Anaplastic oligodendroglioma arising from the brain stem and featuring 1p/19q co‐deletion

With respect to localization, oligodendrogliomas are characterized by a marked preponderance of the cerebral hemispheres. Outside these typical sites, any tumor histopathologically reminiscent of oligodendroglioma a priori is likely to represent one of its morphological mimics, including clear cell ependymoma, neurocytoma, pilocytic astrocytoma or glioneuronal tumors. This is particularly relevant as several of the latter are in principle curable by surgery. Among extrahemispherical sites, bona fide oligodendroglioma – as characterized by loss of heterozygosity (LOH) of chromosome arms 1p and 19q – so far has not been documented to occur in the brain stem. Here, we report the case of a 55‐year‐old female patient with an anaplastic oligodendroglioma (WHO grade III) of the brain stem and cerebellum diagnosed by stereotactic biopsy and featuring combined LOH of 1p and 19q. A morphological peculiarity was a population of interspersed tumor giant cells, a phenomenon that has been referred to as polymorphous oligodendroglioma. Our findings confirm the notion that – although very infrequently – true oligodendrogliomas do occur in the infratentorial compartment.     

Molecular analysis of chromosome 1, 10 and 19 abnormalities in human oligodendroglial tumors: relationship between frequency of LOH grade, age and gender

BACKGROUND: Loss of heterozygosity (LOH) on 1p and 19q is observed in most oligodendroglial tumors. LOH on 10q appears to be less common in these tumors as compared to other gliomas. PATIENTS AND METHODS: We reviewed 14 patients with oligodendroglial tumors (10 low-grade and 4 anaplastic oligodendroglioma) to evaluate the frequency of LOH on 1p, 10q and 19q and correlate it with tumor grade and patients' age and gender; 5 loci on 1p and 5 on 19q as well as 4 on 10q were analyzed for LOH using PCR techniques. RESULTS: LOH on 1p together with 19q was detected in 6 tumors, 1 tumor showed deletion of 19q accompanied with deletion on 10q. Deletion on 1p was associated with deletion of 19q (p < 0.005) and mutual associations among deletions at loci on 19q (p < 0.05) were found. Patients with LOH on 1p were younger on average than patients with retained heterozygosity (p = 0.05). Grade II oligodendrogliomas predominated among younger patients (p < 0.01) while grade III oligodendrogliomas predominated among women (p < 0.005). No association between LOH on 1p nor 19q and tumor grade or patients' gender was found. CONCLUSION: Our study provides several clinically interesting findings and further supports the hypothesis of chromosome 1p and 19q involvement in the oligodendroglial cancerogenesis.     

少突胶质细胞起源肿瘤染色体DNA失衡的比较基因组杂交研究

目的 探讨少突胶质细胞起源肿瘤基因组DNA失衡及其与病理分级的关系.方法 用比较基因组杂交技术检测了33例少突胶质细胞起源肿瘤石蜡包埋组织,分析其全基因组DNA失衡状况.结果 少突胶质细胞瘤(ODG)及间变性少突胶质细胞瘤(AODG)的基因组DNA失衡检出率分别为100%(16/16)和88%(15/17),共发现24个有DNA获得和24个有DNA丢失的染色体区带.其中,-19q、-1p/-19q联合性缺失检出率在ODG组明显高于AODG组(P<0.05),+7p检出率在AODG组明显高于ODG组(P<0.05).在22对常染色体及X染色体中,+1q、+7P、+8P、+8q、+9q、+18p、+18q、+20p及-1p、-19q、-Xq出现频率较高.+2q、+4p、+4q、+6p、+10p、+15q、+20q、+22q仅见ODG组,+11q、+12p、+Xp仅见于AODG组.而-3p、-5q、-8p、-12p、-12q、-15q、-19p、-20q、-XP仅见ODG组,-2q、-4p、-4q、-5p、-6q、-7p、-11q、-14q仅见于AODG组.结论 ODG和AODG均有各自特征性的染色体基因组DNA失衡谱;-1p/-19q是评价国人该类肿瘤生物学行为的重要参考指标,对治疗敏感性及患者预后判断有重要的指导意义;+7p和-19q对评估国人该类肿瘤的生物学行为和患者预后有一定参考价值.

