Alpha-internexin and altered CIC expression as a supportive diagnostic marker for oligodendroglial tumors with the 1p/19q co-deletion

α-Internexin (INA) has been proposed as a biomarker of oligodendroglial tumors with the 1p/19q co-deletion. On the other hand, sequence studies have recently linked the CIC mutation and subsequent altered CIC expression to the 1p/19q co-deletion in oligodendroglial tumors. We assessed the usability of combination immunohistochemical analysis using CIC and INA as a surrogate tool for the 1p/19q status in 39 cases of oligodendroglial tumors. The positive expression of INA was observed in 10 cases (52 %) of oligodendroglial tumors with the 1p/19q co-deletion, and in only 3 cases of oligodendroglial tumors without the 1p/19q co-deletion (15 %, P = 0.012). The lack of CIC expression was detected in 13 cases (68 %) of oligodendroglial tumors with the 1p/19q co-deletion, and in only 1 case of oligodendroglial tumors without the 1p/19q co-deletion (5 %, P < 0.0001). Combined immunohistochemical analysis assessed by INA expression and/or the lack of CIC expression was strongly associated with the 1p/19q co-deletion in oligodendroglial tumors, indicating a potential surrogate marker of the 1p/19q state. Although combined immunohistochemical analysis cannot be totally replaced by molecular genetic analysis as a definitive diagnostic technique, it may contribute to a steady morphological diagnosis by predicting the 1p/19q state in oligodendroglial tumors.     

Significance of IDH mutations varies with tumor histology, grade, and genetics in Japanese glioma patients

Mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 are found frequently in malignant gliomas and are likely involved in early gliomagenesis. To understand the prevalence of these mutations and their relationship to other genetic alterations and impact on prognosis for Japanese glioma patients, we analyzed 250 glioma cases. Mutations of IDH1 and IDH2 were found in 73 (29%) and 2 (1%) cases, respectively. All detected mutations were heterozygous, and most mutations were an Arg132His (G395A) substitution. IDH mutations were frequent in oligodendroglial tumors (37/52, 71%) and diffuse astrocytomas (17/29, 59%), and were less frequent in anaplastic astrocytomas (8/29, 28%) and glioblastomas (13/125, 10%). The pilocytic astrocytomas and gangliogliomas did not have either mutation. Notably, 28 of 30 oligodendroglial tumors harboring the 1p/19q co-deletion also had an IDH mutation, and these alterations were significantly correlated (P < 0.001). The association between TP53 and IDH mutation was significant in diffuse astrocytomas (P = 0.0018). MGMT promoter methylation was significantly associated with IDH mutation in grade 2 (P < 0.001) and grade 3 (P = 0.02) gliomas. IDH mutation and 1p/19q co-deletion were independent favorable prognostic factors for patients with grade 3 gliomas. For patients with grade 3 gliomas and without 1p/19q co-deletion, IDH mutation was strongly associated with increased progression-free survival (P < 0.0001) and overall survival (P < 0.0001), but no such marked correlation was observed with grade 2 gliomas or glioblastomas. Therefore, IDH mutation would be most useful when assessing prognosis of patients with grade 3 glioma with intact 1p/19q; anaplastic astrocytomas account for most of these grade 3 gliomas.     

Occupational exposure to metals and risk of meningioma: a multinational case-control study

