Spinal ependymoma in adults: a multicenter investigation of surgical outcome and progression-free survival

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  • 1 Department of Neurosurgery, Klinikum rechts der Isar, Technical University of Munich;
  • | 2 Department of Neurosurgery, Charité University, Berlin;
  • | 4 Department of Neurosurgery, University Medical Center Hamburg-Eppendorf;
  • | 6 Institute for Medical Statistics and Epidemiology, Technical University of Munich;
  • | 7 Department of Neuroradiology, Klinikum rechts der Isar, Technical University of Munich;
  • | 8 Department of Neurosurgery, University Clinic Johannes Gutenberg–University Mainz;
  • | 9 Department of Neurosurgery, Helios Clinic, Krefeld, Germany;
  • | 3 Department of Neurosurgery, University of Geneva Medical Center, Geneva, Switzerland; and
  • | 5 Department of Neurosurgery, Medical University Innsbruck, Austria
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OBJECTIVE

Spinal ependymomas are rare glial neoplasms. Because their incidence is low, only a few larger studies have investigated this condition. There are no clear data concerning prognosis and therapy. The aim of the study was to describe the natural history, perioperative clinical course, and local tumor control of adult patients with spinal ependymomas who were surgically treated under modern treatment standards.

METHODS

The authors performed a multicenter retrospective study. They identified 158 adult patients with spinal ependymomas who had received surgical treatment between January 2006 and June 2013. The authors analyzed the clinical and histological aspects of these cases to identify the predictive factors for postoperative morbidity, tumor resectability, and recurrence.

RESULTS

Gross-total resection (GTR) was achieved in 80% of cases. At discharge, 37% of the patients showed a neurological decline. During follow-up the majority recovered, whereas 76% showed at least preoperative status. Permanent functional deterioration remained in 2% of the patients. Transient deficits were more frequent in patients with cervically located ependymomas (p = 0.004) and in older patients (p = 0.002). Permanent deficits were independently predicted only by older age (p = 0.026). Tumor progression was observed in 15 cases. The 5-year progression-free survival (PFS) rate was 80%, and GTR (p = 0.037), WHO grade II (p = 0.009), and low Ki-67 index (p = 0.005) were independent prognostic factors for PFS. Adjuvant radiation therapy was performed in 15 cases. No statistically relevant effects of radiation therapy were observed among patients with incompletely resected ependymomas (p = 0.079).

CONCLUSIONS

Due to its beneficial value for PFS, GTR is important in the treatment of spinal ependymoma. Gross-total resection is feasible in the majority of cases, with acceptable rates of permanent deficits. Also, Ki-67 appears to be an important prognostic factor and should be included in a grading scheme for spinal ependymomas.

ABBREVIATIONS

EOR = extent of resection; GTR = gross-total resection; PFS = progression-free survival; PR = partial resection; RT = radiation therapy; STR = subtotal resection.

OBJECTIVE

Spinal ependymomas are rare glial neoplasms. Because their incidence is low, only a few larger studies have investigated this condition. There are no clear data concerning prognosis and therapy. The aim of the study was to describe the natural history, perioperative clinical course, and local tumor control of adult patients with spinal ependymomas who were surgically treated under modern treatment standards.

METHODS

The authors performed a multicenter retrospective study. They identified 158 adult patients with spinal ependymomas who had received surgical treatment between January 2006 and June 2013. The authors analyzed the clinical and histological aspects of these cases to identify the predictive factors for postoperative morbidity, tumor resectability, and recurrence.

RESULTS

Gross-total resection (GTR) was achieved in 80% of cases. At discharge, 37% of the patients showed a neurological decline. During follow-up the majority recovered, whereas 76% showed at least preoperative status. Permanent functional deterioration remained in 2% of the patients. Transient deficits were more frequent in patients with cervically located ependymomas (p = 0.004) and in older patients (p = 0.002). Permanent deficits were independently predicted only by older age (p = 0.026). Tumor progression was observed in 15 cases. The 5-year progression-free survival (PFS) rate was 80%, and GTR (p = 0.037), WHO grade II (p = 0.009), and low Ki-67 index (p = 0.005) were independent prognostic factors for PFS. Adjuvant radiation therapy was performed in 15 cases. No statistically relevant effects of radiation therapy were observed among patients with incompletely resected ependymomas (p = 0.079).

CONCLUSIONS

Due to its beneficial value for PFS, GTR is important in the treatment of spinal ependymoma. Gross-total resection is feasible in the majority of cases, with acceptable rates of permanent deficits. Also, Ki-67 appears to be an important prognostic factor and should be included in a grading scheme for spinal ependymomas.

Primary spinal intradural tumors are extremely rare and are associated with an age-adjusted incidence of 0.97 per 100,000 patients per year.8 Intramedullary neoplasms are even less frequent and represent 5%–10% of all spinal tumors and only 2%–4% of all CNS tumors.24 Of these, spinal ependymoma is the most common adult intramedullary tumor, accounting for > 60% of all intramedullary lesions.5,31 Spinal ependymomas generally demonstrate a relatively benign course in comparison with other spinal cord gliomas. However, their tendency to recur and the ability to promote leptomeningeal spread along the neuraxis frequently result in significant morbidity and mortality.

Because of the low incidence and the slow-growing pattern of adult spinal ependymomas, only a few large clinical series have discussed the optimal therapeutic strategy and prognosis of these entities, and a majority of studies have included patients who have been treated over several decades, implying inhomogeneous criteria due to the continuous changes in diagnostic techniques and surgical standards over time.1,14,15,34 Therefore, we performed a multicenter study involving patients who were treated within the last decade under modern therapy standards. Five high-volume neurosurgery centers supporting the same surgical and oncological treatment policy for spinal ependymomas cooperated for the present research.

