Next Article in Journal
Comment on Santana-Bejarano et al. NRP1 and GFAP Expression in the Medulloblastoma Microenvironment: Implications for Angiogenesis and Tumor Progression. Cancers 2025, 17, 2417
Previous Article in Journal
Prevalence and Risk Factors of Acute Pancreatitis in Childhood Acute Leukemia
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Cancers
Volume 18
Issue 6
10.3390/cancers18060912
cancers-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Systematic Review

Diffuse Leptomeningeal Glioneuronal Tumor: A Systematic Review Highlighting Molecular Heterogeneity and Survival Outcome

by
Chaejin Lee
1,
Ki-Su Park
1,
Seong-Hyun Park
1,
Mee-seon Kim
2 and
Jeong-Hyun Hwang
1,*
1
Department of Neurosurgery, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
2
Department of Pathology, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
*
Author to whom correspondence should be addressed.
Cancers 2026, 18(6), 912; https://doi.org/10.3390/cancers18060912
Submission received: 4 February 2026 / Revised: 7 March 2026 / Accepted: 10 March 2026 / Published: 11 March 2026
(This article belongs to the Section Systematic Review or Meta-Analysis in Cancer Research)
Browse Figures
Versions Notes

Simple Summary

Diffuse leptomeningeal glioneuronal tumor is a very rare brain tumor that mainly affects children and young adults and often spreads along the brain and spinal cord. Because it is uncommon and difficult to diagnose, treatment strategies vary widely and clinical outcomes remain unpredictable. To address this, we reviewed all published cases reported since this tumor was first defined to summarize clinical features, genetic findings, treatments, and survival outcomes. We found that hydrocephalus and spinal involvement were common, and that surgery was associated with longer survival in selected patients. Genetic alterations affecting tumor growth–related pathways were also frequently observed. This summary of current evidence may help clinicians recognize this tumor earlier and consider appropriate management strategies.

Abstract

Background/Objectives: Diffuse leptomeningeal glioneuronal tumor (DLGNT) is a rare central nervous system neoplasm characterized by leptomeningeal dissemination and heterogeneous clinical and molecular features. Owing to its rarity, the prognostic relevance of clinical, radiological, and molecular factors remains poorly defined. This systematic review aimed to comprehensively summarize the clinicopathological characteristics, molecular landscape, treatment strategies, and survival outcomes of patients with DLGNT. Methods: A systematic literature search was conducted in PubMed, Embase, Scopus, and Google Scholar to identify published cases of DLGNT. Studies reporting individual patient data were included. Clinical, molecular, treatment, and survival data were pooled. Overall survival (OS) and progression-free survival (PFS) were analyzed using the Kaplan–Meier method, with subgroup analyses according to clinical and molecular variables. Results: Seventy-five patients were included. Most patients were pediatric, and spinal leptomeningeal dissemination and hydrocephalus were frequent. BRAF alterations, most commonly KIAA1549::BRAF fusion, were frequently identified, although no molecular marker predicted survival. The median OS was 89 months, and the median PFS was 30 months. Surgical resection was associated with significantly longer OS compared with biopsy only, while a trend toward longer PFS was observed. Survival outcomes did not differ significantly according to age group, BRAF status, chemotherapy, or radiotherapy. Conclusions: DLGNT is a rare and heterogeneous tumor with variable presentation and prolonged survival in selected patients. Although surgical resection may be associated with improved survival, interpretation is limited by selection bias. No single molecular alteration reliably predicts prognosis, highlighting the need for prospective multicenter studies with standardized molecular profiling.

1. Introduction

Diffuse leptomeningeal glioneuronal tumor (DLGNT) was first introduced as a distinct entity in the 2016 World Health Organization (WHO) classification of central nervous system tumors [1]. In the 2021 update, two methylation subtypes (DLGNT-MC-1 and DLGNT-MC-2) were proposed, with potential prognostic implications [2]. However, methylation profiling is not yet routinely feasible in many clinical settings due to technical and logistical limitations. DLGNT remains a rare tumor with a low incidence, and the available literature is largely limited to individual case reports or small series. The disease may be misdiagnosed at initial presentation, most commonly as infectious meningitis, due to its nonspecific clinical and radiologic features [3,4,5,6,7,8]. Given these challenges, we conducted a systematic review of published DLGNT cases to better characterize their clinical course, imaging features, pathology, molecular findings, and treatment outcomes.

2. Materials and Methods

2.1. Search Strategy

This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement. The completed PRISMA checklist is provided as Supplementary Material. A comprehensive search of the literature was performed using the following databases: PubMed, Scopus, Embase, and Google Scholar. The search covered the period from 1 January 2016 to 4 June 2024, as DLGNT was first classified as a distinct disease entity in the 2016 WHO classification. MeSH terms and keywords including “diffuse leptomeningeal glioneuronal tumor,” “DLGNT,” “DLGT,” and “DLMGNT” were used in the search. Detailed search strategies and queries for each database are provided in the Supplementary Materials (Table S1).

2.2. Study Selection

Following the database search, a total of 979 records were identified: PubMed (n = 90), Scopus (n = 136), Embase (n = 175), and Google Scholar (n = 578). After removing duplicates, 618 unique records remained. These were independently screened by two authors (C.L. and K.P.) for relevance based on title and abstract. After full-text review, 50 studies comprising 75 individual patients were included in the final analysis.

2.3. Eligibility Criteria

Full-text articles were assessed for eligibility based on predefined criteria. Studies were excluded if they were non-original publications, derived from non-peer-reviewed sources, lacked patient-level data, involved non-human subjects, or were not pathologically confirmed as DLGNT. A total of 535 records were excluded based on these criteria. Full-text assessment was conducted on the remaining 83 articles, of which 32 were excluded for reasons including insufficient data (n = 21), incorrect diagnosis (n = 7), or being review articles without unique patient data (n = 5). Discrepancies between reviewers were resolved by consensus.

2.4. Data Extraction

Data were independently extracted by two authors (C.L. and K.P.), focusing on relevant demographic, clinical, radiological, and histopathological information from the studies. We recorded patient age, sex, presenting symptoms, lesion location, and imaging characteristics. In addition, we collected data on histological and molecular findings (including BRAF status and other mutations), treatment modalities—such as surgery, chemotherapy (CTx), and radiotherapy (RTx)—and survival outcomes, specifically progression-free survival (PFS) and overall survival (OS). The PRISMA flow diagram is presented in Figure 1. Ethical approval was not required for this study, as it was based exclusively on previously published and anonymized data.

2.5. Risk of Bias Assessment

The inclusion of only case reports introduces a potential risk of bias. To mitigate this, the quality of the included studies was cross-checked by three authors (C.L., K.P., and S.P.), and the risk of bias was assessed using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Case Reports (Appendix A Table A1).

2.6. Statistical Analysis

Given the rarity of this pathology, all included studies consisted of case reports or small case series; therefore, the extracted data were primarily summarized using descriptive statistics. Continuous variables are presented as medians with ranges, while categorical variables are reported as frequencies and percentages. Survival outcomes, including OS and PFS, were analyzed using the Kaplan–Meier method. Differences between subgroups were assessed using the log-rank test. A p-value < 0.05 was considered statistically significant. All statistical analyses were performed using SPSS version 24.0 (IBM Corp., Armonk, NY, USA) and RStudio (Version 2025.05.1, Build 513; Posit Software, PBC, Boston, MA, USA).

2.7. Registration

This review was not prospectively registered. Due to the rarity of the disease and the case-report–based nature of the available literature, no formal review protocol was prepared.

