Childhood Gliomatosis Cerebri: A Poor Prognosis Phenotype of Diffuse Glioma with Distinct Molecular Characteristics

Introduction

Gliomatosis cerebri (GC) is a highly invasive form of diffuse glioma. It was initially discarded as an independent pathological type due to its indeterminate molecular characteristics. However, with the advancements in molecular biology, particularly in children, the biological differences of GC are attracting increasing academic attention. Significant disparities in key biological characteristics between pediatric and adult diffuse gliomas have led to a clear molecular distinction between pediatric and adult gliomas in the fifth edition of the World Health Organization (WHO) classification of central nervous system tumors. Nonetheless, the clinical manifestations of different glioma (sub)types may still be overlooked, such as the early-defined GC, which is characterized by a diffuse infiltrative growth pattern in at least three contiguous cortical regions of the brain.

The research team of this paper conducted a multinational retrospective study, aiming to comprehensively describe the radiologic, pathologic, clinical, and (epi)genetic characteristics of 104 pediatric and adolescent GC cases and to explore their molecular characteristics.

Source

This paper was authored by Gunther Nussbaumer and other scholars, involving research from various hospitals and research institutions across Europe, and was published in the journal Neuro-Oncology in 2024. The article is accompanied by a relevant podcast that provides further insights.

Research Design and Methods

Study Subjects and Ethical Review

Inclusion criteria for the study: 1. Age less than 21 years at the time of diagnosis. 2. Magnetic resonance imaging (MRI) at the time of diagnosis showing characteristics of GC. 3. Neuropathological confirmation of diffuse glioma.

A total of 145 patients were screened, and 104 pediatric and adolescent patients meeting the criteria were eventually included. The study was approved by the Ethics Review Committee of Graz Medical University (IRB number: 33–547 ex ²⁰⁄₂₁).

Radiological and Pathological Evaluation

Central neuroimaging review based on the 2007 WHO classification standards ensured the inclusion of only cases with GC characteristics (diffuse infiltration in at least three contiguous lobes of the brain). Pathological validation included a review of tumor types and grades based on the ²⁰⁰⁷⁄₂₀₁₆ WHO classification standards, combined with reclassification based on molecular characteristics.

Molecular Analysis

DNA methylation analysis and whole-exome sequencing were conducted on 52 samples. The samples were sub-classified through the t-distributed stochastic neighbor embedding (t-SNE) method, and methylation data were processed using the Illumina 450k or EPIC array. Additionally, a pan-genomic analysis of gene mutations was performed.

Collection of Major Clinical Data

Collected clinical data included surgical methods and non-surgical tumor treatment methods, with treatment types categorized into radiotherapy, chemotherapy, and combined chemoradiotherapy. Due to the retrospective multi-center design, chemotherapy regimens were highly heterogeneous and thus integrated into three categories: temozolomide (TMZ) only, TMZ combined with other drugs, and non-TMZ regimens.

Research Results and Analysis

Radiological, Clinical, and Pathological Analysis

Among the 104 patients, 50 showed no enhancement, while 49 exhibited local enhancement. Most patients (68 cases) were described as WHO grade III, 21 as grade IV, and 12 as grade II. According to pathological review, most tumors exhibited high-grade characteristics. Kaplan–Meier analysis observed a significant correlation between WHO grade and progression-free survival (PFS) and overall survival (OS).

Molecular Analysis

• Analysis of 52 samples revealed DNA methylation profiles indicative of specific subtypes such as pedHGG_RTK2, pedHGG_MYCN, and pedHGG_A/B subtypes.
• Common mutations included TP53, BCOR, and structural changes on chromosome 6. Notably, high frequencies of BCOR mutations and chromosome 6 rearrangements in the pedHGG_RTK2 subtype suggest this subtype may play a crucial role in GC development.

Summary of Clinical and Molecular Characteristics of Pediatric GC

By integrating molecular data according to the WHO 2021 central nervous system tumor classification standards, most tumors could be classified as diffuse pediatric high-grade gliomas (pedHGG), with mutations mainly including EGFR, BCOR, TP53, and others. The study provides the first evidence of the molecular characteristics of GC, indicating specific molecular features and their association with poor prognosis.

Conclusion

The study establishes the distinct molecular characteristics of pediatric GC, providing new evidence to support its classification as a unique phenotype with poor prognosis. Compared to conventional diffuse gliomas, GC patients exhibit significantly different treatment responses and prognosis, emphasizing the need for specialized treatment strategies and clinical trial designs to explore optimal treatment methods for these tumors.

Value and Significance of the Study

Through this large-scale multi-institutional collaborative study, the unique clinical and molecular characteristics of pediatric GC are revealed, laying the foundation for designing more precise treatment plans in the future. This study broadens our understanding of the biological characteristics of pediatric gliomas, enabling better individualized treatment in the future and providing important references for the application of molecular pathology in tumor classification.

By conducting comprehensive clinical and molecular characteristic analyses, the study suggests that specific molecular markers and subtypes are closely related to the occurrence and development of GC. Future research should further explore the application and significance of these features in other pediatric gliomas.