Methods

Patients ≥ 18 years of age with spinal ependymomas, which had been surgically treated between January 2006 and June 2013 at our hospitals, were retrospectively evaluated. The medical charts of all the identified patients (n = 158) prior to and after the surgery were reviewed for presentation, treatment, and outcome. Preoperative, postoperative, and follow-up MRI data were reviewed for tumor location, extent of resection (EOR), and tumor recurrence. The following formula was used to determine tumor volume: 4/3 × π × ABC/2.12

In all cases the diagnosis was verified by histological examination. The proliferation index Ki-67 was determined in 80 patients (51%). Tumors arising from the filum terminale were considered extramedullary due to their clinical and surgical features.23

The outcome was evaluated at discharge and at the most recent follow-up. The length of follow-up was determined by the date of the last available record of a clinical examination. The clinical performance at the preoperative, discharge, and follow-up stages was gathered from the records of clinical examinations, which were performed by attending neurosurgeons at the respective study centers. The clinical status was evaluated according to the modified McCormick scale.2,3,16,22,25 Postoperative deterioration was classified as slight (i.e., deterioration without any increase in the modified McCormick scale score or an increase in only one grade within the scale [range 1–2]) and significant (i.e., increase to grade ≥ 3 on the modified McCormick scale).

Surgery Protocol

All patients were treated by resection via a microsurgical technique. Patients were placed prone, and for upper cervical tumors the patient’s head was fixed in a Mayfield clamp. Hemilaminectomy or laminectomy was performed via a standard midline posterior approach, followed by a paramedian or median durotomy and median myelotomy or dorsal root entry zone lesioning (or DREZotomy) for intramedullary lesions. For large tumors (≥ 3 segments) and especially in young patients, an osteoplastic laminotomy was performed. In contrast, small lesions were resected via minimally invasive interlaminar fenestration, whenever possible. Intraoperative neuromonitoring (motor and sensory evoked potentials or intraoperative electromyographic monitoring) was performed in all cases of intramedullary lesions and in technically difficult cases of extramedullary ependymomas.

The surgeries were done after induction of propofol-based, totally intravenous anesthesia in the majority of cases. Intraoperatively, we applied an intravenous bolus of 40 mg dexamethasone in almost every case. For the resection of large adherent intradural tumors and intramedullary lesions, we usually first proceed with the debulking with an ultrasound aspirator to reduce traction and manipulation of the surrounding tissue. Afterward, most complete resections of the residual tumor tissue and tumor capsule are performed with dissection and further ultrasound aspiration. Gross-total resection (GTR) was defined as resection of all visible tumor as confirmed by postoperative MRI. Subtotal resection (STR) was defined as resection of the tumor mass with identifiable residual tumor ≤ 20% of the initial size on postoperative MRI. Partial resection (PR) was defined as incomplete resection (< 80%) of the tumor mass.14,19 Recurrence was defined as evidence of tumor tissue visible on MRI after GTR, or an increase in size of residual tumor on follow-up MRI scans after STR or PR.

Postoperative Management and Adjuvant Treatment

Decisions on surgical and adjuvant treatment as well as on follow-up intervals were made by a local interdisciplinary Tumor Board of the respective center, where the departments of oncology, neurosurgery, radiation therapy, neuroradiology, and neuropathology were represented by their senior consultants. In particular cases of incompletely resected tumors, leptomeningeal spread or drop metastases, and anaplastic ependymomas, fractional radiation therapy (RT) with a total dose of 40–60 Gy in 1.8- to 2-Gy fractions was applied following the appropriate consent from the Tumor Board.

The perioperative standard diagnosis included a holospinal MRI session and a CSF cytology study. The first follow-up MRI and examination were done 3 months postoperatively, with further follow-up imaging performed every year in patients with stable findings. In cases of incompletely resected or higher-grade ependymoma, the follow-up intervals were defined according to the internal Tumor Board decision.

Statistical Analysis

Statistical analyses were performed using SPSS Statistics 22 (IBM). Binomial dichotomized data were compared using Fisher’s exact test and categorical data were compared using the chi-square test. The median or mean values were compared using the Student t-test when appropriate. The association between potential predictive factors and both transient and permanent postoperative impairment (follow-up data [or discharge data for those with missing follow-up]), as well as the EOR, was analyzed using multivariate logistic regression models.

The Kaplan-Meier log-rank test and multivariate Cox regression analysis were used to calculate and to compare progression-free survival (PFS). A p value < 0.05 was considered statistically significant. The odds ratio and its 95% confidence interval were specified for statistically significant parameters.

Center effects were accounted for by including the study center as a potential predictor in the model. There was no statistical correlation between the risk for recurrences, postoperative clinical outcome, EOR, and participating center in the regression model (p = 0.815, p = 0.618, and p = 0.192, respectively), suggesting the data were independent of the treating unit.

Ethical Considerations

The study was performed in adherence with the guidelines of the Declaration of Helsinki. The research protocol was approved by the local ethics committees. Patient informed consents were not obtained due to the retrospective design of this study.

Results

Natural History and Presentation

A total of 158 adult patients were identified. There were 75 women and 83 men with a mean age of 46.1 ± 15.0 years (median 45 years; range 18–80 years). There were no statistically relevant differences between the median age of male (45 years) and female (48 years) patients (p = 0.156). At the time of this report, follow-up data were available for 78% (n = 123) of the patients, with a median follow-up duration of 19 months (range 3–127 months). Of the 158 ependymomas, 101 were intramedullary and 57 were filum ependymomas. The vast majority were WHO grade II tumors (66%, n = 105). The distribution of WHO grades did not differ between male and female patients (p = 0.211). There was a significant difference in the mean age across tumor grades (p = 0.03), with the youngest patients having WHO grade III tumors (33.7 ± 9.1) and the oldest having grade II tumors (48.62 ± 14.6). Sixteen patients presented with multifocal (> 1) spinal lesions, 8 had a recent or former intracranial manifestation, and 2 had leptomeningeal spread at the time of the first diagnosis. The clinical characteristics of patients are listed in Table 1.

