Intranasal Administration of Undifferentiated Oligodendrocyte Lineage Cells as a Potential Approach to Deliver Oligodendrocyte Precursor Cells into Brain.

Oligodendrocyte precursor cell (OPC) migration is a mechanism involved in remyelination; these cells migrate from niches in the adult CNS. However, age and disease reduce the pool of OPCs; as a result, the remyelination capacity of the CNS decreases over time. Several experimental studies have introduced OPCs to the brain via direct injection or intrathecal administration. In this study, we used the nose-to brain pathway to deliver oligodendrocyte lineage cells (human oligodendroglioma (HOG) cells), which behave similarly to OPCs in vitro. To this end, we administered GFP-labelled HOG cells intranasally to experimental animals, which were subsequently euthanised at 30 or 60 days. Our results show that the intranasal route is a viable route to the CNS and that HOG cells administered intranasally migrate preferentially to niches of OPCs (clusters created during embryonic development and adult life). Our study provides evidence, albeit limited, that HOG cells either form clusters or adhere to clusters of OPCs in the brains of experimental animals.

H3K27me3 immunostaining is diagnostic and prognostic in diffuse gliomas with oligodendroglial or mixed oligoastrocytic morphology.

Oligodendroglioma is defined by IDH mutation and 1p/19q codeletion. The latter is mutually exclusive to ATRX immunohistochemical loss and has been recently associated with the loss of H3K27me3 immunostaining. We aimed to assess the diagnostic and prognostic value of H3K27me3 immuno-expression in diffuse gliomas with oligodendroglial or mixed oligoastrocytic morphology. H3K27me3 immunostaining was performed in 69 diffuse gliomas with oligodendroglial (n = 62) or oligoastrocytic (n = 7) morphology. The integration with routinely assessed IDH mutations, ATRX immunostaining, and 1p/19q codeletion classified these cases as 60 oligodendroglial and 9 astrocytic. H3K27me3 was lost in 58/60 oligodendrogliomas with retained (n = 47) or non-conclusive (n = 11) ATRX staining, 3/6 IDH-mutant astrocytomas with ATRX loss, and 3/3 IDH-wt astrocytomas. H3K27me3 was retained in 2/60 oligodendrogliomas with retained ATRX, and in 3/6 IDH-mutant astrocytomas, two of which had lost and one retained ATRX. The combination of H3K27me3 and ATRX immunostainings with IDH mutational status correctly classified 55/69 (80%) cases. In IDH-mutant gliomas, ATRX loss indicates astrocytic phenotype, while ATRX retention and H3K27me3 loss identify oligodendroglial phenotype. Only 14 (20%) IDH-mutant cases with retained ATRX and H3K27me3 or inconclusive ATRX immunostaining would have requested 1p/19q codeletion testing to be classified. Furthermore, H3K27me3 retention was associated with significantly shorter relapse-free survival (P < 0.0001), independently from IDH mutation or 1p/19q codeletion (P < 0.005). Our data suggest that adding H3K27me3 immunostaining to the diagnostic workflow of diffuse gliomas with oligodendroglial or mixed morphology is useful for drastically reducing the number of cases requiring 1p/19q codeletion testing and providing relevant prognostic information.

Extent of resection, molecular signature, and survival in 1p19q-codeleted gliomas.

