Glioblastoma With Oligodendroglioma Component Research Articles

An analysis of glioblastomas with oligodendroglioma component based on the integrated diagnosis model

Objective To analyze the histopathologic subtype glioblastoma with oligodendroglioma component (GBMO) based on the integrated diagnosis model by the 2016 WHO (World Health Organization) central nervous system tumor classification (2016 classification). Methods A total of 54 cases diagnosed as GBMO were extracted from the database of Chinese Glioma Genome Atlas(CGGA). Pyrosequencing method was used to detect isocitrate dehydrogenase (IDH) mutations and fluorescence in situ hybridization (FISH) technique was employed to detect 1p/19q abnormalities. Survival curves were estimated using the Kaplan-Meier method. An integrated diagnosis was established based on the 2016 classification. Results Among the 54 patients, the incidence of IDH1 mutation was 37.1% (20/54) and the mutation occurred in 132 (exon 4). IDH2 mutation was not detected in this series. Chromosomal status could be assessed in 40 cases by FISH. The incidence of 1p deletion was 17.5%(7/40), 19p deletion was 20.0%(8/40) and 1p/19q co-deletion was 7.5% (3/40). According to the 2 molecular pathologic features of diffuse glioma by 2016 classification, the 40 patients could be divided into 3 groups: group of IDH wildtype (23 cases), group of IDH mutant and 1p/19q non-codeletion(14 cases), and group of IDH mutation and 1p/19q codeletion(3 cases). There was significantly differences among them in the median survival (P=0.008). The group of IDH mutation and 1p/19q codeletion had the best prognosis (32.3 months). The group of IDH mutant and 1p/19q non-codeletion had the median survival of 24.0 months. The group of IDH wildtype had the worst outcome (14.4 months). Conclusion Rather than an independent glioma subtype, the GBMO seems to be a combination of several tumor types with various molecular genetic and clinical biological characteristics. Key words: Glioma; Pathology, molecular; Glioblastomas with oligodendroglioma component; Integrated diagnosis

Glioblastoma with Oligodendroglioma Component (GBMO) in an adolescent: a case report

Background:Glioblastoma with oligodendroglioma component (GBMO) is a recently classified subtype of glioblastoma, which carries different clinical and prognostic outcomes, being frequently misdiagnosed. Both glioblastoma and GBMO are mainly seen in older ages, such as the 5th and 6th decades of life, being an extremely rare occurrence in children or adolescents and more frequent in male patients. 
 Case report: A 15-year-old girl, presented with history of daily headache, not relieved by painkillers, vomiting, blurred vision and strabismus. Magnetic resonance imaging of the brain revealed expansive tumour on left temporo-occipital lobe. Patient was submitted to intracranial exeresis, along with histopathological examination: glial neoplasm with areas of pleomorphism, hyperchromatism, anaplasia, foci of oligodendroglial component, perinuclear halo and ramified capillaries, resembling oligodendroglioma, necrosis and intense mitotic activity. The immunohistochemical analysis revealed positive Glial Fibrillary Acidic Protein (GFAP), synaptophysin, Ki-67 (MindBomb E3 ubiquitin protein ligase 1 – MIB-1)and hyperexpression of Epidermal Growth Factor Receptor (EGFR), indicating GBMO. Subsequently, Fluorescence in situ Hybridization (FISH) showed 1p/19q codeletion and Isocitrate Dehydrogenase 1 (IDH 1) mutation, suggesting an oligodendroglioma component. Tumour resection was total and symptoms disappeared. Afterwards, she started adjuvant oral chemotherapy with temozolomide. Treatment was completed nine months after the diagnosis, with no greater symptoms or complications and complete remission. 
 Conclusion: GBMO must be considered as a possible diagnosis when confronted with a malignant glioma with oligodendroglial tumour component, independent of age or genre. Necrosis upon histopathological examination has a strong relation to shorter median overall survival. IDH mutation and 1p/19q codeletion should be analyzed by immunohistochemistry. Total tumour resection, with adjuvant treatment (chemotherapy with temozolomide and radiotherapy), increases benefits and improves prognosis.

Histological spectrum of oligodendroglial tumors: Only a subset shows 1p/19q codeletion.

