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N E U RO S U RG E RY A RT I C L Emultiple sites for mutation have been identifiedmaking this marker difficult to assess. Inaddition, the results are semi-quantitative withno clear cut off to define positive or negativestatus, resulting in non-standard interpretationof test results.Figure 2: Histology of a glioblastoma. (a) shows the microvascular proliferation and (b) shows evidence of tumour necrosis –the presence of either of these factors in an astrocytic tumour is sufficient to make a diagnosis of glioblastoma. (Picture courtesyof Dr Kieren Allinson, Addenbrooke’s Hospital, Cambridge).extends beyond the margin on CT, 17-20 contrastenhancedT1-weighted MRI 20-21 and T2-weighted MR. 20-23 These techniques cannotdetermine the margin or the invasiveness ofthese tumours. Advanced imaging methodshave been developed for assessment of thesetumours. These are being used in clinical practiceand are summarised elsewhere. 24Post-operative MRI is the only method ofobjectively assessing the extent of resection.Studies have shown it identifies more cases ofincomplete resection compared to the judgementof the surgeon. 25 Imaging within 72 hoursavoids the post-operative changes that occurlater.HistologyHigh grade gliomas arise from supporting glialcells in the brain. The predominant cell typedetermines the pathological classification.Tumours are graded according to the WorldHealth Organisation (WHO) grading system(Grade I to IV). 26 HGGs comprise of WHOgrade III and IV tumours. Multiple subtypeshave been identified which may alterresponse to treatment and prognosis. Theseinclude subtype III which comprisesanaplastic astrocytoma, oligoastrocytoma,anaplastic oligoastrocytoma as well assubtype IV which includes glioblastoma,glioblastoma with oligodendrocyte componentand gliosarcoma. 27Grade III tumours are diffusely infiltratingastrocytomas with focal or dispersedanaplasia and a marked proliferative potentialwith increased cellularity, distinct nuclearatypia and high mitotic activity while Grade IVtumours show cellular polymorphism, nuclearatypia, brisk mitotic activity, vascular thrombosis,microvascular proliferation and necrosis(see Figure 2).Grading is determined by the most malignantpart of tumour, which makes it essentialfor adequate sampling to determine theproper grade, especially in biopsy procedures.Molecular markers and their significanceOne of the biggest advances in high gradeglioma management has come in the form ofmolecular markers. Three particular markershave been well studied over the past fewyears.Figure 3: Methylation of MGMT inhibits repair of DNAdamaged by both radiotherapy and chemotherapy drugs.1. MGMT Methylation StatusThe MGMT gene encodes O-6-methylguanine-DNA methyltransferase enzyme – a DNA repairenzyme that removes alkyl groups from the O-6 position of guanine, an important site of DNAalkylation. MGMT methylation status has beenused to prognosticate response to alkylatingchemotherapeutic agents like Temozolomide.In the methylated form, it is non-functional(i.e. the enzyme is not produced) thus limitingDNA repair, cf. Figure 3). Two recent retrospectivestudies by Hegi et al 28 and Stupp et al 29analysed this particular molecular marker andfound the methylation phenomenon presentin up to 45% of cases of GBM. Further, in thepresence of methylation, median survival forradiotherapy with Temozolomide was significantlylonger than radiotherapy alone (21.7months, 95% CI 17.4-30.4 vs 15.3 months, 95%CI 13.0-20.9; P=0.007). In comparison, thedifference in survival in the unmethylatedgroup was insignificant (11.8 months, 95% CI9.7-14.1 vs. 12.7 months, 95% CI 11.6-14.4). Asthe methylated group with radiotherapy alonehas better survival than either unmethylatedgroups, it suggests MGMT methylation functionsas a prognostic marker rather than apredictive marker. A prospective analysis byWeller et al shows an improvement in bothprogression free survival (7.5 months vs 6.3months) and overall survival (18.9 months vs11.1 months). 30 MGMT methylation statusassessment is not without its problems –2. IDH-1 MutationThe IDH-1 gene encodes the enzyme isocitratedehydrogenase (IDH-1) gene that convertsisocitrate to α-ketoglutarate within the Krebscycle. This stage generates NADPH thatappears to be important in dealing with cytotoxicoxidative stresses. Mutation of this generesults in an alternative metabolism of isocitrateto 2-hydroxyglutarate. Mutations cause a10 fold increase in the production of 2-hydroxyglutarate.31 Accumulation of 2-hydroxyglutaratealso leads to the breakdown of HIF-1α, afactor important for generating a malignantcell phenotype.Mutation of IDH-1 gene was found in 12% ofGBM patients and seems to confer a bettermedian survival, (3.7 years vs 1.1years). 32Weller et al reconfirmed this via the GermanGlioma Network study which found IDH-1mutations in 16/286 patients (5.6%). They alsofound an improvement in both progressionfree survival (16.2 months vs 6.5 months) andoverall survival (30.2 months vs 11.2months). 30 As with the MGMT mutation, IDH-1mutation is prognostic rather than predictive. 33Virtually all mutations (96%) are a point mutationinvolving arginine 132. This allows animmunohistochemistry test on paraffinembedded tissue.3. Chromosome 1p19q Loss inOligodendroglial TumoursOne of the commonest chromosomal abnormalitiesseen in oligodendrogliomas is theconcurrent loss of part or all of the short armof chromosome 1 (1p) and the long arm ofchromosome 19 (19q). Cairncross et alshowed loss of 1p19q in 50-70% of anaplasticoligodendrogliomas. 34 This mutation had animproved survival with chemotherapy andwas originally thought to be predictive ofchemosensitivity. Results from a trial of radiotherapyvs chemoradiotherapy showed theradiotherapy only arm with 1p19q loss didbetter than the chemoradiotherapy armwithout loss of 1p19q suggesting again theprognostic nature of these molecularmarkers. 35PathogenesisGlioblastomas develop either as primarytumours or arise from pre existing low gradegliomas (Table 1). These primary andsecondary GBMs constitute separate anddistinct disease entities. They affect differentepidemiological groups and carry differentprognoses.Primary gliomas usually are of a de novomanifestation involving older patients with ashorter clinical history. On the other hand,secondary gliomas are usually part of a malignantprogression from low grade to high gradeACNR > VOLUME 12 NUMBER 4 > SEPTEMBER/OCTOBER 2012 > 25