Incidence and predictors of hemorrhage in pediatric low-grade glioma

Pediatric low-grade gliomas (pLGGs) typically have excellent long-term outcomes; intratumoral hemorrhage is a rare, potentially dangerous complication. Hemorrhage risk in the context of molecular alterations and targeted therapies remains poorly characterized. We analyzed the incidence, timing, and independent risk factors for hemorrhage in a large contemporary pLGG cohort.

We conducted a retrospective cohort study of 236 children with pLGG treated at a single center (2011-2025). Clinical, radiographic, and molecular variables were abstracted. The primary endpoint was spontaneous tumoral hemorrhage. Time-to-event analyses utilized Kaplan-Meier methods and Cox proportional hazards modeling; penalized regression mitigated overfitting given the event rarity.

Twelve patients (5.1%) experienced hemorrhage over 2,234 person-years (incidence: 0.54/100 person-years). Hemorrhage typically occurred years after initial tumor diagnosis (median 6.4 years). The presence of a KIAA1549::BRAF fusion in the tumor had the strongest association with hemorrhage, persisting across multivariable models (approximately sixfold increased risk), although estimates were limited by low event number. MAPK inhibitor exposure (specifically binimetinib and tovorafenib) was associated with hemorrhage in univariate analysis but partially confounded by fusion status. CSF diversion independently increased risk at brainstem, optic pathway, and hypothalamic locations. No hemorrhages occurred among patients with underlying genetic syndromes, including neurofibromatosis type 1 and tuberous sclerosis.

Hemorrhage in pLGG is an infrequent late complication associated with tumor biology. KIAA1549::BRAF fusion may identify a higher-risk subgroup, with MAPK inhibitor exposure and CSF diversion further modifying risk. These findings support biology-informed surveillance and personalized management strategies for at-risk children.