Treatment of pediatric Grade II spinal ependymomas: a population-based study

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OBJECT

Grade II spinal cord ependymomas occurring in pediatric patients are exceptionally rare neoplasms. In this paper the authors use a national cancer database to determine patient demographics, treatment patterns, and associated outcomes of this cohort.

METHODS

The Surveillance Epidemiology and End Results (SEER) database was used to analyze subjects younger than 18 years with histologically confirmed diagnoses of Grade II spinal cord ependymoma from the years 1973 to 2008. Descriptive data on the demographic characteristics of this cohort and the associated treatment patterns are shown. The Kaplan-Meier method was used to estimate overall survival at 1, 2, 5, and 10 years.

RESULTS

This cohort comprised 64 pediatric subjects with Grade II spinal ependymoma. The median age was 13 years, nearly half of the patients were male, and most were white (84%). The median follow-up was 9.2 years. Overall survival at 5 and 10 years was 86% and 83%, respectively. Gross-total resection was achieved in 57% of subjects, and radiation therapy was administered to 36%. Radiation therapy was administered to 78% of subjects after subtotal resection but only to 19% of patients after gross-total resection; this difference was significant (p < 0.001). In a multivariate regression model analyzing sex, age at diagnosis, year of diagnosis, radiotherapy, and extent of resection, female sex was found to be an independent predictor of decreased mortality (HR 0.15 [95% CI 0.02–0.94], p = 0.04).

CONCLUSIONS

These data show long-term outcomes for pediatric patients with Grade II spinal ependymoma. Radiotherapy was more likely to be administered in cases of subtotal resection than in cases of gross-total resection. Female sex is associated with decreased mortality, while other demographic or treatment modalities are not.

ABBREVIATIONSGTR = gross-total resection; ICD-O-3 = The International Classification of Diseases for Oncology, Third Edition; NOS = not otherwise specified; OS = overall survival; PFS = progression-free survival; SEER = Surveillance Epidemiology and End Results; STR = subtotal resection.

Abstract

OBJECT

Grade II spinal cord ependymomas occurring in pediatric patients are exceptionally rare neoplasms. In this paper the authors use a national cancer database to determine patient demographics, treatment patterns, and associated outcomes of this cohort.

METHODS

The Surveillance Epidemiology and End Results (SEER) database was used to analyze subjects younger than 18 years with histologically confirmed diagnoses of Grade II spinal cord ependymoma from the years 1973 to 2008. Descriptive data on the demographic characteristics of this cohort and the associated treatment patterns are shown. The Kaplan-Meier method was used to estimate overall survival at 1, 2, 5, and 10 years.

RESULTS

This cohort comprised 64 pediatric subjects with Grade II spinal ependymoma. The median age was 13 years, nearly half of the patients were male, and most were white (84%). The median follow-up was 9.2 years. Overall survival at 5 and 10 years was 86% and 83%, respectively. Gross-total resection was achieved in 57% of subjects, and radiation therapy was administered to 36%. Radiation therapy was administered to 78% of subjects after subtotal resection but only to 19% of patients after gross-total resection; this difference was significant (p < 0.001). In a multivariate regression model analyzing sex, age at diagnosis, year of diagnosis, radiotherapy, and extent of resection, female sex was found to be an independent predictor of decreased mortality (HR 0.15 [95% CI 0.02–0.94], p = 0.04).

CONCLUSIONS

These data show long-term outcomes for pediatric patients with Grade II spinal ependymoma. Radiotherapy was more likely to be administered in cases of subtotal resection than in cases of gross-total resection. Female sex is associated with decreased mortality, while other demographic or treatment modalities are not.

Pediatric primary spinal cord neoplasms are rare tumors, with reported estimated incidences of 0.9–2.6 per 100,000 person-years.32,61 Among these, astrocytomas are the most common subtype, accounting for an estimated 60%–80% of pediatric spinal cord tumors, with ependymoma making up most of the remaining tumors.29,33,34,39,42,44 The reverse pattern is true in adult populations.31,32,42,44 The WHO categorizes spinal ependymomas into 3 histological subtypes: Grade I myxopapillary ependymoma; Grade II ependymoma, which includes the cellular, clear cell, tanycytic, and papillary subtypes; and finally Grade III anaplastic ependymoma.43

Pediatric Grade II spinal ependymomas are generally intramedullary tumors that occur in the proximal spinal cord.7,42 They are slow-growing, indolent tumors with a benign course; in the literature, rates of both overall survival (OS) and progression-free survival (PFS) at 5 years have been reported at 90%–100%.7,42,62 Maximal resection is generally agreed to be the cornerstone of treatment for pediatric spinal ependymomas;2,7,8,34,42,47,50 however, the addition of adjuvant radiation therapy after surgery is the subject of more debate.2,7,8,48 While there are many studies on spinal ependymomas in adults,11,12,16–18,21,24,25,38,41,45,51,56,57,61,65 there are few papers on these tumors in children, and those that do exist tend to be small, single-institution retrospective studies that are not powered for statistical analysis stratified by tumor grade.2,8,13,22,27,42,47,53

The goal of this paper is to use the nationally representative Surveillance Epidemiology and End Results (SEER) database to offer a population-based perspective on pediatric Grade II spinal ependymomas. Specifically, this study provides data on the demographics and treatment patterns in this cohort, as well as the impact of those factors on survival outcomes.