OBJECTIVE: Genomic analysis in neurooncology has underscored the importance of understanding the patterns of survival in different molecular subtypes within gliomas and their responses to treatment. In particular, diffuse gliomas are now principally characterized by their mutation status (IDH1 and 1p/19q codeletion), yet there remains a paucity of information regarding the prognostic value of molecular markers and extent of resection (EOR) on survival. Furthermore, given the modern emphasis on molecular rather than histological diagnosis, it is important to examine the effect of maximal resection on survival in all gliomas with 1p/q19 codeletions, as these will now be classified as oligodendrogliomas under the new WHO guidelines. The objectives of the present study were twofold: 1) to assess the association between EOR and survival for patients with oligodendrogliomas in the National Cancer Database (NCDB), which includes information on mutation status, and 2) to demonstrate the same effect for all patients with 1p/19q codeleted gliomas in the NCDB. METHODS: The NCDB was queried for all cases of oligodendroglioma between 2004 and 2014, with follow-up dates through 2016. The authors found 2514 cases of histologically confirmed oligodendrogliomas for the final analysis of the effect of EOR on survival. Upon further query, 1067 1p/19q-codeleted tumors were identified in the NCDB. Patients who received subtotal resection (STR) or gross-total resection (GTR) were compared to those who received no tumor debulking surgery. Univariable and multivariable analyses of both overall survival and cause-specific survival were performed. RESULTS: EOR was associated with increased overall survival for both histologically confirmed oligodendrogliomas and all 1p/19q-codeleted-defined tumors (p < 0.001 and p = 0.002, respectively). Tumor grade, location, and size covaried predictably with EOR. When evaluating tumors by each classification system for predictors of overall survival, facility setting, age, comorbidity index, grade, location, chemotherapy, and radiation therapy were all shown to be significantly associated with overall survival. STR and GTR were independent predictors of improved survival in historically classified oligodendrogliomas (HR 0.83, p = 0.18; HR 0.69, p = 0.01, respectively) and in 1p/19q-codeleted tumors (HR 0.49, p < 0.01; HR 0.43, p < 0.01, respectively). CONCLUSIONS: By using the NCDB, the authors have demonstrated a side-by-side comparison of the survival benefits of greater EOR in 1p/19q-codeleted gliomas.

Oligodendroglial cell proliferation arising in an ovarian mature cystic teratoma. Clinicopathological, inmunohistochemical, and ultrastructural study of a case that may represent an oligodendroglioma.

Ovarian mature cystic teratoma (OMCT) is an ovarian benign neoplasm with excellent prognosis presenting components of the three germinal layers. However, transformation into a malignant neoplasm is a rare event (so-called somatic transformation). In most of the cases, the malignant component expresses as epidermoid carcinoma, but occasionally central nervous system tumors occur. Some of the previously reported tumors are astrocytoma, glioblastoma, and ependymoma. Somatic transformation of OMCT into an oligodendroglioma is exceptional. We report a 19-year-old female with a left OMCT with an area of oligonedroglial cells proliferation characterized by immunohistochemical studies with positivity for GFAP and S100, with a low Ki67 index (5%). Additionally, electron microscopy revealed oligodendrocytes with parallel bundles of cytoplasmic intermediate filaments, confirming the oligodendroglial nature of the proliferation. The patient was treated only with left oophorectomy, and three and half years after surgery, there is no evidence of disease.

Clinical multiplexed exome sequencing distinguishes adult oligodendroglial neoplasms from astrocytic and mixed lineage gliomas.

Classifying adult gliomas remains largely a histologic diagnosis based on morphology; however astrocytic, oligodendroglial and mixed lineage tumors can display overlapping histologic features. We used multiplexed exome sequencing (OncoPanel) on 108 primary or recurrent adult gliomas, comprising 65 oligodendrogliomas, 28 astrocytomas and 15 mixed oligoastrocytomas to identify lesions that could enhance lineage classification. Mutations in TP53 (20/28, 71%) and ATRX (15/28, 54%) were enriched in astrocytic tumors compared to oligodendroglial tumors of which 4/65 (6%) had mutations in TP53 and 2/65 (3%) had ATRX mutations. We found that oligoastrocytomas harbored mutations in TP53 (80%, 12/15) and ATRX (60%, 9/15) at frequencies similar to pure astrocytic tumors, suggesting that oligoastrocytomas and astrocytomas may represent a single genetic or biological entity. p53 protein expression correlated with mutation status and showed significant increases in astrocytomas and oligoastrocytomas compared to oligodendrogliomas, a finding that also may facilitate accurate classification. Furthermore our OncoPanel analysis revealed that 15% of IDH1/2 mutant gliomas would not be detected by traditional IDH1 (p.R132H) antibody testing, supporting the use of genomic technologies in providing clinically relevant data. In all, our results demonstrate that multiplexed exome sequencing can support evaluation and classification of adult low-grade gliomas with a single clinical test.

