Gliomatosis cerebri in children: A poor prognostic phenotype of diffuse gliomas with a distinct molecular profile

Abstract Background The term gliomatosis cerebri (GC), a radiology-defined highly infiltrating diffuse glioma, has been abandoned since molecular GC-associated features could not be established. Methods We conducted a multinational retrospective study of 104 children and adolescents with GC providing comprehensive clinical and (epi-) genetic characterization. Results Median overall survival (OS) was 15. 5 months (interquartile range, 10. 9–27. 7) with a 2-year survival rate of 28%. Histopathological grading correlated significantly with median OS: CNS WHO grade II: 47. 8 months (25. 2–55. 7) ; grade III: 15. 9 months (11. 4–26. 3) ; grade IV: 10. 4 months (8. 8–14. 4). By DNA methylation profiling (n = 49), most tumors were classified as pediatric-type diffuse high-grade glioma (pedHGG), H3-/IDH-wild-type (n = 31/49, 63. 3%) with enriched subclasses pedHGGRTK2 (n = 19), pedHGGA/B (n = 6), and pedHGGMYCN (n = 5), but only one pedHGGRTK1 case. Within the pedHGG, H3-/IDH-wild-type subgroup, recurrent alterations in EGFR (n = 10) and BCOR (n = 9) were identified. Additionally, we observed structural aberrations in chromosome 6 in 16/49 tumors (32. 7%) across tumor types. In the pedHGG, H3-/IDH-wild-type subgroup TP53 alterations had a significant negative effect on OS. Conclusions Contrary to previous studies, our representative pediatric GC study provides evidence that GC has a strong predilection to arise on the background of specific molecular features (especially pedHGGRTK2, pedHGGA/B, EGFR and BCOR mutations, chromosome 6 rearrangements).