Evaluation of pediatric spinal ependymomas: A 25-year retrospective observational study

Abstract

This study aims to evaluate the clinical and radiological features, histopathological characteristics, treatment modalities, and their effectiveness, as well as long-term follow-up results of pediatric spinal ependymomas treated at a single institution. In this retrospective study, medical records of 14 pediatric patients (3 females and 11 males) who were surgically treated for spinal ependymoma in our institution between 1995 and 2020 were reviewed. Data regarding age, gender, presenting symptoms and signs, radiological findings, postoperative status, extent of resection, histopathological grading, recurrence, tumor growth, seeding, and adjuvant treatment were collected and analyzed. Six patients had myxopapillary ependymoma, 7 patients had grade II ependymoma, and 1 had grade III ependymoma. Median age at diagnosis was 10.5 (range, 1–15) years. The most common presenting symptoms and signs were axial and radicular pain, paresis, and first motor neuron involvement. In 10 patients, gross total tumor resection was achieved. Five patients underwent additional surgeries for disease progression (recurrence or residual tumor growth). Most of the patients who had no disease progression were treated with gross total resection. Two patients experienced seeding. One patient who had a grade III tumor and did not achieve gross total resection died during follow-up. Pediatric spinal ependymomas are uncommon tumors with relatively benign course. Gross total resection should be the primary goal of surgery since it may prevent disease progression, and in case it fails, progression occurs later than those that were treated with subtotal resection.

1. Introduction

Ependymoma is the third most commonly seen central nervous tissue neoplasm of childhood.^[1] Unlike adults in whom the spinal canal is the more common location, the spinal ependymoma constitutes 8% of all ependymoma in children.^[1,2] Also, the pediatric population has a higher survival rate compared with the adult population.^[3]

In the recently published World Health Organization (WHO) classification of central nervous system (CNS) tumors (WHO CNS5), spinal ependymomas were classified as subependymoma; myxopapillary ependymoma (MPE); spinal ependymoma with MYCN amplification; and spinal ependymoma when a molecular analysis fails or unavailable, following Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy–Not Official WHO recommendations.^[4,5] MPE was revised as grade 2 instead of grade I.^[4] Morphological variants such as papillary, clear cell, and tanycytic ependymomas are not listed as ependymoma subtypes.^[4] Moreover, the anaplastic ependymoma term is also no longer listed.^[4] Due to the controversies on the grading of ependymomas, the WHO CNS5 only allows histologically defined diagnosis and requires grading for those without molecular specification.^[4,6]

Though the prognosis is relatively good for spinal ependymomas, recurrence is common, which may require subsequent surgeries and affect quality of life.^[1,7] Since these neoplasms are uncommon in the pediatric population, the literature on long-term follow-up of these neoplasms in this population is limited.

In this study, we aimed to provide >2 decades of experience in spinal ependymoma in a single center.

2. Methods

This retrospective study is approved by the Non-Interventional Clinical Research Ethics Board of Hacettepe University (decision no: 2021/02-52).

The study included 14 consecutive children who were treated surgically for spinal ependymoma between 1995 and 2020 in the Department of Neurosurgery, Hacettepe University, Turkey. In this retrospective study, the cases were identified and collected by reviewing surgical and pathological records of the hospital archive. The data retrieved from the records included sex, signs and symptoms, age at the time of surgery, subsequent surgeries, extent of resection, pathological grade, adjuvant treatment, early outcomes, progression, and survival. The extent of resection was based on postoperative magnetic resonance imaging if present; otherwise, the operating surgeon’s description was used. The patients who had concomitant intracranial ependymoma were excluded from the cohort since it could not be verified which location was the site of origin.

The patients were contacted by phone regarding their current situation. For those who could not be contacted, the last follow-up data were used for the last situation.

1.1. Statistical analysis

IBM SPSS Statistics Version 24 software was utilized for statistical analysis.The continuous variables were expressed as median (minimum–maximum), whereas categorical variables were expressed as count and frequency. Though the number of patients included in the study turned out to be small for a reliable analysis, we still opted to perform a comparative analysis. For univariate analysis between factors and disease progression and survival, the Fisher exact test or the χ² test (when the Fisher exact test was not applicable) for categorical variables. The Mann-Whitney U test was performed for continuous variables. P < .05 was considered statistically significant. Due to the small sample size, no multivariate analysis was performed. Survival analyses were performed by using Kaplan-Meier curves.

