Abstract
Glioblastomas (GBMs) containing foci that resemble oligodendroglioma are defined as GBM with oligodendroglioma component (GBMO). However, whether GBMO is a distinct clinicopathological variant of GBM or merely represents a divergent pattern of differentiation remains controversial. We investigated 219 consecutive primary GBMs, of which 40 (18.3%) were confirmed as GBMOs. The clinical features and genetic profiles of the GBMOs were analyzed and compared with the conventional GBMs. The GBMO group showed more frequent tumor-related seizures (P= .027), higher frequency of IDH1 mutation (31% vs. <5%, P= .015), lower MGMT expression (P= .016), and longer survival (19.0 vs. 13.2 months; P= .022). In multivariate Cox regression analyses, presence of an oligodendroglioma component was predictive of longer survival (P= .001), but the extent of the oligodendroglial component appeared not to be linked to prognosis (P= .664). The codeletions of 1p/19q, somewhat surprisingly, were infrequent (<5%) in both GBMO and conventional GBM. In addition, the response to aggressive therapy differed: the GBMO group had no survival advantage associated with aggressive treatment protocols, whereas a clear treatment effect was observed in the conventional GBM group. Collectively, the clinical behavior and genetic alterations of GBMO thus differs from those of conventional GBM. Presence of an oligodendroglial component may therefore be a useful classification and stratification variable in therapeutic trials of GBMs.
Keywords: glioblastoma with an oligodendroglioma component, IDH1 mutation, LOH 1p 19q, prognostic, therapeutic response
Glioblastoma (GBM) is the most malignant grade of astrocytic tumor (astrocytoma grade IV). However, a subset of GBM (4%–20%)1–4 contains foci that resemble oligodendroglioma and were classified as GBM with an oligodendroglioma component (GBMO), according to the 2007 World Health Organization classification.5 However, no definitive diagnostic criteria currently exist, and whether GBMO is a distinct clinicopathological variant of GBM or merely represents a divergent pattern of differentiation remains controversial because of insufficient evidence regarding their respective clinical and genetic features.5,6
In contrast to astrocytic tumors including GBMs, oligodendrogliomas have a better prognosis associated with codeletions of chromosome arms 1p and 19q.7,8 This has led to the assumption that patients with GBMO might have a similarly better prognosis. And some evidence supports this presupposition, with median overall survival (OS) of 14–26 months in GBMO patients,1–4 compared with <12 months in unselected GBMs.9 However, the combined loss of 1p/19q seems to be infrequent in GBMO patients and occurred in <10% of cases in several reports.1,10,11
GBMO has been pathologically defined as anaplastic oligoastrocytoma with necrosis6,11 and is presumed to develop from a mixed lower-grade glioma, in which some tumor cells, particularly astrocytoma cells, may undergo malignant transformation. Most GBMOs, however, occur de novo, with no history of lower-grade glioma. However, the possibility of rapid progression from a less malignant precursor lesion that escaped clinical diagnosis cannot be excluded. Isocitrate dehydrogenase 1 (IDH1) mutations have recently been shown to be the best molecular markers of secondary GBMs and were associated with an increase in OS.12 Therefore, analysis of IDH1 mutations may help to improve our understanding of the biology of GBMO.
GBMs are currently classified into 4 clinically relevant subtypes on the basis of multidimensional integrated genomic analysis: proneural, neural, classical, and mesenchymal subtypes.13 The proneural subtype is highly enriched with oligodendrocytic signatures, such as platelet-derived growth factor receptor α, NKX2-2, and OLIG2, and contains high frequencies of IDH1 and TP53 mutations. The survival advantage in heavily treated patients varies by subtype, with a significantly delayed mortality in the latter 3 groups, but that is not observed in the proneural subtype. Whether GBMO is related to the proneural subtype in terms of its clinical and genetic characteristics remains unknown.
The aim of this study was to clinically and genetically characterize GBMO, in comparison with conventional GBM, to determine whether the presence of an oligodendroglioma component represents a useful classification and stratification variable.