WT1 expression increases with malignancy and indicates unfavourable outcome in astrocytoma.

AIMS: The zinc finger transcription factor WT1 is expressed in astrocytic neoplasms and therefore is a potential target of immunotherapy in brain tumours. Our aim was to further elucidate the role of WT1 as a diagnostic and prognostic marker in neuropathology, particularly as to the differentiation of astrocytoma from oligodendroglioma as well as to the dependency of WT1 expression on clinically relevant parameters. METHODS: 829 evaluable brain tumour samples were investigated by WT1 immunohistochemistry on full tissue routine slides, consisting of 442 glioblastomas, 303 astrocytomas, 41 oligodendrogliomas and 43 oligoastrocytomas. In addition public WT1 gene expression data of 351 gliomas were analysed. RESULTS: Our data show that WT1 expression in diffuse astrocytic tumours increases with WHO tumour grade and is associated with older age, absence of IDH1 mutation but not related to O(6)- methyl guanine methyl transferase (MGMT) promoter methylation status. Univariable, but not multivariable survival analysis indicates that WT1 expression is associated with worse outcome in patients with diffuse astrocytoma but not glioblastoma. CONCLUSIONS: The significant WT1 expression differences between diffuse astrocytomas, oligoastrocytomas and oligodendrogliomas, which are also present in the Repository for Molecular Brain Neoplasia Data, National Cancer Institute (REMBRANDT, 2005, http://rembrandt.nci.nih.gov) gene database set, provide a rationale for use of WT1 as part of a routine immunohistochemistry panel.

Well-differentiated pediatric glial neoplasms with features of oligodendroglioma, angiocentric glioma and dysembryoplastic neuroepithelial tumors: a morphological diagnostic challenge.

OBJECTIVE: Oligodendrogliomas are rare in the pediatric population, and most oligodendroglioma-like tumors in this age group may belong to other entities. In addition, accurate diagnosis and grading of such lesions using criteria developed for adult oligodendrogliomas prove difficult, and often controversial. MATERIAL AND METHOD: During a study of tumors previously diagnosed as pediatric oligodendroglioma, we identified four tumors displayed features of that resembled oligodendroglioma, angiocentric glioma and dysembryoplastic neuroepithelial tumor but could not be classified as either one of these entities. Ther clinical, histological and immunohistochemical features of these cases were investigated in this study. RESULTS: Two male (both 9 years old) and two female (ages 4 years and 20 months) patients presented with new onset of seizures. All patients were treated surgically, and two required reoperation. Histologically, the tumors were well-differentiated glial neoplasms with focal angiocentric pattern, delicate vascularity, diffuse growth, infiltrative margins, cortical nodules, focal myxoid areas, and leptomeningeal extension. Immunohistochemical studies showed diffuse nuclear positivity with Olig-2 and GFAP antibodies, whereas staining with neuronal markers, EMA, p53, and IDH1 were negative. Fluorescent in-situ hybridization analysis demonstrated intact 1p/19q in all tumors, and there was no ultrastructural evidence of ependymal differentiation. All patients were alive with disease with a mean follow-up of 112 months. CONCLUSION: These four cases illustrate the morphological diversity of well-differentiated, oligodendroglioma-like glial neoplasms and the uncertainty in their classification among pediatric tumors.

Ambient mass spectrometry for the intraoperative molecular diagnosis of human brain tumors.

