Prognostic Impact of Calcification, Corpus Callosum Invasion, and CDKN2A/B Hemizygous Deletion in Oligodendroglioma: A Single-Center Retrospective Study

Prognostic Impact of Calcification, Corpus Callosum Invasion, and CDKN2A/B Hemizygous Deletion in Oligodendroglioma: A Single-Center Retrospective Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Prognostic Impact of Calcification, Corpus Callosum Invasion, and CDKN2A/B Hemizygous Deletion in Oligodendroglioma: A Single-Center Retrospective Study Takuma Sumi, Takeo Uzuka, Hideyuki Kano, Shunsuke Shibao, Hadzki Matsuda, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7622614/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose Oligodendrogliomas generally have a better prognosis than other adult-type diffuse gliomas. However, few prognostic factors have been established, and decisions regarding postoperative treatment remain challenging due to concerns about long-term adverse effects. This study aimed to identify prognostic factors by analyzing clinical, radiological, therapeutic, and genetic data from a single-institution cohort. Methods We retrospectively reviewed adult patients (≥ 18 years) with isocitrate dehydrogenase (IDH)-mutant and 1p/19q-codeleted oligodendrogliomas who underwent surgical resection at our institution between 1999 and 2021, with available preoperative MRI and CT. CDKN2A/B copy number status was assessed using multiplex ligation-dependent probe amplification (MLPA) and confirmed by fluorescence in situ hybridization (FISH). The impact on overall survival (OS) and progression-free survival (PFS) was evaluated using Kaplan–Meier survival analysis and the Cox proportional hazards model. Results Thirty-two patients were included. The median age was 40 years, and the median Karnofsky Performance Status (KPS) was 90. Calcification and corpus callosum invasion were observed in 46.9% and 59.4% of cases, respectively. CDKN2A/B hemizygous deletion was identified in four cases. The 5-year PFS was 62.0%, and the 5-year OS was 86.5%. On univariate Cox proportional hazards analysis, calcification (p = 0.046), corpus callosum invasion (p = 0.022), and CDKN2A/B hemizygous deletion (p = 0.006) were significantly associated with shorter OS. Conclusion Calcification, corpus callosum invasion, and CDKN2A/B hemizygous deletion appear to be important prognostic factors in oligodendroglioma. oligodendroglioma calcification corpus callosum invasion CDKN2A/B MLPA Figures Figure 1 Figure 2 Figure 3 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 (CBTRUS) Statistical Report 44, 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 , 6 , 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 ]. To date, few established prognostic factors for oligodendroglioma exist. This may be attributed to the tumor’s biological heterogeneity, low incidence, and extended survival periods. Consequently, there is an increasing demand for reliable molecular pathological indicators to predict prognosis more accurately. 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. 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 [ 11 , 12 , 13 ]. Calcification is a well-known radiological hallmark in the differential diagnosis of oligodendroglioma [ 14 , 15 ]; 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 [ 16 , 17 ]. 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 or older 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. Data collection Clinical data, including age, sex, and Karnofsky Performance Status (KPS), as well as details of postoperative treatment, were collected from electronic medical records. Tumor location, maximum diameter, invasion of the corpus callosum, and extent of resection were assessed using pre- and postoperative MRI. Corpus callosum invasion was determined when high signal intensity of the tumor extended into the corpus callosum on T2-weighted or FLAIR images. Calcification was defined as the presence of hyperdense areas exceeding 100 Hounsfield Units (HU) within the tumor on preoperative CT scans [ 18 ]. 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. 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) [ 19 ]. 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 [ 20 ]. 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. 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 examined using univariate analysis with the Cox proportional hazards model, and hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated for each variable. 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 males and 11 females, with a median age at diagnosis of 40 years (range: 25–71 years). The median Karnofsky Performance Status (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 19 cases (59.4%). Histologically, 16 cases were classified as WHO grade 2 and 16 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, 8 patients (25.0%) received PAV chemotherapy alone, 4 patients (12.5%) received temozolomide (TMZ) alone, 4 patients (12.5%) underwent radiotherapy alone, 2 patients (6.3%) received combined radiotherapy and PAV, and 3 patients (9.4%) received combined radiotherapy and TMZ (Table 1). The choice of postoperative management was based on the extent of resection, 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 radio-chemotherapy. 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. 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 2 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 findings. 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%). Prognostic factors for OS and PFS Table 2 summarizes univariate analyses of prognostic factors in relation to PFS and OS. Univariate Cox proportional hazards analysis identified KPS 5 cm (p = 0.021, HR = 3.18, 95% CI: 1.19–8.53), and corpus callosum invasion (p = 0.009, HR = 3.55, 95% CI: 1.38–9.15) as significant poor prognostic factors for PFS. In terms of OS, KPS < 90 (p = 0.009, HR = 21.9, 95% CI: 2.19–213), corpus callosum invasion (p = 0.022, HR = 4.96, 95% CI: 1.26–19.6), calcification (p = 0.046, HR = 4.78, 95% CI: 1.03–22.2), and hemizygous deletion of CDKN2A/B (p = 0.006, HR = 7.83, 95% CI: 1.81–33.8) were all identified as significant adverse prognostic factors. Discussion In this study, calcification and corpus callosum invasion were identified as significant adverse prognostic factors in oligodendrogliomas with IDH mutation and 1p/19q codeletion, suggesting that these imaging findings may serve as important indicators for prognostic evaluation. In addition, hemizygous deletion of CDKN2A/B was also suggested to be associated with survival outcomes. Calcification has recently attracted attention as a potential adverse prognostic marker, and in this study, patients with calcified tumors had significantly shorter OS. Calcification has traditionally been recognized as a diagnostic feature of oligodendroglioma. 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 gross total resection more difficult [ 21 ]. 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 [ 21 ]. Corpus callosum invasion was significantly associated with shorter PFS and OS, suggesting its potential role as a poor prognostic factor in the present study. To date, no prior reports have clearly demonstrated the prognostic significance of corpus callosum invasion in oligodendrogliomas. In glioblastoma, however, corpus callosum invasion—so-called “butterfly glioma”—is common and associated with poor OS [ 17 ]. Similarly, in oligodendroglioma, bilateral tumor extension via the corpus callosum, a major interhemispheric white matter tract, may contribute to surgical inaccessibility and early recurrence, thereby negatively affecting prognosis. This study is the first to demonstrate the prognostic impact of corpus callosum invasion in oligodendroglioma, highlighting its potential as a novel prognostic factor. Regarding CDKN2A/B copy number alterations, four cases with hemizygous deletions were identified, and these showed significantly shorter OS. In addition, among the four cases with hemizygous deletion of CDKN2A/B in this study, three showed calcification and two showed corpus callosum invasion. 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. 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 SNP arrays, targeted NGS, MLPA, and FISH—which may have contributed to the heterogeneity of the reported results [ 22 ]. 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 [ 23 ]. 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 [ 24 , 25 ], 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 extent of resection in oligodendroglioma remains controversial across reports [ 24 , 26 ]. Moreover, the extent of resection may be strongly influenced by preoperative factors such as tumor location and corpus callosum invasion [ 24 ], 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. Nancy et al. reported, in a retrospective cohort of patients with WHO grade 3 oligodendroglioma treated with temozolomide (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 [ 27 ]. Given the generally favorable prognosis of oligodendroglioma, flexible treatment strategies that consider long-term toxicities—such as the selective use of stereotactic radiosurgery (SRS)—should be considered [ 28 ]. Although this study has limitations, including its single-center, retrospective design and small sample size—which precluded multivariate analysis for prognostic factors—it is notable for its 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 highlight 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. Statements and Declarations Funding : The authors received no funds, grants, or other support for the preparation of this manuscript. Competing Interests : The authors have no relevant financial or non-financial interests to disclose. Author Contributions : All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Takuma Sumi. The first draft of the manuscript was written by Takuma Sumi, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Data Availability : The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. Ethics Approval : This study was approved by the Ethics Committee of Dokkyo Medical University Hospital (Approval No. R-61-4J) and conducted in accordance with the Declaration of Helsinki. 