Primary Brain Tumors in Adults James D. Battiste, MD, PhD Assistant Professor Department of Neurology The University of Oklahoma Health Sciences Center October 22, 2013, 8:00 AM

OU Neurology

Objectives  Define the 4 brain tumor grades and the 3 subtypes of glioma.  Explain the current issues in the diagnosis of adult gliomas  Report the current ability of molecular markers to make better prognosis for patients  Identify the current treatment options for adult gliomas

OU Neurology

Incidence  Central Brain Tumor Registry United States (CBTRUS) database  62,930 new cases of malignant and non-malignant brain tumors in 2007  Estimated 21,810 new cases of malignant CNS tumors in 2008, estimated deaths 13,070  Relative risks: 1.38 Men vs Women  3.18 Elderly vs Young adults  1.86 Caucasian vs. African-American  Malignant brain tumors (22,070 cases estimated in 2009) account for 1.42% of all primary malignant cancers in the US (American Cancer Society 2009) but account for a disproportionate share of cancer morbidity and mortality (CDC 2008).

OU Neurology

Take Home: per year 60,000+ new brain tumors 22,000+ new malignant brain tumors 200,000+ new brain met’s Brain tumor: Morbidity & Mortality > other cancers

OU Neurology

Definitions Progression Free Survival (PFS) Time to new or progressive symptoms Time to radiographic expansion of tumor

Overall Survival Time to mortality

OU Neurology

Defined based on the Presumed “Cell of Origin”

Glia Neurons Peripheral Nerve Primary Neuro-ectodermal Tumors Ependymal Sellar region/Pituitary Meningeal Lymphocyte OU Neurology

Primary Brain tumors

Distribution of All Primary Brain and CNS Tumors by Histology, CBTRUS 2000-2004

OU Neurology

Gliomas Tumor cell of origin or differentiation sub-type Oligodendroglioma Mixed: Oligoastrocytoma

Grade I, “benign”

Astrocytoma

Pilocytic Astrocytoma

Grade II, Low grade glioma (LGG)

Oligodendroglioma

LGG oligoastrocytoma

Astrocytoma

Grade III, anaplastic

Anaplastic oligodendroglioma

Anaplastic oligodendroglioma

Anaplastic Astrocytoma

Grade IV

GBM with oligodendroglia features

GBM

OU Neurology

Low grade glioma (WHO Grade II) (i.e. astro, oligo or mixed) Risk factors for higher grade: Age > 40, size >6 cm, Astrocytic component Crossing midline Presence of neurologic deficits other than seizures

Median survival decreases from 9.2 years to 0.7 years Prognostic factors for survival in adult patients with cerebral low-grade glioma. Pignatti F, J Clin Oncol. 2002 Apr 15;20(8):2076-84.

OU Neurology

Oligodendroglioma “Fried Egg” perinuclear clearing

Generally, not enhancing.

Calcifications and microbleeds.

Good prognosis: especially with 1p/19q co-deletion and IDH1 or IDH2 mutation Chemosensitive to carmustin, lomustine, or temazolamide

OU Neurology

Oligodendroglioma Low grade (WHO II)

Anaplastic (WHO III)

High cellularity, classic “fried egg” appearance of cells

Highly cellular, mitotic figures, Microvascular prolif, necrosis

Co-deletion of 1p and 19q (>50%) associated with chemosensitivity Mutation in IDH1 or IDH2 also associated with good prognosis

OU Neurology

1p/19q co-deletion  Characteristic pathology in oligodendrogliomas  Scattered reports in other tumor types

Jenkins R B et al. Cancer Res 2006;66:9852-9861

OU Neurology

Low grade astrocytoma (WHO II) No contrast enhancement on MRI

FLAIR

Post-Contrast

H&E, smear

Median survival: 10-15 years

OU Neurology

Anaplastic Astrocytoma (WHO III) T1 + gad

H&E

Heterogeneous Enhancing mass (70%)

High cellularity Pleomorphism, mitosis

Median survival: 5 years

OU Neurology

Mixed Glioma (Oligoastrocytoma)

 Grade for grade – tumors with an “oligo” component do better in terms of overall survival and progression-free survival  They generally do not have 1p/19q co-deletion

OU Neurology

Glioblastoma (IV) T1 + gad

H&E

Enhancing mass, cystic components, variable necrosis

Highly cellular, pseudo-palisading necrosis, microvascular prolif.

Median survival: 14 months

OU Neurology

Bio-Markers and Molecular Characterization MGMT methylation  DNA repair gene  Removes alkyl group from O6 guanine  Epigenetic silencing of the MGMT gene by methylation of the promoter

 Methylated:  Inactive, tumor cell is vulnerable to methylation/alkylation triggering cytotoxicity and apoptosis

 Unmethylated:  Active to repair and “protect” tumor cell. Nature: Gene regulation: Code of silence Judd C. Rice1 & C. David Allis1

Vorinostat? HDAC inhibitor…

Hegi et al., NEJM 2005

OU Neurology

The Cancer Genome Atlas (TCGA)

Integrated Genomic Analysis Identifies Clinically Relevant Subtypes of Glioblastoma Characterized by Abnormalities in PDGFRA, IDH1, EGFR, and NF1

Cancer Cell Volume 17, Issue 1 2010 98 - 110

OU Neurology

Glioblastoma (TCGA)

OU Neurology

Sequencing of GBMs led to the discovery of mutations in Isocitrate Dehydrogenase (IDH)

OU Neurology

Yan et al, NEJM 2009

OU Neurology

Probability of Survi

60

IDH mutations: Better overall survival Excellent prognostic marker 40

IDH mutated

IDH wild-type

20

P=0.002

0 0

A

B

40

50

100

80

60

IDH mutated IDH mutated

40 IDH wild-type

20

P=0.002 0 0

IDH wild-type 10

20

IDH mutated IDH mutated

80

60

40

IDH wild-type IDH wild-type

20

P98%