The prognosis of patients with WHO grade III gliomas is highly dependent on their genomic status such as the isocitrate dehydrogenase (IDH) 1/2 mutation and1p/19q co-deletion. However, difficulties have been associated with determining which tumors have certain genomic profiles by preoperative radiographical modalities, and the role of surgical resection in achieving better outcomes remains unclear. This retrospective study included 124 consecutive patients with newly diagnosed grade III gliomas. The genomic status of IDH1/2 and 1p/19q was analyzed in these patients. Tumors were then divided into 3 subgroups based on their genomic status; the IDH 1/2 mutation with the 1p/19q co-deletion (1p/19q co-del), the IDH 1/2 mutation without the 1p/19q co-deletion (non-1p/19q co-del), and the IDH 1/2 wild type (IDH wt). Survival times were compared between patients who underwent gross total resection and those who did not (GTR versus non-GTR). The relationships between genomic statuses and MR imaging characteristics such as ring-like or nodular enhancements by gadolinium, and very low intensity on T1-weighted images with blurry enhancements (T1VL) were also examined. Among all patients with grade III gliomas, GTR patients had longer median survival and progression-free times than those of non-GTR patients (undefined versus 87 months, p?=?0.097, and 124 versus 34 months, p?=?0.059, respectively). No significant differences were observed in survival between GTR and non-GTR patients in the 1p/19q co-del group (p?=?0.14), or between GTR and non-GTR patients in the IDH wt group (26 and 27 months, p?=?0.29). On the other hand, in non-1p/19q co-del group, survival was significantly longer in GTR patients than in non-GTR patients (undefined versus 77 months, p?=?0.005). Radiographically, T1VL was detected in most tumors in the non-1p/19q co-del group (78.2?%), but only 6 (21.4?%) and 17 (41.5?%) tumors in the 1p/19q co-del and IDH wt groups, respectively. A correlation was not found between other genomic subgroups and MR imaging findings. Strict surgical removal is important to improve the prognosis of patients with grade III gliomas, especially for tumors with the IDH 1/2 mutation without the 1p/19q co-deletion. The MR finding of T1VL can be used to select candidates for more radical resection.     

Calcification on CT is a simple and valuable preoperative indicator of 1p/19q loss of heterozygosity in supratentorial brain tumors that are suspected grade II and III gliomas

Gliomas with 1p/19q loss of heterozygosity (LOH) are known to be associated with longer patient survival and higher sensitivity to treatment than tumors without 1p/19q LOH. This study was designed to clarify whether the preoperative finding of calcification on CT was correlated with 1p/19q LOH in patients with suspected WHO grade II and III gliomas. This study included 250 adult patients who underwent resection for primary supratentorial tumors at Tokyo Women’s Medical University Hospital. The tumors were suspected, based on MRI findings, to be WHO grade II or III gliomas. The presence of calcification on the patients’ CT images was qualitatively evaluated before treatment. After surgery, the resected tumors were examined to determine their 1p/19q status and mutations of IDH1 and p53. The presence of calcification was significantly correlated with 1p/19q LOH (P < 0.0001), with a positive predictive value of 91 %. The tumors of all the 78 patients with calcification were diagnosed as oligodendroglial tumors. Seventy of these patients showed classic oligodendroglial features, while 8 patients showed non-classic features. Calcification on CT is a simple and valuable preoperative indicator of 1p/19q LOH in supratentorial brain tumors that are suspected to be WHO grade II and III gliomas.     

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.     

The clinical importance of medulloblastoma extent of resection: a systematic review

In this study we aimed to identify the anatomic features of 1p/19q co-deletion and investigate the predictive values of tumor location and radiological characteristics for the survival of anaplastic oligodendroglial (AO) glioma patients. Voxel-based lesion-symptom mapping (VLSM) analysis was applied to define the brain regions associated with occurrence of 1p/19q co-deletion in a cohort of 206 AO tumor patients (discovery set) treated between May 2009 and September 2013. Retrospectively, the acquired clusters and radiological features were subjected to Kaplan–Meier survival analysis using data from the Chinese Glioma Genome Atlas (validation set) to evaluate their prognostic role in AO patients. The institutional review board approved this study. The right frontal lobe and right anterior insular lobe were specifically associated with high occurrence of 1p/19q co-deletion. For AO tumors not involving these areas, the absence of contrast enhancement predicted longer progression-free (p?=?0.018) and overall survival (p?=?0.020); moreover, in patients with contrast enhancement, edema could stratify the survival outcome (p?=?0.013 for progression-free survival, p?=?0.016 for overall survival). For AO tumors located in the VLSM-identified regions, edema was also able to stratify the survival outcome of patients without contrast enhancement (p?=?0.025 for progression-free survival, p?=?0.028 for overall survival). The 1p/19q co-deletion showed predilection for specific brain regions. According to the tumor involvement of VLSM-identified regions associated with 1p/19q co-deletion, radiological features were predictive for AO patient survival outcomes.     