Abstract：

Objective To investigate the relationship between genomic DNA imbalance in oligodendroglial tumors and its different classification.Method 16 oligodendrogliomas and 17 anaplastic oligodendrogliomas were investigated by comparative genomic hybridization on Paraffin-Embedded tissue samples, and the chromosomal genomic DNA imbalances were analyzed.Results Chromosome DNA imbalance rates in oligodendrogliomas and anaplastic oligodendrogliomas are 100% and 88% respectively,and chromosomal regions of 24 gains and 24 losses were found in these tumors.19q loss and 1p/19q loss are frequent in oligodendroglioma.The gain of 7p happened predominantly in anaplastic oligodendroglioma, and their differences were significant(P < 0.05 ).+ 1q, + 7p, + 8p, + 8q, + 9q, + 18p, + 18q, + 20p and-1p,-19q,-Xq are frequently occurred in oligodendroglial tumors.+2q, +4p, +4q, +6p, + 10p,+ 15q, + 20q and + 22q are only identified in oligodendroglioma, + 11q, + 12p and + Xp are only identified in anaplastic oligodendroglioma.-3p,-5q,-8p,-12p,-12q,-15q,-19p,-20q and-Xp are only identified in oligodendroglioma, and-2q,-4p,-4q,-5p,-6q,-7p,-11q and-14q are only identified in anaplastic oligodendroglioma.Conclusions The characteristic imbalance spectrum of oligodendroglial tumors is the molecular genetic base to determine their histological phenotype and grade.-1p/-19q are also the important molecular genetic markers to estimate biological behavior,chemotherapy sensitivity of these tumors and patients' prognosis.+7p and-19q may be useful to evaluate the biological behavior of these tumors and patients' prognosis.     

Correlations between molecular profile and tumor location in Chinese patients with oligodendroglial tumors

OBJECTIVE: To investigate possible correlations between molecular alterations and tumor location in Chinese patients with oligodendroglial tumors. METHODS: A series of 105 gliomas, including 42 oligoastrocytomas, and two control groups of 28 oligodendrogliomas and 35 astrocytomas, were retrospectively reviewed. In each case, the radiologic picture and loss of heterozygosity (LOH) on chromosome 1p and 19q detected by denaturing high-performance liquid chromatography (DHPLC) were analyzed. Correlations between molecular profile and tumor location were made by chi-square and Fisher's exact tests. RESULTS: Oligodendroglial tumors located in the nontemporal lobes were significantly more likely to have combination of LOH 1p and LOH 19q than tumors arising in the insula, temporal lobe, and temporal with another lobe (p=0.001). Subgroup analysis confirmed this finding in oligodendrogliomas (p=0.006), but the difference did not reach significance in the oligoastrocytoma group, although the trend was similar (p=0.067). In contrast to the oligodendroglial tumors, we detected no association between molecular alterations and location for diffuse astrocytomas. CONCLUSION: We conclude that molecular subsets of oligodendroglial tumors may arise preferentially in certain lobes of the brain, with tumors having LOH 1p and LOH 19q occurring most frequently in the nontemporal lobes. These findings suggest that molecular subsets of oligodendroglial tumors may arise from site-specific precursor cells, which has provided some information for the current management of these neoplasms in China.     

The impact of molecular and clinical factors on patient outcome in oligodendroglioma from 20 years’ experience at a single centre

The increased chemosensitivity of oligodendroglial tumours has been associated with loss of heterozygosity (LOH) of the p arm of chromosome 1 and the q arm of chromosome 19 (LOH 1p/19q). Other clinical and molecular factors have also been identified as being prognostic and predictive of treatment outcome. We reviewed 105 patients with oligodendroglioma treated at a single centre over 20 years. Median survival in oligodendroglioma patients with LOH 1p/19q was significantly longer (10.9 vs. 2.0 years). In the anaplastic oligodendroglioma group, univariate analysis demonstrated decreased patient age, presentation with seizures, use of adjuvant chemotherapy and LOH 1p/19q as predictors of improved survival. Multivariate analysis confirmed LOH 1p/19q as a significant predictor of improved survival (hazard ratio, 3.4; p = 0.015). Median survival in patients with anaplastic oligodendroglioma with LOH 1p/19q was 15.4 years vs. 1.2 years for those without LOH 1p/19q. This study confirms the utility of LOH 1p/19q as a prognostic marker in oligodendroglioma.     