TABLE 1.

Clinical characteristics of 158 patients with spinal ependymoma

CharacteristicNo. (%) or Mean ± SD
Sex
 Male83 (52.5)
 Female75 (47.5)
Mean age overall in yrs46.1 ± 15.0
 Mean age, WHO I42.8 ± 15.2*
 Mean age, WHO II48.6 ± 14.6*
 Mean age, WHO III33.7 ± 9.1*
WHO grade
 I44 (28)
 II105 (66)
 III9 (6)
Myxopapillary ependymoma35 (22)
Tumor location in spine
 Cervical56 (35)
 Thoracic33 (21)
 Lumbar69 (44)
Tumor location in spinal cord
 Intramedullary101 (64)
 Extramedullary or filum57 (36)
Mean tumor vol in cm35.3 ± 7.6
Multifocal presentation
 Further spinal lesions16 (10)
 Cerebral manifestation8 (5)
 Leptomeningeal spread2 (1)
 Previous external incomplete resection9 (6)
Mean duration of symptoms in mos15.1 ± 20.9

p = 0.003 for differences in mean ages among the different WHO grade groups.

The mean duration of symptoms before the initial diagnosis was 15.1 ± 20.9 months (median 15 months, range 1–96 months). The initial clinical symptoms are listed in Table 2. Preoperative symptoms were usually mild, and were classified as grade 1 or 2 on the modified McCormick scale in 84% of the cases (n = 133). Figure 1 illustrates the intensity of the initial symptoms.

TABLE 2.

Preoperative symptoms in patients with spinal ependymoma

SymptomNo. (%)
Pain111 (70)
Sensory deficits75 (47)
Motor deficits35 (22)
Gait ataxia25 (16)
Bladder &/or bowel dysfunction17 (11)
Incidental9 (6)
FIG. 1.
FIG. 1.

Bar graph showing functional presentation of patients according to the modified McCormick scale.

Surgical Outcome

A GTR was achieved in 80% (n = 127) of the tumors; STR was done in 13% (n = 21) and PR in 6% (n = 10). Tumor volume was the only independent predictor of GTR (p = 0.006; OR 1.000, 95% CI 1.000–1.000) (Table 3). At discharge, 37% (n = 58) of the patients showed a worsening of symptoms. During the follow-up period, 76% (n = 120) recovered to at least preoperative status: 65 patients (41%) were improved, and 55 patients (35%) were unchanged according to comparison with the preoperative symptoms. Permanent significant deterioration remained in 2% (n = 3) (Fig. 2).

TABLE 3.

Results of the multivariate regression analysis identifying factors influencing the EOR

Variablep Value
Tumor vol0.006
Age0.550
Previous ependymoma surgery0.070
WHO grade0.604
Myxopapillary ependymoma0.445
Location cervical vs thoracic vs lumbar0.956
Location extramedullary vs intramedullary0.637
Preop McCormick score0.603

Boldface type indicates statistical significance.

FIG. 2.
FIG. 2.

Bar graph showing early and late postoperative clinical outcomes.

Increasing age (p = 0.002; OR 1.046, 95% CI 1.013–1.081) and cervical tumor location (p = 0.004; OR 5.287, 95% CI 1.940–14.408) were independent predictors of transient postoperative impairment (Table 4). Permanent neurological impairment was independently predicted by older age only (p = 0.026; OR 1.049, 95% CI 1.011–1.088) (Table 5). The amelioration of preoperative symptoms was observed mainly in initially functionally independent patients (McCormick scores 1 or 2) (p = 0.014).

TABLE 4.

Results of the multivariate regression analysis predicting early neurological impairment

Variablep Value
Sex0.347
Increasing age0.002
Tumor vol0.082
Duration of symptoms0.851
Preop McCormick score0.903
Location cervical0.004
Intramedullary location0.204
WHO grade0.516
Myxopapillary ependymoma0.405

Boldface type indicates statistical significance.

TABLE 5.

Results of the multivariate regression analysis predicting permanent neurological impairment

Variablep Value
Increasing age0.026
Male sex0.256
Tumor vol0.420
Duration of symptoms0.321
Preop McCormick score0.069
Location (cervical vs thoracic vs lumbar)0.181
Intramedullary location0.631
WHO grade0.191
Myxopapillary ependymoma0.212

Boldface type indicates statistical significance.

Survival Analysis

During the follow-up period, 15 patients (9 men and 6 women with a median age of 32 years) developed tumor recurrence: WHO grade I (n = 4), WHO II (n = 7), and WHO III (n = 4). Among these 15 patients, 2 patients had a multifocal disease at presentation (1 cerebral, 1 spinal), and GTR was performed in 6 patients, STR in 6, and PR in 3. The PFS at 5 years was 80% according to the Kaplan-Meier analysis. The median PFS was not achieved at the time of reporting (Fig. 3). According to multivariate Cox regression analysis, independent favorable prognostic factors for PFS were GTR (p = 0.037; OR 0.104, 95% CI 0.017–0.648); WHO grade II (p = 0.009; OR 0.288, 95% CI (0.107–0.775); and low Ki-67 proliferation index (p = 0.005; OR 1.135, 95% CI 1.011–1.274) (Table 6). The median PFS values for WHO grade I and III ependymomas were 76 and 68 months, respectively, whereas the median PFS of patients with WHO II tumors was not achieved at the end of the follow-up time (log rank, p = 0.004). The median PFS in patients who underwent GTR was not reached during the follow-up (log rank, p < 0.001). The median PFS after STR (60 months) and PR (43 months) did not differ significantly (log rank, p = 0.921). Tumors were additionally classified as those with Ki-67 ≤ 5% and those with Ki-67 > 5%.17 The median PFS was not reached during our follow-up in patients with a Ki-67 proliferation index ≤ 5%, whereas the patients with > 5% Ki-67 proliferation index had a median PFS of 68 months (log rank, p = 0.008). Figures 46 illustrate these differences in the PFS.

