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Table of Contents
Year : 2021  |  Volume : 4  |  Issue : 4  |  Page : 65-67

The new WHO molecular criteria for adult glioblastoma – Are we a step too far?

1 Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong; Hong Kong and Shanghai Brain Consortium, Shatin, Hong Kong Special Administrative Region, China
2 Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong Special Administrative Region, China

Date of Submission24-Dec-2021
Date of Decision25-Dec-2021
Date of Acceptance25-Dec-2021
Date of Web Publication13-Jan-2022

Correspondence Address:
Prof. Ho-Keung Ng
Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong Special Administrative Region
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/glioma.glioma_19_21

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How to cite this article:
Ng HK, Wong QH, Liu EM, Li KK. The new WHO molecular criteria for adult glioblastoma – Are we a step too far?. Glioma 2021;4:65-7

How to cite this URL:
Ng HK, Wong QH, Liu EM, Li KK. The new WHO molecular criteria for adult glioblastoma – Are we a step too far?. Glioma [serial online] 2021 [cited 2023 Oct 2];4:65-7. Available from: http://www.jglioma.com/text.asp?2021/4/4/65/335760

For many decades, the pathological diagnosis of glioblastomas, the most common malignant brain tumor in adults, remains histological: the presence of necrosis and/or microvascular proliferation, on top of mitoses, increased cellularity, and nuclear atypia.[1],[2] There were no immunohistochemical or molecular biomarkers that can diagnose glioblastomas on their own. cIMPACT-NOW 3 proposed that for IDH wild-type (wt) astrocytomas, one can make a diagnosis of glioblastoma if one of the following molecular biomarkers is present: EGFR amplification, mutation of the TERT promoter (TERTp), and combined whole chromosome 7 gain and 10 loss.[3] This is valid even when the histological features for glioblastoma are absent. cIMPACT-NOW 5 also proposed that for IDH-mutant astrocytomas, the term “glioblastoma” should be discarded and replaced by Grade 4 IDH-mutant astrocytoma, to contrast it from the regular glioblastoma, which is mostly IDH-wt and of poorer prognosis.[4] The molecular criteria for diagnosing Grade 4 IDH-mutant astrocytoma is homozygous deletion of CDKN2A/B.[4] Similar to the situation in IDH-wt gliomas, this is valid in the absence of conventional histological features of glioblastoma. A subsequent extended cIMPACT-NOW 6 and the new WHO Classification of CNS Tumors of 2021 further enshrined these principles.[5],[6] In the WHO 2021 Classification, all IDH-wt astrocytomas are potentially glioblastomas, and IDH-wt lower-grade gliomas have been swept away from the Classification. If an IDH-wt lower-grade glioma does not show histological features of glioblastoma and does not exhibit EGFR amplification, TERTp mutation, or chromosome +7/−10, then it is regarded as not elsewhere classified (NEC) in the Classification.

Neither cIMPACT-NOW nor WHO stipulated the best methodology for studying these genetic aberrations. Most laboratories will test TERTp mutations by Sanger sequencing and chromosomal gains or losses by FISH or methylation profiling. Many centers now routinely send tissue away after surgery for next-generation sequencing (NGS) for “genomic studies” because of financial or other reasons, but NGS is not a very satisfactory method for studying copy number alterations. A common misconception among less well-informed clinicians is that one would now need a molecular diagnosis for all glioblastomas in the new classification. Neither cIMPACT-NOW nor WHO 2021 requires the presence of these molecular alterations as a must for a diagnosis of glioblastoma. For an astrocytic tumor that already shows the conventional histological criteria of anaplasia, necrosis, or microvascular proliferation, there is no further need for molecular studies for a diagnosis of glioblastoma. One must not equate these molecular criteria as necessary, routine tests for diagnosing all glioblastomas. Conventional histology alone is still adequate for diagnosing the majority of adult glioblastomas.