3. Results

3.1. Patient Characteristics

A total of 75 patients with pathologically confirmed DLGNT were included in this study, spanning 50 published reports [4,5,7,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56]. Among the included patients, 65.3% were male and 73.3% were pediatric (age ≤ 18 years). Initial presentation most commonly included headache (44.0%), nausea/vomiting (36.0%), and seizure (21.3%). Cranial nerve-related symptoms (e.g., visual disturbance, diplopia, hearing loss) were reported in 26.7%. Hydrocephalus was reported in 61.3% of patients, with 45.3% requiring cerebrospinal fluid diversion procedures such as ventriculo-peritoneal shunting (VP shunt) or Ommaya reservoir placement. Notably, 17.3% of patients were initially misdiagnosed, most commonly as infectious meningitis, including tuberculosis.
Brain involvement was observed in 63 patients (84.0%), whereas spinal involvement was present in 46 patients (61.3%). Within the brain, supratentorial and infratentorial involvement were identified in 44 (58.7%) and 50 (66.7%) patients, respectively. Because some patients had lesions in both compartments, these percentages do not sum to 100%. Combined brain and spinal disease occurred in 37 patients (49.3%).
Gross total or subtotal resection was performed in 25.3% of patients, whereas 74.7% underwent biopsy only. CTx was administered in 61.3% of cases, with carboplatin/vincristine (38.7%) and temozolomide (26.7%) being the most commonly used agents. RTx was delivered to 28.0% of patients (Table 1).
A comparative analysis between pediatric and adult patients is presented in Supplementary Table S2. Hydrocephalus was significantly more common in pediatric patients (39/55, 70.9%) than in adults (7/20, 35.0%; p = 0.0047), and CTx administration was also more frequent in the pediatric group (40/55, 72.7%) compared with adults (6/20, 30.0%; p = 0.0008). In contrast, surgical resection was performed more often in adults (10/20, 50.0%) than in pediatric patients (9/55, 16.4%; p = 0.0031).

3.2. Molecular and Immunohistochemical Findings

Immunohistochemical analysis showed that synaptophysin and S100 were positive in 44 and 28 cases, respectively, whereas GFAP expression was variable. Olig2 was positive in all 35 cases in which it was assessed.
Pathologic and molecular characteristics are summarized in Table 2. Among chromosomal alterations, 1p deletion was identified in 26 of 30 tested cases (86.7%), while 19q deletion was detected in 15 of 23 tested cases (65.2%). Co-deletion of 1p and 19q was observed in 12 of 23 evaluable cases (52.2%), and 1q gain was identified in two of three tested cases.
Regarding Mitogen-Activated Protein Kinase (MAPK) pathway alterations, BRAF alterations were detected in 25 of 34 tested cases (73.5%). Among these, KIAA1549::BRAF fusion was the most frequent alteration (n = 20), followed by BRAF V600E mutation (n = 4), while other BRAF alterations were identified in one case. The distribution of BRAF alteration subtypes is illustrated in Figure 2.
Additional molecular alterations included ATRX mutations (n = 6) and H3K27M mutations (n = 3). Among the three cases harboring H3K27M mutations, the available reports did not consistently document loss of H3K27me3 immunoreactivity, high-grade histologic features, or clearly worse clinical outcomes; therefore, a definitive association with prognosis could not be established in this cohort. Similarly, methylation subclassification data were available in only three cases (MC-1, n = 1; MC-2, n = 2), precluding meaningful survival comparisons between methylation classes.

3.3. Survival Outcomes and Subgroup Analysis

The median overall survival (OS) for the entire cohort was 89 months, and the median progression-free survival (PFS) was 30 months (Figure 3). Some patients demonstrated prolonged survival beyond 10 years, reflecting the heterogeneous clinical course of this disease. Kaplan–Meier survival curves for OS and PFS according to clinical and molecular subgroups are shown in Figure 4 and Figure 5, respectively, and median survival estimates stratified by subgroup are summarized in Table 3. The number of patients at risk at selected time points is presented in the risk tables accompanying the Kaplan–Meier survival curves. As expected in a cohort derived from heterogeneous case reports, the number of patients at risk decreased progressively over time because of variable follow-up durations and censoring.
There were no significant differences in OS or PFS between pediatric and adult patients (OS: p = 0.155; PFS: p = 0.111). Similarly, BRAF alteration status was not associated with significant differences in survival outcomes (OS: p = 0.118; PFS: p = 0.253). BRAF/MAPK-targeted therapies were reported in only a small subset of patients (4/75, 5.3%) and were generally administered in the salvage setting; therefore, the survival analysis according to BRAF alteration status primarily reflects outcomes in patients treated without targeted therapy. Because the survival data were derived from heterogeneous case reports and small case series with variable follow-up durations, these analyses should be interpreted as exploratory.
Patients who underwent surgical resection, including gross total or subtotal resection, had significantly longer OS compared with those who underwent biopsy only (log-rank p = 0.047). In terms of PFS, surgical resection was associated with a trend toward longer PFS, although this did not reach statistical significance (p = 0.052). However, this finding should be interpreted cautiously because patients undergoing resection likely had more focal or surgically accessible disease, which may reflect lower baseline tumor burden rather than a true treatment effect.
Chemotherapy-treated patients showed a non-significant trend toward longer OS (p = 0.052), whereas no significant difference in PFS was observed according to chemotherapy status (p = 0.295). Radiotherapy was not associated with significant differences in OS or PFS (OS: p = 0.492; PFS: p = 0.954).
Additional subgroup analyses according to tumor location and other molecular variables did not demonstrate statistically significant differences in survival outcomes, likely due to the limited number of cases with available data.

