Gliomatosis cerebri: no evidence for a separate brain tumor entity

Abstract

Gliomatosis cerebri (GC) is presently considered a distinct astrocytic glioma entity according to the WHO classification for CNS tumors. It is characterized by widespread, typically bilateral infiltration of the brain involving three or more lobes. Genetic studies of GC have to date been restricted to the analysis of individual glioma-associated genes, which revealed mutations in the isocitrate dehydrogenase 1 (IDH1) and tumor protein p53 (TP53) genes in subsets of patients. Here, we report on a genome-wide analysis of DNA methylation and copy number aberrations in 25 GC patients. Results were compared with those obtained for 105 patients with various types of conventional, i.e., non-GC gliomas including diffuse astrocytic gliomas, oligodendrogliomas and glioblastomas. In addition, we assessed the prognostic role of methylation profiles and recurrent DNA copy number aberrations in GC patients. Our data reveal that the methylation profiles in 23 of the 25 GC tumors corresponded to either IDH mutant astrocytoma (n = 6), IDH mutant and 1p/19q codeleted oligodendroglioma (n = 5), or IDH wild-type glioblastoma including various molecular subgroups, i.e., H3F3A-G34 mutant (n = 1), receptor tyrosine kinase 1 (RTK1, n = 4), receptor tyrosine kinase 2 (classic) (RTK2, n = 2) or mesenchymal (n = 5) glioblastoma groups. Two tumors showed methylation profiles of normal brain tissue due to low tumor cell content. While histological grading (WHO grade IV vs. WHO grade II and III) was not prognostic, the molecular classification as classic/RTK2 or mesenchymal glioblastoma was associated with worse overall survival. Multivariate Cox regression analysis revealed MGMT promoter methylation as a positive prognostic factor. Taken together, DNA-based large-scale molecular profiling indicates that GC comprises a genetically and epigenetically heterogeneous group of diffuse gliomas that carry DNA methylation and copy number profiles closely matching the common molecularly defined glioma entities. These data support the removal of GC as a distinct glioma entity in the upcoming revision of the WHO classification. 3

European Association for Neuro-Oncology (EANO) guideline on the diagnosis and treatment of adult astrocytic and oligodendroglial gliomas

“…Management recommendations for these NOS categories are included in Table 1, but evidence is low. Oligoastrocytomas and gliomatosis cerebri both lack distinctive genetic and epigenetic profiles 11,12 and are thus no longer considered as distinct glioma entities. 1 Diffuse midline glioma, H3-K27M-mutant, has been introduced as a novel entity characterized by midline tumor location and presence of lysine to methionine mutation at codon 27 of histones 3.3 or 3.1.…”

Gliomatosis cerebri in children shares molecular characteristics with other pediatric gliomas

“…The degree of involvement of gray and/or white matter also varies among affected patients [5]. Finally, it remains uncertain whether GC represents a separate clinical and molecular entity or simply represents the extreme spectrum of infiltrative gliomas [8, 12]. Because of its rarity and the lack of suitable tissue [8], molecular analysis of GC in adults consisted mostly of targeted gene sequencing and copy number abnormalities [7, 11, 12, 17, 19, 21, 25, 28].…”

“…Finally, it remains uncertain whether GC represents a separate clinical and molecular entity or simply represents the extreme spectrum of infiltrative gliomas [8, 12]. Because of its rarity and the lack of suitable tissue [8], molecular analysis of GC in adults consisted mostly of targeted gene sequencing and copy number abnormalities [7, 11, 12, 17, 19, 21, 25, 28]. A recent study, which utilized DNA methylation analysis to assess molecular subgroups and copy number abnormalities, reported that GC in adults was not a distinct molecular entity because its genetic and epigenetic characteristics resembled those found in other high-grade gliomas [12].…”

“…Because of its rarity and the lack of suitable tissue [8], molecular analysis of GC in adults consisted mostly of targeted gene sequencing and copy number abnormalities [7, 11, 12, 17, 19, 21, 25, 28]. A recent study, which utilized DNA methylation analysis to assess molecular subgroups and copy number abnormalities, reported that GC in adults was not a distinct molecular entity because its genetic and epigenetic characteristics resembled those found in other high-grade gliomas [12]. Minimal knowledge is available about the molecular characteristics of pediatric GC [5, 7, 17, 21].…”

Diffuse glioblastoma resembling acute hemorrhagic leukoencephalitis

“…The term "diffuse glioma" is currently used to describe as a special neoplastic pattern indicating a widespread brain invasion involving three or more cerebral lobes, frequent bilateral growth and possible extension to infratentorial structures, common to different glioma subtypes The term "gliomatosis", formerly used in these cases, has been recently dismissed in the 2016 WHO classification (1,2). Here, we discuss the presentation and diagnosis of a diffuse glioblastoma in a young male who was initially suspected of having acute hemorrhagic leukoencephalitis (AHLE), a variant of acute disseminated encephalomyelitis (ADEM), and highlight the need of a synergic radiological and histological work-up to reach a correct diagnosis.…”