2. Results

2.1. Clinical data

The retrospective review of the patient database yielded a cohort of 14 patients (3 females and 11 males) with a median age of 10.5 (range, 1–15) years.

Median symptom duration was 3 (range, 1–30) months. Axial pain was the leading symptom, and motor weakness and first motor neuron involvement were the most common clinical findings in the study population. Three patients had urinary-fecal disturbances.

The thoracic spinal cord was the most commonly affected segment, either alone or together with other segments (85.7%). The distribution of tumor sites was thoracolumbar in 6, thoracic in 4, lumbar in 2, cervicothoracic in 1, and thoracolumbosacral in 1 patient.

The pathological specimens have been evaluated by an experienced neuropathologist in our institution. Grading was performed according to WHO guidelines valid at the time of surgery. Since MPEs were revised as grade 2 recently according to WHO CNS5 and had been reported as grade I in pathology reports, we opted to define MPEs as MPE, rather than with their grade. Six cases had MPE, 7 were ependymoma WHO grade II, and 1 was ependymoma WHO grade III. Though molecular markers gained attention recently, we do not have the relevant data since those techniques were not available in the institution. With this in mind, all tumors (excluding MPE) can be considered spinal ependymoma according to the most recent WHO classification.

Of 11 patients with a preoperative neurological finding, 2 improved, 3 remained the same, and 6 worsened postoperatively. None of the other 3 patients who had normal preoperative neurological examination had worsened postoperatively. One patient (who had a grade III tumor) died during follow-up.

2.2. Surgical treatment

The primary aim of surgery, gross total resection (GTR), was accomplished in 10 patients (71.4%). Four patients had subtotal resection (STR). Four of 6 MPE had GTR, and 6 of 7 patients with grade II tumor GTR. GTR was not achieved in the sole grade III tumor in the cohort.

Five patients underwent subsequent surgeries either for recurrence or tumor growth (3 GTR and 2 STR). Two patients who had STR initially (1 MPE and 1 grade III) had subsequent surgeries between 12 and 16 months, whereas 3 patients who had GTR (2 MPE and 1 grade II) had subsequent surgeries between 24 and 48 months. Of 9 patients who did not show any progression (recurrence or tumor growth), 7 had undergone GTR initially.

Seeding was observed in 2 patients with MPE. One was downward seeding, and the other was both downward seeding and upward seeding.

2.3. Adjuvant treatment

Four patients received adjuvant therapy. The patient with a grade III tumor received chemotherapy after the first surgery and received radiotherapy after the second operation for tumor growth. Two patients with MPE received both radiotherapy and chemotherapy following subsequent surgeries for disease progression. One patient with a grade II tumor received only radiotherapy following subsequent surgery.

The descriptive data and case-specific data are given in Tables 1 and 2, respectively.

Table 1.

Demographic characteristics of the population.

