Cases Of Low-grade Gliomas Research Articles

Abstracts from the 20th International Conference on Brain Tumor Research and Therapy, July 20-22, 2014, Lake Tahoe, California.

BACKGROUND: Low grade gliomas (LGGs) account for approximately half of all gliomas. Although LGGs typically show slower tumor progression and generally better clinical outcomes than high-grade gliomas, their clinical course is invariably indolent and most patients ultimately succumb to death. In contrast to high-grade tumors, our knowledge about the genetic lesions and clonal evolution in LGG is still incomplete. METHODS: To obtain a complete registry of gene mutations involved in LGG pathogenesis and their role in clonal evolution, we performed whole exome sequencing (WES) of paired tumor/normal DNA from 54 cases with LGG. Clonal evolution in LGG was investigated using paired primary/relapsed tumor specimens from 9 cases as well as multiple tumor specimens (median 5) from 4cases. We further performed deep-sequencing of common mutational targets identified by WES and SNP array analysis among a large cohort of 327 LGG cases. RESULTS: Major mutational targets detected in WES included not only previously known mutational genes, including IDH1/2, TP53, ATRX, CIC, FUBP1 and NOTCH1, as well as multiple components of the PI3K pathway and the SWI/SNF complex. Multi-sampling analysis revealed regional and special heterogeneity of LGG. According to the observed variant allele frequencies (VAFs), mutations of IDH1/2 and 1p19q co-deletion were thought to exist in the major clone, representing truncal mutations in most cases., In contrast, mutations in TP53, ATRX, CIC and FUBP1 were more often identified in one or more phylogenic branches in different subclones and involved in parallel evolution, where different mutations of the same genes were found at different time points in different locations. mutations in IDH1/2 were found in 78.6%. 1p19q co-deletion (43.1%), and TP53 mutations (34.6%) with or without ATRX mutations were mutually exclusive with common IDH mutations. VAFs of coexisting IDH1/2 and 1p19q co-deletion were approximately the same, whereas mutations in other genes tended to show lower VAFs than those of IDH1/2. CONCLUSIONS: Combined, our findings revealed two major, mutually exclusive patterns in clonal evolution in LGG; in some cases IDH1/2 mutations and 1p19q co-deletions were trunchal events, followed by CIC, FUBP1, and other mutations in subsequent phylogenic branches. In other cases, predated by the founder IDH1/2 mutations, mutations in TP53 and ATRX seemed to predominate tumor populations later. SECONDARY CATEGORY: Epidemiology & Cancer Control.

Expression of histone deacetylase 1 in astrocytomas

Objective To investigate protein levels of histone deacetylase 1 ( HDAC1 ) in low grade and high grade of astrocytomas and its correlation with clinical prognosis of astrocytomas.Methods Samples from 283 primary gliomas of WHO Ⅱ -Ⅳ and 52 recurrent lesions were evaluated.The histopathologic diagnoses were as follows:59 cases of low-grade gliomas ( grade Ⅱ) and 276 cases of high-grade gliomas (26 grade Ⅲ and 250 glioblastomas).The expression of HDAC1 was immunohistochemically analyzed and its correlation with tumor differentiation,tumor proliferation and survival was analyzed.Results Totally 59.6％ of the tumors showed HDAC1 nuclear expression,and about 19.1％ of them showed more than 50％ nuclear expression. In 6 individuals who underwent tumor relapse with increasing in WHO grade,the immunoreactivity was decreased with tumor progression in 2 cases,remained stable immunoreactivity in 3 cases,and increased in 1 case.In 20 cases who underwent tumor relapse without increasing in WHO grade,HDAC1 immunoreactivity was decreased in 4 cases,remained stable in 4 cases and increased in the rest 12 cases.HDAC1 expression showed no correlations with WHO grade,Ki-67 expression or Nestin expression,and there was no significant association between HDAC1 expression and patients' survival (P ＞ 0.05,respectively).Conclusion Our findings suggest that HDAC1 is strongly expressed in astrocytic tumors and HDAC1 expression is increased during tumor recurrence. Key words: Histone deacetylase 1; Astrocytic tumor

