From Diagnosis Delay to Targeted Therapy: A Retrospective Study of Pediatric DLGNT with a Comprehensive Literature...

Background: Diffuse leptomeningeal glioneuronal tumors (DLGNT) are rare pediatric central nervous system tumors, first recognized in the 2016 WHO classification. Their clinical course is highly heterogeneous, and no international consensus treatment guidelines are currently available. This study aims to describe clinical characteristics, disease evolution, and management strategies for pediatric DLGNT patients, with a focus on aggressive forms. Methods: This retrospective, multicenter, international study (Belgium and France) included pediatric patients diagnosed with DLGNT between 1 February 2016 and 31 December 2024. Clinical, radiological, histopathological, molecular, and therapeutic data were collected. Findings were analyzed and contextualized through an extensive literature review. Results: Eleven patients were enrolled (median age: 8.2 years; median follow-up: 52 months). The median delay between the first MRI and definitive diagnosis was 6.5 months. Symptoms of intracranially elevated pressure were present in 55% of patients. Two-thirds of the patients presented with leptomeningeal dissemination at diagnosis. The primary tumor site could not be identified in two patients. A KIAA1549::BRAF transcript fusion was detected in 82% of cases, and chromosome 1q gain in 38%. All patients underwent surgery at diagnosis. The median number of therapeutic lines was four: 82% received chemotherapy (weekly vinblastine in 55%, vincristine/carboplatin regimen in 45%), 64% received MAPK pathway-targeted therapy, and 18% underwent radiotherapy. Five-year overall survival (OS) was 68.5%, and median progression-free survival (PFS) was 5.3 months after first-line therapy and 16.5 months after the second line. At the end of follow-up, only one patient achieved complete remission, and 78% of survivors presented with persistent neurological deficits. Conclusions: This study underscores the significant diagnostic delay, clinical heterogeneity, and absence of standardized therapeutic approaches in pediatric DLGNT patients. Conventional low-grade glioma chemotherapy constitutes the current treatment backbone, while MAPK pathway-targeted therapies show promising potential. Further studies and the establishment of an international registry are crucial to better characterize aggressive subtypes and optimize management strategies.