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2015 Annual Meeting
Specialty Conference
Evening Specialty Conference - Neuropathology
(EC13-15) Evening Specialty Conference - Neuropathology - Brat - materials -0
Clinical History

Approximately 6 months prior to seeking medical attention, a 54-year-old right-handed man began experiencing recurrent episodes of smelling foul odors. These foul smell sensations were noted more frequently over time and occured with headaches of increasing severity. There was no history of a loss of consciousness or more generalized seizures. Eventually, an MRI was performed that demonstrated a 3 cm, T2-hyperintense, modestly expansile lesion in the left frontal lobe. No enhancement was noted following the administration of contrast material. The patient underwent neurosurgical resection of the lesion. 











The case represents a diffusely infiltrative glioma and demonstrates the use of markers that can be used to appropriately classify and grade these tumors. Approximately 70-80% of grade II and III diffuse astrocytomas, oligodendrogliomas, oligoastrocytomas and secondary GBMs harbor an IDH1 mutation. The large majority of primary (de novo) GBMs are IDH wild type. IDH mutations occur in both those gliomas chartacterized by 1p/19q loss (oligodendrogliomas) and those with TP53 mutations and ATRX loss (astrocytomas).  In general, infiltrating gliomas of all histologies and grades that lack IDH1 mutations have a worse prognosis than their IDH1 mutant counterparts. The prognostic significance of IDH mutations is so strong that IDH1 mutant GBMs actually have a better prognosis than anaplastic astrocytomas that are wild type for IDH1.

IDH is an enzyme family consisting of 5 isoforms that normally catalyzes the conversion of isocitrate to alpha-ketoglutarate. IDH1 is the only isoform localized to the cytoplasm, with the others found in mitochondria. Mutations in IDH1 and IDH2 lead to the production and accumulation of the oncometabolite 2-hydroxyglutarate and lead to a DNA hypermethylation phenotype (G-CIMP). Compared to IDH1 mutations, IDH2 mutations are rare, accounting for less than 5% of total IDH mutations. The overwhelming majority (90%) of IDH1 mutations occur at codon 132 and involve a base exchange of guanine to adenine, resulting in an amino acid change from arginine to histidine (R132H).

Immuohistochemistry for the IDH1 mutant protein is capable of detecting the IDH1 mutation in diffuse gliomas and has become a reliable tool for the pathologist. The R132H antibody, which detects over 90% of all IDH mutations, is most commonly used. Because immunohistochemistry for the IDH1 mutant protein can recognize a small minority of neoplastic cells admixed with normal cells in a biopsy, it has been shown to have comparable sensitivity to PCR or sequencing and is often used instead of these other methods. Importantly, there will be occasions, albeit uncommon, when an IDH1 mutation other than the R132H or an IDH2 mutation will be missed by immunohistochemistry. 

Appin CL, Brat DJ. (2014) Molecular pathways in gliomagenesis and their relevance to neuropathologic diagnosis Adv Anat Pathol 22:50-58.