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06:57:48","extension":"xml","order_by":13,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":71232,"visible":true,"origin":"","legend":"","description":"","filename":"ccd85f02cc494993a3150553f5b249fe1structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7622614/v1/74f1d9bff212ec96bfed56a3.xml"},{"id":92233528,"identity":"a72784bb-ba16-443d-9eaf-09eeda2b8937","added_by":"auto","created_at":"2025-09-26 06:57:48","extension":"html","order_by":14,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":80160,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7622614/v1/01393529b0665672f231c27f.html"},{"id":92233521,"identity":"e5bc3e22-12ad-4c1f-a92f-37d8f722624e","added_by":"auto","created_at":"2025-09-26 06:57:48","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":117195,"visible":true,"origin":"","legend":"\u003cp\u003eTreatment Selection According to Extent of Resection and WHO Tumor Grade, with Treatment Flow Chart\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7622614/v1/a26790fd4578f825ae05323b.png"},{"id":92233527,"identity":"f7f4e068-3ec4-4f7f-b4e9-d61e21b6a433","added_by":"auto","created_at":"2025-09-26 06:57:48","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":337394,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eA\u003c/strong\u003e Electropherogram of MLPA (multiplex ligation-dependent probe amplification) using the P088 probe mix\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eB\u003c/strong\u003e Ratio chart from copy number analysis of the same tumor showing IDH1 R132H mutation, 1p/19q codeletion, and \u003cem\u003eCDKN2A/B\u003c/em\u003e hemizygous deletion with arrowheads indicating the \u003cem\u003eCDKN2A/B\u003c/em\u003e probe region\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7622614/v1/918b96c29339ae667a479ed6.png"},{"id":92233523,"identity":"077dc742-5724-4f9c-a582-d3fa9e20c9ab","added_by":"auto","created_at":"2025-09-26 06:57:48","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":92139,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier analysis and log-rank tests regarding overall survival (OS) and progression free survival (PFS) of patients with oligodendroglioma\u003c/p\u003e\n\u003cp\u003eKaplan–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 smaller (p = 0.015) (Fig. 3a). Cases with calcification exhibited significantly shorter OS (p = 0.028) (Fig. 3b), and those with corpus callosum invasion had significantly shorter PFS and OS (p = 0.005 and p = 0.012, respectively) (Fig. 3c and 3d). Patients with hemizygous deletion of\u003cem\u003e CDKN2A/B \u003c/em\u003ehad significantly shorter OS compared to those with neutral copy number status (p = 0.001) (Fig. 3e). Patients who underwent gross total or subtotal resection (≥90% resection) had significantly better OS than those with \u0026lt;90% resection (p = 0.042) (Fig. 3f).\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7622614/v1/141ccdab4a860b9a0c35a754.png"},{"id":92769168,"identity":"1de6b184-15e9-4cf6-b32e-26f4865a31c8","added_by":"auto","created_at":"2025-10-04 11:08:58","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1129461,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7622614/v1/420747f2-9649-4f3b-871a-669d5c7becdf.pdf"},{"id":92234439,"identity":"0a469989-0595-489d-849e-84c7aa7f94a7","added_by":"auto","created_at":"2025-09-26 07:05:48","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":366971,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-7622614/v1/c2e335ef77bb989b6c42d918.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Prognostic Impact of Calcification, Corpus Callosum Invasion, and CDKN2A/B Hemizygous Deletion in Oligodendroglioma: A Single-Center Retrospective Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eDiffuse gliomas account for approximately 80\u0026ndash;85% of primary malignant brain tumors in adults [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. 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 [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAmong these, oligodendrogliomas frequently localize in the frontal lobe and often present with seizures [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. According to the Central Brain Tumor Registry of the United States (CBTRUS) Statistical Report 44, the incidence of oligodendroglioma is 0.21 per 100,000 and that of anaplastic oligodendroglioma is 0.05\u0026ndash;0.10 per 100,000 in the United States [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. While oligodendrogliomas generally have a better prognosis compared to other adult-type diffuse gliomas, patient outcomes are highly variable [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Radiochemotherapy is considered a standard treatment for oligodendroglioma; however, it may result in long-term cognitive impairment [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. 