GLIAL AND GLIO-NEURONAL TUMORS

Arie Perry, M.D.

School of Medicine

DISCLOSURES (Arie Perry, MD)

• I have no financial relationships to disclose.

- and -

• I will not discuss off label use or investigational use in my presentation

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NEUROPATHOLOGY AND REAL ESTATE

• Location

• Location

• Location

• Patient Age

• Neuroimaging

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GLIOMAS

• Astrocytomas (A)

• Oligodendrogliomas (O)

• Mixed oligoastrocytomas (MOA)?

• Ependymomas

• Diffuse glioma = A, O, or MOA

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GLIOMA GRADING: WHO 2016

• Grade I = Benign

• Grade II = Low-grade

• Grade III = “Anaplastic”

• Grade IV = High-grade malignant, e.g. “GBM”

Distribution of Malignant Primary Brain and CNS Tumors by CBTRUS Histology Groupings and Histology (N = 117,023), CBTRUS Statistical Report: NPCR and SEER, 2008-2012.

Quinn T. Ostrom et al. Neuro Oncol 2015;17:iv1-iv62

© The Centers for Disease Control. Published by Oxford University Press on behalf of the Society for Neuro-Oncology in cooperation with the Central Brain Tumor Registry 2015

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ASTROCYTOMAS

• Diffuse (75%)

– Fibrillary

– Gemistocytic

– Giant Cell

– Small Cell

– Granular Cell

– Epithelioid

• Circumscribed / Favorable (25%)

– Pilocytic

– PXA

– SEGA

– DIA

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ASTROCYTOMA, IDHm (WHO GRADE II)

• Age 30-40

• Insidious / Slow growing

• Non-enhancing

• Frequent progression to grades III or IV

• Survival ~5-8 years

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DIFFUSE ASTROCYTOMA (WHO II)

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ASTROCYTOMA (WHO GRADE II)

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DIFFUSE ASTROCYTOMA (II)

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SECONDARY STRUCTURES OF SCHERER

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ANAPLASTIC ASTROCYTOMA, IDHm (WHO GRADE III)

• Age 40-50

• More rapid onset

• Frequent progression to grade IV

• Survival ~2-3 years

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ANAPLASTIC ASTROCYTOMA, WHO III

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GLIOBLASTOMA (GBM), WHO GRADE IV

• Age 50-60

• Rapid onset and progression

• Rim (or ring)-enhancing

• Survival ~1-year

• Primary form (IDHwt): ~90%

• Secondary form (IDHm): ~10%

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GLIOBLASTOMA (WHO GRADE IV)

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GLIOBLASTOMA (WHO GRADE IV)

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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 primitive neuronal foci

• Epithelioid

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GIANT CELL GBM

GFAP

GLIOSARCOMA

GFAPReticulin

SMA CD34

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• Average age 30-40 years• Corticotropism / seizures common• Cerebral, especially frontal lobe• Slow progression• Survival ~10-20 years for oligo (grade

II); 5-10 years for anaplastic oligo (grade III): microvascular proliferation, high mitotic index, and/or necrosis

OLIGODENDROGLIOMA, IDHm and 1p19q-codel (WHO GRADE II or III)

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OLIGODENDROGLIOMA

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N

N

N

OLIGODENDROGLIOMA, WHO GRADE II

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OLIGODENDROGLIOMA

GFAP

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ANAPLASTIC OLIGODENDROGLIOMA

SYN

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1p321q42

19p1319q13

Oligodendroglioma, IDH-mutant and 1p/19q-codeleted (WHO 2016)

IDH1

PreneoplasticCell

IDHm

TP53mATRXm

IDHmTERTm

1p19q‐codel

IDHwtEGFR‐ampTERTm

9p (CDKN2A/B)  LOH

PIK3CAm?

Astro, IDHm

AA, IDHm

GBM, IDHm

Oligo, IDHm, 1p19q‐codel

AO, IDHm, 1p19q‐codel

GBM, IDHwt

Diffuse midlineglioma, H3‐K27Mm

PIK3R1/PIK3CAm

CICmFUBP1m

4q LOH?

Note: no oligoastro!