4. Discussion

In this study, we conducted a systematic review of 75 reported cases of DLGNT in order to summarize the clinical, radiological, pathological, and molecular characteristics of this rare entity. Our pooled analysis demonstrated a predominance of pediatric cases, frequent neuraxis involvement, and a high prevalence of hydrocephalus. Although BRAF fusion was the most commonly reported molecular alteration, no single marker was predictive of prognosis. Surgical resection appeared to be associated with longer OS compared with biopsy-only procedures; however, this observation should be interpreted with caution. Given the diffuse leptomeningeal growth pattern of DLGNT, complete surgical removal is rarely achievable in most patients. Individuals selected for resection likely had more focal or surgically accessible disease, suggesting a lower baseline tumor burden. Therefore, the observed survival advantage may largely reflect selection bias rather than a direct therapeutic effect of surgical resection itself. In addition, survival estimates in the late follow-up period should be interpreted with caution because the number of patients at risk progressively decreased over time. These findings highlight the inherent challenges in interpreting survival outcomes in rare tumors where treatment selection is strongly influenced by disease distribution and surgical feasibility.
DLGNT predominantly affects pediatric patients and often presents with nonspecific neurological symptoms related to intracranial hypertension or leptomeningeal irritation. In our cohort, hydrocephalus was reported in more than 60% of patients, and approximately half of these required cerebrospinal fluid (CSF) diversion procedures such as ventriculoperitoneal shunting or Ommaya reservoir placement. Although these procedures likely contributed to symptomatic relief, their independent impact on survival could not be evaluated. Diagnostic delay is also a recognized challenge in DLGNT [3,6,8]. In our cohort, 17.3% of patients were initially misdiagnosed, most commonly with infectious meningitis, particularly tuberculous meningitis. This diagnostic overlap reflects the nonspecific clinical and radiologic presentation of the disease and underscores the importance of maintaining a high index of suspicion in patients with unexplained chronic leptomeningeal enhancement. Early multidisciplinary evaluation and timely biopsy may therefore be essential for establishing an accurate diagnosis and avoiding prolonged empirical treatment for infectious conditions. Rare presentations of systemic dissemination have also been reported in DLGNT. Although the tumor is generally confined to the central nervous system, extracranial spread to organs such as the lung, bone, and peritoneum has been described in isolated cases [13,20,26], suggesting that systemic dissemination, while extremely uncommon, may occur during the disease course.
Radiologically, most patients demonstrated diffuse leptomeningeal enhancement involving both the brain and spinal cord, frequently accompanied by nodular or microcystic changes along the leptomeningeal surfaces. These imaging features often reflect widespread involvement of the neuraxis and may be associated with communicating hydrocephalus. Less common radiologic findings included intraparenchymal masses and non-enhancing lesions, which have been reported more frequently in the spine than in intracerebral locations. Notably, radiographically apparent leptomeningeal dissemination may not always be identified at the time of initial presentation [57,58]. In some patients, early imaging findings may appear relatively localized before evolving into more diffuse leptomeningeal disease during follow-up. This radiologic variability complicates early recognition and further highlights the importance of integrating imaging findings with histopathological and molecular data in order to establish an accurate diagnosis.
The molecular landscape of DLGNT is characterized by considerable heterogeneity. In our cohort, alterations involving the MAPK signaling pathway were most frequently observed, particularly the KIAA1549::BRAF fusion. These findings are consistent with previous studies demonstrating that DLGNT represents a biologically distinct entity among pediatric glioneuronal tumors, often characterized by the combination of MAPK pathway activation and chromosomal alterations such as 1p deletion [57,59]. Early descriptions by Rodriguez et al. highlighted the distinctive clinicopathologic features of this tumor, and subsequent studies have further refined its molecular classification [58]. These molecular insights have contributed to the recognition of DLGNT as a separate diagnostic entity within the spectrum of pediatric low-grade glioneuronal tumors and emphasize the importance of molecular testing in cases with atypical clinical or radiologic presentations.
More recently, methylation-based classification has provided additional insights into the biological diversity of DLGNT. Deng et al. proposed two methylation subclasses (MC-1 and MC-2), which appear to reflect differences in molecular profiles and potentially clinical behavior [60]. In particular, previous studies have suggested that certain chromosomal alterations may have prognostic implications. For example, 1q gain has been associated with poorer clinical outcomes and appears to occur more frequently in tumors belonging to the DLGNT-MC-2 methylation subclass [61]. These observations suggest that distinct molecular subgroups of DLGNT may exhibit different biological behaviors and clinical trajectories. However, methylation subclassification data were available in only a small number of cases in our dataset, precluding meaningful survival comparisons between subclasses. Recent comprehensive molecular analyses have further highlighted the genomic diversity of DLGNT and reinforced the central role of MAPK pathway alterations in its pathogenesis [62,63,64,65]. These findings emphasize that DLGNT represents a heterogeneous molecular entity within the broader spectrum of pediatric glioneuronal tumors. From a clinical perspective, these molecular insights are particularly relevant, as MAPK pathway activation may represent a potential therapeutic target and provide a rationale for the use of targeted therapies in selected patients. Accordingly, comprehensive molecular profiling may play an increasingly important role in guiding individualized treatment strategies and improving diagnostic accuracy in this rare tumor entity.
Unlike many previous reports that primarily focused on describing the clinical characteristics of DLGNT, our study attempted to explore the potential prognostic relevance of treatment strategies through pooled survival analysis. In our cohort, patients who received CTx demonstrated a trend toward improved survival, although this association did not reach statistical significance. While these findings should be interpreted cautiously, they provide a preliminary signal that treatment-related factors may influence clinical outcomes in this rare disease. The interpretation of treatment effects in DLGNT is inherently challenging, as therapeutic strategies reported in the literature are highly heterogeneous and are often applied in the setting of disease progression or relapse. Consequently, treatment selection may reflect underlying disease severity rather than true therapeutic efficacy. Previous studies have similarly suggested that markers of tumor burden or aggressive tumor biology may influence outcomes. For example, Wiśniewski et al. [66] reported that a high proliferative index, signs of increased intracranial pressure, and neuraxis dissemination were associated with poorer outcomes, while Policicchio et al. [25] identified hydrocephalus and a high proliferative index as adverse prognostic factors. Taken together, these observations suggest that both baseline disease burden and intrinsic tumor biology likely contribute to the variability in clinical outcomes observed in DLGNT. However, the small number of reported cases and the heterogeneity of available clinical and molecular data continue to limit the identification of robust prognostic markers and the establishment of evidence-based treatment strategies.
Currently, no standard treatment strategy has been established for DLGNT. Reported management approaches have typically included combinations of maximal safe resection, craniospinal irradiation, and chemotherapy, although treatment strategies vary widely across institutions due to the rarity of the disease and the absence of consensus treatment guidelines. In clinical practice, treatment decisions are often individualized and influenced by factors such as patient age, disease distribution, symptom burden, and the presence of molecular alterations. Various chemotherapy regimens have been employed, most commonly carboplatin/vincristine–based protocols such as the International Society of Paediatric Oncology Low-Grade Glioma (SIOP-LGG) 2004 regimen or vinblastine-based therapy, which are widely used in pediatric low-grade gliomas and are frequently extrapolated to the management of DLGNT [67,68]. These regimens are generally favored because of their relatively favorable toxicity profile and their established use in other low-grade gliomas. Temozolomide has also been used in some cases, particularly in the setting of progressive or disseminated disease [11,14,20,28,38,39], although the clinical benefit of this approach remains uncertain due to the limited number of reported cases.
Because alterations of the MAPK signaling pathway are common in DLGNT, molecularly targeted therapies have recently emerged as a potential therapeutic option. For example, trametinib has demonstrated clinical activity in patients with BRAF fusion–positive DLGNT [69], and targeted agents such as larotrectinib have shown efficacy in NTRK fusion–positive glioneuronal tumors [70]. Although these reports remain limited to small case series and individual reports, they highlight the potential role of molecular profiling in guiding individualized therapeutic strategies. As molecular diagnostics become more widely implemented, targeted therapies may play an increasing role in the management of selected patients with DLGNT.
This study has several limitations. First, this systematic review was not prospectively registered and no formal review protocol was established. Given the rarity of DLGNT and the predominance of single case reports in the literature, the review process was conducted in a pragmatic manner to capture all available cases. Nevertheless, we acknowledge that this approach deviates from the best-practice recommendations outlined in PRISMA guidelines. Second, most included publications were single case reports or small case series, introducing potential selection and publication biases. Molecular data were incomplete for many patients, limiting robust genotype–phenotype correlations. Survival outcomes were also inconsistently reported, restricting detailed survival analyses beyond median OS and PFS. Because survival data were derived from heterogeneous case reports and small case series, the Kaplan–Meier analyses should be interpreted as exploratory rather than definitive estimates of treatment effect. In addition, treatment regimens were highly heterogeneous across studies. Various chemotherapy protocols—including carboplatin/vincristine-based regimens, temozolomide, and other agents—were grouped together in the analysis due to the limited number of cases available. Given the molecular heterogeneity of DLGNT, such grouping may not fully reflect the differential therapeutic effects of individual agents. Furthermore, tumor size measurements were inconsistently reported across the included studies, and in many cases, the diffuse leptomeningeal growth pattern of DLGNT precludes reliable measurement of tumor size on imaging. Consequently, quantitative comparisons of baseline tumor burden between resected and biopsy-only cases were not feasible. Finally, although our search strategy focused on studies published after 2016—when DLGNT was first recognized as a distinct entity in the WHO classification of central nervous system tumors—earlier cases that were subsequently reclassified as DLGNT were frequently incorporated into later reports. As a result, these previously reported cases were indirectly captured through the included publications.
Despite these limitations, this review provides an updated synthesis of the clinical, radiologic, and molecular characteristics of DLGNT. Future prospective multicenter registries will be necessary to collect standardized clinical, radiologic, and molecular data—including DNA methylation subclassification—as well as treatment responses and long-term outcomes. Such efforts will be essential for improving risk stratification and developing evidence-based treatment strategies for this rare and heterogeneous tumor.

5. Conclusions

In conclusion, DLGNT is a rare and heterogeneous central nervous system tumor characterized by frequent leptomeningeal dissemination, hydrocephalus, and diverse molecular alterations. This systematic review provides an updated synthesis of the clinical presentation, radiologic characteristics, molecular landscape, and treatment outcomes reported to date. Our findings highlight the predominance of pediatric cases, frequent diagnostic delay, and the absence of reliable prognostic biomarkers despite the frequent involvement of the BRAF/MAPK signaling pathway. Treatment strategies remain highly heterogeneous across reported cases, and current survival analyses are limited by small sample sizes and inconsistent reporting. Future collaborative multicenter studies integrating standardized clinical data, comprehensive molecular profiling, and longitudinal outcome reporting will be essential to better define prognostic factors and guide more rational, individualized therapeutic strategies for patients with this rare tumor.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/cancers18060912/s1, Table S1: Detailed search strategies used for each database (PubMed, Scopus, Embase, and Google Scholar), including specific queries and the number of records retrieved. Table S2: Comparison of clinical and treatment characteristics between pediatric and adult patients.

Author Contributions

All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by C.L., M.-s.K., and K.-S.P., S.-H.P. prepared the figures and tables. The first draft of the manuscript was written by C.L., and all authors commented on previous versions of the manuscript. J.-H.H. supervised the study and finalized the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

This study was conducted in accordance with the principles of the Declaration of Helsinki. This systematic review was based exclusively on previously published data and did not involve human participants or identifiable patient information; therefore, ethical approval and informed consent were not required.

Informed Consent Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable.

Conflicts of Interest

The authors declare no relevant financial or non-financial conflicts of interest. The authors did not use generative artificial intelligence tools for data generation, analysis, or interpretation in this study.