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 [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eTo date, few established prognostic factors for oligodendroglioma exist. This may be attributed to the tumor\u0026rsquo;s biological heterogeneity, low incidence, and extended survival periods. Consequently, there is an increasing demand for reliable molecular pathological indicators to predict prognosis more accurately. In IDH-mutant gliomas, homozygous and hemizygous deletions of the \u003cem\u003eCDKN2A/B\u003c/em\u003e gene locus at chromosome 9p21 are frequently observed. Homozygous deletion of \u003cem\u003eCDKN2A/B\u003c/em\u003e in IDH-mutant astrocytoma is a well-established adverse prognostic factor and is used to define WHO grade 4 tumors. 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 [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Calcification is a well-known radiological hallmark in the differential diagnosis of oligodendroglioma [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]; 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 [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. However, its clinical relevance in oligodendroglioma remains unexplored. In this study, we analyzed copy number alterations of \u003cem\u003eCDKN2A/B\u003c/em\u003e, radiological features, treatment details, and clinical course in patients with oligodendroglioma, and investigated prognostic factors based on cases from a single institution.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eInclusion Criteria\u003c/h2\u003e\u003cp\u003eA retrospective observational study was conducted on patients aged 18 years or older 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.\u003c/p\u003e\u003cp\u003e 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.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eData collection\u003c/h3\u003e\n\u003cp\u003eClinical data, including age, sex, and Karnofsky Performance Status (KPS), as well as details of postoperative treatment, were collected from electronic medical records. Tumor location, maximum diameter, invasion of the corpus callosum, and extent of resection were assessed using pre- and postoperative MRI. Corpus callosum invasion was determined when high signal intensity of the tumor extended into the corpus callosum on T2-weighted or FLAIR images. Calcification was defined as the presence of hyperdense areas exceeding 100 Hounsfield Units (HU) within the tumor on preoperative CT scans [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. 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\u0026nbsp;1.\u003c/p\u003e\n\u003ch3\u003ePathological and molecular analysis\u003c/h3\u003e\n\u003cp\u003eTo 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) [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eFor the detection of \u003cem\u003eCDKN2A/B\u003c/em\u003e 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. \u003cem\u003eCDKN2A/B\u003c/em\u003e copy number status was defined based on the following cutoff values: normal, probe ratio\u0026thinsp;\u0026gt;\u0026thinsp;0.7; hemizygous deletion, 0.4\u0026thinsp;\u0026le;\u0026thinsp;probe ratio\u0026thinsp;\u0026le;\u0026thinsp;0.7; and homozygous deletion, probe ratio\u0026thinsp;\u0026lt;\u0026thinsp;0.4 [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Cases with suspected \u003cem\u003eCDKN2A/B\u003c/em\u003e deletion on MLPA were further examined by fluorescence in situ hybridization (FISH) to verify \u003cem\u003eCDKN2A\u003c/em\u003e deletion. FISH analysis was conducted using a \u003cem\u003eCDKN2A\u003c/em\u003e (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 \u0026ge;\u0026thinsp;15% of tumor cells. Normal cells were expected to show two green signals (CSP9) and two red signals (\u003cem\u003eCDKN2A\u003c/em\u003e); hemizygous deletion was defined as one red signal, and homozygous deletion as complete loss of the red signal.\u003c/p\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\u003cp\u003eStatistical analyses were performed using SPSS version 29.0 (IBM Corp, Armonk, NY, USA), with a significance level set at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05. Overall survival (OS) and progression-free survival (PFS) were evaluated using the Kaplan\u0026ndash;Meier method, and differences between groups were assessed with the log-rank test. The median follow-up was estimated using the reverse Kaplan\u0026ndash;Meier method, defined as the time from surgery to the last known contact. Prognostic factors were examined using univariate analysis with the Cox proportional hazards model, and hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated for each variable.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003eDemographic characteristics\u003c/h2\u003e\n \u003cp\u003eA 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.\u003c/p\u003e\n \u003cp\u003eThis study included 32 patients diagnosed with oligodendroglioma harboring IDH mutation and 1p/19q codeletion. The cohort consisted of 21 males and 11 females, with a median age at diagnosis of 40 years (range: 25\u0026ndash;71 years). The median Karnofsky Performance Status (KPS) was 90 (range: 20\u0026ndash;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\u0026ndash;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 19 cases (59.4%). Histologically, 16 cases were classified as WHO grade 2 and 16 as grade 3. Gross total or subtotal resection (\u0026ge;\u0026thinsp;90% resection) was achieved in 11 patients (34.4%), while partial resection or biopsy (\u0026lt;\u0026thinsp;90% resection) was performed in 21 patients (65.6%).