Embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma, and medulloepithelioma share molecular similarity and comprise a single clinicopathological entity

Andrey Korshunov,Ella Kumirova,Peter Lichter,Manila Antonelli,Marc Remke,Ulrich Schüller,Annie Huang,V Peter Collins,Marina Ryzhova,Volker Hovestadt,Stefan M Pfister,Daniel Picard,Michael D Taylor,Dominik Sturm,Martin Hasselblatt,Torsten Pietsch,Andreas Von Deimling,Olga Zheludkova,Marco Gessi,Eleonora Aronica,Marcel Kool,Arie Perry,Felice Giangaspero,Stéphanie Puget ,Paul A Northcott ,David Jones ,Adelheid Wöehrer ,Marc K Rosenblum

doi:10.1007/s00401-013-1228-0

Abstract

Three histological variants are known within the family of embryonal rosette-forming neuroepithelial brain tumors. These include embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma (EBL), and medulloepithelioma (MEPL). In this study, we performed a comprehensive clinical, pathological, and molecular analysis of 97 cases of these rare brain neoplasms, including genome-wide DNA methylation and copy number profiling of 41 tumors. We identified uniform molecular signatures in all tumors irrespective of histological patterns, indicating that ETANTR, EBL, and MEPL comprise a single biological entity. As such, future WHO classification schemes should consider lumping these variants into a single diagnostic category, such as embryonal tumor with multilayered rosettes (ETMR). We recommend combined LIN28A immunohistochemistry and FISH analysis of the 19q13.42 locus for molecular diagnosis of this tumor category. Recognition of this distinct pediatric brain tumor entity based on the fact that the three histological variants are molecularly and clinically uniform will help to distinguish ETMR from other embryonal CNS tumors and to better understand the biology of these highly aggressive and therapy-resistant pediatric CNS malignancies, possibly leading to alternate treatment strategies.

Highlights

According to the 2007 WHO classification of tumors of the central nervous system (CNS), CNS primitive neuro ectodermal tumors (PNETs) can be further subdivided into CNS neuroblastoma/ganglioneuroblastoma, medulloepithelioma (MEPL), and ependymoblastoma (EBL) [18]
According to published histopathological criteria, the 97 embryonal tumor with multilayered rosettes (ETMR) cases studied were diagnosed as ETANTR (55 cases), EBL (34 cases), or MEPL after central review
A number of refinements have recently been introduced into the current histological classification of pediatric CNS tumors

Summary

Introduction

According to the 2007 WHO classification of tumors of the central nervous system (CNS), CNS primitive neuro ectodermal tumors (PNETs) can be further subdivided into CNS neuroblastoma/ganglioneuroblastoma, medulloepithelioma (MEPL), and ependymoblastoma (EBL) [18]. ETANTR, EBL, and MEPL are rare neoplasms characterized by the presence of similar histological patterns, namely multilayered and pseudo-stratified rosette-forming structures of variable shape and size Both EBL and ETANTR include the socalled “ependymoblastic rosettes” harboring well-formed central round or slit-like lumina in the absence of an outer membrane [4, 6, 11, 12, 14, 18]. Applying FISH analysis, we previously found amplifications at 19q13.42 involving the C19MC cluster in 93 % of tumors diagnosed either as ETANTR, EBL, or MEPL with ETANTR features, but not in any other pediatric brain tumors [15] These results demonstrate that this genetic aberration is highly sensitive and specific to embryonal CNS tumors with multilayered rosettes irrespective of other features and that these subtypes are highly interrelated. To further test whether the three histological variants of ETMR represent a single entity, we performed clinicopathological and molecular analyses in 97 ETMR samples initially designated as ETANTR, EBL, or MEPL

Materials and methods

Results

Discussion