Abbreviations

The following abbreviations are used in this manuscript:
ATRXAlpha thalassemia/mental retardation syndrome X-linked
BRAFB-Raf proto-oncogene, serine/threonine kinase
CSFCerebrospinal fluid
CTxChemotherapy
DLGNTDiffuse leptomeningeal glioneuronal tumor
FISHFluorescence in situ hybridization
GFAPGlial fibrillary acidic protein
H&EHematoxylin and eosin
IRBInstitutional Review Board
JBIJoanna Briggs Institute
MAPKMitogen-activated protein kinase
MRIMagnetic resonance imaging
NGSNext-generation sequencing
OSOverall survival
PFSProgression-free survival
PRISMAPreferred Reporting Items for Systematic Reviews and Meta-Analyses
RTxRadiotherapy
VPVentriculoperitoneal

Appendix A

Table A1. Quality appraisal table of included case reports using Joanna Briggs Institute (JBI) checklist for case reports (D1–D8).
Table A1. Quality appraisal table of included case reports using Joanna Briggs Institute (JBI) checklist for case reports (D1–D8).
Author, YearCase
Number		D1D2D3D4D5D6D7D8Overall
Appraisal
1Al-Ghanem, R. et al. 2022 [9]1yesyesyesyesyesyesyesyesInclude
2Appay, R. et al. 2020 [10]1yesyesunclearyesyesunclearyesyesInclude
3 2yesyesyesyesyesyesyesyesInclude
4Bao, J. et al. 2023 [11]1yesyesyesyesyesyesyesyesInclude
5Bao, Y. et al. 2019 [12]1yesyesyesyesyesNot applicable
(refused treatment)		yesyesInclude
6Battini, S. et al. 2023 [13]1yesyesyesyesyesyesyesyesInclude
7Ozen, A. et al. 2024 [14]1yesyesyesyesyesyesyesyesInclude
8 2yesyesyesyesyesyesyesyesInclude
9 3yesYesyesyesyesyesyesyesInclude
10 4yesYesYesyesyesyesyesyesInclude
11D. V. Davydov et al. 2023 [15]1yesyesyesyesyesyesyesyesInclude
12Torres-Rey et al. 2023 [16]1yesyesyesyesyesyesyesyesInclude
13Madsen et al. 2023 [17]1yesyesyesyesyesyesyesyesInclude
14Lei, X. et al. 2023 [18]1yesyesyesyesyesNot applicable
(refused treatment)		yesyesInclude
15Laghaei Fariman et al. 2023 [19]1yesyesyesyesyesyesyesyesInclude
16Demir, M. et al. 2023 [20]1yesyesunclearyesyesunclearyesyesInclude
17 2yesyesyesyesyesyesyesyesInclude
18 3yesyesyesyesyesyesyesyesInclude
19 4yesyesyesyesyesyesyesyesInclude
20 5yesyesyesyesyesyesyesyesInclude
21Zhang, Z. et al. 2022 [4]1yesyesyesyesyesyesyesyesInclude
22Yamada, S. et al. 2022 [21]1yesyesyesyesyesyesyesyesInclude
23Stapińska-Syniec, A. et al.
2022 [22]		1yesyesyesyesyesyesyesyesInclude
24Sarkinaite, M. et al. 2022 [23]1yesyesyesyesyesyesyesyesInclude
25Rebella, G. et al. 2022 [24]1yesyesyesyesyesyesyesyesInclude
26 2yesyesyesyesyesyesyesyesInclude
27 3yesyesyesyesyesyesyesyesInclude
28Policicchio, D. et al. 2022 [25]1yesyesyesyesyesyesyesyesInclude
29Messiaen, J. et al. 2022 [26]1yesyesyesyesyesyesyesyesInclude
30Malekian, N. et al. 2022 [27]1yesyesyesyesyesyesyesyesInclude
31Lu.V.M. et al. 2022 [28]1yesyesyesyesyesyesyesyesInclude
32 2yesyesyesyesyesyesyesyesInclude
33 3yesyesyesyesyesyesyesyesInclude
34 4yesyesyesyesyesyesyesyesInclude
35Cheng, W. et al. 2022 [29]1yesyesyesyesyesyesyesyesInclude
36Valiakhmetova, A. F. et al.
2021 [30]		1yesyesyesyesyesyesyesyesInclude
37 2yesyesyesyesyesyesyesyesInclude
38Teh, Y.G. et al. 2021 [5]1yesyesyesyesyesNot applicable
(refused treatment)		yesyesInclude
39Sáez-Alegre, M. et al. 2021 [31]1yesyesyesyesyesyesyesyesInclude
40Perez-Vega, C. et al. 2021 [32]1yesyesyesyesyesyesyesyesInclude
41Peer, S. et al. 2021 [7]1yesyesyesyesyesyesyesyesInclude
42Manoharan, N. et al. 2021 [33]1yesyesyesyesyesyesyesyesInclude
43 2yesyesyesyesyesyesyesyesInclude
44Karimzadeh P, et al. 2021 [34]1yesyesyesyesyesyesyesyesInclude
45Xu, H. et al. 2020 [35]1yesyesyesyesyesyesyesyesInclude
46NJ Marianayagam et al. 2020 [36]1yesyesyesyesyesyesyesyesInclude
47Gai, D. et al. 2020 [37]1yesyesyesyesyesyesyesyesInclude
48Chen, W et al. 2020 [38]1yesyesyesyesyesyesyesyesInclude
49Abongwa C et al. 2020 [39]1yesyesyesyesyesyesyesyesInclude
50 2yesyesyesyesyesyesyesyesInclude
51 3yesyesyesyesyesyesyesyesInclude
52Tiwari, N et al. 2019 [40]1yesyesyesyesyesyesyesyesInclude
53Sasaki, S. et al. 2019 [41]1yesyesyesyesyesyesyesyesInclude
54Lu, Q et al. 2019 [42]1yesyesyesyesyesyesyesyesInclude
55Levenbaum et al. 2019 [43]1yesyesyesyesyesyesyesyesInclude
56Yamasaki, T et al. 2018 [44]1yesyesyesyesyesyesyesyesInclude
57Nambirajan, A. et al. 2018 [45]1yesyesyesyesyesNot applicable
(refused treatment)		yesyesInclude
58Kang, J., H, et al. 2018 [46]1yesyesyesyesyesyesyesyesInclude
59Fiaschi, P. et al. 2018 [47]1yesyesyesyesyesNot applicable
(refused treatment)		yesyesInclude
60Schwetye, K. E. et al. 2017 [48]1yesyesyesyesyesyesyesyesInclude
61 2yesyesyesyesyesyesyesyesInclude
62Karlowee, V. et al. 2017 [49]1yesyesyesyesyesyesyesyesInclude
63Cai, S.S. et al. 2019 [50]1yesyesyesyesyesyesyesyesInclude
64JIN Wei, et al. 2018 [51]1yesyesyesyesyesyesyesyesInclude
65Pellerino, A. et al. 2018 [52]1yesyesyesyesyesyesyesyesInclude
66Aguilera, D. et al. 2017 [53]1yesyesyesyesyesyesyesyesInclude
67 2yesyesyesyesyesyesyesyesInclude
68 3yesyesyesyesyesyesyesyesInclude
69 4yesyesyesyesyesyesyesyesInclude
70 5yesyesyesyesyesyesyesyesInclude
71 6yesyesyesyesyesyesyesyesInclude
72 7yesyesyesyesyesyesyesyesInclude
73Dyson K. et al. 2016 [54]1yesyesyesyesyesyesyesyesInclude
74Fetta A. et al. 2022 [55]1yesyesyesyesyesyesyesyesInclude
75Guillén Quesada, A. et al. 2018 [56]1yesyesyesyesyesyesyesyesInclude