Parameter
Age, yr
Median (minimum–maximum)	10.5 (1–15)
Sex
Male, n (%)	11 (78.6%)
Female, n (%)	3 (21.4%)
Symptom duration, mo (n = 11)*
Median (minimum–maximum)	3 (1–30)
Symptoms
Axial pain, n (%)	9 (64.3%)
Radicular pain, n (%)	6 (42.9%)
Gait disturbance, n (%)	4 (24.6%)
Weakness, n (%)	3 (21.4%)
Urinary/fecal disturbance, n (%)	3 (21.4%)
Imbalance, n (%)	1 (7.1%)
Deformity, n (%)	1 (7.1%)
Dermal sinus, n (%)	1 (7.1%)
Neurological examination
Paresis, n (%)	7 (50.0%)
First motor neuron sign, n (%)	7 (50.0%)
Hypoesthesia, n (%)	5 (35.7%)
Deformity, n (%)	3 (21.4%)
Deep sensation, n (%)	3 (21.4%)
Tumor extension
Thoracolumbar, n (%)	6 (42.9%)
Thoracic, n (%)	4 (28.6%)
Lumbar, n (%)	2 (14.3%)
Cervicothoracic, n (%)	1 (7.1%)
Thoracolumbosacral, n (%)	1 (7.1%)
Involved spinal region
Cervical, n (%)	1 (7.1%)
Thoracic, n (%)	12 (85.7%)
Lumbar, n (%)	8 (57.1%)
Sacral, n (%)	1 (7.1%)
Surgical resection
Gross total resection, n (%)	10 (71.4%)
Subtotal resection, n (%)	4 (28.6%)
Number of surgeries
1, n (%)	9 (64.3%)
2, n (%)	3 (21.4%)
3, n (%)	1 (7.1%)
4, n (%)	1 (7.1%)
Histopathological WHO grade
MPE, n (%)	6 (42.9%)
II, n (%)	7 (50.0%)
III, n (%)	1 (7.1%)
Adjuvant therapy
Radiotherapy, n (%)	4 (28.6%)
Chemotherapy, n (%)	3 (21.4%)
Spinal seeding
Present, n (%)	2 (14.3%)
Follow-up period, mo
Median (minimum–maximum)	157.5 (2–277)
Time to progression, mo (n = 5)†
Median (minimum–maximum)	24 (12–48)
Deaths during follow-up, n (%)	1 (7.1%)

MPE = myxopapillary ependymoma, WHO = World Health Organization.

^*Three missing values.

^†Number of cases with progression.

Table 2.

Clinicopathological features of cases.

Case	Sex	Age, yr	Symptom duration, mo	Symptoms	Disease level	Preoperative neurological status	Initial surgery	Postoperative neurological status	WHO grade	Adjuvant treatment	Progression, mo + surgery	Adjuvant treatment	Seeding, mo	Total number of surgeries	Follow-up, mo	Survival status
1	M	14	3	Back pain, leg pain	T8-10	Impaired deep sensation	STR	Spastic paraparesis, urinary incontinence (worse)	II					1	173	Alive
2	F	14	Not reported	Back pain, leg pain	T12-L1	Muscle weakness in the left leg	GTR	No change	MPE		24		53	3	277	Alive
3	M	15	Not reported	Back pain, leg pain, urinary retention	T4-S2	Paraparesis, hypesthesia	STR	No change	MPE		12	RTx-CTx		2	250	Alive
4	M	15	Not reported	Weakness in the right leg	T3	Muscle weakness in the right leg, hypesthesia, increased DTR, clonus	GTR	No change	II					1	2	Alive
5	M	2	2	Gait disturbance, imbalance, constipation	T4-11	Paraparesis, hypesthesia, increased DTR, clonus	STR	Worsened paraparesis, anesthesia below T3 (worse)	III	CTx	16	RTx		4	67	Exitus
6	M	8	3	Back pain	T12-L2	Increased DTR	GTR	Normal (better)	II		48	RTx		2	186	Alive
7	M	11	9	Neck deformity	C2-T4	Cervical kyphosis, increased DTR	GTR	Impaired deep sensation (worse)	II					1	182	Alive
8	M	10	2	Back pain, leg pain, gait disturbance	T12-L4	Ataxic gait	GTR	Normal (better)	MPE		40	RTx-CTx	40	2	179	Alive
9	M	14	30	Back pain, weakness in the leg	T12-L2	Spastic paraparesia, hypesthesia, clonus, Babinski reflex	STR	Urinary retention and constipation (worse)	MPE					1	174	Alive
10	F	7	6	Back pain, left leg pain, gait disturbance	T12-L3	Normal	GTR	No change	II					1	142	Alive
11	M	1	12	Dermal sinus	L5	Normal	GTR	No change	MPE					1	126	Alive
12	M	12	24	Back pain, gait disturbance	T9-L1	Paraparesis, hypesthesia, scoliosis, Rhomberg sign, decreased DTR	GTR	Worsened paraparesis (worse)	II					1	116	Alive
13	M	7	1	Back pain, left leg pain	L1-2	Normal	GTR	No change	MPE					1	93	Alive
14	F	9	1	Leg weakness, urinary incontinence	T2-8	Paraparesis, increased DTR, scoliosis	GTR	Paraplegia, anesthesia below T3, neurogenic bladder and bowel (worse)	II					1	49	Alive

CTx = chemotherapy, DTR = deep tendon reflexes, F = female, GTR = gross total resection, M = male, MPE = myxopapillary ependymoma, RTx = radiotherapy, STR = subtotal resection, WHO = World Health Organization.