The main goal of brain tumor surgery is to maximize tumor resection while preserving brain function. However, existing imaging and surgical techniques do not offer the molecular information needed to delineate tumor boundaries. We have developed a system to rapidly analyze and classify brain tumors based on lipid information acquired by desorption electrospray ionization mass spectrometry (DESI-MS). In this study, a classifier was built to discriminate gliomas and meningiomas based on 36 glioma and 19 meningioma samples. The classifier was tested and results were validated for intraoperative use by analyzing and diagnosing tissue sections from 32 surgical specimens obtained from five research subjects who underwent brain tumor resection. The samples analyzed included oligodendroglioma, astrocytoma, and meningioma tumors of different histological grades and tumor cell concentrations. The molecular diagnosis derived from mass-spectrometry imaging corresponded to histopathology diagnosis with very few exceptions. Our work demonstrates that DESI-MS technology has the potential to identify the histology type of brain tumors. It provides information on glioma grade and, most importantly, may help define tumor margins by measuring the tumor cell concentration in a specimen. Results for stereotactically registered samples were correlated to preoperative MRI through neuronavigation, and visualized over segmented 3D MRI tumor volume reconstruction. Our findings demonstrate the potential of ambient mass spectrometry to guide brain tumor surgery by providing rapid diagnosis, and tumor margin assessment in near-real time.

GFAP-positive neoplastic astrocytes in spontaneous oligodendrogliomas and mixed gliomas of rats.

It is generally said that neoplastic cells are immunohistochemically negative for glial fibrillary acidic protein (GFAP) in rat spontaneous astrocytomas, and there are no reports describing the existence of GFAP-positive neoplastic astrocytes in rat spontaneous oligodendrogliomas and mixed gliomas which contain neoplastic astrocytes. In the present study, to clarify whether GFAP-positive neoplastic astrocytes exist in rat spontaneous oligodendrogliomas and mixed gliomas or not, immunohistochemical examination was performed on spontaneous oligodendrogliomas (26 cases) and mixed gliomas (5 cases) collected from the carcinogenicity studies and short-term toxicity studies. The neoplastic cells that constitute oligodendrogliomas and mixed gliomas were morphologically classified into five types: round A, round B, round C, spindle, and bizarre. The cells of round A, B, and C types were thought to be neoplastic oligodendrocytes because of their positive immunostainability for Olig2.  The origin of bizarre cells was obscure because they were negative for Olig2, GFAP, and nestin. The spindle cells were considered to be neoplastic astrocytes, because some of them were positive for GFAP or nestin, and GFAP-positive spindle cells could be morphologically distinguished from reactive astrocytes.  In conclusion, the present study clarified for the first time that GFAP-positive neoplastic astrocytes exist in rat spontaneous gliomas.

[Guidelines for adult diffuse gliomas WHO grade II, III and IV: pathology and biology. Société franc¸aise de neuropathologie . Réseau de neuro-oncologie pathologique]. / Référentiel gliomes diffus de l'adulte de grade OMS II, III et IV : anatomie pathologique et biologie.

Pathological diagnosis plays a major role in the therapeutic management of adult diffuse gliomas. It is based on the histopathological analysis of a representative specimen. Therefore pathologists might be aware of the neuroradiological features of the lesions. Pathologists play a major role in the management of biological resources. Pathologists should classify adult gliomas according to WHO 2007 classification (histological subtype and grade). In addition, in order to provide the histomolecular classification of adult gliomas, search for molecular markers of diagnostic, prognostic or predictive of therapeutic responses must be performed by appropriate and validated immunohistochemical and molecular techniques. In all diffuse gliomas, whatever their grade, search for IDH1 R132H and P53 expression is required. Search for IDH1 minor mutations and IDH2 mutations is required in grade II and III IDH1 R132H negative gliomas whereas 1p19q codeletion should be searched for in grade II and III gliomas with an oligodendroglial component. Search for EGFR amplification and MGMT promoter methylation is recommended. It is strongly recommended to fill the standardized form for pathology and molecular features (validated by the French Society of Neuropathology) in all adult diffuse gliomas.

Selection of DNA aptamers against glioblastoma cells with high affinity and specificity.

