|Year : 2018 | Volume
| Issue : 1 | Page : 27-33
Be cautious to bid farewell to GBMO: evidence from a propensity score analysis
Haihui Jiang1, Yong Cui2, Xiaohui Ren2, Song Lin2
1 Department of Neurosurgery, First Hospital of Tsinghua University, Beijing, China; Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, China National Clinical Research Center for Neurological Diseases, Center of Brain Tumor, Beijing Institute for Brain Disorders, Beijing Key Laboratory of Brain Tumor, Beijing, China
2 Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, China National Clinical Research Center for Neurological Diseases, Center of Brain Tumor, Beijing Institute for Brain Disorders, Beijing Key Laboratory of Brain Tumor, Beijing, China
|Date of Web Publication||28-Feb-2018|
Dr. Song Lin
Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, China National Clinical Research Center for Neurological Diseases, Center of Brain Tumor, Beijing Institute for Brain Disorders, Beijing Key Laboratory of Brain Tumor, Beijing 100050
Source of Support: None, Conflict of Interest: None
Background: Glioblastomas with an oligodendroglioma component (GBMO) represents a pathology entity with indefinite diagnostic criterion and controversial prognosis, which prevents it from clinical application. The aim of this study is to disclose the clinical and genetic features of GBMO. Methods: A total of 169 glioblastoma multiforme (GBM) and 86 GBMO were reviewed. To reduce bias in patient selection, propensity score analysis was performed, and 68 pairs of GBMO-GBM were thereby generated. The survival time of the two groups was compared using the Kaplan–Meier method. Independent predictors of survival were identified using the Cox proportional-hazards model. Results: Compared to GBM, GBMO was correlated with younger age, higher frequencies of isocitrate dehydrogenase (IDH) mutation, and 1p19q co-deletion (P < 0.05). Among the propensity-score-matched pairs of patients, GBMO patients displayed both prolonged progression-free survival (12 months vs. 9 months, P = 0.005) and overall survival (18.5 months vs. 15 months, P = 0.007) than GBM patients. On top of IDH and 1p/19q, GBMO and GBM could be reclassified into subgroups with the distinct clinical outcome (P < 0.05). Conclusion: GBMO, a subgroup associated with younger age, high frequencies of IDH mutation f and 1p19q co-deletion, confers a favorable prognosis. It should be cautious to propose the deletion of GBMO in the new World Health Organization classification of tumors of the central nervous system.
Keywords: Classification, glioblastoma with an oligodendroglioma component, pathology, propensity score matching
|How to cite this article:|
Jiang H, Cui Y, Ren X, Lin S. Be cautious to bid farewell to GBMO: evidence from a propensity score analysis. Glioma 2018;1:27-33
|How to cite this URL:|
Jiang H, Cui Y, Ren X, Lin S. Be cautious to bid farewell to GBMO: evidence from a propensity score analysis. Glioma [serial online] 2018 [cited 2022 Nov 30];1:27-33. Available from: http://www.jglioma.com/text.asp?2018/1/1/27/226436
| Introduction|| |
Anaplastic oligoastrocytoma with necrosis is classified as glioblastoma with an oligodendroglioma component (GBMO), according to the 2007 central nervous system (CNS) World Health Organization (WHO) classification. As a new pathology entity, there are still several pending issues yet to be solved, such as the diagnostic criteria regarding the percentage of the oligodendroglial components (OCs) and the prognostic significance of OC.,,,,,,,,,,,,,,,,, Furthermore, it is unclear whether GBMO represents a distinct entity with defining molecular alterations and clinical features or only a collection of genomically disparate tumors containing similar morphologic elements.,,,,,, The feasibility of GBMO has therefore been controversial, and current issues have directly attributed to the proposal of deleting GBMO in the 2016 CNS WHO classification.
Regarding precision medicine, a more in-depth and comprehensive understanding of GBMO from the aspects of the clinical characteristic, genetic feature, and prognosis may help to improve individual treatment decision-making.,, Therefore, in this study, we investigated the survival time of patients with GBMO or glioblastoma multiforme (GBM) by conducting propensity score matching (PSM) analysis. In addition, the differences of clinical and genetic features between GBMO and GBM were investigated. Finally, we have proposed a molecular classification scheme of GBMO based on the status of isocitrate dehydrogenase (IDH) and 1p/19q.
| Materials and Methods|| |
Records from a series of 255 patients with a histological diagnosis of primary GBMO (86, 33.7%) or GBM (169, 66.3%) between January 2009 and January 2015 were retrieved from our institution. Patients who underwent needle biopsies before resection and/or prior adjuvant therapy (radiotherapy or chemotherapy) were excluded from the analysis. This was done to create a more uniform patient population. The baseline information, including patients' demographics, tumor characteristics, performance status, treatment strategy, and genetic features were recorded when the protocol was designed. This study was performed according to the standards of the Institutional Ethics Committee and the Helsinki Declaration of 1975, as revised in 1983 and approved by the Institutional Review Board of Capital Medical University. All patients who enrolled for the study provided written informed consent.
