Northcott PA, Korshunov A, et al. Molecular subgroups of medulloblastoma: thecurrent consensus. Acta Neuropathol 2012;123:465-472.

9. The 2016 World Health Organization classification of tumors of the central nervous system: a

summary. [not yet published; courtesy of Dr. Arie Perry]


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• Classified 500 ependymal tumors using DNA methylationprofiling into nine molecular subgroups

•

This molecular classification outperforms the currenthistopathological grading in the risk stratification ofpatients


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'/+&8&! ;)6"+)0)A:

WHO

gradeAstrocytoma Oligodendroglioma

Mixed

oligoastrocytoma

IIDiffuse

astrocytoma Oligodendroglioma Oligoastrocytoma

III Anaplastic

astrocytoma

Anaplastic

oligodendroglioma

Anaplastic

oligoastrocytoma

IV Glioblastoma N/A

GBM with

oligodendroglialfeatures

2


80/82

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1.

Overall restructuring

2.

Diffuse astrocytoma, grades II and III

3.

Oligodendroglioma4. Oligoastrocytoma

5.

Glioblastoma

6.

Diffuse midline glioma, H3 K27M mutant


81/82

`D HU&6$00 6&'%67/%761*A

•

In the past all astrocytic tumors had been

grouped together, but now all diffuse gliomas

(whether astrocytic or oligodendroglial) are

grouped together.•

Diffuse astrocytoma is more similar to

oligodendroglioma than it is to pilocytic

astrocytoma

Fig. 2 Two examples of primary ETANTR (a, c) with further tumor transformation in either EBL(b) or MEPL (d) histology as it has been identified during analysis of the recurrence samples


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update on cns pathology-dubai 2015

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