Diffuse leptomeningeal glioneuronal tumor (DLGNT): a comprehensive clinical and molecular analysis

Abstract

Diffuse leptomeningeal glioneuronal tumors (DLGNTs) are rare, and optimal treatment remains undefined. We aim to comprehensively characterize their clinical and molecular features, offering granular insights into presentations and therapies to elucidate prognostic factors and therapeutic targets. Histologic, molecular, and clinical data of 30 patients with DLGNT were analyzed. Median age at diagnosis was 7.5 years (range: 0.9-20 years). Disease was localized at diagnosis in 16 patients (53.3%), predominantly in the spinal cord (14/16, 87.5%). KIAA1549::BRAF fusion occurred in 27 (96.4%) of 28 patients. DNA methylation profiling of 23 tumors classified 4 (17.4%) as DLGNT MC-1, 3 (13.0%) as DLGNT MC-2, and 16 (69.6%) as DLGNT, but not to a specific subclass. Median follow-up was 57.5 months. Most patients (90.0%) received adjuvant therapy. Chemotherapy was the first-line adjuvant therapy in 19 patients (70.4%); targeted therapy in 5 patients (18.5%), and radiotherapy in 2 patients (7.4%). Median progression-free survival (PFS) after first chemotherapy, targeted therapy, or radiotherapy was 44 (1-77) months, 18 (4-39) months, and 16.5 (9-23) months, respectively. Five-year PFS was 15.9% ± 8.0, and 5 year overall survival (OS) was 83.3% ± 8.8. Patients older than 9 years at diagnosis (p = 0.002) and those with MC-2 (p = 0.04) had worse 5 year OS. Multi-omic analysis revealed simultaneous activation of multiple signaling pathways, which may serve as potential therapeutic targets. DLGNT remains challenging to treat, with poor outcomes across modalities. Further investigation of treatment, including targeted therapies addressing activated pathways, is needed to improve patient survival.

Keywords: Activated signaling pathways; DLGNT; Diffuse leptomeningeal glioneuronal tumor; Patient outcomes; Treatment responses.

Fig. 1

Genetic alterations and clinical characteristics of the study cohort. Patient/tumors are arranged in columns, with categories labeled along the rows. DLGNT = diffuse leptomeningeal glioneuronal tumor; MC-1 = DLGNT Methylation Class-1; MC-2 = DLGNT Methylation Class-2; CSI = craniospinal irradiation

Fig. 2

Swimmer plot of patients with DLGNT. Events and interventions are described in the figure key. DLGNT = diffuse leptomeningeal glioneuronal tumor; STR = subtotal resection; NTR = near-total resection; GTR = gross total resection

Fig. 3

Kaplan–Meier curves of cohort outcomes. a PFS and OS of the whole cohort. b PFS and OS based on age, with 9 years as a threshold. c PFS and OS based on disease spread at diagnosis, localized vs. disseminated. d PFS and OS based on methylation class status. e PFS and OS based on Ki-67, with 4% as a threshold. f PFS and OS based on 1q status. P-value calculated by performing log-rank testing. DLGNT = diffuse leptomeningeal glioneuronal tumor; MC-1 = DLGNT Methylation Class-1; MC-2 = DLGNT Methylation Class-2; No match = matched to DLGNT, but not to a DLGNT subclass

Fig. 4

Kaplan–Meier curves of treatment outcomes. a PFS after surgery. b PFS after the use of the different treatment modalities. c PFS after radiotherapy, focal vs craniospinal irradiation (CSI). d PFS after different lines of therapy, from the first line to the seventh line. P-value calculated by performing log-rank testing

Fig. 5

Study design (a) and gene set enrichment analysis (b) comparing genes in the differentially methylated regions in DLGNT vs. normal CNS tissue

Fig. 6

Transcriptome analysis showing activation of multiple pathways in DLGNT