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N E U RO S U RG E RY A RT I C L EVairavan Narayanandid his basic Neurosurgical trainingin Malaysia and completed histraining in Addenbrooke’s Hospital,Cambridge in 2011. He is currently ajunior consultant neurosurgeon inUniversity Malaya, Malaysia. Hisclinical interest lies in neurooncologyand skull base surgery.Krunal Patelgraduated from the University ofCambridge & University CollegeLondon Medical Schools in 2006.He is currently working as aSpecialist Registrar in Neurosurgeryat Addenbrooke’s Hospital inCambridge.Stephen Priceis a NIHR Clinician Scientist at theUniversity of Cambridge and anHonorary ConsultantNeurosurgeon at Addenbrooke’sHospital, Cambridge. His interest isin surgical neuro-oncology and hisresearch interest involves usingimaging based methods to betterunderstand the heterogeneity ofglioma pathology in individualpatients.Correspondence to:Mr. Stephen J Price PhDFRCS(Neuro.Surg),Neurosurgery Division,Department of ClinicalNeurosciences,Box 167,Addenbrooke’s Hospital,Cambridge CB2 0QQ,Tel. +44 (0)1223 274295Fax. +44 (0)1223 216926Email: sjp58@cam.ac.ukHigh Grade Gliomas:Pathogenesis, Managementand PrognosisHigh grade gliomas are the most commontype of brain tumours, accounting for upto 85% of all new cases of malignantprimary brain tumours diagnosed every year.They carry a very large disease burden withgreatest years of life lost for any cancer. Despiterecent advances in the understanding of pathogenesisand management, the median survivalstill ranges between 12 to 18 months. Surgeryalong with adjuvant chemo and radiotherapyremains the mainstay of management. Thisreview summarises the diagnosis and managementas well as recent advances in the understandingand treatment of high grade gliomas.IntroductionThe term high grade glioma(HGG), is usuallyused to describe WHO grade III and IV tumours.The incidence of these tumours is approximately5/100,000 person years in Europe and NorthAmerica. 1 Of these, glioblastomas account for 60to 70%, anaplastic astrocytomas for 10 to 15%,anaplastic oligodendrogliomas and anaplasticoligoastrocytomas for about 10%, whileanaplastic ependymoma and anaplastic gangliogliomamake up the rest.There has been a recent increase in incidenceof HGGs in the Western world, particularly in theelderly population. This probably reflects the easyavailability of vastly improved diagnosticimaging. 2 The median age of onset is 45 for GradeIII and 60 for Grade IV tumours. 3 There is a 40%greater incidence among males. 4In the majority of cases, no causative factors canbe attributed. However, exposure to ionising radiation,such as from treatment of previous cancer isan established risk factor. 5 Many other factors havebeen studied including head injury, foods with N-nitrose compounds, electromagnetic fields,smoking and most recently usage of cellularphones, all of which have not been shown to berisk factors in the development of HGG. 6-8Approximately 5% of patients with HGG have afamily history of gliomas. 9 Some of these arefamilial and associated with genetic syndromessuch as neurofibromatosis types 1 & 2, Li-Fraumeni syndrome and Turcot’s syndrome.Recent studies have also shown links betweenDNA repair genes and tumour aggressiveness. 10-12PresentationMost patients with HGG present with signs andsymptoms of raised ICP from mass effect, oedemaor haemorrhage. These frequently manifest asheadaches, nausea & vomiting, reduced visualacuity, diplopia, drowsiness and confusion. 13Other presentations include focal neurologicaldeficits, symptoms which are dependent on thelocation of the tumour such as aphasia, limbweakness, altered sensorium and neurocognitivedefects including disinhibition and personalitychanges. 14 Approximately 50% of grade III and25% of Grade IV tumours present with seizurescompared to 80% of low grade gliomas.ImagingThe initial imaging modality is usually a contrastenhanced Computed Tomography (CT).However, Magnetic Resonance Imaging (MRI) ismore sensitive than CT and is now the imagingmodality of choice for all patients with braintumours – especially if considered for surgery.HGG typically appear as irregular, ill-definedmasses with associated vasogenic oedema onboth CT and MR. Enhancement typically isaround the rim of the mass with a central area ofnon-enhancing tissue. Enhancement per se,cannot be taken as a diagnostic feature asbetween 30-50% of anaplastic tumours fail toenhance on CT, 15 and 16% fail to enhance onMRI. 16 In addition, 20% of low grade gliomas (typicallyoligodendrogliomas) enhance on CT 15 and35% enhance on MRI 16 (see Figure 1).Identification of tumour margins is notpossible with conventional imaging. Both postmortem and biopsy studies have shown tumourFigure 1: Imaging of a glioblastoma. (a) An unenhanced CT andcontrast enhanced CT (b) show the lesion and the oedema. Thelatter is better identified on the FLAIR imaging (c). Contrastenhanced T1-weighted imaging shows a small focus ofenhancement separate from the main body of the tumour thatwas not identified by other methods.24 > ACNR > VOLUME 12 NUMBER 4 > SEPTEMBER/OCTOBER 2012
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
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