Axial Diffusivity and Tensor Shape as Early Markers to Assess Cerebral White Matter Damage Caused by Brain Tumors Using Quantitative Diffusion Tensor Tractography

We investigated the usefulness of diffusion tensor tractography (DTT) for differentiating between histological pathologies and evaluating white matter (WM) damage resulting from brain tumors. We also sought to categorize the appearance of brain tumor-related WM tract changes. A total of 18 inpatients with intracranial neoplasms were enrolled. MRI examinations were performed at 3 T using an 8-channel phased array coil. DTT was reconstruction from the raw data of diffusion tensor imaging. WM tract-based analysis of the mean diffusivity (MD), eigenvalues (λ(1) , λ(2) , λ(3) ), and fractional anisotropy (FA) was performed by the manual placement of regions of interest (ROIs) on the color-coded FA maps using DTIStudio software. The axial diffusivity (DA, namely λ(1) ) and the tensor shape (Cl, namely (λ(1) -λ(2) )/3 (λ)) were also compared between groups. P values <0.05 were considered statistically significant. In cases of low-grade glioma (LGG), the tracts adjacent to the tumors displayed the highest levels of invasion. Tract disruption was mainly observed in cases of high-grade glioma (HGG). We found significant differences regarding the FA, MD, DA, and radial diffusivity between ROIs in patients with LGG or HGG. There were also significant differences in DA and tensor shape (Cl) between patients with LGG and HGG. Axial diffusivity and Cl may be useful early markers for differentiating between LGG and HGG.

A subset of human gliomas shows over-expression of KIT without its amplification

Receptor tyrosine kinase (RTK) encoded by proto-oncogene KIT is known to be involved in different types of cancers. Reportedly, KIT expression has been associated with higher grade of gliomas. Initial RT-PCR based KIT expression observed in low grade glioma cases evoked our interest to ascertain its status in glioma patients who underwent resection during 2008–2009. Contrary to earlier reports, over-expression of the RTK was observed in 32.5% glioma cases across low/high grades (n=40). Using quantitative PCR (qPCR), an up-regulation of the receptor (KIT) and its ligand (KITLG) was detected in most of the immunopositive cases at the transcript level. Sequence analysis of KIT showed two nucleotide substitutions in exons 10 and 17, in 4 and 2 cases, respectively though their pathological significance remained unclear. qPCR detected gene amplification in 2/13 glioma and allele loss in 1/13 glioma cases. This was in accordance with FISH results of these KIT positive neoplastic tissues. The data suggest that deranged expression of KIT is independent of gene amplification (p>0.05). Aberrant KIT expression is significantly associated with transcriptional up-regulation (p<0.001), though the precise mechanism(s) for transcriptional activation remain unclear.

Reorganizacja funkcjonalna ośrodków językowych u pacjentów z guzami OUN w badaniu funkcjonalnego rezonansu magnetycznego.

The aim of this study was to determine the reorganization of the language areas in patients with tumors located near speech centers using functional magnetic resonance imaging (fMRI). fMRI was performed prior to the surgical treatment of 11 right-handed patients with tumors located close to the Broca's or Wernicke's areas of the left hemisphere. The analysis included a record of the activity in four regions of interest (ROIs): Broca's and Wernicke's areas, and their anatomic homologues in the right hemisphere. For each patient a regional lateralization index was calculated separately for Broca's area versus its right-hemisphere homolog and Wernicke's area versus its right-hemisphere homolog. The results were correlated with the histopathological type of the tumor and its size. Our fMRI examinations showed activation of the Broca's area in the right hemisphere in 3/4 cases of low grade gliomas (LGG) localized in the left frontal lobe. In one case of the high grade glioma (HGG) only the left hemisphere Broca's area was activated (LI=1). Activation in Wernicke's area in both hemispheres was obtained irrespective of the size and histological type of the tumor. All tumors localized in the left temporal lobe were HGG. We obtained activation only in the right hemisphere Wernicke's area in 4/5 of the cases. In 4/5 of the cases activation in Broca's area was present- in 2 cases in the left hemisphere, in 1 case in the right hemisphere and in 1 case bilateral. The presence of a neoplastic lesion in close topographic relationship to language areas induces their functional reorganization. fMRI is an useful method for determination of language areas localization in pre-operative planning. HGG tumors localized near Wernicke's area lead to transfer its function to the healthy hemisphere and/or to decreased activity in the affected hemisphere.