FIG. 3.
FIG. 3.

Kaplan-Meier PFS curve of all 158 patients with spinal ependymoma.

TABLE 6.

Results of the multivariate Cox regression analysis identifying favorable prognostic factors for PFS

Variablep Value
Age0.129
Male sex0.448
Location (cervical vs thoracic vs lumbar)0.134
Location (extramedullary vs intramedullary)0.568
Multifocal manifestation0.447
GTR0.037
WHO grade II0.009
Low Ki-67 index0.005

Boldface type indicates statistical significance.

FIG. 4.
FIG. 4.

Kaplan-Meier PFS curves showing differences depending on the EOR.

FIG. 5.
FIG. 5.

Kaplan-Meier PFS curves showing differences depending on the WHO grades.

FIG. 6.
FIG. 6.

Kaplan-Meier PFS curves showing differences depending on the Ki-67 proliferation index.

Radiation Therapy

Radiation therapy was applied in 15 of the 158 patients after the first surgery: in 9 cases following incomplete tumor resection of WHO grade II or III ependymomas; in 6 cases because of multifocal disease; and in 5 of the cases with incomplete resection, for which RT was administered due to the histology of anaplastic ependymoma. Table 7 presents the clinical features of these patients.

TABLE 7.

Characteristics of patients who received adjuvant RT after the first surgery

Case No.WHO GradeEORAdditional Spinal ManifestationCerebral Manifestation
1IIGTRYesNo
2IIGTRYesYes
3IIGTRNoNo
4IIGTRNoNo
5IIGTRNoNo
6IISTRNoNo
7IISTRYesNo
8IISTRNoNo
9IIPRYesNo
10IIPRYesNo
11IIIGTRYesYes
12IIISTRNoNo
13IIISTRNoYes
14IIIPRYesYes
15IIIPRYesNo

The PFS of patients treated with adjuvant RT after the first surgery was significantly shorter than that of patients who underwent surgery alone (median PFS of patients with surgery and adjuvant RT 43 months, vs not reached in patients without RT, p < 0.001). Additionally, we compared the PFS of a subgroup with incompletely resected ependymomas. Among them, the patients who did not undergo RT exhibited a longer median PFS of 75 months versus 43 months in those receiving RT, but this difference was not statistically significant (p = 0.079) (Fig. 7). A reliable analysis of patients harboring anaplastic ependymomas or leptomeningeal spread was not possible because of the low number of patients in each group.

FIG. 7.
FIG. 7.

Kaplan-Meier PFS curves of patients with and without RT after incomplete tumor resection.

Discussion

Natural History

Similar to the results reported in previous clinical series, the results of our study demonstrate a predominance of male patients.4–6,15,19,25,34 The median age and the malignancy grades did not differ between men and women. However, there was a significant difference in the median age of patients with tumors of different WHO grades, with the youngest patients harboring anaplastic lesions. This finding can be explained by the more aggressive growth patterns commonly observed in young adult patients, which are similar to those in pediatric and adolescent patients.28 The cervical and lumbar portions of the spinal cord, including the filum terminale, are the most common sites of ependymomas.5,31,34 This allocation pattern was also observed in our series.

The WHO system classifies ependymomas into 1 of 3 histological grades.21 Most spinal ependymomas are grade II tumors; WHO grade III ependymomas occur rarely in the spine (approximately 2% of all spinal ependymomas).5,34 This histological proportion was also reflected in our study. Due to the predominantly benign nature of spinal ependymoma, preoperative symptoms are mild and nonspecific, and the tumors are often discovered very late.24,25,31,34 The average duration from onset of symptoms to diagnosis was 15 months in our patients.

Surgery Protocol

Currently, GTR of spinal ependymomas can be achieved in approximately 80% of cases in experienced surgical centers;4,5,19 the rates of GTR have significantly increased over the past decades compared with rates of 45%–70% in earlier clinical series.7,10,13 This considerable improvement can be attributed to rapid advances in imaging diagnostics and surgical standards, such as mandatory use of a microscope, ultrasonic aspirator, and intraoperative neuromonitoring.

The risk of transient neurological decline after surgery has been reported to range from 20% to 60%.3,11,14,19 In our series, 37% of patients experienced new early deficits. During the follow-up the majority of these patients recovered, and only 3 patients had permanent disabling deterioration. The high rates of neurological decline immediately after the surgery, mainly due to the intraoperative spinal cord manipulation and the separation of posterior columns, and the subsequent recovery during the first follow-up months reflect the typical postoperative clinical course of spinal ependymomas.5 Our multivariate regression revealed increasing age (p = 0.002) and cervical tumor location (p = 0.004) as being predictive for transient neurological impairment. Cervical intramedullary tumor location carries a potential risk of postoperative respiratory dysfunction or quadriplegia. Even if transient, these symptoms are associated with significant functional disability. However, the cervical location was not found to be crucial in predicting permanent clinical impairment.

This marked recovery of initially affected patients is promoted by an abundant blood supply of the cervical spinal cord in contrast to the other levels, and by advances in respiratory equipment capable of supporting patients with respiratory dysfunction.18 Increasing age was the only negative predictor for permanent impairment, confirming findings of previously conducted research.11,14 Possible reasons for the early impairment and reduced potential for later rehabilitation of older patients include preexisting medical comorbidities as well as microcirculatory spinal cord instability, similar to neurological dysfunction in such patients after surgery for aortic dissection.9 However, these explanations are not supported by the present analysis and should be verified by additional research.