(H3 G34R/V)

PILOCYTIC ASTROCYTOMA

PILOCYTIC ASTROCYTOMA

Nat Genet 45: 927-932, 2013

MAPKpathway

BRAFKIAA1549

PILOMYXOID ASTROCYTOMA, WHO?

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Komotar et al. Neurosurgery 54:72, 2004

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LONG-TERM EPILEPSY ASSOCIATED TUMORS (LEAT)

• Glioneuronal– Ganglioglioma (GG), WHO I

– Dysembryoplastic neuroepithelial tumor (DNET), WHO I

– Others: mixed GG/DNET, PGNT, EVN

• Gliomas– Pleomorphic xanthoastrocytoma (PXA), WHO II/III

– Diffuse LGGs, WHO II

– Pilocytic astrocytoma, WHO I

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GANGLIOGLIOMA (WHO I)

• Most common LEAT

• Children/young adults

• Temporal lobe

• Benign/surgically curable

• Anaplasia rare: definition?– WHO grade III (grade II eliminated in 2007)

• BRAF-V600E in up to half

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GANGLIOGLIOMA (WHO I)

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GANGLIOGLIOMA (WHO I)

SYN NFP

Neu-N

CD34

BRAF V600E

Ganglioglioma

ANA GG, WHO GRADE III

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DNET (WHO I)

• LEAT of children/young adults

• Temporal lobe

• Benign/surgically curable

• Tumor vs. hamartoma

• Simple, complex, ‘non-specific’ variants

• BRAF-V600E: 0-50%; FGFR1-alt: 58%?, IDHwt, no 1p19q-codeletion

GFAP

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PXA, WHO II-III

PXA, WHO GRADE II

PXA, WHO GRADE II

PXA, WHO GRADE II

Reticulin

PXA, WHO GRADE II

GFAP

PXA, WHO GRADE II

SYN NFP

PXA, WHO GRADE II

CD34

PXA, WHO GRADE II

PXA c ANA transformation, WHO GRADE III

Ki-67

PXA c ANA transformation, WHO GRADE III

BRAF-V600E

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EPENDYMOMA (WHO GRADE I, II, III)

• Kids: 4th ventricle, supratentorial

• Adults: spinal cord

• Prognostic Variables

– Extent of resection / location

– Patient age (poor if <2 years old)

– Histologic grade?

• Subependymoma or MPE, WHO grade I

• Ependymoma, WHO grade II

• Anaplastic ependymoma, WHO grade III

– Molecular subgroups

Subependymoma, WHO GRADE I

MPE, WHO GRADE I

TrichromePAS

MPE, WHO GRADE I

NFP

Ependymoma, WHO GRADE II

Ependymoma, WHO GRADE II

Ependymoma, WHO GRADE II

GFAP

EMA CD99

Tanycytic ependymoma

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EPENDYMOMA: PROGNOSIS

Tihan T, et al., Mod Pathol 2008: 21, 165–177

Pajtler et al., 2015, Cancer Cell 27, 728–743

Clear cell ependymoma

Clear cell ependymoma

L1CAM

Clear cell (RELA fusion+) ependymoma

UCSF 500 NGS

H3K27me3

PF-A Ependymoma PF-B Ependymoma

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Neuropathology CD Recording

• Neuropathology songs

• Common disorders

• 2nd Year medical students

• Memorization aid

• Fun way to learn!

www.neuropathsongs.comiTunes or amazon.com

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O----ligodendroglio-oh-oh-ma, diffuse cerebral tumor of adultsInvading cortex, causing epilepsy; on imaging, often you are calcifiedAnd although, you tend to progress over time, for long periods your fineYou're famous for your rounded nuclei, Clear haloes look like honeycombs or fried eggsWith branching chicken wire capillaries, and perineuronal satellitosis

O----ligodendroglio-oh-oh-ma, genetically, you are quite uniqueWith 1p and 19q deletions, from translocation with loss of one derivativeRepresents a genetically favorable set, when FISH criteria are met

Anaplastic cases grow more rapidly, assigned a W.H.O. grade IIIWith microvascular proliferation, or increased mitotic activityO----ligodendroglio-oh-oh-ma

OligodendrogliomaMusic to Ave Maria by F. Schubert, Lyrics by Arie Perry, MD