Correlation of chromosomes 1p and 19q status and expressions of O6-methylguanine DNA methyltransferase (MGMT), p53 and Ki-67 in diffuse gliomas of World Health Organization (WHO) grades II and III: a clinicopathological study

Aims: The objective of the present study was to verify the correlation of chromosomes 1p and 19q status and expressions of O⁶-methylguanine DNA methyltransferase (MGMT), p53 and Ki-67 in diffuse gliomas of World Health Organization grades II and III. Methods: A series of 146 diffuse gliomas, including 45 oligodendrogliomas, 42 oligoastrocytomas and 59 astrocytomas, were analysed by denaturing high-performance liquid chromatography for 1p and 19q status and by immunohistochemistry for MGMT, p53 and Ki-67 expression patterns. The molecular alterations were then correlated with clinicopathological characteristics and with each other. Results: Loss of heterozygosity (LOH) on 1p, combined LOH on 1p and 19q, low MGMT expression and high Ki-67 expression were associated with oligodendroglial tumours, whereas high p53 expression was associated with astrocytic and mixed tumours. LOH on 1p and low MGMT expression were associated with grade II oligodendroglial tumours, whereas high expressions of p53 and Ki-67 were associated with grade III oligodendroglial tumours. In addition, high Ki-67 expression was associated with grade III astrocytomas. LOH on 1p and LOH on 19q were associated with nontemporal oligodendroglial tumours. Nonrandom associations were found between LOH on 1p and LOH on 19q, MGMT expression and p53 expression, and MGMT expression and Ki-67 expression, whereas mutual exclusions were found between LOH on 1p and 19q and p53 expression, and LOH on 1p and Ki-67 expression. Conclusions: The present study revealed significant interrelationships of the investigated molecular alterations and clinicopathological characteristics in diffuse gliomas of World Health Organization grades II and III, which support a promising role of molecular markers in the diagnostic assessment of these neoplasms.     

Clinical, histological, and immunohistochemical features predicting 1p/19q loss of heterozygosity in oligodendroglial tumors

To identify a better diagnostic criteria for oligodendroglial tumors, we investigated the clinical, histological, and immunohistochemical features that would be able to predict a 1p/19q loss of heterozygosity (LOH) in these tumors. We performed a PCR-based LOH test with the 1p and 19q microsatellite markers by microdissecting tumor in 56 samples (44 oligodendrogliomas and 12 mixed oligoastrocytomas) of paraffin-embedded tissue. Patients with oligodendroglial tumors with 1p/19q LOH had a statistically significant better prognosis for overall survival. Comparative analysis of several features indicated that the 1p/19q LOH tumors were associated with two histological features, tumor cellularity and perinuclear halo, and low O⁶-methylguanine-DNA-methyltransferase (MGMT) expression and high cytoplasmic glutathione S-transferase pi (GST-) expression. In addition, the incidence of 1p/19q LOH was infrequent in the youngest age category (less than 20 years old) studied. Using the new features, we could predict the 1p/19q status of oligodendroglial tumors with greater than 90% accuracy. Therefore, applying these features in clinical practice, would be helpful in clarifying oligodendroglial tumor diagnosis.     

Tumour necrosis and microvascular proliferation are associated with 9p deletion and CDKN2A alterations in 1p/19q-deleted oligodendrogliomas

A subset of oligodendrogliomas and oligoastrocytomas has been associated with 1p/19q deletion. Subsequently, this genetic alteration was linked to chemosensitivity and classic histology of oligodendrogliomas. Tumoural progression includes deletions of 9p, 10q and alterations of CDKN2A. However, these (epi)genetic changes have not been associated with specific histological features. In a series of 45 gliomas including oligodendrogliomas, oligoastrocytomas and astrocytomas, deletions of chromosomal regions implied in these tumours (1p, 9p, 10, 17p13, 19q and 22) were looked for by microsatellite analysis. Tumours that were deleted for 1p and 19q were selected. Subsequently, presence of deletions in the other studied regions, (epi)genetic changes in p14ARF, CDKN2A and CDKN2B, as well as histological features, were associated to these tumours. 1p/19q deletion was observed in 22 tumours. Twenty-one of them presented regions of classic histology of oligodendroglioma. A deletion of 9p was found in eight of them, always in association with tumour necrosis and/or microvascular proliferation. In addition, (epi)genetic alterations of CDKN2A were observed in 71% of these tumours. Presence of regions of classic histology of oligodendroglioma in a tumour sample is predictive of 1p/19q deletions. Necrosis and/or microvascular proliferation are signs of an additional 9p deletion. Finally, as CDKN2A (epi)genetic alterations were found in 71% of the 1p/19q/9p-deleted oligodendrogliomas, CDKN2A may have a role in oligodendroglioma-associated microvascular proliferation.     