\u003c/p\u003e\n \u003cp\u003ePostoperative management consisted of observation alone in 11 patients (34.4%) and adjuvant therapy in 21 patients (65.6%). Among those receiving adjuvant therapy, 8 patients (25.0%) received PAV chemotherapy alone, 4 patients (12.5%) received temozolomide (TMZ) alone, 4 patients (12.5%) underwent radiotherapy alone, 2 patients (6.3%) received combined radiotherapy and PAV, and 3 patients (9.4%) received combined radiotherapy and TMZ (Table\u0026nbsp;1).\u003c/p\u003e\n \u003cp\u003eThe choice of postoperative management was based on the extent of resection, 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\u0026mdash;exclusively those with Grade 3 tumors\u0026mdash;received combined radio-chemotherapy. 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\u0026rsquo;s discretion based on individual patient factors.\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eEvaluation of IDH Mutation and\u003c/strong\u003e \u003cstrong\u003eCDKN2A/B\u003c/strong\u003e \u003cstrong\u003eStatus\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eIn the evaluation of IDH mutations, IDH1 mutations were identified in 30 cases (93.8%) and IDH2 mutations in 2 cases (6.2%) through IDH1 R132H immunohistochemistry and Sanger sequencing (Table\u0026nbsp;1).\u003c/p\u003e\n \u003cp\u003eRegarding \u003cem\u003eCDKN2A/B\u003c/em\u003e 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 findings.\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eSurvival outcomes\u003c/h3\u003e\n\u003cp\u003eAmong 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\u0026ndash;180.0; range, 5\u0026ndash;245 months). The 5-year PFS was 62.0% (95% CI: 44.2\u0026ndash;79.8%), and the 5-year OS was 86.5% (95% CI: 74.2\u0026ndash;98.9%).\u003c/p\u003e\n\u003ch3\u003ePrognostic factors for OS and PFS\u003c/h3\u003e\n\u003cp\u003eTable\u0026nbsp;2 summarizes univariate analyses of prognostic factors in relation to PFS and OS. Univariate Cox proportional hazards analysis identified KPS\u0026thinsp;\u0026lt;\u0026thinsp;90 (p\u0026thinsp;=\u0026thinsp;0.008, HR\u0026thinsp;=\u0026thinsp;5.77, 95% CI: 1.59\u0026ndash;20.9), tumor size\u0026thinsp;\u0026gt;\u0026thinsp;5 cm (p\u0026thinsp;=\u0026thinsp;0.021, HR\u0026thinsp;=\u0026thinsp;3.18, 95% CI: 1.19\u0026ndash;8.53), and corpus callosum invasion (p\u0026thinsp;=\u0026thinsp;0.009, HR\u0026thinsp;=\u0026thinsp;3.55, 95% CI: 1.38\u0026ndash;9.15) as significant poor prognostic factors for PFS.\u003c/p\u003e\n\u003cp\u003eIn terms of OS, KPS\u0026thinsp;\u0026lt;\u0026thinsp;90 (p\u0026thinsp;=\u0026thinsp;0.009, HR\u0026thinsp;=\u0026thinsp;21.9, 95% CI: 2.19\u0026ndash;213), corpus callosum invasion (p\u0026thinsp;=\u0026thinsp;0.022, HR\u0026thinsp;=\u0026thinsp;4.96, 95% CI: 1.26\u0026ndash;19.6), calcification (p\u0026thinsp;=\u0026thinsp;0.046, HR\u0026thinsp;=\u0026thinsp;4.78, 95% CI: 1.03\u0026ndash;22.2), and hemizygous deletion of \u003cem\u003eCDKN2A/B\u003c/em\u003e (p\u0026thinsp;=\u0026thinsp;0.006, HR\u0026thinsp;=\u0026thinsp;7.83, 95% CI: 1.81\u0026ndash;33.8) were all identified as significant adverse prognostic factors.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, calcification and corpus callosum invasion were identified as significant adverse prognostic factors in oligodendrogliomas with IDH mutation and 1p/19q codeletion, suggesting that these imaging findings may serve as important indicators for prognostic evaluation. In addition, hemizygous deletion of \u003cem\u003eCDKN2A/B\u003c/em\u003e was also suggested to be associated with survival outcomes.\u003c/p\u003e\u003cp\u003eCalcification has recently attracted attention as a potential adverse prognostic marker, and in this study, patients with calcified tumors had significantly shorter OS. Calcification has traditionally been recognized as a diagnostic feature of oligodendroglioma. 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 gross total resection more difficult [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. 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 [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eCorpus callosum invasion was significantly associated with shorter PFS and OS, suggesting its potential role as a poor prognostic factor in the present study. To date, no prior reports have clearly demonstrated the prognostic significance of corpus callosum invasion in oligodendrogliomas. In glioblastoma, however, corpus callosum invasion\u0026mdash;so-called \u0026ldquo;butterfly glioma\u0026rdquo;\u0026mdash;is common and associated with poor OS [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Similarly, in oligodendroglioma, bilateral tumor extension via the corpus callosum, a major interhemispheric white matter tract, may contribute to surgical inaccessibility and early recurrence, thereby negatively affecting prognosis. This study is the first to demonstrate the prognostic impact of corpus callosum invasion in oligodendroglioma, highlighting its potential as a novel prognostic factor.