Methods

Study Population

Data for this analysis were obtained from the SEER program (1973–2008) of the National Cancer Institute. This cancer registry includes data from 17 geographic areas in the US and represents approximately 26% of the US population. For the purposes of the present analysis, cases from Louisiana were not used as suggested by SEER due to noncontinuous reporting of data from the impact of Hurricanes Katrina and Rita in the Gulf Coast region. Site and histology codes of The International Classification of Diseases for Oncology, Third Edition (ICD-O-3) were used to identify cases. Patients younger than 18 years old classified as having histopathologically confirmed ependymoma including cellular, clear cell, tanycytic, and ependymoma not otherwise specified (NOS) (ICD-O-3 Code 9391) and papillary ependymoma (ICD-O-3 Code 9393) in a location classified as spinal cord (C72.0) or cauda equina (C72.1) were included in this study. We included only individuals for whom the ependymoma was their only or first primary tumor. Myxopapillary ependymoma (ICD-O-3 Code 9394) was not included. Subsequent tumors or recurrences were not considered for this analysis. Patients with a survival time of 0 months (n = 3) had their survival time changed to 0.5 months to avoid any bias that could result from the exclusion of these subjects. SEER data are publicly available, and exempt status as non–human subjects research was granted by our institutional review board.

Surgical Procedure Data

In the SEER database, surgical procedure codes were extracted by trained coders to determine the extent of resection. The SEER program has a standardized methodology for coders to look in detail at operative reports, surgeon intraoperative assessment, radiology reports, pathology reports, and medical record notes, and to enter the data according to the FORDS (Facility Oncology Registry Data Standards) manual established by the Commission on Cancer with the American College of Surgeons. We cannot independently confirm the coding assignments. The variable containing surgery codes for the cases diagnosed between 1998 and 2007 was named “RX Summ-Surg Prim Site (1998+)” and was based on the American College of Surgeons Commission on Cancer's Facility Oncology Registry Data Standards.55 Field codes for patients diagnosed between 1983 and 1997 were included in the “Site Specific surgery (1983–1997)” variable. Any case diagnosed prior to 1983 was coded using a nonspecific scheme (yes/no/unknown). To create a new variable for analysis that includes cases from all time periods, we recoded the surgical procedures for all years into 6 previously established categories.1 Briefly, these categories included: no surgery (pre-1998 codes 00, 01, 03, 04, and 07; for 1998+, code 00); biopsy (pre-1998 code 02; for 1998+, code 20); partial resection (pre-1998 codes 20 and 40; for 1998+, code 40); gross-total resection (GTR) (pre-1998 codes 30, 50, 60; for 1998, code 55); surgery NOS (pre-1998 codes 10 and 90; for 1998+, codes 10 and 90); and surgery status unknown (pre-1998 codes 05, 06, 09, and 80; for 1998+, code 99).39,68

Covariates

Age at diagnosis, sex, race (white, black, American Indian, Asian/Pacific Islander, and other/unknown), Hispanic ethnicity (yes/no), surgery (no surgery/biopsy/partial resection/ GTR/surgery not otherwise specified/unknown), radiation therapy (yes/no/unknown), were evaluated in this analysis. For the surgery variable, “no surgery,” “biopsy,” and “surgery NOS” were collapsed into “no resection,” partial resection was “subtotal resection” (STR), and GTR remained as is; unknown status retained its own category but was excluded from most statistical analyses. Detailed patient and treatment-related factors such as chemotherapeutic regimens, radiotherapy technique, radiation dose, and comorbid conditions were unaccounted for in the SEER database and are therefore not evaluated in the present analysis.

Statistical Analysis

Descriptive analyses were conducted to evaluate the distribution of patient and tumor-related characteristics. The Kaplan-Meier method was used to estimate 10-year, 5-year, 2-year, and 1-year survival; log-rank analyses were conducted to evaluate differences in survival curves. Multivariate Cox proportional hazards models for tumor subsets were conducted to estimate the hazard function using variables identified for analysis based on a priori assumptions of associations with survival. A reverse Kaplan-Meier estimator (using censorship as the event of interest) was used to calculate median follow-up times.15 Chi-square tests were used to compare categorical variables; unpaired t-tests were used to compare continuous variables. Statistical significance was defined as p ≤ 0.05. The statistical analyses were carried out using STATA version 12 (Stata Corp.).