References

  1. Louis, D.N.; Perry, A.; Reifenberger, G.; von Deimling, A.; Figarella-Branger, D.; Cavenee, W.K.; Ohgaki, H.; Wiestler, O.D.; Kleihues, P.; Ellison, D.W. The 2016 World Health Organization classification of tumors of the central nervous system: A summary. Acta Neuropathol. 2016, 131, 803–820. [Google Scholar] [CrossRef] [PubMed]
  2. Louis, D.N.; Perry, A.; Wesseling, P.; Brat, D.J.; Cree, I.A.; Figarella-Branger, D.; Hawkins, C.; Ng, H.K.; Pfister, S.M.; Reifenberger, G.; et al. The 2021 WHO Classification of Tumors of the Central Nervous System: A summary. Neuro Oncol. 2021, 23, 1231–1251. [Google Scholar] [CrossRef] [PubMed]
  3. Lee, J.K.; Ko, H.C.; Choi, J.G.; Lee, Y.S.; Son, B.C. A case of diffuse leptomeningeal glioneuronal tumor misdiagnosed as chronic tuberculous meningitis without brain biopsy. Case Rep. Neurol. Med. 2018, 2018, 1391943. [Google Scholar] [CrossRef]
  4. Zhang, Z.; Li, J.; Han, Y.; Zhu, W.; Pan, H.; Li, N.; Zhang, Z. A case of diffuse leptomeningeal glioneuronal tumor resembling meningitis. Chin. J. Neurol. 2022, 55, 358–362. [Google Scholar] [CrossRef]
  5. Teh, Y.G.; Azizan, N.; Mohd Naim, N.A.; Ng, C.Y.; Wong, K.J.; Mohd Zaki, F. Case report: Unusual high-grade diffuse leptomeningeal glioneuronal tumor mimicking tuberculous meningitis in a child from an endemic region. Front. Pediatr. 2021, 9, 767614. [Google Scholar] [CrossRef]
  6. Kumar, N.; Nael, A.; Sato, M.; Crawford, J.R. Delayed diagnosis of diffuse leptomeningeal glioneuronal tumour in a young child presenting with communicating hydrocephalus. BMJ Case Rep. 2022, 15, e253238. [Google Scholar] [CrossRef]
  7. Peer, S.; Murumkar, V.; Kulanthaivelu, K.; Prasad, C.; Rao, S.; Santosh, V. Diffuse leptomeningeal glioneuronal tumor with high-grade features masquerading as tubercular meningitis—A case report. Egypt. J. Radiol. Nucl. Med. 2021, 52, 146. [Google Scholar] [CrossRef]
  8. Lepreux, S.; Sagnier, S.; Perez, J.T.; Léger, F.; Sibon, I.; Vital, A. Primary diffuse leptomeningeal gliomatosis: Do we miss the diagnosis? Clin. Neuropathol. 2017, 36, 222–226. [Google Scholar] [CrossRef]
  9. Al-Ghanem, R.; Luque Barona, R.; Godoy-Hurtado, A.; Galicia Bulnes, J.M.; El-Rubaidi, O. Diffuse leptomeningeal glioneuronal tumor: A review of diagnosis and management with an illustrative case. Neurocirugia 2022, 33, 389–393. [Google Scholar] [CrossRef]
  10. Appay, R.; Pages, M.; Colin, C.; Jones, D.T.W.; Varlet, P.; Figarella-Branger, D. Diffuse leptomeningeal glioneuronal tumor: A double misnomer? A report of two cases. Acta Neuropathol. Commun. 2020, 8, 95. [Google Scholar] [CrossRef]
  11. Bao, J.; Sweeney, J.F.; Liu, Y.; Genovese, F.L.; Adamo, M.A.; Heller, R.S. Rapidly progressive diffuse leptomeningeal glioneuronal tumor in an adult female: Illustrative case. J. Neurosurg. Case Lessons 2023, 5, CASE22502. [Google Scholar] [CrossRef] [PubMed]
  12. Bao, Y.; Xiao, J.; Cheng, Z.; Qin, Y.; Xie, D.; Wu, H.; Liu, G. Characteristics of diffuse leptomeningeal glioneuronal tumor with first-episode headache and rapid blindness misdiagnosed as viral meningoencephalitis. J. Med. Cases 2019, 10, 241–245. [Google Scholar] [CrossRef] [PubMed]
  13. Battini, S.; Gokden, M.; Palys, V.; Santos Horta, E. Diffuse leptomeningeal glioneuronal tumor: First description of metastasis to the lung and bone marrow. Cureus 2023, 15, e48185. [Google Scholar] [CrossRef] [PubMed]
  14. Ozen, A.; Tanrikulu, B.; Danyeli, A.E.; Ozek, M.M. Pediatric diffuse leptomeningeal glioneuronal tumors: Diagnosis, follow-up, and treatment options. Turk. Neurosurg. 2024, 34, 441–447. [Google Scholar] [CrossRef]
  15. Davydov, D.V.; Bobin, A.N.; Gizatullin, S.K.; Krylov, V.V.; Kondratyev, A.N.; Parfenov, V.E. Diffuse leptomeningeal glioneuronal tumor: Literature review and clinical case. Ross. Neirokhir. Zh. Im. Prof. A. L. Polenova 2023, 15, 132–138. [Google Scholar] [CrossRef]
  16. Torres-Rey, A.; Vigo-Prieto, J.; De Jesus, O. Aggressive diffuse leptomeningeal glioneuronal tumor in a pediatric patient presenting with mismatch repair gene mutations. Cureus 2023, 15, e47905. [Google Scholar] [CrossRef]
  17. Madsen, P.J.; Hollawell, M.L.; Santi, M.; Storm, P.B. Diffuse leptomeningeal glioneuronal tumor in a child masquerading as an intramedullary spinal pilocytic astrocytoma. Neurooncol. Adv. 2023, 5, vdad049. [Google Scholar] [CrossRef]
  18. Lei, X.; Liu, Y.; Han, F.; Yu, H. Diffuse leptomeningeal glioneuronal tumor involving the circle of Willis and spinal nerve roots. Neurology 2023, 100, 387–388. [Google Scholar] [CrossRef]
  19. Laghaei Farimani, P.; Rebchuk, A.D.; Chang, S.J.; DeSanto, J.; Gupta, N.; Berger, M.S. Malignant transformation of adult-onset pilocytic astrocytoma to diffuse leptomeningeal glioneuronal tumor within the thoracic spine: A case report and review of the literature. Acta Neurochir. 2023, 165, 2775–2782. [Google Scholar] [CrossRef]
  20. Demir, M.K.; Yapıcıer, Ö.; Kılıç, T.; Çelik, H.; Yılmaz, B.; Özdemir, H. Diffuse leptomeningeal glioneuronal tumors: A case series of five patients with parenchymal forms and an analysis of the diagnostic challenges, treatment options and outcomes. Curr. Med. Imaging 2023, 19, 1415–1426. [Google Scholar] [CrossRef]
  21. Yamada, S.; Tanikawa, M.; Shibata, H.; Nakamura, M.; Kinoshita, M.; Yamashita, K.; Hirose, T. DNA methylation array analysis for diffuse leptomeningeal glioneuronal tumor with conspicuous hypothalamic mass: A case report. Neuropathology 2022, 42, 512–518. [Google Scholar] [CrossRef]
  22. Stapińska-Syniec, A.; Gogol, A.; Kordek, R.; Biernat, W. Atypical clinical presentation mimicking stroke in an adult patient caused by a rare diffuse leptomeningeal glioneuronal tumour. Pol. J. Pathol. 2022, 73, 371–375. [Google Scholar] [CrossRef] [PubMed]
  23. Sarkinaite, M.; Devyziene, I.; Makstiene, J.; Matukevicius, A.; Gleizniene, R. Diffuse leptomeningeal glioneuronal tumour with 9-year follow-up: Case report and review of the literature. Diagnostics 2022, 12, 342. [Google Scholar] [CrossRef]
  24. Rebella, G.; Milanaccio, C.; Morana, G.; Rossi, A.; Garre, M.L.; Schiavetti, I.; Capra, V.; Ravegnani, M.; Pavanello, M.; Tortora, D.; et al. Calcifications in diffuse leptomeningeal glioneuronal tumors: A case series. Quant. Imaging Med. Surg. 2022, 12, 2985–2994. [Google Scholar] [CrossRef] [PubMed]
  25. Policicchio, D.; Boccaletti, R.; Cuccu, A.S.; Sturiale, C.L.; Maira, G.; Colonnese, C. Atypical and aggressive diffuse leptomeningeal glioneuronal tumor in a young adult: A case report and review of the literature. Surg. Neurol. Int. 2022, 13, 214. [Google Scholar] [CrossRef]