\u003c/p\u003e\u003cp\u003eRegarding \u003cem\u003eCDKN2A/B\u003c/em\u003e copy number alterations, four cases with hemizygous deletions were identified, and these showed significantly shorter OS. In addition, among the four cases with hemizygous deletion of \u003cem\u003eCDKN2A/B\u003c/em\u003e in this study, three showed calcification and two showed corpus callosum invasion. While homozygous deletion of \u003cem\u003eCDKN2A/B\u003c/em\u003e is known to be a poor prognostic factor in IDH-mutant astrocytomas, the clinical relevance of \u003cem\u003eCDKN2A/B\u003c/em\u003e deletions\u0026mdash;particularly hemizygous deletions\u0026mdash;in oligodendrogliomas remains unclear. A recent systematic review and meta-analysis by Nakasu et al. reported that homozygous deletions of \u003cem\u003eCDKN2A/B\u003c/em\u003e 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 \u003cem\u003eCDKN2A/B\u003c/em\u003e copy number alterations\u0026mdash;such as SNP arrays, targeted NGS, MLPA, and FISH\u0026mdash;which may have contributed to the heterogeneity of the reported results [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. 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 \u003cem\u003eCDKN2A/B\u003c/em\u003e deletion, the results should be interpreted with caution. Notably, in the GLASS dataset, hemizygous deletion of \u003cem\u003eCDKN2A\u003c/em\u003e 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 [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Since oligodendrogliomas are considered to be molecularly closely related to astrocytomas, hemizygous deletion of \u003cem\u003eCDKN2A/B\u003c/em\u003e may also impact prognosis in oligodendrogliomas. Further investigation using larger cohorts and standardized assessment methods is warranted.\u003c/p\u003e\u003cp\u003eAmong other clinical prognostic factors, a KPS\u0026thinsp;\u0026lt;\u0026thinsp;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 [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], 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 extent of resection in oligodendroglioma remains controversial across reports [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Moreover, the extent of resection may be strongly influenced by preoperative factors such as tumor location and corpus callosum invasion [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e], making it difficult to assess based on resection rate alone.\u003c/p\u003e\u003cp\u003eIn this study, postoperative radiotherapy was generally avoided in WHO grade 2 cases, unless chemotherapy was declined by the patient or precluded by medical contraindications. Nancy et al. reported, in a retrospective cohort of patients with WHO grade 3 oligodendroglioma treated with temozolomide (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 [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Given the generally favorable prognosis of oligodendroglioma, flexible treatment strategies that consider long-term toxicities\u0026mdash;such as the selective use of stereotactic radiosurgery (SRS)\u0026mdash;should be considered [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAlthough this study has limitations, including its single-center, retrospective design and small sample size\u0026mdash;which precluded multivariate analysis for prognostic factors\u0026mdash;it is notable for its comprehensive evaluation of imaging findings (calcification and corpus callosum invasion), \u003cem\u003eCDKN2A/B\u003c/em\u003e copy number alterations, and clinical data, all based on the molecular definitions outlined in the 2021 WHO classification. These findings highlight 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 \u003cem\u003eCDKN2A/B\u003c/em\u003e deletions.\u003c/p\u003e"},{"header":"Statements and Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e: The authors received no funds, grants, or other support for the preparation of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e: The authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e: All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Takuma Sumi. The first draft of the manuscript was written by Takuma Sumi, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Approval\u003c/strong\u003e: This study was approved by the Ethics Committee of Dokkyo Medical University Hospital (Approval No. R-61-4J) and conducted in accordance with the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to Participate\u003c/strong\u003e: Informed consent was obtained from all individual participants included in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to Publish\u003c/strong\u003e: Not applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eOstrom QT, Gittleman H, Truitt G, et al. (2018) CBTRUS Statistical Report: Primary brain and other central nervous system tumors diagnosed in the United States in 2011\u0026ndash;2015. Neuro Oncol 20(Suppl 