Skip to main content

Advertisement

SpringerLink
Log in

Distinct disease-risk groups in pediatric supratentorial and posterior fossa ependymomas

  • Original Paper
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

Abstract

No reliable classification is in clinical use for the therapeutic stratification of children with ependymoma, such that disease risk might be identified and patients treated to ensure a combination of maximal cure rates and minimal adverse therapeutic effects. This study has examined associations between clinicopathologic and cytogenetic variables and outcome in a trial cohort of children with ependymoma, with the aim of defining a practical scheme for stratifying this heterogeneous tumor. Intracranial ependymomas (n = 146) from children treated on the RT1 trial at St. Jude Children’s Research Hospital were evaluated for the status of multiple pathological features. Interphase FISH (iFISH) defined the status of loci on chromosomes 1q (EXO1), 6q (LATS1) and 9, including 9p21 (CDKN2A). Data relating to these clinicopathological and cytogenetic variables were compared with survival data in order to model disease risk groups. Extent of surgical resection was a significant determinant of outcome in both supratentorial and infratentorial compartments. Tumor cell density and mitotic count were associated with outcome among children with posterior fossa ependymomas (n = 119). Among pathologic features, only brain invasion was associated with outcome in children with supratentorial ependymomas (n = 27). For posterior fossa tumors, gain of 1q was independently associated with outcome and in combination with clinicopathological variables defined both a two-tier and three-tier system of disease risk. Among children developing posterior fossa ependymomas treated with maximal surgical resection and conformal radiotherapy, key clinicopathological variables and chromosome 1q status can be used to define tiers of disease risk. In contrast, risk factors for pediatric supratentorial tumors are limited to sub-total resection and brain invasion.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Bennetto L, Foreman N, Harding B, Hayward R, Ironside J, Love S, Ellison D (1998) Ki-67 immunolabelling index is a prognostic indicator in childhood posterior fossa ependymomas. Neuropathol Appl Neurobiol 24(6):434–440

    Article  PubMed  CAS  Google Scholar 

  2. Bouffet E, Perilongo G, Canete A, Massimino M (1998) Intracranial ependymomas in children: a critical review of prognostic factors and a plea for cooperation. Med Pediatr Oncol 30(6):319–329

    Article  PubMed  CAS  Google Scholar 

  3. Bouffet E, Tabori U, Huang A, Bartels U (2009) Ependymoma: lessons from the past, prospects for the future. Childs Nerv Syst 25 (11):1383–1384 (author reply 1385. doi:10.1007/s00381-009-0915-6)

    Google Scholar 

  4. Carter M, Nicholson J, Ross F, Crolla J, Allibone R, Balaji V, Perry R, Walker D, Gilbertson R, Ellison DW (2002) Genetic abnormalities detected in ependymomas by comparative genomic hybridisation. Br J Cancer 86(6):929–939

    Article  PubMed  CAS  Google Scholar 

  5. Conklin HM, Li C, Xiong X, Ogg RJ, Merchant TE (2008) Predicting change in academic abilities after conformal radiation therapy for localized ependymoma. J Clin Oncol 26(24):3965–3970. doi:10.1200/JCO.2007.15.9970

    Article  PubMed  Google Scholar 

  6. Dyer S, Prebble E, Davison V, Davies P, Ramani P, Ellison D, Grundy R (2002) Genomic imbalances in pediatric intracranial ependymomas define clinically relevant groups. Am J Pathol 161(6):2133–2141

    Article  PubMed  CAS  Google Scholar 

  7. Ellison DW, Dalton J, Kocak M, Nicholson SL, Fraga C, Neale G, Kenney AM, Brat DJ, Perry A, Yong WH, Taylor RE, Bailey S, Clifford SC, Gilbertson RJ (2011) Medulloblastoma: clinicopathological correlates of SHH, WNT, and non-SHH/WNT molecular subgroups. Acta Neuropathol 121(3):381–396. doi:10.1007/s00401-011-0800-8