  26. Messiaen, J.; Claeys, A.; Shetty, A.; Dewaele, B.; Van Dorpe, J.; Van Coster, R.; Benoit, Y.; Vandesompele, J.; Speleman, F.; De Paepe, A.; et al. Generation of patient-derived models from a metastatic pediatric diffuse leptomeningeal glioneuronal tumor with KIAA1549::BRAF fusion. Acta Neuropathol. 2022, 144, 793–797. [Google Scholar] [CrossRef] [PubMed]
  27. Malekian, N.; Okhovat, A.A.; Fatehi, F.; Abdi, S.; Sinaei, F.; Sikaroodi, H.; Saffar, H.; Hajiabadi, M.; Ghorbani, A. Diffuse leptomeningeal glioneuronal tumor (DLGNT) with hydrocephalus as an initial symptom mimicking tuberculous meningitis: A case report. Curr. J. Neurol. 2022, 21, 136–138. [Google Scholar] [CrossRef]
  28. Lu, V.M.; Di, L.; Gernsback, J.; Eichberg, D.G.; Luther, E.M.; Shah, A.H.; Daniels, D.J.; Maher, O.M.; Niazi, T.N. Contemporary outcomes of diffuse leptomeningeal glioneuronal tumor in pediatric patients: A case series and literature review. Clin. Neurol. Neurosurg. 2022, 218, 107265. [Google Scholar] [CrossRef]
  29. Cheng, W.; He, L.; Zhu, J.; Fan, X. Diffuse leptomeningeal glioneuronal tumor without KIAA1549-BRAF fusion and 1p deletion: A case report and review of literature. Childs Nerv. Syst. 2022, 38, 279–285. [Google Scholar] [CrossRef]
  30. Valiakhmetova, A.F.; Papusha, L.I.; Artemov, A.V.; Kazantsev, A.N.; Krylova, A.A. Diffuse leptomeningeal glioneuronal tumor in children: MR characteristics, clinical features and outcome. Four clinical cases. Ross. Bioter. Zhurnal 2021, 20, 42–55. [Google Scholar] [CrossRef]
  31. Sáez-Alegre, M.; Saceda Gutiérrez, J.M.; Utrilla Contreras, C.; Aracil Santos, F.J.; García-Feijoo, P.; Carceller Benito, F. Diffuse leptomeningeal glioneuronal tumour: Where to biopsy? Case report and literature review. Childs Nerv. Syst. 2021, 37, 2405–2408. [Google Scholar] [CrossRef]
  32. Perez-Vega, C.; Akinduro, O.O.; Cheek, B.J.; Beier, A.D. Spinal cord diffuse leptomeningeal glioneuronal tumor presenting without leptomeningeal dissemination. Pediatr. Neurosurg. 2021, 56, 563–568. [Google Scholar] [CrossRef] [PubMed]
  33. Manoharan, N.; Ajuyah, P.; Senapati, A.; Zaben, M.; Santarius, T. Diffuse leptomeningeal glioneuronal tumour (DLGNT) in children: The emerging role of genomic analysis. Acta Neuropathol. Commun. 2021, 9, 147. [Google Scholar] [CrossRef] [PubMed]
  34. Karimzadeh, P.; Nilipour, Y.; Khalili, M.; Nikkhah, A.; Taghavijelodar, M.; Moradi, E. A case of diffuse leptomeningeal glioneuronal tumor in a 10-year-old boy: First report from Iran. Clin. Case Rep. 2021, 9, e05199. [Google Scholar] [CrossRef] [PubMed]
  35. Xu, H.; Chen, F.; Zhu, H.; Luo, L.; Zhang, R. Diffuse leptomeningeal glioneuronal tumor in a Chinese adult: A novel case report and review of literature. Acta Neurol. Belg. 2020, 120, 247–256. [Google Scholar] [CrossRef]
  36. Marianayagam, N.J.; Ben-Shalom, N.; Toledano, H.; Constantini, S. Diffuse leptomeningeal glioneuronal tumor: Case report and review of literature. J. Pediatr. Neurol. Neurosci. 2020, 4, 43–46. [Google Scholar] [CrossRef]
  37. Gai, D.; Christie, M.; Gaillard, F. Adult diffuse leptomeningeal glioneuronal tumour with limited leptomeningeal involvement, lack of 1p deletion and BRAF V600E mutation. J. Clin. Neurosci. 2020, 79, 215–218. [Google Scholar] [CrossRef]
  38. Chen, W.; Kong, Z.; Fu, J.; Zhang, J.; Wang, Y.; Zhang, Y. Diffuse leptomeningeal glioneuronal tumour (DLGNT) with hydrocephalus as an initial symptom: A case-based update. Childs Nerv. Syst. 2020, 36, 459–468. [Google Scholar] [CrossRef]
  39. Abongwa, C.; Cotter, J.; Tamrazi, B.; Dhall, G.; Davidson, T.; Margol, A. Primary diffuse leptomeningeal glioneuronal tumors of the central nervous sys-tem: Report of three cases and review of literature. Pediatr. Hematol. Oncol. 2020, 37, 248–258. [Google Scholar] [CrossRef]
  40. Tiwari, N.; Tamrazi, B.; Robison, N.; Dhall, G. Unusual radiological and histological presentation of a diffuse leptomeningeal glioneuronal tumor (DLGNT) in a 13-year-old girl. Childs Nerv. Syst. 2019, 35, 1609–1614. [Google Scholar] [CrossRef]
  41. Sasaki, S.; Hirose, T.; Nobusawa, S.; Sugiyama, K.; Arai, H. Anaplastic diffuse leptomeningeal glioneuronal tumor associated with H3 K27M mutation. Hum. Pathol. Case Rep. 2019, 17, 200310. [Google Scholar] [CrossRef]
  42. Lu, Q.; Zou, L.P.; Gui, Q.P.; Zhao, H. Diffuse leptomeningeal glioneuronal tumor presented with language developmental delay. Neuroendocrinol. Lett. 2019, 40, 161–165. [Google Scholar] [PubMed]
  43. Levenbaum, E.; Ellika, S.; Korones, D.N. Bevacizumab in treating the cystic components of pediatric low-grade gliomas: A report of four patients. Pediatr. Blood Cancer 2019, 66, e27525. [Google Scholar] [CrossRef]
  44. Yamasaki, T.; Sakai, N.; Shinmura, K.; Akiyama, Y.; Yamada, S. Anaplastic changes of diffuse leptomeningeal glioneuronal tumor with polar spongioblastoma pattern. Brain Tumor Pathol. 2018, 35, 209–216. [Google Scholar] [CrossRef]
  45. Nambirajan, A.; Suri, V.; Kedia, S.; Garg, A.; Sharma, M.C.; Sarkar, C. Paediatric diffuse leptomeningeal tumor with glial and neuronal differentiation harbouring chromosome 1p/19q co-deletion and H3.3 K27M mutation: Unusual molecular profile and its therapeutic implications. Brain Tumor Pathol. 2018, 35, 186–191. [Google Scholar] [CrossRef] [PubMed]
  46. Kang, J.H.; Buckley, A.F.; Nagpal, S.; Fischbein, N.; Peters, K.B. A diffuse leptomeningeal glioneuronal tumor without diffuse leptomeningeal involvement: Detailed molecular and clinical characterization. J. Neuropathol. Exp. Neurol. 2018, 77, 751–756. [Google Scholar] [CrossRef]
  47. Fiaschi, P.; Badaloni, F.; Cagetti, B.; Consales, A.; Piatelli, G.; Pavanello, M. Disseminated oligodendroglial-like leptomeningeal tumor in the adult: Case report and review of the literature. World Neurosurg. 2018, 114, 53–57. [Google Scholar] [CrossRef]
  48. Schwetye, K.E.; Kansagra, A.P.; McEachern, J.; Schmidt, R.E. Unusual high-grade features in pediatric diffuse leptomeningeal glioneuronal tumor: Comparison with a typical low-grade example. Hum. Pathol. 2017, 70, 105–112. [Google Scholar] [CrossRef]
  49. Karlowee, V.; Kolakshyapati, M.; Amatya, V.J.; Takeshima, Y. Diffuse leptomeningeal glioneuronal tumor (DLGNT) mimicking Whipple’s disease: A case report and literature review. Childs Nerv. Syst. 2017, 33, 1411–1414. [Google Scholar] [CrossRef]
  50. Cai, S.S.; Liu, X.Y.; Chen, Y.P.; Zhang, J.; Liu, Z. Diffuse leptomeningeal glioneuronal tumor: Report of a case. Zhonghua Bing Li Xue Za Zhi 2019, 48, 253–255. [Google Scholar]
  51. Jin, W.; Huang, X.R.; Wang, Q.; Gui, Q.P. Diffuse leptomeningeal glioneuronal tumor. Chin. J. Contemp. Neurol. Neurosurg. 2018, 18, 527–534. [Google Scholar]
  52. Pellerino, A.; Rudà, R.; Bertero, L.; Soffietti, R.; Trevisan, E. Successful use of bevacizumab in an adult primary diffuse leptomeningeal glioneuronal tumor. J. Neurosurg. Sci. 2018, 62, 229–232. [Google Scholar] [CrossRef]