No differences in functional outcome were observed between patients with intramedullary and extramedullary ependymomas (p = 0.204). Filum ependymoma resection can be safely achieved if the tumor is small and encapsulated. However, due to their slowly progressive growth patterns, ependymomas frequently remain undiagnosed for a very long time and may achieve large sizes, leading to rupture of the tumor capsule and subsequent infiltration of surrounding neural tissue, so that intraoperative traction and detachment may result in new deficits after surgery in such cases.4,30 Therefore, these tumors may harbor a risk of postsurgical morbidity similar to that in intramedullary tumors.

Similarly to previously reported findings,6,19,31 our finding of improved functional outcome in the follow-up examination was observed mainly in patients without disabling deficits before surgery (McCormick scores of 1 and 2 [p = 0.014]). Furthermore, with the delayed diagnosis, ependymoma may reach a large volume, which appears to be a significant obstacle for GTR according to our results (p = 0.006). Consequently, early diagnosis and resection of spinal ependymomas are essential, because at that stage the probability of functional improvement of a mild neurological deficit and the chances of achieving GTR of small tumors are significantly higher.

Tumor Progression

The 5-year PFS after resection of a spinal ependymoma ranges from 70% to 89%.4,6,27 Consistent with these data, the 5-year PFS was 80% in our series. Using multivariate Cox regression, 3 favorable prognostic factors of PFS were identified: 1) GTR, 2) histological grade II on the WHO scale, and 3) low Ki-67 proliferation index.

Together with other large clinical series,4–6,11,19,20,27,34 our results indicate that GTR is associated with significantly longer PFS after spinal ependymoma surgery. The reason for this association is not clearly apparent from our data and should be examined by an additional randomized study. A possible explanation may be an a priori less aggressive and less invasive nature of ependymomas, which could be resected completely in our cohort. Patients who underwent STR fared better (median PFS of 60 months) than those who underwent PR (median PFS 43 months). However, this difference in PFS was not statistically significant (p = 0.921), which may be attributed to the relatively wide range of residual tumor sizes among partially resected ependymomas.

One of the most common oncological prognostic tools is the WHO tumor grading system. However, the prognostic value of the WHO classification of ependymomas has been increasingly called into question by several recent works.1,6,28,30,32,34 The discrepancy between the often aggressive oncological behavior and the benign diagnosis (WHO grade I) of primarily myxopapillary ependymomas is usually explained by the currently misleading WHO classification, which ignores the evidence of upregulation of specific genes and growth factors in tumor tissue.1,32 Another explanation is the frequently observed rupture of the tumor capsule and subsequent infiltration and adherence of large WHO grade I myxopapillary ependymomas to surrounding cauda fibers, which can hamper surgery and result in incomplete resection, leading to a significant risk of later recurrence.4,30

In our study, the longest PFS was observed in patients with WHO grade II tumors, followed by grade I and III ependymomas, respectively (multivariate Cox regression, p = 0.009; log rank p = 0.004), which is similar to results reported previously.28,34 The Ki-67 proliferation index appeared to be a more reliable prognostic factor (multivariate Cox regression, p = 0.005). Evidence for the accuracy of its predictive value for survival prognosis in patients harboring intracranial ependymomas has been reported.17,29,33 The correlation between the Ki-67 index and PFS of patients with spinal ependymomas has not been previously described. Immunochemical assessment of Ki-67 is not yet a routine procedure in histopathological analysis for spinal ependymomas. Therefore, this factor was available only in approximately half of our patients, which may affect our results. Nevertheless, we recommend including Ki-67 as a standard in a grading scheme for spinal ependymomas, which has already been agreed upon for intracranial ependymal tumors.

Radiation Therapy

The use of adjuvant RT remains controversial, and although there is no consensus among authors, the majority agree that there is no benefit in RT after GTR.5,6,34 Treatment with RT is usually recommended in cases of leptomeningeal spread or anaplastic ependymoma.20 However, there are no guidelines concerning indications for RT, and decisions are usually made on a case-by-case basis. Table 7 presents the inhomogeneity of our patients who received RT. The PFS of the patients with adjuvant RT was significantly shorter than that of the patients who received surgery alone. The most likely explanation is an a priori worse prognosis in patients who had been assigned to receive RT, due to either incomplete resection, anaplastic lesion, or dissemination, rendering this finding a mere reflection of clinically inhomogeneous patients in both groups. Therefore, we compared the PFS of incompletely resected ependymomas with regard to subsequent RT. These patients had no statistically significant differences in PFS. Nevertheless, these results should be seen as merely indicative. An objective evaluation of the true benefit of RT is not possible with our data because of the small number and inhomogeneous characteristics of patients who received adjuvant treatment, and because of the nonrandomized design of the present study. Similarly, previously conducted studies, which had evaluated the role of RT for ependymomas, cannot be regarded as a template for guidelines due to their nonrandomized design.6,19,20,26 According to current expert opinions, we would recommend that practitioners refrain from adjuvant RT after GTR of grade I or II ependymomas. In cases of anaplastic ependymomas, adjuvant RT should be performed. After STR or PR of grade I or II ependymomas, an indication for RT should be discussed individually within the Tumor Board, taking into account other clinical and histological parameters.

