Abstract
Oligodendrogliomas generally have a better prognosis than other adult-type diffuse gliomas. However, although several clinical and radiological prognostic factors have been reported, long-term outcomes remain heterogeneous, and decisions regarding postoperative treatment remain challenging because of concerns about long-term adverse effects. This study aimed to explore prognostic factors by analyzing clinical, radiological, therapeutic, and genetic data from a single-institution cohort.
We retrospectively reviewed adult patients (≥18 years) with isocitrate dehydrogenase-mutant and 1p/19q-codeleted oligodendrogliomas who underwent surgical resection at our institution between 1999 and 2021, with available preoperative magnetic resonance imaging and computed tomography. CDKN2A/B copy number status was assessed using multiplex ligation-dependent probe amplification and confirmed by fluorescence in situ hybridization. Overall survival and progression-free survival were analyzed using the Kaplan-Meier method and Cox proportional hazards models. For overall survival, simple multivariable Cox models adjusted for age and Karnofsky Performance Status were constructed.
A total of 32 patients were included. The median age was 40 years, and the median Karnofsky Performance Status was 90. Calcification and corpus callosum invasion were observed in 46.9% and 40.6% of cases, respectively, and CDKN2A/B hemizygous deletion was identified in four cases. The 5-year progression-free survival was 62.0%, and the 5-year overall survival was 86.5%. On univariable Cox analysis for overall survival, corpus callosum invasion, calcification, and CDKN2A/B hemizygous deletion were significant adverse prognostic factors. In simple multivariable Cox models, CDKN2A/B hemizygous deletion remained associated with shorter overall survival.
Calcification, corpus callosum invasion, and CDKN2A/B hemizygous deletion may be prognostic markers in oligodendroglioma.
Keywords: oligodendroglioma, calcification, corpus callosum invasion, CDKN2A/B, MLPA
Introduction
Diffuse gliomas account for approximately 80%-85% of primary malignant brain tumors in adults.1) According to the fifth edition of the World Health Organization (WHO) Classification of Tumors of the Central Nervous System, adult-type diffuse gliomas are categorized as isocitrate dehydrogenase (IDH)-mutant astrocytoma, IDH-mutant and 1p/19q-codeleted oligodendroglioma, and IDH-wildtype glioblastoma.2)
Among these, oligodendrogliomas frequently localize in the frontal lobe and often present with seizures.3) According to the Central Brain Tumor Registry of the United States Statistical Report, the incidence of oligodendroglioma is 0.21 per 100,000 and that of anaplastic oligodendroglioma is 0.05-0.10 per 100,000 in the United States.4) While oligodendrogliomas generally have a better prognosis compared to other adult-type diffuse gliomas, patient outcomes are highly variable.5-7) Radiochemotherapy is considered a standard treatment for oligodendroglioma; however, it may result in long-term cognitive impairment.8) Given the relatively favorable overall prognosis and the non-curative nature of current treatments, it remains difficult to determine whether postoperative radiochemotherapy should be administered or whether observation is appropriate.9,10)
Several clinical, radiological, and pathological factors have been reported as prognostic markers in oligodendroglioma. Younger age, seizure at initial presentation, frontal lobe location, higher Karnofsky Performance Status (KPS), and a greater extent of resection (EOR) are considered favorable prognostic factors, whereas contrast enhancement and anaplastic histopathological features such as increased mitotic activity are associated with a worse prognosis.11-13) However, these conventional prognostic factors alone cannot fully account for the heterogeneity in long-term outcomes observed among patients. Therefore, to further refine risk stratification, additional prognostic markers, including molecular genetic alterations and imaging features, are needed.
