- Letter to the Editor
- Open Access
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.
Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D et al (2021) The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol 23:1231–1251
Rodriguez D, Calmon R, Aliaga ES, Warren D, Warmuth-Metz M, Jones C et al (2022) MRI and molecular characterization of pediatric high-grade midline thalamic gliomas: the HERBY phase II trial. Radiology 304:174–182
Dyson K, Rivera-Zengotita M, Kresak J, Weaver K, Stover B, Fort J et al (2016) FGFR1 N546K and H3F3A K27M mutations in a diffuse leptomeningeal tumour with glial and neuronal markers. Histopathology 69:704–707
Nambirajan A, Suri V, Kedia S, Goyal K, Malgulwar PB, Khanna G et al (2018) 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 35:186–191
Deng MY, Sill M, Chiang J, Schittenhelm J, Ebinger M, Schuhmann MU et al (2018) Molecularly defined diffuse leptomeningeal glioneuronal tumor (DLGNT) comprises two subgroups with distinct clinical and genetic features. Acta Neuropathol (Berl) 136:239–253
Navarro RE, Golub D, Hill T, McQuinn MW, William C, Zagzag D et al (2021) Pediatric midline H3K27M-mutant tumor with disseminated leptomeningeal disease and glioneuronal features: case report and literature review. Childs Nerv Syst ChNS Off J Int Soc Pediatr Neurosurg 37:2347–2356
Schüller U, Iglauer P, Dorostkar MM, Mawrin C, Herms J, Giese A et al (2021) Mutations within FGFR1 are associated with superior outcome in a series of 83 diffuse midline gliomas with H3F3A K27M mutations. Acta Neuropathol (Berl) 141:323–325
Nakano Y, Yamasaki K, Sakamoto H, Matsusaka Y, Kunihiro N, Fukushima H et al (2019) A long-term survivor of pediatric midline glioma with H3F3A K27M and BRAF V600E double mutations. Brain Tumor Pathol 36:162–168
Sievers P, Sill M, Schrimpf D, Stichel D, Reuss DE, Sturm D et al (2021) A subset of pediatric-type thalamic gliomas share a distinct DNA methylation profile, H3K27me3 loss and frequent alteration of EGFR. Neuro Oncol 23:34–43
Joyon N, Tauziède-Espariat A, Alentorn A, Giry M, Castel D, Capelle L et al (2017) K27M mutation in H3F3A in ganglioglioma grade I with spontaneous malignant transformation extends the histopathological spectrum of the histone H3 oncogenic pathway. Neuropathol Appl Neurobiol 43:271–276
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.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Additional file 1. Table S1
: Summary of clinical data of cases from current series.
Additional file 2. Table S2
: Summary of histopathological and molecular data of cases from current series.
Additional file 3: Fig. S1
. 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).
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
About this article
Cite this article
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