*Progression is either recurrence or tumor growth.

2.4. Survival rates

The median follow-up duration was 157.5 (range, 2–277) months.

Five patients showed progression (recurrence, tumor growth, or death), and all occurred within postoperative 5 years. Both 5- and 10-year progression-free survival (PFS) rates were 64.3%. Similar to overall survival (OS), only mean PFS time could be calculated and that was 122.77 ± 20.92 months (Fig. 1).

Figure 1.

Progression-free survival in pediatric spinal ependymoma.

The 5- and 10-year OS rates were 100.0% and 92.9%, respectively. Since more than half of the population survived, median survival time could not be calculated. The mean OS time was 259.5 ± 16.75 months. The OS plot is shown in Figure 2.

Figure 2.

Overall survival in pediatric spinal ependymoma.

2.5. Factor analysis for PFS and OS

Age, sex, symptoms, signs, tumor location, extent of resection, and WHO grade did not affect PFS (all P > .05). On the other hand, both radiotherapy and chemotherapy were more frequently used for progressed disease (P = .005 and P = .027; Table 3).

Table 3.

Disease progression and related factors.

Parameter	Progression		P value
	No (n = 9)	Yes (n = 5)
Age, yr			.898
Median (minimum–maximum)	11 (1–15)	10 (2–15)
Sex			1.000
Male, n (%)	7 (77.8%)	4 (80.0%)
Female, n (%)	2 (22.2%)	1 (20.0%)
Symptom duration, mo	(n = 8)	(n = 3)	.279
Median (minimum–maximum)	7.5 (1–30)	2 (2–3)
Symptoms
Axial pain, n (%)	5 (55.6%)	4 (80.0%)	.580
Radicular pain, n (%)	3 (33.3%)	3 (60.0%)	.580
Gait disturbance, n (%)	2 (22.2%)	2 (40.0%)	.580
Weakness, n (%)	3 (33.3%)	0 (0.0%)	.258
Urinary/fecal disturbance, n (%)	1 (11.1%)	2 (40.0%)	.505
Imbalance, n (%)	0 (0.0%)	1 (20.0%)	.357
Deformity, n (%)	1 (11.1%)	0 (0.0%)	1.000
Dermal sinus, n (%)	1 (11.1%)	0 (0.0%)	1.000
Neurological examination
Paresis, n (%)	4 (44.4%)	3 (60.0%)	1.000
First motor neuron sign, n (%)	5 (55.6%)	2 (40.0%)	1.000
Hypoesthesia, n (%)	3 (33.3%)	2 (40.0%)	1.000
Deformity, n (%)	3 (33.3%)	0 (0.0%)	.258
Deep sensation, n (%)	2 (22.2%)	1 (20.0%)	1.000
Tumor extension*			.380
Thoracolumbar, n (%)	3 (33.3%)	3 (60.0%)
Thoracic, n (%)	3 (33.3%)	1 (20.0%)
Lumbar, n (%)	2 (22.2%)	0 (0.0%)
Cervicothoracic, n (%)	1 (11.1%)	0 (0.0%)
Thoracolumbosacral, n (%)	0 (0.0%)	1 (20.0%)
Involved spinal region
Cervical, n (%)	1 (11.1%)	0 (0.0%)	1.000
Thoracic, n (%)	7 (77.8%)	5 (100%)	.505
Lumbar, n (%)	4 (44.4%)	4 (80.0%)	.301
Sacral, n (%)	0 (0.0%)	1 (20.0%)	.357
Surgical resection			.580
Gross total resection, n (%)	7 (77.8%)	3 (60.0%)
Subtotal resection, n (%)	2 (22.2%)	2 (40.0%)
Histopathological WHO grade*			.155
MPE, n (%)	3 (33.3%)	3 (60.0%)
II, n (%)	6 (66.7%)	1 (20.0%)
III, n (%)	0 (0.0%)	1 (20.0%)
Adjuvant therapy
Radiotherapy, n (%)	0 (0.0%)	4 (80.0%)	.005†
Chemotherapy, n (%)	0 (0.0%)	3 (60.0%)	.027†

