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Keywords:

  • dysembryoplastic neuroepithelial tumor;
  • glioneuronal tumors;
  • oligodendroglioma;
  • pathology;
  • WHO

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

Dysembryoplastic neuroepithelial tumor (DNT) is a benign glioneuronal tumor, occurring in children and adolescents, typically associated with drug-resistant partial seizures. Pathologically, DNT is characterized by a specific glioneuronal element that is comprised of oligodendroglia-like cells (OLC) and floating neurons. The definition of DNT is currently controversial and the incidence of DNT varies among institutions. In this study we characterize the morphologic profiles of OLC and floating neurons by performing immunohistochemical and morphometric studies on seven cases of a simple form of DNT. While a majority of OLC was positive for oligodendrocyte transcription factor 2 (Olig2), only floating neurons and a few small cells were positive for neuronal nuclear antigens (NeuN). Double immunofluorescence studies revealed co-localization of Olig2 and galectin 3 in OLC, but no co-localization of Olig2 and NeuN. The distribution pattern of NeuN-positive nuclei within the tumor tissue was not different from that in the adjacent neural tissue. A section cut perpendicular to the cortex stained with NeuN showed a continuous laminar arrangement with the adjacent cortex. Densities of NeuN-positive nuclei from tumors embedded in the white matter were significantly lower than those from tumors in the gray matter. Our results suggest that the NeuN-positive small and large cells observed within the specific glioneuronal element are in fact entrapped granular and pyramidal cells within the cortex and that OLCs are essentially glial and not neuronal in nature. DNT is thus a pure glial tumor rather than a glioneuronal tumor, that is, the equivalent of non-infiltrating oligodendroglioma, grade I.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

Dysembryoplastic neuroepithelial tumor (DNT) is a benign glioneuronal tumor (GNT) that was first described by Daumas-Duport in 1988.[1] DNT is considered the second most prevalent cause of intractable epilepsy in children and adolescents. However, the incidence reported in individual hospitals varies unacceptably[2-5] (Table 1). For example, Plate et al.[2] from Zurich identified only one DNT case among 224 consecutive epilepsy surgeries. On the other hand, Pasquier et al.[5] from Grenoble identified 49 cases of DNT out of a total of 327 resections. The higher incidence reported by Pasquier et al. is 30 times greater than that reported by Plate. In our institute, Oda et al.[4] reported an incidence of 1.2% for DNT among 327 resections. Although this is of course older data, in a recent study, we found a similar percentage and currently are seeing approximately one or two DNT per every 100 resections for intractable epilepsy (unpublised data).

Table 1. Incidence of tumors in intractable epilepsy
 Plate[2]Wolf[3]Oda[4]Pasquier[5]
  1. a

    Including non-specific histological form of DNT. AA, anaplastic astrocytoma; AO, anaplastic oligodendroglioma; DA, diffuse astrocytoma; GG, ganglioglioma; O, oligodendroglioma; PA, Pilocytic astrocytoma; PXA, pleomorphic xanthoastrocytoma; DNT, dysembryoplastic neuroepithelial tumor.

PA13 (5.8%)17 (7.9%)3 (0.9%)0 (0%)
PXA2 (0.9%)1 (0.5%)1 (0.3%)4 (1.2%)
DA23 (10.3%)6 (2.8%)2 (0.6%)0 (0%)
AA11 (4.9%)1 (0.5%)0 (0%)0 (0%)
O27 (12.0%)10 (4.6%)1 (0.3%)0 (0%)
AO6 (2.7%)0 (0%)0 (0%)0 (0%)
GG17 (8.0%)34 (15.7%)12 (3.7%)29 (8.9%)
DNT1 (0.5%)6 (2.8%)4 (1.2%)49 (15.0%)
Others26 (11.6%)0 (0%)7 (2.1%)12 (3.7%)a
Total resections224 (100%)216 (100%)327 (100%)327 (100%)