Patients and Methods
Patients and Tumor Samples
A consecutive series of 219 adults with primary GBMs were surgically treated at the Glioma Therapy Center of Beijing Tiantan Hospital from March 2005 through June 2009. The diagnostic criterion of GBMO was based on the association of 2 distinct parts in the same tumor.5,14 The first was represented by standard GBM showing nuclear atypia, mitotic activity, vascular proliferation, and necrosis. The second consisted of highly anaplastic oligodendroglia-like cells and cytoplasmic glial fibrillary acidic protein (GFAP) negativity (Figure 1). GBMs with scattered oligodendroglial cells were excluded. All specimens were independently re-evaluated by 2 experienced neuropathologists, who were blinded to the clinical outcome of the patients, according to the World Health Organization 2007 criteria.5 In case of a discrepancy, the 2 observers simultaneously reviewed the slides to achieve a consensus. The GBMs with a history of lower-grade glioma were classified as secondary GBMs and were also excluded from the present study.
Fig. 1.
Histopathological features of 2 glioblastoma (GBM) with oligodendroglial components (GBMO). First row (patient 24, with an oligodendroglial component of 5%), H&E staining demonstrated conventional GBM areas with nuclear atypia, microvascular proliferation, and pseudopalisading necrosis (×100) (A), and astrocytic like cells with enlarged, irregularly hyperchromatic nuclei (×200) (B). However, a minor foci (arrow) showed oligodendroglial differentiation (GFAP-negative) among extensive GFAP-positive areas (×400) (C). Second row (patient 6, with an oligodendroglial component of 60%), H&E staining showed the typical appearance of glioblastoma multiforme. In addition, a large area showed anaplastic oligodendroglial-like cells (×200) (E) and was mostly GFAP-negative (×400) (F).
The characteristics of the patients with GBMO are summarized in Table 1 and Supplementary material, Table S1. Tumors frequently affected >1 lobe; for the purposes of statistical analysis, gliomas involving the temporal and those involving the temporal plus another lobe were grouped as temporal tumors. Other gliomas were grouped as nontemporal tumors. OS was calculated from the date of surgical resection until death or the last known follow-up. All patients with GBM underwent at least subtotal resection confirmed by postoperative enhanced MRI within 72 h. Radiotherapy at a total dose of 60 Gy was administered within 1 month after surgery (2 Gy each dose, with 5 fractions administered per week). The tumor volume initially treated included the contrast-enhanced lesion and surrounding edema identified by preoperative MRI, plus a 2–3-cm margin. After 46 Gy had been administered, treatment was confined to the contrast-enhanced lesion only. Adjuvant chemotherapy consisted of a scheme based on 1-(4-amino-2- methylpyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU-based; ACNU [90 mg/m2, day 1] and VM26 [60 mg/m2, days 1–3]; both given at 6-week intervals) or a scheme based on temozolomide (TMZ-based; 75 mg/m2 during radiotherapy and/or 200 mg/m2, 5 days/cycle after radiotherapy).
Table 1.
Clinical characteristics of patients with glioblastoma with oligodendroglial component (GBMO) and conventional glioblastoma (GBM)
| Variable | GBMO (n = 40) | Conventional GBM (n = 179) | P |
|---|---|---|---|
| Age (years) | |||
| Median (range) | 45.0(19–62) | 48.0(21–70) | |
| Mean | 43.2 | 46.8 | .085 |
| Sex | |||
| Female (%) | 17(42.5) | 66(36.9) | .507 |
| Tumor location | |||
| Temporal (%) | 17(42.5) | 82(45.8) | .704 |
| Presenting symptoms | |||
| Epilepsya (%) | 14(35.0) | 34(19.0) | .027 |
| Preoperative KPS | |||
| Median (range) | 80(50–90) | 80(50–100) | .588 |
| Surgical resection | |||
| Gross total (%) | 14(35.0) | 80(44.7) | .263 |
| Radiation | |||
| Yes (%) | 34(85.0) | 143(87.2) (n = 164)b | .713 |
| Chemotherapy | |||
| Yes (%) | 25(64.1) (n = 39)b | 113(68.9) (n = 164)b | .564 |
aPresence of seizures as presenting symptom.
bExcluding patients lacking relevant information.
