Neoplastic Oligodendrocytes Research Articles

Intra- and Intertumoral Microglia/Macrophage Infiltration and Their Associated Molecular Signature Is Highly Variable in Canine Oligodendroglioma: A Preliminary Evaluation.

The goal of this study was to define the glioma-associated microglia/macrophage (GAM) response and associated molecular landscape in canine oligodendrogliomas. Here, we quantified the intratumoral GAM density of low- and high-grade oligodendrogliomas compared to that of a normal brain, as well as the intratumoral concentration of several known GAM-derived pro-tumorigenic molecules in high-grade oligodendrogliomas compared to that in a normal brain. Our analysis demonstrated marked intra- and intertumoral heterogeneity of GAM infiltration. Correspondingly, we observed significant variability in the intratumoral concentrations of several GAM-associated molecules, unlike what we previously observed in high-grade astrocytomas. However, high-grade oligodendroglioma tumor homogenates (n = 6) exhibited an increase in the pro-tumorigenic molecules hepatocyte growth factor receptor (HGFR) and vascular endothelial growth factor (VEGF), as we observed in high-grade astrocytomas. Moreover, neoplastic oligodendrocytes displayed robust expression of GAL-3, a chimeric galectin implicated in driving immunosuppression in human glioblastoma. While this work identifies shared putative therapeutic targets across canine glioma subtypes (HGFR, GAL-3), it highlights several key differences in the immune landscape. Therefore, a continued effort to develop a comprehensive understanding of the immune microenvironment within each subtype is necessary to inform therapeutic strategies going forward.

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.

Gliomatosis Cerebri and Pituitary Adenoma: Case Report and Literature Review

The diagnosis of Gliomatosis cerebri (GC) is known to be difficult and is still a matter of debate. We describe an in vivo case of GC associated with a pituitary tumor. A 47-year-old woman presented with short-term memory loss. A MRI revealed the presence of a pituitary enhancing tumor and a diffuse lesion involving the brain. A left pterional craniotomy with partial temporal lobectomy and removal of the pituitary lesion were performed in order to obtain diagnosis. The histological analyses showed a pituitary non-functioning tumor and a GC consisting of neoplastic oligodendrocytes and astrocytes. Both lesions showed nuclear immunoreactivity for progesterone receptors (PGr) and estrogen receptors (EGr). This result could suggest there is a common receptor substrate in these tumors. In this case hormones could constitute a common step in tumorigenesis of both lesions.

Id4 and FABP7 are preferentially expressed in cells with astrocytic features in oligodendrogliomas and oligoastrocytomas

BackgroundOligodendroglioma (ODG) and oligoastrocytoma (OAC) are diffusely infiltrating primary brain tumors whose pathogenesis remains unclear. We previously identified a group of genes whose expression was inversely correlated with survival in a cohort of patients with glioblastoma (GBM), and some of these genes are also reportedly expressed in ODG and OAC. We examined the expression patterns and localization of these survival-associated genes in ODG and OAC in order to analyze their possible roles in the oncogenesis of these two tumor types.MethodsWe used UniGene libraries derived from GBM and ODG specimens to examine the expression levels of the transcripts for each of the 50 GBM survival-associated genes. We used immunohistochemistry and cDNA microarrays to examine expression of selected survival-associated genes and Id4, a gene believed to control the timing of oligodendrocyte development. The expression of FABP7 and Id4 and the survival of patients with ODG and OAC were also analyzed.ResultsTranscripts of most survival-associated genes as well as Id4 were present in both GBM and ODG tumors, whereas protein expression of Id4 and one of the survival-associated genes, brain-type fatty acid-binding protein (FABP7), was present in cells with astrocytic features, including reactive and neoplastic astrocytes, but not in neoplastic oligodendrocytes. Id4 was co-expressed with FABP7 in microgemistocytes in ODG and in neoplastic astrocytes in OAC. Id4 and FABP7 expression, however, did not correlate with the clinical outcome of patients with ODG or OAC tumors.ConclusionExpression of Id4 and some of our previously identified GBM survival-associated genes is present in developing or mature oligodendrocytes. However, protein expression of Id4 and FABP7 in GBM, ODG, and OAC suggests that this group of functionally important genes might demonstrate two patterns of expression in these glioma subtypes: one group is universally expressed in glioma cells, and the other group of genes is expressed primarily in neoplastic astrocytes but not in neoplastic oligodendrocytes. Differential protein expression of these two groups of genes in ODG and OAC may be related to the cellular origins and the histological features of the neoplastic cells.