DNT is primarily composed of so-called “specific glioneuronal elements”, the elements of which are oligodendroglia-like cells (OLCs) and “floating neurons,” the latter being given ground for its position within GNTs.[6] Daumas-Duport had subsequently proposed three subclassifications: simple, complex and non-specific forms.[6-8] The simple form is comprised of only specific glioneuronal elements, whereas the complex form is also accompanied by glial nodules.[6-8] The non-specific form is defined as any glioma with a cortical topography recognizable on MRI that induces partial seizures with onset before age 20 without neurological deficits.[7] This is a controversial suggestion and one that is far from being universally accepted.[9] The above-mentioned large differences in incidence may be due to two possibilities. First, there is no clear definition as to what constitutes DNT, particularly with regard to the specific glioneuronal element. Second, the presence of related or mimicking lesions such as subcortical DNT has yet to be taken into consideration with regard to the definition of DNT. As per the WHO classification,[6] the current definition of DNT refers to key features that include a cortical location, multinodularity and a columnar architecture termed the specific glioneuronal element. The latter is composed of OLCs and floating neurons with a normal cytology. OLCs are GFAP-negative but S-100 protein- and oligodendrocyte transcription factor 2 (Olig 2)-positive. Therefore, in actuality, the current definition can be considered to be fairly vague.

In the literature, a variety of tumors have been reported under the umbrella of DNT. Leung first reported unusual subcortical DNT in 1994.[10] In their two cases, there appeared to be neurocytic differentiation in both cases, while one case involved perivascular rosettes. Yamamoto reported observing multinodular masses in the hypothalamus, cerebellum and spinal cord.[11] Cervera-Pierot et al. described DNT and DNT-like lesions located in the caudate and septum pellucidum.[12] In a case of a cerebellar DNT reported by Kuchelmeister,[13] the microcystic area resembled a specific glioneuronal element. However, this type of tumor does not exhibit nodularity and its rosettes display definite neuronal differentiation. Subsequently, in 2002, we identified this tumor type as a new entity: rosette-forming glioneuronal tumor.[14]

To address the above-mentioned controversial issues, we attempted to critically characterize the morphological and immunohistochemical profiles of specific glioneuronal elements, particularly those for OLCs and floating neurons in DNT.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

Inclusion criteria and demographic features

We set strict inclusion criteria for classic DNT that corresponded to the simple form of DNT (WHO 2007), that is, a predominately cortical topography, a nodular architecture and the presence of specific glioneuronal elements composed of OLCs, floating neurons and a columnar to alveolar architecture (Fig. 1). Using these criteria, we were able to identify seven patients from the pathological records in Tokyo Metropolitan Neurological Hospital and the Saitama Medical University Hospital. The age of the patients ranged from 13 to 36 years; mean 21.4 years, three female and four male. All patients underwent surgical resection for drug-resistant temporal lobe epilepsy. MRI confirmed their predominant cortical topography.

figure

Figure 1. A typical view of a simple form of dysembryoplastic neuroepithelial tumor. A specific glioneuronal element in the cortex with an alveolar pattern showing nodularity (A). A specific glioneuronal element with a typical columnar architecture. Oligodendroglia-like cells arrange along a cord-like neuropil (B). Scale bar = 200 μm.

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Histology and immunohistochemistry