An unselected independent series of 30 primary conventional GBMs (12 female and 18 male patients; mean age, 46.2 years, median preoperative Karnofsky performance status [KPS] score, 80) was used as a control group for genetic analysis. IDH1 mutation, 1p/19q deletion, and p53, EGFR, and MGMT expression were detected. The study was approved by the Beijing Tiantan Hospital Research Ethics Board.
Pyrosequencing for IDH1 Mutation and MGMT Promoter Methylation
For IDH1 mutation analysis, genomic DNA was isolated from frozen tumor tissues using the QIAamp DNA Mini Kit (Qiagen). The primers used were IDH1-forward 5′-GCTTGTGAGTGGATGGGTAAAAC-3′ and IDH1-reverse 5′- TTGCCAACATGACTTACTTGATC-3′. For MGMT promoter methylation analysis, bisulite modification of the DNA was performed using the EpiTect Kit (Qiagen). The primers used were 5′-GTTTYGGATATGTTGGGATA-3′ and reverse: 5′-biotin-ACCCAAACACTCACCAAATC-3′. Pyrosequencing analysis of IDH1 mutation and MGMT promoter methylation was performed by Gene Tech (Shanghai, China).
Fluorescence In Situ Hybridization (FISH) for 1p/19q Abnormalities
For FISH analysis, representative tumor areas were marked on hematoxylin and eosin–stained sections. The corresponding areas were identified on the paraffin blocks, and new 4-µm sections were prepared. The material was deparaffinized with xylene, incubated with 0.3% pepsin in 10 mM HCl at 37°C for 10 min, and then denatured at 85°C for 10 min. Dual-color FISH hybridizations were performed using LSI probe sets 1p36/1q25 and 19q13/19p13 (spectrum orange-labeled 1p36 and 19q13 probes; spectrum green-labeled 1q25 and 19p13 probes; Vysis) and assessed in at least 200 nonoverlapping nuclei with intact morphology.
Immunohistochemistry for p53, EGFR, and MGMT
Immunoperoxidase staining for p53, EGFR, and MGMT (Santa Cruz Biotechnology) was performed on formalin-fixed, paraffin-embedded tissue sections, according to the manufacturer's instructions. Each stained slide was jointly scored by 2 pathologists blinded to the clinical information. For statistical analysis, high expression of EGFR and MGMT was defined as >30% of positive-stained cells in the tumor. The p53 protein accumulation was defined as strong nuclear staining in at least 30% of the tumor cells. Two blinded pathologists independently evaluated the slides. In case of a discrepancy, the 2 observers simultaneously reviewed the slides to achieve a consensus.
Statistical Analysis
SPSS, version 13.0 (SPSS), was used for all statistical analyses. We applied t tests, χ2 tests, or Fisher's exact tests for statistical analysis of the correlations between 2 independent variables. Survival curves were estimated using the Kaplan-Meier method, and statistical differences were evaluated using the 2-sided log-rank test. Multivariate analysis was performed with the Cox regression model. A P <.05 (two-sided) was considered to be statistically significant.
Results
Patient Demographic Characteristics
Forty (18.3%) of the 219 primary GBMs selected fulfilled the criteria for GBMO. The areas that resemble oligodendroglioma are variable extent (5%–75%), and 15 of the tumors contained an oligodendroglial component of ≤30%. The ages of the 40 patients with GBMO (23 men and 17 women) ranged from 19 to 62 years (mean, 43.2 years; median, 45.0 years). The preoperative KPS score ranged from 50 to 100 (median, 80). Fourteen patients (35%) had seizure attacks (12 secondary generalized seizures and 2 partial seizures) as presenting symptoms (Supplementary material, Table S1). The median follow-up period for all 219 patients was 34 months (range, 21–74 months).
The patients with GBMO were more likely to present with seizures than were patients with conventional GBM (P= .027, χ2 test) (Table 1). Although the age at diagnosis of the patients with GBMO was slightly lower than that of patients with conventional GBM, the difference was borderline nonsignificant (P= .085, t test). There were no significant differences in sex, KPS score, tumor location, or adjuvant chemo- or radiological therapy between the groups (Table 1).