MPE = myxopapillary ependymoma, WHO = World Health Organization.

^*χ2.

^†Statistically significant.

Age, sex, symptoms, signs, tumor location, extent of resection, radiotherapy, and chemotherapy did not affect OS (all P > .05). On the other hand, WHO grade was significantly associated with survival (P = .001; Table 4).

Table 4.

Mortality and related factors.

Parameter	Mortality		P value
	No (n = 14)	Yes (n = 1)
Age, yr
Median (minimum–maximum)	11 (1–15)	2 (2–2)	.286
Sex			1.000
Male, n (%)	10 (76.9%)	1 (100%)
Female, n (%)	3 (23.1%)	0 (0.0%)
Symptom duration, mo	(n = 10)
Median (minimum–maximum)	4.50 (1–30)	2 (2–2)	.545
Symptoms
Axial pain, n (%)	9 (69.2%)	0 (0.0%)	.357
Radicular pain, n (%)	6 (46.2%)	0 (0.0%)	1.000
Gait disturbance, n (%)	3 (23.1%)	1 (100%)	.286
Weakness, n (%)	3 (23.1%)	0 (0.0%)	1.000
Urinary/fecal disturbance, n (%)	2 (15.4%)	1 (100%)	.214
Imbalance, n (%)	0 (0.0%)	1 (100%)	.071
Deformity, n (%)	1 (7.7%)	0 (0.0%)	1.000
Dermal sinus, n (%)	1 (7.7%)	0 (0.0%)	1.000
Neurological examination
Paresis, n (%)	6 (46.2%)	1 (100%)	1.000
First motor neuron sign, n (%)	6 (46.2%)	1 (100%)	1.000
Hypoesthesia, n (%)	4 (30.8%)	1 (100%)	.357
Deformity, n (%)	3 (23.1%)	0 (0.0%)	1.000
Deep sensation, n (%)	3 (23.1%)	0 (0.0%)	1.000
Tumor extension*			.611
Thoracolumbar, n (%)	6 (46.2%)	0 (0.0%)
Thoracic, n (%)	3 (23.1%)	1 (100%)
Lumbar, n (%)	2 (15.4%)	0 (0.0%)
Cervicothoracic, n (%)	1 (7.7%)	0 (0.0%)
Thoracolumbosacral, n (%)	1 (7.7%)	0 (0.0%)
Involved spinal region
Cervical, n (%)	1 (7.7%)	0 (0.0%)	1.000
Thoracic, n (%)	11 (84.6%)	1 (100%)	1.000
Lumbar, n (%)	8 (61.5%)	0 (0.0%)	.429
Sacral, n (%)	1 (7.7%)	0 (0.0%)	1.000
Surgical resection			.286
Gross total resection, n (%)	10 (76.9%)	0 (0.0%)
Subtotal resection, n (%)	3 (23.1%)	1 (100%)
Histopathological WHO grade*			.001†
MPE, n (%)	6 (46.2%)	0 (0.0%)
II, n (%)	7 (53.8%)	0 (0.0%)
III, n (%)	0 (0.0%)	1 (100%)
Adjuvant therapy
Radiotherapy, n (%)	3 (23.1%)	1 (100%)	.286
Chemotherapy, n (%)	2 (15.4%)	1 (100%)	.214

MPE = myxopapillary ependymoma, WHO = World Health Organization.

^*χ2.

^†Statistically significant.

