Gliomatosis cerebri in children: a poor prognostic, highly infiltrative phenotype of diffuse pediatric high-grade gliomas with distinct molecular features

Abstract Gliomatosis cerebri (GC), a radiologically defined highly infiltrating supratentorial glioma, is no longer considered a distinct entity since the 2016 WHO classification for tumors of the central nervous system (CNS). So far, neither prognostic factors, nor molecular GC-associated features have been established. We conducted a multinational retrospective study of 104 children and adolescents with GC providing comprehensive radiological, clinical and (epi-)genetic characterization. Within a median follow-up of 15.5 months (range, 2.3–138.8), 93 patients (89.4%) had died, four (3.8%) were lost to follow-up and seven (6.8%) were alive with stable/progressive disease. Median progression-free- (PFS) and overall survival (OS) were 8.6 months (interquartile range, 4.3–14.0) and 15.5 months (10.9–27.7), respectively. Available 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). In GC with high-grade features, radiochemotherapy achieved longest PFS (median 9.6 months [5.7–14.0]). According to methylation profiling [n=49] and exome-sequencing [n=45], most cases were considered as IDH-/H3-wildtype gliomas (n=32/52, 61.5%) enriched with the subclasses pedHGG_RTK2A/B (n=19), pedHGG_A/B (n=6) and pedHGG_MYCN (n=5), but exhibited only one pedHGG_RTK1A/B/C case. Within the IDH-/H3-wildtype gliomas, EGFR-alterations were most common (n=10). Expected genetic alterations of unselected hemispheric pedHGG affecting CDKN2A/B, ATRX or PDGFRA were virtually absent. Additionally, we observed structural aberrations in chromosome 6 comprising complex genomic rearrangements, large areas of loss, or even gain/amplification at similar breakpoints in 16/49 cases (32.7%). We assembled the largest pediatric GC cohort providing evidence that GC may have a strong predilection to arise on the background of specific molecular features (pedHGG_RTK2A/B, pedHGG_A/B and pedHGG_MYCN; EGFR- and chromosome 6-alterations). Taken together, these findings expand on the current understanding of GC and provide insight into disease biology of extensively infiltrating gliomas in children.