BACKGROUND: Glioblastoma is the most common and most lethal form of brain tumor in human. Unfortunately, there is still no effective therapy to this fatal disease and the median survival is generally less than one year from the time of diagnosis. Discovery of ligands that can bind specifically to this type of tumor cells will be of great significance to develop early molecular imaging, targeted delivery and guided surgery methods to battle this type of brain tumor. METHODOLOGY/PRINCIPAL FINDINGS: We discovered two target-specific aptamers named GBM128 and GBM131 against cultured human glioblastoma cell line U118-MG after 30 rounds selection by a method called cell-based Systematic Evolution of Ligands by EXponential enrichment (cell-SELEX). These two aptamers have high affinity and specificity against target glioblastoma cells. They neither recognize normal astraglial cells, nor do they recognize other normal and cancer cell lines tested. Clinical tissues were also tested and the results showed that these two aptamers can bind to different clinical glioma tissues but not normal brain tissues. More importantly, binding affinity and selectivity of these two aptamers were retained in complicated biological environment. CONCLUSION/SIGNIFICANCE: The selected aptamers could be used to identify specific glioblastoma biomarkers. Methods of molecular imaging, targeted drug delivery, ligand guided surgery can be further developed based on these ligands for early detection, targeted therapy, and guided surgery of glioblastoma leading to effective treatment of glioblastoma.

Evaluation of the expression of C-kit (CD117) in ependymomas and oligodendrogliomas.

C-kit is a proto-oncogene located on the long arm of chromosome 4. Its product, CD117, is a specific immunohistochemical (IHQ) marker that is associated with response to a potent tyrosine kinase inhibitor therapy with STI-571 (Gleevec®) in chronic myelogenous leukemia and GISTs. In our study, we aimed to evaluate the expression of CD117 in glial tumors as this finding may guide therapeutic approaches for these brain tumors. Ependymomas and oligodendrogliomas, in formalin fixed and paraffin embedded blocks were assayed for CD117 immunoreactivity using anti-c-kit (CD117, DAKO). GISTs were used as positive control. We observed immunoreactivity of CD117 protein in 25.5% of tumors in both histological types. In oligodendrogliomas, there was an association between older age at diagnosis and positivity for CD117 (P=0.039). In addition, we observed an association between higher tumor grade (grade III) and positivity for CD117 (P=0.007). No clinical association was observed in ependymomas (P>0.05). This study encourages further investigations, considering that CD117 may be a possible oncogenic factor in some glial tumors. In this case, tumors that express this marker may eventually benefit from a therapy with selective inhibitors of receptor kinases.

First step toward the "fingerprinting" of brain tumors based on synchrotron radiation X-ray fluorescence and multiple discriminant analysis.

Synchrotron-radiation-based X-ray fluorescence was applied to the elemental microimaging of neoplastic tissues in cases of various types of brain tumors. The following cases were studied: glioblastoma multiforme, gemistocytic astrocytoma, oligodendroglioma, anaplastic oligodendroglioma, ganglioglioma, fibrillary astrocytoma, and atypical transitional meningioma. Apart from neoplastic tissue, the analysis included areas of tissue apparently without malignant infiltration. The masses per unit area of P, S, Cl, K, Ca, Fe, Cu, Zn, Br, and Rb were used to construct a diagnostic classifier for brain tumors using multiple discriminant analysis. It was found that S, Cl, Cu, Fe, K, Br, and Zn are the most significant elements in the general discrimination of tumor type. The highest similarity in elemental composition was between atypical transitional meningioma and fibrillary astrocytoma. The smallest differentiation was between glioblastoma multiforme and oligodendroglioma. The mean percentage of correct classifications, estimated according to the a posteriori probabilities procedure, was 99.9%, whereas the mean prediction ability of 87.6% was achieved for ten new cases excluded previously from the model construction. The results showed that multiple discriminant analysis based on elemental composition of tissue may be a potentially valuable method assisting differentiation and/or classification of brain tumors.