Surgical specimens were fixed in 10% buffered formalin and processed for paraffin embedding. HE stain as well as KB stain were utilized for a routine histological analysis. Representative sections were immunostained with antibodies directed against the following antigens: synaptophysin (SYP: SY38, 1:50, Dako Cytomation, Carpinteria, CA, USA), neurofilament protein (NFP: 2F11, 1:50, Dako Cytomation), neuronal nuclear antigen (NeuN) (A60, 1:10, Chemicon, Temecula, CA, USA), GFAP (polyclonal, 1:400, Dako Cytomation), Olig2 (polyclonal, 1:40, IBL, Takasaki, Gumma, Japan), galectin 3 (monoclonal, 1:400, Novocastra, Newcastle-Upon-Tyne, UK), homeobox protein Nkx-2.2 (polyclonal, 1:40, Santa Cruz Biotechnology, Santa Cruz, CA, USA), platelet-derived growth factor receptor α (PDGFRα, polyclonal, 1:100, Santa Cruz Biotechnology), excitatory amino acid transporter 2 (EAAT2, polyclonal, 1:200, Abcam, Cambridge, UK) and CD56 (123C3, monoclonal, ready-to-use, Dako Cytomation). The sections were incubated overnight with primary antibodies and antigens were manually visualized using the detection kit (EnVision +kit/HRP, Dako Cytomation) with diaminobenzidine as the chromogen.

A double-labeling immunofluorescent study was undertaken to elucidate the spatial association among Olig2, NeuN and galectin 3. After antigen retrieval pretreatment with autoclaving and incubation in 5% non-fat milk, the sections were incubated overnight in a cocktail of two primary antibodies (monoclonal and polyclonal). After immersion in 0.3% hydrogen peroxide for 30 min, depending upon the primary antibodies coupled, the sections were incubated in a cocktail of either goat cy 2-conjugated anti-mouse or ant-rabbit IgG (H + L) (1:500; Vector Labs., Burlingame, CA, USA) and rabbit cy 3-conjugated anti-goat IgG (H + L) antibody.

Morphometry

The captured images (on ×200 magnification) of NeuN-positive and Olig2-positive nuclei in five fields from each case were manually traced and then the traces were converted into binary images, which were analyzed using an image analysis system (MacSCOPE, Mitani Corporation, Tokyo, Japan).

Statics

The data were statistically analyzed with a computer software system (Stat-View 4.0; Abacus Concept; Berkeley, CA, USA). A comparative analysis between two groups was conducted and Mann–Whitney's U-test and analysis of variance (ANOVA) post hoc test (Scheffe's F) was used for group comparisons. A P-value of less than 0.05 was considered significant.

Fluorescence in situ hybridization (FISH)

Using a locus-specific probe that targeted chromosome 1p36 (BAC clone RP11-219C24, GenoTechs, Tsukuba, Japan) labeled with SpectrumGreen (Nick Translation Kit, Vysis, Downers Grove, IL, USA) and a probe for the centromeric region of chromosome 1 labeled with SpectrumOrange (CEP1 (D1Z5); Vysis), we performed a FISH analysis on six of the seven cases. The cut-off value for 1p36/CEP1 was <0.7.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

Immunohistochemistry

On immunohistochemistry, whereas GFAP was only able to label small numbers of OLCs, galectin 3 was able to label the nuclei and cytoplasm of occasional OLCs, although their numbers did vary from case to case (Fig. 2). While Olig2 was diffusely and consistently positive for OLCs in all cases, immunolabelling of Nkx 2.2 varied from weakly focally positive to moderately diffusely positive. PDGFRα was positive for small numbers of OLCs (Fig. 3). The background for specific glioneuronal elements was PDGFRα-positive. Regarding the neuronal markers, NeuN labeled the medium to large cells. In addition, synaptophysin and CD56 displayed background immunoreactivities (Fig. 4). The floating neurons exhibited no epiperikaryal immunoreactivity for synaptophysin, which is the accepted characteristic marker for neoplastic neurons in the cerebral cortex. For stem cell markers, we applied nestin, CD34 and EAAT 2 (Fig. 5). However, only nestin was convincingly positive for the cytoplasm of the OLCs.

figure

Figure 2. A specific glioneuronal element expressing astrocytic markers. GFAP is positive for the medium cells whereas galectin 3 is positive for some small cells. Case1 (A, D, G), case 3 (B, E, H) and case 4 (C, F, I). GFAP (D, E, F) and galectin 3 (G, H, I). Scale bar = 100 μm.

