CNS UPDATE 2: DIFFUSE GLIOMAS AND PA

Arie Perry, M.D. Director, Neuropathology

Distribution of Childhood Primary Brain and CNS Tumors by Histology and Age (Ages 0-14) (N = 15,398), CBTRUS Statistical Report: NPCR and SEER, 2006-2010.

Ostrom Q T et al. Neuro Oncol 2013;15:ii1-ii56

© The Centers for Disease Control and Prevention. Published by Oxford University Press on behalf of the Society for Neuro-Oncology in cooperation with the Central Brain Tumor Registry 2013.

• Disease entities should be defined as narrowly as

possible in order to establish highly biologically

uniform groups (i.e., as previously undertaken by

the hematopathology community)

• Molecular information will be incorporated into the

definitions of some diagnostic entities

• For some diagnostic entities, histology will remain

the basis for definition and diagnosis

ISN-Haarlem conclusions (1)

• Grade will reflect natural history and will be

based on histological findings; for some

diagnoses, avoiding a histological grade may be

preferable

• Some pediatric tumor types will require the

creation of entities independent of their adult

histological “look-alikes”

1. ‘Pediatric GBM’

2. ‘Pediatric oligodendroglioma’

ISN-Haarlem conclusions (2)

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ASTROCYTOMAS

• Diffuse

– Fibrillary

– Gemistocytic

– Giant Cell

– Small Cell

– Granular Cell

– Others

• Circumscribed / Favorable

– Pilocytic

– PXA

– SEGA

– DIA

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DIFFUSE ASTROCYTOMAS

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DIFFUSE ASTROCYTOMA GRADING

Atypia

Mitoses

Endothelial Proliferation (MVP, EH)

Necrosis

WHO II=A; III=A+M; IV=A+M+(E or N)

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ASTROCYTOMA (WHO GRADE II)

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ANAPLASTIC ASTROCYTOMA, WHO III

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GEMISTOCYTIC ASTROCYTOMAS

p53

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GLIOBLASTOMA (GBM), WHO GRADE IV

• WHO dropped “multiforme” in 2000

• Rapid onset and progression

• Rim (or ring)-enhancing, but can be less clear in kids

• Survival ~1-year, but highly variable

• More often brainstem and thalamus in kids, but also cerebral hemispheres

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GBM, WHO IV

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BRAINSTEM GLIOMA

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‘BRAINSTEM GLIOMA’

• Diffuse intrinsic pontine glioma (DIPG): malignant

• Dorsal, exophytic cervicomedullary astrocytoma (pilocytic)

• Focal tectal glioma (pilocytic)

• NF1-associated (pilocytic)

H3.3 K27M

Brain Pathology 23 (2013) 565-73

PDGFRα CEP4

IDH1R132H mutant GBM maybe further subdivided based

upon PDGFRA amplification

Log-rank test, p<0.05

Nat Genet 46: 462-466, 2014

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GBM VARIANTS / PATTERNS

• Fibrillary (Classic)

• Gemistocytic

• Giant Cell

• Gliosarcoma

• Adenoid / Epithelioid / Metaplastic

• Lipidized

• Inflammation-rich

• Granular Cell

• Small Cell

• GBM with an oligodendroglial component

• GBM with PNET-like foci

• Rhabdoid / Epithelioid

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GIANT CELL GBM

GFAP

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GIANT CELL GBM

19p13

19q14

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GIANT CELL GBM/GS

• ~1-5% of GBMs and gliosarcomas

• Clinical DDx: Meningioma, pleomorphic sarcoma, or metastasis

• Pathology DDx: PXA (EGBs; BRAF V600E)

• Less infiltrative

• Clinically a primary GBM, but younger patients, TP53 mutations common and EGFR-AMP rare; Mostly IDH1-R132H-neg

• Small subset with better prognosis

• May be overrepresented in Turcot disease

19: 81-90, 2009

GFAP

Neu-N SYN

NSE

p53 MIB-1

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GBM with PNET-like Features

PTEN DMBT1

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GBM with PNET-like Features

CEP2 N-myc

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GBM/GS WITH A PNET COMPONENT

• <1% of diffuse gliomas

• DDx: CNS PNET, lymphoma, metastatic small cell carcinoma

• Behaves locally like a GBM, but many develop CSF dissemination

• Can be either a primary or secondary GBM: PTEN-del in most cases, MYCN-AMP or MYCC-AMP in PNET-like area in >40%; IDH1-R132H in 16%

• Misdiagnosed CNS PNETs in kids?

AJSP 2010; 34:341-54

AJSP 2013; 37:658-98

SOX2 GFAP

BRAF-V600E

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RHABDOID/EPITHELIOID GBM

• Younger patients

• Superficial and circumscribed

• -22 in more rhabdoid cases?

• Focal INI1 loss?