In IDH-mutant gliomas, homozygous and hemizygous deletions of the CDKN2A/B gene locus at chromosome 9p21 are frequently observed. Homozygous deletion of CDKN2A/B in IDH-mutant astrocytoma is a well-established adverse prognostic factor and is used to define WHO grade 4 tumors, and more recently it has also been reported as an adverse prognostic marker in oligodendrogliomas.14) However, the clinical significance of hemizygous deletion remains unclear, especially in oligodendroglioma, where few studies have addressed its impact. Recent advances have highlighted the potential of non-invasive imaging modalities in preoperative tumor assessment.15-17) Calcification is a well-known radiological hallmark in the differential diagnosis of oligodendroglioma;18,19) however, its prognostic value remains uncertain, particularly in the era of molecular-based diagnosis. In glioblastoma, corpus callosum invasion is a recognized poor prognostic factor, where it presents as the characteristic “butterfly” pattern.20,21) However, its clinical relevance in oligodendroglioma remains unexplored. In this study, we analyzed copy number alterations of CDKN2A/B, radiological features, treatment details, and clinical course in patients with oligodendroglioma, and investigated prognostic factors based on cases from a single-institution.
Materials and Methods
Inclusion criteria
A retrospective observational study was conducted on patients aged ≥18 years who underwent surgery at the Department of Neurosurgery, Dokkyo Medical University Hospital between 1999 and 2021 and were diagnosed with oligodendroglioma harboring IDH mutation and 1p/19q codeletion according to the 2021 WHO classification. A total of 57 cases were initially enrolled, all of which were confirmed to have IDH1 or IDH2 mutations and 1p/19q codeletion based on pathological and molecular pathological examinations.
Written informed consent was obtained from all participants, and all analyses using human specimens were approved by the Ethics Committee of Dokkyo Medical University Hospital (Approval No. R-61-4J).
Data collection
Clinical data, including age, sex, and KPS, and details of postoperative treatment, were collected from electronic medical records. Tumor location, maximum diameter, invasion of the corpus callosum, and EOR were assessed using pre- and postoperative magnetic resonance imaging (MRI). Corpus callosum invasion was determined when high signal intensity of the tumor extended into the corpus callosum on T2-weighted or Fluid-attenuated inversion recovery (FLAIR) images. Calcification was defined as the presence of hyperdense areas exceeding 100 Hounsfield Units (HU) within the tumor on preoperative computed tomography (CT) scans.22) Using preoperative and early postoperative MRI, tumor volumes were measured, and the EOR was defined as EOR = (preoperative volume − postoperative volume) / preoperative volume × 100%. For cases with contrast enhancement, volumes were derived from the contrast-enhancing lesion on postcontrast T1-weighted images (T1CE), whereas for predominantly non-enhancing tumors, volumes were derived from the hyperintense lesion on T2/FLAIR. Postoperative treatment was categorized into radiotherapy alone, chemotherapy alone, or a combination of both. Chemotherapy regimens included temozolomide (TMZ) or a combination of procarbazine, nimustine, and vincristine (PAV therapy). The clinical characteristics of the patients are summarized in Table 1.
Table 1.