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figure

Figure 3. A specific glioneuronal element expressing antigens for oligodendroglioma. While oligodendrocyte transcription factor 2 (Olig2) is diffusely positive for oligodendroglia-like cells (OLCs), homeobox protein Nkx 2.2 (Nkx 2.2) and platelet-derived growth factor receptor α (PDGFRα) are weakly focally positive. Case1 (A, D, G), case 3 (B, E, H) and case 4 (C, F, I). Olig2 (A, B, C), Nkx 2.2 (D, E, F) and PDGFRα (G, H, I). Scale bar = 100 μm.

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figure

Figure 4. A specific glioneuronal element expressing neuronal markers. Neuronal nuclear antigen (NeuN) is positive for the medium to large cells. Synaptophysin and CD56 is only positive for the background. Case1 (A, D, G), case 3 (B, E, H) and case 4 (C, F, I). NeuN (A, B, C), synaptophysin (D, E, F) and CD56 (G, H, I). Scale bar = 100 μm.

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figure

Figure 5. A specific glioneuronal element expressing stem cell markers. Nestin is positive for the oligodendroglia-like cells (OLCs) whereas CD34 for the endothelial cells and excitatory amino acid transporter 1 (EAAT1) for the background. Case 1 (A, D, G), case 3 (B, E, H) and case 4 (C, F, I). Nestin (A, B, C), CD34 (D, E, F) and EAAT2 (G, H, I). Scale bar = 100 μm.

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We next quantified the positive rate for nuclear antigens in OLCs (Table 2). Galectin 3, an astrocytic marker, varied 0.7% to 24% on a case-to-case basis. On average, galectin 3 was positive in 10% of the OLCs. Olig2 was diffusely positive with a positive rate of 88%. On the other hand, NeuN-positive OLCs were rare, exhibiting a positive rate of only 0.7%. To further characterize OLCs and floating neurons, we performed double fluorescent immunohistochemistry (Fig. 6). For this procedure, we first confirmed that galectin 3 colocalized with GFAP in the cytoplasm and the processes of astrocytes (figures not shown). Galectin 3 also labeled the nuclei of astrocytes. While galectin 3 and Olig2 were colocalized in the nuclei of the OLCs, both NeuN and Olig2 were mutually exclusive. In general, the number of NeuN-positive cells was greater than that of floating neurons, with NeuN-positive nuclei being found to be much larger than Olig2-positive nuclei.

figure

Figure 6. Double-labeling immunofluorescent staining. Oligodendroglia-like cells (OLCs) are double-labeled by galectin 3 (green) and oligodendrocyte transcription factor 2 (Olig2) (red) (A) while no cells are double-labeled by neuronal nuclear antigen (NeuN) antibody (green) and Olig2 (red) (B). Note NeuN-positive cells are larger than Olig2-positive cells (B). Scale bar = 50 μm.

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Table 2. Positive rates for nuclear antigens in oligodendroglia-like cells
CaseGalectin 3Olig2Nkx 2.2NeuN
  1. Olig2, oligodendrocyte transcription factor 2; Nkx 2.2, homeobox protein Nkx 2.2; NeuN, neuronal nuclear antigen.

10.110.800.570.003
20.020.930.820.005
30.040.830.480.011
40.100.930.770.006
50.140.890.560.006
60.24weakweak0.017
70.0070.88weak0.000
mean0.100.880.640.007

Qualitative and quantitative observations

Sections cut perpendicular to the cortex were selected for evaluation. In such sections, the specific glioneuronal elements were embedded within the surface of the cortex and the NeuN-positive cells appeared to be sparser in the center compared to that seen in the periphery of the lesion. In addition, the NeuN-positive cells possessed a continuous laminar arrangement that was continuous with the adjacent cortex (Fig. 7). In contrast, a specific glioneuronal element within the white matter contained no NeuN-positive cells (Fig. 8).

figure

Figure 7. A section cut perpendicular to the cortex stained with neuronal nuclear antigen (NeuN) showing a continuous laminar arrangement that was continuous with the adjacent cortex. Scale bar = 200 μm.