3. Discussion

To our knowledge, this is one of the largest published pediatric spinal ependymoma series, excluding database studies. In our series, the entity was more frequent in males. The median follow-up was 157.5 (2–277) months. The 5- and 10-year OS rates were 100.0% and 92.9%. No patient died because of MPE or grade II ependymoma. The PFS rate was 64.3% both at 5 and 10 years, indicating that every progression occurred before the fifth year. Neither the extent of resection nor tumor grade affected disease progression or survival. That being said, these findings must be interpreted cautiously since the population size is small.

Due to the low incidence of spinal pediatric ependymoma, the relevant data in the literature are scarce. To the best of our knowledge, there is no prospective study on pediatric spinal ependymoma, which forces physicians to still rely on data from case series. In many studies, pediatric spinal ependymomas were investigated either in the adult population, intracranial ependymoma, or other type of tumors,^[1,3,7–14] Interestingly, when those publications were reviewed, it can be seen that a significant number of pediatric ependymoma cases have been included in these studies. However, the inclusion of both adult and pediatric ependymomas, or both cranial and spinal ependymomas, or both ependymomas and other spinal tumors provide little insight into pediatric spinal ependymomas specifically, and the findings in these studies could be misleading in understanding this neoplasm in the pediatric age group. This leaves us with few studies that are comparable to our findings.^[15–17] Of these, Khalid et al^[17] performed a survival analysis on 279 pediatric patients with spinal ependymoma using a large-scale database. Szathmari et al^[15] performed a retrospective analysis on 28 pediatric spinal ependymoma cases. Sofuoğlu and Abdallah^[16] analyzed 3 cases of pediatric spinal ependymomas. On the other hand, some studies focused on particular subgroups of spinal ependymoma, especially MPE, in children which provide more in-depth analysis for those subgroups.^{[8–10,13,18]}

Intracranial ependymomas have a tendency to peak around 5 years of age.^[19] However, the data on spinal ependymomas is scarce. In the study by Lundar et al (n = 33), which included patients up to 22 years old, the median age was 12 years.^[1] In the study by Looi et al on MPE (n = 12), which included patients up to 21 years old, the median age was 13.5. In the study by Khalid et al that included 279 pediatric spinal ependymomas using a large-scale database, the mean age was 6.05 ± 5.22 years.^[17] However, they did not find any association between age and survival, nor in univariate and multivariate analyses.^[17] In our population, the median age was 10.5 years. However, when categorized into 5-year intervals, 2 were below 5 years, 5 were between 6 and 10, 7 were between 11 and 15, and none was ≥16. The discrepancy between retrospective studies and large-scale database studies may come from small sample sizes (as in our case) and the inclusion of patients above 18 years old. Regardless, Khalid et al^[17] found no effect of age on survival in their study, which is in conjunction with our findings.

In the literature, the lack or presence of sex predominance varies by the study population. In the study by Szathmari et al,^[15] which is the most directly comparable retrospective study to ours, they found a male predominance. With 11 males and 3 females, our study supports their findings. However, Khalid et al^[17] found no significant sex predominance in their registry-based study (54.5% female vs 45.5% male). Regarding sex and survival association, an association between female sex and survival in grade II spinal ependymoma was reported by Lin et al.^[20] In our series, the patient who died was male, but he also had a grade III tumor, which appears to be the actual cause of the worse outcome. Similar to sex predominance, Khalid et al^[17] found no effect of sex on survival rates in these patients. Our findings also support these findings.

Ependymomas are mostly located in the cervical region where the GTR rate is the highest.^[3,21] Since thoracic ependymomas typically involve >3 levels, they carry a higher risk of postoperative neurological deficit.^[3] On the other hand, Oh et al^[21] found more favorable survival rates for upper spinal cord ependymomas. MPEs are typically located in conus medullaris, cauda equina, and filum terminale.^[22] In contrast, the thoracic region was the most commonly involved spine region (85.7%) in our series, either alone (28.6%) or in conjunction with other segments (57.1%), despite the fact that MPE constituted 42.9% of the cases. Also, in all cases that had worse neurological examination, postoperatively thoracic region was involved, but this might have resulted from selection bias as most cases had tumors in the thoracic region.