    Article  PubMed  CAS  Google Scholar 

  8. Ellison DW, Kocak M, Figarella-Branger D, Felice G, Catherine G, Pietsch T, Frappaz D, Massimino M, Grill J, Boyett JM, Grundy RG (2011) Histopathological grading of pediatric ependymoma: reproducibility and clinical relevance in European trial cohorts. J Negat Results Biomed 10:7. doi:10.1186/1477-5751-10-7

    Article  PubMed  Google Scholar 

  9. Figarella-Branger D, Civatte M, Bouvier-Labit C, Gouvernet J, Gambarelli D, Gentet JC, Lena G, Choux M, Pellissier JF (2000) Prognostic factors in intracranial ependymomas in children. J Neurosurg 93(4):605–613

    Article  PubMed  CAS  Google Scholar 

  10. Gerszten PC, Pollack IF, Martinez AJ, Lo KH, Janosky J, Albright AL (1996) Intracranial ependymomas of childhood. Lack of correlation of histopathology and clinical outcome. Pathol Res Pract 192(6):515–522

    Article  PubMed  CAS  Google Scholar 

  11. Godfraind C (2009) Classification and controversies in pathology of ependymomas. Childs Nerv Syst 25(10):1185–1193. doi:10.1007/s00381-008-0804-4

    Article  PubMed  Google Scholar 

  12. Grundy RG, Wilne SA, Weston CL, Robinson K, Lashford LS, Ironside J, Cox T, Chong WK, Campbell RH, Bailey CC, Gattamaneni R, Picton S, Thorpe N, Mallucci C, English MW, Punt JA, Walker DA, Ellison DW, Machin D (2007) Primary postoperative chemotherapy without radiotherapy for intracranial ependymoma in children: the UKCCSG/SIOP prospective study. Lancet Oncol 8(8):696–705

    Article  PubMed  Google Scholar 

  13. Hirose Y, Aldape K, Bollen A, James CD, Brat D, Lamborn K, Berger M, Feuerstein BG (2001) Chromosomal abnormalities subdivide ependymal tumors into clinically relevant groups. Am J Pathol 158(3):1137–1143

    Article  PubMed  CAS  Google Scholar 

  14. Johnson RA, Wright KD, Poppleton H, Mohankumar KM, Finkelstein D, Pounds SB, Rand V, Leary SE, White E, Eden C, Hogg T, Northcott P, Mack S, Neale G, Wang YD, Coyle B, Atkinson J, DeWire M, Kranenburg TA, Gillespie Y, Allen JC, Merchant T, Boop FA, Sanford RA, Gajjar A, Ellison DW, Taylor MD, Grundy RG, Gilbertson RJ (2010) Cross-species genomics matches driver mutations and cell compartments to model ependymoma. Nature 466(7306):632–636. doi:10.1038/nature09173

    Article  PubMed  CAS  Google Scholar 

  15. Korshunov A, Witt H, Hielscher T, Benner A, Remke M, Ryzhova M, Milde T, Bender S, Wittmann A, Schottler A, Kulozik AE, Witt O, von Deimling A, Lichter P, Pfister S (2010) Molecular staging of intracranial ependymoma in children and adults. J Clin Oncol 28(19):3182–3190. doi:10.1200/JCO.2009.27.3359

    Article  PubMed  Google Scholar 

  16. Massimino M, Gandola L, Barra S, Giangaspero F, Casali C, Potepan P, Di Rocco C, Nozza P, Collini P, Viscardi E, Bertin D, Biassoni V, Cama A, Milanaccio C, Modena P, Balter R, Tamburrini G, Peretta P, Mascarin M, Scarzello G, Fidani P, Milano GM, Sardi I, Genitori L, Garre ML (2011) Infant ependymoma in a 10-year AIEOP (Associazione Italiana Ematologia Oncologia Pediatrica) experience with omitted or deferred radiotherapy. Int J Radiat Oncol Biol Phys 80(3):807–814. doi:10.1016/j.ijrobp.2010.02.048