Canonical oligodendroglial tumors (ODGs) are characterized genetically by chromosomes 1p/19q codeletion. This study was essentially aimed at the detection of frequency of 1p/19q codeletion in the different histological spectrum of ODG tumors in a large cohort of Indian patients. All the ODG tumors evaluated for 1p/19q by fluorescence in-situ hybridization (FISH) during 2009-2015 were correlated with histology, immunohistochemical expression for p53 protein and clinical features. A total of 676 cases included both pediatric (n = 18) and adult (n = 658) patients. Histologically, 346 pure ODGs [oligodendroglioma (OD) and anaplastic oligodendroglioma (AOD)] and 330 mixed ODGs [oligoastrocytomas (OA), anaplastic oligoastrocytomas (AOA) and glioblastoma with oligodendroglioma component (GBM-O)] were included. 1p/19q co-deletion was noted in 69% (60/87), 55.9% (145/259), 18.2% (18/99), 10.5% (18/172), and in 5.1% (3/59) cases of OD, AOD, OA, AOA, and GBM-O, respectively. In the pediatric age-group, 1p/19q codeletion was seen in 25% (2/8) of pure ODGs and in 10% (1/10) of mixed ODGs. In adults, it was observed in 60% (203/338) cases of pure ODGs and in 11.9% (38/320) cases of mixed ODGs. In adults, pure ODG histology (P = 0.00), frontal location (P = 0.004), calcification [in pure ODGs] (P = 0.03), and lack of p53 protein overexpression (P = 0.00) showed significant statistical correlation with 1p/19q codeletion. This study is unique in being one of the largest on ODGs for 1p/19q co-deletion including both pediatric and adult age groups of Indian patients. The results showed co-deletion in 60% of adult ODGs and 25% of pediatric pure ODGs. This reemphasizes the occurrence of 1p/19q codeletion, even though rare, in the pediatric age group.

Wnt5a, Ryk and Ror2 expression in glioblastoma subgroups

BackgroundWnt5a, a non-canonical Wnt ligand, has been shown to play tumor-promoting or tumor-suppressive roles in different neoplasms. Increased Wnt5a expression and Wnt5a-dependent invasive activity that is mediated by one of its receptors, Ryk, have been reported in glioblastomas. MethodsWe investigated the protein expression of Wnt5a, its receptors Ryk and Ror2, and the canonical Wnt pathway marker β-catenin in 186 cases of glioblastoma and its variants. Associations with clinicopathological and molecular variables and prognosis were analyzed. ResultsAll glioblastoma cases expressed Wnt5a, Ryk and Ror2 with a different grade. The expression of both Ryk and Ror2 correlated with that of Wnt5a in glioblastomas. The expression of β-catenin did not correlate with any of Wnt5a, Ryk or Ror2. Wnt5a expression was significantly different among subgroups of the glioblastoma. However, none of Wnt5a, Ryk or Ror2 had a prognostic impact on glioblastoma. For β-catenin, a shorter progression-free survival was noted in the glioblastoma with oligodendroglioma component (GBMO) subgroup. ConclusionsOur results corroborated previous findings of Ryk-mediated Wnt5a effect, and suggested a role for Ror2 in the Wnt5a machinery in glioblastoma.

Prognosis of Glioblastoma With Oligodendroglioma Component is Associated With the IDH1 Mutation and MGMT Methylation Status

Glioblastoma (GBM) with oligodendroglioma component (GBMO) is a newly described GBM subtype in the 2007 World Health Organization classification. However, its biological and genetic characteristics are largely unknown. We investigated the clinicopathological and molecular features of 34 GBMOs and compared the survival rate of these patients with those of patients with astrocytoma, oligodendroglioma, anaplastic oligoastrocytoma (AOA), and conventional GBMs in our hospital. GBMO could be divided into two groups based on the presence of an IDH1 mutation. The IDH1 mutation was more frequently found in secondary GBMO, which had lower frequencies of EGFR amplification but higher MGMT methylation than the wild type IDH1 group, and patients with mutant IDH1 GBMO were on average younger than those with wild-type IDH1. Therefore, GBMO is a clinically and molecularly heterogeneous subtype, largely belonging to a proneural and classical subtype of GBM. The survival rate of GBMO patients itself was worse than that of AOA patients but not significantly better than that of conventional GBM patients. GBMO survival was independent of the dominant histopathological subtype i.e., astrocyte-dominant or oligodendroglioma -dominant, but it was significantly associated with the IDH1 mutation and MGMT methylation status. Therefore, GBMO should be regarded as a separate entity from AOA and must be classified as a subtype of GBM. However, further study is needed to determine whether it is a pathologic variant or a pattern of GBM because GBMO has a similar prognosis to conventional GBMs.