Correlation of histology and molecular genetic analysis of 1p, 19q, 10q, TP53, EGFR, CDK4, and CDKN2A in 91 astrocytic and oligodendroglial tumors.

PURPOSE: The histological diagnosis of human gliomas is of great importance for estimating patient prognosis and guiding therapy but suffers from being subjective and, therefore, variable. We hypothesized that molecular genetic analysis could provide a more objective means to classify tumors and, thus, reduce diagnostic variability. EXPERIMENTAL DESIGN: We performed molecular genetic analysis on 91 nonselected gliomas for 1p, 19q, 10q, TP53, epidermal growth factor receptor, and cyclin-dependent kinase 4 abnormalities and compared with the consensus diagnoses established among four independent neuropathologists. RESULTS: There were six astrocytomas, seven anaplastic astrocytomas, 45 glioblastomas, 21 oligodendrogliomas, eight anaplastic oligodendrogliomas, three oligoastrocytomas, and one anaplastic oligoastrocytoma. Twenty-nine cases had either 1p or 19qloss of heterozygosity (LOH) while retaining both copies of 10q, of which 25 (86%) were histologically oligodendroglioma, anaplastic oligodendroglioma, oligoastrocytoma, or anaplastic oligoastrocytoma. As for the oligodendroglial tumors, unanimous agreement of the initial diagnoses was almost restricted to those cases with combined 1p/19qLOH, whereas all nine tumors without 1p loss initially received variable diagnoses. Interestingly, TP53 mutation was inversely related to 1pLOH in all gliomas (P = 0.0003) but not 19qLOH (P = 0.15). CONCLUSIONS: These data demonstrate that molecular genetic analysis of 1p/19q/10q/TP53 has significant diagnostic value, especially in detecting oligodendroglial tumors. In addition, 1pLOH and TP53 mutations in gliomas may be markers of oligodendroglial and astrocytic pathways, respectively, which may separate gliomas with the same histological diagnosis, especially oligodendroglial tumors and glioblastomas. Testing for those molecular genetic alterations would be essential to obtain more homogeneous sets of gliomas for the future clinical studies.     

Anaplastic oligodendroglial tumors harboring 1p/19q deletion can be successfully treated without radiotherapy

Although anaplastic oligodendroglial tumors are known to be chemosensitive, patients under this diagnosis have been traditionally treated with radiotherapy. To avoid possible neurotoxicity, we prospectively treated patients with anaplastic oligodendroglial tumors harboring 1p/19q deletion, with exclusive procarbazine, ACNU, and vincristine chemotherapy without radiotherapy. Twenty-five patients were enrolled in the study (12 with 1p/19q co-deletion, 2 with 1p mono-deletion, 2 with 19q mono-deletion, and 9 without 1p/19q deletion). The median progression-free survival (PFS) was 50 months for all the patients, and those with tumors harboring 1p/19q deletion were progression free for a significantly longer period than those without the deletion (p=0.0391). The median overall survival (OS) time was not reached in both patient groups with and without 1p/19q deletion (p=0.230), and the 5-year OS rate was 62.2% for all patients. The excellent treatment results warrant a large-scale clinical study to confirm the efficacy of upfront chemotherapy omitting radiotherapy as initial therapy for anaplastic oligodendroglial tumors with 1p/19q deletion.     