Results

Overall, this cohort comprised 64 pediatric patients with Grade II spinal ependymoma. The median age was 13 years, nearly half of the patients were male, and most were white (84%). Among those who underwent surgery, GTR was attained in 57% and STR was attained in 43%. Only about one-third of the cohort (36%) received radiation therapy. Adjuvant radiotherapy was statistically significantly more likely to be administered in cases of STR than in cases of GTR (p < 0.001). After STR, 11 (79%) of 14 patients received radiation treatment, while after GTR, only 4 (19%) of 21 patients did. This pattern has not significantly varied over the 3.5 decades examined in the study cohort (Table 1).

TABLE 1

Characteristics in 64 patients with Grade II spinal ependymoma

VariableValue*
Sex
 Male30 (46.9)
 Female34 (53.1)
Age at diagnosis in yrs
 Mean ± SD11.9 ± 4.7
 Median13
 0–59 (14.1)
 6–1114 (21.9)
 12–1741 (64.1)
Race
 White54 (84.4)
 Black5 (7.8)
Asian/Pacific Islander3 (4.7)
Unknown2 (3.1)
Hispanic Ethnicity
 No55 (85.9)
 Yes9 (14.1)
Period of diagnosis
 1973–200033
 2001–200831
Tumor location
 Spinal cord62 (96.9)
 Cauda equina2 (3.1)
Received radiotherapy
 No37 (57.8)
 Yes23 (35.9)
 Unknown4 (6.2)
Extent of resection
 No resection23 (35.9)
 STR16 (25)
 GTR21 (32.8)
 Unknown4 (6.2)
Follow-up in yrs
 Median9.2
 95% CI6.9–12.7
Survival (95% CI)
 1 yr93.6% (83.8–97.5%)
 2 yrs92% (81.7–96.6%)
 5 yrs86% (73.7–92.8%)
 10 yrs83.2% (69.8–91.1%)

Values are number of patients (%) unless stated otherwise.

Of the 64 subjects, 55 were alive after a median follow-up of 9.2 years (95% CI 6.9–12.7 years), and 9 died after a median of 15 months (range 0–96 months). The survival curve is shown in Fig. 1. Overall survival was 94% at 1 year, 92% at 2 years, 86% at 5 years, and 83% at 10 years. Survival at 10 years was 93% for females and 74% for males; this difference was nearly significant by log-rank testing (p = 0.059) (Fig. 2). Overall, chi-square analysis found that females were statistically significantly less likely to die than males (p = 0.045). Multivariate regression analyses adjusted for age, year of diagnosis, radiotherapy, and extent of resection found a significant association between female sex and decreased mortality at 10 years (HR 0.15 [95% CI 0.02–0.94], p = 0.04). This study found no statistically significant association between OS and age, race/ethnicity, diagnosis year, radiation treatment status, or extent of resection in chi-square, t-test, log-rank, or multivariate regression analyses.

FIG. 1.
FIG. 1.

Kaplan-Meier graph depicting the 10-year survival curve for patients with Grade II ependymoma. Figure is available in color online only.

FIG. 2.
FIG. 2.

Kaplan-Meier graph of 10-year survival of pediatric spinal ependymoma patients stratified by sex. Figure is available in color online only.

The Kaplan-Meier survival estimate at 10 years for those who underwent STR was 87.5% and for those those who underwent GTR it was 93.8%; this difference was not statistically significant. However, among the patients who did not survive, the survival time for the patient who received a GTR was 55 months, and for the 2 patients who received an STR it was 8 and 15 months. The Kaplan-Meier survival estimate at 10 years for those who underwent radiation therapy was 87.4%, and for those who did not, it was 75.1%; this difference was not statistically significant (Tables 2 and 3).

TABLE 2

Patient characteristics and survival outcome*

VariableSurvived (n = 55)Died (n = 9)p Value
Sex0.05
 Male237
 Female322
Age at diagnosis in yrs
 Mean ± SD11.8 ± 4.812.3 ± 4.30.75
 Median1313
 10th–90th percentile3–174–17
 0–5810.66
 6–11113
 12–17365
Race0.69
 White477
 Black41
 Asian/Pacific Islander21
Hispanic ethnicity0.78
 No478
 Yes81
Period of diagnosis0.79
 1973–2000285
 2001–2008274
Received radiation0.25
 No334
 Yes185
Surgery type0.61
 No resection203
 STR142
 GTR201
Time to death in mos
 Mean30.4
 Median15
 Range0–98

Values are presented as the number of patients unless stated otherwise.

Statistically significant.

Unknowns are not shown.

TABLE 3

Multivariate analysis of risk factors for 10-year mortality

VariableHR95% CIp Value
Sex
 Male1.000Reference
 Female0.1510.024–0.9400.043*
Age at diagnosis0.8920.737–1.0800.241
Year of diagnosis
 1973–20001.000Reference
 2001–20085.6150.853–36.9690.073
Received radiation
 No1.000Reference
 Yes2.358050.486–11.4400.287
Extent of resection
 No resection1.000Reference
 STR0.8960.125–6.4170.913
 GTR0.5710.053–6.1660.645

Statistically significant.

Unknowns are not shown.

Discussion

To our knowledge, this is the largest published series of pediatric Grade II spinal ependymoma cases to date, with 64 subjects overall. The median follow-up was 9.2 years. Overall survival was 86% at 5 years and 83% at 10 years. Adjuvant radiation therapy was much more likely to be used in cases of STR than in cases of GTR. Females were significantly more likely to survive than males. Neither extent of resection nor adjuvant radiotherapy significantly affected OS.

Characteristics and Demographics

Grade II ependymomas, including cellular, clear cell, tanycytic, papillary, and ependymoma NOS, are slowgrowing, indolent tumors.7,42 Our study found 5- and 10-year OS to be 86% and 83%, respectively, which is consistent with the reported literature. In a 2010 retrospective study using the Hirntumor (HIT) database (n = 17 Grade II ependymomas), Benesch et al. reported 100% OS and 94% PFS after 4 years of follow-up.8 In a 2012 retrospective single-institution study (n = 11 Grade II ependymomas), Stephen et al. reported 100% PFS and OS after a mean of 51 months of follow-up.62 In a 2013 literature review of more than 30 series (n = 43 Grade II ependymomas), Safaee et al. reported a 5-year OS of greater than 90% and a PFS of approximately 80%.59

This study found that females were much more likely to survive than males among pediatric subjects with Grade II spinal ependymoma. To the best of our knowledge, such a finding in this neoplasm subgroup has not been previously reported. Published studies on this topic have not been powered for analysis stratified by grade. However, an association between male sex and mortality has been reported among intracranial ependymomas in adult populations.45,57 Further prospective studies are warranted to elucidate the possible role of sex in the prognosis of pediatric spinal Grade II ependymoma. The data in our study are observational and cannot provide explanations for this sex-related disparity in survival outcomes. Our results are in keeping with reports in the literature. The higher incidence and worse outcomes of parenchymal CNS tumors in male versus female patients, independent of age, race, tumor histology (including gliomas, ependymomas, and medulloblastomas), and country of residence/origin, has been reported in the literature.3,30,35,37,46,52,58,63,70 Sun et al., in a review examining this disparity, postulated that it may be due to sexually dimorphic biology, specifically sex chromosome–based mechanisms of growth regulation.63 Male embryos are larger, contain more cells, and show differential expression of genes important for glucose metabolism (G6PD and HPRT1), cellular growth (XIAP), and gene regulation (DMNT3A and DMNT3B); these differences are evident at the blastocyst stage, before gonadal differentiation at 8 weeks.9,10,36,60,67 These differences are reported to have physiologically relevant manifestations; male embryos display increased glucose and pyruvate uptake and lactate production, while female embryos display greater G6PD activity and increased activity through the pentose phosphate pathway.9,10,23,49 The Warburg effect describes the observation that tumor cells prefer anaerobic glycolysis as an energy source, and thus would be expected to have increased uptake of glucose and production of lactate. These metabolic differences may affect the probability, rate, or severity of oncogenic transformation in the CNS. Alternate explanations include sex-based differential activation of the MAPK pathway, differential sensitivity to estradiol-mediated suppression of the MAPK pathway (correlating with differential rates of proliferation and apoptosis), and differential regulation of CREB, a growthregulating transcription factor.5,19,28,64,69 In an intracranial xenograft model of glioblastoma, estradiol induced tumor cell apoptosis and promoted survival.6 Although SEER data cannot provide further explanation for disparity in outcome based on sex, there is ongoing work reported in the literature to gain understanding of these differences.

This cohort had no significant association between age or race/ethnicity and outcomes in Grade II ependymoma. With regard to spinal ependymoma in general, Safaee et al. (n = 80) found a significant association between age and mortality,59 while Benesch et al. (n = 29) did not.8 However, neither paper provides outcome analysis stratified by tumor grade.

