Pediatric spinal pilocytic astrocytomas form a distinct epigenetic subclass from pilocytic astrocytomas of other locations and diffuse leptomeningeal glioneuronal tumours

Abstract

Pediatric spinal low-grade glioma (LGG) and glioneuronal tumours are rare, accounting for less 2.8–5.2% of pediatric LGG. New tumour types frequently found in spinal location such as diffuse leptomeningeal glioneuronal tumours (DLGNT) have been added to the World Health Organization (WHO) classification of tumours of the central nervous system since 2016, but their distinction from others gliomas and particularly from pilocytic astrocytoma (PA) are poorly defined. Most large studies on this subject were published before the era of the molecular diagnosis and did not address the differential diagnosis between PAs and DLGNTs in this peculiar location. Our study retrospectively examined a cohort of 28 children with LGGs and glioneuronal intramedullary tumours using detailed radiological, clinico-pathological and molecular analysis. 25% of spinal PAs were reclassified as DLGNTs. PA and DLGNT are nearly indistinguishable in histopathology or neuroradiology. 83% of spinal DLGNTs presented first without leptomeningeal contrast enhancement. Unsupervised t-distributed stochastic neighbor embedding (t-SNE) analysis of DNA methylation profiles showed that spinal PAs formed a unique methylation cluster distinct from reference midline and posterior fossa PAs, whereas spinal DLGNTs clustered with reference DLGNT cohort. FGFR1 alterations were found in 36% of spinal tumours and were restricted to PAs. Spinal PAs affected significantly younger patients (median age 2 years old) than DLGNTs (median age 8.2 years old). Progression-free survival was similar among the two groups. In this location, histopathology and radiology are of limited interest, but molecular data (methyloma, 1p and FGFR1 status) represent important tools differentiating these two mitogen-activated protein kinase (MAPK) altered tumour types, PA and DLGNT. Thus, these molecular alterations should systematically be explored in this type of tumour in a spinal location.

Spinal Cord Neoplasms

“…Metastatic dissemination is present in about a quarter of patients, with involvement of the leptomeninges or brain. Pilocytic astrocytomas are molecularly characterized by mitogen-activated protein kinase (MAPK) pathway activation, most commonly through an aberrant fusion protein KIAA1549-BRAF, other BRAF variations such as BRAF V600E , or alterations in the FGFR gene 20 . Although these alterations are also seen in intracranial pilocytic astrocytomas, spinal pilocytic astrocytomas form a distinct DNA methylation cluster from their intracranial counterparts.…”

Epilepsy in gliomas: recent insights into risk factors and molecular pathways

“…Several groups have proposed new molecular subgrouping based on DNA methylation techniques in the attempt to improve the histological classification [22,24,25 ▪ ], but the correlations with the risk of seizures are still unknown.…”