Fresh paraffin-embedded tumor tissue specimens were sectioned into 4 μm thick slides and stained with hematoxylin and eosin. All specimens were independently reviewed by three experienced neuropathologists (Junmei Wang, Guang Li, and Lin Luo), who were blinded to the clinical outcome of each patient. Diagnoses were rendered using the CNS WHO classification criteria. When confronted with a discrepancy, the three observers simultaneously reviewed the slides to achieve a consensus. The corresponding immunohistochemical staining was performed, when necessary.
1p/19q abnormality was determined by fluorescence in situ hybridization with 1p36/1q25 or 19q/19p locus-specific identifier DNA dual color probes (Vysis). The specific experiment protocol and interpretation principle have been reported in detail in a previous study. For each probe, >100 nonoverlapping nuclei were enumerated per hybridization. Tumors with more than 30% of nuclei showing DNA loss were defined as a tumor with the chromosomal loss. O6-methylguanine-DNA-methyltransferase (MGMT), promoter methylation status, was evaluated using methylation-specific PCR, and IDH mutation was detected using sequence analysis, as described in a previous paper from our group.
Propensity score matching
A propensity score study was developed to reduce bias in patient selection. PSM was used to generate matched pairs of patients to compare survival time between patients diagnosed with GBMO or GBM. Propensity scores were estimated using a logistic regression model based on the following variables: age, gender, tumor size, Karnofsky performance score (KPS), the extent of resection (EOR), chemotherapy, and radiotherapy, which were possibly associated with survival time independent of pathology type. One-to-one matching without replacement was performed using a 0.1 caliper width, and the resulting score-matched pairs were used in subsequent analyses as indicated.
All patients enrolled for the study were treated according to the latest National Comprehensive Cancer Network guidelines. Postoperative radiotherapy was delivered to patients within 1 month after surgery. The total dose was 60 Gy, which was divided into 30 daily fractions of 2 Gy each. The adjuvant chemotherapy regimens were mainly classic temozolomide-based protocol (temozolomide: 75 mg/m 2 during radiotherapy and/or 150–200 mg/m 2, 5 days/cycle after radiotherapy) and nimustine (ACNU)-based protocol (ACNU: 90 mg/m 2, day 1 and VM26: 60 mg/m 2, days 1–3). The common course of chemotherapy was 4–6 cycles, which depended on the tolerance of toxic effects.
Posttreatment follow-ups of all surviving patients, which included contrast-enhanced magnetic resonance imaging, were performed at an interval of 3 months or more frequently if necessary until death, or dropout from the follow-up program. Progression-free survival (PFS) was defined as the time from the first operation to the time of tumor recurrence. Overall survival (OS) was defined as the period between the first operation and death. Patient followed-ups ranged from 1 to 80 months, and the median follow-up time was 17 months.
Continuous variables are expressed as a mean ± standard deviation and compared using the independent-samples t-test. Categorical variables were compared using the Chi-square test or Fisher's exact test. Survival was analyzed using the Kaplan–Meier method, and group results were compared using the Log-rank test. To identify independent prognostic factors, multivariate analysis was carried out using the Cox proportional-hazards model. All statistical analyses were performed with SPSS (SPSS Inc., Chicago, USA). For all tests, the value of P < 0.05 was considered statistically significant.
| Results|| |
Characteristics of all the study patients
The comparison of clinicopathologic characteristics between the GBMO and GBM is shown in [Table 1]. In general, clinical characteristics were similar between the two groups. Specifically, there were no significant differences in gender ratios, tumor size, KPS score, treatment protocols (chemotherapy and radiotherapy) (all P > 0.05). However, patients with GBM were older (P = 0.023) and had a higher EOR degree (P = 0.014) compared to those in the group of GBMO.
|Table 1: Comparison of clinicopathologic data of glioblastoma multiforme and glioblastomas with oligodendroglioma component|
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Particularly, the frequencies of 1p/19q co-deletion and mutant IDH in patients with GBMO was 19.8% and 39.5%, respectively. Both frequencies were significantly higher than those in patients with GBM (P< 0.001). While the rate of MGMT promotor methylation between GBMO and GBM was almost the same (52.3% vs. 41.4%, P = 0.098) [Figure 1]A.
