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Disseminated diffuse midline gliomas, H3K27-altered mimicking diffuse leptomeningeal glioneuronal tumors: a diagnostical challenge!
Acta Neuropathologica Communications volume 10, Article number: 119 (2022)
Diffuse midline gliomas (DMG) are divided into four subtypes depending on their molecular characteristics, and/or location: DMG, H3.3 K27-mutant; DMG, H3.1 or H3.2 K27—mutant; DMG, H3-wildtype, with EZHIP overexpression and DMG, EGFR-altered . Leptomeningeal dissemination at diagnosis has been variably reported depending on the series (up to 42%) . Very little genetic and epigenetic data is available for those disseminated cases, with one case harboring a concomitant FGFR1 mutation  and another a 1p deletion . Consequently, their relationship with diffuse leptomeningeal glioneuronal tumors (DLGNT), remains unclarified.
Herein, we describe the histopathological, neuroradiological and molecular (including DNA-methylation profiling) features of three initially disseminated H3K27-altered tumors with glioneuronal features including two cases with an associated MAPK pathway alteration.
The cases concerned three females, aged 14, 13 and 40-year-old (see Additional file 1: Table S1). At the initial diagnosis, in all cases, the tumors were disseminated with supra-tentorial and infra-tentorial leptomeningeal infiltration. An intraparenchymal mono-thalamic involvement was observed in cases 1 and 2; case 3 did not present any intraparenchymal involvement, until the end of the follow-up (Fig. 1). A leptomeningeal biopsy was performed in all cases. Histopathologically, all tumors presented a glioneuronal immunophenotype, and, one of them also had numerous microcalcifications (Fig. 2 and Additional file 2: Table S2). A 1p deletion was evidenced in case 1 and therefore a diagnosis of DLGNT was suggested (Fig. 2D). NGS sequencing showed a FGFR1 N546K mutation (case 1), a BRAF V600E mutation (case 2) and a H3F3A K27M mutation (case 3). The DNA-methylation profiling classified cases 1 and 3 as DMG, H3K27-altered, subtype H3K27M/EZHIP overexpressing (calibrated scores 0.99 and 0.82 respectively) and case 2 as DMG H27K27-altered, subtype EGFR-altered (calibrated score 0.95) (Additional file 3: Fig. S1). Complementary analyses found a loss of H3K27me3 (in all cases), an EZHIP overexpression (cases 1 and 2) (Fig. 2), but no EGFR alteration (all exons were tested by whole exome sequencing, and an amplification was ruled out by FISH analyses) was evidenced. Case 1 received several lines of chemotherapy and craniospinal radiation therapy but passed away 16 months after the initial diagnosis, whereas the case 2, treated by chemotherapy and targeted anti-BRAF therapy, is still alive with a stable disease, 7 months after the initial diagnosis. The patient 3 received chemotherapy and craniospinal irradiation but died 4 months after the diagnosis.
DLGNTs are glioneuronal tumors molecularly defined by a chromosome arm 1p deletion and a MAPK pathway alterations . Contrary to what their name suggest, they can present a parenchymal component, which can include a thalamic location, with or without leptomeningeal involvement . The already published H3K27M-mutant cases with a disseminated radiological presentation (including a case with a 1p deletion) raises the question of a potential overlap between DLGNT and DMG [3, 4, 6]. However, those cases did not have DNA-methylation analysis, and their relationship to DMG, H3 K27–altered remains open in the last version of the World Health Organization classification . Herein, we present three initially disseminated leptomeningeal tumors, including one case with a 1p deletion and two with BRAF/FGFR1 mutations, classified as DMG using DNA-methylation profiling. Like patients with DMG-H3K27 mutant with concomitant BRAF or FGFR1 mutation, the two current disseminated cases H3K27-altered (one with EZHIP overexpression) with a MAPK mutation were older than classical DMG and histologically presented a glioneuronal immunophenotype and /or microcalcifications [7, 8]. The case 2, classified as DMG, H3K27-altered (EGFR-mutant) proven by DNA-methylation analysis, represents the first example of a disseminated presentation of this typically bithalamic tumor type . Another particularity of this case was its having a BRAF V600E mutation without an EGFR alteration (as 20%, 8/40 of all published cases), representing the second example of this discrepancy between genetic and epigenetic results (the first being reported as unilateral thalamic) . Gliomas with concomitant mutations of H3K27M and BRAF/FGFR1 are supposed to be associated with a better prognosis than other DMG, H3K27-altered according to some publications [7, 8]. As a result, it can be suggested that these molecular alterations (MAPK and H3K27M/EZHIP alterations) confer a different biological behavior, with a metastatic phenotype and/ or a slower local progression ultimately allowing the development of disseminated lesions. Arguing for this hypothesis, a previously published monothalamic tumor classified as ganglioglioma, H3K27M- and BRAF V600E-mutant presented secondary leptomeningeal dissemination 7 years after the initial diagnosis . Further data is needed to understand this disseminated phenotype in detail.
In summary, we showed that despite the histopathological and molecular overlaps with DLGNT, DMG, H3K27-altered may be found to have, in exceptional cases, an initial disseminated radiological presentation.
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We would like to thank the laboratory technicians at the GHU Paris Neuro Sainte-Anne for their assistance, as well as the Integragen platform for their help with DNA-methylation analyses and the RENOCLIP-LOC Network. RENOCLIP-LOC is the clinico-pathological network instrumental in the central histopathological review supported by the Institut National du Cancer (INCa). We would like to Philipp Sievers from Heidelberg to perform the t-SNE analysis.
The authors declare that they have not received any funding.
The authors declare that they have no conflict of interest directly related to the topic of this article.
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: Summary of clinical data of cases from current series.
: Summary of histopathological and molecular data of cases from current series.
. Methylation-based t-SNE distribution. t-distributed stochastic neighbor embedding (t-SNE) analysis of DNA methylation profiles from the investigated tumors alongside selected reference samples. Reference DNA methylation classes: diffuse midline glioma H3 K27M mutant/EZHIP overexpressing (DMG_K27), diffuse midline glioma EGFR_altered (DMG_EGFR), glioblastoma, IDH wildtype, H3.3 G34 mutant (GBM_G34), pediatric glioblastoma, IDH wildtype, subclass MYCN (GBM_pedMYCN), glioblastoma, IDH wildtype, subclass RTK1 (GBM_RTK1), glioblastoma, IDH wildtype, subclass RTK2 (GBM_RTK2), pediatric glioblastoma, IDH wildtype, subclass RTK1 (GBM_pedRTK1), pediatric glioblastoma, IDH wildtype, subclass RTK2 (GBM_pedRTK2), glioblastoma, IDH wildtype, subclass mesenchymal (GBM_MES), diffuse leptomeningeal glioneuronal tumor, subtype 1 (DLGNT_1), and diffuse leptomeningeal glioneuronal tumor, subtype 2 (DLGNT_2).
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Tauziède-Espariat, A., Siegfried, A., Uro-Coste, E. et al. Disseminated diffuse midline gliomas, H3K27-altered mimicking diffuse leptomeningeal glioneuronal tumors: a diagnostical challenge!. acta neuropathol commun 10, 119 (2022). https://doi.org/10.1186/s40478-022-01419-3