The ependymoma is a rare neuroepithelial tumor that accounts for only 6.9% of primary central nervous system (CNS) tumors diagnosed annually [14]. Ependymomas predominantly originate from the ependymal cells of the ventricular system and the central canal of the spinal cord [10]. Ependymomas can grow in the brain’s supratentorial region, posterior cranial fossa, or spinal cord [29]. The anatomical distribution of ependymomas demonstrates a distinct age-dependent predilection, with pediatric cases predominantly arising from intracranial locations, while adult cases exhibit a higher incidence within the spinal cord [12,35].

Posterior cranial fossa is located in the lower posterior part of the cranial cavity, and includes important structures such as brainstem, fourth ventricle, and cerebellum. Posterior cranial fossa is the most common location for pediatric ependymomas [12]. Given the anatomical complexity of this region, tumors in this location can exert profound and multifaceted effects on the patient’s neurological and systemic functions. According to the World Health Organization (WHO) 2021 classifications of CNS tumors, posterior cranial fossa ependymomas are divided into posterior fossa group A (PFA) and posterior fossa group B (PFB) ependymomas based on the methylation group, and the WHO grading is II/III [16].

Brainstem is the most important structure in the posterior cranial fossa and even in the human body. To date, our current understanding of brainstem ependymomas is still insufficient. There are also differences between children and adults with brainstem ependymomas. The Surveillance, Epidemiology, and End Results (SEER) database contains clinical data on brainstem ependymomas collected over the past two decades. Therefore, we conducted a comprehensive retrospective study utilizing the SEER database to systematically analyze the clinical features and prognostic indicators for pediatric and adult brainstem ependymomas.

This study did not require review by the Ethics Committee of West China Hospital because the SEER database is publicly and freely available.

Ependymomas are rare CNS tumors. There are many differences between pediatric and adult patients, such as tumor location, tumor type, and prognosis [29]. Therefore, it is very important to discuss pediatric and adult ependymomas separately. Recently, a study reported the clinical features of brainstem ependymomas [11]. However, the investigation did not stratify the analysis between pediatric and adult cohorts. To address this limitation, our study analysed the pediatric and adult patients with brainstem ependymoma separately.

In this population-based study, 269 pediatric patients and 432 adult patients with brainstem ependymomas were enrolled. According to previous research reports, posterior cranial fossa was the most common location for pediatric ependymomas [12]. However, more adult patients were recorded in this study. It is unclear whether it is caused by the special part of the brainstem, and further research and exploration are needed. The median age of pediatric patient was 3.0 years old and the adult was 46.0 years old. Previous studies reported that the average age of diagnosis for adults with ependymomas was 45 years, while the average age of diagnosis for children with posterior fossa ependymomas was 5 years [17]. The average age of children with brainstem ependymomas was even younger. Brainstem ependymomas had a greater impact on males which are observed in both pediatric and adult patients. This is consistent with previous research findings [23]. The highest proportion of race was white in both pediatric and adult patients. According to a prior study, childhood ependymomas were less common in African Americans and Native Americans, whereas a greater degree of European genetic ancestry was related to an increased risk of ependymomas [38].

The tumor size in children was larger than that in adult patients. And meanwhile, high-grade ependymomas were more common in pediatric patients. Compared to patients with PFB, those with PFA are younger, and are more likely to experience recurrence, metastasis at recurrence, and death [37]. This indicates that posterior fossa ependymomas in children may have a higher degree of malignancy. In our study, pediatric patients tended to receive more surgery, radiation, and chemotherapy. When dealing with pediatric patients, treatments may be more comprehensive.

Previous study reported that ependymomas had two distributional peaks (0-4 and 55-59 years of age) [13]. We also found that children under the age of 4 accounted for 50% of all pediatric patients. Interestingly, the number of adult cases gradually decreased as age increases. Therefore, we further analyzed the different age groups in pediatric and adult patients separately. Among all pediatric patients, we found that younger children patients tended to be ependymoma, anaplastic, and the tumor size was larger. This suggests that the younger the age, the more malignant the tumor may be. Older pediatric patients had a higher proportion receiving radiation and a lower proportion receiving chemotherapy. For children over 18 months, they are required to receive post-operative radiation [13]. The brain is at risk during radiation because of its toxicity, particularly in younger children [21,28]. Alternative adjuvant therapy such as chemotherapy is recommended for younger pediatric patients [33]. This may be the reason for the above phenomenon. Among adult patients, younger adult patients tended to be ependymoma, anaplastic, and the tumor size was larger. High grade ependymomas may be more common in younger adult patients. There was no significant difference in GTR treatment and chemotherapy between the two groups of adult patients. However, younger adult patients had a higher proportion receiving radiation. Which may be associated with the higher proportion of high-grade tumors in younger adult patients.

Pediatric patients generally have worse prognoses than adults [29]. However, we did not observe the same outcome in our study. We speculate that this may be related to the special area of the brainstem. In terms of demographics, adult patients over 50 years old, male, and black individuals exhibit poorer prognosis (p<0.01). However, in pediatric patients, we found that age and gender have no effect on prognosis. Black patients exhibited poorer prognosis, and black race was also identified as an independent risk factor within the pediatric cohort. Aging and cancer have a very important relationship [20]. Among multiple types of cancer, elderly patients exhibit poorer prognosis [6,36]. Accumulating evidence indicate that ependymoma mortality risk may follow a bimodal distribution, peaking in both pediatric and geriatric populations [7,25-27]. Previous studies have reported that ependymoma patients aged ≥60 years face more than fourfold higher mortality risk compared to those aged 18-59 years [2]. However, the exact underlying mechanisms remain unclear. Notably, age-related alterations, including cognitive decline, endocrine changes, and increased comorbidity burden (e.g., diabetes and cardiovascular diseases), may interact with conventional prognostic factors, thereby modifying survival probabilities [2,4]. And meanwhile, the shorter life expectancy in older individuals is also considered. This finding highlights the imperative for future investigations specifically targeting elderly ependymoma patients.

Gender significantly impacts ependymoma patient prognosis. A pooled analysis across all age groups identified male as an independent predictor of poorer outcomes [27]. Age-stratified analyses revealed male as a significant risk factor exclusively in pediatric group, with no prognostic effect observed in adults [7]. Notably, our study further reported an age-dependent sex effect in the prognosis of brainstem ependymomas. While no sex-based survival difference emerged in pediatric cohorts, adult male patients demonstrated significantly worse prognosis. The underlying mechanisms remain unclear. Whether attributable to brainstem-specific pathophysiology or other factors requires further investigation. Race has a significant impact on survival prognosis. Compared to white people, African American patients have poor prognosis [1]. This may be associated with household income, educational attainment, and health care [31]. The pathological type of tumors is an important factor affecting prognosis. Although we did not observe statistical differences in the survival analysis of different pathological types in both pediatric and adult patients, it is evident that the prognosis of ependymoma, anaplastic was worse. Besides, we did not observe the impact of tumor size on survival prognosis in both pediatric and adult patients.

Surgery and radiation are the main treatment options for pediatric and adult ependymomas [15,18,28,39]. GTR has been identified to be associated with better prognosis for ependymomas [19]. In patients with cerebral ependymomas, the advantages of postoperative radiation also have been shown in survival rates [15]. In our study, we found that surgery, especially GTR, and radiation, was beneficial for the survival of both pediatric and adult patients. The role of chemotherapy in the management of ependymomas remains unclear. Multiple retrospective studies analyzing the efficacy of chemotherapy in cohorts of pediatric or adult patients have failed to demonstrate a survival benefit [8,9,22,24]. Overall, the role of chemotherapy is limited in treating ependymomas, particularly in the pediatric patients [29]. In our study, we are the first to report that chemotherapy is a risk factor for pediatric patients with brainstem ependymomas. This may be related to the unique location of brainstem ependymomas. There are genetic differences between supratentorial and infratentorial ependymomas, which may influence their biological behavior [3,30,32]. Previous studies have reported that, compared to supratentorial ependymomas in children, infratentorial ependymomas respond poorly to chemotherapy and may even exhibit disease progression during treatment [34]. However, the exact mechanisms remain unclear and warrant further in-depth research in the future. Through combination therapy analysis, we found that GTR combined with radiation was the best treatment option for both pediatric and adult patients. When GTR proves unattainable, maximal safe tumor debulking followed by adjuvant radiation demonstrates significant therapeutic efficacy.

Our study also has some limitations. Firstly, according to the latest classification by WHO in 2021, posterior fossa ependymomas are divided into PFA group and PFB group, but unfortunately, this information is currently not available in the SEER database. Patients in the PFA group are younger, and the tumors may be more malignant [37]. Secondly, some important information, including tumor specific location, treatment details, is lacking. Tumor location is associated with the survival prognosis, and the tumor in the midbrain indicates a better prognosis [5]. Thirdly, we only used public data for analysis, lacking real-world data for validation. Fourthly, retrospective studies utilizing large databases inevitably face potential selection bias, information bias, and other limitations. Additionally, the limitations in database-derived data collection may preclude comprehensive adjustment for potential confounding variables.

In the SEER-based population analysis, this study comprehensively investigated the clinical features and survival outcomes of pediatric and adult brainstem ependymomas. We have identified that black and chemotherapy are independent risk factors for pediatric brainstem ependymomas, and age over 50 years, male, and black for adult brainstem ependymomas. Overall, there is a significant difference between pediatric patients and adult patients. The best recommended treatment method is surgery combined with radiation.