WHO Grade Loses Its Prognostic Value in Molecularly Defined Diffuse Lower-Grade Gliomas

Abstract

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.

The clinical value of proneural, classical and mesenchymal protein signatures in WHO 2021 adult-type diffuse lower-grade gliomas

“…The study cohort included 183 patients, ≥ 18 years of age, with histologically verified WHO grade 2 or 3 diffuse gliomas, operated at Sahlgrenska University Hospital, Gothenburg, Sweden between 2007 and 2016 and included in our institutional dLGG database [ 26 ]. A total of 183 primary tumors and 49 recurrent tumor samples were examined.…”

Seizures in patients with IDH-mutated lower grade gliomas

“…Time to surgery was calculated from the diagnostic scan date. Eloquent tumor location was assessed according to Chang et al [ 12 ] For volume segmentation, semi-automatic segmentations with the software 3DSlicer version 4.6.2 or newer was made as described earlier [ 11 , 13 ]. For biopsied patients, residual tumor volume was registered as equal to the preoperative tumor volume if no postoperative segmentation was made.…”

“…LGG is of lesser importance in prognostication [10,11]. In the light of these updates, it makes sense analyzing the more homogenous group of purely IDH-mut glioma with respect to epileptic seizures.…”

“…We now consider the IDH -mut the hallmark of the true LGG [ 8 , 9 ]. With better classification, several authors note that the clinical importance of the distinction between WHO grade 2 and grade 3 IDH -mut LGG is of lesser importance in prognostication [ 10 , 11 ]. In the light of these updates, it makes sense analyzing the more homogenous group of purely IDH -mut glioma with respect to epileptic seizures.…”

WHO CNS5 2021 classification of gliomas: a practical review and road signs for diagnosing pathologists and proper patho-clinical and neuro-oncological cooperation

“…The growth fraction as determined by the Ki-67 proliferation index is usually < 4% for grade 2 IDH-mutant astrocytomas. In grade 3 tumours, the Ki-67 proliferation index is usually in the range of 4-10%, but it can overlap with values for grade 2 tumours at one end of the range and grade 4 tumours at the other side [11,13,16].…”