Molecular analysis of pediatric CNS-PNET revealed nosologic heterogeneity and potent diagnostic markers for CNS neuroblastoma with FOXR2-activation

• Main Authors: Andrey Korshunov, Konstantin Okonechnikov, Felix Schmitt-Hoffner, Marina Ryzhova, Felix Sahm, Damian Stichel, Daniel Schrimpf, David E. Reuss, Philipp Sievers, Abigail Kora Suwala, Ella Kumirova, Olga Zheludkova, Andrey Golanov, David T. W. Jones, Stefan M. Pfister, Marcel Kool, Andreas von Deimling
• Format: Article
• Language: English
• Published: BMC 2021-02-01
• Series: Acta Neuropathologica Communications
• Subjects: CNS-PNET; Neuroblastoma; FOXR2-activation; SOX10
• Online Access: https://doi.org/10.1186/s40478-021-01118-5

Abstract Primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) are highly malignant neoplasms posing diagnostic challenge due to a lack of defining molecular markers. CNS neuroblastoma with forkhead box R2 (FOXR2) activation (CNS_NBL) emerged as a distinct pediatric brain tumor entity from a pool previously diagnosed as primitive neuroectodermal tumors of the central nervous system (CNS-PNETs). Current standard of identifying CNS_NBL relies on molecular analysis. We set out to establish immunohistochemical markers allowing safely distinguishing CNS_NBL from morphological mimics. To this aim we analyzed a series of 84 brain tumors institutionally diagnosed as CNS-PNET. As expected, epigenetic analysis revealed different methylation groups corresponding to the (1) CNS-NBL (24%), (2) glioblastoma IDH wild-type subclass H3.3 G34 (26%), (3) glioblastoma IDH wild-type subclass MYCN (21%) and (4) ependymoma with RELA_C11orf95 fusion (29%) entities. Transcriptome analysis of this series revealed a set of differentially expressed genes distinguishing CNS_NBL from its mimics. Based on RNA-sequencing data we established SOX10 and ANKRD55 expression as genes discriminating CNS_NBL from other tumors exhibiting CNS-PNET. Immunohistochemical detection of combined expression of SOX10 and ANKRD55 clearly identifies CNS_NBL discriminating them to other hemispheric CNS neoplasms harboring “PNET-like” microscopic appearance. Owing the rarity of CNS_NBL, a confirmation of the elaborated diagnostic IHC algorithm will be necessary in prospective patient series.