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. 2012 Mar 6;22(5):689–697. doi: 10.1111/j.1750-3639.2012.00574.x

Analysis of Chromosome 19q13.42 Amplification in Embryonal Brain Tumors with Ependymoblastic Multilayered Rosettes

Sumihito Nobusawa 1,✉, Hideaki Yokoo 1, Junko Hirato 2, Akiyoshi Kakita 3, Hitoshi Takahashi 3, Takashi Sugino 4, Kazuhiro Tasaki 5, Hideaki Itoh 6, Tsutomu Hatori 7, Yoshie Shimoyama 8, Atsuko Nakazawa 9, Shigeru Nishizawa 10, Hiroshi Kishimoto 11, Keiko Matsuoka 12, Masahiro Nakayama 12, Naoki Okura 13, Yoichi Nakazato 1
PMCID: PMC8057628  PMID: 22324795

Abstract

Recently, it was reported that ependymoblastoma and embryonal tumor with abundant neuropil and true rosettes (ETANTR) show 19q13.42 amplification at a high frequency, suggesting that these tumors may constitute a single entity. As ependymoblastic rosettes are the most prominent features in both subtypes, embryonal tumor with multilayered rosettes (ETMR) was proposed, for which 19q13.42 amplification represents a specific molecular hallmark. However, ependymoblastic rosettes are not specific to ependymoblastoma and ETANTR, and are also found in a few other embryonal tumors as well as immature teratomas, and knowledge on 19q13.42 amplification in these tumors is limited. In this study, we performed fluorescence in situ hybridazation (FISH) analysis and differential polymerase chain reaction (PCR), and detected 19q13.42 amplification in three out of four ETANTR, one ependymoblastoma and one medulloepithelioma with ETANTR components, whereas none of the two atypical teratoid/rhabdoid tumors (AT/RT) with ependymoblastic rosettes nor two immature teratomas with developing neuroectodermal structures showed such amplification, suggesting that medulloepitheliomas would possibly be included in ETMR, and ependymoblastic rosettes in AT/RT do not signify that these tumors constitute ETMR. Also, we found C19MC rather than miR‐371‐373 was amplified in one ETANTR, suggesting that C19MC miRNA cluster seems to be more closely linked to the pathogenesis of ETMR.

Keywords: 19q13.42, embryonal tumor with multilayered rosettes, ependymoblastic rosettes, ependymoblastoma, ETANTR, medulloepithelioma

INTRODUCTION

Embryonal brain tumors are a group of malignant neoplasms that most commonly affect the pediatric population. In the 2007 World Health Organization (WHO) classification of central nervous system (CNS) tumors, three histological entities are included: medulloblastoma, atypical teratoid/rhabdoid tumors (AT/RT), and CNS primitive neuroectodermal tumor (PNET) (23). CNS PNET is composed of undifferentiated or poorly differentiated neuroepithelial cells which may show divergent differentiation along neuronal, astrocytic and ependymal lines, and is subdivided into three variants: CNS neuroblastoma/ganglioneuroblastoma, medulloepithelioma and ependymoblastoma (23).

Embryonal tumor with abundant neuropil and true rosettes (ETANTR) was first described by Eberhart et al as “pediatric neuroblastic tumor containing abundant neuropil and true rosettes”(11). This tumor contains multilayered rosettes with essentially the same features as those described in ependymoblastoma, that is, ependymoblastic rosettes. In addition to such rosettes, ETANTR demonstrates evidence of neuronal differentiation, neurocytes and ganglion cells in a neuropil‐like background. This tumor is not recognized as a distinct entity in the current WHO classification (23).

Recently, Korshunov et al showed using fluorescence in situ hybridazation (FISH) analysis that ependymoblastoma and ETANTR have a common genetic signature, amplification at 19q13.42, at a high frequency of 93% (19), which suggests that these two embryonal neoplasms share an origin from a common precursor cell population and may constitute a single tumor entity. The 19q13.42 amplification is associated with up‐regulation of two miRNA clusters, C19MC and miR‐371‐373 21, 27. As ependymoblastic rosettes are the most prominent histological feature in both subtypes, Paulus and Kleihues proposed the term “Embryonal tumor with multilayered rosettes (ETMR),” a new entity for which amplification at 19q13.42 represents a specific molecular hallmark (26).

