Dirven, Linda

Dubbink, Hendrikus J.

French, Pim J.

Hazelbag, Hans M.

Kros, Johan M.

Maas, Sybren L.N.

Tesileanu, C. Mircea S.

Van Den Bent, Martin J.

Van Dis, Vera

Vincent, Arnaud J.P.E.

Wijnenga, Maarten M.J.

English

In the 2021 revised World Health Organization Classification of Central Nervous System Tumours (WHO CNS5) classification, isocitrate dehydrogenase 1/2 -wild-type (IDHwt) gliomas lacking necrosis and/or vascular proliferations, but with a TERT-promotor (TERTp) mutation, and/or EGFR amplification, and/or combined gain of chromosome 7 and loss of chromosome 10 (7+/10−), are now classified as IDHwt glioblastoma.1 These formerly labeled "diffuse astrocytomas, IDH wild-type, with genetic features of glioblastoma" are not separated anymore from histologically defined glioblastomas. However, there is still discussion if these gliomas are truly the same in terms of first presentation and survival.2 In 2021, a French series concluded that glioblastoma patients with histology lacking high-grade features have a favorable outcome, with a median overall survival (OS) of 88 months in cases lacking anaplasia, increased mitotic activity, necrosis, or vascular proliferations when only a TERTp mutation is present.3 This challenges the concept of the proposed CNS5 classification of glioblastoma. Therefore, we expanded and re-analyzed a previously published cohort of 71 glioblastoma patients that lacked high-grade features in the original histopathological diagnosis and also showed imaging features that are more compatible with a lower-grade glioma.4,5 To investigate if histological grading had impact on OS in glioblastoma, we reevaluated the histological grade by 2 independent reviewers. We assessed OS for the different histological grades and also specifically investigated the OS impact of isolated TERTp mutations.</p

