Failure of endoscopic third ventriculostomy (ETV) to relieve hydrocephalus in patients with midline brain tumors may be an early indication of an underlying histone H3K27M mutation, according to a recently published study.

The study’s revelation provides critical insights for prognosis and treatment of patients with new brain tumors who fail ETV.

An eight-year retrospective analysis of 74 patients with midline gliomas showed 27% carried the H3K27M mutation — a genetic alteration that reclassifies these tumors as World Health Organization Grade IV diffuse midline gliomas (DMGs) regardless of histological appearance.

Three-quarters of patients with the H3K27M mutation presented with hydrocephalus, compared with only 16.7% of those with wild-type tumors. This strong association highlights the importance of considering this mutation in the management pathway.

When a patient with a midline tumor presents with hydrocephalus, an H3K27M mutation should be considered regardless of the patient’s age.

Ventriculoperitoneal shunts (VPS) demonstrated superior outcomes in managing hydrocephalus in H3K27M-positive patients, while tumor resection offered the longest hydrocephalus-free survival in wild-type tumors

The study of newly diagnosed pediatric and adult patients with midline tumors was conducted by clinicians and researchers with Norton Research Institute; Norton Healthcare Brain Tumor Center; Norton Children’s Cancer Institute, affiliated with the UofL School of Medicine; and Norton Children’s Neuroscience Institute, affiliated with the UofL School of Medicine.

The study, “Initial Endoscopic Ventricular Failure to Relieve Hydrocephalus in Patients With Obstructing Brain Tumors Predicts a Histone 3K27M Mutation,” was published in the journal Cureus in February.

The authors note that H3K27M mutation analysis is not immediately available when patients first present, meaning surgeons must rely on their clinical judgment. This study suggests that early ETV failure could itself serve as a clinical predictor of mutation status.

The importance of the H3K27M mutation

The H3K27M mutation carries significant prognostic implications, with generally poorer outcomes in pediatric populations, though, interestingly, better survival compared with high-grade wild-type tumors in adults. This study showed that overall survival was similar between patients with and without hydrocephalus, suggesting that while the approaches to managing hydrocephalus differ, appropriate management can mitigate its impact on survival.

The study also highlights that the mechanism of ETV failure in H3K27M patients may not be solely attributable to leptomeningeal carcinomatosis, as only two of 11 patients with cerebrospinal fluid (CSF) sampling showed tumor cells. This suggests other biological mechanisms, potentially involving inflammation or altered CSF dynamics, may be at play.

The failure of an ETV to relieve hydrocephalus in a patient with an obstructing midline brain tumor should heighten suspicion for an H3K27M mutation, potentially guiding more vigilant monitoring and earlier consideration of alternative CSF diversion strategies.

As molecular diagnostics continue to evolve but still require time for results, such clinical correlations provide valuable decision-making support in the acute management of these challenging patients.

The study’s authors were Lisa B. Shields, M.D.; Michael W. Daniels, M.Sc.; Lennea E. Coombs, MHS, PA-C; Alexandra Vaynerman; Kaylyn D. Sinicrope, M.D.; Mustafa Barbour, M.D.; Aaron C. Spalding, M.D., Ph.D.; William C. Gump, M.D.; Ian S. Mutchnick, M.D.; and David A. Sun, M.D., Ph.D.