The primary aim of surgical treatment in ependymoma, whether it is spinal or cranial, is GTR since it is highly effective compared with STR.^[2,3,22,23] Safaee et al^[24] found GTR as the only factor associated with PFS in the pediatric population. Fortunately, GTR in spinal ependymoma is achievable in the majority of the cases.^[14,22] In a systematic review covering the 1974 to 2017 era, the mean GTR rate in spinal ependymomas was 69.1%.^[3] The GTR rate in our study was similar to this number, but lower and higher GTR rates had also been reported in various studies.^[1,15,25] This could be due to the development of the surgical tools and techniques that facilitate GTR. However, Lopez-Rivera et al^[10] found an opposite trend (increased rate of STR and decreased rate of GTR) in 2016 compared with 2004 where the study included adults and intracranial ependymoma as well. In their epidemiological study, Khalid et al^[17] found that GTR correlated with higher survival rates. In our series, 7 of 10 GTR cases and 2 of 4 STR cases did not show progression; however, there was no significant difference. Still, it must be noted that some studies did not find GTR impacting survival. Abdallah et al^[13] did not find any association between the extent of resection and progression in pediatric MPE, but their sample size was low. In another study that excluded MPE, GTR was not found to affect survival, but that study included adults.^[10] The only patient that died in our series had undergone STR, but our analysis did not show any effect of the extent of resection on mortality.

The importance of grading is controversial in ependymomas. Ependymomas are usually considered benign. However, some studies that included both children and adult populations reported poor prognosis for ependymomas, particularly for grade III tumors.^[3,26,27] In our series, the only patient who died had grade III ependymoma. However, there is an ongoing debate on the utility of grading of ependymomas.^[5,28] Recently, molecular factors have gained importance. Ghasemi et al^[29] reported MYCN amplified ependymomas associated with aggressive behavior, early metastasis, dissemination, resistance to treatment, low GTR achievability, and high rate of mortality despite aggressive treatment. Possibly because of this, WHO CNS5 used histopathological definition for ependymomas and included subtypes based on molecular analysis while leaving grading optional.^[4] Of note, MPE was designated as grade II in the latest WHO classification.^[4]

The role of radiotherapy and chemotherapy is not clear in pediatric spinal ependymomas.^[25] Still, European Association of Neuro-Oncology recommends radiotherapy after surgical removal of grade III tumors regardless of the extent of resection.^[22] It recommends postoperative radiotherapy after STR of grade II tumors and MPE but not after GTR.^[22] However, some recommend postoperative radiotherapy also after GTR of pediatric MPE due to the high rate of recurrence.^[30] In our series, the grade III ependymoma case received chemotherapy after the initial operation and radiotherapy after the second operation. Other patients received radiotherapy and chemotherapy only after the disease progressed. In univariate analysis, both radiotherapy and chemotherapy were significantly higher in patients with disease progression, apparently due to the fact that patients without disease progression were not given any adjuvant therapy. On the other hand, none of the adjuvant therapies affected the mortality of the disease.

Lundar et al^[1] reported that 30% of children and adolescents required subsequent surgeries for spinal ependymoma. Hamilton et al^[3] reported a 10-year PFS rate of 75%. Weber et al^[31] reported a 5- and 10-year PFS of 69.5% and 61.2%. Abdallah et al^[13] reported a progression-free course in 2 patients who had undergone GTR for MPE. Szathmari et al^[15] reported a 51% 5-year PFS and no progression in 64% of the patients all of whom had undergone GTR. In our population, all progression occurred within 5 years where 5-year PFS was 64.3%, which is in line with the literature. Also, 70% of patients who were undergone GTR showed no progression, similar to the results of Szathmari et al.

Studies on spinal pediatric MPE report a 100% 5-year OS rate.^[8,13] Weber et al^[31] reported a 92.4% 10-year survival for MPE. In a systematic review by Hamilton et al,^[3] which included both adult and pediatric spinal ependymoma, 5- and 10-year OS rates were 97% and 91%, respectively. In our study, which is limited to patients younger than 18 years, 5- and 10-year OS rates were 100% and 92.9%, respectively. Similarly, Szathmari et al^[15] reported a 100% 5-year OS in their study, which also included only patients younger than 18 years.