    Article  PubMed  Google Scholar 

  17. McGuire CS, Sainani KL, Fisher PG (2009) Both location and age predict survival in ependymoma: a SEER study. Pediatr Blood Cancer 52(1):65–69. doi:10.1002/pbc.21806

    Article  PubMed  Google Scholar 

  18. Mendrzyk F, Korshunov A, Benner A, Toedt G, Pfister S, Radlwimmer B, Lichter P (2006) Identification of gains on 1q and epidermal growth factor receptor overexpression as independent prognostic markers in intracranial ependymoma. Clin Cancer Res 12(7 Pt 1):2070–2079. doi:10.1158/1078-0432.CCR-05-2363

    Article  PubMed  CAS  Google Scholar 

  19. Merchant TE (2009) Three-dimensional conformal radiation therapy for ependymoma. Childs Nerv Syst 25(10):1261–1268. doi:10.1007/s00381-009-0892-9

    Article  PubMed  Google Scholar 

  20. Merchant TE, Fouladi M (2005) Ependymoma: new therapeutic approaches including radiation and chemotherapy. J Neurooncol 75(3):287–299. doi:10.1007/s11060-005-6753-9

    Article  PubMed  Google Scholar 

  21. Merchant TE, Li C, Xiong X, Kun LE, Boop FA, Sanford RA (2009) Conformal radiotherapy after surgery for paediatric ependymoma: a prospective study. Lancet Oncol 10(3):258–266

    Article  PubMed  Google Scholar 

  22. Monoranu CM, Huang B, Zangen IL, Rutkowski S, Vince GH, Gerber NU, Puppe B, Roggendorf W (2008) Correlation between 6q25.3 deletion status and survival in pediatric intracranial ependymomas. Cancer Genet Cytogenet 182(1):18–26. doi:10.1016/j.cancergencyto.2007.12.008

    Article  PubMed  CAS  Google Scholar 

  23. Prayson RA (1999) Clinicopathologic study of 61 patients with ependymoma including MIB-1 immunohistochemistry. Ann Diagn Pathol 3(1):11–18

    Article  PubMed  CAS  Google Scholar 

  24. Preusser M, Heinzl H, Gelpi E, Hoftberger R, Fischer I, Pipp I, Milenkovic I, Wohrer A, Popovici F, Wolfsberger S, Hainfellner JA (2008) Ki67 index in intracranial ependymoma: a promising histopathological candidate biomarker. Histopathology 53(1):39–47

    Article  PubMed  CAS  Google Scholar 

  25. Puget S, Grill J, Valent A, Bieche I, Dantas-Barbosa C, Kauffmann A, Dessen P, Lacroix L, Geoerger B, Job B, Dirven C, Varlet P, Peyre M, Dirks PB, Sainte-Rose C, Vassal G (2009) Candidate genes on chromosome 9q33-34 involved in the progression of childhood ependymomas. J Clin Oncol 27(11):1884–1892. doi:10.1200/JCO.2007.15.4195

    Article  PubMed  CAS  Google Scholar 

  26. Rodriguez D, Cheung MC, Housri N, Quinones-Hinojosa A, Camphausen K, Koniaris LG (2009) Outcomes of malignant CNS ependymomas: an examination of 2408 cases through the Surveillance, Epidemiology, and End Results (SEER) database (1973–2005). J Surg Res 156(2):340–351. doi:10.1016/j.jss.2009.04.024

    Article  PubMed  Google Scholar 

  27. Rousseau A, Idbaih A, Ducray F, Criniere E, Fevre-Montange M, Jouvet A, Delattre JY (2010) Specific chromosomal imbalances as detected by array CGH in ependymomas in association with tumor location, histological subtype and grade. J Neurooncol 97(3):353–364. doi:10.1007/s11060-009-0039-6

