Reclassification of Glioblastoma Multiforme According to the 2021 World Health Organization Classification of Central Nervous System Tumors: A Single Institution Report and Practical Significance

Abstract

Introduction The 2021 World Health Organization (WHO) classification of tumors of the central nervous system (CNS) has introduced significant changes to tumor taxonomy. One of the most significant changes in the isolation of isocitrate dehydrogenase (IDH) mutant forms of glioblastoma multiforme (GBM) into separate entities, as well as no longer allowing for entries to be classified as not otherwise specified (NOS). As a result, this entity now includes only the most aggressive adult-type tumors. As such, established prognostic factors no longer apply, as they now form the criteria of different disease entries or have been established based on a mixed cohort. Herein, we aimed to reclassify glioblastoma cases diagnosed per the 2016 WHO tumors of the CNS classification into the 2021 WHO tumors of the CNS classification and establish a patient survival pattern based on age, gender, tumor location, and size as well as tumor O-6-methylguanine-DNA methyltransferase (MGMT) mutation. Materials and methods A retrospective, non-clinical approach was utilized. Biopsy specimens of adults diagnosed with GBM, WHO grade 4, NOS in the period February 2018-February 2021 were reevaluated. The data regarding the patient's gender and age were withdrawn from the medical documentation. Immunohistochemistry was performed with mouse monoclonal anti-IDH R132H and rabbit polyclonal anti-MGMT. Radiology data on tumor location and size were pulled from the radiology repository. Data were statistically analyzed for significance, using Kaplan-Meier survival analysis, with a 95% confidence interval and p<0.05 defined as significant. Results A total of 58 cases fit the set criteria, with eight of them (13.7%) harboring an IDH R132H mutation and were hence reclassified as diffuse astrocytoma IDH-mutant, WHO CNS grade 4. The cases that retained their GBM classification included n=28 males and n=22 females, a male to female ratio of 1.27:1, and a mean age of 65.3 years (range 43-86 years). The MGMT mutational status revealed a total of n=17 positive cases (35%), while the remaining cases were negative. No hemispheric predilection could be established. Lobar predilection was as follows: temporal (37.78%), parietal (28.89%), frontal (24.44%), and occipital (8.89%). The mean tumor size measured on neuroradiology across the cohort was 50.51 mm (range 20-76 mm). The median survival across cases was 255.96 days (8.41 months), with a range of 18-1150 days (0.59-37.78 months). No statistical correlation could be established between patient survival and gender, hemispheric location, lobar location, and tumor size. A significant difference in survival was established only when comparing the 41-50 age groups to the 71-80 and 81-90 age groups and MGMT positive versus negative tumors (p=0.0001). Conclusion From a practical standpoint, the changes implemented in the new classification of CNS tumors define GBM as the most aggressive adult type of tumor. Based on their significantly more favorable prognosis, the reclassification of IDH mutant forms of astrocytomas has had little epidemiological impact on this relatively common malignancy but has significantly underlined the dismal prognosis. The changes have also led to MGMT promoter methylation status being the only significant prognostic factor for patient survival in clinical use, based on its prediction for response to temozolomide therapy in this nosological unit clinically presenting when it has already reached immense size.

Keywords: demographics; glioblastoma multiforme; idh; mgmt; survival pattern; who 2021.

Figure 1. Morphological and immunohistochemical comparison of glioblastoma multiforme, WHO CNS grade 4, IDH wildtype and diffuse astrocytoma, WHO CNS grade 4, IDH mutant.

(A) Glioblastoma multiforme, WHO CNS grade 4 with pseudopalisadic necrosis (arrow), H&E stain, original magnification ×80; (B) same tumor from (A), immunohistochemically negative for IDH R132H mutation, original magnification ×200; (C) diffuse astrocytoma, WHO CNS grade 4 with glomeruloid neovascular proliferation (arrows), H&E stain, original magnification ×200; (D) same tumor from (C), immunohistochemically positive for IDH R132H mutation, original magnification ×200. WHO: World Health Organization; CNS: central nervous system; H&E: hematoxylin and eosin; IDH R132H: isocitrate dehydrogenase mutation variant.

Figure 2. MGMT status in glioblastoma.

(A) MGMT positive tumor, IHC marking for MGMT, original magnification ×200; (B) MGMT positive tumor, IHC marking for MGMT, original magnification ×400. MGMT: O‐6‐methylguanine‐DNA methyltransferase; IHC: immunohistochemistry.

Figure 3. Kaplan-Meier survival analysis curves.

(A) Survival comparison between females and males (p>0.05); (B) survival comparison between left-sided and right-sided tumors (p>0.05); (C) survival comparison between location in lobe (p>0.05); (D) survival comparison between tumor sizes (p>0.05).

Figure 4. Kaplan-Meier survival analysis curve between age groups (p=0.0059).

Figure 5. Kaplan-Meier survival analysis curve between MGMT positive and negative tumors (p<0.0001).

MGMT: O‐6‐methylguanine‐DNA methyltransferase.