Giulia Berzero1,2,3, Anna Luisa Di Stefano1,2,4, Susanna Ronchi5, Franck Bielle5, Chiara Villa6, Erell Guillerm7, Laurent Capelle8, Bertrand Mathon8, Alice Laurenge1,2, Marine Giry1, Yohann Schmitt1, Yannick Marie1,9, Ahmed Idbaih1,2, Khe Hoang-Xuan1,2, Jean-Yves Delattre1,2,9, Karima Mokhtari1,5,9, Marc Sanson1,2,9. 1. Sorbonne University, Brain and Spinal Cord Institute, Paris, France. 2. University Hospitals of Pitié Salpêtrière, Charles Foix, Department of Neurology 2 Mazarin, Paris, France. 3. Department of Brain and Behavioral Sciences, University of Pavia, Italy. 4. Department of Neurology, Foch Hospital, Suresnes, France. 5. University Hospitals of Pitié Salpêtrière, Charles Foix, R Escourolle Laboratory, Paris, France. 6. Department of Pathology, Foch Hospital, Suresnes, France. 7. University Hospitals of La Pitié Salpêtrière, Charles Foix, Functional Unit of Oncogenetics and Molecular Angiogenetics, Department of Genetics, Paris, France. 8. University Hospitals of La Pitié Salpêtrière, Charles Foix, Department of Neurology 2, Paris, France. 9. Onconeurotek Tumor Bank, University Hospitals of Pitié Salpêtrière, Charles Foix, Paris, France.
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.
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.
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