Clinical and Molecular Features (n = 32)
| Variables | Total (n = 32) |
|---|---|
| Sex | |
| Female | 11 (34.4%) |
| Male | 21 (65.6%) |
| Age, median (range) | 40 (25-71) |
| KPS | |
| Median (range) | 90 (20-100) |
| ≥90% | 27 (84.4%) |
| <90% | 5 (15.6%) |
| Preoperative symptoms | |
| Incidental | 12 (37.5%) |
| Seizure | 15 (46.9%) |
| Other | 5 (15.6%) |
| Tumor size (cm), median (range) | 4.7 (2.4-8.8) |
| Tumor location | |
| Frontal | 23 (71.9%) |
| Parietal | 4 (12.5%) |
| Temporal | 2 (6.3%) |
| Other | 3 (9.4%) |
| MRI finding | |
| Corpus callosum invasion (+) | 13 (40.6%) |
| Corpus callosum invasion (-) | 19 (59.4%) |
| CT finding | |
| Calcification (+) | 15 (46.9%) |
| Calcification (-) | 17 (53.1%) |
| EOR | |
| >90% | 11 (34.4%) |
| ≤90% | 21 (65.6%) |
| Postoperative management | |
| Observation | 11 (34.4%) |
| Adjuvant therapy | 21 (65.6%) |
| Chemotherapy | 12 (37.5%) |
| PAV | 8 (25.0%) |
| TMZ | 4 (12.5%) |
| Radiotherapy | 4 (12.5%) |
| Radio-chemotherapy | 5 (15.6%) |
| Radiotherapy + PAV | 2 (6.3%) |
| Radiotherapy + TMZ | 3 (9.4%) |
| WHO grade | |
| 2 | 14 (43.8%) |
| 3 | 18 (56.3%) |
| IDH status | |
| IDH1-mutant | 30 (93.8%) |
| IDH2-mutant | 2 (6.2%) |
| CDKN2A status | |
| Homozygous deletion (Homo del) | 0 (0%) |
| Hemizygous deletion (Hemi del) | 4 (12.5%) |
| Copy-neutral | 28 (87.5%) |
CT: computed tomography; EOR: extent of resection; IDH: isocitrate dehydrogenase; KPS: Karnofsky Performance Scale; MRI: magnetic resonance imaging; PAV: procarbazine, nimustine, and vincristine; TMZ: temozolomide; WHO: World Health Organization
Pathological and molecular analysis
To detect IDH1 mutations, immunohistochemistry was performed using an anti-IDH1 R132H antibody (H09, RTU; dianova). Cases negative for IDH1 R132H were further evaluated using Sanger sequencing. The status of 1p and 19q deletions was assessed by microsatellite analysis using microsatellite markers to evaluate loss of heterozygosity (LOH).23)
For the detection of CDKN2A/B copy number alterations, Multiplex Ligation-dependent Probe Amplification (MLPA) analysis was performed using the SALSA MLPA P088 Oligodendroglioma 1p/19q probe set (MRC-Holland), and data were analyzed with Coffalyser.Net. CDKN2A/B copy number status was defined based on the following cutoff values: normal, probe ratio >0.7; hemizygous deletion, 0.4 ≤ probe ratio ≤ 0.7; and homozygous deletion, probe ratio <0.4.24) Cases with suspected CDKN2A/B deletion on MLPA were further examined by fluorescence in situ hybridization (FISH) to verify CDKN2A deletion. FISH analysis was conducted using a CDKN2A (9p21)-specific probe from Abbott Molecular (USA) and observed under an epifluorescence microscope (Olympus, Tokyo, Japan). For each case, 100 tumor cell nuclei were evaluated. A deletion was defined when abnormal signal patterns were observed in ≥15% of tumor cells. Normal cells were expected to show two green signals (CSP9) and two red signals (CDKN2A); hemizygous deletion was defined as one red signal, and homozygous deletion as complete loss of the red signal.
Statistical analysis
Statistical analyses were performed using SPSS version 29.0 (IBM Corp., Armonk, NY, USA), with a significance level set at p < 0.05. Associations between categorical variables were assessed primarily using Pearson's chi-square test; when more than 20% of cells had an expected count of <5, Fisher's exact test was used instead. Overall survival (OS) and progression-free survival (PFS) were evaluated using the Kaplan-Meier method, and differences between groups were assessed with the log-rank test. The median follow-up was estimated using the reverse Kaplan-Meier method, defined as the time from surgery to the last known contact. Prognostic factors were first examined using univariate analysis with the Cox proportional hazards model, and hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated for each variable. Furthermore, because the number of events was limited and to avoid overfitting, we constructed three simple multivariable Cox models in which age and KPS were included as common covariates, and each model additionally included one of the following variables: corpus callosum invasion, calcification, or CDKN2A/B hemizygous deletion.
Results
Demographic characteristics
A total of 57 cases were initially enrolled, and additional genetic analysis using MLPA was performed in 43 of these cases. Fourteen cases were excluded due to the absence of frozen tissue samples, which made additional analysis infeasible. Among the 43 cases eligible for MLPA analysis, 32 cases with available preoperative CT and MRI imaging data were ultimately included in the final analysis.
