Low-grade epilepsy-associated neuroepithelial tumours with a prominent oligodendroglioma-like component: the diagnostic challenges.

Aim 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 WHO classification of CNS tumours. Material and methods Centralized pathological examination was performed as well as targeted molecular analysis of BRAF and FGFR1 by multiplexed digital PCR (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 3 groups: ganglioglioma (GG, n=14), dysembryoplastic neuroepithelial tumours (DNT, n=19) and glioneuronal tumours/paediatric-type low grade glioma 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 NTRK2 in 9/25 cases. DNA-methylation profiling found 12/46 cases with a calibrated score ≥0.9. Unsupervised hierarchical clustering revealed 2 clusters: cluster 1 was enriched with cases classified as DNT at histology, belonging to the LGG-DNT methylation class (MC), with CD34 negativity and FGRF1 alterations; cluster 2 was enriched with cases classified at histology as GG, belonging to the LGG-GG MC methylation class, 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 belonged to cluster 2 whereas diffuse LGG MAPK pathway-altered were equally distributed among the two clusters. This led us to build an algorithm to classify LEATs with a prominent oligodendroglioma-like component. Conclusions Integrated histomolecular diagnosis of LEATs with a prominent oligodendroglioma-like component remains challenging. Because these tumours can be split into two major clusters of biological significance, the clinico-pathological relevance of the four types recognized by the WHO CNS5 within this spectrum of tumours is questionable.