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Figure 8. A specific glioneuronal element in the white matter with mucoid-matrix (A) (KB stain). No neuronal nuclear antigen (NeuN)-positive neurons are present (B). Scale bar = 200 μm.

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For the quantitative analysis, we measured the density of the NeuN-positive cells in the specific glioneuronal elements within the cortex and those within the white matter (Table 3). As a control, we also measured the cells in the adjacent cortex. The density of the NeuN-positive cells in the specific glioneuronal elements in the cortical area was 35% compared to the density of the NeuN-positive cells found in the adjacent normal cortex. In contrast, the density of the NeuN-positive cells in the specific glioneuronal elements in the white matter was only 2.6%. These differences were statistically significant.

Table 3. Density of the neuronal nuclear antigen-positive cells in the specific glioneuronal elements within the cortex and those within the white matter
CaseElements/cortexElements/WMAdjacent cortex
  1. *P < 0.001, **P < 0.0001, NA, not available, ANOVA post hoc test (Scheffe's F), WM, white matter.

15.6 ± 2.0NA8.8 ± 3.6
23.0 ± 1.41.0 ± 1.222 ± 11
318 ± 2.7NA26 ± 5.2
46.6 ± 1.5NA12 ± 5.9
55.0 ± 2.10.6 ± 0.514 ± 6.0
65.0 ± 1.60.2 ± 0.511 ± 2.9
73.5 ± 2.40.2 ± 0.433 ± 3.5
mean6.41 ± 5.16*0.47 ± 0.70**18.1 ± 10.9

Morphometry

In order to confirm that the floating neurons are NeuN-positive, we decolorized representative sections with HE and then performed NeuN immunohistochemistry on the same section (Fig. 9). All of floating neurons were NeuN-positive and some OLCs were also positive for NeuN. We next manually traced the captured images of the nuclei of the NeuN-positive cells and then converted the traces into binary images (Fig. 10), which were analyzed using an image analysis system. The mean value and standard deviation of the area of the NeuN-positive nuclei in these elements were identical to those of the nuclei in the adjacent cortex (Table 4). However, the perimeters of the nuclei were significantly shorter in the areas in the elements. In addition, the circulatory factor, which represents the roundness of nuclei, was significantly larger in these elements.

figure

Figure 9. A HE section (A) was decolorized and then performed neuronal nuclear antigen (NeuN) immunohistochemistry (B). The floating neurons in A are all positive for NeuN (arrows). Small ganglion cells in the matrix do not have any cytological atypia. Note some of oligodendroglia-like cells (OLCs) are also NeuN-positive. Scale bar = 50 μm.

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figure

Figure 10. Representative views of neuronal nuclear antigen (NeuN) (A) and oligodendrocyte transcription factor 2 (Olig2)- (C) positive cells and their manually converted traces, respectively (B, D). Scale bar = 100 μm.

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Table 4. Morphometry of the neuronal nuclear antigen-positive nuclei in specific glioneuronal elements and those of nuclei in adjacent cortex
 Elements/cortexAdjacent cortex
  1. *P < 0.0001, Mann–Whitney U-test.

Area21.0 ± 4.8821.1 ± 4.05
Perimeter30.2 ± 7.79*35.7 ± 8.41
Circularity factor0.27 ± 0.06*0.19 ± 0.04
Maximum length10.7 ± 2.42*12.6 ± 2.49
Length/breadth1.27 ± 0.201.31 ± 0.25
Direction88.2 ± 62.977.7 ± 62.9

Next, we performed morphometry on the nuclear areas of the Olig2-positive cells. The area of the NeuN-positive nuclei was approximately two times greater than that of the Olig2-positive nuclei (Fig. 11). This difference was statistically significant. In addition, the areas of the NeuN- and Olig2-positive nuclei exhibited some notable overlap.

figure

Figure 11. Distribution of nuclear areas of the oligodendrocyte transcription factor 2 (Olig2)-positive and neuronal nuclear antigen (NeuN)-positive cells. The nuclear areas of NeuN-positive cells are significantly larger than those of Olig2-positive cells (Mann–Whitney U-test).