• IDH1-neg

• BRAF V600E in more epithelioid cases

• Subset with better survival

Sturm et al.,

Cancer Cell

2012;22:425-437

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• Rare in kids (2-3% of gliomas)

• Oligo mimics more common: DNT, pilocytic astrocytoma, central neurocytoma, clear cell ependymoma

• Series with long followup rare since often transfer care as adults

• Same biology as adults?

• Genetics appear to be different

OLIGODENDROGLIOMA

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OLIGODENDROGLIOMA, WHO GRADE II

GFAP

GFAP

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ANAPLASTIC OLIGODENDROGLIOMA

SYN

IDH1-R132H

ADULT TYPE OLIGODENDROGLIOMA

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1p32

1q42

19p13

19q13

ADULT TYPE OLIGODENDROGLIOMA

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Raghavan et al. JNEN 62:530, 2003

Oligodendroglioma phenotype

Astrocytoma phenotype

Glioblastoma phenotype

Diffuse glioma, indeterminate, “mixed” or ambiguous phenotype

Histologic

diagnosis

Grade II, III, IV, ungraded

IDH, ATRX, 1p/19q IDH, ATRX, 1p/19q

Grade II, III, IV, ungraded

1) Histology and molecular concordant: Diagnosis, grade, molecular findings

2) Indeterminate or mixed histology: Diagnose and grade based on molecular profile

3) Histology and molecular discordant: Diffuse glioma, histologic phenotype, molecular profile

4) Molecular testing not performed: Histologic diagnosis, NOS

Integrated Diagnosis

Molecular

information

Adult (some teenagers) Diffuse Glioma

ADULT TYPE ASTROCYTOMA

IDH1 p53 ATRX

Integrated diagnosis:

Oligodendroglioma, WHO grade II, IDH-

mut, 1p/19q codeleted

Histological classification:

Diffuse glioma, oligodendroglioma phenotype

WHO grade:

Grade II

Molecular information:

IDH-mut, 1p/19q codel, ATRX intact

Adult Type Oligodendroglioma

Histologic classification

Diffuse astrocytoma Oligodendroglioma “Oligoastrocytoma” or ambiguous

histology

IDH-mut, 1p/19q-

nondel, ATRX loss

Diffuse astrocytoma, ATRX loss of

expression

Diffuse glioma (oligodendroglioma

phenotype), 1p/19q non-deleted,

ATRX loss of expression

Diffuse astrocytoma, ATRX loss of

expression

info

rma

tio

n

IDH-mut, 1p/19q-codel,

ATRX intact

Diffuse glioma (astrocytoma phenotype),

1p/19q-codeleted

Oligodendroglioma, 1p/19q-

codeleted Oligodendroglioma, 1p/19q-codeleted

Mole

cula

r

IDH wild type Diffuse astrocytoma, IDH wild type* Diffuse glioma (oligodendroglioma

phenotype), IDH wild type Diffuse astrocytoma, IDH wild type*

Testing not performed Diffuse astrocytoma, NOS Oligodendroglioma, NOS “Diffuse glioma, NOS”

Pediatric AA/GBM

Primary GBM

Pilocytic astrocytoma

PXA

IDH1-mutated infiltrating adult gliomas

Diffuse astrocytoma Oligodendroglioma

Anaplastic astrocytoma,

GBM

Anaplastic oligodendroglioma

H3F3A, DAXX TP53, ATRX

EGFR, PDGFRA PTEN, TP53 CDKN2A/B, NF1 TERT promoter

BRAF

IDH1,2

TP53 ATRX

1p/19q CIC, FUBP1 TERT promoter

RB1,CDK4 CDKN2A, MDM2, PTEN

Neural

Progenitor

Cell

RB1,CDK4 CDKN2A

Courtesy of Dr. Dan Brat

PILOCYTIC ASTROCYTOMA

• Child / young adult

• Cerebellum, hypothalamus/3rd v., optic pathway, spinal cord

• NF1-associated OPG

• Insidious onset / slow growth

• Surgically “curable” (WHO I)

• 20-year survival = 80%

PILOCYTIC ASTROCYTOMA

PILOCYTIC ASTROCYTOMA

OPG-JPA

Nat Genet 45: 927-932, 2013

MAPK pathway

BRAF KIAA1549

LOWER-GRADE GLIOMA GENETICS

• BRAF-KIAA1549 duplication/fusion

– pilocytic astrocytomas (~70% in cerebellum; less in other locations)

– PMA (1/3rd to ½)

– MEK inhibitors?

• BRAF V600E mutation:

– PXA (~67%), GG (20-50%), DNET (20-30%), PA (~10%), GBM (5-10%)

– BRAF inhibitors, especially in recurrent or disseminated cases?

VIRTUALLY ‘ALL’ PEDIATRIC BRAIN TUMORS

Pediatric Neuro-Oncologist Pediatric Pathologist/Neuropathologist

Did you order BRAF testing? On this???

Really??

PILOMYXOID ASTROCYTOMA, WHO II

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Komotar et al. Neurosurgery 54:72, 2004

QUESTIONS?