3.1. Limitations

Despite covering a 25-year span, our sample size is relatively small, which can be attributed to a low incidence of spinal ependymoma in children. This is an issue that both limits the generalizability of the findings and prevents a reliable statistical analysis. It was possible to include patients up to 22 years old as in some studies, but we kept our cohort at and below 18 years at the expense of sample size because the prognostic factors can vary depending on age groups.^[1,2,25] In addition, since many studies are not homogenous regarding age, tumor location, and tumor type, as discussed above, our results may not be directly comparable to such studies, and differences might have arisen from this fact. In fact, to the best of our knowledge, there were 3 studies that were directly comparable to ours because they included similar age groups and focused on spinal ependymoma.^[15–17] Knowing this, we provided data for each individual case to provide as much detail as possible to be used in future studies. Though database studies can gather data from a much larger population, they can be limited in terms of data on preoperative and postoperative conditions, presenting symptoms, disease location, and recurrence/progression and do not allow verification of pathological and imaging studies. Another limitation is the lack of details regarding adjuvant therapies (radiation sessions and doses, and chemotherapy regimens). Not only they might have affected the final outcome but also the evolved treatment regimens during the timespan of this study might have also resulted in variations in the effectiveness of these treatments.

In the past decades, molecular studies revealed that some subtypes can affect prognosis. MYCN amplification is rare but is associated with poor prognosis despite intensive treatment regimens.^[29] Also, it is frequently present in grade III anaplastic astrocytomas and associated with poor prognosis.^[32] Recently, “spinal ependymoma, MYCN-amplified” has been defined as a distinct subtype in the most recent WHO classification alongside spinal ependymoma, MPE, and subependymoma.^[4] However, molecular analysis and genetic profiling are not routinely performed and are not widely available, particularly in developing countries. Thus, physicians still rely on other factors to foresee prognosis and plan treatment. In recognition of this fact, WHO CNS5 allows using the term “spinal ependymoma” when a molecular analysis fails or is unavailable.^[4] We also do not have any molecular data for our cohort, and having such data would have helped to understand our results better. However, our cohort still complies with WHO CNS5, though not in the most ideal way. Still, considering that the 2 cases who died in our cohort had grade III ependymoma, it is possible that 2 had MYCN amplification as suggested by Ghasemi et al.^[29] Changes in the grading of ependymoma may also have led to heterogeneity in the cohort.

4. Conclusion

Pediatric spinal ependymomas are uncommon tumors, which are considered relatively benign. Despite this, recurrence is frequent, and higher grades are associated with mortality. Gross total removal of these tumors can prevent or delay disease progression compared with those who underwent subtotal resection. Though they are not extremely rare and a sufficient number of cases had been included in previous studies, specific knowledge on this type of neoplasms remained limited due to the fact that they were rarely assessed on their own and instead investigated together with intracranial counterparts, adulthood ependymomas, and other spinal cord tumors. In order to improve the knowledge base on this disease, future studies should focus specifically on spinal ependymoma in the pediatric population.

Author contributions

Conceptualization: Firat Narin, Sinan Bahadir, Şahin Hanalioğlu, Burçak Bilginer

Data curation: Firat Narin, Sinan Bahadir, Şahin Hanalioğlu, Dicle Karakaya, Diaa Yahya, Hidir Özer, Figen Söylemezoğlu

Investigation: Firat Narin, Sinan Bahadir, Şahin Hanalioğlu, Dicle Karakaya, Diaa Yahya, Hidir Özer, Figen Söylemezoğlu, Burçak Bilginer

Methodology: Firat Narin, Sinan Bahadir, Burçak Bilginer

Writing – original draft: Firat Narin, Sinan Bahadir

Writing – review & editing: Firat Narin, Sinan Bahadir, Figen Söylemezoğlu, Burçak Bilginer

Formal analysis: Sinan Bahadir, Hidir Özer, Burçak Bilginer

Resources: Dicle Karakaya, Diaa Yahya

Supervision: Burçak Bilginer