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In 80 specimens of human glioma the production of glial fibrillary acidic protein (GFAP) by tumour cells invading meninges or connective tissue was studied immuno-cytochemically by the PAP technique. In 38 of 55 cases of astrocytoma, glioblastoma, gliosarcoma, and oligoastrocytoma, GFAP immunoreactivity was greater in the invading cells as compared with the main part of the neoplasm. Fifty-eight percent of the astroglial tumours invading the leptomeninges, all astroglial tumours invading connective tissue and all gliosarcomas showed enhanced GFAP immuno-reactivity of tumour cells getting in contact with collagenous tissue, whereas meningeal infiltrates of 25 non-astroglial tumours (oligodendroglioma, ependymoma, medulloblastoma) remained GFAP-negative like the main part of the respective tumours. In the majority of astroglial tumours an increase of GFAP immunoreactivity was found also in perivascular cells of the main part of the tumour. It is concluded that glioma cells are capable of adapting their cytoskeleton to their micro-environment. Contact with dense collagenous tissue appears as an important factor able to induce an increased production of GFAP by adjacent glial cells.

Background and Objective IDH1 (isocitrate dehydrogenase 1) is a potential biomarker and drug target. Genomic and epigenetic data on astrocytoma have demonstrated that the IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Furthermore, recent studies have also indicated that a mutant IDH1 inhibitor induced demethylation of histone H3K9me3 and expression of genes associated with gliogenic differentiation. As the presence of the p.R132H mutation in the IDH1 gene seems to be a more powerful prognostic marker than O6-methylguanine-DNA methyltransferase promoter status, we evaluated the presence of IDH1 mutation in Polish patients with astrocytoma, glioblastoma, oligoastrocytoma, ganglioglioma, oligodendroglioma, and ependymoma. Methods The IDH1 mutation status at codon 132 was determined using a mouse monoclonal antibody specific for the R132H mutation, direct sequencing, and Co-amplification at Lower Denaturation Temperature (COLD) polymerase chain reaction (PCR) high-resolution melting-curve analysis (HRM). Results Wild-type (WT) IDH1 was detected in cases with a World Health Organization (WHO) grade I astrocytoma. The IDH1 c.G395A; p.R132H mutation was observed in 56 and 94 % of grade II and grade III astrocytoma cases, respectively. Significant differences in the median overall survival were observed in astrocytoma patients grouped on the basis of the presence of IDH1 mutation: survival was 24 months longer in grade II astrocytoma and 12 months longer in glioblastoma. Overall survival was compared between grade II astrocytoma patients with low or high expression of the mutant protein. Interestingly, lower R132H expression correlated with better overall survival. Conclusion Our results indicate the usefulness of assessing the R132H IDH1 mutation in glioma patients: the presence or absence of the R132H mutation can help pathologists to distinguish pilocytic astrocytomas (IDH1 WT) from diffuse ones (R132H IDH1/WT). Moreover, low IDH1 p.R132H expression was related to better prognosis. This clinical implication appears to be important for personalization of prognosis and treatment by oncologists.

The optimal management of patients with low-grade glioma (LGG) is controversial. The controversy largely stems from the lack of well-designed clinical trials with adequate follow-up to account for the relatively long progression-free survival and overall survival of patients with LGG. Nonetheless, the literature increasingly suggests that expectant management is no longer optimal. Rather, there is mounting evidence supporting active management including consideration of surgical resection, radiotherapy, chemotherapy, molecular and histopathologic characterization, and use of modern imaging techniques for monitoring and prognostication. In particular, there is growing evidence favoring extensive surgical resection and increasing interest in the role of chemotherapy (especially temozolomide) in the management of these tumors. In this review, we critically analyze emerging trends in the literature with respect to management of LGG, with particular emphasis on reports published during the past year.