Both cIMPACT-NOW and the WHO Classification are by their nature consensus statements from groups of expert neuropathologists and clinicians, with a lot of overlap of authors between the two. More recently, the validity of these molecular criteria for IDH-wt glioblastomas has been questioned,[7] and the removal of proper grouping for IDH-wt lower-grade astrocytomas renders diagnosis and management of these patients difficult as well-informed patients will be confused by pathological reports, which described their tumors as “not elsewhere classified,” resulting in unnecessary anxiety. One of the problems of both sets of molecular criteria for IDH-mutant and IDH-wt glioblastomas is that these have been based on some excellent publications, which studied IDH-wt and IDH-mutant lower-grade astrocytomas, respectively.[8],[9],[10],[11],[12] In these papers, it was shown that lower-grade astrocytomas, either IDH-wt or IDH-mutant, showing those molecular alterations behaved much more aggressively than those that did not show those molecular abnormalities. However, whether the worsened prognosis in those histologically lower-grade astrocytomas is equivalent to the dismal prognosis of the regular glioblastomas is more debatable.

In terms of sensitivity as diagnostic tests, for IDH-wt astrocytomas, the seminal paper by Stichel et al. showed that EGFR amplification, TERTp mutation, or +7/−10 had a combined sensitivity of 77% in diagnosing IDH-wt glioblastomas.[13] The sensitivity is relatively restricted. In our unpublished materials, the overall coverage of the three molecular criteria for IDH-wt glioblastomas is 60%–70%. It must be noted that a proportion of IDH-wt glioblastomas may not show any of these molecular alterations for diagnostic scenarios. Moreover, it is uncertain if these criteria can be applied to the young adult patients with IDH-wt glioblastomas; although it is well known, a proportion of glioblastomas in younger patients are IDH-mutant. In our series of 50 glioblastomas of adolescents and young adults (AYA), only 33% of cases showed one of the three molecular criteria.[14] For IDH-mutant glioblastomas in adults, in our data, only 55% of cases exhibited homozygous deletion of CDKN2A/B.[15] The conclusion has to be that the new molecular criteria for diagnosing both IDH-wt and IDH-mutant glioblastomas have to be applied with due respect to their sensitivity and exercised with special caution when one is presented with astrocytomas from AYA.

The main publications on promoting these molecular criteria had evaluated their survival impact on the lower-grade astrocytomas and that those tumors possessing these molecular alterations showed a poor overall survival.[8],[9],[12] Whether these lower-grade astrocytomas possessing poor prognostic markers really have the same dismal prognosis of glioblastomas and are therefore their equivalents is less well studied. In a recent paper, in a large French series of lower-grade IDH-wt astrocytomas where radiologically suspicions for glioblastomas had been vigorously excluded, cases meeting cIMPACT-NOW criteria for glioblastomas displayed a median survival of 42 months, which was significantly longer than the survival of the regular IDH-wt glioblastomas of 17–18 months.[16] Moreover, for Grade II astrocytomas, which met the cIMPACT-NOW criteria because of an isolated TERTp mutation (16/26, 62%), in this series, the median survival was 88 months, and that was hardly the survival of the regular glioblastomas. In some previous papers, lower-grade gliomas possessing one of those molecular alterations despite having a more aggressive behavior than those without also had an overall survival marginally better than what we normally associate with glioblastoma.[9],[10]

The French paper[16] is important as it evaluated TERTp mutation, which is by far the most common criterion of the three molecular criteria to be met for IDH-wt glioblastoma, being present in 70%–80% of cases in most series. Two recent papers supposedly validated the three cIMPACT-NOW criteria for IDH-wt lower-grade gliomas. In a Dutch series, TERTp mutant of IDH-wt astrocytomas showed an overall survival of 14.4 months, and their regular IDH-wt glioblastomas showed a median overall survival of only 19.2 months, but there was no statistical significance.[17] In the other study from Japan, the authors merely confirmed the poor survival prediction of TERTp mutation in IDH-wt lower-grade gliomas,[18] but we do not know the prognostic significance of TERTp mutation-only in these tumors. In many of these studies, histological grades remain an important survival predictor.[8],[9],[16],[17],[18] Good histological studies are still vital in assigning a prognosis in a patient with a lower-grade astrocytoma.