However, ependymoblastic rosettes are not a structure specific to ependymoblastoma and ETANTR, and are also found in the histopathological setting of typical CNS PNET, medulloblastoma and AT/RT (18). In AT/RT, ependymoblastic rosettes were identified in about 5% of cases (7). It is not clear whether the amplification at 19q13.42 is associated with ependymoblastic differentiation or limited only to ependymoblastoma and ETNATR. Gessi et al recently demonstrated that a single AT/RT case with ependymoblastic rosettes did not have the chromosome19q13.42 amplification, suggesting that the amplification is not merely related to ependymoblastic differentiation but seems to be restricted to ependymoblastoma and ETANTR (16).

Medulloepithelioma is a rare variant of CNS PNET, histologically characterized by papillary, tubular or trabecular arrangements of neoplastic neuroepithelium with an external limiting membrane resembling the embryonal neural tube, and the tubular structures are sometimes referred to as “medulloepithelial rosettes.” In addittion, some medulloepitheliomas were reported to have ependymoblastic rosettes 3, 8. Medulloepithelioma cases have never been tested for chromosome19q13.42 amplification by FISH analysis.

Immature teratoma is one entity in CNS germ cell tumors that contains incompletely differentiated components resembling fetal tissues. Particularly common are stromal elements with a hypercellularity and high mitotic activity reminiscent of embryonic mesenchyme, and primitive neuroectodermal elements (34). The latter elements include ependymoblastic rosettes, neuroepithelial rosettes and canalicular arrays bearing a striking resemblance to characteristic features of medulloepithelioma.

In this study, we investigated four ETANTR, one ependymoblastoma, one medulloepithelioma with ETANTR components, five AT/RT (two with ependymoblastic rosettes) and two immature teratomas with developing neuroectodermal structures for chromosome 19q13.42 amplification using FISH analysis. Differential polymerase chain reaction (PCR) was also performed to detect the amplification of miR‐371, miR‐372 and miR‐373 in the MIR‐371‐373 locus, and two microRNAs (miR‐517c and miR‐520g), which were shown to be overexpressed and to have an oncogenic potential among various miRNAs encoded in the C19MC locus (21).

MATERIALS AND METHODS

Tumor samples

Four ETANTR, one ependymoblastoma, one medulloepithelioma with ETANTR components, five AT/RT (two with ependymoblastic rosettes) and two immature teratomas with developing neuroectodermal structures were collected for this study (Table 1). Eleven cases were from the consultation files of three authors (J.H., H.T. and Y.N.). Two cases were from the pathology archives of Resource Branch for Brain Disease Research, Brain Research Institute, Niigata University. All cases were subjected to a central histopathological review either by J.H. or Y.N. Sections for genetic analyses and immunohistochemistry were prepared from the formalin‐fixed, paraffin‐embedded tissue specimens. The study protocol was approved by the Ethics Committee (Gunma University).

Table 1.

Summary of cases. Abbreviations: ETANTR = embryonal tumor with abundant neuropil and true rosettes; AT/RT = atypical teratoid/rhabdoid tumor

Case Histology Age Sex Location
 1 ETANTR 1 year Male Basal ganglia
 2 ETANTR 2 years Female Temporal lobe
 3 ETANTR 2 years Female Parietal lobe
 4 ETANTR 3 months Female Cerebellum
 5 Ependymoblastoma 3 years Female Frontal lobe
 6 Medulloepithelioma with ETANTR components 8 years Male Frontal lobe
 7 AT/RT with ependymoblastic rosettes 1 month Male Cerebellum
 8 AT/RT with ependymoblastic rosettes 2 months Female Cerebellum
 9 AT/RT 36 years Male Temporal lobe
10 AT/RT 1 year Male Cerebellum
11 AT/RT 9 months Male Fourth ventricle
12 Immature teratoma with developing neuroectodermal structures 7 months Male Third ventricle
13 Immature teratoma with developing neuroectodermal structures 1 month Male Third ventricle
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Immunohistochemistry

Three primary antibodies directed against the following antigens were applied for all cases: synaptophysin (27G12, 1:200, Novocastra, Newcastle upon Tyne, UK), glial fibrillary acidic protein (GFAP; 1:5000) (24) and BAF47/INI1 (BAF47; 1:100; BD Bioscience, San Jose, CA, USA). For coloration, a commercially available biotin‐streptavidin immunoperoxidase kit (Histofine, Nichirei, Tokyo, Japan) and diaminobenzidine were employed.