Surgery and Adjuvant Radiation Therapy

Maximally safe resection is the cornerstone of care in the management of pediatric Grade II spinal ependymomas.7,42,50 In this cohort, GTR was attained in 57% of subjects who underwent resection, which is on par with published accounts of 50%–100% in the pediatric literature.8,59,62 Our study did not find a statistically significant relationship between extent of resection and OS; data on tumor progression were not available. Of note, among the 3 patients in our study who underwent resection and eventually died, the patient who achieved GTR survived 55 months, while the 2 patients with STR survived 8 and 13 months. While this small number is not amenable for statistical analysis, this finding is consistent with the widely reported connection between GTR and outcomes listed in the literature. An association between GTR and increased OS and PFS in cases of spinal ependymoma has been well documented in the adult literature and in a handful of pediatric studies; however, few studies provide analysis stratified by grade.11,12,14,16,17,59,62 Safaee et al. reported that among 43 Grade II ependymomas, GTR was associated with increased PFS.59 Benesch et al. (n = 29) did not find a statistically significant relationship between extent of resection and OS; however, they found that GTR trended toward an association with increased PFS (p = 0.088).8

The role of adjuvant radiation therapy in the treatment of pediatric spinal ependymomas has historically been a subject of debate, as the rarity of these neoplasms has led to a paucity of data. Our study shows that in practice, about one-third of this cohort received radiation therapy, which is slightly lower than previously reported rates of 49%–58%.8,59,62 Our data also found that radiation therapy is statistically significantly more likely to be administered in conjunction with STR as opposed to GTR (p < 0.001). Benesch et al. reported a similar pattern in their 2010 study; however, it did not reach statistical significance.8 This study did not find a significant relationship between radiation treatment and OS. It should be noted that, given the limited nature of the data regarding radiation therapy in SEER, it is difficult to draw conclusions regarding the impact of radiation therapy on outcomes in this study cohort. These findings are consistent with what has been published before in the literature. Safaee et al. (n = 43 Grade II ependymomas, total n = 80) found no significant association between radiotherapy and PFS in multivariate analyses pooling Grade I, II, and III spinal ependymoma.59 Lonjon et al. published a cohort (n = 17 Grade II ependymomas, total n = 20) that achieved 90% 10-year OS rates and 70% 10-year PFS rates without the use of additional adjuvant radiation therapy.42 Neither study provided statistical analyses stratified by tumor grade. In the adult literature, the role of adjuvant radiation in the management of spinal ependymomas is also a matter of debate: some studies recommend postoperative radiation therapy in cases of STR but not GTR,18,40,41,65,66 others advocate for postoperative radiation therapy after GTR,38 and some maintain that radiation is not indicated regardless of degree of resection.20,26,42 Further studies are needed to determine the optimal management of these rare tumors.

Limitations

There are limitations to this study, many of which are related to the nature of the underlying data set. There is a lack of data about the focality, location, clinical symptoms, and functional status of the patients, which other studies have shown to be important prognostic indicators of outcome.54,59 The outcome available for examination is survival; there are no data about tumor progression or recurrence. This limits the ability to calculate PFS, which other studies have shown to be more influenced by treatment modalities than OS.8,59 There are no data regarding functional status preoperatively or postoperatively, which are highly clinically relevant. SEER does not contain information regarding the type, dose, field, timing, or duration of radiation therapy, rendering it difficult to derive conclusions about the impact of radiation treatment in this study cohort. There is also a lack of data on chemotherapeutic regimens in SEER; however, chemotherapy is not typically used in the treatment of Grade II spinal ependymomas.4,7,42,47,50 For each case, to what extent the “extent of resection” was coded based on operative reports/surgeon estimates versus postoperative imaging cannot be known from SEER. We do not have access to primary imaging data, and an independent comparison of pre- and postoperative scans to confirm the extent of resection was not possible. Likewise, while tumor histology is coded according to standardized methodology by coders with access to pathology reports, histological data were not available to us for independent verification and review. There are also no data about comorbid conditions that may have influenced the management or outcomes of the subjects in this cohort. The longitudinal nature of the database reflects the evolution of diagnostic and surgical care over the decades of observation. Changes in the histological classification criteria of Grade II spinal ependymomas over the time period examined in this study may lead to heterogeneity within the data. MRI was not developed until 1973, and mainstream incorporation of diagnostic MRI followed over the next 2 decades. This could result in heterogeneity within the “extent of resection” variable; specifically, it may be difficult to interpret “gross-total resection” in pre–MRI era patients, as they may have been classified as “subtotal resection” in the post-MRI era. Finally, as with all population-based studies, these data are observational in nature and cannot be used to deduce causality or to influence clinical decision making.

Conclusions

This study examined 64 cases of pediatric Grade II spinal ependymoma with a median of 9.2 years of follow-up and reported the demographic characteristics, treatment trends, and outcomes. Overall survival at 5 and 10 years was 86% and 83%, respectively. Subjects were significantly more likely to undergo radiation therapy after STR than GTR. Female sex was associated with increased survival; other demographic factors, extent of resection, and radiation treatment were not.

Author Contributions

Conception and design: Lam. Acquisition of data: Lam, Melkonian. Analysis and interpretation of data: Lam, Lin, Melkonian. Drafting the article: Lin. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Lam. Statistical analysis: Lin, Melkonian. Administrative/technical/material support: Lam, Jea. Study supervision: Lam.