This study included 32 patients diagnosed with oligodendroglioma harboring IDH mutation and 1p/19q codeletion. The cohort consisted of 21 men and 11 women, with a median age at diagnosis of 40 years (range: 25-71 years). The median KPS was 90 (range: 20-100), indicating relatively good functional status. The most common initial presentation was seizure, observed in 15 patients (46.9%), followed by incidental findings in 12 patients (37.5%). The median maximum tumor diameter was 4.7 cm (range: 2.4-8.8 cm), and the frontal lobe was the most common tumor location, accounting for 71.9% of cases. Preoperative imaging revealed calcification on CT in 15 cases (46.9%) and corpus callosum invasion on MRI in 13 cases (40.6%). Histologically, 14 cases were classified as WHO grade 2 and 18 as grade 3. Gross total or subtotal resection (≥90% resection) was achieved in 11 patients (34.4%), while partial resection or biopsy (<90% resection) was performed in 21 patients (65.6%).
Postoperative management consisted of observation alone in 11 patients (34.4%) and adjuvant therapy in 21 patients (65.6%). Among those receiving adjuvant therapy, eight patients (25.0%) received PAV chemotherapy alone, four patients (12.5%) received temozolomide (TMZ) alone, four patients (12.5%) underwent radiotherapy alone, two patients (6.3%) received combined radiotherapy and PAV, and three patients (9.4%) received combined radiotherapy and TMZ (Table 1).
The choice of postoperative management was based on the EOR, tumor grade. Observation was generally selected for patients who underwent gross total resection (GTR). A subset of GTR cases received adjuvant therapy, all of which had grade 3 histology. Among non-GTR cases, observation or chemotherapy was commonly chosen, and a subset of patients―exclusively those with grade 3 tumors―received combined radiochemotherapy. Radiotherapy alone was administered only in non-GTR cases when chemotherapy was either declined by the patient or precluded by medical contraindications. No standardized criteria governed selection between PAV and TMZ; regimen choice was left to the treating physician's discretion based on individual patient factors (Figure 1).
Figure 1.
Treatment selection according to extent of resection and WHO tumor grade, with treatment flow chart.
WHO: World Health Organization
Evaluation of IDH mutation and CDKN2A/B status
In the evaluation of IDH mutations, IDH1 mutations were identified in 30 cases (93.8%) and IDH2 mutations in two cases (6.2%) through IDH1 R132H immunohistochemistry and Sanger sequencing (Table 1).
Regarding CDKN2A/B copy number alterations, MLPA analysis revealed deletions in four cases. These cases were further analyzed by FISH, and all were confirmed to have hemizygous deletions, consistent with the MLPA finding.
Associations between imaging findings and clinical/molecular factors
Associations between imaging findings and clinical/molecular characteristics are summarized in Table 2.
Table 2.