IDH‐mutated astrocytomas with 19q‐loss constitute a subgroup that confers better prognosis

IDH‐mutant gliomas are classified into astrocytic or oligodendroglial tumors by 1p/19q status in the WHO 2016 classification, with the latter presenting with characteristic morphology and better prognosis in general. However, the morphological and genetic features within each category are varied, and there might be distinguishable subtypes. We analyzed 170 WHO grade II‐IV gliomas resected in our institution. 1p/19q status was analyzed by microsatellite analysis, and genetic mutations were analyzed by next‐generation sequencing and Sanger sequencing. For validation, the Brain Lower Grade Glioma dataset of The Cancer Genome Atlas was analyzed. Of the 42 grade III IDH‐mutated gliomas, 12 were 1p‐intact/19q‐intact (anaplastic astrocytomas [AA]), 7 were 1p‐intact/19q‐loss (AA), and 23 showed 1p/19q‐codeletion (anaplastic oligodendrogliomas). Of the 88 IDH‐wild type glioblastomas (GBMs), 14 showed 1p‐intact/19q‐loss status. All of the seven 1p‐intact/19q‐loss AAs harbored TP53 mutation, but no TERT promotor mutation. All 19q‐loss AAs had regions presenting oligodendroglioma‐like morphology, and were associated with significantly longer overall survival compared to 19q‐intact AAs (P = .001). This tendency was observed in The Cancer Genome Atlas Lower Grade Glioma dataset. In contrast, there was no difference in overall survival between the 19q‐loss GBM and 19q‐intact GBM (P = .4). In a case of 19q‐loss AA, both oligodendroglial morphology and 19q‐loss disappeared after recurrence, possibly indicating correlation between 19q‐loss and oligodendroglial morphology. We showed that there was a subgroup, although small, of IDH‐mutated astrocytomas harboring 19q‐loss that present oligodendroglial morphology, and also were associated with significantly better prognosis compared to other 19q‐intact astrocytomas.     

Epidermal growth factor receptor (EGFR) amplification rates observed in screening patients for randomized trials in glioblastoma

Journal of Neuro-Oncology - Chromosomes 1p/19q co-deletion is a robust molecular marker for the diagnosis of oligodendroglial tumors, and has been included in the 2016 WHO modified classification....     

Immunohistochemical ATRX expression is not a surrogate for 1p19q codeletion

The IDH-mutant and 1p/19q co-deletion (1p19q codel) provides significant diagnostic and prognostic value in lower-grade gliomas. As ATRX mutation and 1p19q codel are mutually exclusive, ATRX immunohistochemistry (IHC) may substitute for 1p19q codel, but this has not been comprehensively examined. In the current study, we performed ATRX-IHC in 78 gliomas whose ATRX statuses were comprehensively determined by whole exome sequencing. Among the 60 IHC-positive and 18 IHC-negative cases, 86.7 and 77.8% were ATRX-wildtype and ATRX-mutant, respectively. ATRX mutational patterns were not consistent with ATRX-IHC. If our cohort had only used IDH status and IHC-based ATRX expression for diagnosis, 78 tumors would have been subtyped as 48 oligodendroglial tumors, 16 IDH-mutant astrocytic tumors, and 14 IDH-wildtype astrocytic tumors. However, when the 1p19q codel test was performed following ATRX-IHC, 8 of 48 ATRX-IHC-positive tumors were classified as “1p19q non-codel” and 3 of 16 ATRX-IHC-negative tumors were classified as “1p19q codel”; a total of 11 tumors (14%) were incorrectly classified. In summary, we observed dissociation between ATRX-IHC and actual 1p19q codel in 11 of 64 IDH-mutant LGGs. In describing the complex IHC expression of ATRX somatic mutations, our results indicate the need for caution when using ATRX-IHC as a surrogate of 1p19q status.     