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FISH

All six of the cases studied were 1p loss-negative (figures not shown).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

Previous studies have shown that small numbers of OLCs exhibit neuronal differentiation.[15] However, the exact morphological differences between OLCs and neurocytes remain controversial. OLCs exhibit non-specific ultrastructural features and round, heterochromatic nuclei. Intracytoplasmic organelles are poor. Microtubules but not intermediate filaments are seen.[15] Oligodendrogliomas with the chromosome 1p/19q codeletion exhibit identical features.[16] The nucleus is heterochromatic and the cytoplasm contains mitochondria, a small rough endoplasmic reticulum (ER) and ribosomes, as well as a few microtubules. The neurocytes contain a small rough ER and are rich in mitochondria; however, direct synaptic attachments on the cell surface are rarely seen.

In general, ganglion cells are regarded as being part of the tumor when they exhibit atypia. Daumas-Duport listed two reasons why floating neurons that lack atypia are not entrapped pre-existing neurons.[8] First, no cytological variations are seen within normal cortical neurons. Second, these neurons are always present in the subcortical white matter. Since the nuclear size generally correlates with the cytoplasmic size, our morphometric study indicated that the neurons in the specific glioneuronal element possessed cytological variations that are also seen in normal cortical neuron and that they were same in size but rounder compared to normal neurons. In addition, floating neurons were absent or extremely rare in DNT lesions involving the subcortical white matter in our study. Moreover, Miyanaga reported a case of DNT that extended into the subarachnoid space.[17] In that case, no floating neurons were identified in the specific glioneuronal element within the subarachnoid space. These observations strongly suggest that Daumas-Duport's theory might indeed not be a valid assumption. Based on the above results, particularly the fact that Olig2 and NeuN are mutually exclusive, we naturally came to the conclusion that the NeuN-positive small and large cells observed within the element are in fact entrapped granular and pyramidal cells within the cortex. We also concluded that OLCs are essentially glial and not neuronal in nature. If our assumption is correct, then DNT might very well be pure glial tumors as opposed to glioneuronal tumors. Although OLCs lack both 1p/19 loss[18] and PDGFRα overexpression[19] which are characteristic features in oligodendrogliomas, OLCs otherwise share a common phenotype with oligodendrogliomas.

In conclusion, our results suggest that DNTs are more akin to oligodendroglioma than glioneuronal tumors, although their biological and genetic nature is clearly distinguishing form oligodendroglioma. In the WHO 2007 Classification of Tumors, astrocytomas are essentially divided into non-infiltrating astrocytomas, grade I and infiltrating astrocytomas, grades II–IV. If this scheme is adapted for DNT, DNT can be classified as non-infiltrating oligodendroglioma, grade I. In order to further clarify these controversial issues regarding DNT, it is necessary to perform a much more strict epigenetic characterization of floating neurons.

Acknowledgment

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

We thank Dr. Takanori Hirose (Saitama Medical University; presently, Tokushima Prefectural Central Hospital) for FISH testing and Dr. Hiroyoshi Suzuki (NHO Sendai Medical Center) for their valuable comments and discussion.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References
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    Miyanaga T, Hirato J, Sasaki A et al. A case of dysembryoplastic neuroepithelial tumor (DNT), complex form, involving the subarachnoid space. Neuropathology 2006; 26: A17.
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    Jenkins RB, Blair H, Ballman KV et al. A t(1;19)(q10;p10) mediates the combined deletions of 1p and 19q and predicts a better prognosis of patients with oligodendroglioma. Cancer Res 2006; 66: 98529861.
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