Limitations of the Study

A significant limitation of the present and previous studies concerning natural history and treatment of spinal ependymomas is the retrospective design, which fails to provide strictly defined selection criteria for treatment procedures, such as RT and EOR. For the same reason, the follow-up period is variable and in some patients is too short. It is evident from previous publications that recurrences of adult spinal ependymoma are relatively rare, and occur at an unpredictable point of time, as observed even within the short follow-up in our series. For an adequate analysis of the long-term clinical and oncological prognosis of patients with these tumors, a prospective observation for several decades is required, which unfortunately appears to be hardly feasible because of the mainly benign natural history and slow-growing patterns of spinal ependymomas. Moreover, a continuous and gapless acquisition of several important parameters was not possible: e.g., Ki-67 data were available only in approximately half of our patients, which may have affected the analysis and weakens our statements. Regarding these limitations, the above-mentioned list of negative prognostic factors should be regarded as an observation only, partly supported by the evidence of previously published investigations.

Conclusions

Gross-total resection of spinal ependymomas can be achieved in the vast majority of cases, with acceptable rates of permanent deficits. Due to its beneficial prognostic value for PFS, GTR remains the primary goal in treatment of spinal ependymoma. Older age of patients should be considered as a relevant predictor of postoperative morbidity, and particular attention must be given to prevention of age-related perioperative complications and intensified postoperative rehabilitation in older patients. In contrast to the recent WHO grading system, the Ki-67 index appears to be an accurate prognostic factor and should be included as a standard in a grading scheme for spinal ependymomas.

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: Wostrack, Stoffel, Onken. Acquisition of data: Wostrack, Eicker, Jägersberg, Kerschbaumer, Shiban, Onken. Analysis and interpretation of data: Wostrack, Friedrich, Onken. Critically revising the article: Ringel, Eicker, Schaller, Onken. Reviewed submitted version of manuscript: Ringel, Eicker, Jägersberg, Schaller, Kerschbaumer, Thomé, Shiban, Stoffel, Friedrich, Kehl, Vajkoczy, Meyer, Onken. Approved the final version of the manuscript on behalf of all authors: Wostrack. Statistical analysis: Kehl. Administrative/technical/material support: Onken. Study supervision: Schaller, Thomé, Vajkoczy, Meyer.

Supplemental Information

Previous Presentations

Preliminary results of this study have been orally presented at the 9th Congress of the German Spine Society (DWG) in December 2014, in Leipzig, Germany, and at the 66th Congress of the German Neurosurgical Society (DGNC) in June 2015, in Karlsruhe, Germany.

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    • Export Citation
  • 4

    Boström A, von Lehe M, Hartmann W, Pietsch T, Feuss M, Boström JP, et al.: Surgery for spinal cord ependymomas: outcome and prognostic factors. Neurosurgery 68:302309, 2011

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Brotchi J, Fischer G: Spinal cord ependymomas. Neurosurg Focus 4(5):e2, 1998

  • 6

    Chang UK, Choe WJ, Chung SK, Chung CK, Kim HJ: Surgical outcome and prognostic factors of spinal intramedullary ependymomas in adults. J Neurooncol 57:133139, 2002

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Cooper PR, Epstein F: Radical resection of intramedullary spinal cord tumors in adults. Recent experience in 29 patients. J Neurosurg 63:492499, 1985

  • 8

    Duong LM, McCarthy BJ, McLendon RE, Dolecek TA, Kruchko C, Douglas LL, et al.: Descriptive epidemiology of malignant and nonmalignant primary spinal cord, spinal meninges, and cauda equina tumors, United States, 2004–2007. Cancer 118:42204227, 2012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Ehrlich MP, Schillinger M, Grabenwöger M, Kocher A, Tschernko EM, Simon P, et al.: Predictors of adverse outcome and transient neurological dysfunction following surgical treatment of acute type A dissections. Circulation 108 (Suppl 1):II318II323, 2003

    • Search Google Scholar
    • Export Citation
  • 10

    Ferrante L, Mastronardi L, Celli P, Lunardi P, Acqui M, Fortuna A: Intramedullary spinal cord ependymomas—a study of 45 cases with long-term follow-up. Acta Neurochir (Wien) 119:7479, 1992

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Garcés-Ambrossi GL, McGirt MJ, Mehta VA, Sciubba DM, Witham TF, Bydon A, et al.: Factors associated with progression-free survival and long-term neurological outcome after resection of intramedullary spinal cord tumors: analysis of 101 consecutive cases. J Neurosurg Spine 11:591599, 2009

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Guan S, Shen R, Lafortune T, Tiao N, Houghton P, Yung WK, et al.: Establishment and characterization of clinically relevant models of ependymoma: a true challenge for targeted therapy. Neuro Oncol 13:748758, 2011

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Guidetti B, Mercuri S, Vagnozzi R: Long-term results of the surgical treatment of 129 intramedullary spinal gliomas. J Neurosurg 54:323330, 1981

  • 14

    Klekamp J: Spinal ependymomas. Part 1: Intramedullary ependymomas. Neurosurg Focus 39(2):E6, 2015

  • 15

    Klekamp J: Spinal ependymomas. Part 2: Ependymomas of the filum terminale. Neurosurg Focus 39(2):E7, 2015

  • 16

    Klekamp J: Treatment of intramedullary tumors: analysis of surgical morbidity and long-term results. J Neurosurg Spine 19:1226, 2013

  • 17

    Kurt E, Zheng PP, Hop WC, van der Weiden M, Bol M, van den Bent MJ, et al.: Identification of relevant prognostic histopathologic features in 69 intracranial ependymomas, excluding myxopapillary ependymomas and subependymomas. Cancer 106:388395, 2006

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Kyoshima K, Akaishi K, Tokushige K, Muraoka H, Oikawa S, Watanabe A, et al.: Surgical experience with resection en bloc of intramedullary astrocytomas and ependymomas in the cervical and cervicothoracic region. J Clin Neurosci 11:623628, 2004

