BackgroundWhile molecular insights to diffuse lower-grade glioma (dLGG) have improved the basis for prognostication, most established clinical prognostic factors come from the pre-molecular era. For instance, WHO grade as a predictor for survival in dLGG with isocitrate dehydrogenase (IDH) mutation has recently been questioned. We studied the prognostic role of WHO grade in molecularly defined subgroups and evaluated earlier used prognostic factors in the current molecular setting.Material and MethodsA total of 253 adults with morphological dLGG, consecutively included between 2007 and 2018, were assessed. IDH mutations, codeletion of chromosomal arms 1p/19q, and cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) deletions were analyzed.ResultsThere was no survival benefit for patients with WHO grade 2 over grade 3 IDH-mut dLGG after exclusion of tumors with known CDKN2A/B homozygous deletion (n=157) (log-rank p=0.97). This was true also after stratification for oncological postoperative treatment and when astrocytomas and oligodendrogliomas were analyzed separately. In IDH-mut astrocytomas, residual tumor volume after surgery was an independent prognostic factor for survival (HR 1.02; 95% CI 1.01–1.03; p=0.003), but not in oligodendrogliomas (HR 1.02; 95% CI 1.00–1.03; p=0.15). Preoperative tumor size was an independent predictor in both astrocytomas (HR 1.03; 95% CI 1.00–1.05; p=0.02) and oligodendrogliomas (HR 1.05; 95% CI 1.01–1.09; p=0.01). Age was not a significant prognostic factor in multivariable analyses (astrocytomas p=0.64, oligodendrogliomas p=0.08).ConclusionOur findings suggest that WHO grade is not a robust prognostic factor in molecularly well-defined dLGG. Preoperative tumor size remained a prognostic factor in both IDH-mut astrocytomas and oligodendrogliomas in our cohort, whereas residual tumor volume predicted prognosis in IDH-mut astrocytomas only. The age cutoffs for determining high risk in patients with IDH-mut dLGG from the pre-molecular era are not supported by our results.
Background The subventricular zone (SVZ) of the human brain is a site of adult stem cell proliferation and a microenvironment for neural stem cells (NSCs). It has been suggested that NSCs in the SVZ are potential cells of origin containing driver mutations of glioblastoma, but their role in the origin of diffuse lower-grade gliomas (dLGG) is not much studied. Methods We included 188 patients ≥18 years with IDH-mutated dLGG (WHO grade 2–3) histologically diagnosed between 2007–2020. Tissue microarrays of tumor samples for patients between 2007–2016 were used for immunodetection of Nestin, SOX2, SOX9, KLF4, NANOG, CD133 cMYC and Ki67. DNA methylation profile was used for stemness index (mDNAsi). Tumor contact with the SVZ was assessed and the distance was computed. Results Overall, 70.2% of the dLGG had SVZ contact. Tumors with SVZ contact were larger (102.4 vs. 30.9 ml, p<0.01), the patients were older (44.3 vs. 40.4 years, p=0.04) and more often had symptoms related to increased intracranial pressure (ICP) (31.8% vs. 7.1%, p<0.01). The expression of SOX2, SOX9, Nestin and Ki67 showed inter-sample variability, but no difference was found between tumors with or without SVZ contact, nor with the actual distance to the SVZ. mDNAsi was similar between groups (p=0.42). Conclusion We found no statistical relationship between proximity with the SVZ and mDNAsi or expression of SOX2, SOX9, Nestin and Ki67 in IDH-mutated dLGG. Our data suggests that the potential impact of SVZ on IDH-mutated dLGG is probably not associated with a more stemness-like tumor profile.
Objectives Accumulating evidence shows that mesenchymal transition of glioblastomas is associated with a more aggressive course of disease and therapy resistance. In WHO2021-defined adult-type diffuse gliomas of lower grade (dLGG), the transition of the tumor phenotype over time, has not been studied. Most efforts to correlate proneural, classical or mesenchymal phenotype with outcome in dLGG were made prior to the WHO 2021 classification. Here, we set out to investigate if phenotype predicted survival and tumor recurrence in a clinical cohort of dLGGs, re-classified according to the 2021 WHO criteria. Methods Using a TMA-based approach with five immunohistochemical markers (EGFR, p53, MERTK, CD44 and OLIG2), we investigated 183 primary and 49 recurrent tumors derived from patients with previously diagnosed dLGG. Of the 49 relapses, nine tumors recurred a second time, and one a third time. Results In total, 71.0% of all tumors could be subtyped. Proneural was most dominant in IDH-mut tumors (78.5%), mesenchymal more common among IDH-wt tumors (63.6%). There was a significant difference in survival between classical, proneural and mesenchymal phenotypes in the total cohort (p<0.001), but not after molecular stratification (IDH-mut: p = 0.220, IDH-wt: p = 0.623). Upon recurrence, proneural was retained in 66.7% of the proneural IDH-mut dLGGs (n = 21), whereas IDH-wt tumors (n = 10) mainly retained or gained mesenchymal phenotype. No significant difference in survival was found between IDH-mut gliomas remaining proneural and those shifting to mesenchymal phenotype (p = 0.347). Conclusion Subtyping into classical, proneural and mesenchymal phenotypes by five immunohistochemical markers, was possible for the majority of tumors, but protein signatures did not correlate with patient survival in our WHO2021-stratified cohort. At recurrence, IDH-mut tumors mainly retained proneural, while IDH-wt tumors mostly retained or gained mesenchymal signatures. This phenotypic shift, associated with increased aggressiveness in glioblastoma, did not affect survival. Group sizes were, however, too small to draw any firm conclusions.
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