Survival
The patients with GBMO had significantly more favorable clinical outcomes, with a median OS time of 571 days (95% confidence interval [CI], 471–671 days), compared with 396 days (95% CI, 354–438 days) for patients with conventional GBM (P= .022, log-rank test) (Table 2 and Fig. 2 ). In multivariate Cox regression analysis, including age at diagnosis, sex, preoperative KPS score, adjuvant radiotherapy, and chemotherapy, the presence of an oligodendroglioma component was predictive of longer survival (P= .001; hazard ratio, 0.43; 95% CI, 0.26–0.69) (Table 2). To clarify the clinical value of the percentage of oligodendroglioma cells, the GBMOs were classified into 2 clusters: the ≤30% oligodendroglial component group and the larger proportion oligodendroglial component group. The results showed that the extent of the oligodendroglial component was not linked to prognosis (P= .664, log-rank test).
Table 2.
Presence of an oligodendroglial component and clinical outcome of glioblastomas (GBMs)
| Variable | n | Univariate analysis |
Multivariate analysisa |
|---|---|---|---|
| Median OS (95% CI) (days) | HR (95% CI) | ||
| GBMO | 37b | 571 (471–671) | |
| conventional GBM | 174b | 396 (354–438) | 0.43 (0.26–0.69) |
| P for trend | 0.022 | 0.001 |
Abbreviations: CI, confidence interval; HR, hazard ratio; OS, overall survival.
aThe multivariate Cox regression model initially included age at diagnosis, gender, preoperative KPS score, adjuvant radiotherapy and chemotherapy. A backward stepwise elimination with a threshold of P = .05 was used to select variables in the final model.
bPatients who died in the peroperative period or from non-glioma-related causes were excluded from survival analysis.
Fig. 2.
Kaplan-Meier curve demonstrating survival of glioblastoma (GBM) and glioblastoma with oligodendroglial component (GBMO).
Genetic Characteristics
There were 29 frozen GBMO tissues available for the analysis of IDH1 status. Of the 29 GBMOs analyzed, 9 (31%) contained an IDH1 mutation. All mutations were located at amino acid residue 132, and all were G → A mutations (Arg → His). In contrast, only 1 (4.2%) of 24 analyzed GBMs contained an IDH1 mutation (P= .015, Fisher's exact test) (Table 3).
Table 3.
Genetic characteristics of patients with 40 glioblastomas with an oligodendroglial component (GBMOs) and 30 patients with conventional glioblastomas (GBMs)
| Variable | GBMO (n = 40) | conventional GBM (control) (n = 30) | P |
|---|---|---|---|
| LOH 1p | |||
| Yes (%) | 5(17.9) (n = 28) | 1(4.8) (n = 21) | .219a |
| LOH 19q | |||
| Yes (%) | 6(21.4) (n = 28) | 0(0.0) (n = 21) | .031a |
| LOH 1p or 19q | |||
| Yes (%) | 10(35.7) (n = 28) | 1(4.8) (n = 21) | .014a |
| LOH 1p &19q | |||
| Yes (%) | 1(3.6) (n = 28) | 0(0.0) (n = 21) | 1.000a |
| IDH1 mutation | |||
| Yes (%) | 9(31.0) (n = 29) | 1(4.2) (n = 24) | .015a |
| p53 | |||
| High expression (%) | 28(70.0) | 20(66.7) (n = 29) | .927 |
| EGFR | |||
| Overexpression (%) | 19(47.5) | 13(43.3) | .729 |
| MGMT | |||
| High expression (%) | 22(55.0) | 24(82.8) (n = 29) | .016 |
| MGMT promoter gene | |||
| Methylated (%) | 8(44.4) (n = 18) | 3(21.4) (n = 14) | .174 |
aFisher’s exact test.
Chromosomal status could be assessed in only 28 of 40 GBMOs and 21 of 30 analyzed conventional GBMs, because of poor in situ hybridization signal intensities in some samples. Among the patients with GBMO, 5 (17.9%) had 1p loss, 6 (21.4%) had 19q loss, and only 1 (3.6%) had combined 1p/19q loss. In contrast to the detection of 1p and/or 19q deletions in roughly 70% of our anaplastic oligodendrogliomas (data not shown), these abnormalities were infrequent in both GBMOs and conventional GBMs. However, solitary 19q deletion was slightly more frequent in the GBMO group than in the conventional GBM group (P= .031, Fisher's exact test) (Table 3).