Assessment of Type of Allergy and Antihistamine Use in the Development of Glioma

Allergies have been associated with decreased risk of glioma; but, associations between duration and timing of allergies, and antihistamine use and glioma risk have been less consistent. The objective was to investigate this association by analyzing types, number, years since diagnosis, and age at diagnosis of allergies, and information on antihistamine usage, including type, duration, and frequency of exposure. Self-report data on medically diagnosed allergies and antihistamine use were obtained for 419 glioma cases and 612 hospital-based controls from Duke University and NorthShore University HealthSystem. High- and low-grade glioma cases were statistically significantly less likely to report any allergy than controls (OR = 0.66, 95% CI: 0.49-0.87 and OR = 0.44, 95% CI: 0.25-0.76, respectively). The number of types of allergies (seasonal, medication, pet, food, and other) was inversely associated with glioma risk in a dose-response manner (P value for trend < 0.05). Age at diagnosis and years since diagnosis of allergies were not associated with glioma risk. Oral antihistamine use was statistically significantly inversely associated with glioma risk, but when stratified by allergy status, remained significant only for those with high-grade glioma and no medically diagnosed allergy. All types of allergies appear to be protective with reduced risk for those with more types of allergies. Antihistamine use, other than in relationship with allergy status, may not influence glioma risk. A comprehensive study of allergies and antihistamine use using standardized questions and biological markers will be essential to further delineate the biological mechanism that may be involved in brain tumor development.

EGFR immunolabeling pattern may discriminate low-grade gliomas from gliosis

Overexpression of epidermal growth factor receptor (EGFR) is common in gliomas. Gliomas are infiltrating tumors in which neoplastic glial cells can be intermingled with reactive glial cells, particularly in diffuse low-grade gliomas. As overexpression of EGFR has also been described in gliosis, it can be difficult to evaluate EGFR immunolabeling in diffuse low-grade gliomas because of this cell mix. We compared EGFR immunolabeling between gliosis and low-grade gliomas in order to identify distinctive criteria. We studied EGFR expression in 28 cases of gliosis and 39 diffuse low-grade gliomas (23 astrocytomas and 16 oligodendrogliomas). EGFR immunohistochemistry staining was performed on paraffin-embedded sections with a mouse monoclonal antibody (clone 2-18C9; Dako). Co-expression of EGFR with Olig2, Mib-1, and p53 was assessed in seven cases of low-grade gliomas using double immunolabeling. Then, EGFR immunostaining was blindly tested on 22 small specimens of indeterminate glial lesions provided by a reference neuropathological center. Two pathologists of our local center were asked to classify the lesions into diffuse low-grade glioma or gliosis according to the pattern of EGFR expression. Weak expression of EGFR was commonly detected in gliosis (23/28 cases). Strongly-stained cells were absent. Positive cells had reactive glial cell morphology. EGFR expression in gliomas was characterized by constant strongly-stained cells (39/39 cases). All strongly-stained cells had a high nucleus-to-cytoplasm ratio, with minimal to moderate nuclear atypia. Most of the strongly EGFR-positive cells were Olig2-positive. All the cases displayed cells co-expressing EGFR and Mib-1. In three p53-positive tumors, many p53-positive cells were strongly EGFR-positive. On the basis of EGFR expression, 14 out of the 22 indeterminate cases were classified as gliomas and eight as gliosis by both pathologists. Concordance with the initial diagnosis established by the reference center and concordance between the pathologists were 100%. Our results confirm that weak EGFR expression can be detected by immunohistochemistry in gliosis. They show that strong EGFR expression may be specific for neoplastic glial cells. As all low-grade gliomas contained strongly-stained cells in our study, we believe that EGFR immunohistochemistry could be a useful tool for detection of neoplastic glial cells in case of indeterminate glial lesions.

