Skip to main content
PMC home page
Brain Pathology logoLink to Brain Pathology
. 2006 Apr 5;13(3):376–385. doi: 10.1111/j.1750-3639.2003.tb00037.x

Anaplasia and Grading in Medulloblastomas

Charles G Eberhart 1,✉, Peter C Burger 1
PMCID: PMC8096053  PMID: 12946027

Abstract

The variable clinical outcomes of medulloblastoma patients have prompted a search for markers with which to tailor therapies to individuals. In this review, we discuss clinical, histological and molecular features that can be used in such treatment customization, focusing on how histopathological grading can impact both patient care and research on the molecular basis of CNS embryonal tumors. Medulloblastomas span a histological spectrum ending in overtly malignant large cell/anaplastic lesions characterized by increased nuclear size, marked cytological anaplasia, and increased mitotic and apoptotic rates. These “high‐grade” lesions make up approximately one quarter of medulloblastomas, and recur and metastasize more frequently than tumors lacking anaplasia. We believe anaplastic change represents a type of malignant progression common to many medulloblastoma subtypes and to other CNS embryonal lesions as well. Correlation of these histological changes with the accumulation of genetic events suggests a model for the histological and molecular progression of medulloblastoma.

Full Text

The Full Text of this article is available as a PDF (756.3 KB).