OLIG-1 and 2 gene expression and oligodendroglial tumours.

OLIG 1/2 genes encode basic helix-loop-helix transcription factors that play a critical role in motor neurone and oligodendrocyte fate specification during development. Two recent studies in which OLIG transcripts were detected by in situ hybridization have reported a high expression of the OLIG genes in oligodendrogliomas. This suggests that the detection of these lineage markers could become an adjunct to the classic morphological diagnosis of these tumours. There are problems in the diagnosis of oligodendroglioma. To date, all other known oligodendrocyte lineage markers have failed to label specifically neoplastic oligodendrocytes. Deletions on chromosome 1p and 19q are much more frequent in oligodendrogliomas than in astrocytomas but these molecular alterations are not constant. For the future, when routinely available, immunohistochemical techniques using anti-OLIG antibodies on paraffin embedded tissues will allow a systematic study of a large series of tumours so that we will know the specificity and sensitivity of this investigation in diagnosis. At another level, it is possible that expression of OLIG in neoplastic oligodendrocyte might participate in the oncogenesis of oligodendrogliomas. Initial work suggests that this is probably not the case. However further in vitro and in vivo studies analysing the functional consequence of OLIG overexpression in terms of proliferation and tumour progression are needed.

OLIG2 as a specific marker of oligodendroglial tumour cells

OLIG2 is a recently identified transcription factor involved in the specification of cells in the oligodendroglial lineage. We investigated the expression of OLIG2 by in-situ hybridisation in 21 brain tumours: nine grade II and III oligodendrogliomas, three grade II oligoastrocytomas, and nine non-oligodendroglial tumours (four grade IV astrocytomas, two meningiomas, a dysembryoplastic neuroepithelial tumour, and two metastases). OLIG2-positive cells corresponding to neoplastic oligodendrocytes were present in all oligodendrogliomas and oligoastrocytomas. By contrast, OLIG2 expression was not detected in the non-oligodendroglial tumours. Thus, oligodendroglioma probably arise from oligodendrocyte precursor cells. OLIG2 should prove a useful marker for the diagnosis of oligodendroglial tumours.

APO2L/TRAIL expression in human brain tumors.

APO2 ligand (APO2L)/TRAIL is a novel member of the tumor necrosis factor cytokine family and a potent inducer of apoptosis in tumor cell lines. We recently reported that APO2L is consistently expressed in low-grade astrocytomas, anaplastic astrocytomas, glioblastomas, and cell lines derived thereof, and that malignant glioma cell lines are susceptible to APO2L-induced apoptosis. In this study, we investigated whether APO2L is expressed in medulloblastoma or neuroblastoma cell lines and whether these cells are sensitive to APO2L-induced apoptosis. Immunoblot analyses revealed full-length APO2L protein expression in one (DAOY) of three medulloblastoma cell lines but not in two neuroblastoma cell lines (SKN-BE and SKN-LE). Viability assay performed after exposure to soluble APO2L for 16 h showed that DAOY medulloblastoma cells were the most sensitive and that apoptosis induced by APO2L was greatly enhanced when protein synthesis was inhibited by cycloheximide. Neuroblastoma cell lines were almost completely resistant to APO2L-induced apoptosis. We also carried out APO2L immunohistochemistry in a total of 115 tumors of the nervous system with different histogenesis and biological behavior. In all 9 pilocytic astrocytomas, the areas of dense fibrillary network showed diffuse and strong APO2L expression. In oligodendrogliomas, APO2L expression was observed in areas with a significant admixture of astrocytic cells, but was absent in neoplastic oligodendrocytes. In 13 of 14 ependymomas, APO2L was expressed in perivascular pseudorosettes. In all 12 medulloblastomas, strong APO2L expression was observed in intra-tumoral-reactive astrocytes, but neoplastic cells did not show APO2L immunoreactivity. Thus, the pattern of APO2L expression was largely similar to that of glial fibrillary acidic protein (GFAP), except for choroid plexus tumors and 3 of 8 anaplastic meningiomas, in which APO2L was focally expressed without concomitant GFAP expression. APO2L expression was absent in meningiomas, neurocytomas, and schwannomas. Thus, there is considerable heterogeneity of APO2L expression and susceptibility to APO2L-induced apoptosis among human brain tumors.

A histopathological contribution to supratentorial glioma grading, definition of mixed gliomas and recognition of low grade glioma with Rosenthal fibers.