鈴木二郎・高久晃教授の低悪性度神経膠腫手術記録から学ぶべきこと

鈴木二郎・高久晃教授の低悪性度神経膠腫手術記録から学ぶべきこと

Low grade diffuse gliomas: Shared cellular composition and morphometric differences

Low grade diffuse gliomas arising in the brain are challenging to treat because of their ability to infiltrate adjacent tissue. We attempted to clarify the cellular composition and histopathological features of low grade gliomas by utilizing morphometric and immunohistochemical analyses. Seventy-eight cases of low grade gliomas were examined including 21 diffuse astrocytomas (DA), 36 oligodendrogliomas (OL), and 21 oligoastrocytomas (OA), based on the WHO classification system. Moreover, OL were subdivided into three types based on the morphological characteristics advocated by Daumas-Duport et al.: OL type I, OL type II, and OL type III. The cellularity, nuclear form factor, and conditional entropy corresponding to the nuclear pleomorphism were measured in each sample by the image analysis software "Gunmetry." Twenty-two cases were immunohistochemically analyzed for the expression of several antigens. Morphometric data indicated that the cellularity of OL type II was significantly higher than that of DA, and that the conditional entropy of OL type III was significantly lower than that of DA. Although the results of the immunohistochemical studies were almost consistent with previous reports, there were significant differences in the expression of GFAP, nestin and p53 between DA and OL. Double immunostaining revealed that expression of Olig2 and GFAP, and Olig2 and nestin was mutually exclusive in most glioma cells. Moreover, the coexpression of nestin and GFAP occurred in DA and OA, but not in OL. We conclude that each glioma include cells expressing GFAP, cells expressing nestin, and cells expressing Olig2 in a characteristic proportion for each tumor type. We suggest that diffuse gliomas share cellular compositions in different ratios and that they can be distinguished by morphometrical analysis.

Detection of human cytomegalovirus in different histological types of gliomas

The association between human cytomegalovirus (HCMV) infection and glioblastoma has been a source of debate in recent years because of conflicting laboratory reports concerning the presence of the virus in glioma tissue. HCMV is a ubiquitous herpesvirus that exhibits tropism for glial cells and has been shown to transform cells in vitro. Using sensitive immunohistochemical and in situ hybridization methods in 50 glioma samples, we detected HCMV antigen and DNA in 21/21 cases of glioblastoma, 9/12 cases of anaplastic gliomas and 14/17 cases of low-grade gliomas. Reactivity against the HCMV IE1 antigen (72 kDa) exhibited histology-specific patterns with more nuclear staining for anaplastic and low-grade gliomas, while GBMs showed nuclear and cytoplasmic staining that likely occurs with latent infection. Using IHC, the number of HCMV-positive cells in GBMs was 79% compared to 48% in lower grade tumors. Non-tumor areas of the tissue contained only four and 1% of HCMV-positive cells for GBMs and lower grade tumors, respectively. Hybridization to HCMV DNA in infected cells corresponded to patterns of immunoreactivity. Our findings support previous reports of the presence of HCMV infection in glioma tissues and advocate optimization of laboratory methods for the detection of active HCMV infections. This will allow for detection of low-level latent infections that may play an important role in the initiation and/or promotion of malignant gliomas.