The glioneuronal tumor with neuropil-like islands (GTNI) is an uncommon histopathological entity composed of diffuse astrocytic or oligoastrocytic elements interspersed with sharply delimited, micronodular loci of neuronal differentiation. Despite its initial description over 10 years ago [10], the lineage classification of GTNI remains speculative. The clinical features of GTNI, its infiltrative growth characteristics, typically dominating astroglial components, and frequent p53 expression, are all consistent with a fundamental linkage to the diffuse astrocytic tumor group. Supporting this notion are reports documenting, by comparative genomic hybridization, an astrocytoma-like profile of 7q21.1-qter gain and 9p21-pter loss in one case [8] and the absence of oligodendroglioma-associated 1p/19q deletions in a series assessed by polymerase chain reaction-based loss of heterozygosity analysis [3]. Point mutations in the isocitrate dehydrogenase enzymes, IDH1 and IDH2, are found in the majority of WHO grade II and III diffuse gliomas—both astrocytic and oligodendroglial—as well as secondary glioblastomas (GBM), but they are almost entirely absent from primary GBM [7, 9, 11]. As such, they appear to represent a defining early genomic lesion in the pathogenesis of diffuse glioma variants exhibiting step-wise malignant evolution. Glioma-associated IDH mutations invariably involve active site arginine residues—R132 and R172 for IDH1 and IDH2, respectively—and, while their precise pathogenic mechanism remains unclear, they appear to promote the generation of the cancer-predisposing toxic metabolite, R(-)-2-hydroxyglutarate [6]. We assembled 12 cases of GTNI (Table 1) seen at the Memorial Hospital Department of Pathology, along with pertinent clinical information from the patients’ medical records. To evaluate whether IDH1 and IDH2 mutations were present in our sample set, we performed custom genotyping assays on the Sequenom platform [1, 2] and/or employed validated immunohistochemical staining (IHC) for the most common IDH mutation, IDH1 R132H [5]. We found that every tumor in our sample set (12/12) exhibited evidence of the IDH1 R132H mutation by either one or both of our assay methods (Fig. 1a–d), and concordant results were achieved for all cases screened by both Sequenom® and IHC (Table 1). Both glial and neuronal components exhibited immuno-expression of mutant IDH1 in all examined cases (Fig. 1d). Table 1 Cases included in GTNI study cohort listed with patient age at first diagnosis, sex, histopathological grade (Grade), Sequenom® genotyping result (Sequenom) and IHC for IDH1 R132H (R132H IHC) Fig. 1 GTNI is characterized by IDH1 R132H mutations. a A mutation-positive Sequenom® spectrum from a representative GTNI sample displays an additional extension product of different mass, due to the G to A point mutation. Photomicrographs of a representative ... The primary significance of our findings lies in strengthening the pathogenic link between GTNIs and the diffuse glioma tumor group. Studies to date indicate that within primary brain tumors, IDH mutations are largely restricted to diffuse gliomas evolving via step-wise malignant evolution (i.e., diffuse astrocytomas, oligodendrogliomas, and oligoastrocytomas). Combined with the frequent p53 immunoreactivity and general absence of 1p/19q chromosomal co-deletions previously documented in this setting, a high incidence of IDH1 mutations would fundamentally ally GTNIs with the diffuse astrocytoma and 1p/19q-intact oligoastrocytoma group. Indeed, the 100% incidence of IDH mutation in our sample set is even higher than that documented in diffuse astrocytoma so far (~80%) [7, 11]. As an aside, recent work has also identified IDH mutation as a prevalent feature of oligodendrogliomas with neurocytic differentiation [4], further emphasizing that focally prominent neuronal morphology falls well within the histopathological spectrum of diffuse gliomas in general. The invariable presence of the specific IDH1 R132H mutation in our GTNIs may represent an artifact of small sample number, but, nevertheless, it is striking. Whether other IDH1 or IDH2 mutational variants exist in GTNI and whether a genotypic restriction to IDH1 R132H alone would have any functional significance remain unclear.

24 cases of cystic cerebral astrocytoma represent 11% of 217 supratentorial tumors of the pediatric age group operated. Both macro- and microscopically, such tumors resembled in most cases the well-known cerebellar astrocytoma, presenting as a large cyst with a mural nodule with the pattern of a pilocytic astrocytoma (i.e. spongioblastoma of the German school). The preferential site of incidence was the temporal lobe and the age peaks were of 7 and 16 years without sex prevalence. The surgical technique consisted in the extirpation of the mural nodule, preceded by emptying the cyst, followed by opening the contiguous ventricular wall. The extirpation was partial in one-third of the cases of whom the minority underwent radiotherapy. 1 patient died after the operation while 2 others died from tumor recurrence after 3 and 4 years, respectively, both being mixed tumors (oligoastrocytoma) that were irradiated postoperatively. The follow-up ranged from 10 to 29 years in 70% of the cases. The long-term functional results of the available 17 patients are as follows: good (perfectly well), 12 cases (70%); fair (minor troubles), 5 cases (30%). 3 of the 5 cases with a fair result all had a partial resection.