FISH analysis

Dual‐probe hybridization using an intermittent microwave irradiation method was applied to paraffin‐embedded, 4‐µm‐thick tissue sections, as described before (38). Two different 19q13.42 probes were prepared from bacterial artificial chromosome (BAC) clones, RP11‐381E3 and RP11‐634C1, labeled with ENZO Orange‐dUTP (Abbott Molecular Inc., Des Plaines, IL, USA), and a 19p13.11 probe was prepared from BAC clone RP11‐451E20 labeled with ENZO Green‐dUTP (Abbott Molecular Inc.). BAC clones RP11‐381E3 and RP11‐634C1 have previously been used for 19q13.42 probes 16, 19, 21, 27. Corresponding positions of these probes on chromosome 19 are illustrated in Figure 1. Two miRNA clusters, C19MC and MIR‐371‐373, are located at the RP11‐381E3 locus (Figure 1). Either of the 19q13.42 probes was used with the 19p13.11 probe in a hybridization reaction. The slides were observed with a fluorescence microscope with appropriate filters, and the resulting images were captured using a charge‐coupled device camera (Biozero, Keyence, Osaka, Japan). Signals were scored in at least 100 nonoverlapping, intact cells. Specimens were considered to have 19q13.42 amplification when the target/reference ratio was >2.0 or tight clusters of signals of the 19q13.42 locus probe were observed.

Figure 1.

Figure 1

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Relative map positions of the two microRNA clusters, C19MC and MIR‐371‐373, and three bacterial artificial chromosome (BAC) clones, RP11‐451E20, RP11‐381E3 and RP11‐634C1. C19MC and MIR‐371‐373 are located at the RP11‐381E3 locus.

Differential PCR

DNA was extracted from paraffin‐embedded sections, as previously described (25). For a case of medulloepithelioma with ETANTR components (Case 6), DNA was extracted separately from the typical medulloepithelioma area and from an area with ependymoblastic rosettes resembling the ETANTR histology. To screen for amplification of miR‐517c, miR‐520g, miR‐371, miR‐372 and miR‐373 genes located at 19q13.42, differential PCR was performed as previously reported (32), using the CF sequence as a reference (35). The primer sequences were as follows: 5′‐TGG GCG ACT CCA TCT CAA AA‐3′ (sense) and 5′‐ACT GCC TGA GAT CTT CTT GCT C‐3′ (antisense) for miR‐517c (PCR product, 98 bp); 5′‐GCA AGA AGA TCC CAT GC TGT‐3′ (sense) and 5′‐GCT TTT CCC AAA CGG TAA CAC T‐3′ (antisense) for miR‐520g (PCR product, 104 bp); 5′‐GCA CTT TCT GCT CTC TGG TGA A‐3′ (sense) and 5′‐CCC CTC ACC CAA TCA AA ATG‐3′ (antisense) for miR‐371 (PCR product, 100 bp); 5′‐TAT GGC CGT TTC CTC GTG AT‐3′ (sense) and 5′‐TGT CGC AGC ACT TTC CAC TT‐3′ (antisense) for miR‐372 (PCR product, 120 bp); 5′‐TGT CGC AGC ACT TTC CAC TT‐3′ (sense) and 5′‐ACA CCC CAA AAT CGA AGC AC‐3′ (antisense) for miR‐373 (PCR product, 113 bp); and 5′‐GGC ACC ATT AAA GAA AAT ATC ATC TT‐3′ (sense) and 5′‐GTT GGC ATG CTT TGA TGA CGC TTC‐3′ (antisense) for the CF (PCR product, 79 bp). PCR was carried out with 28 cycles (annealing temperature, 55°C). The PCR products were loaded onto 8% polyacrylamide gels and stained with ethidium bromide. Quantitative analysis of the signal intensity was performed using the ATTO Densitograph (ATTO, Tokyo, Japan). Using DNA from 14 nontumoral tissues from healthy individuals, we found the mean ratios of miR‐517c : CF, miR‐520g : CF, miR‐371:CF, miR‐372:CF and miR‐373:CF to be 0.90, 0.98, 1.17, 0.92 and 1.00, with standard variations of 0.17, 0.09, 0.19, 0.15 and 0.20, respectively. Threshold values of 2.31, 2.22, 2.93, 2.30 and 2.62 were regarded as evidence for amplification of miR‐517c, miR‐520g, miR‐371, miR‐372 and miR‐373, respectively, as previously reported (32).

RESULTS

Pathological findings

ETANTR cases (Cases 1–4) were composed of predominantly undifferentiated embryonal cells arranged in a neuropil‐like background (Figure 2A). Ependymoblastic rosettes were frequently observed in scattered hypercellular foci of embryonal components (Figure 2B).