    Article  PubMed  Google Scholar 

  28. Rousseau E, Palm T, Scaravilli F, Ruchoux MM, Figarella-Branger D, Salmon I, Ellison D, Lacroix C, Chapon F, Mikol J, Vikkula M, Godfraind C (2007) Trisomy 19 ependymoma, a newly recognized genetico-histological association, including clear cell ependymoma. Mol Cancer 6:47. doi:10.1186/1476-4598-6-47

    Article  PubMed  Google Scholar 

  29. Shu HK, Sall WF, Maity A, Tochner ZA, Janss AJ, Belasco JB, Rorke-Adams LB, Phillips PC, Sutton LN, Fisher MJ (2007) Childhood intracranial ependymoma: twenty-year experience from a single institution. Cancer 110(2):432–441. doi:10.1002/cncr.22782

    Article  PubMed  Google Scholar 

  30. Taylor MD, Poppleton H, Fuller C, Su X, Liu Y, Jensen P, Magdaleno S, Dalton J, Calabrese C, Board J, Macdonald T, Rutka J, Guha A, Gajjar A, Curran T, Gilbertson RJ (2005) Radial glia cells are candidate stem cells of ependymoma. Cancer Cell 8(4):323–335. doi:10.1016/j.ccr.2005.09.001

    Article  PubMed  CAS  Google Scholar 

  31. Tihan T, Zhou T, Holmes E, Burger PC, Ozuysal S, Rushing EJ (2008) The prognostic value of histological grading of posterior fossa ependymomas in children: a Children’s Oncology Group study and a review of prognostic factors. Mod Pathol 21(2):165–177. doi:10.1038/modpathol.3800999

    PubMed  Google Scholar 

  32. Wani K, Armstrong TS, Vera-Bolanos E, Raghunathan A, Ellison D, Gilbertson R, Vaillant B, Goldman S, Packer RJ, Fouladi M, Pollack I, Mikkelsen T, Prados M, Omuro A, Soffietti R, Ledoux A, Wilson C, Long L, Gilbert MR, Aldape K (2012) A prognostic gene expression signature in infratentorial ependymoma. Acta Neuropathol. doi:10.1007/s00401-012-0941-4

    PubMed  Google Scholar 

  33. Witt H, Mack SC, Ryzhova M, Bender S, Sill M, Isserlin R, Benner A, Hielscher T, Milde T, Remke M, Jones DT, Northcott PA, Garzia L, Bertrand KC, Wittmann A, Yao Y, Roberts SS, Massimi L, Van Meter T, Weiss WA, Gupta N, Grajkowska W, Lach B, Cho YJ, von Deimling A, Kulozik AE, Witt O, Bader GD, Hawkins CE, Tabori U, Guha A, Rutka JT, Lichter P, Korshunov A, Taylor MD, Pfister SM (2011) Delineation of two clinically and molecularly distinct subgroups of posterior fossa ependymoma. Cancer Cell 20(2):143–157. doi:10.1016/j.ccr.2011.07.007

    Article  PubMed  CAS  Google Scholar 

  34. Zamecnik J, Snuderl M, Eckschlager T, Chanova M, Hladikova M, Tichy M, Kodet R (2003) Pediatric intracranial ependymomas: prognostic relevance of histological, immunohistochemical, and flow cytometric factors. Mod Pathol 16(10):980–991. doi:10.1097/01.MP.0000087420.34166.B6

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

The authors gratefully acknowledge support from the CERN foundation, Musicians Against Childhood Cancer (MACC), The Noyes Brain Tumor Foundation, National Cancer Institute (P30CA21765), American Lebanese Syrian Associated Charities (ALSAC), and Fonds National de la Recherche Scientifique, Belgium.

Ethical standard

This study was conducted with institutional ethics committee approval—St. Jude Children’s Research Hospital XPD07-107/IRB.