Low-grade oligodendroglioma of the pineal gland: a case report and review of the literature.

BACKGROUND: Gliomas are a very rare subtype of pineal region tumours, whereas oligodendrogliomas of the pineal region are exceedingly rare, since there have been only 3 cases of anaplastic oligodedrogliomas reported this far. METHODS-RESULTS: We present a case of a low-grade oligodendroglioma arising in the pineal gland of a 37 year-old woman. The patient presented with diplopia associated with a cystic pineal region mass demonstrated on MRI. Total resection was performed and histological examination showed that the cystic wall consisted of tumour cells with a central nucleus a perinuclear halo and minimal pleomorphism. Immnunohistochemical analysis showed that these cells were diffusely positive for CD57, and negative for GFAP, CD10, CD99, cytokeratins, neurofilaments and synaptophysin. FISH analysis was performed in a small number of neoplastic cells, which were not exhausted after immunohistochemistry and did not reveal deletion of 1p and 19q chromosome arms. However, the diagnosis of a low grade oligodendroglioma of the pineal gland was assigned. CONCLUSION: Although the spectrum of tumours arising in the pineal gland is broad, the reports of oligodendrogliomas confined to this location are exceedingly rare, and to the best of our knowledge there is no report of a low-grade oligodendroglioma. However, they should be added in the long list of tumours arising in the pineal gland.

Leptomeningeal dissemination of a pediatric neoplasm with 1p19q deletion showing mixed immunohistochemical features of an oligodendroglioma and neurocytoma.

Leptomeningeal dissemination of an oligodendroglioma is rarely reported in the neurosurgical literature, especially in cases with a classical 1p19q deletion. The authors describe a case wherein a 1p19q deletion in a disseminated tumor with mixed immunohistochemical features of oligodendroglioma and neurocytoma was encountered and treated. Stereotactic right frontal craniotomy was undertaken for obtaining definitive histological diagnosis. The results revealed a neuroectodermal neoplasm with histologic and immunohistochemical features of oligodendroglioma and neurocytoma. FISH analysis confirmed classical 1p19q deletion. The patient was treated postoperatively with chemotherapy and radiation therapy. He showed good clinical response and remains alive 16 months after diagnosis.

Comparative analysis of annexin-1 in neuroepithelial tumors shows altered expression with the grade of malignancy but is not associated with survival.

In various types of cancer, the expression of members of the annexin family of calcium- and phospholipid-binding anti-inflammatory proteins is dysregulated. Annexin-1 (ANXA1, lipocortin-1) is involved in proliferation, differentiation and apoptosis. It serves as a substrate for the epidermal growth factor receptor (EGFR), which is frequently amplified in primary gliomas. It is unclear how annexin-1 is expressed in various neuroepithelial tumors, and whether there is any association with tumor malignancy or survival. We studied annexin-1 expression in 394 glial neoplasms of all grades of malignancy and 81 normal brain samples by immunohistochemistry using tissue microarrays. The results were validated using western blot and reverse transcription-PCR (RT-PCR). In the normal human brain, the expression of annexin-1 is limited to ependymal cells and subependymal astrocytes, but is also upregulated in reactive astrocytes. Ependymomas and astrocytomas showed significantly higher mean annexin-1 expression levels in the cytoplasm compared with oligodendrogliomas (both: P<0.0001). In addition, nuclear staining of annexin-1 in oligodendroglial tumor cells was significantly reduced (P=0.0002), which may be used as a diagnostic tool for differentiating between astrocytomas and oligodendrogliomas. Although annexin-1 expression in ependymomas decreased with the grade of malignancy, diffuse astrocytomas showed a significant increase in cytoplasmic annexin-1-positive tumor cells. However, survival analysis showed that the expression of annexin-1 is not associated with patient survival. Similar to the EGFR amplification profile, primary glioblastomas had a higher annexin-1 expression level compared with secondary glioblastomas. Thus, annexin-1 upregulation in astrocytomas may contribute to tumor progression and its expression profile is similar to its substrate, EGFR, suggesting a possible regulation thereof.