Figure 2.

Figure 2

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Microscopic appearance of embryonal tumor with abundant neuropil and true rosettes (ETANTR) (A,B), ependymoblastoma (C) and medulloepithelioma with ETANTR components (D–H). A. Ependymoblastic rosettes embedded in a neuropil‐like area (Case 2). B. Ependymoblastic rosettes forming distinctive multilayered structures with a small, round, central lumen. Tumor cells along the outer edge of the rosette merge into the surroundings (Case 2). C. Ependymoblastic rosettes intermingled with clusters of small, poorly differentiated cells without a neuropil‐like area (Case 5). A medulloepithelioma with ETANTR components case (Case 6) shows a biphasic pattern (D) featuring neural tube‐like structures (E) or ependymoblastic rosettes scattered within a neuropil‐like area resembling the ETANTR histology (F); the neuropil‐like area is immunohistochemically positive for synaptophysin (G) but negative for glial fibrillary acidic protein (GFAP) (H). Original magnification: ×40 (D), ×100 (A,E–H), ×200 (C), ×400 (B).

An ependymoblastoma case (Case 5) contained ependymoblastic rosettes formed by poorly differentiated cells without a neuropil‐like matrix (Figure 2C).

A medulloepithelioma with ETANTR components case (Case 6) showed a biphasic pattern (Figure 2D) featuring neural tube‐like structures with an external limiting membrane (Figure 2E) or ependymoblastic rosettes scattered within a neuropil‐like area (Figure 2F) which was immunohistochemically positive for synaptophysin (Figure 2G). The former pattern, which accounted for approximately 70% of the specimen, lacked neuropil‐like area among the neural tube‐like structures (Figure 2E). The latter pattern histologically resembled ETANTR (Figure 2F).

Among the five AT/RT patients, two cases (Cases 7, 8) focally showed ependymoblastic rosettes (Figure 3A). Rhabdoid cells with eosinophilic globular cytoplasmic inclusions were focally found (Figure 3B). Tumor cells were immunohistochemically negative for BAF47/INI1 in all five AT/RT cases (Figure 3C). Other distinctive features were primitive squamous epithelia and fetal‐type glands observed in Case 8 (Figure 3D,E).

Figure 3.

Figure 3

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Microscopic appearance of atypical teratoid/rhabdoid tumors (AT/RT) with ependymoblastic rosettes (A–E) and immature teratoma with developing neuroectodermal structures (F–H). A. Focally ependymoblastic rosettes are found (Case 8). B. Rhabdoid cells with eosinophilic globular cytoplasmic inclusions (Case 8). C. Tumor cells are immunohistochemically negative for BAF47/INI1. Endothelial cells are labeled as an internal positive control (Case 7). Primitive squamous epithelia (D) and fetal‐type glands (E) are observed in an AT/RT (Case 8). F. Primitive neuroectodermal elements including ependymoblastic rosettes, and neuroepithelial rosettes and canalicular arrays (Case 13). Primitive squamous epithelia (G; Case 12) and fetal‐type glands (H; Case 13) are observed in immature teratomas. Original magnification: ×100 (F,G), ×200 (A–E,H).

Immature teratoma cases (Cases 12 and 13) were predominantly composed of embryonic mesenchyme‐like stroma and primitive neuroectodermal elements including ependymoblastic rosettes, neuroepithelial rosettes and canalicular arrays (Figure 3F). Primitive squamous epithelia (Figure 3G), fetal‐type glands (Figure 3H), and mature elements such as differentiated glands and cartilage tissue were observed.

FISH analysis

FISH analysis using two different 19q13.42 probes revealed a high‐level focal amplification of the 19q13.42 locus in three out of four ETANTR, one ependymoblastoma and one medulloepithelioma with ETANTR components (Figure 4, Table 2). As for Case 6, 19q13.42 amplification was observed both in the typical medulloepithelioma area and in area with ependymoblastic rosettes resembling the ETANTR histology. One ETANTR (Case 4), five AT/RT (two with ependymoblastic rosettes) and two immature teratomas with developing neuroectodermal structures did not show the amplification pattern (Table 2). No difference was seen between the results obtained by RP11‐381E3 and RP11‐634C1 probes in any cases (Table 2).

Figure 4.

