Supratentorial CNS-PNETs in children; a Swedish population-based study with molecular re-evaluation and long-term follow-up

Abstract

Background: Molecular analyses have shown that tumours diagnosed as supratentorial primitive neuro-ectodermal tumours of the central nervous system (CNS-PNETs) in the past represent a heterogenous group of rare childhood tumours including high-grade gliomas (HGG), ependymomas, atypical teratoid/rhabdoid tumours (AT/RT), CNS neuroblastoma with forkhead box R2 (FOXR2) activation and embryonal tumour with multi-layered rosettes (ETMR). All these tumour types are rare and long-term clinical follow-up data are sparse. We retrospectively re-evaluated all children (0-18 years old) diagnosed with a CNS-PNET in Sweden during 1984-2015 and collected clinical data.

Methods: In total, 88 supratentorial CNS-PNETs were identified in the Swedish Childhood Cancer Registry and from these formalin-fixed paraffin-embedded tumour material was available for 71 patients. These tumours were histopathologically re-evaluated and, in addition, analysed using genome-wide DNA methylation profiling and classified by the MNP brain tumour classifier.

Results: The most frequent tumour types, after histopathological re-evaluation, were HGG (35%) followed by AT/RT (11%), CNS NB-FOXR2 (10%) and ETMR (8%). DNA methylation profiling could further divide the tumours into specific subtypes and with a high accuracy classify these rare embryonal tumours. The 5 and 10-year overall survival (OS) for the whole CNS-PNET cohort was 45% ± 12% and 42% ± 12%, respectively. However, the different groups of tumour types identified after re-evaluation displayed very variable survival patterns, with a poor outcome for HGG and ETMR patients with 5-year OS 20% ± 16% and 33% ± 35%, respectively. On the contrary, high PFS and OS was observed for patients with CNS NB-FOXR2 (5-year 100% for both). Survival rates remained stable even after 15-years of follow-up.

Conclusions: Our findings demonstrate, in a national based setting, the molecular heterogeneity of these tumours and show that DNA methylation profiling of these tumours provides an indispensable tool in distinguishing these rare tumours. Long-term follow-up data confirms previous findings with a favourable outcome for CNS NB-FOXR2 tumours and poor chances of survival for ETMR and HGG.

Keywords: CNS NB-FOXR2; CNS-PNET; DNA methylation profiling; ETMR; Epigenetics; Long term survival.

Fig. 1

Cohort overview. A. Distribution of tumour types after histopathological and molecular re-evaluation of 71 supratentorial CNS-PNETs; B and C. Further subdivision of the tumour types based on the histopathological re-evaluation; HGGs (n = 25) and OTHER diagnoses (n = 14) Abbreviations: HGG, high-grade glioma; AT/RT, atypical teratoid/rhabdoid tumour; CNS NB-FOXR2, CNS neuroblastoma, FOXR2-activated; ETMR, embryonal tumour with multilayered rosettes; EPN, ependymoma; DHG, H3 G34-mutant, diffuse hemispheric glioma H3 G34-mutant; DMG, K27, diffuse midline glioma H3 K27-altered; IHG, infant-type hemispheric glioma; HGG NOS, high-grade glioma not otherwise specified; PBL, pineoblastoma; CPC, choroid plexus carcinoma

Fig. 2

DNA methylation-based classification of 47 CNS-PNETs. Sankey plot of the re-evaluated histopathological diagnoses (WHO 2021) (left) and corresponding methylation group (right). Abbreviations: AT/RT, atypical teratoid/rhabdoid tumour; DHG, H3 G34-mutant, diffuse hemispheric glioma H3 G34-mutant; DMG, K27, diffuse midline glioma H3 K27-altered; HGG NOS, high-grade glioma not otherwise specified; IHG, infant-type hemispheric glioma; ETMR, embryonal tumour with multilayered rosettes

Fig. 3

Methylation profiling of 13 CNS-PNETs (black dots) with a calibrated score < 0.9 presented in a t-distributed stochastic neighbor embedding (t-SNE) analysis shows clustering against reference classes from the published MNP data set (only reference samples with diagnoses relevant for this study were included) [19]. Case 2 clustered among the low-grade tumours and case 13 could not be classified by methylation. Abbreviations: AT/RT, atypical teratoid/rhabdoid tumour; CNS NB-FOXR2, CNS neuroblastoma FOXR2-activated; DMG, K27, diffuse midline glioma H3 K27-altered; ETMR, embryonal tumour with multilayered rosettes; DHG, H3 G34-mutant, diffuse hemispheric glioma H3 G34-mutant; HGG_OTHER, including subtype RTK I, II, mesenchymal and midline; IHG, infant-type hemispheric glioma; PXA, pleomorphic xanthoastrocytoma; LGG, low-grade gliomas

Fig. 4

Histopathology (haematoxylin and eosin stain, left) and copy number alterations (CNA, right) plots for A CNS NB-FOXR2-activated tumour with methylation calibrated score (CS) 0.99 and gain of chromosome 1q, loss of chromosome 3p and partial loss of 16q. B Embryonal tumour with multilayered rosettes with methylation CS 0.93 and gain of chromosome 2 and amplification of microRNA cluster on chromosome 19q

Fig. 5

Long-term probability of progression free survival (PFS) and overall survival (OS) of (A and B) the whole CNS-PNET cohort and (C and D) for the same cohort of patients grouped according to the histopathological re-evaluation