Previous glioma studies have described separate grading systems for oligodendrogliomas and astrocytomas. Many of these gliomas contain mixtures of neoplastic astrocytes and oligodendrocytes. Prognosis may be related to the percentages of these neoplastic components. Previous survival/grading studies have been limited to histopathological features but have not evaluated the importance of percentages of neoplastic components. This study attempted to perceive the relative importance of percentages of neoplastic astrocytes and oligodendrocytes for definition of astroglial, oligodendroglial and mixed oligoastroglial tumors. After determination of these limits we explored the possibility to develop a grading system for common supratentorial gliomas based on reproducible histopathological features. A retrospective study was performed of 362 cases of unselected supratentorial glioma. One hundred and thirty-eight binary and nine continuous histopathological variables, amongst which percentages of neoplastic astrocytes and oligodendrocytes, were scored and related to survival. Only well reproducible histological features were accepted in Cox regression to define glioma grades. Supratentorial gliomas appeared to be composed of variable percentages of neoplastic oligodendrocytes and astrocytes, but this spectrum did not correspond to a continuous change in prognosis. Gliomas containing 30% or more neoplastic oligodendrocytes had a slightly better outcome (p < 0.0432) but higher percentages did not further improve prognosis. Percentages of neoplastic astrocytes were not correlated to survival. We therefore propose to designate gliomas containing 30% or more neoplastic oligodendrocytes as oligodendroglial tumors, and others as astroglial tumors. From a prognostic point of view there is no need to recognize mixed oligoastrocytomas. An interesting finding was the recognition of a low grade glioma group with Rosenthal fibers, which had the longest postoperative survival. Another prognosticator of interest concerns the mitotic rate as a continuous variable. Atypical mitoses indicated the worst survival, after necrosis. It was possible to develop a grading system for all supratentorial gliomas using six reproducible histological parameters: necrosis, atypical mitoses, the mitotic rate, endothelial proliferative activity, percentage of neoplastic oligodendrocytes and Rosenthal fibers. This resulted in four grades for astroglial tumors (p < 0.002) and three grades for oligodendroglial tumors (p < 0.008) which differed significantly within each group with respect to survival.

Immunohistochemical detection of vascular endothelial growth factor (VEGF) in the vasculature of oligodendrogliomas.

Vascular endothelial growth factor (VEGF) appears to be implicated in tumour angiogenesis. In the present study immunohistochemical expression of VEGF was evaluated in 34 oligodendrogliomas (13 grade II, 21 grade III [WHO]). VEGF immunoreactivity was found in 31 of 34 cases. Expression of VEGF was observed in endothelial cells and some vascular smooth muscle cells, but not in neoplastic oligodendrocytes. Vessel counts, percentages of VEGF-positive vessels and vessels with vascular endothelial proliferation were assessed. The degree of VEGF labelling and vascular-endothelial proliferation in each vessel were evaluated using a 3 degree intensity score. Expression of VEGF was higher in grade III than in grade II oligodendrogliomas as assessed by percentage of VEGF positive vessels (55.8 +/- 29.2% vs 17.0 +/- 19.0% [P < 0.001]) and by VEGF immunostaining intensity (1.90 +/- 0.60 vs 0.90 +/- 0.40 [P < 0.001]). VEGF expression did not correlate with vessel density. Intensity of VEGF expression correlated positively with that of vascular-endothelial proliferation in grade III tumours (r = +0.47 [P < 0.05]). The percentage of VEGF positive vessels showed some degree of positive correlation with the percentage of vessels showing vascular-endothelial proliferation (r = +408 [P < 0.10]). Within individual grade III tumours 67.5 +/- 29.6% of all vessels with vascular-endothelial proliferation were VEGF-positive and 31.0 +/- 20.5% of all VEGF-positive vessels showed no evidence of vascular-endothelial proliferation. We conclude that (i) expression of VEGF is observed in the vasculature of oligodendrogliomas; (ii) marked expression of VEGF is observed in grade III oligodendrogliomas; (iii) VEGF may be one of the interrelated causative stimuli acting in concert to induce vascular-endothelial proliferation.

Oligoastrocytomas: a clinicopathological study of 52 cases.