Figure 4

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Examples of 19q13.42 amplification detected by fluorescence in situ hybridazation (FISH) analysis. A. Embryonal tumor with abundant neuropil and true rosettes (ETANTR) (Case 1). B. Medulloepithelioma with ETANTR components (Case 6). Bacterial artificial chromosome (BAC) clones RP11‐381E3 and RP11‐634C1 were used for 19q13.42 probes labeled in orange for A and B, respectively. The reference probe corresponding to the 19p13.11 locus is labeled in green.

Table 2.

Results of differential PCR for amplification of miR‐517c, miR‐520g, miR‐371, miR‐372 and miR‐373 genes and FISH for 19q13.42 amplification. Abbreviations: PCR = polymerase chain reactio; FISH = fluorescence in situ hybridization; BAC = bacterial artificial chromosome

Case Differential PCR FISH
miR‐517c miR‐520g miR‐371 miR‐372 miR‐373 RP11‐381E3* RP11‐634C1*
 1 + + + + + + +
 2 + + + + + + +
 3 + + − − − + +
 4 − − − − − − −
 5 + + + + + + +
 6 + + + + + + +
 7 − − − − − − −
 8 − − − − − − −
 9 − − − − − − −
10 − − − − − − −
11 − − − − − − −
12 − − − − − − −
13 − − − − − − −
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*

BAC clones RP11‐381E3 and RP11‐634C1 were used for 19q13.42 probes.

Differential PCR

Differential PCR revealed that amplifications of all miR‐517c, miR‐520g, miR‐371, miR‐372 and miR‐373 were detected in two out of four ETANTR (Cases 1 and 2), one ependymoblastoma and one medulloepithelioma with ETANTR components (Figure 5, Table 2). Regarding the medulloepithelioma with ETANTR components case (Case 6), the typical medulloepithelioma area and area with the ETANTR histology showed the same results (Table 2). One ETANTR (Case 3) showed only amplifications of miR‐517c and miR‐520g, both of which were encoded in the C19MC locus (Figure 5, Table 2). Another ETANTR (Case 4), where 19q13.42 amplification was not detected by FISH analysis, as mentioned previously, five AT/RT (two with ependymoblastic rosettes), and two immature teratomas with developing neuroectodermal structures showed no amplification of miR‐517c,miR‐520g, miR‐371, miR‐372 or miR‐373 genes (Figure 5, Table 2).

Figure 5.

Figure 5

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Differential polymerase chain reaction (PCR) was performed to assess the amplification of miR‐517c, miR‐520g, miR‐371, miR‐372 and miR‐373 genes; PCR product sizes are 98, 104, 100, 120 and 113 bp, respectively. Numbers below each band indicate the ratio of amplification of the target gene compared with the CF reference gene. Asterisks indicate amplification. AT/RT = atypical teratoid/rhabdoid tumors; ETANTR = embryonal tumor with abundant neuropil and true rosettes.

DISCUSSION

Analyzing a series of 20 ETANTRs and 21 ependymoblastomas, Korshunov et al identified a focal amplification at 19q13.42 in 95% of ETANTR and 90% of ependymoblastomas. Although 19q13.42 amplification was found at a markedly high frequency in those tumors, a few cases did not bear the amplification (19). In this study analyzing four ETANTR and one epenymoblastoma, there was also one ETANTR without 19q13.42 amplification (Case 4). It is a well‐known fact that the vast majority of AT/RT show inactivation of SMARCB1 (commonly known as INI1), which is a member of the ATP‐dependent SWI/SNF chromatin‐remodeling complex. Recently, however, one AT/RT case was reported to show loss of SMARCA4, which is another member of the complex, but retain SMARCB1 expression (17). Similarly to AT/RT, a minority of ETANTR and ependymoblastomas without 19q13.42 amplification may have alterations of some gene involved in an as‐yet‐unidentified oncogenic mechanism in which 19q13.42 amplification may be involved.

The 19q13.42 locus encompasses two miRNA clusters, C19MC and MIR‐371‐373. Several studies have linked the expression of members of both clusters with the miRNA signature characteristic of human embryonic stem cells 20, 22, 29. Evidence for the oncogenic potentials of miRNAs encoded in these clusters was reported in some tumors; miR‐371‐373 has been implicated in testicular germ cell tumors (36), and miR‐371‐373 and C19MC were activated in a subgroup of thyroid adenomas by chromosomal translocation (31).