Immunohistochemistry on IDH 1/2, ATRX,p53 and Ki-67 substitute molecular genetic testing and predict patient prognosis in grade III adult diffuse gliomas

The molecular subgrouping of diffuse gliomas was recently found to stratify patients into prognostically distinct groups better than histological classification. Among several molecular parameters, the key molecules for the subtype diagnosis of diffuse gliomas are IDH mutation, 1p/19q co-deletion, and ATRX mutation; 1p/19q co-deletion is undetectable by immunohistochemistry, but is mutually exclusive with ATRX and p53 mutation in IDH mutant gliomas. Therefore, we applied ATRX and p53 immunohistochemistry instead of 1p/19q co-deletion analysis. The prognostic value of immunohistochemical diagnosis for Grade III gliomas was subsequently investigated. Then, the same immunohistochmical diagnostic approach was expanded for the evaluation of Grade II and IV diffuse glioma prognosis. The results indicate immunohistochemical analysis including IDH1/2, ATRX, p53, and Ki-67 index is valuable for the classification of diffuse gliomas, which is useful for the evaluation of prognosis, especially Grade III gliomas and lower-grade gliomas (i.e., Grade II and III).     

Comparison of 1p and 19q status of glioblastoma by whole exome sequencing,array-comparative genomic hybridization,and fluorescence in situ hybridization

According to the 2016 World Health Organization classification of tumors of the central nervous system, detecting 1p/19q co-deletion became essential in clinical neuropathology for gliomas with oligodendroglioma-like morphology. Here, we assessed genomic profiles of glioblastoma in 80 cases including 1p/19q status using fluorescent in situ hybridization (FISH), array-comparative genomic hybridization (aCGH), and/or whole exome sequencing (WES). Paraffin-embedded tumor tissues were subjected to FISH analysis, and the corresponding frozen tissues from the same tumors were evaluated for aCGH and/or WES for 1p/19q co-deletion and other genetic parameters, which included IDH1-R132H, ATRX, TP53, CIC, and NOTCH1 mutations and MGMT methylation status. We also evaluated correlations between 1p/19q co-deletion status and molecular markers or clinical outcomes. The FISH analyses revealed 1p/19q co-deletion in two cases, isolated deletion of 1p in six cases, and 19q in two cases, whereas the aCGH and WES results showed isolated deletion of 19q in four cases and 19 monosomy in only one case. Eleven cases showed discordant 1p/19q results between aCGH/WES and FISH analysis, and in most of them, 1p and/or 19q deletion on FISH analysis corresponded to the partial deletions at 1p36 and/or 19q13 on aCGH/WES. Our cohort exhibited IDH1-R132H mutations (5.4%), MGMT promotor methylation (34.6%), and mutations in ATRX (9.5%), TP53 (33.3%), and NOTCH1 (3.8%) but not in CIC (0%). In addition, MGMT methylation and ATRX mutation were significantly associated with clinical prognosis. In glioblastomas, partial deletions of 1p36 and/or 19q13 were uncommon, some of which appeared as 1p and/or 19q deletions on FISH analysis.     

BAC array CGH distinguishes mutually exclusive alterations that define clinicogenetic subtypes of gliomas

The pathological classification of gliomas constitutes a critical step of the clinical management of patients, yet it is frequently challenging. To assess the relationship between genetic abnormalities and clinicopathological characteristics, we have performed a genetic and clinical analysis of a series of gliomas. A total of 112 gliomas were analyzed by comparative genomic hybridization on a BAC array with a 1 megabase resolution. Altered regions were identified and correlation analysis enabled to retrieve significant associations and exclusions. Whole chromosomes (chrs) 1p and 19q losses with centromeric breakpoints and EGFR high level amplification were found to be mutually exclusive, permitting identification of 3 distinct, nonoverlapping groups of tumors with striking clinicopathological differences. Type A tumors with chrs 1p and 19q co-deletion exhibited an oligodendroglial phenotype and a longer patient survival. Type B tumors were characterized by EGFR amplification. They harbored a WHO high grade of malignancy and a short patient survival. Finally, type C tumors displayed none of the previous patterns but the presence of chr 7 gain, chr 9p deletion and/or chr 10 loss. It included astrocytic tumors in patients younger than in type B and whose prognosis was highly dependent upon the number of alterations. A multivariate analysis based on a Cox model shows that age, WHO grade and genomic type provide complementary prognostic informations. Finally, our results highlight the potential of a whole-genome analysis as an additional diagnostic in cases of unclear conventional genetic findings.     