Paradoxically, in IDH-mutant lower-grade astrocytomas, TERTp mutation conferred a good prognostic significance in a high-profile study,[19] but TERTp mutations are usually rare events in IDH-mutant gliomas.[15],[20] For IDH-mutant lower-grade astrocytomas, the key paper to support the current molecular criteria showed the prognostic significance of CDKN2A in Grade 3 astrocytomas only.[11] Our study suggested that homozygous deletion of CDKN2A would be a better prognostic predictor for IDH-mutant lower-grade astrocytomas when combined with other biomarkers such as CDK4 and PDGFRA amplifications.[20]

WHO Classifications are consensus views of what is known at the time of the consensus meetings of the experts and the first author of this article had the privilege to participate in those meetings. The consensus meetings of the upcoming WHO 2021 Classification were held in August 2020, and inevitably, the Classification should already be slightly out of date. At the time of writing this Editorial, the proper WHO 2021 Classification was not yet published and only a summary was published by the consensus group including the first author of this article.[6] It is hoped that bigger series can critically re-evaluate the issues of molecular diagnosis both in IDH-wt and IDH-mutant 1p19q nondeleted astrocytomas in the absence of classical histological features and in those without molecular characteristics. In the meantime, in our view, there is probably still a need to diagnose IDH-wt lower-grade astrocytomas that do not meet histological or molecular criteria for glioblastomas, if anything, for patient management and counseling. These tumors still need to be defined by those clinical trials which specifically target these patients. To have 20%–30% of one's IDH-wt lower-grade astrocytomas, which are common in any neuro-oncology service, diagnosed as tumors NEC as per the new recommendations, will be confusing to many clinicians. In our view, it is unfair to patients as these tumors are not “unknowns”; a wealth of literature exists on their natural history and treatments.

Conflicts of interest

There are no conflicts of interest.

Editor Note: HKN is an Editorial Board member of Glioma. He was blinded from reviewing or making decisions on the manuscript. The article was subject to the journal's standard procedures, with peer review handled independently of this Editorial Board member and their research groups.