Author information

Authors and Affiliations

  1. Laboratory of Pathology, Université Catholique de Louvain, Brussels, Belgium

    Catherine Godfraind

  2. Department of Pathology MS# 250, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA

    Joanna M. Kaczmarska, James Dalton & David W. Ellison

  3. Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN, 38105, USA

    Mehmet Kocak

  4. Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN, 38105, USA

    Karen D. Wright & Amar Gajjar

  5. Department of Surgery, St. Jude Children’s Research Hospital, Memphis, TN, 38105, USA

    Robert A. Sanford & Fredrick A. Boop

  6. Department of Radiological Sciences, St. Jude Children’s Research Hospital, Memphis, TN, 38105, USA

    Thomas E. Merchant

Authors
  1. Catherine Godfraind
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joanna M. Kaczmarska
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mehmet Kocak
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. James Dalton
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Karen D. Wright
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Robert A. Sanford
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Fredrick A. Boop
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Amar Gajjar
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Thomas E. Merchant
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. David W. Ellison
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David W. Ellison.

Additional information

C. Godfraind and J. M. Kaczmarska contributed equally.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Fig. 1. Progression-free survival (a) and overall survival (b) – survival curves split by tumor location; supratentorial (green) and posterior fossa (red).

Supplementary Fig. 2. Progression-free survival (a) and overall survival (b) – survival curves for all patients split by extent of surgical resection; gross total resection (green) and incomplete resection (red). Progression-free survival (c) and overall survival (d) – survival curves for patients with posterior fossa tumors split by extent of surgical resection; gross total resection (green) and incomplete resection (red).

Supplementary Fig. 3. Progression-free survival (a) and overall survival (b) survival curves for patients with posterior fossa tumors split by mitotic count; mitotic count < 4 (green) and mitotic count ≥ 4 (red). Progression-free survival (c) and overall survival (d) survival curves for patients with posterior fossa tumors split by cell density; low (green) and high (red).

Supplementary Fig. 4. Regression analysis for scoring of mitotic counts. (a) Reviewer 1 versus reviewer 2 (Spearman’s rank correlation = 0.87, P < 0.0001); (b) Reviewer 1 versus reviewer 3 (Spearman’s rank correlation = 0.82, P < 0.0001); (c) Reviewer 2 versus reviewer 3 (Spearman’s rank correlation = 0.79, P < 0.0001).

Supplementary Fig. 5. Models of disease-risk for posterior fossa ependymoma. Model 1 (three-tier, a): Progression-free survival, low-risk (green) = totally resected tumors with mitotic count < 4/10hpfs and no 1q gain; high-risk (red) = subtotally resected tumors with mitotic count ≥ 4/10hpfs or 1q gain. Remaining tumors (blue) were classified as intermediate-risk. Model 2 (two-tier, b): Progression-free survival (c) and overall survival (d), high-risk (blue) = subtotally resected tumors with mitotic count ≥ 4/10hpfs or 1q gain. Remaining tumors (green) were classified as standard-risk. Both models produce highly significant (P < 0.0001) differences in survival curves.

Supplementary Fig. 6. Progression-free survival – survival curves for all patients split by combinations of cytogenetic (copy number) abnormalities; tumors with polysomy 9 and/or loss of chromosome 6 - monosomy 6 or hemizygous deletion of LATS1 - (green), tumors with a balanced profile on chromosomes 1, 6, and 9 (blue), tumors with gain of 1q and/or homozygous deletion of CDKN2A (red).

Supplementary material 1 (DOCX 94 kb)

Supplementary material 2 (DOCX 123 kb)

Supplementary material 3 (DOCX 124 kb)

Supplementary material 4 (DOCX 96 kb)

Supplementary material 5 (DOCX 112 kb)

Supplementary material 6 (DOCX 67 kb)

Supplementary material 7 (XLSX 9 kb)

Supplementary material 8 (XLSX 9 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Godfraind, C., Kaczmarska, J.M., Kocak, M. et al. Distinct disease-risk groups in pediatric supratentorial and posterior fossa ependymomas. Acta Neuropathol 124, 247–257 (2012). https://doi.org/10.1007/s00401-012-0981-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-012-0981-9

Keywords

Search

Navigation