Characterization of the MAL2-positive compartment in oligodendrocytes.

Oligodendrocytes (OLs), the myelin-producing cells of the central nervous system, segregate different surface subdomains at the plasma membrane as do other differentiated cells such as polarized epithelia and neurons. To generate the complex membrane system that characterizes myelinating OLs, large amounts of membrane proteins and lipids need to be synthesized and correctly targeted. In polarized epithelia, a considerable fraction of apical proteins are transported by an indirect pathway involving a detour to the basolateral membrane before being internalized and transported across the cell to the apical membrane by a process known as transcytosis. The apical recycling endosome (ARE) or its equivalent, the subapical compartment (SAC), of hepatocytes is an intracellular trafficking station involved in the transcytotic pathway. MAL2, an essential component of the machinery for basolateral-to-apical transcytosis, is an ARE/SAC resident protein. Here, we show that, after differentiation, murine oligodendrocyte precursor and human oligodendroglioma derived cell lines, Oli-neu and HOG, respectively, up-regulate the expression of MAL2 and accumulate it in an intracellular compartment, exhibiting a peri-centrosomal localization. In these oligodendrocytic cell lines, this compartment shares some of the main features of the ARE/SAC, such as colocalization with Rab11a, sensitivity to disruption of the microtubule cytoskeleton with nocodazole, and lack of internalized transferrin. Therefore, we suggest that the MAL2-positive compartment in oligodendrocytic cells could be a structure analogous to the ARE/SAC and might have an important role in the sorting of proteins and lipids for myelin assembly during oligodendrocyte differentiation.

Oligodendrogliomas in relation to astrocytes differentiation. Clinicopathologic and immunohistochemical study.

Oligodendroglioma usually arise in adults and rarely in children. The objective of the current study was to evaluate the immunoexpression of glial fibrillary acidic protein (GFAP) and heat shock proteins (HSP70), endothelial vascular growth factor (EVGF), and endothilial vascular growth factor receptor type II (EFGF-R) expression in relation to the proliferation labeling index (proliferating cell nuclear antigen [PCNA]) and vascular density in patients with oligodendroglioma. We studied 28 cases of oligodendrogliomas--20 (71.4%) were oliodendrogliomas (grade II), and 8 (28.6%) cases were anaplastic oligodendroglioma (grade II according to World Health Organization classification). Eleven cases were male (39.28%) and 9 (32.14%) cases were female. Mitosis were found in grade II (0.35 +/- 1.14) and grade III (3.88 +/- 1.81) (P = .0001*) and pleomorphism in grade II (4.40 +/- 0.99) and grade III (9.50 +/- 9.20) (P = .028). The GFAP was positive in grade II (1.45 +/- 0.60) and grade III (2.63 +/- 0.52) (P = .000); HSP70 was immunoreactive in grade II (1.35 +/- 0.59) and grade III (2.50 +/- 0.53) (P = .001); and EVGF was immunoreactive in grade II (22.70 +/- 6.10) and grade III (36 +/- 1.63) (P = .043). The EVGF-RII was immunoreactive in grade II, 18.30 +/- 6.11 and 31.63 +/- 4.93 (P = .045). The microvascular density labeling index rates were 20.70 +/- 4.34 (grade II) and 33.38 +/- 5.29 (P = .000), and the PCNA labeling index rates were 32.95 +/- 5.89 (grade II) and 56.88 +/- 5.62 (grade III) (P = .045). We observed astrocyte differentiation in oligodendrogliomas grade III. We found a higher PGAF, HSP70, EVGF, and EFGF-R expression in relation with the PCNA and vascular density (CD34) in patients with oligodendroglioma grade III than in oligodendroglioma grade II. There was a significant relationship between mitosis, glial fibrillary acidic protein (GFAP), HSP70, EVGF, EVGF-receptor II expression, and the histologic grade and size of the tumor. For that reason, we suggest that the correlation between GFAP and HSP70 could have a relationship with the protection mechanism of the tumor itself.

Nogo-a expression in glial CNS tumors: a tool to differentiate between oligodendrogliomas and other gliomas?

Gliomas are the most frequent primary brain tumors. In a minority of cases, the differentiation between astrocytomas and oligodendrogliomas based on morphologic characteristics alone can be difficult; though it is important, as patients with oligodendrogliomas follow a more favorable clinical course. Here we report on the immunohistochemical expression pattern of the oligodendrocytic marker Nogo-A in 113 central nervous system tumors including 28 oligodendrogliomas [15, World Health Organization (WHO) grade II; 13, grade WHO III], 50 astrocytomas [10, grade WHO II; 11, grade WHO III; 29 glioblastoma multiforme (GBM)], 11 ependymomas WHO grade II, 7 central neurocytomas, 2 dysembryoplastic neuroepithelial tumors (DNTs), 5 clear cell meningiomas, and 10 metastases to the brain. The oligodendrocytic marker Nogo-A was found to be strongly expressed in 71% of oligodendrogliomas, but in 0% of ependymomas WHO grade II, astrocytomas WHO grade II or III, DNTs, central neurocytomas, or clear cell meningiomas. In GBM, a subgroup of tumors (24%) showed strong expression of Nogo-A coincidently with Ki67 positivity but glial fibrillary acidic protein-negativity. However, neither in oligodendrogliomas nor GBM was a correlation between the loss of 1p19q and the extent of Nogo-A expression observed. Our findings indicate that Nogo-A is strongly expressed in the majority of oligodendrogliomas and might be a helpful marker to distinguish oligodendrogliomas from astrocytomas WHO grades II and III as well as ependymomas. They also support the hypothesis that GBM may be a heterogeneous group of tumors derived from different progenitor cells.

Immunohistochemical and ultrastructural characterization of brain tumors in S100beta-v-erbB transgenic rats.

Transgenic rats expressing v-erbB (viral form of the EGF receptor) under transcriptional regulation by the S100beta promoter develop brain tumors (Ohgaki et al. J Neuropathol Experimental Neurol 65: 1111-1117, 2006). In the present study, we carried out detailed immunohistochemical and ultrastructural characterization of the brain tumors that developed in these rats. Of 49 homozygous transgenic rats between 16 and 94 weeks of age (mean, 59 weeks), 31 rats were autopsied because they showed severe neurological symptoms and/or became moribund. Among these, 30 rats had brain tumors, which were classified histologically as malignant glioma, anaplastic oligodendroglioma, and low-grade oligodendroglioma. Six transgenic rats developed two different histologic types of brain tumor, which were considered to be of multiclonal origin, because of the lack of histological transitions. All brain tumors contained neoplastic cells immunoreactive for S100 and GFAP. Diffuse immunoreactivity for Olig2 and Nkx2.2 was observed in neoplastic cells in all seven anaplastic oligodendrogliomas and in all three low-grade oligodendrogliomas analyzed, but in none of 26 malignant gliomas. Electron microscopy, carried out on four malignant gliomas and four anaplastic oligodendrogliomas, revealed the presence of intermediate filament bundles devoid of side arms, indicating glial differentiation. There was no evidence of cilia, microvilli, neurosecretory granules, synaptic structures or neurofilaments, excluding the possibility of ependymal or neuronal tumors. The present study thus provides additional evidence that the brain tumors developing in S100beta-v-erbB transgenic rats are of glial origin, with or without oligodendroglial differentiation. Reproducible development of three distinct histologic types of brain tumor in unique localizations may be explained by activation of the v-erbB transgene driven by the S100beta promoter in specific precursor cells during development of the brain. Thus, S100beta-v-erbB transgenic rats may be useful to study the histogenesis and molecular mechanisms of development of glial tumors due to disruption of the EGFR pathway.