|Figure 1: (A) The comparison of 1p/19q co-deletion, mutant isocitrate dehydrogenase and O6-methylguanine-DNA-methyltransferase promoter methylation rates between glioblastomas with an oligodendroglioma component and glioblastoma multiforme. **P < 0.001. (B) Comparison of survival time between patients with glioblastoma multiforme and glioblastomas with an oligodendroglioma component. In all patients, glioblastomas with an oligodendroglioma component showed significant longer progression-free survival (P = 0.02), but similar overall survival (P = 0.072) compared with glioblastoma multiforme. In the cohort of patients after propensity score matching, both the progression-free survival and overall survival of glioblastomas with an oligodendroglioma component were significantly longer than those with glioblastoma multiforme (P < 0.01). (C) On the basis of the molecular biomarkers (1p/19q and isocitrate dehydrogenase), glioblastoma multiforme and glioblastomas with an oligodendroglioma component could be divided into subgroups with distinct survival time (P < 0.05)|
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Survival analysis of all study patients
The comparison of survival time between patients with GBM and GBMO is shown in [Figure 1]B. The median PFS of patients with GBMO was 12 months, which was significantly longer than patients with GBM (9.5 months) (P = 0.020). The OS of patients with GBMO was also relatively longer than GBM. However, this finding was not statistically significant (P = 0.072). Several factors linked to prognosis were taken into account in the further survival analysis. Univariate analysis identified the following prognostic factors that predicted increased PFS and OS: gross total resection (GTR), 1p/19q co-deletion, mutant IDH, and MGMT promotor methylation (P< 0.05) [Table 2]. Multivariate analysis, including GTR, 1p/19q co-deletion, mutant IDH, MGMT promotor methylation, and pathology type, showed that 1p/19q co-deletion and GTR were independent prognostic factors conferred longer survival time (P< 0.05) [Table 3].
|Table 2: Univariate analysis to identify factors that predict survival in all patients and in patients after propensity score matching|
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|Table 3: Multivariate analysis to identify factors that predict survival in all patients and in patients after propensity score matching|
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Characteristics of patients selected in the propensity model
Patients diagnosed with GBM or GBMO were matched one-to-one using PSM for minimizing the confounding clinical factors which could influence the prognosis of patients. Clinical variables entered after PSM were age, gender, tumor size, KPS score, EOR, chemotherapy, and radiotherapy. Sixty-eight pair patients were matched in each group. There were no significant differences between the two groups regarding the following factors: age, gender, tumor size, KPS score, EOR, chemotherapy, and radiotherapy (P > 0.05) [Table 4].
|Table 4: Comparison of clinicopathologic data of glioblastoma multiforme and glioblastomas with oligodendroglioma component after propensity score matching|
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Survival analysis of patients selected in the propensity model
Comparison of survival time between patients with GBM and GBMO after PSM is shown in [Figure 1]B. After matching, both the median PFS and OS of patients with GBMO were significantly longer than those in patients with GBM (12 months vs. 9 months, P = 0.005 for PFS; 18.5 months vs. 15 months, P = 0.007 for OS). Univariate analysis showed that GTR, 1p/19q co-deletion, mutant IDH, and MGMT promotor methylation were favorable prognostic factors (all P < 0.05, except the P value of GTR predicting OS in the cohort of patients after PSM was 0.079) [Table 2]. Regarding multivariate analysis which considered GTR, 1p/19q co-deletion, mutant IDH, and MGMT promotor methylation and pathology type as covariates, 1p/19q co-deletion, and GTR were confirmed as independent prognostic factors associated with both longer PFS and OS (P< 0.05) [Table 3].
Clinical significance of molecular classification based on isocitrate dehydrogenase and 1p/19q status
Based on IDH mutation status, patients with GBM were divided into two subgroups with distinct prognoses. According to the survival analysis results, the median PFS and OS of GBM with mutant IDH was 14 months and 20 months, respectively, which were significantly longer than those with wild-type IDH (P = 0.031 for PFS and P = 0.023 for OS) [Figure 1]C.
Meanwhile, according to the status of the molecular biomarker of IDH and 1p/19q, patients with GBMO were split into three subgroups. In the following survival analysis, the median PFS and OS of GBMO with mutant IDH and 1p/19q co-deletion was 21 months and 29 months, respectively, which were significantly longer than those with mutant IDH and intact 1p/19q or wild-type IDH (P = 0.001 for PFS and P = 0.003 for OS). Nevertheless, the survival time of patients with mutant IDH and intact 1p/19q were similar to those harboring wild-type IDH (P = 0.341 for PFS and P = 0.732 for OS) [Figure 1]C.
| Discussion|| |
The present study was performed to assess the prognostic significance of OC in GBM, with a focus on the clinical and genetic features of GBMO. In this study, GBMO was found in 86 (33.7%) patients of our sample series, which seemed to be higher compared with other studies reporting 18.3% and 27.3%., These inconsistencies may arise from the lack of definitive diagnostic criteria regarding the percentage of OC in the GBMO. Furthermore, in the current study, secondary GBM which mostly progressed from low-grade diffuse astrocytoma or anaplastic astrocytoma were excluded. This, to some extent, increased the incidence of GBMO.
