IDH1 Mutation and World Health Organization 2016 Diagnostic Criteria for Adult Diffuse Gliomas

2-HG: 2-hydroxyglutarate GBM: glioblastoma multiform IDH: isocitrate dehydrogenase MGMT: O6-methylguanine DNA-methyltransferase MRS: magnetic resonance spectroscopy NADPH: nicotinamide adenine dinucleotide phosphate NCF: neurocognitive function NOS: not otherwise specified OS: overall survival PFS: progression-free survival WHO: World Health Organization The presence of an isocitrate dehydrogenase gene (IDH1 or IDH2) mutation has become one of the most critical biomarkers for molecular classification and prognostication in adult diffuse gliomas.1 Here, we review the translational impact of IDH1/2 mutation on neurosurgical oncology, with a focus on how this emerging knowledge has advanced the precision of our surgical approach to these diseases. Generally speaking, there are 2 major goals for the initial surgical procedure in a patient with suspected adult diffuse glioma. The first goal is to obtain sufficient tissue for diagnostic classification. In the era preceding the recent World Health Organization (WHO) 2016 revised criteria,2 there were limitations on diagnosis imposed by surgical sampling error. In other words, the extent of surgery and subsequent diagnostic grading of an adult diffuse glioma had been shown to be tightly linked.3,4 Patients who underwent biopsy only, unfortunately, would too often have inaccurate diagnoses, due to so-called undergrading, as there would be insufficient material for pathological review. This undergrading complicated the retrospective analyses of surgical treatment, since biopsy-only diagnoses were frequently inaccurate. However, with the molecular genomic component of classifiers codified into the revised diagnostic criteria (primarily IDH1 mutation and 1p/19q-codeletion, as described below), this scenario has occurred more rarely,5 since less tissue is required for molecular testing. The second goal of surgery, in most cases, is to perform therapeutic cytoreduction to secure a prolonged survival and preservation of neurological function for the patient. For glioblastoma multiform (GBM), this has traditionally meant that "complete resection of enhancement" was the intended surgical goal,6,7 while for lower grade lesions, which are mostly nonenhancing, this has meant "complete resection of T2/FLAIR hyper-intensity"8 (Figure A). The evidence base that supports these surgical strategies requires updating in the context of the new WHO 2016 diagnostic criteria.FIGURE. For: IDH1 wild-type tumors, the surgical goal is "complete resection of enhancement," while for IDH1 mutant astrocytomas, which are mostly nonenhancing, the goal is "complete resection of T2/FLAIR hyper-intensity" A and B. Further studies are needed to determine the optimal targeting of radiation therapy for IDH1 mutant gliomas C.ETIOLOGY AND CLASSIFICATION FOR IDH MUTANT GLIOMAS Recurrent mutations of the IDH1 gene were initially identified in 12% of grade IV GBM within a broad sequence screen of more than 20,000 genes.9 Subsequently, more focused large sample studies confirmed that IDH1 mutation is found in the majority of secondary GBM, and only rarely found in primary GBM and GBM in children.9-11 In addition, 50% to 80% of lower grade gliomas (categorized as grade II or III by the legacy WHO 2007 criteria) harbored IDH1 mutation.10-13 The IDH1 gene mutation is almost always localized within exon 4 to codon 132 and >90% of alterations are c.395G>A (R132H) substitutions, followed by R132C as the second-most common alteration.10,12,14 Although the frequency is rare, mutations in the homologous gene IDH2 are also found in gliomas categorized as grade II or III by the legacy WHO 2007 criteria, and secondary GBM.11,15 From a classification perspective, the discovery of IDH1 mutation allows the clear distinction between primary GBM, which frequently harbors epidermal growth factor receptor, PTEN loss, and cyclin-dependent kinase inhibitor 2A (CDKN2A) gene, deletions, versus secondary GBM, which harbors IDH1 mutation.10,12,16,17 With the revision of adult diffuse glioma classification, the 2016 WHO Classification of Tumors of the Central Nervous System integrated phenotypic and genotypic parameters.2 For IDH1 mutant gliomas, tumors are grouped as diffuse astrocytic or oligodendroglial tumors. This group was histologically and genetically divided based on the presence of IDH mutations (typically IDH1R132 and IDH2R172) and 1p/19q codeletion. As an additional reinforcement of this molecular