1p/19q-driven prognostic molecular classification for high-grade oligodendroglial tumors.

The subjectivity in pathological diagnosis of anaplastic oligoastrocytoma (AOA) and uncertainty in designation of glioblastoma with oligodendroglioma component (GBMO) were two major dilemmas which puzzled neuro-pathologists and neurosurgeons. The present study was designed to project a molecular classification scheme based on the status of chromosome 1p and 19q. Patients (n=117) with histological diagnosis of primary high-grade oligodendroglial tumors (HGOs) enrolled in the study. Fluorescence in situ hybridization (FISH) for chromosomes 1p and 19q was performed. Univariate analysis showed that higher tumor grade, 1p/19q maintenance and 1q/19p co polysomy were confirmed as risk factors in HGOs (P<0.01). Accordingly, patients with HGOs were divided into four subtypes which conferred remarkably distinct prognosis based on the number of risk factors (0 risk factor: HGOs-1, 1 risk factor: HGOs-2, 2 risk factors: HGOs-3, 3 risk factors: HGOs-4). Cox regression model revealed that the tumor grade was no longer independently associated with survival, while the molecular classification scheme showed a marked prognostic significance (HR=0.359, 95% CI 0.261-0.494, P<0.001 for progression-free survival (PFS); HR=0.393, 95% CI 0.283-0.546, P<0.001 for overall survival (OS)). The classification scheme incorporating traditional pathology with molecular information can be served as a supplement of the current WHO classification system and contribute to the personalized treatment decision-making.

Immunohistochemical evaluation of O6‐methylguanine DNA methyltransferase (MGMT) expression in 117 cases of glioblastoma

Temozolomide (TMZ) is an oral alkylating agent which is widely used in the treatment of glioblastoma (GBM) and is composed of astrocytic and/or oligodendroglial tumors, and the evaluation of O(6) -methylguanine DNA methyltransferase (MGMT) expression is important to predict the response to TMZ therapy. In this study, we conducted immunohistochemical analysis of 117 cases of Japanese GBM including 19 cases of GBM with oligodendroglioma component (GBMO), using a scoring system for quantitative evaluation of staining intensity and proportion of MGMT, and performed survival analysis of these patients. Immunohistochemically, 55 cases (47%) were positive for MGMT with various intensities and proportions (total score (TS) ≥ 2), while 62 cases (53%) were negative (TS = 0). The distribution of MGMT expression pattern was not affected by any clinicopathological parameters such as the histological subtype (GBM vs. GBMO), age and gender. The survival analysis of these patients revealed that the minimal expression of MGMT (TS ≥ 2) was a significant unfavorable prognostic factor (P < 0.001) as well as resectability (P = 0.004). Moreover, multivariate analysis showed that minimal MGMT expression in GBM was the most potent independent predictor for progression free survival (P < 0.001) and also overall patient survival (P < 0.001). This is the first report employing the scoring system for both staining intensity and proportion to evaluate immunohistochemical MGMT expression in GBM. In addition, our results emphases the clinicopathological values of the immunohistochemical approach for MGMT expression in glioma patients as a routine laboratory examination.

Glioblastoma with Oligodendroglioma Component (GBM‐O): Molecular Genetic and Clinical Characteristics

Glioblastoma (GBM) is an aggressive primary brain tumor with an average survival of approximately 1 year. A recently recognized subtype, glioblastoma with oligodendroglioma component (GBM-O), was designated by the World Health Organization (WHO) in 2007. We investigated GBM-Os for their clinical and molecular characteristics as compared to other forms of GBM. Tissue samples were used to determine EGFR, PTEN, and 1p and 19q status by fluorescence in situ hybridization (FISH); p53 and mutant IDH1 protein expression by immunohistochemistry (IHC); and MGMT promoter status by methylation-specific polymerase chain reaction (PCR). GBM-Os accounted for 11.9% of all GBMs. GBM-Os arose in younger patients compared to other forms of GBMs (50.7 years vs. 58.7 years, respectively), were more frequently secondary neoplasms, had a higher frequency of IDH1 mutations and had a lower frequency of PTEN deletions. Survival was longer in patients with GBM-Os compared to those with other GBMs, with median survivals of 16.2 and 8.1 months, respectively. Most of the survival advantage for GBM-O appeared to be associated with a younger age at presentation. Among patients with GBM-O, younger age at presentation and 1p deletion were most significant in conferring prolonged survival. Thus, GBM-O represents a subset of GBMs with distinctive morphologic, clinical and molecular characteristics.