Associations between Imaging Findings and Clinical/Molecular Factors
| Variable | Calcification(+) n = 15 | Calcification(-) n = 17 | p-Value | CC invasion(+) n = 13 | CC invasion(-) n = 19 | p-Value |
|---|---|---|---|---|---|---|
| Age | ||||||
| >45 | 6 (40.0%) | 7 (41.2%) | 0.95 | 4 (30.8%) | 9 (47.4%) | 0.35 |
| KPS | ||||||
| <90 | 4 (26.6%) | 1 (5.9%) | 0.16 | 4 (30.8%) | 1 (5.3%) | 0.13 |
| Tumor size | ||||||
| >5 cm | 9 (60.0%) | 6 (35.2%) | 0.16 | 10 (76.9%) | 5 (26.3%) | 0.01 |
| CT | ||||||
| Calcification (+) | – | – | – | 9 (69.2%) | 6 (31.6%) | 0.04 |
| EOR | ||||||
| > 90% | 4 (26.6%) | 7 (41.2%) | 0.39 | 2 (15.4%) | 9 (47.4%) | 0.13 |
| Adjuvant therapy | 12 (80.0%) | 8 (47.1%) | 0.06 | 7 (53.8%) | 13 (68.4%) | 0.47 |
| WHO grade 3 | 7 (46.7%) | 9 (52.9%) | 0.72 | 5 (38.5%) | 11 (57.9%) | 0.28 |
| CDKN2A/B status | ||||||
| Hemizygous deletion | 3 (20.0%) | 1 (5.9%) | 0.32 | 2 (15.4%) | 2 (10.5%) | 1.00 |
CC invasion: corpus callosum invasion; CT: computed tomography; EOR: extent of resection; KPS: Karnofsky Performance Scale; WHO: World Health Organization
Adjuvant treatments such as chemotherapy and/or radiotherapy were more frequently administered to tumors with calcification than to those without calcification (80.0% [12/15] vs 47.1% [8/17]), but this difference was not statistically significant (p = 0.06). By comparison, the frequency of adjuvant therapy did not differ according to the presence or absence of corpus callosum invasion. Tumors with corpus callosum invasion were significantly more likely to have a maximal diameter greater than 5 cm compared with those without invasion (76.9% [10/13] vs 26.3% [5/19], p = 0.01), and calcification on CT was also observed significantly more frequently in tumors with corpus callosum invasion (69.2% [9/13] vs 31.6% [6/19], p = 0.04).
Furthermore, when we examined the association with CDKN2A/B hemizygous deletion, tumors with calcification showed a numerically higher frequency of CDKN2A/B hemizygous deletion than non-calcified tumors (20% [3/15] vs 5.9% [1/17]), but this difference was not statistically significant (p = 0.32). Similarly, the frequency of CDKN2A/B hemizygous deletion did not differ according to the presence or absence of corpus callosum invasion (15.4% [2/13] vs 10.5% [2/19], p = 1.00), and no clear association was demonstrated between imaging findings and CDKN2A/B alterations.
Survival outcomes
Among the 32 cases included in the analysis, 20 patients (63%) were alive at the time of data collection. The median follow-up was 129.0 months (95% CI, 78.0-180.0; range, 5-245 months). The 5-year PFS was 62.0% (95% CI: 44.2%-79.8%), and the 5-year OS was 86.5% (95% CI: 74.2%-98.9%).
Kaplan-Meier analysis showed that patients with tumors larger than 5 cm in diameter on preoperative imaging had significantly shorter PFS compared to those with tumors 5 cm or 9 smaller (p = 0.015) (Figure 2a). Cases with calcification exhibited significantly shorter OS (p = 0.028) (Figure 2c), and those with corpus callosum invasion had significantly shorter PFS and OS (p = 0.005 and p = 0.012, respectively) (Figure 2b and d). Patients with hemizygous deletion of CDKN2A/B had significantly shorter OS compared to those with neutral copy number status (p = 0.001) (Figure 2e). Patients who underwent gross total or subtotal resection (≥90% resection) had significantly better OS than those with <90% resection (p = 0.042) (Figure 2f).
Figure 2.
Kaplan–Meier analysis and log-rank tests regarding overall survival (OS) and progression free survival (PFS) of patients with oligodendroglioma.
Prognostic factors for OS and PFS
Table 3A summarizes univariate analyses of prognostic factors in relation to PFS and OS. Univariate Cox proportional hazards analysis identified KPS <90 (HR = 5.77, 95% CI: 1.59-20.9, p = 0.008), tumor size >5 cm (HR = 3.18, 95% CI: 1.19-8.53, p = 0.021), and corpus callosum invasion (HR = 3.55, 95% CI: 1.38-9.15, p = 0.009) as significant poor prognostic factors for PFS. In terms of OS, KPS <90 (HR = 21.9, 95% CI: 2.19-213, p = 0.009), corpus callosum invasion (HR = 4.96, 95% CI: 1.26-19.6, p = 0.022), calcification (HR = 4.78, 95% CI: 1.03-22.2, p = 0.046), and hemizygous deletion of CDKN2A/B (HR = 7.83, 95% CI: 1.81-33.8, p = 0.006) were all identified as significant adverse prognostic factors.