classification, astrocytic gliomas containing IDH1 mutation also near-universally contain TP53 and ATRX gene mutation, whereas oligodendrogliomas are IDH1 mutant with 1p/19q codeletion, often with concomitant CIC and FUBP1 gene and TERT promoter mutation.18,19 These co-occurring genetic abnormalities are mutually exclusive in the vast majority of cases.18-22 Accordingly, most tumors are classified as follows: (1) diffuse astrocytoma (grade II) or anaplastic astrocytoma (grade III) or glioblastoma (grade IV); IDH-mutant, -wild type, or not otherwise specified (NOS); (2) oligodendroglioma (grade II) or anaplastic oligodendroglioma (grade III; IDH mutant and 1p/19q-codeleted or NOS). Remaining cases, which are IDH1 wild type, are classified as (1) oligoastrocytoma (grade II), anaplastic oligoastrocytoma (grade III) (NOS); or (2) diffuse midline glioma (H3K27M-mutant). IDH-wild type glioblastoma (about 90% of cases) is known as primary GBM, while IDH mutant glioblastoma (about 10% of cases) corresponds to secondary GBM.2 PROGNOSTIC SIGNIFICANCE OF IDH1 MUTATION IN GLIOMAS In GBM, Parsons and colleagues9 initially demonstrated that the overall survival (OS) in IDH1-mutant GBM was more than 3-fold longer than that in IDH1 wild-type GBM. Independent groups rapidly replicated the finding that IDH1 mutation is a favorable prognostic biomarker of both progression-free survival (PFS) and OS when compared to IDH1 wild type in low-grade glioma and high-grade glioma.11,13,23 Subsequently, the majority of clinical studies indicated that IDH mutation was an independent prognostic factor in grade II and III gliomas.11,23-29 This evidence indicates that IDH1 mutation is a favorable prognostic factor in adult gliomas. Among these studies, the prospective randomized study NOA-04 revealed IDH1 mutation, hypermethylation of the O6-methylguanine DNA-methyltransferase (MGMT) promoter, age, extent of resection, and oligodendroglial histology are independent prognostic factors in anaplastic gliomas.24 Of note, the impact of IDH1 mutation conferred a stronger risk reduction than 1p/19q codeletion, MGMT promoter methylation, or histology.24 In secondary high-grade gliomas, IDH mutations are also stronger prognostic markers of both PFS and OS than the MGMT promoter methylation status.30 Notably, the prognosis of IDH1 mutant GBM is better than anaplastic astrocytoma without IDH1 mutation.31 Taken together, IDH1 mutation has proven to be a powerful prognostic factor in gliomas, irrespective of tumor grade and histology. Additional clinical characteristics in the IDH1 mutant gliomas are the tumor location and age distribution of the patients upon presentation. Compared with IDH wild type, IDH1 mutant gliomas were predominantly located in the frontal lobe.32-36 Patients with GBM or anaplastic astrocytoma with IDH1 mutation were significantly younger than that with IDH1 wild type.9,11 Intriguingly, the patient age at diagnosis of grade II IDH1 mutant astrocytoma is nearly identical grade III IDH1 mutant anaplastic astrocytoma. Also, the age of IDH1 mutant GBM was only 4 yr older than that of IDH1 mutant grade II and III astrocytoma.37 These findings highlighted the fact that grading, per se, had not been validated as a prognostic marker within the genomically homogeneous cohorts of IDH1 mutant vs wild-type tumors, and serves as a cautionary note for future analyses. Notably in this regard, Suzuki et al29 classified gliomas that were grades II and III by WHO 2007 criteria on the basis of the presence of IDH1 mutation, TP53 mutation, and 1p/19q codeletion. Accordingly, tumors were classified into 3 groups: type I (IDH1 mutant with 1p/19q codeletion; favorable prognostic group), type II (IDH1 mutant with TP53 mutation; intermediate group), and type III (IDH1 wild type; poor prognostic group).29 Survival difference between grade II and grade III were observed only in type II (astrocytic), but not in type I (oligodendroglial) gliomas,29 findings consistent with the results from large randomized studies of grade II and III oligodendrogliomas.38,39 TREATMENT EVIDENCE FOR IDH1 MUTANT GLIOMAS Although scant class I evidence exists, accumulating evidence supports the proposal that more extensive surgical resection has a pivotal role in improving survival in adults with glioma. Extensive resection has been demonstrated to be associated with a survival benefit in low-grade glioma and also in GBM (IDH1 wild type).6,8,40,41 Of note, magnetic resonance (MR) imaging studies have demonstrated IDH1 mutant tumors to be rarely located in