In ETANTR and ependymoblastomas, 19q13.42 amplification was shown to lead to the up‐regulation of C19MC and miR‐371‐373 (27). Using an miRNA array, however, Li et al found robust expression of several C19MC miRNAs but only modest expression of miR‐371‐373 in a subset of CNS PNET with 19q13.41 amplification exhibiting predominantly ependymoblastic and ependymal differentiation, and indicated that miR‐517c and ‐520g encoded in the C19MC locus had an oncogenic potential (21). Besides, the significant copy number gain of miR‐372, only one miRNA gene examined in MIR‐371‐373, was not detected using quantitative PCR in some CNS PNET with 19q13.41 amplification in the same report (21). In our current study, differential PCR analysis showed that amplifications of miR‐517c and ‐520g were seen but none of the three miRNAs in MIR‐371‐373 was amplified in one ETANTR with 19q13.42 amplification (Case 3). Taken together, C19MC seems to be more closely linked to the oncogenesis of ETMR than miR‐371‐373.

Gessi et al recently reported that an AT/RT case with ependymoblastic rosettes did not have the chromosome 19q13.42 amplification (16). In this study, we demonstrated that two additional AT/RT cases with ependymoblastic rosettes did not harbor the amplification, supporting their suggestion that 19q13.42 amplification is not merely related to ependymoblastic differentiation (16).

The histology of AT/RT is variable and complex. Rarely, elements of chondroid‐like tissue and tissues resembling embryonal structures such as primitive squamous epithelia, ependymoblastic rosettes, classical neurotubular structures and germ cells with yolk sac differentiation were reported to be encountered in AT/RT 1, 6, 18, 33. In addition, one AT/RT with ependymoblastic rosettes in our study showed fetal‐type glands (Figure 3E), which are commonly seen in immature teratomas (Figure 3H) (34). Similarly to ependymoblastic rosettes formed in immature teratoma, ependymoblastic rosettes in AT/RT may constitute a part of its teratoid feature and may be substantially distinct from ependymoblastic rosettes in CNS PNET despite their histological resemblance.

There have been quite rare cases of medulloepithelioma reported to present ependymoblastic rosettes 3, 8. In this study, Case 6 showed predominant areas with medulloepithelioma histology and areas resembling the characteristic features of ETANTR with ependymoblastic rosettes embedded in neurocytes and neuropil (Figure 2F), and was revealed to possess 19q13.42 amplification. Buccoliero et al previously described one case with a composite morphology: the ETANTR histology (specimen from the initial surgery); the medulloepithelioma histology with mesenchymal and epithelial areas (specimen from the second surgery performed 1 week after the initial surgery) (5). This case was subsequently shown to carry 19q13.42 amplification in the report by Korshunov et al (19), supporting our hypothesis that medulloepitheliomas—at least ones with ependymoblastic rosettes—would possibly be included in ETMR.

Molecular genetic studies of medulloepitheliomas are very scarce (28). Fan et al investigated a medulloepithelioma using comparative genomic hybridization (CGH) analysis and found gains on chromosomal arms 3p, 5p, 6p, 14q, 15q and 20q, but no aberration in 19q (12). Considering the fact that 19q13.42 amplification was not reported in ependymoblastomas and ETANTR by cytogenetic analyses such as conventional CGH carried out before Pfister et al first demonstrated amplification in an ETANTR case 9, 14, 15, 27, 30, the possibility cannot be ruled out that medulloepitheliomas may have frequent amplification at 19q13.42.

CNS PNET with 19q13.42 amplification and/or ETANTR‐like histology are associated with younger age and very poor clinical outcomes 10, 15, 19, 21. Radiologic findings are hardly specific in distinguishing subtypes of CNS PNET, AT/RT and immature teratoma 1, 2, 4, 9, 11, 13, 15. Moreover, owing to sampling bias, it may be sometimes difficult to correctly diagnose ependymoblastoma and ETANTR missing their characteristic features in the specimens 2, 9, 16. It is also of note that the recent report of an ETANTR case showed that the typical histology of ETANTR disappeared during progression, while 19q13.42 amplification was still present, providing another argument for the hypothesis that ETMR cases with 19q13.42 amplification but without ependymoblastic rosettes may occur (37). The findings obtained in this study indicate that 19q13.42 amplification is a useful and specific diagnostic marker to determine this distinct subgroup of CNS PNET, ETMR, which may share potential therapeutic targets (21).

ACKNOWLEDGMENTS

We thank Mr. Koji Isoda (Gunma University) for his excellent technical assistance.

This work was supported in part by the Collaborative Research Project (2011–2307) of the Brain Research Institute, Niigata University, Japan.

The authors declare no conflict of interest.

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