Ependymoma‐like tumor with mesenchymal differentiation harboring C11orf95‐NCOA1/2 or ‐RELA fusion: A hitherto unclassified tumor related to ependymoma

Abstract

Recurrent fusion genes involving C11orf95, C11orf95-RELA, have been identified only in supratentorial ependymomas among primary CNS tumors. Here, we report hitherto histopathologically unclassifiable high-grade tumors, under the tentative label of "ependymoma-like tumors with mesenchymal differentiation (ELTMDs)," harboring C11orf95-NCOA1/2 or -RELA fusion. We examined the clinicopathological and molecular features in five cases of ELTMDs.Except for one adult case (50 years old), all cases were in children ranging from 1 to 2.5 years old. All patients presented with a mass lesion in the cerebral hemisphere. Histologically, all cases demonstrated a similar histology with a mixture of components. The major components were embryonal-appearing components forming well-delineated tumor cell nests composed of small uniform cells with high proliferative activity, and spindle-cell mesenchymal components with a low-to high-grade sarcoma-like appearance. The embryonal-appearing components exhibited minimal ependymal differentiation including a characteristic EMA positivity and tubular structures, but histologically did not fit with ependymoma because they lacked perivascular pseudorosettes, a histological hallmark of ependymoma, formed well-delineated nests, and had diffuse and strong staining for CAM5.2. Molecular analysis identified C11orf95-NCOA1, -NCOA2, and -RELA in two, one, and two cases, respectively. t-distributed 2 of 14 | TOMOMASA eT Al.

Supratentorial non-RELA, ZFTA-fused ependymomas: a comprehensive phenotype genotype correlation highlighting the number of zinc fingers in ZFTA-NCOA1/2 fusions

“…In our series, all three tumors presenting with sarcoma histology were classified in cluster 4. None of the cases in our series or from those in the literature exhibited significant nuclear expression of NFκB [ 7 , 8 ], which supports previous studies showing that p65 immunoexpression is highly correlated to the presence of RELA fusion [ 3 , 25 , 26 ]. However, all except two cases [ 6 , 7 , 9 ] showed L1CAM immunoexpression to varying degrees and intensities, confirmed by the RNA expression data [ 4 ].…”

“…ST non- RELA ZFTA -fused EPN presented high morphological heterogeneity with only rare cases having histopathological and immunohistochemical features of ZFTA:RELA- fused EPN [ 8 , 9 ]. In the literature, their histological appearance was sarcoma-like, PXA-like, high-grade glioma-like, malignant teratoma-like, embryonal tumor-like, or had neuronal differentiation and a granular cell component [ 6 , 7 , 9 ]. We also identified four cases with astroblastoma-like features.…”

“…The landscape of gene partners of ZFTA -fused EPN (without RELA ) is wide, the main being MAML2 (21/51 cases), NCOA2 (14/51 cases), and NCOA1 (9/51 cases) genes [ 6 – 9 ]. These fusions alone are sufficient to drive tumorigenesis in vivo [ 6 , 7 , 9 ]. In the original report, the main cases of ZFTA:MAML2 fusion were in cluster 2 and showed ependymal features [ 9 ].…”

“…However, these alternative partners to RELA seem to produce original morphological patterns which challenge the histopathological diagnosis. In fact, recent studies have reported a large spectrum of morphologies, including glial, glioneuronal, embryonal and even mesenchymal and epithelial patterns in tumors harboring C11orf95- fusions without RELA [ 6 , 7 , 9 ]. In this study, we performed a clinico-pathological and molecular analysis (including DNA-methylation profiling and the identification of the new clusters of methylation) of 13 new cases of ST-EPN with C11orf95 (now called ZFTA for Zing Finger Translocation Associated by the new HUGO gene Nomenclature Committee) fusion without the RELA gene to more suitably characterize these tumors and compare them with their counterparts which have classical ZFTA:RELA fusion.…”

Recurrent fusions inPLAGL1define a distinct subset of pediatric-type supratentorial ependymoma

“…Within the supratentorial compartment, two molecularly defined types of ependymoma are characterized by recurrent gene fusions, one involving the gene ZFTA (formerly referred to as C11orf95, most frequently fused to RELA), and the other involving YAP1 2,5 . More recently, several reports have expanded on the spectrum of gene fusions observed in supratentorial ependymoma and ependymoma-like tumors, in particular in the pediatric setting [11][12][13] . Implementing these molecular markers into the WHO classification for brain tumors is of paramount importance in overcoming the challenges of histologically diverse tumor types and in increasing diagnostic accuracy.…”