Molecular genetic alterations in glioblastomas with oligodendroglial component

Glioblastoma multiforme is the most malignant astrocytic glioma and usually resistant to chemotherapy. A small fraction of glioblastomas may contain areas with histological features of oligodendroglial differentiation. To determine the molecular genetic alterations in such "glioblastomas with oligodendroglial component", we investigated 13 of these tumors for genetic alterations and/or expression of the TP53, CDKN2A, PTEN, and EGFR genes. In addition, we performed microsatellite analyses for loss of heterozygosity (LOH) on chromosome arms 1p, 19q and 10q. None of tumors showed evidence for LOH on 10q. LOH on 1p was detected in 3 tumors, 1 of which additionally showed LOH on 19q. The 3 tumors with LOH on 1p showed neither TP53 mutations nor nuclear p53 accumulation. In contrast, 9 of 10 tumors without demonstrated losses on 1p showed nuclear p53 accumulation. TP53 mutations were identified in 3 of these cases. Further aberrations detected were epidermal growth factor receptor (EGFR) overexpression (3 of 13 tumors), homozygous CDKN2A deletion (2 of 11 tumors), and PTEN mutation (1 of 13 tumors). Taken together, our results indicate that "glioblastomas with oligodendroglial component" carry heterogeneous genetic alterations. LOH on 10q, PTEN mutation, and homozygous CDKN2A deletion appear to be less common in these tumors as compared to ordinary glioblastomas. Furthermore, a subset of these tumors demonstrates LOH on 1p, i.e., an alteration that has recently been linked to chemosensitivity and good prognosis in anaplastic oligodendrogliomas.     

Genetically distinct astrocytic and oligodendroglial components in oligoastrocytomas

Oligoastrocytomas are glial tumours consisting of a mixture of neoplastic astrocytic and oligodendroglial cells. Genetic alterations of oligoastrocytomas include loss of heterozygosity of chromosomes 1p and/or 19q (LOH 1p/19q), typically occurring in oligodendrogliomas, and mutations of TP53, frequently occurring in astrocytomas. To investigate whether these neoplastic cell types in oligoastrocytomas have different genetic profiles, we examined the two different components of oligoastrocytomas in comparison with the histological diagnosis of the specific tumour area for LOH 1p/19q and TP53 mutations by using microdissection technique. We found a variety of lost markers for 1p and 19q, and the presence of two different TP53 mutations in the tumour samples. In the majority of cases (9/11), the oligodendroglial and astrocytic components of an individual oligoastrocytoma displayed the same genotype. We present two cases of biphasic oligoastrocytomas with aberrant findings, suggesting the coexistence of genetically and morphologically distinct tumour cell clones in these tumours. In one case, the oligodendroglial part of the tumour showed LOH19q, whereas the astrocytic part showed TP53 mutation (codon 273). In another case, we found LOH 1p/19q in the oligodendroglial component, but two retained areas on chromosome 1p in the astrocytic component of the tumour. No evidence was found for the coexistence of tumour cells with the two genotypical changes within the same morphological region of one individual tumour. The two cases of biphasic oligoastrocytomas in our sample that display a different genotype in the astrocytic and oligodendroglial part of the tumour show that different components of an oligoastrocytoma may be derived from different cell clones during neoplastic transformation.     

Losses of chromosomes 1p and 19q are rare in pediatric oligodendrogliomas

Pediatric oligodendrogliomas are rare neoplasms and have not been characterized extensively either pathologically or genetically. Given the recent interest in the significance of chromosomal losses in predicting the clinical course and in establishing uniform diagnoses of adult oligodendrogliomas, we reviewed the pathological and clinical features of a series of pediatric oligodendrogliomas and determined their 1p and 19q status using fluorescence in situ hybridization. Of 19 tumors originally diagnosed as oligodendroglioma, 7 were oligodendroglioma, 3 were anaplastic oligodendroglioma, 3 were oligoastrocytoma, and 6 were reclassified. Only one tumor, an anaplastic oligodendroglioma, had 1p loss; none had 19q loss. The single patient whose tumor had 1p loss did not have a particularly favorable clinical course. These results suggest that pediatric oligodendrogliomas arise by molecular alterations distinct from adult oligodendrogliomas, and such molecular alterations do not hold immediate promise as an adjunct to the diagnosis of pediatric oligodendrogliomas.     