  53. Aguilera, D.; Castellino, R.C.; Janss, A.; Schniederjan, M.; MacDonald, T.J. Clinical responses of patients with diffuse leptomeningeal glioneuronal tumors to chemotherapy. Childs Nerv. Syst. 2018, 34, 329–334. [Google Scholar] [CrossRef] [PubMed]
  54. Dyson, K.; Rivera-Zengotita, M.; Kresak, J.; Weaver, J.; Nallur, V. FGFR1 N546K and H3F3A K27M mutations in a diffuse leptomeningeal tumour with glial and neuronal markers. Histopathology 2016, 69, 704–707. [Google Scholar] [CrossRef] [PubMed]
  55. Fetta, A.; Pruccoli, J.; Biasucci, G.; Garone, G.; Parisi, P. Hemiplegic-migraine–like attacks as first manifestation of diffuse leptomeningeal glioneuronal tumor: A case report. J. Pediatr. Hematol. Oncol. 2022, 44, e765–e769. [Google Scholar] [CrossRef]
  56. Guillen Quesada, A.; Puerta Roldan, P.; Morales la Madrid, A.; Lassaletta, A.; Carceller Benito, F. Diffuse leptomeningeal glioneuronal tumour simulating tuberculous meningitis in a 13-year-old girl. Pediatr. Neurosurg. 2018, 53, 140–142. [Google Scholar] [CrossRef]
  57. Chiang, J.C.H.; Harreld, J.H.; Orr, B.A.; Sharma, S.; Ismail, A.; Segura, A.D.; Ellison, D.W. Low-grade spinal glioneuronal tumors with BRAF gene fusion and 1p deletion but without leptomeningeal dissemination. Acta Neuropathol. 2017, 134, 159–162. [Google Scholar] [CrossRef]
  58. Rodriguez, F.J.; Perry, A.; Rosenblum, M.K.; Krawitz, S.; Cohen, K.J.; Lin, D.; Mosier, S.; Lin, M.T.; Eberhart, C.G.; Burger, P.C. Disseminated oligodendroglial-like leptomeningeal tumor of childhood: A distinctive clinicopathologic entity. Acta Neuropathol. 2012, 124, 627–641. [Google Scholar] [CrossRef]
  59. Haizel-Cobbina, J.; Thakkar, R.; Richard, K.; Du, L.; Levine, A.; Bennett, J.; Hawkins, C.; Tabori, U.; Dewan, M.C. Clinical and molecular features of disseminated pediatric low-grade glioma and glioneuronal tumors: A systematic review and survival analysis. Neurooncol. Adv. 2022, 4, vdac122. [Google Scholar] [CrossRef]
  60. Deng, M.Y.; Sill, M.; Chiang, J.; Schittenhelm, J.; Ebinger, M.; Schuhmann, M.U.; Monoranu, C.-M.; Milde, T.; Wittmann, A.; Hartmann, C.; et al. Molecularly defined diffuse leptomeningeal glioneuronal tumor (DLGNT) comprises two subgroups with distinct clinical and genetic features. Acta Neuropathol. 2018, 136, 239–253. [Google Scholar] [CrossRef]
  61. Chiang, J.; Dalton, J.; Upadhyaya, S.A.; Patay, Z.; Qaddoumi, I.; Li, X.; Segura, A.D.; Sharma, S.; Ismail, A.; Shurtleff, S.A.; et al. Chromosome arm 1q gain is an adverse prognostic factor in localized and diffuse leptomeningeal glioneuronal tumors with BRAF gene fusion and 1p deletion. Acta Neuropathol. 2019, 137, 179–181. [Google Scholar] [CrossRef] [PubMed]
  62. Bajin, I.Y.; Levine, A.; Dewan, M.C.; Bennett, J.; Tabori, U.; Hawkins, C.; Bouffet, E. Understanding diffuse leptomeningeal glioneuronal tumors. Childs Nerv. Syst. 2024, 40, 2359–2366. [Google Scholar] [CrossRef] [PubMed]
  63. Campanelli, A.; Metais, A.; Bouchoucha, Y.; Beccaria, K.; Laprie, A.; Blauwblomme, T.; Guida, L.; Benichi, S.; Dufour, C.; Guerrini-Rousseau, L.; et al. Diffuse leptomeningeal glioneuronal tumour: Molecular diagnosis, evolution and treatment. Acta Neuropathol. Commun. 2025, 13, 208. [Google Scholar] [CrossRef] [PubMed]
  64. Mikkelsen, M.K.; Li, X.; Yu, K.; High, A.A.; Tan, H.; Furtado, L.V.; Leelatian, N.; Bell, J.; Berry, J.D.; Boue, D.R.; et al. Diffuse leptomeningeal glioneuronal tumor (DLGNT): A comprehensive clinical and molecular analysis. Acta Neuropathol. 2025, 150, 18. [Google Scholar] [CrossRef]
  65. De Carli, R.; Minichini, V.; Lebrun, L.; Van Damme, A.; Chantrain, C.; Fohn, A.; Jacobs, S.; De Smet, F.; Leblond, P.; André, N.; et al. From Diagnosis Delay to Targeted Therapy: A Retrospective Study of Pediatric DLGNT with a Comprehensive Literature Review. Cancers 2026, 18, 549. [Google Scholar] [CrossRef]
  66. Wiśniewski, K.; Brandel, M.G.; Gonda, D.D.; Crawford, J.R.; Levy, M.L. Prognostic factors in diffuse leptomeningeal glioneuronal tumor (DLGNT): A systematic review. Childs Nerv. Syst. 2022, 38, 1663–1673. [Google Scholar] [CrossRef]
  67. Gnekow, A.K.; Walker, D.A.; Kandels, D.; Picton, S.; Giorgio, P.; Grill, J.; Stokland, T.; Sandstrom, P.E.; Warmuth-Metz, M.; Pietsch, T.; et al. A European randomised controlled trial of the addition of etoposide to standard vincristine and carboplatin induction as part of an 18-month treatment programme for childhood (≤16 years) low-grade glioma—A final report. Eur. J. Cancer 2017, 81, 206–225. [Google Scholar] [CrossRef]
  68. Lassaletta, A.; Scheinemann, K.; Zelcer, S.M.; Hukin, J.; Wilson, B.A.; Jabado, N.; Carret, A.S.; Lafay-Cousin, L.; Larouche, V.; Hawkins, C.E.; et al. Phase II weekly vinblastine for chemotherapy-naive children with progressive low-grade glioma: A Canadian Pediatric Brain Tumor Consortium study. J. Clin. Oncol. 2016, 34, 3537–3543. [Google Scholar] [CrossRef]
  69. Valiakhmetova, A.; Papusha, L.; Druy, A.; Zubkov, A.; Druy, M. Pediatric diffuse leptomeningeal glioneuronal tumor: Two clinical cases of successful targeted therapy. Pediatr. Blood Cancer 2020, 67, e28251. [Google Scholar] [CrossRef]
  70. Tadipatri, R.; Eschbacher, J.; Fonkem, E.; Chen, Z. Larotrectinib in NTRK fusion-positive high-grade glioneuronal tumor: A case report. Cureus 2022, 14, e31449. [Google Scholar] [CrossRef]
Cancers 18 00912 g001
Figure 1. PRISMA flow diagram of study selection process for systematic review of DLGNT cases. Study selection based on case reports and series published between 2016 and 2024.
Figure 1. PRISMA flow diagram of study selection process for systematic review of DLGNT cases. Study selection based on case reports and series published between 2016 and 2024.
Cancers 18 00912 g001
Cancers 18 00912 g002
Figure 2. Distribution of immunohistochemical and molecular alterations in DLGNT. Blue bars represent positive findings and orange bars represent negative findings. The inset box summarizes the distribution of BRAF alteration subtypes among the 25 BRAF-altered cases. Values are presented as numbers (%) unless otherwise indicated.
Figure 2. Distribution of immunohistochemical and molecular alterations in DLGNT. Blue bars represent positive findings and orange bars represent negative findings. The inset box summarizes the distribution of BRAF alteration subtypes among the 25 BRAF-altered cases. Values are presented as numbers (%) unless otherwise indicated.
Cancers 18 00912 g002
Cancers 18 00912 g003
Figure 3. Kaplan–Meier survival curves of the overall DLGNT cohort. (A) OS curve for the entire cohort (n = 75). The median OS was 89 months. (B) PFS curve for the same cohort. The median PFS was 30 months. The number of patients at risk at selected time points is shown below the curves.