Prognostic Implication of Histological Oligodendroglial Tumor Component: Clinicopathological Analysis of 111 Cases of Malignant Gliomas

The favorable prognosis of high-grade oligodendroglial tumor such as glioblastoma (GBM) with oligodendroglioma component (GBMO) has been suggested; however, the studies which examine the prognostic significance of oligodendroglial tumor were limited. In this study, we performed a histopathology-based reevaluation of 111 cases of high grade gliomas according to the latest World Health Organization (WHO), and compared the clinical outcomes between oligodendroglial tumors and pure astrocytic tumors. The survival analysis revealed that the patients with high grade oligodendroglial tumor including GBMO significantly indicated better prognosis compared to the patients with high grade pure astrocytic tumors (GBM and AA, anaplastic astrocytoma) as expected, and the obtained survival curves were almost identical to those from the patients with conventional Grade III or Grade IV tumors, respectively. Moreover, if the cases of oligodendroglial tumor were histopathologically excluded, the patients with AA exhibited extremely poor prognosis which was similar to that of GBM, suggesting that the histological identification of oligodendroglial tumor component, even partially, prescribe the prognosis of high grade glioma patients. This is the prominent report of retrospective clinicopathological analysis for high-grade gliomas throughout Grade III and IV, especially referring to the prognostic value of histological oligodendroglial tumor component; in addition, our results might offer an alternative aspect for the grading of high-grade astrocytic/oligodendroglial tumors.

IDH1 mutation as a potential novel biomarker for distinguishing pseudoprogression from true progression in patients with glioblastoma treated with temozolomide and radiotherapy

The purpose of this study was to distinguish pseudoprogression (PP) from early true progression in patients with glioblastoma (GBM) based on the presence of a mutation in isocitrate dehydrogenase 1 (IDH1). We retrospectively surveyed 32 patients with GBM or GBM with oligodendroglioma component (GBMO) who underwent biopsy or maximal tumor resection followed by concurrent radiotherapy and temozolomide (TMZ). We then selected patients with early radiological progression in magnetic resonance imaging within 6 months after concurrent radiotherapy and TMZ treatment. DNA was extracted from their tumor blocks. The IDH1 mutation was analyzed in the genomic region by direct sequencing as a biomarker for PP. Twenty-eight patients were diagnosed with GBM and four with GBMO. Eleven patients were discovered to have early radiological progression. PP was detected in two patients (6.3%) diagnosed with GBMO and one patient with GBM. Both of the GBMO patients with PP had the IDH1 mutation, the one GBM patient with PP and the other eight patients with early true progression with wild type. The sensitivity and specificity of the IDH1 mutation for detecting PP were 66.7 and 100%, respectively. This study suggests the IDH1 mutation may become a novel molecular biomarker for PP. Analyzing the IDH1 mutation, in the case of recognizing early radiological progression, may enable distinction of PP from early true progression, and we could determine the need for second-look surgery.

Molecular characteristics of glioblastoma with 1p/19q co-deletion

Recent developments in molecular analysis have revealed genetic alterations in human gliomas. Loss of heterozygosity (LOH) is a critical molecular marker for classification of human glioma, and is useful for predicting outcome. Our previous LOH study identified a small subgroup of glioblastoma (GBM), with 1p/19q co-deletion, with a favorable clinical outcome. In this study, we investigated molecular pathological features of eight GBM with 1p/19q co-deletion compared with "classic" GBM and anaplastic oligodendroglioma (AO). We estimated EGFR gene amplification, EGFRvIII expression, CDKN2A (p16) homozygous deletion, and isocitrate dehydrogenase 1/2 (IDH1/2) gene mutations. We also conducted an analysis of the expression of proneural genes (DLL3, OLIG2, SOX2). On histopathological review, only one GBM was diagnosed as glioblastoma with oligodendroglioma component (GBMO). Loss of chromosomes 10 and 17p is common, and neither IDH1/2 mutations nor EGFRvIII expression were detected in GBM with 1p/19q co-deletion. The expression profile revealed high expression of the OLIG2 gene in this subgroup. High expression of proneural gene OLIG2 without EGFRvIII expression may be associated with a favorable clinical outcome; however, IDH1/2 gene status and the extent of LOH regions may indicate that this small subgroup of GBM is a distinct genetic subgroup from oligodendroglial tumors.