Histopathological-molecular genetic correlations in referral pathologist-diagnosed low-grade "oligodendroglioma"

Allelic loss of chromosome 1p predicts increased chemosensitivity and better survival in oligodendroglial tumors. Clinical testing for 1p loss in oligodendroglial tumors at our hospital has allowed us to postulate that certain histological appearances are associated with 1p allelic status. Forty-four cases received for genetic testing were diagnosed by referring pathologists as pure low-grade oligodendroglioma. Central neuropathological review divided the series equally into 22 cases with classical oligodendroglioma histology and 22 with more astrocytic features. Molecular genetic analyses demonstrated 1p loss in 19 of 22 classic oligodendrogliomas (86%) and maintenance of both 1p alleles in 16 of 22 gliomas with astrocytic features (73%). No glial fibrillary acidic protein-positive cell type (gliofibrillary oligodendrocyte, minigemistocyte, cellular processes) was associated with 1p allelic status. Fourteen of the 44 cases were treated with chemotherapy at tumor progression: 3 "astrocytic" gliomas with 1p loss responded to PCV chemotherapy and 2 classic oligodendrogliomas that maintained both 1p alleles included a responder and a non-responder. These results suggest that histological appearance correctly predicts genotype in approximately 80% of low-grade gliomas, but that tumor genotype more closely predicts chemosensitivity. As a result, such objective molecular genetic analyses should be incorporated into patient management and into clinical trials of low-grade diffuse gliomas.     

Oligodendrogliomas: impact of molecular genetics on treatment

The interest in oligodendrogliomas has increased since it became evident that a subset of these tumors respond to chemotherapy or radiation. This interest was augmented when the combined loss of the short arm of chromosome 1 and the long arm of chromosome 19 was identified as a powerful prediction factor for response. Lack of stringent morphological criteria allow high-interobserver variation with regard to classification and grading of oligodendroglial tumors. The prospect of beneficial chemotherapy prompted neuropathologists to diagnose more 'oligodendroglioma' than before. Therefore, there is great demand for unambiguous classification of oligodendroglial tumors. Supplementary analysis of the integrity of chromosomal arms 1p and 19q may greatly assist diagnostic characterization of tumors with oligodendroglial phenotype. The underlying mechanisms for these deletions are not known. Tumor suppressor genes on 1p and 19q relevant for oligodendroglioma have not yet been identified. Knowledge of these genes and the mechanisms of their inactivation might help to understand why oligodendroglial tumors do respond better to chemotherapy and radiotherapy than astrocytomas. This review compiles clinical, pathological and molecular genetic findings on oligodendrogliomas and oligoastrocytomas of WHO Grades II and III to present a brief overview on recent developments.     

Phenotype versus genotype correlation in oligodendrogliomas and low-grade diffuse astrocytomas

Oligodendrogliomas typically show loss of heterozygosity (LOH) on chromosomes 1p and 19q, which correlates with their response to chemotherapy, whereas low-grade astrocytomas are characterized by frequent TP53 mutations and lack of sensitivity to alkylating therapeutic agents. Unequivocal histological distinction of low-grade diffuse astrocytomas from oligodendrogliomas and oligoastrocytomas is often difficult. To elucidate the relationships between morphological phenotype and genetic profile, we screened 19 oligodendrogliomas (WHO grade II) and 23 low-grade diffuse astrocytomas (WHO grade II) for TP53 mutations and LOH on 1p and 19q. In oligodendrogliomas, LOH on chromosomes 1p and/or 19q was found in 15 cases (79%) and TP53 mutation was detected in 4 cases (21%). The presence of a typical perinuclear halo in >50% of tumour cells and a chicken-wire vascular pattern were significantly associated with LOH on 1p or 19q (93% of cases). This suggests that oligodendrogliomas with classical histologic features are likely to have a better prognosis. In low-grade diffuse astrocytomas, LOH on chromosomes 1p and/or 19q was found in three cases (13%) and TP53 mutation was detected in ten cases (43%). Histologically, five low-grade astrocytomas (22%) contained small areas with oligodendroglial differentiation, but this did not correlate with the presence of TP53 mutations or LOH on 1p and 19q. In both oligodendrogliomas and astrocytomas, LOH on chromosomes 1p or 19q and TP53 mutation were mutually exclusive. Methylation of the promoter of the gene for O (6)-methylguanine-DNA methyltransferase (MGMT), a DNA repair protein, which confers resistance to chemotherapy with alkylating agents, was detected in 47% of oligodendrogliomas and 48% of low-grade diffuse astrocytomas. There was no correlation with LOH on chromosomes 1p/19q, suggesting that MGMT may not be a prognostic marker for oligodendrogliomas.     