Figure 3. Kaplan–Meier survival curves of the overall DLGNT cohort. (A) OS curve for the entire cohort (n = 75). The median OS was 89 months. (B) PFS curve for the same cohort. The median PFS was 30 months. The number of patients at risk at selected time points is shown below the curves.
Cancers 18 00912 g003
Cancers 18 00912 g004
Figure 4. Kaplan–Meier subgroup analysis of OS in patients with DLGNT. Kaplan–Meier curves for OS stratified by: (A) Age group (pediatric ≤ 18 years vs. adult > 18 years); (B) BRAF alteration status; (C) Surgical extent (resection vs. biopsy only); (D) CTx; (E) RTx. Resection was significantly associated with longer OS (p = 0.047), and CTx showed a nonsignificant trend toward longer OS (p = 0.052). Other subgroup comparisons did not reach statistical significance. The number of patients at risk at selected time points is shown below the curves.
Figure 4. Kaplan–Meier subgroup analysis of OS in patients with DLGNT. Kaplan–Meier curves for OS stratified by: (A) Age group (pediatric ≤ 18 years vs. adult > 18 years); (B) BRAF alteration status; (C) Surgical extent (resection vs. biopsy only); (D) CTx; (E) RTx. Resection was significantly associated with longer OS (p = 0.047), and CTx showed a nonsignificant trend toward longer OS (p = 0.052). Other subgroup comparisons did not reach statistical significance. The number of patients at risk at selected time points is shown below the curves.
Cancers 18 00912 g004
Cancers 18 00912 g005
Figure 5. Kaplan–Meier subgroup analysis of PFS in patients with DLGNT. Kaplan–Meier curves for PFS stratified by: (A) Age group; (B) BRAF mutation status; (C) Surgical extent; (D) CTx; (E) RTx. Patients who underwent surgical resection showed a trend toward longer PFS compared with those who underwent biopsy only (p = 0.052). The number of patients at risk at selected time points is shown below the curves.
Figure 5. Kaplan–Meier subgroup analysis of PFS in patients with DLGNT. Kaplan–Meier curves for PFS stratified by: (A) Age group; (B) BRAF mutation status; (C) Surgical extent; (D) CTx; (E) RTx. Patients who underwent surgical resection showed a trend toward longer PFS compared with those who underwent biopsy only (p = 0.052). The number of patients at risk at selected time points is shown below the curves.
Cancers 18 00912 g005
Table 1. Patient characteristics and treatment courses.
Table 1. Patient characteristics and treatment courses.
CharacteristicsOverall (N = 75)Missing Data (%)
Demographics
Sex, n (%) 1 (1.4)
Male49 (65.3)
Female25 (33.3)
Age, years, n (%) 0 (0)
>1820 (26.7)
≤1855 (73.3)
Clinical presentation, n (%) 8 (10.7)
Headache33 (44.0)
Nausea or vomiting27 (36.0)
Seizure16 (21.3)
Altered mental status15 (20.0)
Cranial nerve symptoms †20 (26.7)
Motor weakness16 (21.3)
Back pain6 (8.0)
Disease burden/Clinical course at diagnosis
Hydrocephalus, n (%)46 (61.3)0 (0)
CSF diversion procedure, n (%)34 (45.3)0 (0)
Initial misdiagnosis, n (%)13 (17.3)0 (0)
Radiologic features
Involved lesion, n (%) 7 (9.3)
Supratentorial involvement 44 (58.7)
Infratentorial involvement50 (66.7)
Spinal involvement46 (61.3)
Combined brain and spinal involvement37 (49.3)
Systemic metastasis3 (4.0)
Enhancement patterns, n (%) 7 (9.3)
Diffuse leptomeningeal enhancement22 (29.3)
Focal nodular or microcystic change12 (16.0)
Mixed34 (45.3)
Calcification, n (%)5 (6.7)7 (9.3)
Brain parenchymal mass, n (%)23 (30.6)7 (9.3)
Spine parenchymal mass, n (%)28 (37.3)7 (9.3)
Treatment
Surgery, n (%) 0 (0)
Biopsy56 (74.7)
Subtotal resection5 (6.7)
Gross total resection14 (18.7)
Chemotherapy, n (%)46 (61.3)0 (0)
Carboplatin/Vincristine29 (38.7)
Temozolomide20 (26.7)
BRAF/MAPK-targeted therapy4 (5.3)
Bevacizumab3 (4.0)
Radiotherapy, n (%)21 (28.0)0 (0)
† Includes ophthalmologic symptoms (e.g., visual disturbance, diplopia), ptosis, facial numbness or weakness, hearing disturbance, etc.
Table 2. Pathologic and molecular characteristics.
Table 2. Pathologic and molecular characteristics.
CharacteristicOverall
Histopathologic featuresAnaplastic features11 (14.7%)
MAPK pathway alterationsAny BRAF alteration25 (73.5%)
KIAA1549::BRAF fusion20 (58.8%)
BRAF V600E4 (11.8%)
Other BRAF alterations1 (2.9%)
Copy number alterations1p deletion26/30 (86.7%)
19q deletion15/23 (65.2%)
1p/19q co-deletion12/23 (52.2%)
1q gain2/3 (66.7%)
Epigenetic subclassificationMC-11/3 (33.3%)
MC-22/3 (66.7%)
Values are presented as number (%) or number positive/number tested (%), as appropriate. Denominators vary because molecular testing methods and reporting differed across the included studies.
Table 3. Median overall survival and progression-free survival according to clinical and molecular subgroups.
Table 3. Median overall survival and progression-free survival according to clinical and molecular subgroups.
CharacteristicMedian OS (Months)Median PFS (Months)
Age
Pediatric21.0 (12.0–66.0)10.0 (4.0–24.0)
Adult10.5 (1.0–51.0)10.5 (1.8–44.2)
BRAF
wild-type15.5 (6.8–63.0)8.0 (3.0–27.5)
Altered19.0 (12.0–34.5)16.0 (9.0–24.0)
Surgical extent
Resection (GTR/STR)30.0 (17.0–61.5)19.0 (9.8–50.2)
Biopsy only14.5 (3.8–55.5)8.0 (3.0–21.5)
Chemotherapy
Yes26.0 (12.0–72.0)14.5 (5.8–28.5)
No12.0 (1.0–30.0)8.0 (1.0–18.0)
Radiotherapy
Yes27.0 (12.0–66.8)18.5 (6.8–40.5)
No16.0 (5.0–54.0)8.0 (3.0–21.0)
Median overall survival (OS) and progression-free survival (PFS) according to clinical and molecular subgroups in patients with diffuse leptomeningeal glioneuronal tumor (DLGNT). Survival outcomes are presented as median (interquartile range), in months. OS and PFS were estimated using the Kaplan–Meier method.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Lee, C.; Park, K.-S.; Park, S.-H.; Kim, M.-s.; Hwang, J.-H. Diffuse Leptomeningeal Glioneuronal Tumor: A Systematic Review Highlighting Molecular Heterogeneity and Survival Outcome. Cancers 2026, 18, 912. https://doi.org/10.3390/cancers18060912

AMA Style

Lee C, Park K-S, Park S-H, Kim M-s, Hwang J-H. Diffuse Leptomeningeal Glioneuronal Tumor: A Systematic Review Highlighting Molecular Heterogeneity and Survival Outcome. Cancers. 2026; 18(6):912. https://doi.org/10.3390/cancers18060912

Chicago/Turabian Style

Lee, Chaejin, Ki-Su Park, Seong-Hyun Park, Mee-seon Kim, and Jeong-Hyun Hwang. 2026. "Diffuse Leptomeningeal Glioneuronal Tumor: A Systematic Review Highlighting Molecular Heterogeneity and Survival Outcome" Cancers 18, no. 6: 912. https://doi.org/10.3390/cancers18060912

APA Style

Lee, C., Park, K.-S., Park, S.-H., Kim, M.-s., & Hwang, J.-H. (2026). Diffuse Leptomeningeal Glioneuronal Tumor: A Systematic Review Highlighting Molecular Heterogeneity and Survival Outcome. Cancers, 18(6), 912. https://doi.org/10.3390/cancers18060912

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop