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.
Highlights
Primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) are highly malignant neoplasms that predominantly affect children and adolescents [2, 3, 7, 8, 10, 18, 24, 27]
CNS EFT-CIC frequently impose as high-grade gliomas, CNS HGNET-MN1 often are diagnosed as astroblastoma, and CNS HGNET-BCOR exhibit histopathological features resulting in grouping with ependymomas
Our analysis showed that the 84 CNS-PNET samples matched with established methylation classes recognized by the Brain Tumor Classifier [5, 6, 23]: (1) CNS neuroblastoma with forkhead box R2 (FOXR2) activation (CNS_NBL; n = 20; 24%): (2) Glioblastoma, IDH wild-type, subclass H3.3 G34 mutant (GBM_G34; n = 22; 26%); (3) Glioblastoma, IDH wild-type, subclass MYCN (GBM_MYCN; n = 18; 21%), and (4) Ependymoma, with RELA_C11orf95 fusion (EPN_RELA; n = 24; 29%)
Summary
Primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) are highly malignant neoplasms that predominantly affect children and adolescents [2, 3, 7, 8, 10, 18, 24, 27]. The “2016 replacement” was the introduction of the designation “other CNS embryonal tumors” used for pooling a heterogeneous set of poorly differentiated neuroepithelial tumors, including the medulloepithelioma, CNS neuroblastoma/ganglioneuroblastoma and CNS embryonal tumor, NOS This concept has experienced major reshuffling again to be introduced in the upcoming 2020 WHO classification. Four novel and previously undetermined molecular entities designated respectively as CNS neuroblastoma with forkhead box R2 “CNS NB-FOXR2”, “CNS Ewing sarcoma family tumor with CIC alteration (CNS EFT-CIC),” “CNS high-grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1),” and “CNS high-grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR)” were identified and characterized in detail Among these tumor groups arising from the former PNET commonality, CNS NB-FOXR2 (CNS_NBL) poses a special diagnostic problem due to its closest resemblance to various undifferentiated CNS neoplasms. We performed integrative DNA- and RNA-based molecular analysis of a cohort of pediatric brain tumors histologically designated as “CNS-PNET”, which were diagnosed and treated in a single Centre aiming to determine their “institutional” nosologic spectrum, establish molecular diagnostic markers and evaluate the effectiveness of treatment within the different molecularly defined entities
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