Table 3A.
Univariate Analyses of Prognostic Factors
| Variable | PFS HR (95% CI) | p-Value | OS HR (95% CI) |
p-Value |
|---|---|---|---|---|
| Age | ||||
| >45 | 0.55 (0.20-1.46) | 0.217 | 1.46 (0.44-4.86) | 0.535 |
| Sex | ||||
| Male | 0.92 (0.36-2.34) | 0.858 | 0.54 (0.16-1.82) | 0.544 |
| KPS | ||||
| <90% | 5.77 (1.59-20.9) | 0.008 | 21.6 (2.19-213) | 0.009 |
| Incidental | 0.77 (0.29-2.08) | 0.612 | 0.72 (0.18-2.80) | 0.630 |
| Seizures | 0.64 (0.25-1.67) | 0.362 | 0.47 (0.13-1.74) | 0.259 |
| Tumor size | ||||
| >5 cm | 3.18 (1.19-8.53) | 0.021 | 1.58 (0.45-5.49) | 0.475 |
| MRI | ||||
| Corpus callosum invasion | 3.55 (1.38-9.15) | 0.009 | 4.96 (1.26-19.6) | 0.022 |
| CT | ||||
| Calcification | 1.50 (0.59-3.82) | 0.399 | 4.78 (1.03-22.2) | 0.046 |
| EOR | ||||
| > 90% | 0.72 (0.27-1.95) | 0.526 | 0.16 (0.02-1.22) | 0.077 |
| WHO grade | ||||
| 2 | 1 (ref) | 1 (ref) | ||
| 3 | 1.15 (0.46-2.95) | 0.758 | 0.96 (0.29-3.17) | 0.951 |
| CDKN2A/B status | ||||
| Copy-neutral | 1 (ref) | 1 (ref) | ||
| Hemizygous deletion | 1.37 (0.31-6.04) | 0.681 | 7.83 (1.81-33.8) | 0.006 |
CT: computed tomography; EOR: extent of resection; KPS: Karnofsky Performance Scale; MRI: magnetic resonance imaging; OS: overall survival; PFS: progression-free survival; WHO: World Health Organization
Because the number of events was limited and to avoid overfitting, we constructed three simple multivariable Cox models for OS (Table 3B). Cox model 1 included corpus callosum invasion, model 2 included calcification, and model 3 included CDKN2A/B hemizygous deletion, with age and KPS entered as common covariates in all models. In model 1, the adjusted hazard ratio for corpus callosum invasion was 4.22 (95% CI: 0.90-19.8, p = 0.07), and in model 2 the adjusted hazard ratio for calcification was 4.23 (95% CI: 0.76-23.5, p = 0.10); however, neither association reached statistical significance. KPS <90 was also not statistically significant in models 1 and 2 (p = 0.06 for both). By contrast, in model 3, CDKN2A/B hemizygous deletion remained a significant adverse prognostic factor after adjustment (HR = 9.82, 95% CI: 1.23-78.32, p = 0.03), and KPS <90 was likewise significantly associated with shorter OS (HR = 20.7, 95% CI: 1.81-236.36, p = 0.02).
Table 3B.