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Lee SH, Chung CK, Kim CH, Yoon SH, Hyun SJ, Kim KJ, et al.: Long-term outcomes of surgical resection with or without adjuvant radiation therapy for treatment of spinal ependymoma: a retrospective multicenter study by the Korea Spinal Oncology Research Group. Neuro Oncol 15:921929, 2013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Lin YH, Huang CI, Wong TT, Chen MH, Shiau CY, Wang LW, et al.: Treatment of spinal cord ependymomas by surgery with or without postoperative radiotherapy. J Neurooncol 71:205210, 2005

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, et al.: The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114:97109, 2007

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Manzano G, Green BA, Vanni S, Levi AD: Contemporary management of adult intramedullary spinal tumors-pathology and neurological outcomes related to surgical resection. Spinal Cord 46:540546, 2008

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    McCormick PC, Post KD, Stein BM: Intradural extramedullary tumors in adults. Neurosurg Clin N Am 1:591608, 1990

  • 24

    McCormick PC, Stein BM: Intramedullary tumors in adults. Neurosurg Clin N Am 1:609630, 1990

  • 25

    McCormick PC, Torres R, Post KD, Stein BM: Intramedullary ependymoma of the spinal cord. J Neurosurg 72:523532, 1990

  • 26

    Oh MC, Ivan ME, Sun MZ, Kaur G, Safaee M, Kim JM, et al.: Adjuvant radiotherapy delays recurrence following subtotal resection of spinal cord ependymomas. Neuro Oncol 15:208215, 2013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Oh MC, Kim JM, Kaur G, Safaee M, Sun MZ, Singh A, et al.: Prognosis by tumor location in adults with spinal ependymomas. J Neurosurg Spine 18:226235, 2013

  • 28

    Oh MC, Tarapore PE, Kim JM, Sun MZ, Safaee M, Kaur G, et al.: Spinal ependymomas: benefits of extent of resection for different histological grades. J Clin Neurosci 20:13901397, 2013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29

    Preusser M, Heinzl H, Gelpi E, Höftberger R, Fischer I, Pipp I, et al.: Ki67 index in intracranial ependymoma: a promising histopathological candidate biomarker. Histopathology 53:3947, 2008

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Sakai Y, Matsuyama Y, Katayama Y, Imagama S, Ito Z, Wakao N, et al.: Spinal myxopapillary ependymoma: neurological deterioration in patients treated with surgery. Spine (Phila Pa 1976) 34:16191624, 2009

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    Schwartz TH, McCormick PC: Intramedullary ependymomas: clinical presentation, surgical treatment strategies and prognosis. J Neurooncol 47:211218, 2000

  • 32

    Stephen JH, Sievert AJ, Madsen PJ, Judkins AR, Resnick AC, Storm PB, et al.: Spinal cord ependymomas and myxopapillary ependymomas in the first 2 decades of life: a clinicopathological and immunohistochemical characterization of 19 cases. J Neurosurg Pediatr 9:646653, 2012

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 33

    Suzuki S, Oka H, Kawano N, Tanaka S, Utsuki S, Fujii K: Prognostic value of Ki-67 (MIB-1) and p53 in ependymomas. Brain Tumor Pathol 18:151154, 2001

  • 34

    Tarapore PE, Modera P, Naujokas A, Oh MC, Amin B, Tihan T, et al.: Pathology of spinal ependymomas: an institutional experience over 25 years in 134 patients. Neurosurgery 73:247255, 2013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • View in gallery

    Bar graph showing functional presentation of patients according to the modified McCormick scale.

  • View in gallery

    Bar graph showing early and late postoperative clinical outcomes.

  • View in gallery

    Kaplan-Meier PFS curve of all 158 patients with spinal ependymoma.

  • View in gallery

    Kaplan-Meier PFS curves showing differences depending on the EOR.

  • View in gallery

    Kaplan-Meier PFS curves showing differences depending on the WHO grades.

  • View in gallery

    Kaplan-Meier PFS curves showing differences depending on the Ki-67 proliferation index.

  • View in gallery

    Kaplan-Meier PFS curves of patients with and without RT after incomplete tumor resection.

  • 1

    Armstrong TS, Vera-Bolanos E, Bekele BN, Aldape K, Gilbert MR: Adult ependymal tumors: prognosis and the M. D. Anderson Cancer Center experience. Neuro Oncol 12:862870, 2010

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2

    Bellut D, Burkhardt JK, Mannion AF, Porchet F: Assessment of outcome in patients undergoing surgery for intradural spinal tumor using the multidimensional patient-rated Core Outcome Measures Index and the modified McCormick Scale. Neurosurg Focus 39(2):E2, 2015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Boström A, Kanther NC, Grote A, Boström J: Management and outcome in adult intramedullary spinal cord tumours: a 20-year single institution experience. BMC Res Notes 7:908, 2014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Boström A, von Lehe M, Hartmann W, Pietsch T, Feuss M, Boström JP, et al.: Surgery for spinal cord ependymomas: outcome and prognostic factors. Neurosurgery 68:302309, 2011

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Brotchi J, Fischer G: Spinal cord ependymomas. Neurosurg Focus 4(5):e2, 1998

  • 6

    Chang UK, Choe WJ, Chung SK, Chung CK, Kim HJ: Surgical outcome and prognostic factors of spinal intramedullary ependymomas in adults. J Neurooncol 57:133139, 2002

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Cooper PR, Epstein F: Radical resection of intramedullary spinal cord tumors in adults. Recent experience in 29 patients. J Neurosurg 63:492499, 1985

  • 8

    Duong LM, McCarthy BJ, McLendon RE, Dolecek TA, Kruchko C, Douglas LL, et al.: Descriptive epidemiology of malignant and nonmalignant primary spinal cord, spinal meninges, and cauda equina tumors, United States, 2004–2007. Cancer 118:42204227, 2012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Ehrlich MP, Schillinger M, Grabenwöger M, Kocher A, Tschernko EM, Simon P, et al.: Predictors of adverse outcome and transient neurological dysfunction following surgical treatment of acute type A dissections. Circulation 108 (Suppl 1):II318II323, 2003