4):iv1\u0026ndash;iv86. https://doi.org/10.1093/neuonc/noy131\u003c/li\u003e\n \u003cli\u003eBrat DJ, Aldape K, Colman H, et al. (2020) cIMPACT-NOW update 5: Recommended grading criteria and terminologies for IDH-mutant astrocytomas. Acta Neuropathol 139(3):603\u0026ndash;608. https://doi.org/10.1007/s00401-020-02127-9\u003c/li\u003e\n \u003cli\u003eLebrun C, Fontaine D, Ramaioli A, et al. (2004) Long-term outcome of oligodendrogliomas. \u003cstrong\u003eNeurology\u003c/strong\u003e 62(10):1783\u0026ndash;1787. https://doi.org/10.1212/01.WNL.0000125196.88449.89\u003c/li\u003e\n \u003cli\u003eOstrom QT, Price M, Neff C, et al. (2024) CBTRUS Statistical Report: Primary brain and other central nervous system tumors diagnosed in the United States in 2017\u0026ndash;2021. Neuro Oncol 26(Suppl 6):vi1\u0026ndash;vi85. https://doi.org/10.1093/neuonc/noae145\u003c/li\u003e\n \u003cli\u003eBrat DJ, Verhaak RGW, Aldape KD, et al. (2015) Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N Engl J Med 372(26): 2481\u0026ndash;2498. https://doi.org/10.1056/NEJMoa1402121\u003c/li\u003e\n \u003cli\u003eEckel-Passow JE, Lachance DH, Molinaro AM, et al. (2015) Glioma groups based on 1p/19q, IDH, and TERT promoter mutations in tumors. N Engl J Med 372(26):2499\u0026ndash;2508. https://doi.org/10.1056/NEJMoa1407279\u003c/li\u003e\n \u003cli\u003eHalani SH, Yousefi S, Velazquez Vega J, et al. (2018) Multi-faceted computational assessment of risk and progression in oligodendroglioma implicates NOTCH and PI3K pathways. NPJ Precis Oncol 2:24. https://doi.org/10.1038/s41698-018-0067-9\u003c/li\u003e\n \u003cli\u003eZadeh G, Khan OH, Vogelbaum M, Schiff D. (2015) Much debated controversies of diffuse low-grade gliomas. Neuro Oncol 17(3):323\u0026ndash;326. https://doi.org/10.1093/neuonc/nou368\u003c/li\u003e\n \u003cli\u003eMohile NA, Messersmith H, Gatson NT, et al. (2022) Therapy for diffuse astrocytic and oligodendroglial tumors in adults: ASCO-SNO guideline. J Clin Oncol 40(4):403\u0026ndash;426. https://doi.org/10.1200/JCO.21.02036\u003c/li\u003e\n \u003cli\u003eWeller M, van den Bent M, Preusser M, et al. (2021) EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood. Nat Rev Clin Oncol 18(3):170\u0026ndash;186. https://doi.org/10.1038/s41571-020-00447-z\u003c/li\u003e\n \u003cli\u003eLi M, Ren X, Chen X, et al. (2022) Combining hyperintense FLAIR rim and radiological features in identifying IDH-mutant 1p/19q non-codeleted lower-grade glioma. Eur Radiol 32(6):3869\u0026ndash;3879. https://doi.org/10.1007/s00330-021-08500-w\u003c/li\u003e\n \u003cli\u003ePatel SH, Poisson LM, Brat DJ, et al. (2017) T2-FLAIR mismatch, an imaging biomarker for IDH and 1p/19q status in lower-grade gliomas: a TCGA/TCIA project. Clin Cancer Res 23(20):6078\u0026ndash;6085. https://doi.org/10.1158/1078-0432.CCR-17-0560\u003c/li\u003e\n \u003cli\u003eZhao K, Sun G, Wang Q, et al. (2021) The diagnostic value of conventional MRI and CT features in the identification of the IDH1-mutant and 1p/19q co-deletion in WHO grade II gliomas. Acad Radiol 28(10):e189\u0026ndash;e198. \u003cstrong\u003ehttps://doi.org/10.1016/j.acra.2020.03.008\u003c/strong\u003e\u003c/li\u003e\n \u003cli\u003eSaito T, Muragaki Y, Maruyama T, et al. (2016) 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. Brain Tumor Pathol 33(3):175\u0026ndash;182. https://doi.org/10.1007/s10014-016-0249-5\u003c/li\u003e\n \u003cli\u003evan Lent DI, van Baarsen KM, Snijders TJ, Robe P. (2020) Radiological differences between subtypes of WHO 2016 grade II\u0026ndash;III gliomas: a systematic review and meta-analysis. Neurooncol Adv 2(1):vdaa044. https://doi.org/10.1093/noajnl/vdaa044\u003c/li\u003e\n \u003cli\u003eMickevicius NJ, Paulson ES, Prah MA, Schmainda KM. (2015) Location of brain tumor intersecting white matter tracts predicts patient prognosis. J Neurooncol 125(2):393\u0026ndash;400. \u003cstrong\u003ehttps://doi.org/10.1007/s11060-015-1928-5\u003c/strong\u003e\u003c/li\u003e\n \u003cli\u003eHazaymeh M, L\u0026ouml;ber-Handwerker R, D\u0026ouml;ring K, et al. (2022) Prognostic differences and implications on treatment strategies between butterfly glioblastoma and glioblastoma with unilateral corpus callosum infiltration. Sci Rep 12:19208. https://doi.org/10.1038/s41598-022-23794-6\u003c/li\u003e\n \u003cli\u003eGo JL, Zee CS. (1998) Unique CT imaging advantages: Hemorrhage and calcification. Neuroimaging Clin N Am 8(3):541\u0026ndash;558.