IDH-wildtype lower-grade diffuse gliomas: the importance of histological grade and molecular assessment for prognostic stratification

Abstract

Background: Isocitrate dehydrogenase (IDH) wildtype (wt) grade II gliomas are a rare and heterogeneous entity. Survival and prognostic factors are poorly defined.

Methods: We searched retrospectively all patients diagnosed with diffuse World Health Organization (WHO) grades II and III gliomas at our center (1989-2020).

Results: Out of 517 grade II gliomas, 47 were "diffuse astrocytomas, IDHwt." Tumors frequently had fronto-temporo-insular location (28/47, 60%) and infiltrative behavior. We found telomerase reverse transcriptase (TERT) promoter mutations (23/45, 51%), whole chromosome 7 gains (10/37, 27%), whole chromosome 10 losses (10/41, 24%), and EGFR amplifications (4/43, 9%), but no TP53 mutations (0/22, 0%). Median overall survival (OS) was 59 months (vs 19 mo for IDHwt grade III gliomas) (P < 0.0001). Twenty-nine patients (29/43, 67%) met the definition of molecular glioblastoma according to cIMPACT-NOW update 3. Median OS in this subset was 42 months, which was shorter compared with patients with IDHwt grade II gliomas not meeting this definition (median OS: 57 mo), but substantially longer compared with IDHwt grade III gliomas meeting the definition for molecular glioblastoma (median OS: 17 mo, P < 0.0001). Most patients with IDHwt grade II gliomas met cIMPACT criteria because of isolated TERT promoter mutations (16/26, 62%), which were not predictive of poor outcome (median OS: 88 mo). Actionable targets, including 5 gene fusions involving FGFR3, were found in 7 patients (24%).

Conclusions: Our findings highlight the importance of histological grading and molecular profiling for the prognostic stratification of IDHwt gliomas and suggest some caution when assimilating IDHwt grade II gliomas to molecular glioblastomas, especially those with isolated TERT promoter mutation.

Keywords: FGFR3; IDH-wildtype; diffuse low grade gliomas; gene fusion; molecular markers.

Fig. 1

Algorithm for patient selection.

Fig. 2

Radiological patterns of progression in IDHwt grade II gliomas. Panel A-D: example of an infiltrative pattern of progression. Compared with images at diagnosis (panel A, B), images at progression (panel C, D) show a substantial extension of tumor infiltration along the right temporal and insular lobe and the ipsilateral thalamus (panel C), without the appearance of enhancing abnormalities (panel D). Panel E-H: example of a nodular pattern of progression. Compared with images at diagnosis (panel E, F), images at progression (panel G, H) show the appearance of a gross nodule of contrast enhancement in the right insula (panel H), surrounded by extensive perilesional edema (panel G, H).

Fig. 3

Overall survival in IDHwt grade II gliomas compared with IDHmut grade II (panel A) and to IDHwt grade III (panel B) gliomas; overall survival in IDHwt grade II and III gliomas meeting the cIMPACT-NOW definition for “Diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma (grade IV)” (panel C-F). Panel A: survival curves for IDHmut 1p/19q codeleted (black line) vs IDHmut 1p/19q non-codeleted (dark gray line) vs IDHwt (light gray line) grade II gliomas (median OS: 176 vs 101 vs 59 mo, P < 0.0001). Panel B: survival curves for IDHwt grade II (gray line) vs IDHwt grade III (black line) gliomas (median OS: 59 vs 19 months, P < 0.0001). Panel C: survival curves for patients with IDHwt grade III gliomas meeting (black line) and not meeting (gray line) the cIMPACT definition for molecular glioblastoma (median OS: 17 vs 23 months, P = 0.07). Panel D: survival curves for patients with IDHwt grade II (gray line) and IDHwt grade III (black line) gliomas meeting the cIMPACT definition of molecular glioblastoma (median OS: 42 vs 17 months, P < 0.0001). Panel E: survival curves for patients with IDHwt grade II (gray line) and grade III (black line) gliomas meeting the cIMPACT definition for molecular glioblastoma because of isolated TERT promoter mutations (median OS: 88 vs 22 mo, P = 0.002). Panel F: survival curves for patients with IDHwt grade II (gray line) and grade III (black line) meeting the cIMPACT definition for molecular glioblastoma because of EGFR amplifications and/or the +7/−10 signature (median OS: 37 vs 18 mo, P = 0.02).