IDH-1 Immunohistochemistry in Glioma Diagnosis

Kieren Allinson

Lecture plan

• Classification of brain tumours

• Grading of common gliomas

• IDH-1 mutations in glioblastoma

• Mutation-specific antibodies to IDH-1

• practical uses of IDH-1 immunohistochemistry

WHO Classification of tumours

Second edition 1993

Fourth edition 2007

First edition 1978

Third edition 2000

Primary brain tumours

Primary brain tumours (children & adults)

70%

Glioblastoma Picture c/o Dr Dominic O’Donovan

Grading Gliomas

Infiltrating Astrocytomas

Grade 2

Diffuse astrocytoma

Grade 3

Anaplastic astrocytoma

Grade 4

Glioblastoma (GBM)

Oligodendrogliomas

Grade 2

Oligodendroglioma

Grade 3

Anaplastic oligodendroglioma

Grade determines prognosis

Infiltrating Astrocytomas

Grade 2

Diffuse astrocytoma

Grade 3

Anaplastic astrocytoma

Grade 4

Glioblastoma (GBM)

Oligodendrogliomas

Grade 2

Oligodendroglioma

Grade 3

Anaplastic oligodendroglioma

5 to 10 years

2 to 3 years

6 to 12 months

10 years

3 years

Grade progression in gliomas

Parsons DW, Jones S, Zhang X, et al. An integrated genomic analysis of human glioblastoma multiforme. Science. 2008;321:1807–1812.

Sequenced 20,661 protein coding genes,

Parsons DW, Jones S, Zhang X, et al. An integrated genomic analysis of human glioblastoma multiforme. Science. 2008;321:1807–1812.

Sequenced 20,661 protein coding genes,

Parsons DW, Jones S, Zhang X, et al. An integrated genomic analysis of human glioblastoma multiforme. Science. 2008;321:1807–1812.

Sequenced 20,661 protein coding genes,

Metabolism unhinged: IDH mutations in cancer John R Prensner1, & Arul M Chinnaiyan2, Nature Medicine Volume: 17, Pages: 291–293 Yea(2011)

Stem cell

IDH-1 mutation

p53 mutation 1p/19q loss

Oligodendroglioma (Gr 2) Astrocytoma (Gr 2)

LOH 10q LOH 10q

Anaplastic astrocytoma (Gr 3)

Anaplastic oligodendroglioma (Gr 3)

Secondary glioblastoma(Gr 4)

EGFR amplication PTEN mut etc

Stem cell

Primary glioblastoma(Gr 4)

EGFR amplication PTEN mutations LOH 10q P53 mutations Etc.

IDH-1 mutation is an early event in gliomagenesis

Stem cell

IDH-1 mutation

p53 mutation 1p/19q loss

Oligodendroglioma (Gr 2) Astrocytoma (Gr 2)

LOH 10q LOH 10q

Anaplastic astrocytoma (Gr 3)

Anaplastic oligodendroglioma (Gr 3)

Secondary glioblastoma(Gr 4) 5%

EGFR amplication PTEN mut etc

Stem cell

Primary glioblastoma(Gr 4) 95%

EGFR amplication PTEN mutations LOH 10q P53 mutations Etc.

IDH-1 mutation is an early event in gliomagenesis

IDH-1 mutated IDH-1 wild type

Hai Yan et al. New England Journal of Medicine 2009

14 patients

115 patients

Hai Yan et al. New England Journal of Medicine 2009

38 patients

14 patients

Hai Yan et al. New England Journal of Medicine 2009

Hartmann et al. Acta Neuropathol. 2010, 120, 707-718 (382 patients from two trials)

IDH-1 mutation & survival

Monoclonal antibodies to mutant IDH-1 • Mutation specific • Recognise the R132H mutation (90% of IDH-1 mutations) • False negative if tumour carries a rarer IDH-1 mutation • Does not recognise IDH-2 mutations • Positive staining is nuclear and cytoplasmic • Native glia, neurons & endothelial cells provide negative control

All gliomas

Diagnostic and prognostic uses

1. Glioma versus reactive gliosis – positive reaction diagnostic; negative reaction doesn’t help

2. Diffuse astrocytoma versus pilocytic astrocytoma, pleomorphic astrocytoma, ependymoma etc. - positive reaction diagnostic; negative reaction doesn’t help

3. Evaluating resection margins - only helpful in gliomas with the common mutation

4. As a prognostic marker in Glioblastoma

40 M Right insular biopsies

H&E IDH-1 R132H Dx – ANAPLASTIC ASTROCYTOMA (Grade 3)

Evaluating resection margins

44 M Right parietal lobe biopsies

H&E IDH-1 R132H Dx – Secondary Glioblastoma (Grade 4) – better prognosis than primary GBM

The future – targeted therapies