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)

Purpose Patients with anaplastic gliomas have a more favorable overall survival than patients with glioblastomas. In most analyses, WHO grade III and IV tumors are not analyzed separately. The present analysis reports outcome after postoperative radiotherapy in patients with WHO grade III gliomas. Patients and methods Between January 1988 and January 2007, 127 patients with WHO grade III tumors were treated with radiotherapy; the histological classification was pure astrocytoma in 104 patients, oligoastrocytoma in 12 and pure oligodendroglioma in 11 patients. Median age was 48 years. After the primary diagnosis, a biopsy had been performed in 72 patients; subtotal and total resections were performed in 37 and 18 patients, respectively. In all patients radiotherapy was applied with a median dose of 60 Gy in conventional fractionation. The median follow-up time was 18 months. Results Median overall survival was 17 months. Overall survival was significantly influenced by the extent of surgery. Median overall survival was 32 months after complete resection, 36 months after subtotal resection, and 12 months after biopsy. Median overall survival was 7 months for patients with anaplastic astrocytomas, 44 months for patients with mixed tumors, and 47 months for those with pure oligodendrogliomas. Age significantly influenced overall survival. Median progression-free survival was 9 months; the extent of neurosurgical resection significantly influenced progression-free survival. Conclusion Patients with WHO grade III anaplastic astrocytomas, oligodendrogliomas and oligoastrocytomas show favorable overall survival after postoperative radiotherapy compared with glioblastoma patients and should therefore be analyzed separately. Radiochemotherapy might further improve outcome.

This study focused on changes of E-cadherin (CDH1), adenomatous polyposis coli (APC) and beta-catenin (CTNNB1) in a palette of 50 CNS tumors. All gene products are components of adherens junctions, but are also involved in the Wnt signalling. PCR amplification of D16S752 polymorphism linked to CDH1 gene was used to test loss of heterozygosity (LOH) in tumors. Instability of APC gene was investigated by PCR/LOH using RFLP, and changes of CTNNB1 were tested by heteroduplex. The results showed LOH of CDH1 gene in 31% of meningiomas examined (correlation significant at 0.002 level). One LOH was also found in germinoma, while other tumor types did not show changes of CDH1. Fourteen samples (29.2%) with changes of APC were observed. The changes were distributed to: 33.3% of glioblastomas, 27% of meningiomas, 1 LOH in five informative astocytomas (20%), and 1 in six informative neurinomas (17%). One oligoastrocytoma showed LOH at exon 11 and one medulloblastoma had allelic imbalance at two exons. Ten % of our sample (two meningiomas, an astrocytoma, a glioblastoma, and a germinoma) showed heteroduplexes encompassed in β -catenin’ s exon 3. Our results suggest that genetic changes of the wnt components are involved in brain tumor genesis. Changes of CDH1 are involved in meningiomas, while changes of APC are distributed among different tumor types, with glioblastomas showing the highest percentage.

Human telomerase is a structurally complex ribonucleoprotein that is responsible for the maintenance of telomeric DNA at the ends of the chromosomes. The enzyme is proposed as having an important role in cell immortalization and oncogenesis. A limited number of studies have been performed on the telomerase system in brain tumors, and these studies are somewhat conflicting. The relative ineffectiveness of current therapies for malignant gliomas led to the need for novel targets for more promising approaches. In order to clarify the prognostic significance of telomerase expression in gliomas and to speculate on therapeutic implications, we examined telomerase activity by the telomeric repeat amplification protocol (TRAP) assay in 42 gliomas, (32 multiform glioblastomas, 4 anaplastic astrocytomas, 4 differentiated astrocytomas, 1 oligoastrocytoma and 1 oligosarcoma). Telomerase messenger expression (hTERT mRNA) was evaluated by reverse transcription-PCR analysis in the same group of tumors. High telomerase activity was detected in 21/42 gliomas (50%). The levels of telomerase in terms of its messenger level expression overlapped the activity; in fact, a significant association between telomerase activity and hTERT mRNA expression was found (chi2 test; p