Oligoastrocytomas form a poorly defined subgroup of glial tumors, and few clinical series have been reported. We performed a retrospective study to elucidate the histopathological features of these tumors and to relate the clinical signs and symptoms and proliferative potential to survival. Oligoastrocytomas were defined as glial tumors with at least 10% neoplastic astrocytes and 10% neoplastic oligodendrocytes; tumors were graded with the St. Anne-Mayo criteria for astrocytomas and oligodendrogliomas. Proliferative potential was estimated with antibodies against proliferating cell nuclear antigen (PCNA). Median survival of 52 patients (median age, 42 years) was 75 weeks (range 2-703 weeks). Actuarial 1-, 2-, 3-, and 5-year survival rates were 67%, 43%, 40%, and 29%, respectively. For 15 patients with grade 3 and 33 with grade 4 lesions (St. Anne-Mayo astrocytoma classification), median survival was 217 and 55 weeks, respectively. For 19 patients with grade 2 and 33 with grade 3 lesions (St. Anne-Mayo oligodendroglioma classification), median survival was 305 and 55 weeks, respectively. Interobserver agreement between three experienced neuropathologists on identification of astrocytes, oligodendrocytes, and unclassifiable cells was low, indicating considerable subjectivity in the histopathological diagnosis. Median PCNA labeling indices correlated with tumor grade, but individual values varied so widely within grades that they had no predictive value for survival. In a multivariate analysis, symptoms of increased intracranial pressure and microvascular proliferation were independently associated with poor prognosis. The biological behavior of subgroups appeared to be distinctly less aggressive than that of 'pure' astrocytomas of similar grade. Better histopathological definition of oligoastrocytomas and improved assessment of percentages of constituent cell types may allow more accurate prognosis.

Oligodendrogliomas. Part I: Patterns of growth, histological diagnosis, clinical and imaging correlations: a study of 153 cases.

The present study has attempted to demonstrate that the morphological spectrum of oligodendrogliomas includes tumors which are traditionally misinterpreted as 'diffuse fibrillary astrocytoma'. We have shown that these tumors are in fact made of isolated neoplastic oligodendrocytes which are entrapped in a fibrillary background composed of axons and fibrillary reactive gliosis. Analysis in a series of 153 'pure' supratentorial oligodendrogliomas composed of 'classical' or pseudo 'diffuse fibrillary oligodendrogliomas' diagnosed by imaging-based serial stereotactic biopsies showed that 2/3 of the tumors were exclusively made of isolated tumor cells (ITCs) (structure type III) and that only 1/3 of them exhibited both ITCs and solid tumor tissue components (structure type II). The tumor tissue destroys the brain parenchyma and contains new formed microblood vessels whereas ITCs do not destroy the parenchyma and are not associated with microangiogenesis. These fundamentally opposite morphological characteristics were reflected by the following findings: 1) contrast enhancement was observed in 64% of structure type II but was never seen in structure type III oligodendrogliomas. 2) a neurological deficit occurred in 57% of structure type II but in only 8% of structure type III oligodendrogliomas. 3) using the new grading system described in the companion paper to this study, we found that the biological behavior of oligodendrogliomas was also closely related to the patterns of tumor growth. From a synthesis of data gathered in this study it is suggested that emergence of microangiogenesis within a tumor which at first grows slowly with a structure type III pattern is a crucial event toward more aggressive behavior.

A study of glutamine synthetase in normal human brain and intracranial tumours

Glutamine synthetase (GS) activity was measured in selected areas of three normal brains and in 262 biopsies from patients with suspected intracranial tumours. In general, levels were higher in grey matter than in white matter and the highest activities of all were found in the hypothalamus which is consistent with its high glutamatergic activity. In the biopsy material, GS activity was greatest in gliotic brain, in keeping with the predominantly astrocytic localization of the enzyme. High levels were also found in astrocytomas and oligodendrogliomas but there was considerable variation between tumours, suggesting a random loss of GS expression during neoplastic transformation or heterogeneity in their cellular origin. The immunocytochemical demonstration of GS in neoplastic oligodendrocytes and in meningioma cells argues against absolute cell-type specificity for this enzyme.

Cytokeratin immunoreactivity in gliomas

Monoclonal antibodies (AE1/3, CAM 5.2 and PKK-1) and polyclonal antisera against the cytokeratin proteins were reacted with a range of astrocytic tumours, oligodendrogliomas and ependymomas. Seven of 12 cases (58%) of glioblastoma multiforme, five of eight (63%) anaplastic astrocytomas and two of five (40%) well-differentiated astrocytomas were immunoreactive with AE1/3 but not with the other anti-cytokeratin antibodies. In oligodendrogliomas, AE1/3 stained isolated astrocyte-like cells as well as scattered neoplastic oligodendrocytes in four of eight cases (50%) cases. Four ependymomas were negative for all cytokeratin markers examined. The immunostaining of astrocytomas and oligodendrogliomas with AE1/3 might represent co-expression of cytokeratin with glial fibrillary acidic protein by gliomas and calls for caution in the use of these antibodies in the differential diagnosis between gliomas and carcinomas.