Oligodendroglioma: Impact of molecular biology on its definition,diagnosis and management

Molecular genetics and biology have been having significant influence on the practice of neuro‐oncology in recent years, with oligodendrogliomas being the most prominent example. The majority of oligodendrogliomas show remarkable sensitivity to chemotherapy, and the finding that the loss of chromosome 1p was tightly associated with the response opened a new era in which the treatment can be tailored for each tumor patient based on molecular genetic diagnosis. It has been noticed that histological features, when closely examined, are also correlated with the molecular genetic data, such as losses of 1p/19q/10q and TP53 mutation. Furthermore, expression profiling using microarray technology showed that oligodendrogliomas with 1p loss express high levels of neuronal genes, suggesting that the progenitor of those tumors may be shared with neurons. Considering the rapid progress of the knowledge in neural developmental biology, it is possible that the classification, definition and diagnosis of gliomas will be rewritten based on such knowledge at the molecular level in the near future, if they reflect the biological features of each tumor better than the histological diagnosis based mostly on morphology.     

Loss of heterozygosity analysis in an anaplastic oligodendroglioma arising after radiation therapy

OBJECTIVE AND IMPORTANCE: Oligodendroglial tumors rarely occur after radiation therapy. Here, we report a rare case of anaplastic oligodendroglioma arising after radiation therapy, in which genetic analysis was performed. CLINICAL PRESENTATION AND INTERVENTION: A 41-year-old man who had received radiation therapy for a tumor of the suprasellar and pineal regions 31 years previously, presented with headache and progressive right hemiparesis. Magnetic resonance (MR) images revealed a ring-enhanced mass lesion in the left frontal lobe. Total removal of the tumor was performed through left frontoparietal craniotomy, and the histologic diagnosis was anaplastic oligodendroglioma. Using 23 microsatellite markers, the allelic status of chromosomes 1p, 10, 17p and 19q was evaluated by a PCR-based loss of heterozygosity (LOH) assay. Markers on chromosomes 1p, 17p and 19q revealed LOH, but none of the markers on chromosome 10 showed LOH. Based on the genetic analysis, this tumor was considered to be sensitive to chemotherapy. Two courses of chemotherapy, with procarbazine, ACNU and vincristine, were performed. However, tumor recurrence was detected only 3 months after the surgery. Despite additional radiochemotherapy, the tumor aggressively increased in size and the patient died with multiple recurrent tumors 1 year after surgery. CONCLUSION: The anaplastic oligodendroglioma presented in this report showed a more aggressive clinical course than was expected from the genetic analysis. The significance of 1p and 19q LOH in radiation-induced oligodendroglial tumors might differ from that in spontaneous counterparts.     

Chromosome 1p and 19q status and p53 and p16 expression patterns as prognostic indicators of oligodendroglial tumors: A clinicopathological study using fluorescence in situ hybridization