PET Imaging of cerebral astrocytoma with 13N-ammonia

We performed this study in order to assess the clinical potential of (13)N-ammonia PET in patients with cerebral astrocytoma. Dynamic 13N-ammonia PET was performed in 25 patients with suspected cerebral gliomas or recurrent cerebral astrocytomas (19 male and 6 female patients; age range 18-64 years) detected by MRI. The histopathological diagnoses were made for all cases either by biopsy or craniotomy, except for one patient with brain infarction and one patient with brain radiation necrosis confirmed by repeated MRI imaging. PET images were visually inspected, and the tumor-to-white matter count (T/W) ratios and the perfusion index (PI) of the tumors were determined. Six out of nine cases of low-grade gliomas were detected with 13N-ammonia PET, and three non-astrocytoma low-grade gliomas were not detected with 13N-ammonia PET. All 11 high-grade astrocytomas exhibited markedly increased uptake of 13N-ammonia. The five non-neoplastic lesions exhibited low uptake, low T/W ratios and low PI. The significant differences were observed between high-grade and low-grade gliomas with respect to both the T/W ratios and PI (T/W ratios: 5.92+/-2.27, n=11 vs. 1.66+/-0.61, n=9, P<0.01; PI: 5.22+/-1.67, n=11 vs. 1.60+/-0.54, n=9, P<0.01). There were the significant differences between the T/W ratios and PI in low-grade astrocytomas and that in non-neoplastic lesions (T/W ratios: 2.00+/-0.42, n=6 vs. 0.97+/-0.11, n=5, P<0.01; PI: 1.89+/-0.37, n=6 vs. 0.99+/-0.03, n=5, P<0.01). There is a substantial uptake of 13N-ammonia in cerebral astrocytomas. 13N-ammonia PET may enable differentiation between low- and high-grade astrocytomas, and has the potential to enable differentiation between low-grade astrocytomas and non-neoplastic lesions.

Different Aetiology of Familial Low-Grade and High-Grade Glioma? A Nationwide Cohort Study of Familial Glioma

An increased risk for first-degree relatives (FDR) of glioma patients has previously been observed. The novel objective of this study was to investigate differences in familial risk among FDR of low-grade glioma (LGG) and high-grade glioma (HGG) cases, respectively. Two cohorts were constructed, one from 15,321 FDR of LGG cases and the other from 26,635 FDR of HGG cases calculating standardised incidence ratios (SIR). The risk for LGG among FDR of LGG cases was significantly increased, SIR 3.65 (95% CI 2.31–5.47). The risk was even higher in the cohort of siblings, SIR 7.00 (95% CI 3.35–12.87), and especially in the younger siblings (<40 years), SIR 9.01 (95% CI 4.31–16.57). When calculating the risk for HGG in the LGG cohort and the risk for HGG in the HGG cohort, there was a generally twofold increased risk, but no trends of increased risk in relatives of younger probands. Two different methods calculating familial risk displayed similar results. LGG families apparently have features manifesting a distinct pedigree pattern with sibpairs affected at a young age. These families could provide new insights into the aetiology of glioma.

Deletion and 5’CPG island methylation of pl5 gene in brain glioma

Objective: To investigate the abnormality of p15 gene in brain glioma and the correlation of it with occurrence or malignant progression of brain glioma. Methods: Deletion and 5'CPG island methylation of p15 gene were detected by the methods of PCR and PCRbased methylation in 56 cases of brain glioma. Results: Out of 43 cases of high grade glioma, 14 cases were found to have homozygous deletion of p15E1, while none of the 13 cases of low grade glioma was found to have deletion of pl5E1 (P<0.05). Methylation of 5'CPG Island of p15 gene was found only in four cases of glioma. Conclusion: Abnormality of p15 gene may involved in the occurrence and malignant progression of brain glioma. Homozygous deletion of gene is the major mechanism of inactivation for p15 gene in brain glioma.

Low grade glioma in intractable epilepsy: lesionectomy versus epilepsy surgery.

