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. 2024 Nov 18;12(1):176.
doi: 10.1186/s40478-024-01881-1.

Diffuse pediatric high-grade glioma of methylation-based RTK2A and RTK2B subclasses present distinct radiological and histomolecular features including Gliomatosis cerebri phenotype

Arnault Tauziède-Espariat  1   2 , Lea L Friker  3 , Gunther Nussbaumer  4 , Brigitte Bison  5   6 , Volodia Dangouloff-Ros  7   8 , Alice Métais  9   10 , David Sumerauer  11 , Josef Zamecnik  12 , Martin Benesch  4 , Thomas Perwein  4 , Dannis van Vuurden  13 , Pieter Wesseling  13   14 , Andrés Morales La Madrid  15 , Maria Luisa Garrè  16 , Manila Antonelli  17 , Felice Giangaspero  17 , Torsten Pietsch  3 , Dominik Sturm  18   19   20   21 , David T W Jones  18   19   20 , Stefan M Pfister  21   22   23   24 , Yura Grabovska  25 , Alan Mackay  25 , Chris Jones  25 , Jacques Grill  26   27 , Yassine Ajlil  26   27 , André O von Bueren  28   29 , Michael Karremann  30 , Marion Hoffmann  31 , Christof M Kramm  31 , Robert Kwiecien  32 , David Castel  26   27 , Gerrit H Gielen  3 , Pascale Varlet  9   10
Affiliations

Diffuse pediatric high-grade glioma of methylation-based RTK2A and RTK2B subclasses present distinct radiological and histomolecular features including Gliomatosis cerebri phenotype

Arnault Tauziède-Espariat et al. Acta Neuropathol Commun. .

Abstract

Diffuse pediatric-type high-grade gliomas (pedHGG), H3- and IDH-wildtype, encompass three main DNA-methylation-based subtypes: pedHGG-MYCN, pedHGG-RTK1A/B/C, and pedHGG-RTK2A/B. Since their first description in 2017 tumors of pedHGG-RTK2A/B have not been comprehensively characterized and clinical correlates remain elusive. In a recent series of pedHGG with a Gliomatosis cerebri (GC) growth pattern, an increased incidence of pedHGG-RTK2A/B (n = 18) was observed. We added 14 epigenetically defined pedHGG-RTK2A/B tumors to this GC series and provided centrally reviewed radiological, histological, and molecular characterization. The final cohort of 32 pedHGG-RTK2A/B tumors consisted of 25 pedHGG-RTK2A (78%) and seven pedHGG-RTK2B (22%) cases. The median age was 11.6 years (range, 4-17) with a median overall survival of 16.0 months (range 10.9-28.2). Seven of 11 of the newly added cases with imaging available showed a GC phenotype at diagnosis or follow-up. PedHGG-RTK2B tumors exhibited frequent bithalamic involvement (6/7, 86%). Central neuropathology review confirmed a diffuse glial neoplasm in all tumors with prominent angiocentric features in both subclasses. Most tumors (24/27 with available data, 89%) diffusely expressed EGFR with focal angiocentric enhancement. PedHGG-RTK2A tumors lacked OLIG2 expression, whereas 43% (3/7) of pedHGG-RTK2B expressed this glial transcription factor. ATRX loss occurred in 3/6 pedHGG-RTK2B samples with available data (50%). DNA sequencing (pedHGG-RTK2A: n = 18, pedHGG-RTK2B: n = 5) found EGFR alterations (15/23, 65%; predominantly point mutations) in both subclasses. Mutations in BCOR (14/18, 78%), SETD2 (7/18, 39%), and the hTERT promoter (7/19, 37%) occurred exclusively in pedHGG-RTK2A tumors, while pedHGG-RTK2B tumors were enriched for TP53 alterations (4/5, 80%). In conclusion, pedHGG-RTK2A/B tumors are characterized by highly diffuse-infiltrating growth patterns and specific radiological and histo-molecular features. By comprehensively characterizing methylation-based tumors, the chance to develop specific and effective therapy concepts for these detrimental tumors increases.