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  • 37

    Kohler BAWard EMcCarthy BJSchymura MJRies LAEheman C: Annual report to the nation on the status of cancer, 1975–2007, featuring tumors of the brain and other nervous system. J Natl Cancer Inst 103:7147362011

  • 38

    Kopelson GLinggood RMKleinman GMDoucette JWang CC: Management of intramedullary spinal cord tumors. Radiology 135:4734791980

  • 39

    Lam SLin YMelkonian S: Analysis of risk factors and survival in pediatric high-grade spinal cord astrocytoma: a population-based study. Pediatr Neurosurg 48:2993052012

  • 40

    Lee TTGromelski EBGreen BA: Surgical treatment of spinal ependymoma and post-operative radiotherapy. Acta Neurochir (Wien) 140:3093131998

  • 41

    Lin YHHuang CIWong TTChen MHShiau CYWang LW: Treatment of spinal cord ependymomas by surgery with or without postoperative radiotherapy. J Neurooncol 71:2052102005

  • 42

    Lonjon MGoh KYEpstein FJ: Intramedullary spinal cord ependymomas in children: treatment, results and follow-up. Pediatr Neurosurg 29:1781831998

  • 43

    Louis DNOhgaki HWiestler ODCavenee WKBurger PCJouvet A: The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114:971092007

  • 44

    McGuire CSSainani KLFisher PG: Incidence patterns for ependymoma: a surveillance, epidemiology, and end results study. J Neurosurg 110:7257292009

  • 45

    McLaughlin MPMarcus RB JrBuatti JMMcCollough WMMickle JPKedar A: Ependymoma: results, prognostic factors and treatment recommendations. Int J Radiat Oncol Biol Phys 40:8458501998

  • 46

    Mehrazin MRahmat HYavari P: Epidemiology of primary intracranial tumors in Iran, 1978–2003. Asian Pac J Cancer Prev 7:2832882006

  • 47

    Merchant TEKiehna ENThompson SJHeideman RSanford RAKun LE: Pediatric low-grade and ependymal spinal cord tumors. Pediatr Neurosurg 32:30362000

  • 48

    Milano MTJohnson MDSul JMohile NAKorones DNOkunieff P: Primary spinal cord glioma: a Surveillance, Epidemiology, and End Results database study. J Neurooncol 98:83922010

  • 49

    Mittwoch U: The elusive action of sex-determining genes: mitochondria to the rescue?. J Theor Biol 228:3593652004

  • 50

    Nadkarni TDRekate HL: Pediatric intramedullary spinal cord tumors. Critical review of the literature. Childs Nerv Syst 15:17281999

  • 51

    Nagasawa DTSmith ZACremer NFong CLu DCYang I: Complications associated with the treatment for spinal ependymomas. Neurosurg Focus 31:4E132011

  • 52

    Nomura EIoka ATsukuma H: Trends in the incidence of primary intracranial tumors in Osaka, Japan. Jpn J Clin Oncol 41:2912942011

  • 53

    O'Sullivan CJenkin RDDoherty MAHoffman HJGreenberg ML: Spinal cord tumors in children: long-term results of combined surgical and radiation treatment. J Neurosurg 81:5075121994

  • 54

    Oh MCSayegh ETSafaee MSun MZKaur GKim JM: Prognosis by tumor location for pediatric spinal cord ependymomas. J Neurosurg Pediatr 11:2822882013

  • 55

    Phillips JSStewart AK: FORDS: Facility Oncology Revised Data Standards Revised for 2004 ChicagoAmerican College of Surgeons2002. (https://www.facs.org/~/media/files/quality%20programs/cancer/coc/fords/fordsrevised0904.ashx) [Accessed October 26 2014]

  • 56

    Pica AMiller RVillà SKadish SPAnacak YAbusaris H: The results of surgery, with or without radiotherapy, for primary spinal myxopapillary ependymoma: a retrospective study from the rare cancer network. Int J Radiat Oncol Biol Phys 74:111411202009

  • 57

    Reni MGatta GMazza EVecht C: Ependymoma. Crit Rev Oncol Hematol 63:81892007

  • 58

    Rigau VZouaoui SMathieu-Daudé HDarlix AMaran ATrétarre B: French brain tumor database: 5-year histological results on 25 756 cases. Brain Pathol 21:6336442011

  • 59

    Safaee MOh MCKim JMAranda DTarapore PECage TA: Histologic grade and extent of resection are associated with survival in pediatric spinal cord ependymomas. Childs Nerv Syst 29:205720642013

  • 60

    Sánchez FJVilain E: Genes and brain sex differences. Prog Brain Res 186:65762010

  • 61

    Schellinger KAPropp JMVillano JLMcCarthy BJ: Descriptive epidemiology of primary spinal cord tumors. J Neurooncol 87:1731792008