Twenty-two (55%) of the 40 GBMOs displayed high MGMT expression, which was significantly lower than the frequency in conventional GBMs (82.8%; P= .016, χ2 test). There are only 18 GBMOs and 14 control cases with results of status of MGMT promoter methylation in this cohort. MGMT promoter methylation was found in 8 cases (44.4%) of the GBMOs and 3 cases (21.4%) of the conventional GBMs. There were no significant differences in p53 and EGFR expression between the GBMO and conventional GBM groups (Table 3).
Treatment Efficacy Differs Between GBMO and Conventional GBM
We examined the effects on survival of more intensive treatment, defined as concurrent chemo- and radiotherapy or >3 cycles of chemotherapy after surgical resection.13 Sixteen GBMO patients and 71 conventional GBM patients received intensive regimens, whereas 21 GBMO patients and 93 conventional GBM patients underwent less intensive therapy (nonconcurrent regimens, short chemotherapy regimens, or absence of treatment). Surprisingly, aggressive treatment did not generally improve survival in the GBMO group (P = .438, log-rank test), but it significantly reduced mortality in the conventional GBM group (P < .001, log-rank test) (Fig. 3).
Fig. 3.
Survival by treatment type and glioblastoma subtype. More intensive therapy: concurrent chemo- and radiotherapy >3 cycles of chemotherapy after surgical resection. Less intensive therapy: nonconcurrent regimens or short chemotherapy regimens or absence of treatment.
Discussion
Clinical and pathological studies of GBMO are currently scarce. Its exact incidence is thus largely unknown and has ranged from 4% to 27% of all GBMs in previous studies,1–4 with an incidence of 18.3% in the current study. The inconsistencies may arise from the lack of definitive diagnostic criteria and consequent differences in the selection of the subgroups. In the current study, distinct foci of oligodendroglial cells in a standard GBM were included, but those with only scattered oligodendroglial cells were excluded. Secondary GBMs were also excluded, because they have frequently been reported to contain oligodendroglial components (42%)3 and seem to form a distinct group with different tumorigenic pathways and a better prognosis.5
Long-term survival of patients with GBM is rare, despite intensive multimodality therapy.15 The DNA repair protein MGMT is part of an important mechanism involved in glioma resistance to chemotherapeutic drugs.16 MGMT gene silencing was more frequent in GBMOs in the current series, which may contribute to the longer survival of patients with GBMOs. Although oligodendroglial tumors show better outcomes associated with the presence of chromosome 1p and 19q deletions,7,8 the presence of an oligodendroglial component as an intrinsic prognostic factor remains unclear. The present study showed a median OS for GBMO was 19 months, which was better than the 13.2 months for patients with conventional GBMs. Similarly, several reports of GBMOs from different populations showed favorable outcomes, with OS ranging from 14 to 27 months, and 2-year survival rates of 20%–60% (Table 4).1–4,9,10,15 The age at diagnosis remains one of the most important prognostic factors for patients with GBM.9 In our cohort, not including patients with secondary GBMs or the pediatric population, the age of the patients with GBMO was slightly lower than that of patients with conventional GBM. In multivariate analysis with adjustments for age, sex, preoperative KPS, and treatment, the presence of an oligodendroglioma component was predictive of longer OS. However, codeletion of 1p/19q seems to be infrequent in GBMOs,10,11 with an incidence of only 3.6% in the current series, similar to that observed in conventional GBMs. The result indicates that the longer survival of patients with GBMO may not be linked to LOH 1p/19q.
Table 4.
