Oligoastrocytomas: a clinicopathological study of 52 cases

Oligoastrocytomas form a poorly defined subgroup of glialtumors, and few clinical series have been reported.We performed a retrospective study to elucidate thehistopathological features of these tumors and to relatethe clinical signs and symptoms and proliferative potentialto survival. Oligoastrocytomas were defined as glial tumorswith at least 10% neoplastic astrocytes and 10%neoplastic oligodendrocytes; tumors were graded with the St.Anne-Mayo criteria for astrocytomas and oligodendrogliomas. Proliferative potentialwas estimated with antibodies against proliferating cell nuclearantigen (PCNA). Median survival of 52 patients (medianage, 42 years) was 75 weeks (range 2–703weeks). Actuarial 1-, 2-, 3-, and 5-year survivalrates were 67%, 43%, 40%, and 29%, respectively.For 15 patients with grade 3 and 33with grade 4 lesions (St. Anne-Mayo astrocytoma classification),median survival was 217 and 55 weeks, respectively.For 19 patients with grade 2 and 33with grade 3 lesions (St. Anne-Mayo oligodendroglioma classification),median survival was 305 and 55 weeks, respectively.Interobserver agreement between three experienced neuropathologists on identificationof astrocytes, oligodendrocytes, and unclassifiable cells was low,indicating considerable subjectivity in the histopathological diagnosis. MedianPCNA labeling indices correlated with tumor grade, butindividual values varied so widely within grades thatthey had no predictive value for survival. Ina multivariate analysis, symptoms of increased intracranial pressureand microvascular proliferation were independently associated with poorprognosis. The biological behavior of subgroups appeared tobe distinctly less aggressive than that of pureastrocytomas of similar grade. Better histopathological definition ofoligoastrocytomas and improved assessment of percentages of constituentcell types may allow more accurate prognosis.     

少突胶质细胞瘤、室管膜瘤的细胞学诊断及胶质纤维酸蛋白免疫细胞化学染色

用抗胶质纤维酸蛋白单克隆抗体对12例常规细胞学诊断为少突胶质细胞瘤、35例诊断为室管膜瘤的涂片标本作了免疫细胞化学染色,并与同一瘤组织的组织学诊断作对照,结果表明常规细胞学误诊5例,其中4例经胶质纤维酸蛋白(GFAP)免疫细胞化学染色后得到确诊.本文分析了常规细胞学误诊原因,并提出其鉴别要点。在经组织学证实的23例少突胶质细胞瘤内,11例经GFAP免疫细胞化学染色后可见阳性细胞,其形态介于少突胶质细胞与星形细胞之间,从形态学上支持少突胶质细胞瘤内出现GFAP是该类细胞向星形细胞转化的观点。在有组织学证实的31例室管膜瘤中,仅5例可见少数GFAP阳性的室管膜瘤细胞,其形态呈现tanycyte的特征,为室管膜细胞的一个亚型.因此,GFAP阳性细胞的出现并不反映这两类肿瘤的分化程度.     

A phase I trial of surgical resection with Gliadel Wafer placement followed by vaccination with dendritic cells pulsed with tumor lysate for patients with malignant glioma

High grade gliomas are associated with poor prognosis and high mortality. Conventional treatments and management of high grade gliomas have shown little improvement in 5-year overall survival. This phase I trial evaluated the safety, immunogenicity, and potential synergy of surgical resection with Gliadel Wafer implantation, followed by autologous tumor lysate-pulsed dendritic cell (DC) vaccine in patients with malignant glioma. Primary end points of this study were safety and surrogate markers of immunogenicity, overall survival, and progression free survival. Following surgical resection, Gliadel Wafers were placed along the resection cavity. Patients subsequently received intradermal injections of autologous tumor lysate-pulsed DC vaccines 3 times at 2 week intervals. Treatment response was evaluated clinically and through MRI at regular intervals. Twenty-eight patients received Gliadel Wafers and DC vaccination: 11 newly diagnosed (8 glioblastoma [GBM], 2 anaplastic astrocytoma [AA], and 1 anaplastic oligodendroglioma [AO]) and 17 recurrent (15 GBMs, 1 AA, and 1 AO) high grade gliomas. Immunogenicity data was collected for 20 of the 28 patients. Five of 20 patients showed elevated IFN-γ responses following vaccination. Median progression-free survival and overall survival for all GBM patients in the trial from the start of vaccination were 3.6 months and 16.9 months respectively. Comparisons between vaccine responders and non-vaccine responders were not statistically significant. Adjuvant autologous dendritic cells pulsed with tumor-lysate following resection and Gliadel Wafer placement is safe, elicits modest immunogenicity and shows similar clinical outcomes in patients who had DC vaccination in previous studies.     