The prognostic significance of OC in GBM has always been controversial. Some experts have found that GBMO conferred a relatively better clinical outcome than the traditional GBM.,,,,,,,,, However, studies maintained that no obvious prognostic difference existed between GBMO and GBM have been consecutively published in recent years.,,,,, In 2014, we reported a subgroup of GBMO short-term survivors showing a median OS of merely 10 months which was significantly shorter than GBM. It was undeniable that the prognosis of patients could be influenced by numerous external factors such as age, tumor size, KPS score, and EOR.,,, The conflict findings of the prognostic potential of OC might be in relation to these interfering factors.
According to our results based on the sample before PSM, GBMO showed longer PFS but similar OS compared with GBM. In the comparison of clinicopathologic data, the GBMO patients had a younger age but lower EOR than GBM. This was consistent with previous reports, which also discovered a relatively younger age of patients with GBMO.,,,, It is believed that age at diagnosis and the EOR are two factors correlated with survival time.,, However, the two factors were considered as interference elements in the Log-rank test between GBMO and GBM in this study. To minimize the interference effect of the two factors, we used PSM to generate 68 pairs of GBMO and GBM patients. Results showed more uniform baseline concerning the clinicopathologic data. Further survival analysis results showed that GBMO had a significant advantage in both PFS and OS over GBM. Thus, we believe that GBMO is a pathology entity offering better prognostic value than GBM.
The molecular genetic feature is another variant that could be used to distinguish whether GBMO is a distinct pathology entity or not. MGMT promoter methylation is a well-established predictor of increased chemotherapy sensitivity and longer survival time in GBM.,, The reported frequency of MGMT promoter methylation in GBMO ranged from 44.4% to 54.5%.,, The results showed that the proportion of methylated MGMT in GBMO was slightly higher than GBM (52.3% vs. 41.4%). Given that, prognostic potential of MGMT showed in the present study, its seemed to be reasonable to accept the fact that GBMO had a survival advantage over GBM.
Mutant IDH is the most vital biomarker in low-grade glioma and secondary GBM but rarely found in primary GBM.,,, The frequency of mutant IDH of GBMO in our series was significantly higher than GBM (39.5% vs. 9.5%), which was in accordance with previous reports.,, Mutant IDH was also a useful prognostic factor associated with better clinical outcome., In this study, patients with mutant IDH showed both prolonged PFS and OS relative to those without.
1p/19q co-deletion is a recognized marker linked to the diagnosis, prognosis, and treatment of glioma, especially for the oligodendroglial tumors.,,,, The reported rate of 1p/19q co-deletion has been shown to be 4%–12% in GBM ,, and 3%–19.4% in GBMO.,,,,,, As expected, 1p/19q co-deletion occurred more frequently in GBMO compared with GBM (19.8% vs. 4.1%). In the multivariate analysis, 1p/19q co-deletion was an independent predictor of longer survival regardless of pathology type. All these results suggest that GBMO arise from typical oligodendroglial genetic pathways and confer better prognoses.
Considering the subjectivity and uncertainty regarding a precise diagnosis of glioma, especially mixed glioma,,, GBMO was reclassified into three subtypes based on the objective biomarkers (1p/19q and IDH). Comparing the survival time of these molecular subtypes, the median OS of GBMO with mutant IDH and 1p/19q co-deletion was 29 months, which was significantly longer than GBM. However, the survival time of patients with mutant IDH and intact 1p/19q or wild-type IDH was close to GBM. The molecular classification scheme could contribute to refining GBMO stratification and guiding personalized therapeutic regimens.
The current study has some limitations. First, it is a single-institution study. Moreover, the retrospective nature made this study vulnerable to potential bias, even after PSM, these biases still may not be completely avoided. Therefore, in the future, we will try to launch a multi-center, prospective, randomized, control trial to further validate these results.
In conclusion, GBMO is a distinct subgroup associated with a relatively younger population, higher frequencies of mutant IDH and 1p/19q co-deletion, and commonly confers favorable prognostic value. It should be cautious to propose the deletion of GBMO in the new CNS WHO classification.
The author appreciates Dr. Lin Luo for pathology diagnosis, the Pathology department, Beijing Neurosurgical Institute, and Dr. Guang Li, Pathology department, Beijing Tiantan Hospital, Capital Medical University.
Financial support and sponsorship
The study was financial support by the National Natural Science Foundation of China (81571632), and the Capital Health Research and Development of Special (2014-2-2042).
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]