Molecular–genetic and clinical characteristics of gliomas with astrocytic appearance and total 1p19q loss in a single institutional consecutive cohort

The prognostic significance of 1p19q loss in astrocytic gliomas has been inconclusive.We collected 57 gliomas with total 1p19q loss from among 218 cases of WHO grade-II/III gliomas operated at Keio University Hospital between 1990 and 2010. These tumors were classified as oligodendroglial or “astrocytic” by a WHO-criteria-based institutional diagnosis. Chromosomal copy number aberrations (CNAs), IDH 1/2 mutations, MGMT promoter methylation, and expression of p53 and ATRX were assessed. Survival outcome was compared between the two histological groups.Of the 57 codeleted gliomas, 37, 16, and four were classified as oligodendroglial, “astrocytic”, and unclassified, respectively. Comparative genomic hybridization revealed that although chromosome 7q/7 gain was more frequent in “astrocytic” gliomas, other CNAs occurred at a similar frequency in both groups. None of the “astrocytic” gliomas showed p53 accumulation, and ATRX loss was found in three of the 15 “astrocytic” gliomas. The estimated overall survival (OS) curves in the patients with codeleted oligodendroglial and “astrocytic” gliomas overlapped, and the median OS was 187 and 184 months, respectively. Histopathological re-assessment by a single pathologist showed consistent results.Gliomas with total 1p19q loss with “astrocytic” features have molecular and biological characteristics comparable to those of oligodendroglial tumors.     

Chromosomal alterations in oligodendroglial tumours over multiple surgeries: is tumour progression associated with change in 1p/19q status?

BACKGROUND: Oligodendroglial neoplasms have morphologic and genotypic heterogeneity. Loss of heterozygosity (LOH) of 1p and/or 19q is associated with increased treatment responsiveness and overall survival. However, the pathogenesis of treatment-resistance is unknown. We sought to determine if tumour progression is due to a proliferating sub-population of tumour cells with intact 1p, or if recurrent tumours retain 1p/19q LOH. METHODS: 24 patients with oligodendroglial neoplasms, possessing biopsy samples taken at diagnosis and at progression, were identified. 53 tumour specimens were available for LOH analysis of 1p and 19q, using PCR amplification of multiple microsatellite markers. 40 were also tested for 9p and 10q. RESULTS: At diagnosis, the median age was 34 (24-66) years, 14 were male. 19 tumours were WHO Grade II, and 5 were high grade. The most common genomic status was 19q LOH (70%). 13 (54%) tumours were 1p LOH at diagnosis: of these, 12 were 19q LOH, and 1 was 19q uninformative. All 12 patients with 1p/19q LOH primary tumours had persistent co-deletion at progression. 9 (38%) tumours were 1p intact at diagnosis, and 8 remained 1p intact in the progressed tumours. There was little heterogeneity of 9p and 10q between tumours at diagnosis and progression. CONCLUSION: 100% of oligodendroglial tumours with 1p/19q LOH, demonstrated persistent 1p/19q LOH in the progressed tumour. Therefore, progression of these tumours is not due to a proliferating sub-population of treatment-resistant, 1p intact tumour cells. We propose that additional mutations contribute to this aggressive phenotype, however, 9p LOH or 10q LOH are unlikely to be involved.     

Distinct patterns of 1p and 19q alterations identify subtypes of human gliomas that have different prognoses