Multivariable Analyses Comparing Corpus Callosum Invasion, Calcification, and CDKN2A/B Hemizygous Deletion for OS
| Variable | Cox model 1 | Cox model 2 | Cox model 3 | |||||
|---|---|---|---|---|---|---|---|---|
| HR (95% CI) | p-Value | HR (95% CI) | p-Value | HR (95% CI) | p-Value | |||
| Age | ||||||||
| >45 | 1.56 (0.39-6.31) | 0.53 | 1.75 (0.41-7.36) | 0.45 | 0.52 (0.10-2.70) | 0.44 | ||
| KPS | ||||||||
| <90 | 10.06 (0.88-115.53) | 0.06 | 9.93 (0.88-112.66) | 0.06 | 20.7 (1.81-236.36) | 0.02 | ||
| MRI | ||||||||
| Corpus callosum invasion | 4.22 (0.90-19.83) | 0.07 | – | – | – | – | ||
| CT | ||||||||
| Calcification | – | – | 4.23 (0.76-23.54) | 0.10 | – | – | ||
| CDKN2A/B status | ||||||||
| Hemizygous deletion | – | – | – | – | 9.82 (1.23-78.32) | 0.03 | ||
Cox model 1 included age (>45 vs ≤45 years), KPS (<90 vs ≥90), and corpus callosum invasion (present vs absent).
Cox model 2 included age, KPS, and calcification (present vs absent).
Cox model 3 included age, KPS, and CDKN2A/B hemizygous deletion (present vs absent).
“–” indicates that the variable was not entered into the corresponding model.
CI: confidence interval; CT: computed tomography; HR: hazard ratio; KPS, Karnofsky Performance Scale; MRI: magnetic resonance imaging; OS: overall survival
Discussion
In this study, we focused on three potential prognostic markers―calcification, corpus callosum invasion, and CDKN2A/B hemizygous deletion―in oligodendrogliomas with IDH mutation and 1p/19q codeletion, evaluating their prognostic significance by univariate analyses for PFS and OS and by simple multivariable Cox models for OS.
Calcification has recently attracted attention as a potential adverse prognostic marker, and in our study, patients with calcified tumors showed significantly shorter OS in univariate analysis. However, calcification did not remain an independent prognostic factor after adjustment for age and KPS. Tumors with calcification typically exhibit low signal intensity on T2-weighted images and high HU on CT, reflecting their sclerotic characteristics. These tumors are often associated with indistinct margins and rigidity, potentially making GTR more difficult.25) Furthermore, calcified oligodendrogliomas have been associated with larger tumor size, lower resection rates, and increased frequency of midline-crossing, and calcification has been identified as an independent poor prognostic factor for OS.25) Thus, although our multivariable analysis did not confirm calcification as an independent prognostic factor―likely due in part to the limited sample size and number of events―the direction of its effect on survival was broadly consistent with these findings.
In this study, corpus callosum invasion was associated with shorter PFS and OS in univariable analyses, whereas the association with OS did not reach statistical significance after adjustment for age and KPS (HR 4.22, p = 0.07). These findings suggest that corpus callosum invasion may reflect more aggressive disease, although it did not emerge as an independent prognostic factor in this small cohort. An important point here is that the definition of corpus callosum invasion evaluated in this study is distinct from the contralateral (midline-crossing) extension used in the Pignatti model.26) Whereas midline-crossing represents a later consequence of interhemispheric spread, corpus callosum invasion reflects an earlier, tract-level stage of interhemispheric involvement that can be detected more frequently with preoperative MRI. Accordingly, corpus callosum invasion may serve as a more sensitive and clinically relevant surrogate for “interhemispheric progression risk” than overt midline-crossing. To our knowledge, no prior reports have clearly demonstrated the prognostic significance of corpus callosum invasion specifically in oligodendroglioma. By contrast, in glioblastoma, lesions with corpus callosum involvement―the so-called “butterfly glioma”―are common and corpus callosum invasion has been shown to be associated with shorter OS.21) Similarly, in oligodendroglioma, bilateral extension via the corpus callosum, a major commissural white-matter pathway, may limit resectability and facilitate early recurrence, thereby adversely affecting prognosis. This is the first study to suggest that corpus callosum invasion may have prognostic relevance in oligodendroglioma.