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Neuro-Oncology Advances5(1), 1–2, 2023 | https://doi.org/10.1093/noajnl/vdad075 | Advance Access date 21 June 20231Maarten M.J. Wijnenga , Sybren L.N. Maas, Vera van Dis , C. Mircea S. Tesileanu, Johan M. Kros,  Linda Dirven , Hans M. Hazelbag, Hendrikus J. Dubbink, Arnaud J.P.E. Vincent, Pim J. French, and Martin J. van den BentDepartment of Neurology, Brain Tumor Center, Erasmus MC Cancer Institute, Rotterdam, The Netherlands(M.M.J.W., C.M.S,T., P.J.F., M.J.vdB); Department of Pathology, Brain Tumor Center, Erasmus MC Cancer Institute, Rotterdam, The Netherlands(S.L.N.M., V.vD., J.M.K., H.J.D.); Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands(S.L.N.M.); Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands(L.D.); Department of Pathology, Medical Center Haaglanden, The Hague, The Netherlands(H.M.H.); Department of Neurosurgery, Brain Tumor Center, Erasmus MC Cancer Institute, Rotterdam, The Netherlands(A.J.P.E.V.)Corresponding Author: Maarten M.J. Wijnenga, MD PhD, Department of Neurology, Erasmus MC Cancer Institute, PO Box 5201, 3008AE Rotterdam, The Netherlands(m.wijnenga@erasmusmc.nl).In the 2021 revised World Health Organization Classification of Central Nervous System Tumours (WHO CNS5) classifica-tion, isocitrate dehydrogenase 1/2 -wild-type (IDHwt) gliomas lacking necrosis and/or vascular proliferations, but with a TERT-promotor (TERTp) mutation, and/or EGFR amplification, and/or combined gain of chromosome 7 and loss of chromo-some 10 (7+/10−), are now classified as IDHwt glioblastoma.1 These formerly labeled “diffuse astrocytomas, IDH wild-type, with genetic features of glioblastoma” are not separated an-ymore from histologically defined glioblastomas. However, there is still discussion if these gliomas are truly the same in terms of first presentation and survival.2 In 2021, a French series concluded that glioblastoma patients with histology lacking high-grade features have a favorable outcome, with a median overall survival (OS) of 88 months in cases lacking anaplasia, increased mitotic activity, necrosis, or vascular proliferations when only a TERTp mutation is present.3 This challenges the concept of the proposed CNS5 classification of glioblastoma. Therefore, we expanded and re-analyzed a previ-ously published cohort of 71 glioblastoma patients that lacked high-grade features in the original histopathological diagnosis and also showed imaging features that are more compat-ible with a lower-grade glioma.4,5 To investigate if histological grading had impact on OS in glioblastoma, we reevaluated the histological grade by 2 independent reviewers. We assessed OS for the different histological grades and also specifically in-vestigated the OS impact of isolated TERTp mutations.We identified 132 cases from 3 Dutch hospitals, which were initially histologically classified as grade 2 or 3 gliomas, but molecularly upgraded to GBM. Cases with ring-like contrast enhancement and/or central necrosis at time of diagnostic surgery were excluded, as a low-grade histology would then suggest the infiltration border was sampled and not the true histological appearance of the tumor. Two dedicated neuro-pathologists (SLNM/VD) blinded for clinical information in-dependently revised the histological grade. Discordant cases were discussed to reach consensus. Out of 132 cases, tissue was available for revisions in 102 cases. Criteria for his-tology, analog to grade 3 in the 2016 WHO classification cri-teria, were anaplasia as defined by high cell density, nuclear polymorphism and/or nuclear hyperchromasia as well as increased mitotic activity. Detection of necrosis and/or en-dothelial proliferation warranted a grade 4. Patients were mo-lecularly classified with a tailored NGS panel as described before.4 We compared OS in this cohort with OS of a histor-ical histologically defined glioblastoma cohort (197 patients with MRI characteristics of glioblastoma (GBM) and GBM his-tology), of which characteristics were described before.4 For readability and clarity, we refer to “m-GBM“ for the glioblas-toma cases lacking high-grade features, and “h-GBM” for the historical cohort in further text. Depending on each institution’s policy, the study received approval for exemption from review or was waived from review by the institution and was con-ducted according to national and local regulations.Out of the 81 histological grade 2 cases (original diagnostics) in the m-GBM cohort, upon pathology review 60 patients were still classified as grade 2 histology, in 15 patients the histology was revised into grade 3 as defined above, and in 6 patients into grade 4 as (small foci of) necrosis or vascular proliferation were detected upon reinvestigation. Out of the 21 histological © The Author(s) 2023. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.Glioblastoma lacking necrosis or vascular proliferations: Different clinical presentation but similar outcome, regardless of histology or isolated TERT promoter mutation  This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.Downloaded from https://academic.oup.com/noa/article/5/1/vdad075/7204729 by Erasmus University Rotterdam user on 16 August 2023Wijnenga et al.: Glioblastoma lacking necrosis or vascular proliferations 2grade 3 patients, 11 were again classified as grade 3 his-tology after revisions. Five patients were revised as grade 2 histology, and the other 5 as grade 4 for reasons listed above. Median age did not differ between groups (grade 2 histology: 61 years, grade 3 histology: 58 years, grade 4 histology: 64 years, h-GBM: 55 years). Clinical pres-entation of m-GBM was different compared to h-GBM. m-GBM lacking high-grade features more often presented with seizures than h-GBM (56% vs. 27%). Primary sur-gical strategy was also different with a lower percentage of resections (m-GBM: 20% vs. h-GBM: 80%) similar to our previous analysis of the smaller cohort.4,5 We found no sig-nificant OS difference between histological grades in our m-GBM cohort and no difference with h-GBM (Figure 1A). Additionally, in cases with grade 2 histology, we found no difference in OS between patients with an isolated TERTp mutation compared to cases with additional EGFR amplifi-cation and/or 7+/10− (Figure 1B).To conclude, in our cohort of glioblastomas with grade 2 histology and imaging characteristics of low-grade glioma, we observed a different clinical presentation compared to histologically defined glioblastoma. However, we could not confirm the results of Berzero et al., where histological grade impacts OS and where isolated TERTp mutations are associ-ated with longer OS.3 Although our series is larger and sup-ports the concept of the proposed CNS5 classification, we feel more independent series with pathology reviews that investigate the course of GBMs lacking high-grade features are needed to fully answer this grade issue.References1. Louis DN, Perry A, Wesseling P, et al. The 2021 WHO classification of tumors of the central nervous system: A summary. Neuro Oncol. 2021;23(8):1231–1251.2. Lassman AB, van den Bent MJ. What is a glioblastoma? Neuro Oncol. 2023;25(6):1015–1016.3. Berzero G, Di Stefano AL, Ronchi S, et al. IDH-wildtype lower-grade dif-fuse gliomas: The importance of histological grade and molecular as-sessment for prognostic stratification. Neuro Oncol. 2021;23(6):955–966.4. Tesileanu CMS, Dirven L, Wijnenga MMJ, et al. Survival of diffuse as-trocytic glioma, IDH1/2 wildtype, with molecular features of glioblas-toma, WHO grade IV: A confirmation of the cIMPACT-NOW criteria. Neuro Oncol. 2020;22(4):515–523.5. van Opijnen MP, Tesileanu CMS, Dirven L, et al. IDH1/2 wildtype gliomas grade 2 and 3 with molecular glioblastoma-like profile have a distinct course of epilepsy compared to IDH1/2 wildtype glioblastomas. Neuro Oncol. 2023;25(4):701–709.100%m-GBM garde 2EGFR ampl and/or 7+/10-Isolated TERTp mutationm-GBM garde 3m-GBM garde 4h-GBMOS: histological grades in m-GBM vs h-GBMA B OS in grade 2: isolated TERTp vs EGFR ampl and/or 7+/10-75%p = 0.38Number at risk Number at riskp = 0.5950%Survival probability25%0%0100%75%50%25%0%01 2 3 4 5 6 70 1 2 3 4Follow–up in years Follow–up in years5 6 765 38 16 7 5 0 0 026 12 5 1 1 1 0 011 5 1 0 0 0 0 0197 142 61 30 11 10 8 61 2 3 4 5 6 7 8 9 100 1 2 3 4 5 6 7 8 9 1032 20 10 5 3 1 0 0 0 0 033 22 11 6 2 1 1 1 1 1 0Figure 1. Panel A: overall survival curves for histological grades in m-GBM and the h-GBM cohort. Survival was defined as time from first sur-gery till date of death or censorship. OS for grade 2 patients was 17 months versus 18 months in h-GBM patients. Panel B: overall survival curves of grade 2 patients within the m-GBM group; patients with an isolated TERTp mutation (so absence of EGFR amplification and/or 7+/10−) versus patients with an EGFR amplification and/or 7+/10− with or without a TERTp mutation (all but 2 of these patients also harbored a TERTp muta-tion). OS was 17 months for isolated TERTp mutation versus 21 months for patients with EGFR amplification and/or 7+/10−.Downloaded from https://academic.oup.com/noa/article/5/1/vdad075/7204729 by Erasmus University Rotterdam user on 16 August 2023

Glioblastoma lacking necrosis or vascular proliferations:Different clinical presentation but similar outcome, regardless of histology or isolated TERT promoter mutation

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Glioblastoma lacking necrosis or vascular proliferations:Different clinical presentation but similar outcome, regardless of histology or isolated TERT promoter mutation

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