IDH mutant diffuse and anaplastic astrocytomas have similar age at presentation and little difference in survival: a grading problem for WHO

Reuß, David; Mamatjan, Yasin; Schrimpf, Daniel; Capper, David; Hovestadt, Volker; Kratz, Annekathrin; Sahm, Felix; Koelsche, Christian; Korshunov, Andrey; Olar, Adriana; Hartmann, Christian; Reijneveld, Jaap C.; Wesseling, Pieter; Unterberg, Andreas; Platten, Michael; Wick, Wolfgang; Herold‐Mende, Christel; Aldape, Kenneth; Deimling, Andreas von

doi:10.1007/s00401-015-1438-8

Cited by 291 publications

(231 citation statements)

References 25 publications

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“…Importantly, there were no significant differences in PFS among the three groups when based on grade (II or III). This reinforces prior studies that found no significant prognostic differences between IDH-MT grade II and III tumors [31,32]. In fact, Suzuki et al stated that grade III IDH-MT tumors showed OS comparable to corresponding grade II tumors and recommended managing them as low-grade tumors [33].…”

Section: Discussionsupporting

confidence: 85%

Imaging correlates for the 2016 update on WHO classification of grade II/III gliomas: implications for IDH, 1p/19q and ATRX status

et al. 2017

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BACKGROUND The 2016 World Health Organization Classification of Tumors of the Central Nervous System incorporates the use of molecular information into the classification of brain tumors, including grade II and III gliomas, providing new prognostic information that cannot be delineated based on histopathology alone. We hypothesized that these genomic subgroups may also have distinct imaging features. METHODS A retrospective single institution study was performed on 40 patients with pathologically proven infiltrating WHO grade II/III gliomas with a pre-treatment MRI and molecular data on IDH, chromosomes 1p/19q and ATRX status. Two blinded Neuroradiologists qualitatively assessed MR features. The relationship between each parameter and molecular subgroup (IDH-wildtype; IDH-mutant-1p/19q codeleted-ATRX intact; IDH-mutant-1p/19q intact-ATRX loss) was evaluated with Fisher’s exact test. Progression free survival (PFS) was also analyzed. RESULTS A border that could not be defined on FLAIR was most characteristic of IDH-wildtype tumors, whereas IDH-mutant tumors demonstrated either well-defined or slightly ill-defined borders (p = 0.019). Degree of contrast enhancement and presence of restricted diffusion did not distinguish molecular subgroups. Frontal lobe predominance was associated with IDH-mutant tumors (p = 0.006). The IDH- wildtype subgroup had significantly shorter PFS than the IDH-mutant groups (p < 0.001). No differences in PFS were present when separating by tumor grade. CONCLUSIONS FLAIR border patterns and tumor location were associated with distinct molecular subgroups of grade II/III gliomas. These imaging features may provide fundamental prognostic and predictive information at time of initial diagnostic imaging.

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Section: Discussionsupporting

confidence: 85%

Imaging correlates for the 2016 update on WHO classification of grade II/III gliomas: implications for IDH, 1p/19q and ATRX status

et al. 2017

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“…Large-scale DNA methylation profiling using Infinium ® HumanMethylation450 beadchip arrays has proven very useful for the elucidation of biologically distinct subgroups of medulloblastoma [10], ependymoma [15], glioblastoma [2,12,19], as well as diffuse and anaplastic gliomas [16,17,23]. In the present study of GC patients, 450k analyses revealed that DNA methylation profiles corresponded to those of several previously defined molecular subgroups of gliomas.…”