Vascular endothelial growth factor expression correlates with tumour grade and vascularity in gliomas

AIMS: Tumour vascularity and vascular endothelial growth factor (VEGF) expression were studied in 41 primary brain tumours of astrocytic and oligodendroglial origin, in order to define the potential role of VEGF in the vascularization and growth of these tumours. METHODS AND RESULTS: Two commercial monoclonal antibodies to the VEGF protein (from R&D Systems and NeoMarkers), raised against different isoforms, were utilized. Each monoclonal antibody consistently detected the expression of VEGF in different cell types. The R&D Systems antibody only produced surface staining of endothelial cells in tumour capillaries, whereas staining with the Neomarkers antibody was largely confined to tumour cell cytoplasm. High levels of staining were seen with the R&D Systems and NeoMarkers antibodies in 13 and 14 of 15 glioblastomas, respectively, four and three of five oligodendrogliomas, four and seven of 10 anaplastic astrocytomas, one and three of six low-grade astrocytomas and none and none of five pilocytic astrocytomas. There was a close correlation between VEGF expression, tumour vascularity and grade. CONCLUSIONS: These findings support a role for VEGF in the angiogenesis of glioblastoma, anaplastic astrocytoma and oligodendroglioma. The distinct immunoreactivities of the two commercial monoclonal antibodies indicate either there is expression of different splice variants of VEGF or that the epitopes are differentially revealed during synthesis, secretion and receptor-binding of the growth factor. This highlights the importance of using more than one antibody in the evaluation of tissue VEGF expression.     

Dysembryoplastic neuroepithelial tumor (DNT)‐like oligodendrogliomas or DNTs evolving into oligodendrogliomas: Two illustrative cases

A review of dysembryoplastic neuroepithelial tumors (DNTs) in 14 patients over a 12‐year period revealed four patients re‐operated because of changes on magnetic resonance imaging (MRI) suggesting tumor recurrence or progression. In three of these, the histological features were identical to the initial DNT. In the fourth patient, persistent DNT was surrounded by WHO grade 2 oligoastrocytoma. In one of the other 10 patients, WHO grade 2 oligodendroglioma was present in white matter deep to and completely separate from a cortically based DNT. Fluorescence in situ hybridization showed codeletion of 1p and 19q in both the DNT and oligodendroglioma and oligoastrocytoma components. Deletions were not identified in any other tumor. Our findings corroborate other studies that 1p and 19q deletions are uncommon in DNT. These two unusual tumors also raise the possibility that rare DNTs may evolve into oligodendroglioma or oligoastrocytoma. DNTs with this altered biology can be identified by 1p and 19q deletion analysis.     

Pathology of oligodendroglia: An overview

Oligodendroglia are cells responsible for creating myelin sheaths for axons in the CNS. However, pathologies of oligodendroglia other than demyelination are not well understood due to the lack of adequate methods of characterizing pathological conditions affecting oligodendroglia in human tissue. This review discusses three major topics with the aim of clarifying some of the controversies in the study of oligodendroglia. The oligodendroglioma, a relatively indolent form of diffuse gliomas thought to originate in oligodendrocytes, has never demonstrated myelin formation on electron microscopy nor shown a constant expression of myelin‐related proteins. Oligodendrogliomas instead share an immune phenotype with oligodendrocyte progenitor cells (OPCs). Another type of cell that resembles OPCs are oligodendroglia‐like cells (OLCs), which occur in many types of low‐grade tumors and focal cortical dysplasia. In neurodegenerative disorders, oligodendroglia can be a target of abnormal aggregations of proteins such as tau. Tau‐positive oligodendroglial inclusions in progressive supranuclear palsy and corticobasal generation differ from each other morphologically, ultrastructurally and biochemically, suggesting disparate underlying pathological processes despite significant overlapping of the clinical manifestations. To promote the study of oligodendroglia, novel methods for detecting OLCs in situ are urgently required.     