Regarding CDKN2A/B copy number alterations, four cases with hemizygous deletions were identified. In univariate analyses, these cases showed significantly shorter PFS and OS, and in a simple multivariable Cox model adjusting for age and KPS, hemizygous deletion remained significantly associated with shorter OS. While homozygous deletion of CDKN2A/B is known to be a poor prognostic factor in IDH-mutant astrocytomas, the clinical relevance of CDKN2A/B deletions―particularly hemizygous deletions―in oligodendrogliomas remains unclear. A recent systematic review and meta-analysis by Nakasu et al.14) reported that homozygous deletions of CDKN2A/B in oligodendrogliomas were significantly associated with shorter OS, and multivariate analysis confirmed their independent prognostic value after adjusting for WHO grade and age. While hemizygous deletions were found more frequently (approximately 15.9%), no statistically significant association with prognosis was reported in that meta-analysis. In the included studies, various methods were used to assess CDKN2A/B copy number alterations―such as Single nucleotide polymorphism (SNP) arrays, targeted Next-generation sequencing (NGS), MLPA, and FISH―which may have contributed to the heterogeneity of the reported results.14) In contrast, the present study employed a consistent two-step evaluation approach using MLPA followed by confirmation with FISH. However, given the very small number of cases with hemizygous CDKN2A/B deletion, the results should be interpreted with caution. Notably, in the GLASS dataset, hemizygous deletion of CDKN2A in IDH-mutant astrocytomas was significantly associated with shorter OS at both initial diagnosis and recurrence, and was identified as an independent poor prognostic factor.27) Since oligodendrogliomas are considered to be molecularly closely related to astrocytomas, hemizygous deletion of CDKN2A/B may also impact prognosis in oligodendrogliomas. Further investigation using larger cohorts and standardized assessment methods is warranted.
Among other clinical prognostic factors, a KPS <90 was significantly associated with shorter PFS and OS in this study. KPS has long been recognized as a prognostic indicator in lower-grade gliomas,28,29) and the current findings are consistent with previous reports. Although tumor resection rate did not reach statistical significance in this study, the prognostic impact of EOR in oligodendroglioma remains controversial across reports.28,30) Moreover, the EOR may be strongly influenced by preoperative factors such as tumor location and corpus callosum invasion,28) making it difficult to assess based on resection rate alone.
In this study, postoperative radiotherapy was generally avoided in WHO grade 2 cases, unless chemotherapy was declined by the patient or precluded by medical contraindications. Bush et al.31) reported, in a retrospective cohort of patients with WHO grade 3 oligodendroglioma treated with TMZ, that concurrent radiotherapy plus TMZ significantly improved PFS compared with TMZ alone, whereas OS did not differ between groups. Based on these findings, they suggested that delaying the initiation of radiotherapy may help preserve quality of life, particularly in younger patients.31) Given the generally favorable prognosis of oligodendroglioma, flexible treatment strategies that consider long-term toxicities―such as the selective use of stereotactic radiosurgery―should be considered.32)
There are several limitations to this study. First, it was a single-center retrospective analysis of a small cohort collected over a period of >20 years. During this extended enrollment period, treatment strategies for oligodendroglioma evolved, and postoperative management―including radiotherapy, chemotherapy, or their combination―was determined at the discretion of each treating physician, influenced by factors such as EOR, tumor grade, and patient background. In addition, although we constructed three simple multivariable Cox models adjusted for age and KPS to evaluate the prognostic impact of calcification, corpus callosum invasion, and CDKN2A/B hemizygous deletion, the limited number of events precluded the development of a comprehensive multivariable model incorporating all candidate prognostic factors, and the possibility of residual confounding cannot be completely excluded. Given the small sample size, long enrollment period, and heterogeneity of treatment, the findings of this study should be interpreted as exploratory and hypothesis-generating. Despite these limitations, this study provides a comprehensive evaluation of imaging findings (calcification and corpus callosum invasion), CDKN2A/B copy number alterations, and clinical data, all based on the molecular definitions outlined in the 2021 WHO classification. These findings suggest novel potential prognostic markers in oligodendroglioma. Future multicenter prospective studies are needed to establish prognostic models that integrate imaging findings, pathological features, and genomic information including CDKN2A/B deletions.
Conflicts of Interest Disclosure
All authors have no conflict of interest.
References
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