Immunohistochemical characterization of oligodendrogliomas: an analysis of multiple markers

Twenty-eight oligodendrogliomas and seven oligoastrocytomas were immunotested by the peroxidase-antiperoxidase (PAP) method with antiglial fibrillary acidic protein (GFAP) serum, anti-Leu 7 monoclonal antibody (Mab), anti-myelin-associated glycoprotein (MAG) Mab, anti-myelin basic protein (MBP) serum, anti-carbonic anhydrase C (CA C) serum and anti-neuron-specific enolase (NSE) serum. The immunoreactivity of their vascular pattern was studied with Ulex europaeus type I lectin (UEA I). According to their morphology and distribution GFAP-positive cells were respectively interpreted as reactive astrocytes, neoplastic astrocytes and neoplastic oligodendrocytes. Reactive astrocytes were found in the tumor, around the tumor and surrounding the supporting blood vessels. Neoplastic astrocytes were mainly found in the oligoastrocytomas and usually closely intermingled with neoplastic oligodendrocytes. GFAP-positive neoplastic oligodendrocytes were found in the typical oligodendrogliomatous areas. They had central nuclei and GFA positivity was mainly found in the perinuclear cytoplasm. They correspond to the "gliofibrillary oligodendrocytes" described by Herpers and Budka. Of the oligodendrogliomas 91% displayed Leu 7 positivity, but anti-Leu 7 cannot be considered as a specific marker for oligodendrogliomas since other neuroepithelial tumors have been reported to react with this antibody. MAG-, CA C- and NSE-positivities were found in a number of tumor cells in a few oligodendrogliomas. All the tumor cells were MBP-negative, but myelin sheaths and fragments of myelin in the infiltrated white matter were clearly demonstrated by this antiserum. UEA I strikingly demonstrated the vascular pattern of the tumors, and its usefulness as a discriminating marker for the supportive endothelial cells was confirmed.

Immunohistochemical studies on human brain tumors using anti-Leu 7 monoclonal antibody in paraffin-embedded specimens.

Using the four-step peroxidase-antiperoxidase (PAP) method, the presence of the antigen recognized with anti-Leu 7 monoclonal antibody was investigated in paraffin-embedded human brain tissue and tumors. The antigen was demonstrated in the myelin sheaths, oligodendrocytes, and some choroid plexus cells in normal brain and in oligodendrogliomas, some astrocytomas and choroid plexus papillomas. The technique can be used to identify normal and neoplastic oligodendrocytes.

Glial fibrillary acidic protein (GFAP) in oligodendroglial tumors: gliofibrillary oligodendroglioma and transitional oligoastrocytoma as subtypes of oligodendroglioma.

Immuno-reactivity to glial fibrillary acidic protein (GFAP) is mainly regarded as a sign of astroglial histogenesis and/or differentiation. The presence of astrocytes in oligodendrogliomas is a well known phenomenon; in addition, GFAP-positive neoplastic oligodendrocytes have also been described but have not yet been studied systematically. Using an anti-GFAP serum in the peroxidase-antiperoxidase antiperoxidase (PAP) technique, 50 oligodendrogliomas and 16 mixed oligodendrocytomas were investigated; they had been diagnosed by routine histological stains. In half of all oligodendrogliomas, and only in a few (12%) of the mixed oligoastrocytomas, GFAP-positive oligodendrocytes were found in some areas of the classical honey-comb texture with a prominent vascular stroma. The term 'gliofibrillary oligodendrocyte' (gfoc) is proposed for these immuno-reactive cells. The existence of a tumour cell combining morphological characteristics of oligodendroglia with GFAP production in its cytoplasm may be considered analogous to transient GFAP expression by myelin-forming glia during normal development (Choi and Kim 1984), thus suggesting the return to a foetal behaviour by some neoplastic oligodendrocytes. Three tumours of the present series consisted largely of gfocs and, therefore, may be termed gliofibrillary oligodendrogliomas. In about 32% of all oligodendrogliomas, but only once in the mixed tumour group, a gradual morphological transition from gfocs to gemistocytic astrocytes was observed.(ABSTRACT TRUNCATED AT 250 WORDS)