The clinical outcome of selected series of glioblastomas with oligodendroglial component (GBMOs) and conventional glioblastomas (GBMs)
| Population (ref.) | Patient group | Number of patients | Incidence of GBMO | Treatment | Median OS (months) | 2-year OS |
|---|---|---|---|---|---|---|
| Italy9 | all GBM | 1059 | — | post-OP RT + chemo in 70.7% | 9.5 | 24.8% |
| Europe (EORTC 26981)15 | all GBM | 287 | — | post-OP RT + chemo | 14.6 | 26.5% |
| Germany1 | GBMO | 12 | 4.2% | post-OP RT, chemo in 2/12 | 26.0 | near 60%a |
| Italy2 | GBMO | 36 | 8.0% | post-OP RT + chemo | 20.9 | 55% |
| Brazil10 | GBMO | 24 | 27.3% | post-OP RT in 54%, RT + chemo in 21% | 14.9 | n.a. |
| America4 | GBMO | 27 | 6.0% | n.a. | 27.4 | n.a. |
| Switzerland3 | GBMO | 80 | 19.9% | n.a. | 10.3b | n.a. |
| China (present study) | conventional GBM | 179 | — | post-OP RT in 87%, RT + chemo in 65% | 13.2 | 27.0% |
| China (present study) | GBMO | 40 | 18.3% | post-OP RT in 85%, RT + chemo in 62% | 19.0 | 35.0% |
Abbreviations: n.a., not available; OP, operation; RT, radiation treatment.
aEstimated value from graph.
bIn the authors’ cohort, median OS of conventional GBMs, 8.2 months.
Another curious issue is whether the extent of the oligodendroglial component is correlated with the clinical outcome of GBMO. However, our statistical analysis showed that the extent of the oligodendroglial component was not related to prognosis. This conclusion should be regarded with caution because of the rough semiquantitative analysis (boundary, 30%) and a small sample size.
Of interest, tumor-related seizures were more frequent in the GBMO patients (35%) than in conventional GBM patients (19.7%). A higher frequency of seizures is usually associated with lower-grade tumors and may reflect the chronicity of tumor growth and the time necessary for local epileptogenic changes to occur.17 All the GBMOs in our series were de novo with no sign of prior lower-grade glioma (all patients’ symptoms beginning not >3 months before diagnosis).
IDH1 mutation has recently been confirmed as the best available genetic hallmark of secondary GBMs, complementing clinical criteria for distinguishing them from primary GBMs12,18 and predicting a more protracted clinical course.18 GBMOs in our series had a very high frequency of IDH1 mutation (31%), compared with <5% in primary conventional GBMs. Furthermore, of the 9 cases carrying IDH1 mutations, 7 (77.8%) also had p53 protein accumulation and low EGFR expression (p53+/EGFR−), which represent classic genetic profiles of secondary GBM.19 This suggests that at least some GBMOs may be clinically silent secondary GBMs.
The response to aggressive therapy also differed between GBMO patients and conventional GBM patients. Our results suggest that aggressive treatment protocols conferred no survival advantage in the GBMO group, whereas a clear treatment effect was observed in the primary conventional GBM group. This trait is similar to that in the proneural GBM subtype,13 which shows clinical and genetic profiles similar to those of secondary GBMs. However, the origin of the oligodendroglial cells is still unclear. LOH on 1p and 19q are known as common markers of oligodendroglial tumors. Although solitary 1p or 19q deletion were slightly more common in the GBMO group (17.9% vs. 21.4%), compared with the conventional GBM group, combined 1p/19q loss was infrequent compared to a frequency of 40%–60% in anaplastic oligoastrocytomas.6 Two recent studies10,11 demonstrated, using a microdissection technique, that the 2 different parts (astrocytoma and oligodendroglioma) of GBMOs showed a similar genotype, providing strong evidence for their monoclonal origin. This suggests that some of the multipotent precursor cells of the glioblastoma differentiate into oligodendroglioma-like tumor cells.20
In summary, the results of this study suggest that the clinical behavior and genetic alterations of GBMOs differ from those of primary conventional GBMs but resemble those of secondary GBMs. The presence of GBMO appears to be a favorable prognostic and predictive factor, in line with oligodendroglial neoplasms in general, but lacking the association with LOH 1p/19q. GBMO thus represents a potentially useful classification and stratification variable in therapeutic trials of GBMs.
Supplementary Material
Funding
This work was supported by National Key Project of Science and Technology Supporting Programs of China (No. 2007BAI05B08) and the National Basic Research Program of China (973 Program; No. 2010CB529406, 2011CB707804).
Supplementary Material
Acknowledgments
We thank Yuling Yang for tissue sample collection and clinical data retrieval. Authors Y.W. and S.L. contributed equally to this work. T.J. and C.K. contributed equally as senior authors.
Conflict of interest statement. None declared.
References
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