  • 62

    Stephen JHSievert AJMadsen PJJudkins ARResnick ACStorm PB: Spinal cord ependymomas and myxopapillary ependymomas in the first 2 decades of life: a clinicopathological and immunohistochemical characterization of 19 cases. J Neurosurg Pediatr 9:6466532012

  • 63

    Sun TWarrington NMRubin JB: Why does Jack, and not Jill, break his crown? Sex disparity in brain tumors. Biol Sex Differ 3:32012

  • 64

    Tatevossian RGLawson ARForshew THindley GFEllison DWSheer D: MAPK pathway activation and the origins of pediatric low-grade astrocytomas. J Cell Physiol 222:5095142010

  • 65

    Wahab SHSimpson JRMichalski JMMansur DB: Long term outcome with post-operative radiation therapy for spinal canal ependymoma. J Neurooncol 83:85892007

  • 66

    Whitaker SJBessell EMAshley SEBloom HJBell BABrada M: Postoperative radiotherapy in the management of spinal cord ependymoma. J Neurosurg 74:7207281991

  • 67

    Wilson CADavies DC: The control of sexual differentiation of the reproductive system and brain. Reproduction 133:3313592007

  • 68

    Wong APDahdaleh NSFessler RGMelkonian SCLin YSmith ZA: Risk factors and long-term survival in adult patients with primary malignant spinal cord astrocytomas. J Neurooncol 115:4935032013

  • 69

    Zhang LLi BsZhao WChang YHMa WDragan M: Sex-related differences in MAPKs activation in rat astrocytes: effects of estrogen on cell death. Brain Res Mol Brain Res 103:1112002

  • 70

    Zhou DZhang YLiu HLuo SLuo LDai K: Epidemiology of nervous system tumors in children: a survey of 1,485 cases in Beijing Tiantan Hospital from 2001 to 2005. Pediatr Neurosurg 44:971032008

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Article Information

Correspondence Sandi Lam, Department of Neurosurgery, Baylor College of Medicine, Texas Children's Hospital, 6701 Fannin St., Ste. 1230, Houston, TX 77030. email: sklam@texaschildrens.org.

INCLUDE WHEN CITING Published online December 19, 2014; DOI: 10.3171/2014.9.PEDS1473.

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

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Kaplan-Meier graph depicting the 10-year survival curve for patients with Grade II ependymoma. Figure is available in color online only.

  • View in gallery

    Kaplan-Meier graph of 10-year survival of pediatric spinal ependymoma patients stratified by sex. Figure is available in color online only.

References

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Houten JKWeiner HL: Pediatric intramedullary spinal cord tumors: special considerations. J Neurooncol 47:2252302000

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Hsu SQuattrone MOstrom QRyken TCSloan AEBarnholtz-Sloan JS: Incidence patterns for primary malignant spinal cord gliomas: a Surveillance, Epidemiology, and End Results study. J Neurosurg Spine 14:7427472011

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Huisman TA: Pediatric tumors of the spine. Cancer Imaging 9:Spec No AS45482009

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Jallo GIKim BSEpstein F: The current management of intramedullary neoplasms in children and young adults. Ann Neurosurg 1:1132001

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Kobayashi SIsotani AMise NYamamoto MFujihara YKaseda K: Comparison of gene expression in male and female mouse blastocysts revealed imprinting of the X-linked gene, Rhox5/Pem, at preimplantation stages. Curr Biol 16:1661722006

37

Kohler BAWard EMcCarthy BJSchymura MJRies LAEheman C: Annual report to the nation on the status of cancer, 1975–2007, featuring tumors of the brain and other nervous system. J Natl Cancer Inst 103:7147362011

38

Kopelson GLinggood RMKleinman GMDoucette JWang CC: Management of intramedullary spinal cord tumors. Radiology 135:4734791980

39

Lam SLin YMelkonian S: Analysis of risk factors and survival in pediatric high-grade spinal cord astrocytoma: a population-based study. Pediatr Neurosurg 48:2993052012

40

Lee TTGromelski EBGreen BA: Surgical treatment of spinal ependymoma and post-operative radiotherapy. Acta Neurochir (Wien) 140:3093131998

41

Lin YHHuang CIWong TTChen MHShiau CYWang LW: Treatment of spinal cord ependymomas by surgery with or without postoperative radiotherapy. J Neurooncol 71:2052102005

42

Lonjon MGoh KYEpstein FJ: Intramedullary spinal cord ependymomas in children: treatment, results and follow-up. Pediatr Neurosurg 29:1781831998

43

Louis DNOhgaki HWiestler ODCavenee WKBurger PCJouvet A: The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114:971092007

44

McGuire CSSainani KLFisher PG: Incidence patterns for ependymoma: a surveillance, epidemiology, and end results study. J Neurosurg 110:7257292009

45

McLaughlin MPMarcus RB JrBuatti JMMcCollough WMMickle JPKedar A: Ependymoma: results, prognostic factors and treatment recommendations. Int J Radiat Oncol Biol Phys 40:8458501998