  References Top

Louis DN, Brat DJ, Ohgaki H, Stupp R, Suvà ML, Biernat W, et al. Glioblastoma, IDH-wildtype. In: Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, editors. WHO Classification of Tumours of the Central Nervous System. Ch. 1. Lyon: International Agency for Research on Cancer (IACC); 2007:28-45.  Back to cited text no. 1
Ohgaki H, Reifenberger G, Kleihues P, Yan H, von Deimling A, Weller M, et al. Glioblastoma, IDH-mutant. In: Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, editors. WHO Classification of Tumours of the Central Nervous System. Ch. 1. Lyon: International Agency for Research on Cancer (IACC); 2007:52-9.  Back to cited text no. 2
Brat DJ, Aldape K, Colman H, Holland EC, Louis DN, Jenkins RB, et al. cIMPACT-NOW update 3: Recommended diagnostic criteria for Diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV. Acta Neuropathol 2018;136:805-10.  Back to cited text no. 3
Brat DJ, Aldape K, Colman H, Figrarella-Branger D, Fuller GN, Giannini C, et al. cIMPACT-NOW update 5: Recommended grading criteria and terminologies for IDH-mutant astrocytomas. Acta Neuropathol 2020;139:603-8.  Back to cited text no. 4
Louis DN, Wesseling P, Aldape K, Brat DJ, Capper D, Cree IA, et al. cIMPACT-NOW update 6: New entity and diagnostic principle recommendations of the cIMPACT-Utrecht meeting on future CNS tumor classification and grading. Brain Pathol 2020;30:844-56.  Back to cited text no. 5
Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D, et al. The 2021 WHO classification of tumors of the central nervous system: A summary. Neuro Oncol 2021;23:1231-51.  Back to cited text no. 6
Giannini C, Giangaspero F. TERT promoter mutation: Is it enough to call a WHO grade II astrocytoma IDH wild-type glioblastoma? Neuro Oncol 2021;23:865-6.  Back to cited text no. 7
Aibaidula A, Chan AK, Shi Z, Li Y, Zhang R, Yang R, et al. Adult IDH wild-type lower-grade gliomas should be further stratified. Neuro Oncol 2017;19:1327-37.  Back to cited text no. 8
Aoki K, Nakamura H, Suzuki H, Matsuo K, Kataoka K, Shimamura T, et al. Prognostic relevance of genetic alterations in diffuse lower-grade gliomas. Neuro Oncol 2018;20:66-77.  Back to cited text no. 9
Appay R, Dehais C, Maurage CA, Alentorn A, Carpentier C, Colin C, et al. CDKN2A homozygous deletion is a strong adverse prognosis factor in diffuse malignant IDH-mutant gliomas. Neuro Oncol 2019;21:1519-28.  Back to cited text no. 10
Shirahata M, Ono T, Stichel D, Schrimpf D, Reuss DE, Sahm F, et al. Novel, improved grading system(s) for IDH-mutant astrocytic gliomas. Acta Neuropathol 2018;136:153-66.  Back to cited text no. 11
Wijnenga MM, Dubbink HJ, French PJ, Synhaeve NE, Dinjens WN, Atmodimedjo PN, et al. Molecular and clinical heterogeneity of adult diffuse low-grade IDH wild-type gliomas: Assessment of TERT promoter mutation and chromosome 7 and 10 copy number status allows superior prognostic stratification. Acta Neuropathol 2017;134:957-9.  Back to cited text no. 12
Stichel D, Ebrahimi A, Reuss D, Schrimpf D, Ono T, Shirahata M, et al. Distribution of EGFR amplification, combined chromosome 7 gain and chromosome 10 loss, and TERT promoter mutation in brain tumors and their potential for the reclassification of IDHwt astrocytoma to glioblastoma. Acta Neuropathol 2018;136:793-803.  Back to cited text no. 13
Shi ZF, Li KK, Wong QJ, Wang WW, Kwan JS, Chen H, et al. Molecular landscape of IDHwt, H3wt Adolescent and Young Adult (AYA) glioblastoma. Neuropathol Appl Neurobiol, accepted.  Back to cited text no. 14
Wong QH, Li KK, Wang WW, Malta TM, Noushmehr H, Grabovska Y, et al. Molecular landscape of IDH-mutant primary astrocytoma Grade IV/glioblastomas. Mod Pathol 2021;34:1245-60.  Back to cited text no. 15
Berzero G, Di Stefano AL, Ronchi S, Bielle F, Villa C, Guillerm E, et al. IDH-wildtype lower-grade diffuse gliomas: The importance of histological grade and molecular assessment for prognostic stratification. Neuro Oncol 2021;23:955-66.  Back to cited text no. 16
Tesileanu CM, Dirven L, Wijnenga MM, Koekkoek JA, Vincent AJ, Dubbink HJ, et al. Survival of diffuse astrocytic glioma, IDH1/2 wildtype, with molecular features of glioblastoma, WHO grade IV: A confirmation of the cIMPACT-NOW criteria. Neuro Oncol 2020;22:515-23.  Back to cited text no. 17
Fujimoto K, Arita H, Satomi K, Yamasaki K, Matsushita Y, Nakamura T, et al. TERT promoter mutation status is necessary and sufficient to diagnose IDH-wildtype diffuse astrocytic glioma with molecular features of glioblastoma. Acta Neuropathol 2021;142:323-38.  Back to cited text no. 18
Eckel-Passow JE, Lachance DH, Molinaro AM, Walsh KM, Decker PA, Sicotte H, et al. Glioma groups based on 1p/19q, IDH, and TERT promoter mutations in tumors. N Engl J Med 2015;372:2499-508.  Back to cited text no. 19
Yang RR, Shi ZF, Zhang ZY, Chan AK, Aibaidula A, Wang WW, et al. IDH mutant lower grade (WHO Grades II/III) astrocytomas can be stratified for risk by CDKN2A, CDK4 and PDGFRA copy number alterations. Brain Pathol 2020;30:541-53.  Back to cited text no. 20

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