Keywords: Gliomatosis cerebri; Methylation; Pediatric high-grade glioma; RTK2A; RTK2B; Receptor tyrosine kinase; pedHGG.

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Conflict of interest statement

Declarations Ethics approval and consent to participate This study was approved by the Medical University of Graz (35–085 ex 22/23). Consent for publication Not applicable. Competing interests The authors declare that they have no conflicts of interest directly related to the topic of this article.

Figures

Fig. 1
Fig. 1
Design of the study. GC, gliomatosis cerebri; HGG, high-grade glioma; ped, pediatric
Fig. 2
Fig. 2
Comparison of main clinical parameters in pedHGG-RTK2A/B (pedHGG-RTK2A = red; pedHGG-RTK2B = purple) a Sex distribution and age according to subclass. Children with pedHGG-RTK2B were significantly younger (Graphic in the bottom row each ranging from 0 to 20 years of age; p = 0.01). b T2-weighted axial MR images of patients with pedHGG-RTK2A and pedHGG-RTK2B tumors, respectively. pedHGG-RTK2A (left); a diffuse infiltrating glioma mainly affecting the left parietal lobe at diagnosis is shown. This patient developed a gliomatosis cerebri (GC) phenotype (secondary GC) at progression; (right): a case with GC phenotype at diagnosis (primary GC). pedHGG-RTK2B (left); a glioma with diffuse infiltration of the midline (mesencephalon, basal ganglia and opticohypothalamic region) reaching the right temporal lobe. (right): a bithalamic tumor. c Kaplan–Meier plot displaying the overall survival (50% survival probability marked) of the two methylation-based subclasses
Fig. 3
Fig. 3
Histopathological features in pedHGG-RTK2A/B. a–c Common angiocentric growth pattern of pedHGG-RTK2A and B a, astrocytic differentiation (GFAP expression). b diffuse infiltrating growth is highlighted by an axonal NF staining c. d–i Typical histological characteristics of pedHGG-RTK2A tumors d–i are OLIG2 negativity e, ATRX preservation f, perineuronal satellitosis (g; marked by stars), EGFR expression with angiocentric enhancement h and high Ki-67 index (20%). J–o pedHGG-RTK2B with heterogeneous OLIG2 expression (OLIG2 positive and OLIG2 negative tumor cell populations) k, loss of ARTX l, multinucleated giant cells m, diffuse EGFR positivity n and Ki-67 index of 15%. Scale bars; 20 µm a, g, 60 µm b–f, h–o
Fig. 4
Fig. 4
Overview of the main clinical and molecular features in the pedHGG-RTK2A/B cohort. Epigenetically defined pedHGG-RTK2A (n = 25) and pedHGG-RTK2B (n = 7) cases are presented in columns and mutational status or clinical characteristics in rows. Molecular information was derived from DNA sequencing and DNA methylation array analyses, except for immunohistological data of ATRX expression. Fulfilled primary GC criteria on MRI (i.e., involvement of at least three contiguous cerebral lobes at diagnosis) is indicated as ‘GC at diagnosis’. Other abbreviations are as follow. CNV: copy-number variations; CNAs: copy-number alterations; CN_neutral: copy-number neutral; hom_deletion homozygous deletion; NGS: next-generation DNA sequencing; promoter_mut: promoter mutation; ATRX_IHC: ATRX expression assessed by immunohistochemistry
Fig. 5
Fig. 5
Summary of pedHGG-RTK2A/B main characteristics. Most frequent radiological, histolopathological and molecular features detected in the RTK2A (left) and RTK2B (right) subclasses are displayed. Abbreviations: pedHGG: pediatric high-grade glioma. T1 CE: T1-weighted image after application of a gadolinium based contrast agent
See this image and copyright information in PMC

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