In approximately 30% of patients with intractable partial epilepsy, an intra-axial cerebral lesion is the aetiology of the seizure disorder. Lesions adjacent to mesiotemporal structures often result in secondary epileptogenicity in the same region. The authors present 22 cases of low-grade gliomas associated with intractable epilepsy. In 15 cases the location was temporal (8 extra-hippocampal and 7 with invasion of the amygdalo-hippocampus), 7 cases were extratemporal in eloquent areas. The eight extra-hippocampal tumours were originally treated with lesionectomy. The seizure outcome was class 1 in only 4 cases, the remaining 4 were class 4 according to Engel's classification. The 4 cases with class 4 outcome required additional temporal lobectomy associated with amygdalo-hippocampectomy for seizure control. The 2 cases with associated hippocampal atrophy at MRI after lobectomy had outcome class 1. The 2 cases without hippocampal atrophy at MRI presented outcome class 2. The 7 cases with invasion of amygdala and hippocampus were treated with selective lesionectomy+amygdalo-hippocampectomy. In all these cases convergence of focal structural abnormality, ictal onset of epileptiform EEG abnormality and interictal epileptiform EEG abnormality provided powerful evidence of focal epileptogenicity. All these patients had a favourable epilepsy outcome (class 1-2). In the seven extratemporal cases the first step was lesionectomy. In 1 case located in the parietal region intraoperative mapping was required. 5 had class 1 outcome, one case had outcome class 2 and one case had an outcome class 4. The last patient required a second step operation with intraoperative strip and deep electrode monitoring that led subsequently to a frontal lobectomy. This patient is seizure free 2 years after surgery. There was no perioperative mortality and post-operative morbidity was 3/22. This study indicates that lesionectomy may be the first step procedure if the structural abnormality is localized to extra-temporal eloquent cortex and concordance is documented. Patients may subsequently be candidates for a cortical resection as a second step procedure if the lesionectomy does not provide an adequate reduction in seizure tendency. Since MRI identified hippocampal atrophy was predictive in this study of an unsatisfactory seizure outcome after lesionectomy, MRI defined dual pathologies consisting of a temporal lesion plus hippocampal atrophy necessitate temporal lobectomy+amygdalo-hippocampectomy. In patients with negative MRI findings of hippocampal atrophy and temporal lobe lesions, intraoperative electrocorticography and deep electrode monitoring are indicated for planning the surgical strategy.

Clinicopathological Study on Low Grade Glioma

The clinical status of patients with glioma is influenced by 1) the histological malignancy of the tumor, 2) the tumor volume, 3) secondary status such as brain edema or intracranial hypertension due to the tumor, and 4) the host immunity. Due to some improvement in at least 2) and 3) by the initial treatment, most low grade glioma cases pass through a clinically silent postsurgical period. However, at a certain point, transition to a high grade tumor malignant transformation may occur with exacerbation of the symptoms. Twenty-two cases of histologically established low grade glioma experienced over the past 7 years, in which immunological status was evaluated, were analyzed. Nine cases (41%) showed malignant transformation. Characteristic pictures of the clinical symptoms, computed tomography (CT) scan findings, immunological status, and morphological findings (mainly immunohistochemical examination) in nine cases were delineated. The findings at the time of exacerbation of the symptoms were as follows. In all cases CT scan demonstrated the change in the main lesion from low density to mixed density and were compatible with a high grade glioma. Reduction in host immunity was verified. Morphological increase in the tumor volume, increase in histological malignancy and deterioration in the secondary status due to the tumor were confirmed. Necrosis of the tumor cells as well as increase in giant cells and gemistocytes were observed. Immunohistochemical analysis revealed a decrease and irregularity in glial fibrillary acidic protein positive cells and positive processes as well as increase in vimentin intensity. These findings demonstrate change in the biological characteristics of the tumor.(ABSTRACT TRUNCATED AT 250 WORDS)