Trisomy 19 ependymoma, a newly recognized genetico-histological association, including clear cell ependymoma

Abstract

Ependymal tumors constitute a clinicopathologically heterogeneous group of brain tumors. They vary in regard to their age at first symptom, localization, morphology and prognosis. Genetic data also suggests heterogeneity. We define a newly recognized subset of ependymal tumors, the trisomy 19 ependymoma. Histologically, they are compact lesions characterized by a rich branched capillary network amongst which tumoral cells are regularly distributed. When containing clear cells they are called clear cell ependymoma. Most trisomy 19 ependymomas are supratentorial WHO grade III tumors of the young. Genetically, they are associated with trisomy 19, and frequently with a deletion of 13q21.31-31.2, three copies of 11q13.3-13.4, and/or deletions on chromosome 9. These altered chromosomal regions are indicative of genes and pathways involved in trisomy 19 ependymoma tumorigenesis. Recognition of this genetico-histological entity allows better understanding and dissection of ependymal tumors.

Figure 1

Clinico-pathological analysis of paraffin embedded supra-tentorial ependymal tumors, sub-ependymomas excluded, and of posterior fossa ependymomas presenting deletions of chromosome 9. Tumors are divided in between trisomy 19 ependymomas and ependymomas.

Figure 2

A) Array-CGH ideograms of the most frequently observed chromosomal anomalies in trisomy 19 ependymomas. Blue dots: ratio between tumor DNA and control DNA; red dots: ratio between control DNA and tumor DNA. Ratio of 1 indicates normal DNA content (presence of two alleles, chromosome 2: A6). Separation of the lines corresponds to gain of tumoral DNA (blue dots going up, chromosome 19: A1, A2 and A9 and, chromosome 11: A4) or loss of tumoral DNA (blue dots going down, chromosome 13: A6 and, chromosome 9: A4). B) Scheme of array-CGH results of trisomy 19 ependymomas. Altogether 118 genetic anomalies detected, mean: 13 per tumor, consisting of 74 gains (64%) and 44 losses (36%). Numbers correspond to tumors. C) Genetic alterations presented at least in 66% (6/9) of trisomy 19 ependymomas (A1-A9) compared to two controls (Ep.: B1 and B19). Trisomy 19 observed in all cases, although in one tumor (A4) the telomeric long arm was not amplified. Deletion of 13q21.31-31.2 and deletions on chromosme 9 (M: monosomy; M: monosomy without 9qter loss; 9p: 9p deletion and Int: intertitial p and q deletions) were found in 7/9 tumors (78%). Amplification of 11q13.3-13.4 was detected in 6/9 (66%) of the tumors.

Figure 3

Histological characteristics of trisomy 19 ependymoma: compactness with clear cut border (A, HE, 30×); rich branched capillary network (B, HE, 90×); perivascular pseudorosettes, always observed, but can be rare (C, HE, 250×); GFAP positivity, always observed (D, GFAP, 125×) but can be focal with large GFAP negative area (E, GFAP, 125×); focal region of tumoral cells with intra-cytoplasmic EMA dots, always found (F, EMA, 310×); Ki67 >10% (G, Ki67, 60×); neuronal markers: negative in the tumor, positive in the surrounding brain parenchyma (H: NF, 30× and I: Neu-N, 30×).

Figure 4

Three phenotypic variants of trisomy 19 ependymomas. Clear cells, indicative of clear cell ependymoma, a subgroup of trisomy 19 ependymoma (HE: A, 250× and B, 60×); PNET-like appearance, because tumoral cells almost devoid of cytoplasm, presence of rounded nuclei and nuclei-free regions not always centered on vessels (HE: E, 190×; F, 60×; I, 375×; J, 90×; M, 130× and N, 30×); and oligo-astrocytoma appearance, due to large eosinophilic tumoral cells and presence of chicken-wire vessels (HE: Q, 125× and R, 60×). Ependymal nature confirmed by GFAP positivity of end-feets (D, 125×; H, 60×; L, 160×; P, 375× and T, 375×) and intra-cytoplasmic EMA dots (C, 160×; G,160×; K, 250×, O, 250× and S, 500×). Pictures A, B, C and D correspond to tumor A1; pictures E, F, G and H to tumor A2; pictures I, J, K and L to tumor A4; pictures M, N, O and P to tumor A3, pictures Q, R, S and T to tumor A8.

Figure 5

Scheme of pathways involved in trisomy 19 ependymoma. Cancer occurs because of accumulation of defects implying cell cycle, cell proliferation, differentiation, apoptosis, cell interaction with surrounding stroma and angiogenesis. All these pathways could be deregulated when considering genes located in the 4 chromosomic regions most frequently altered in trisomy 19 ependymomas.