    • Search Google Scholar
    • Export Citation
  • 10

    Ferrante L, Mastronardi L, Celli P, Lunardi P, Acqui M, Fortuna A: Intramedullary spinal cord ependymomas—a study of 45 cases with long-term follow-up. Acta Neurochir (Wien) 119:7479, 1992

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Garcés-Ambrossi GL, McGirt MJ, Mehta VA, Sciubba DM, Witham TF, Bydon A, et al.: Factors associated with progression-free survival and long-term neurological outcome after resection of intramedullary spinal cord tumors: analysis of 101 consecutive cases. J Neurosurg Spine 11:591599, 2009

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Guan S, Shen R, Lafortune T, Tiao N, Houghton P, Yung WK, et al.: Establishment and characterization of clinically relevant models of ependymoma: a true challenge for targeted therapy. Neuro Oncol 13:748758, 2011

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Guidetti B, Mercuri S, Vagnozzi R: Long-term results of the surgical treatment of 129 intramedullary spinal gliomas. J Neurosurg 54:323330, 1981

  • 14

    Klekamp J: Spinal ependymomas. Part 1: Intramedullary ependymomas. Neurosurg Focus 39(2):E6, 2015

  • 15

    Klekamp J: Spinal ependymomas. Part 2: Ependymomas of the filum terminale. Neurosurg Focus 39(2):E7, 2015

  • 16

    Klekamp J: Treatment of intramedullary tumors: analysis of surgical morbidity and long-term results. J Neurosurg Spine 19:1226, 2013

  • 17

    Kurt E, Zheng PP, Hop WC, van der Weiden M, Bol M, van den Bent MJ, et al.: Identification of relevant prognostic histopathologic features in 69 intracranial ependymomas, excluding myxopapillary ependymomas and subependymomas. Cancer 106:388395, 2006

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Kyoshima K, Akaishi K, Tokushige K, Muraoka H, Oikawa S, Watanabe A, et al.: Surgical experience with resection en bloc of intramedullary astrocytomas and ependymomas in the cervical and cervicothoracic region. J Clin Neurosci 11:623628, 2004

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Lee SH, Chung CK, Kim CH, Yoon SH, Hyun SJ, Kim KJ, et al.: Long-term outcomes of surgical resection with or without adjuvant radiation therapy for treatment of spinal ependymoma: a retrospective multicenter study by the Korea Spinal Oncology Research Group. Neuro Oncol 15:921929, 2013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Lin YH, Huang CI, Wong TT, Chen MH, Shiau CY, Wang LW, et al.: Treatment of spinal cord ependymomas by surgery with or without postoperative radiotherapy. J Neurooncol 71:205210, 2005

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, et al.: The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114:97109, 2007

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Manzano G, Green BA, Vanni S, Levi AD: Contemporary management of adult intramedullary spinal tumors-pathology and neurological outcomes related to surgical resection. Spinal Cord 46:540546, 2008

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    McCormick PC, Post KD, Stein BM: Intradural extramedullary tumors in adults. Neurosurg Clin N Am 1:591608, 1990

  • 24

    McCormick PC, Stein BM: Intramedullary tumors in adults. Neurosurg Clin N Am 1:609630, 1990

  • 25

    McCormick PC, Torres R, Post KD, Stein BM: Intramedullary ependymoma of the spinal cord. J Neurosurg 72:523532, 1990

  • 26

    Oh MC, Ivan ME, Sun MZ, Kaur G, Safaee M, Kim JM, et al.: Adjuvant radiotherapy delays recurrence following subtotal resection of spinal cord ependymomas. Neuro Oncol 15:208215, 2013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Oh MC, Kim JM, Kaur G, Safaee M, Sun MZ, Singh A, et al.: Prognosis by tumor location in adults with spinal ependymomas. J Neurosurg Spine 18:226235, 2013

  • 28

    Oh MC, Tarapore PE, Kim JM, Sun MZ, Safaee M, Kaur G, et al.: Spinal ependymomas: benefits of extent of resection for different histological grades. J Clin Neurosci 20:13901397, 2013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29

    Preusser M, Heinzl H, Gelpi E, Höftberger R, Fischer I, Pipp I, et al.: Ki67 index in intracranial ependymoma: a promising histopathological candidate biomarker. Histopathology 53:3947, 2008

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Sakai Y, Matsuyama Y, Katayama Y, Imagama S, Ito Z, Wakao N, et al.: Spinal myxopapillary ependymoma: neurological deterioration in patients treated with surgery. Spine (Phila Pa 1976) 34:16191624, 2009

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    Schwartz TH, McCormick PC: Intramedullary ependymomas: clinical presentation, surgical treatment strategies and prognosis. J Neurooncol 47:211218, 2000

  • 32

    Stephen JH, Sievert AJ, Madsen PJ, Judkins AR, Resnick AC, Storm PB, et al.: Spinal cord ependymomas and myxopapillary ependymomas in the first 2 decades of life: a clinicopathological and immunohistochemical characterization of 19 cases. J Neurosurg Pediatr 9:646653, 2012

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 33

    Suzuki S, Oka H, Kawano N, Tanaka S, Utsuki S, Fujii K: Prognostic value of Ki-67 (MIB-1) and p53 in ependymomas. Brain Tumor Pathol 18:151154, 2001

  • 34

    Tarapore PE, Modera P, Naujokas A, Oh MC, Amin B, Tihan T, et al.: Pathology of spinal ependymomas: an institutional experience over 25 years in 134 patients. Neurosurgery 73:247255, 2013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

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