The histological subclassification of gliomas is increasingly assisted by the underlying molecular genetics which has major importance in guiding clinical management of the disease. However, the assessment of several molecular events for improving clinical care remains a challenge. Herein, we report on comparative genomic hybridization (CGH) and immunohistochemical (IHC) assessment of EGFR, PTEN, p53, and MIB-1 expression in 13 oligodendrogliomas (10 WHO grade II, 3 WHO grade III), one oligoastrocytoma (WHO grade III) and 23 high-grade astrocytomas (3 WHO grade III, 20 glioblastoma multiforme). The most frequent imbalances in oligodendroglial tumors including the oligoastrocytic case were, in decreasing order of frequency, +7q, -1p, and -4q and in astrocytomas +7q, -10q, +7p, -9p, -10p, +20q, and +20p. Some individual imbalances were associated with increasing numbers of chromosomal changes, that were +7q in both oligodendrogliomas and astrocytomas, and -9p, -10q, +20p, and +20q in astrocytomas. The markers p53 and MIB-1 were significantly higher expressed in astrocytomas than in oligodendrogliomas and expression levels of p53 and EGFR were inversely associated within the astrocytic group. In addition, p53 overexpression correlated positively with +7q and negatively with -1p in the oligodendroglial group whereas EGFR overexpression correlated positively with -1p in the oligodendroglial and positively with +7p and -10p in the astrocytic group. Short overall survival was significantly associated with +7p and -10q in astrocytomas. Collectively, these results contribute to the increasing clinical relevance of assessing tumor biological markers in gliomas.

Background In the 2016 WHO classification, the diagnosis of oligodendroglioma has been restricted to IDH mutated, 1p19q codeleted tumors (IDHmut-codel). IDHmut oligoastrocytoma is now classified either as oligodendroglioma or astrocytoma based on presence of 1p19q codeletion. There is growing evidence that this molecular classification more closely reflects patient outcome. Due to the strong association between IDHmut-codel with oligodendroglial morphology, the additional impact of these markers on prognostic accuracy is largely unknown. Our aim was to assess the prognostic impact of IDHmut-codel in an unselected cohort of morphologically classified oligodendroglial tumors. Methods We performed a retrospective chart review of oligodendroglial tumors (WHO grade II and III) operated since 1983. A total of 214 tumors were included, and molecular information was available for 96 tumors. The prognostic impact of IDHmut-codel together with clinical parameters was analyzed by multivariate Cox regression. Results IDHmut-codel was registered in 64 tumors while for 150 tumors the molecular profile was negative for IDHmut-codel, unknown or incomplete. Comparison between the two groups showed that patients with IDHmut-codel tumors were younger (42 vs. 48 years), had more frequent frontal tumor location (48 vs. 33%) and presented more often with seizures (72 vs. 51%) and no signs of neurological impairment (14 vs. 30%) than patients harboring tumors with unknown or incomplete molecular profile. Multivariate survival analysis identified young age (HR 1.78 ≥ 40 years), the absence of neurological deficits or personality changes (HR 0.57), frontal tumor location (HR 0.64) and the presence of IDHmut-codel (HR 0.50) as independent predictors for longer survival, whereas tumor grade was not. Conclusion In this unselected single-institution cohort, the presence of IDHmut-codel was associated with more beneficial clinical parameters and was identified as an independent prognostic factor. We conclude that the classical oligodendroglioma genotype provides additional prognostic data beyond clinical characteristics, morphology and tumor grade.

Diffuse gliomas with clear cell morphology are represented in the 2007 WHO classification of brain tumors as oligoastrocytomas and oligodendrogliomas of grades II and III. Although preoperative neuroimaging of these brain tumors are often successful, histopathologic evaluation of neurosurgically removed tumor specimens is still required for a definite diagnosis and subsequent molecular analysis. Such CNS tumors show an extensive variety of histological and cytological appearance making diagnosis in clear cell gliomas somewhat difficult, especially as oligoastrocytomas are often less clearly defined. There is an ongoing debate whether these tumors indeed constitute an entity or whether they represent a mixed bag containing both astrocytomas and oligodendroglioma. Recent advances with molecular data on these tumors have a major impact on neuopathological typing, prognosis and therapy of the patients. This neuro-oncologic review focuses on neuropathological and molecular features of the different types of diffusely infiltrating gliomas. Core features and distinct patterns and variants are also introduced and illustrated. Recent advances in immunohistochemistry and molecular biology have contributed to an improved classification and are discussed. Different methodologies for molecular analysis of 1p/19q codeletion, ATRX loss, MGMT promoter methylation and isocitrate dehydrogenase mutations are presented in detail and their prognostic and predictive implications for therapy are discussed.