Phase II study of imatinib mesylate and hydroxyurea for recurrent grade III malignant gliomas

Purpose Recent reports demonstrate the activity of imatinib mesylate, an ATP-mimetic, tyrosine kinase inhibitor, plus hydroxyurea, a ribonucleotide reductase inhibitor, in patients with recurrent glioblastoma multiforme. We performed the current phase 2 study to evaluate this regimen among patients with recurrent WHO grade III malignant glioma (MG). Patients and method Patients with grade III MG at any recurrence, received imatinib mesylate plus hydroxyurea (500 mg twice a day) orally on a continuous, daily schedule. The imatinib mesylate dose was 500 mg twice a day for patients on enzyme inducing anti-epileptic drugs (EIAEDs) and 400 mg once a day for those not on EIAEDs. Clinical assessments were performed monthly and radiographic assessments were obtained at least every 2 months. The primary endpoint was 6-month progression-free survival (PFS) rate. Results Thirty-nine patients were enrolled. All patients had progressive disease after prior radiotherapy and at least temozolomide-based chemotherapy. The median number of episodes of prior progression was 2 (range, 1–7) and the median number of prior treatment regimens was 3 (range, 1–8). With a median follow-up of 82.9 weeks, 24% of patients were progression-free at 6 months. The radiographic response rate was 10%, while 33% achieved stable disease. Among patients who achieved at least stable disease at first evaluation, the 6-month and 12-month PFS rates were 53% and 29%, respectively. The most common grade 3 or greater toxicities were hematologic and complicated less than 4% of administered courses. Conclusion Imatinib mesylate plus hydroxyurea, is well tolerated and associated with anti-tumor activity in some patients with recurrent grade 3 MG. Supported by National Institutes of Health grant nos. 1-P50-CA108786-01, NS20023 and CA11898 and by grant no. MO1 RR 30 through the General Clinical Research Centers Program, National Center for Research Resources, National Institutes of Health.     

Stem cell protein BMI-1 is an independent marker for poor prognosis in oligodendroglial tumours

Aims: The polycomb factor BMI‐1 has recently been implicated in tumorigenesis of the central nervous system in several experimental animal models. However, the significance of BMI‐1 in human glioma has not been investigated. Here we describe expression of the polycomb protein BMI‐1 and its downstream targets p16^Ink4a and MDM2 in both high‐ and low‐grade human glioma. Methods: Tumour samples were collected from 305 adult patients treated for primary grades 2–4 gliomas between 1980 and 2006 in Finland and Germany. BMI‐1, p16 and MDM2 expression was evaluated using immunohistochemistry in representative paraffin‐embedded tumour tissue. The significance of observed immunoreactivity, age at onset, gender, histopathological findings and proliferative index was analysed in univariate and multivariate survival models. Results: BMI‐1 was expressed in all histologic types of diffuse gliomas. We found a significant correlation (P = 0.007) between the frequency of BMI‐1 immunoreactive tumour cells and poor survival in World Health Organization grades II–III oligodendrogliomas and oligoastrocytomas (n = 62). The median survival of patients grouped by low, intermediate or high frequency of BMI‐1 immunoreactive tumour cells was 191 months, 151 months and 68 months, respectively. This association was also significant in the Cox multivariate regression model. Nuclear p16 immunopositivity predicted better survival in astrocytomas and an inverse correlation between p16 expression and the Ki‐67 mitotic index was also observed. Conclusions: BMI‐1 is found in all histological types of gliomas and the relative protein expression of BMI‐1 is a novel independent prognostic marker in oligodendroglial tumours.