Section: Discussionsupporting

confidence: 49%

Gliomatosis cerebri: no evidence for a separate brain tumor entity

et al. 2015

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Gliomatosis cerebri (GC) is presently considered a distinct astrocytic glioma entity according to the WHO classification for CNS tumors. It is characterized by widespread, typically bilateral infiltration of the brain involving three or more lobes. Genetic studies of GC have to date been restricted to the analysis of individual glioma-associated genes, which revealed mutations in the isocitrate dehydrogenase 1 (IDH1) and tumor protein p53 (TP53) genes in subsets of patients. Here, we report on a genome-wide analysis of DNA methylation and copy number aberrations in 25 GC patients. Results were compared with those obtained for 105 patients with various types of conventional, i.e., non-GC gliomas including diffuse astrocytic gliomas, oligodendrogliomas and glioblastomas. In addition, we assessed the prognostic role of methylation profiles and recurrent DNA copy number aberrations in GC patients. Our data reveal that the methylation profiles in 23 of the 25 GC tumors corresponded to either IDH mutant astrocytoma (n = 6), IDH mutant and 1p/19q codeleted oligodendroglioma (n = 5), or IDH wild-type glioblastoma including various molecular subgroups, i.e., H3F3A-G34 mutant (n = 1), receptor tyrosine kinase 1 (RTK1, n = 4), receptor tyrosine kinase 2 (classic) (RTK2, n = 2) or mesenchymal (n = 5) glioblastoma groups. Two tumors showed methylation profiles of normal brain tissue due to low tumor cell content. While histological grading (WHO grade IV vs. WHO grade II and III) was not prognostic, the molecular classification as classic/RTK2 or mesenchymal glioblastoma was associated with worse overall survival. Multivariate Cox regression analysis revealed MGMT promoter methylation as a positive prognostic factor. Taken together, DNA-based large-scale molecular profiling indicates that GC comprises a genetically and epigenetically heterogeneous group of diffuse gliomas that carry DNA methylation and copy number profiles closely matching the common molecularly defined glioma entities. These data support the removal of GC as a distinct glioma entity in the upcoming revision of the WHO classification. 3

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“…In fact, recent evidence points to only minor differences in clinical characteristics between patients with IDHmut diffuse A II and A III [2,15,18,22]. We strongly recommend to use every possibility to come to this diagnosis by IHC with IDH1-R132H specific antibodies and, if required by sequencing exons 4 of IDH1 and IDH2.…”

Section: Implication For Future Diagnostic Approach To Diffuse and Anmentioning

confidence: 98%

Adult IDH wild type astrocytomas biologically and clinically resolve into other tumor entities

et al. 2015

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IDH wild type (IDHwt) anaplastic astrocytomas WHO grade III (AA III) are associated with poor outcome. To address the possibilities of molecular subsets among astrocytoma or of diagnostic reclassification, we analyzed a series of 160 adult IDHwt tumors comprising 120 AA III and 40 diffuse astrocytomas WHO grade II (A II) for molecular hallmark alterations and established methylation and copy number profiles. Based on molecular profiles and hallmark alterations the tumors could be grouped into four major sets. 124/160 (78 %) tumors were diagnosed as the molecular equivalent of conventional glioblastoma (GBM), and 15/160 (9 %) as GBM-H3F3A mutated (GBM-H3). 13/160 (8 %) exhibited a distinct methylation profile that was most similar to GBM-H3-K27, however, lacked the H3F3A mutation. This group was enriched for tumors of infratentorial and midline localization and showed a trend towards a more favorable prognosis. All but one of the 120 IDHwt AA III could be assigned to these three groups. 7 tumors recruited from the 40 A II, comprised a variety of molecular signatures and all but one were reclassified into distinct WHO entities of lower grades. Interestingly, TERT mutations were exclusively restricted to the molecular GBM (78 %) and associated with poor clinical outcome. However, the GBM-H3 group lacking TERT mutations appeared to fare even worse. Our data demonstrate that most of the tumors diagnosed as IDHwt astrocytomas can be allocated to other tumor entities on a molecular basis. exhibited a distinct methylation profile that was most similar to GBM-H3-K27, however, lacked the H3F3A mutation. This group was enriched for tumors of infratentorial and midline localization and showed a trend towards a more favorable prognosis. All but one of the 120 IDHwt AA III could be assigned to these three groups. 7 tumors recruited from the 40 A II, comprised a variety of molecular signatures and all but one were reclassified into distinct WHO entities of lower grades. Interestingly, TERT mutations were exclusively restricted to the molecular GBM (78%) and associated with poor clinical outcome. However, the GBM-H3 group lacking TERT mutations appeared to fare even worse.Our data demonstrate that most of the tumors diagnosed as IDHwt astrocytomas can be allocated to other tumor entities on a molecular basis. The diagnosis of IDHwt diffuse astrocytoma or anaplastic astrocytoma should be used with caution.

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IDH mutant diffuse and anaplastic astrocytomas have similar age at presentation and little difference in survival: a grading problem for WHO

Cited by 291 publications

References 25 publications

Imaging correlates for the 2016 update on WHO classification of grade II/III gliomas: implications for IDH, 1p/19q and ATRX status

Imaging correlates for the 2016 update on WHO classification of grade II/III gliomas: implications for IDH, 1p/19q and ATRX status

Gliomatosis cerebri: no evidence for a separate brain tumor entity

Adult IDH wild type astrocytomas biologically and clinically resolve into other tumor entities

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