To verify the prognostic implications of the statuses of chromosome 1p and 19q and the expressions of p53, p16 and GFAP in oligodendrogliomas, we investigated these parameters and correlated the results with patient outcome. Twenty-seven cases of low-grade oligodendroglioma (LO) and 29 cases of anaplastic oligodendroglioma (AO) were analyzed by FISH for 1p and 19q status and by immunohistochemistry for p53, p16, and GFAP expression using a tissue microarray. Direct sequencing of the p53 gene was also performed. 1p deletion was observed in 39 of 56 patients (69.9%), and 19q deletion in 41 of 56 (73.2%). Combined loss of 1p and 19q was found in 38 of 56 (67.9%) and exhibited distinct concomitant deletion (P = 0.000). p53 overexpression was observed in 17 cases (30.3%), GFAP expression in 18 cases (32.1%), and p16 loss in 40 cases (74%) of oligodendrogliomas. The expressions of p53 and GFAP were more frequent in AO than in LO (P = 0.015 and 0.001). In contrast, p53 expression was more common in oligodendrogliomas with an intact 19q (P = 0.029), or an intact 1p (P = 0.071). Only five of 14 patients with p53 expression showed TP53 mutation, which was inversely correlated with 1p deletion (P = 0.036). Patients with combined loss of 1p and 19q exhibited better overall survival (P = 0.045). Patients with p53 expression without combined 1p and 19q loss showed poor overall survival (P < 0.000). However, TP53 mutation along with 1p and 19q status could not predict patient outcome. Patients with p16 loss without combined 1p and 9q loss showed poor overall survival (P = 0.011). Therefore, in oligodendrogliomas, the absence of the combined deletion of 1p and 19q and the aberrant expression of p53 or loss of p16 could be used as poor prognostic markers.     

Utility of in situ demonstration of 1p loss and p53 overexpression in pathologic diagnosis of oligodendroglial tumors

To improve the diagnostic accuracy of oligodendroglial tumors and to find more convenient parameters that could predict the cytogenetic status, oligodendroglial and astrocytic tumors were cytogenetically and immunohistochemically investigated. Materials included 22 oligodendroglial tumors (15 oligodendrogliomas and 7 oligoastrocytomas) and 20 astrocytic tumors. 1p loss was examined with the fluorescence in situ hybridization (FISH) method. Expression of GFAP, Olig2 and p53 was immunohistochemically investigated and co‐localization of GFAP and Olig2 was evaluated on double‐immunostained sections. Furthermore, TP53 mutation analyses were carried out on three oligodendroglial tumors showing p53 protein overexpression with a direct sequence analysis. Our FISH studies demonstrated 1p loss in 73% of oligodendroglial tumors (80% oligodendrogliomas and 57% oligoastrocytomas) and in only 10% of astrocytic tumors. There were no clear‐cut morphologic differences between 1p‐deleted and 1p‐intact oligodendroglial tumors. GFAP and Olig2 were expressed in most oligodendroglial and astrocytic tumors, and their cellular localization was almost independent of each other. Overexpression of p53 was observed in five oligodendroglial tumors, all of which were 1p‐intact. In comparison, 16 oligodendroglial tumors with 1p deletion showed no overexpression of p53. TP53 missense mutations were detected in three of the p53 overexpressed oligodendroglial tumors studied. Our results suggest that 1p loss is almost specific to oligodendroglial tumors. Although the prediction of 1p status based solely on the morphologic features seems to be difficult, the immunohistochemistry for p53 is a useful tool in that p53 overexpression is closely related to the 1p‐intact status in oligodendroglial tumors.     

Correlation between tumor-related seizures and molecular genetic profile in 103 Chinese patients with low-grade gliomas: a preliminary study

Tumor-related seizures are a well-known presenting symptom of primary brain tumors, particularly low-grade gliomas (LGGs). The objective of the present study was to investigate the possible correlation between tumor-related seizures and molecular genetic profile in Chinese patients with LGGs. A series of 103 LGGs, including 27 oligodendrogliomas, 41 oligoastrocytomas and 35 astrocytomas, was analyzed by denaturing high-performance liquid chromatography (DHPLC) for 1p and 19q status, with particular emphasis on correlations with tumor-related seizures. Most oligodendrogliomas and oligoastrocytomas had LOH 1p and LOH 19q, which were rarely seen in combination in astrocytomas (p<0.001). LOH 1p and LOH 19q were also closely associated (p=0.022). The majority of patients with LGGs presented with seizures at disease onset (68.9% of all patients). The most common seizure type was secondary generalized seizures (81.7% of patients with seizures). Patients without LOH 19q were more likely to present with seizures (p=0.033), particularly secondary generalized seizures (p=0.005), than those with this alteration. The current study presented an update on studies on tumor-related seizures and molecular genetic profile, and brought forward putative candidate genes for secondary generalized seizures on chromosome 19q, based on the assumption that common molecular genetic pathways may exist for glioma development and tumor-related seizures.