46

Mehrazin MRahmat HYavari P: Epidemiology of primary intracranial tumors in Iran, 1978–2003. Asian Pac J Cancer Prev 7:2832882006

47

Merchant TEKiehna ENThompson SJHeideman RSanford RAKun LE: Pediatric low-grade and ependymal spinal cord tumors. Pediatr Neurosurg 32:30362000

48

Milano MTJohnson MDSul JMohile NAKorones DNOkunieff P: Primary spinal cord glioma: a Surveillance, Epidemiology, and End Results database study. J Neurooncol 98:83922010

49

Mittwoch U: The elusive action of sex-determining genes: mitochondria to the rescue?. J Theor Biol 228:3593652004

50

Nadkarni TDRekate HL: Pediatric intramedullary spinal cord tumors. Critical review of the literature. Childs Nerv Syst 15:17281999

51

Nagasawa DTSmith ZACremer NFong CLu DCYang I: Complications associated with the treatment for spinal ependymomas. Neurosurg Focus 31:4E132011

52

Nomura EIoka ATsukuma H: Trends in the incidence of primary intracranial tumors in Osaka, Japan. Jpn J Clin Oncol 41:2912942011

53

O'Sullivan CJenkin RDDoherty MAHoffman HJGreenberg ML: Spinal cord tumors in children: long-term results of combined surgical and radiation treatment. J Neurosurg 81:5075121994

54

Oh MCSayegh ETSafaee MSun MZKaur GKim JM: Prognosis by tumor location for pediatric spinal cord ependymomas. J Neurosurg Pediatr 11:2822882013

55

Phillips JSStewart AK: FORDS: Facility Oncology Revised Data Standards Revised for 2004 ChicagoAmerican College of Surgeons2002. (https://www.facs.org/~/media/files/quality%20programs/cancer/coc/fords/fordsrevised0904.ashx) [Accessed October 26 2014]

56

Pica AMiller RVillà SKadish SPAnacak YAbusaris H: The results of surgery, with or without radiotherapy, for primary spinal myxopapillary ependymoma: a retrospective study from the rare cancer network. Int J Radiat Oncol Biol Phys 74:111411202009

57

Reni MGatta GMazza EVecht C: Ependymoma. Crit Rev Oncol Hematol 63:81892007

58

Rigau VZouaoui SMathieu-Daudé HDarlix AMaran ATrétarre B: French brain tumor database: 5-year histological results on 25 756 cases. Brain Pathol 21:6336442011

59

Safaee MOh MCKim JMAranda DTarapore PECage TA: Histologic grade and extent of resection are associated with survival in pediatric spinal cord ependymomas. Childs Nerv Syst 29:205720642013

60

Sánchez FJVilain E: Genes and brain sex differences. Prog Brain Res 186:65762010

61

Schellinger KAPropp JMVillano JLMcCarthy BJ: Descriptive epidemiology of primary spinal cord tumors. J Neurooncol 87:1731792008

62

Stephen JHSievert AJMadsen PJJudkins ARResnick ACStorm PB: Spinal cord ependymomas and myxopapillary ependymomas in the first 2 decades of life: a clinicopathological and immunohistochemical characterization of 19 cases. J Neurosurg Pediatr 9:6466532012

63

Sun TWarrington NMRubin JB: Why does Jack, and not Jill, break his crown? Sex disparity in brain tumors. Biol Sex Differ 3:32012

64

Tatevossian RGLawson ARForshew THindley GFEllison DWSheer D: MAPK pathway activation and the origins of pediatric low-grade astrocytomas. J Cell Physiol 222:5095142010

65

Wahab SHSimpson JRMichalski JMMansur DB: Long term outcome with post-operative radiation therapy for spinal canal ependymoma. J Neurooncol 83:85892007

66

Whitaker SJBessell EMAshley SEBloom HJBell BABrada M: Postoperative radiotherapy in the management of spinal cord ependymoma. J Neurosurg 74:7207281991

67

Wilson CADavies DC: The control of sexual differentiation of the reproductive system and brain. Reproduction 133:3313592007

68

Wong APDahdaleh NSFessler RGMelkonian SCLin YSmith ZA: Risk factors and long-term survival in adult patients with primary malignant spinal cord astrocytomas. J Neurooncol 115:4935032013

69

Zhang LLi BsZhao WChang YHMa WDragan M: Sex-related differences in MAPKs activation in rat astrocytes: effects of estrogen on cell death. Brain Res Mol Brain Res 103:1112002

70

Zhou DZhang YLiu HLuo SLuo LDai K: Epidemiology of nervous system tumors in children: a survey of 1,485 cases in Beijing Tiantan Hospital from 2001 to 2005. Pediatr Neurosurg 44:971032008

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