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

Louise Carstam; Alba Corell; Anja Smits; Anna Dénes; Hanna Barchéus; Klara Modin; Helene Sjögren; Sandra Ferreyra Vega; Thomas Olsson Bontell; Helena Carén; Asgeir Store Jakola

doi:10.3389/fonc.2021.803975

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

Front Oncol. 2022 Jan 10:11:803975. doi: 10.3389/fonc.2021.803975. eCollection 2021.

Authors

Louise Carstam^{1

2}, Alba Corell^{1

2}, Anja Smits^{2

3}, Anna Dénes², Hanna Barchéus², Klara Modin², Helene Sjögren⁴, Sandra Ferreyra Vega^{2

5}, Thomas Olsson Bontell^{2

6}, Helena Carén⁵, Asgeir Store Jakola^{1

2

7}

Affiliations

¹ Department of Neurosurgery, Sahlgrenska University Hospital, Gothenburg, Sweden.
² Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
³ Department of Neurology, Sahlgrenska University Hospital, Gothenburg, Sweden.
⁴ Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, Sweden.
⁵ Sahlgrenska Center for Cancer Research, Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
⁶ Department of Clinical Pathology and Cytology, Sahlgrenska University Hospital, Gothenburg, Sweden.
⁷ Department of Neurosurgery, St. Olavs University Hospital, Trondheim, Norway.

Abstract

Background: While 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 methods: A 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.

Results: There 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).

Conclusion: Our 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.

Keywords: CDKN2A/B deletion; IDH-mut; WHO grade; astrocytoma; extent of resection; lower-grade glioma; oligodendroglioma; prognostic factors.