Low‐grade epilepsy‐associated neuroepithelial tumours with a prominent oligodendroglioma‐like component: The diagnostic challenges

Abstract

Aims: We searched for recurrent pathological features and molecular alterations in a retrospective series of 72 low-grade epilepsy-associated neuroepithelial tumours (LEATs) with a prominent oligodendroglioma-like component, in order to classify them according to the 2021 World Health Organization (WHO) classification of central nervous system (CNS) tumours. Methods: Centralised pathological examination was performed as well as targeted molecular analysis of v-Raf murine sarcoma viral oncogene homologue B (BRAF) and fibroblast growth factor receptor 1 (FGFR1) by multiplexed digital polymerase chain reaction (mdPCR). DNA methylation profiling was performed in cases with sufficient DNA. In cases with no genetic alteration by mdPCR and sufficient material, RNA sequencing was done. Results: We first reclassified our cohort into three groups: ganglioglioma (GG, n = 14), dysembryoplastic neuroepithelial tumours (DNTs, n = 19) and glioneuronal tumours/ paediatric-type low-grade glioma (LGG) not otherwise specified (GNT/PLGG NOS, n = 39). mdPCR found an alteration in 38/72 cases. Subsequent RNA sequencing revealed a fusion transcript involving BRAF, FGFR1/2/3 or neurotrophic tyrosine kinase receptor type 2 [NTRK2] in 9/25 cases. DNA methylation profiling found 12/46 cases with a calibrated score ≥0.9. Unsupervised hierarchical clustering revealed two clusters: Cluster 1 was enriched with cases classified as DNT at histology, belonging to the LGG-DNT methylation class (MC), with haematopoietic progenitor cell antigen (CD34) negativity and FGRF1 alterations; Cluster 2 was enriched with cases classified at histology as GG, belonging to the LGG-GG MC MC, with BRAF V600E mutation and CD34 positivity. The tumours reclassified as GNT/PLGG NOS were equally distributed across both clusters. Interestingly, all polymorphous low-grade neuroepithelial tumour of the young Romain Appay and Mélanie Pagès contributed equally to this study.

Clinico-pathological and epigenetic heterogeneity of diffuse gliomas with FGFR3::TACC3 fusion

“…Diffuse gliomas with FGFR3::TACC3 fusion have been mainly reported in the adult setting where they account for 3.1–11.8% of cases with pathological features of glioblastoma [ 4 , 13 , 22 , 30 , 31 ]. The frequency of FGFR3::TACC3 fusion in gliomas with pathological features of low grade is more difficult to appreciate but does not exceed 4% in some studies [ 16 , 23 , 31 ]. Importantly, fewer than 15 FGFR3::TACC3 pediatric gliomas, presenting initially with LGG histological features, have been reported to date, including one case of PLNTY with secondary malignant transformation [ 1 , 6 , 12 , 17 , 18 , 20 , 23 , 25 , 28 ].…”

“…These cases were retrieved from 8 University Hospital Centers: GHU Paris Psychiatry and Neurosciences, Marseille, Lille, Lyon, Toulouse, Nice, Montpellier and Rennes. Three cases (#13, #16 and #19) have been previously reported [ 2 , 23 ]. Written informed consent to be included in this study was provided by the participants or participants’ legal guardian/next of kin.…”

“…Of interest, we and others have reported that these histopathological features are also shared by some pediatric-type diffuse LGG, i.e. PLNTY and a subgroup of diffuse LGG, MAPK pathway-altered [ 17 , 23 ]. These two distinct tumor types might display FGFR3::TACC3 fusion.…”

“…These two distinct tumor types might display FGFR3::TACC3 fusion. However, fewer than 15 pediatric cases are reported in the literature and their prognosis is unknown, leading to difficulties in their clinical management [ 12 , 17 , 20 , 23 , 25 , 28 ].…”

Newly recognised Tumour Types in Glioneuronal tumours according to the 5th edition of the CNS WHO Classification

“…The current 5 th edition of WHO Classification published in 2021 3 partly amended this gap, adopting several molecular diagnostic tools that have improved diagnostic reliability and lead to the recognition of three new tumour types in this group. More and more lesions underlying drug-resistant focal epilepsy have extensively been studied by integrated molecular-histological approach and classified 20 , in spite of their morphological similarity 21 .…”