We studied the status of chromosomes 1 and 19 in 363 astrocytic and oligodendroglial tumors. Whereas the predominant pattern of copy number abnormality was a concurrent loss of the entire 1p and 19q regions (total 1p/19q loss) among oligodendroglial tumors and partial deletions of 1p and/or 19q in astrocytic tumors, a subset of apparently astrocytic tumors also had total 1p/19q loss. The presence of total 1p/19q loss was associated with longer survival of patients with all types of adult gliomas independent of age and diagnosis (P = .041). The most commonly deleted region on 19q in astrocytic tumors spans 885 kb in 19q13.33–q13.41, which is telomeric to the previously proposed region. Novel regions of homozygous deletion, including a part of DPYD (1p21.3) or the KLK cluster (19q13.33), were observed in anaplastic oligodendrogliomas. Amplifications encompassing AKT2 (19q13.2) or CCNE1 (19q12) were identified in some glioblastomas. Deletion mapping of the centromeric regions of 1p and 19q in the tumors that had total 1p/19q loss, indicating that the breakpoints lie centromeric to NOTCH2 within the pericentromeric regions of 1p and 19q. Thus, we show that the copy number abnormalities of 1p and 19q in human gliomas are complex and have distinct patterns that are prognostically predictive independent of age and pathological diagnosis. An accurate identification of total 1p/19q loss and discriminating this from other 1p/19q changes is, however, critical when the 1p/19q copy number status is used to stratify patients in clinical trials.     

Polysomy of chromosomes 1 and 19: an underestimated prognostic factor in oligodendroglial tumors

The clinical significance of chromosomes 1 and 19 deletion was well established in oligodendroglial tumors (ODGs). This study was designed to evaluate the prognostic implication of chromosomes 1 and 19 polysomy in gliomas. 584 patients with histological diagnosis of primary gliomas enrolled in the study. Chromosomes 1 and 19 status was detected with fluorescence in situ hybridization (FISH). Of the 584 cases, the frequency of 1q and 19p polysomy in mixed gliomas was significantly higher than ODGs or astrocytic tumors (1q P = 0.032 and P = 0.044; 19p P = 0.024 and P = 0.027); the frequency of 1q and 19p polysomy in low-grade gliomas (WHO II) was relatively lower compared with WHO III or WHO IV (1q P = 0.097 and P = 0.026; 19p P = 0.04 and P = 0.002). 1q, 19p and co-polysomy were confirmed as risk factors conveyed unfavorable outcomes, which has been further validated in both anaplastic oligodendroglial tumors (AOGs) (P = 0.07, P = 0.028 and P = 0.054 for PFS; P = 0.007, P = 0.001 and P = 0.002 for OS, respectively) and glioblastomas with oligodendroglioma component (GBMOs) (P = 0.005, P < 0.001 and P < 0.001 for PFS; P = 0.136, P = 0.006 and P = 0.051 for OS, respectively). Based on chromosomes 1/19 co-deletion and co-polysomy, AOGs and GBMOs could be divided into three subgroups which harbored distinct prognosis (AOGs P < 0.001 for PFS and P < 0.001 for OS; GBMOs P < 0.001 for PFS and P = 0.012 for OS). Chromosomes 1/19 polysomy are potential prognostic factors which confer unfavorable outcomes. The molecular prognostic grouping model based on chromosomes 1/19 co-polysomy and co-deletion better predicts prognosis and provides a more reliable information for treatment decision-making.     

Granular cells in oligodendroglioma suggest a neoplastic change rather than a reactive phenomenon: case report with molecular characterisation

Oligodendrogliomas are diffuse gliomas characterised by IDH mutation and 1p/19q co-deletion. Classical oligodendrocytes, minigemistocytes, gliofibrillary oligodendrocytes, granular cells, and mucocytes are morphologic cell types described in oligodendroglioma. Even though the occurrence of granular cells in oligodendroglioma is known, exact nature of these cells and their molecular characteristics remain undetermined. We describe a case of oligodendroglioma with granular cells, in which we have attempted to molecularly characterise the granular cells. These granules were stained blue on Luxol fast blue and red on Masson’s trichrome. The cells showed a distinct pattern of immunoreactivity to GFAP and IDH1. In addition, they exhibited mitotic activity and increased Ki-67 labelling. Molecularly, both the granular cells and classical oligodendroglial cells in the tumor showed 1p/19q co-deletion which is the diagnostic hallmark of an oligodendroglioma. Thus, we opine that granular cells are neoplastic and represent a morphological variant of neoplastic oligodendrocyte.