idh-1 immunohistochemistry in glioma diagnosis · lecture plan • classification of brain tumours...
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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