\u003c/li\u003e\n \u003cli\u003eOtani R, Uzuka T, Higuchi F, et al. (2018) IDH-mutated astrocytomas with 19q-loss constitute a subgroup that confers better prognosis. Cancer Sci 109(8):2327\u0026ndash;2335. https://doi.org/10.1111/cas.13635\u003c/li\u003e\n \u003cli\u003eUmehara T, Arita H, Yoshioka E, et al. (2019) Distribution differences in prognostic copy number alteration profiles in IDH-wild-type glioblastoma cause survival discrepancies across cohorts. Acta Neuropathol Commun 7:99. https://doi.org/10.1186/s40478-019-0749-8\u003c/li\u003e\n \u003cli\u003eZhu Q, Jiang H, Cui Y, et al. (2024) Intratumoral calcification: not only a diagnostic but also a prognostic indicator in oligodendrogliomas. Eur Radiol 34(6): 3674\u0026ndash;3685. https://doi.org/10.1007/s00330-023-10405-9\u003c/li\u003e\n \u003cli\u003eNakasu S, Deguchi S, Nakasu Y. (2024) Frequency and prognostic impact of CDKN2A/B alteration in oligodendrogliomas: systematic review and meta-analysis. Neurol Med Chir (Tokyo) 64(12):442\u0026ndash;450. https://doi.org/10.2176/jns-nmc.2024-0105\u003c/li\u003e\n \u003cli\u003eKocakavuk E, Johnson KC, Sabedot TS, et al. (2023) Hemizygous CDKN2A deletion confers worse survival outcomes in IDHmut-noncodel gliomas. Neuro Oncol 25(9):1721\u0026ndash;1723. https://doi.org/10.1093/neuonc/noad095\u003c/li\u003e\n \u003cli\u003evan der Vaart T, Wijnenga M, van Garderen KA, et al. (2024) Differences in the prognostic role of age, extent of resection and tumor grade between astrocytoma IDHmt and oligodendroglioma: a single-center cohort study. Clin Cancer Res 30(17): 3837\u0026ndash;3844. https://doi.org/10.1158/1078-0432.CCR-24-0901\u003c/li\u003e\n \u003cli\u003eFisher B, Naumova E, Leighton C, et al. (2002) Ki-67: a prognostic factor for low-grade glioma? Int J Radiat Oncol Biol Phys 52(4):996\u0026ndash;1001. https://doi.org/10.1016/S0360-3016(01)02720-1\u003c/li\u003e\n \u003cli\u003eKinslow CJ, Garton ALA, Rae A, et al. (2019) Extent of resection and survival foroligodendroglioma: a U.S. population-based study. J Neurooncol 144(3):591\u0026ndash;601. https://doi.org/10.1007/s11060-019-03261-5\u003c/li\u003e\n \u003cli\u003eOberheim Bush NA, Young JS, Zhang Y, et al. (2021) A single institution retrospective analysis on survival based on treatment paradigms for patients with anaplastic oligodendroglioma. J Neurooncol 153(3):447\u0026ndash;454. https://doi.org/10.1007/s11060-021-03781-z\u003c/li\u003e\n \u003cli\u003eKano H, Niranjan A, Khan A, et al. (2009) Does radiosurgery have a role in the management of oligodendrogliomas? J Neurosurg 110(3):564\u0026ndash;571. https://doi.org/10.3171/2008.5.17582\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 and 3 are available in the Supplementary Files section\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"oligodendroglioma, calcification, corpus callosum invasion, CDKN2A/B, MLPA","lastPublishedDoi":"10.21203/rs.3.rs-7622614/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7622614/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e\u003cp\u003eOligodendrogliomas generally have a better prognosis than other adult-type diffuse gliomas. However, few prognostic factors have been established, and decisions regarding postoperative treatment remain challenging due to concerns about long-term adverse effects. This study aimed to identify prognostic factors by analyzing clinical, radiological, therapeutic, and genetic data from a single-institution cohort.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eWe retrospectively reviewed adult patients (\u0026ge;\u0026thinsp;18 years) with isocitrate dehydrogenase (IDH)-mutant and 1p/19q-codeleted oligodendrogliomas who underwent surgical resection at our institution between 1999 and 2021, with available preoperative MRI and CT. \u003cem\u003eCDKN2A/B\u003c/em\u003e copy number status was assessed using multiplex ligation-dependent probe amplification (MLPA) and confirmed by fluorescence in situ hybridization (FISH). The impact on overall survival (OS) and progression-free survival (PFS) was evaluated using Kaplan\u0026ndash;Meier survival analysis and the Cox proportional hazards model.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eThirty-two patients were included. The median age was 40 years, and the median Karnofsky Performance Status (KPS) was 90. Calcification and corpus callosum invasion were observed in 46.9% and 59.4% of cases, respectively. \u003cem\u003eCDKN2A/B\u003c/em\u003e hemizygous deletion was identified in four cases. The 5-year PFS was 62.0%, and the 5-year OS was 86.5%. On univariate Cox proportional hazards analysis, calcification (p\u0026thinsp;=\u0026thinsp;0.046), corpus callosum invasion (p\u0026thinsp;=\u0026thinsp;0.022), and \u003cem\u003eCDKN2A/B\u003c/em\u003e hemizygous deletion (p\u0026thinsp;=\u0026thinsp;0.006) were significantly associated with shorter OS.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eCalcification, corpus callosum invasion, and \u003cem\u003eCDKN2A/B\u003c/em\u003e hemizygous deletion appear to be important prognostic factors in oligodendroglioma.\u003c/p\u003e","manuscriptTitle":"Prognostic Impact of Calcification, Corpus Callosum Invasion, and CDKN2A/B Hemizygous Deletion in Oligodendroglioma: A Single-Center Retrospective Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-26 06:57:43","doi":"10.21203/rs.3.rs-7622614/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"36a7897c-88d9-4553-94e3-f2deb584e1ea","owner":[],"postedDate":"September 26th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-10-04T11:08:30+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-26 06:57:43","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7622614","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7622614","identity":"rs-7622614","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}