high-risk (so-called eloquent) areas of the brain, with a typically unilateral pattern of growth, sharp tumor margin, and less contrast enhancement,32,42 implying IDH1 mutant gliomas are relatively more feasible for resection, when compared to their wild-type counterparts. Intriguingly, patients with IDH1 wild-type gliomas also display reduced neurocognitive function (NCF) and lower performance score than those with IDH1 mutant gliomas.43 In addition, glioma tumor volume was not associated with NCF for patients with IDH1 mutant tumors, but was associated decreased NCF in IDH1 wild-type tumors.43 Diffusion-tensor imaging studies demonstrate that IDH mutant GBM have a less invasive phenotype compared to IDH wild-type lesions.44 Interestingly, we found that extensive resection including nonenhancing area prolonged survival in IDH1 mutant anaplastic astrocytoma and glioblastoma. Since IDH1 mutant gliomas were predominantly located in frontal lobe and the less functional disturbance of adjacent normal brain, IDH1 mutant gliomas were also more amenable to maximal resection.35 These findings were consistent with an independent study, on a separate cohort, demonstrating that the gross total resection was associated with extended survival in grade III IDH1 mutant gliomas without 1p/19q codeletion, but not in IDH1 wild-type or IDH1 mutant gliomas with 1p/19q codeletion.45 Altogether, these findings suggest that extensive resection of both enhancing and nonenhancing (T2/FLAIR hyperintense) disease should be considered for IDH1 mutant gliomas, especially astrocytoma, regardless of WHO grade46 (Figure A and B). To assess for mutant IDH1 noninvasively, several MR techniques including diffusion tensor imaging, relative cerebral blood volume, and magnetic resonance spectroscopy (MRS) have been reported.47-49 MRS can detect 2-hydroxyglutarate (2-HG), which is produced by the IDH mutant enzyme product and is found at levels 100-fold higher in tumors, than that of normal brain.50-58 Additionally, intraoperative technologies to rapidly assess for IDH1 mutation have been established.59-61 Advances in these technologies may allow the surgical strategy to determine the degree of resection to be adjusted intraoperatively during a surgical procedure, based on the IDH1 mutation status of the tumor. Although there is no level I evidence that radiation therapy extends survival in glioma patients with IDH1 mutation, experimental investigations have revealed that forced IDH1 mutant expression in glioma cells results in increased reactive oxygen species, by inhibiting nicotinamide adenine dinucleotide phosphate (NADPH) production, which promotes sensitivity to radiation therapy.62-64 Indeed, 65% of the total NADPH production capacity in GBM is provided for by wild-type IDH activity and introduction of the IDH1 mutation reduced this capacity by 38%.65 In addition, MRS demonstrated that IDH1 mutation decreased glutathione level compared with those with IDH1 wild type.51 Intriguingly, in ATRX mutant tumors, nonhomologous end joining was impaired and increased sensitivity to DNA damaging agents that induce double-stranded DNA breaks.66 These findings may support the recent clinical data that patients with IDH mutant, 1p/19q non-codeleted (astrocytic) tumors treated with radiotherapy had a longer PFS than those treated with temozolomide, whereas no differences in PFS for patients with IDH mutant, 1p/19q codeleted (oligodendroglial), and IDH wild-type (GBM-like) tumors.67 Recently, MRS detected 2-HG has been piloted in the clinical assessment of treatment response and treatment planning in radiotherapy,56,68,69 indicating the potential for clinical application of noninvasively assessed 2-HG. Further work is needed to determine the optimal targeting of radiation therapy for IDH1 mutant gliomas (Figure C). CONCLUSION In conclusion, with the revision of the WHO diagnostic criteria, surgery for adult diffuse gliomas has become even more tightly integrated with radiology and pathology, in both the diagnostic phase as well as the treatment phase of these diseases. Certain cases, namely IDH1 mutant astrocytic gliomas, display a substantial survival benefit in association with maximal resection, regardless of tumor grade under the legacy criteria. Thus, individualization of surgical strategy for patients with IDH1 mutant gliomas has advanced significantly in the modern era. Disclosures This work was supported by NIH P50CA165962 and Burroughs-Wellcome CAMS # 1007616.02. The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article.