Phenotypic and epigenetic heterogeneity in FGFR2-fused glial and glioneuronal tumours

Abstract

Aims: FGFR-fused central nervous system (CNS) tumours are rare and are usually within the glioneuronal and neuronal tumours or the paediatric-type diffuse low-grade glioma spectrum. Among this spectrum, FGFR2 fusion has been documented in tumours classified by DNA-methylation profiling as polymorphous low-grade neuroepithelial tumours of the young (PLNTY), a recently described tumour type. However, FGFR2 fusions have also been reported in glioneuronal tumours, highlighting the overlapping diagnostic criteria and challenges.

Methods: We investigated the FGFR2 fusion landscape in a French national series of tumours sent to the RENOCLIP-LOC network. We comprehensively analysed histology, radiology and molecular data including DNA-methylation profiling for 16 FGFR2-fused glioneuronal tumours.

Results: Most tumours were located in the temporal or parietal lobe with a median age at diagnosis of 7 years [1-44]. Epilepsy was the most frequent symptom. Five patients had tumour progression or recurrence with a median progression-free survival of 22.6 months. Histological phenotypes corresponding to PLNTY, GG, MVNT or unclassified tumours were recorded. Epigenetic profiling could not properly distinguish epigenetic clusters related to the GG and PLNTY methylation classes among FGFR2-fused glioneuronal tumours. However, a neuroradiological review identified strikingly distinct neuroradiological patterns.

Conclusion: While delineating tumour types among the FGFR2-fused glioneuronal tumour spectrum, by histopathology or DNA-methylation profiling, remains challenging, neuroimaging data revealed two distinct patterns that could correlate to PLNTY and ganglioglioma. However, more series including extensive histo-radio-molecular data are needed to confirm this hypothesis.

Keywords: FGFR2 fusion; ganglioglioma; glioneuronal tumours; molecular pathology; polymorphous low‐grade neuroepithelial tumour of the young.

FIGURE 1

Histopathological features of FGFR2‐fused glial and glioneuronal tumours. Histopathological features of ganglioglioma (A–C) with neoplastic ganglion cells indicated by a black arrowhead (A) (scale bar 100 μm), expression of chromogranin A (B) (scale bar 100 μm) and patchy ramified extravascular CD34 expression (C) (scale bar 500 μm). Histopathological features of multinodular vacuolating neuronal tumour (D–F) (scale bar 200 μm) displaying an immature eosinophilic neuronal component indicated by a black arrowhead (D), chromogranin A negativity (E) with synaptophysin and OLIG2 co‐expression (F). Histopathological features of polymorphous low‐grade neuroepithelial tumour of the young (G–I) (scale bar 100 μm): an oligodendroglioma‐like neoplasm with microcalcification (G), OLIG2 expression (H) and strong and diffuse CD34 extravascular expression (I). GG, ganglioglioma; MVNT, multinodular and vacuolating neuronal tumour; PLNTY, polymorphous low‐grade neuroepithelial tumour of the young.

FIGURE 2

FISH analysis of FGFR2‐fused glial/glioneuronal tumour. FISH analysis performed on a histological multinodular and vacuolating neuronal tumour (A) (scale bar = 100 μm), shows the presence of an FGFR2 rearrangement (B) and (C) (X800, grey arrowhead, indicating a separated red signal), in cells displaying non‐specific granular probe attachment compatible with neuronal cells vesicles (white arrowhead, magnification ×800).

FIGURE 3

Radiological features of FGFR2‐fused glial/glioneuronal tumours. Illustration of type A and B neuroradiological patterns. Type A pattern (left panel) was characterised by heterogeneous well‐delineated masses with variable enhancement, and coarse calcification, involving the cortex and subcortical white matter with possible ventricular contact with no or minimal oedema type B pattern (right panel) was characterised by ill‐delineated high FLAIR signal intensity frequently associated with microcysts. No contrast enhancement is observed in these cases.

FIGURE 4

Unsupervised hierarchical clustering of DNA‐methylation data. Unsupervised hierarchical clustering of 23 FGFR2‐fused glial/glioneuronal tumours (15 samples of the present series and eight samples (LGNET‐FGFR2) from Gupta et al. [9]) based on the 10,000 most variably methylated probes (only 2000 CpG are displayed on the heat map for easier reading). Samples with calibrated scores (CS) >0.9 were considered as matching with the methylation classes (MC) proposed by the v12.5 version of the DKFZ classifier, CS ≤0.9 were considered not matching. DNT, dysembryoplastic neuroepithelial tumour; GG, ganglioglioma; HEMIS, hemispheric; LGNET, low‐grade neuroepithelial tumour; MC, methylation class; MVNT, multinodular and vacuolating neuronal tumour; NA, not available; NOS, not otherwise specified; PA, pilocytic astrocytoma; PLNTY, polymorphous low‐grade neuroepithelia tumour of the young; SEGA, subependymal giant cell astrocytoma; t‐SNE, t‐distributed stochastic neighbour embedding.

FIGURE 5

t‐Distributed stochastic neighbour embedding DNA‐methylation profiling data analysis of FGFR2‐fused glial/glioneuronal tumours and density‐based spatial clustering of applications with noise (DBSCAN) clustering of t‐SNE results for GG and FGFR2 cases. (A) Fifteen samples of the present series (FGFR2_fused_cases) and eight samples (LGNET‐FGFR2) from Gupta et al. [9] were compared to a reference data set built up with institutional cases matching with the DKFZ classifier methylation classes listed below, and from previously published studies [17, 18, 19]. Dysembryoplastic neuroepithelial tumour (DNET); ganglioglioma (GG); diffuse leptomeningeal glioneuronal tumour (DLGNT); high‐grade astrocytoma with piloid features (HGAP); low‐grade glioma hemispheric pilocytic astrocytoma (LGG_PA_HEMI); low‐grade glioma, midline pilocytic astrocytoma (LGG_PA_MID); low‐grade glioma, posterior fossa pilocytic astrocytoma (LGG_PA_PF); low‐grade glioma, spinal pilocytic astrocytoma (LGG_PA_SPINE); low‐grade glioma, rosette‐forming glioneuronal tumour (LGG_RGNT); pleomorphic xanthoastrocytoma (PXA); polymorphous low‐grade neuroepithelial tumour of the young (PLNTY); control tissue, cerebral hemisphere (CONTR_HEMI); control tissue, tumour microenvironment (CONTR_REACT); control tissue, cerebral white matter (CONTR_WM); extraventricular neurocytoma (EVN). (B) selection of the t‐SNE data on which DBSCAN was performed. (C) DBSCAN clustering of t‐SNE results for GG and FGFR2 cases. The plot displays the DBSCAN clustering results applied to the t‐SNE transformed data of GG and FGFR2 cases, using parameters ε = 175 and MinPts = 5.