Impact of molecular classification on prognosis in children and adolescents with spinal ependymoma: Results from the HIT-MED database

Abstract

Background: Ependymomas of the spinal cord are rare among children and adolescents, and the individual risk of disease progression is difficult to predict. This study aims to evaluate the prognostic impact of molecular typing on pediatric spinal cord ependymomas.

Methods: Eighty-three patients with spinal ependymomas ≤22 years registered in the HIT-MED database (German brain tumor registry for children, adolescents, and adults with medulloblastoma, ependymoma, pineoblastoma, and CNS-primitive neuroectodermal tumors) between 1992 and 2022 were included. Forty-seven tumors were analyzed by DNA methylation array profiling. In 6 cases, HOXB13 and MYCN proteins were detected as surrogate markers for specific methylation classes. Ten patients had NF2-related schwannomatosis.

Results: With a median follow-up time of 4.9 years, 5- and 10-year overall survival (OS) were 100% and 86%, while 5- and 10-year progression-free survival (PFS) were 65% and 54%. Myxopapillary ependymoma (SP-MPE, n = 32, 63%) was the most common molecular type followed by spinal ependymoma (SP-EPN, n = 17, 33%) and MYCN-amplified ependymoma (n = 2, 4%). One case could not be molecularly classified, and one was reclassified as anaplastic pilocytic astrocytoma. 5-year PFS did not significantly differ between SP-MPE and SP-EPN (65% vs. 78%, P = .64). MYCN-amplification was associated with early relapses (<2.3 years) in both cases and death in one patient. Patients with SP-MPE subtype B (n = 9) showed a non-significant trend for better 5 years-PFS compared to subtype A (n = 18; 86% vs. 56%, P = .15). The extent of resection and WHO tumor grades significantly influenced PFS in a uni- and multivariate analysis.

Conclusions: Molecular typing of pediatric spinal ependymomas aids in identifying very high-risk MYCN-amplified ependymomas. Further insights into the molecular heterogeneity of spinal ependymomas are needed for future clinical decision-making.

Keywords: DNA methylation; MYCN-amplification; molecular type; pediatric spinal ependymoma; radiotherapy.

Figure 1.

Consort diagram on the patient selection process and collection of DNA methylation profiles. In cases of insufficient tumor material for DNA methylation profiling, HOXB13 and MYCN protein expressions were used as surrogate markers for SP-MPE and to exclude SP-EPN-MYCN, respectively. Abbreviations: y, years; IHC, immunohistochemistry; ANA-PA, anaplastic pilocytic astrocytoma; SP-MPE, spinal myxopapillary ependymoma; SP-EPN, spinal ependymoma.

Figure 2.

Cohort overview. (A) Patient characteristics. *One patient was excluded due to molecular reclassification of tumor material as anaplastic pilocytic astrocytoma (ANA-PA). **SP-MPE subtyping was impossible in those classified as SP-MPE by immunohistochemistry (n = 2) and was missing in n = 2 because of unavailable IDAT files. ***In 4 patients, initial adjuvant treatment was not specified. (B) Allocation of histological WHO tumor grades to DNA methylation profiles. (C) Overall and progression-free survival in pediatric spinal ependymoma. Abbreviations: n, number; myx, myxopapillary; SP-MPE, spinal myxopapillary ependymoma; SP-EPN, spinal ependymoma; SP-EPN-MYCN, MYCN-amplified SP-EPN; SP-MPE-A, SP-MPE subtype A; SP-MPE-B, SP-MPE subtype B; GTR, gross total resection; <GTR, less than GTR (subtotal or partial resection); RT, radiotherapy; CT, chemotherapy; RCT, radiochemotherapy; OS, overall survival; PFS, progression-free survival.

Figure 3.

(A) Univariate and (B) multivariate progression-free survival analysis in pediatric spinal ependymoma. Univariate survival analysis was calculated using the Kaplan–Meier estimator if not stated otherwise. *calculated using Cox Regression. Multivariate survival analysis was performed with Cox Regression. DNA methylation was excluded from the final multivariate model as it did not meet the proportional hazards assumption and induced a strong selection bias due to the reduction of total patient count to n = 41. Dissemination at diagnosis was also removed because it did not meet the proportional hazards assumption. Subvariables with few or zero events were either combined if applicable (cervicomedullary and cervical, lumbosacral and sacral tumor localization) or excluded from the final model (coccygeal tumor localization, MYCN-amplification, chemotherapy). Cases excluded due to missing values: n = 13. Likelihood ratio test: χ² = 45.21 (P = .00004), Wald test: χ² = 28.44 (P = .01), Score test: χ² = 43.35 (P = .00008), Concordance = 0.836. Abbreviations: PFS, progression-free survival; NF2, NF2-related schwannomatosis; GTR, gross total resection; <GTR, less than GTR (subtotal or partial resection); HR, hazard ratio.

Figure 4.

General prognostic factors in pediatric patients with spinal ependymoma. (A) OS stratified by WHO tumor grade. Factors significantly influencing PFS in the univariate analysis included (B) WHO tumor grade, (C) extent of resection, and (D) tumor localization. Involvement of caudal spinal segments resulted in worse PFS (P = .033). PFS was 100% in cervicomedullary tumor localization, 89% [95% CI: 67.9–100] in cervical, 76% [46.6–100] in cervicothoracic, 50% [0–100] in thoracic, 42% [7.1–76.3] in thoracolumbar, 68% [45.8–90.2] in lumbar, 44% [0–88.8] in lumbosacral, 50% [0–100] in sacral, and 50% [0–100] in coccygeal tumor localization. Abbreviations: OS, overall survival; PFS, progression-free survival; GTR, gross total resection; < GTR, less than GTR (subtotal or partial resection); myx, myxopapillary; y, year; CI, confidence interval.

Figure 5.

Impact of methylation groups on prognosis in pediatric spinal ependymoma. (A) OS and (B) PFS stratified by methylation group. PFS did not differ between methylation groups, whereas MYCN amplification significantly impacted PFS. (C) Influence of SP-MPE subtypes A and B on PFS. (D) PFS is significantly impacted by the extent of resection in SP-MPE but not in SP-EPN. (E) PFS analysis for the use of adjuvant treatment in SP-MPE after GTR or <GTR, and (F) after M0-GTR, M0-<GTR, or M+. Abbreviations: OS, overall survival; PFS, progression-free survival; SP-MPE, spinal myxopapillary ependymoma; SP-EPN, spinal ependymoma; SP-EPN-MYCN, MYCN-amplified spinal ependymoma; SP-MPE-A, SP-MPE subtype A; SP-MPE-B, SP-MPE subtype B; GTR, gross total resection; < GTR, less than GTR (subtotal or partial resection); WS, wait-and-see strategy; adj. Tx, adjuvant treatment; M0-GTR, GTR in the non-metastatic state; M0-<GTR, <GTR in the non-metastatic state; M+, metastatic state irrespective of the extent of resection.