References

  • 1. Aldosari N, Bigner SH, Burger PC, Becker L, Kepner JL, Friedman HS, McLendon RE (2002) MYCC and MYCN oncogene amplification in medulloblastoma. A fluorescence in situ hybridization study on paraffin sections from the Children's Oncology Group. Arch Pathol Lab Med 126:540–544. [DOI] [PubMed] [Google Scholar]
  • 2. Bailey CC, Gnekow A, Wellek S, Jones M, Round C, Brown J, Phillips A, Neidhardt MK (1995) Prospective randomised trial of chemotherapy given before radiotherapy in childhood medulloblastoma. International Society of Paediatric Oncology (SIOP) and the (German) Society of Paediatric Oncology (GPO): SIOP II. Med Pediatr Oncol 25:166–178. [DOI] [PubMed] [Google Scholar]
  • 3. Batra SK, McLendon RE, Koo JS, Castelino‐Prabhu S, Fuchs HE, Krischer JP, Friedman HS, Bigner DD, Bigner SH (1995) Prognostic implications of chromosome 17p deletions in human medulloblastomas. J Neurooncol 24:39–45. [DOI] [PubMed] [Google Scholar]
  • 4. Bayani J, Zielenska M, Marrano P, Kwan NgY, Taylor MD, Jay V, Rutka JT, Squire JA (2000) Molecular cytogenetic analysis of medulloblastomas and supratentorial primitive neuroectodermal tumors by using conventional banding, comparative genomic hybridization, and spectral karyotyping. J Neurosurg 93:437–448. [DOI] [PubMed] [Google Scholar]
  • 5. Beckwith JB (1998) National Wilms Tumor Study: an update for pathologists. Pediatr Dev Pathol 1:79–84. [DOI] [PubMed] [Google Scholar]
  • 6. Biegel JA, Janss AJ, Raffel C, Sutton L, Rorke LB, Harper JM, Phillips PC (1997) Prognostic significance of chromosome 17p deletions in childhood primitive neuroectodermal tumors (medulloblastomas) of the central nervous system. Clin Cancer Res 3:473–478. [PubMed] [Google Scholar]
  • 7. Brown HG, Kepner JL, Perlman EJ, Friedman HS, Strother DR, Duffner PK, Kun LE, Goldthwaite PT, Burger PC (2000) “Large cell/anaplastic” medulloblastomas: a Pediatric Oncology Group Study. J Neuropathol Exp Neurol 59:857–865. [DOI] [PubMed] [Google Scholar]
  • 8. Burger PC, Scheithauer BW, Vogel FS (2002): Surgical Pathology of the Central Nervous System And Its Coverings, 4th ed. Philadelphia : Churchill Livingstone. [Google Scholar]
  • 9. Caputy AJ, McCullough DC, Manz HJ, Patterson K, Hammock MK (1987) A review of the factors influencing the prognosis of medulloblastoma. The importance of cell differentiation. J Neurosurg 66:80–87. [DOI] [PubMed] [Google Scholar]
  • 10. Chang CH, Housepian EM, Herbert C, Jr. (1969) An operative staging system and a megavoltage radiotherapeutic technic for cerebellar medulloblastomas. Radiology 93:1351–1359. [DOI] [PubMed] [Google Scholar]
  • 11. Chatty EM, Earle KM (1971) Medulloblastoma. A report of 201 cases with emphasis on the relationship of histologic variants to survival. Cancer 28:977–983. [DOI] [PubMed] [Google Scholar]
  • 12. Chintagumpala M, Berg S, Blaney SM (2001) Treatment controversies in medulloblastoma. Curr Opin Oncol 13:154–159. [DOI] [PubMed] [Google Scholar]
  • 13. Coffin CM, Braun JT, Wick MR, Dehner LP (1990) Aclinicopathologic and immunohistochemical analysis of 53 cases of medulloblastoma with emphasis on synaptophysin expression. Mod Pathol 3:164–170. [PubMed] [Google Scholar]
  • 14. Cogen PH, Daneshvar L, Metzger AK, Duyk G, Edwards MS, Sheffield VC (1992) Involvement of multiple chromosome 17p loci in medulloblastoma tumorigenesis. Am J Hum Genet 50:584–589. [PMC free article] [PubMed] [Google Scholar]
  • 15. Danjoux CE, Jenkin RD, McLaughlin J, Grimard L, Gaspar LE, Dar AR, Fisher B, Whitton AC, Kraus V, Springer CD, et al. (1996) Childhood medulloblastoma in Ontario, 1977–1987: population‐based results. Med Pediatr Oncol 26:1–9. [DOI] [PubMed] [Google Scholar]
  • 16. Duffner PK, Horowitz ME, Krischer JP, Burger PC, Cohen ME, Sanford RA, Friedman HS, Kun LE (1999) The treatment of malignant brain tumors in infants and very young children: an update of the Pediatric Oncology Group experience. Neurooncol 1:152–161. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17. Eberhart CG, Cohen KJ, Tihan T, Goldthwaite PT, Burger PC (2003) Medulloblastomas with systemic metastases: evaluation of tumor histopathology and clinical behavior in 23 patients. J Pediatr Hematol Oncol 25:198–203. [DOI] [PubMed] [Google Scholar]
  • 18. Eberhart CG, Kaufman WE, Tihan T, Burger PC (2001) Apoptosis, neuronal maturation, and neurotrophin expression within medulloblastoma nodules. J Neuropathol Exp Neurol 60:462–469. [DOI] [PubMed] [Google Scholar]
  • 19. Eberhart CG, Kepner JL, Goldthwaite PT, Kun LE, Duffner PK, Friedman HS, Strother DR, Burger PC (2002) Histopathologic grading of medulloblastomas: a Pediatric Oncology Group study. Cancer 94:552–560. [DOI] [PubMed] [Google Scholar]
  • 20. Eberhart CG, Kratz JE, Schuster A, Goldthwaite P, Cohen KJ, Perlman EJ, Burger PC (2002) Comparative genomic hybridization detects an increased number of chromosomal alterations in large cell/anaplastic medulloblastomas. Brain Pathol 12:36–44. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21. Ellison D (2002) Classifying the medulloblastoma: insights from morphology and molecular genetics. Neuropathol Appl Neurobiol 28:257–282. [DOI] [PubMed] [Google Scholar]
  • 22. Emadian SM, McDonald JD, Gerken SC, Fults D (1996) Correlation of chromosome 17p loss with clinical outcome in medulloblastoma. Clin Cancer Res 2:1559–1564. [PubMed] [Google Scholar]
  • 23. Freeman CR, Taylor RE, Kortmann RD, Carrie C (2002) Radiotherapy for medulloblastoma in children: a perspective on current international clinical research efforts. Med Pediatr Oncol 39:99–108. [DOI] [PubMed] [Google Scholar]
  • 24. Giangaspero F, Perilongo G, Fondelli MP, Brisigotti M, Carollo C, Burnelli R, Burger PC, Garre ML (1999) Medulloblastoma with extensive nodularity: a variant with favorable prognosis. J Neurosurg 91:971–977. [DOI] [PubMed] [Google Scholar]
  • 25. Giangaspero F, Rigobello L, Badiali M, Loda M, Andreini L, Basso G, Zorzi F, Montaldi A (1992) Large‐cell medulloblastomas. A distinct variant with highly aggressive behavior. Am J Surg Pathol 16:687–693. [PubMed] [Google Scholar]
  • 26. Gilbertson R, Wickramasinghe C, Hernan R, Balaji V, Hunt D, Jones‐Wallace D, Crolla J, Perry R, Lunec J, Pearson A, Ellison D (2001) Clinical and molecular stratification of disease risk in medulloblastoma. Br J Cancer 85:705–712. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27. Gilbertson RJ, Jaros E, Perry RH, Kelly PJ, Lunec J, Pearson AD (1997) Mitotic percentage index: a new prognostic factor for childhood medulloblastoma. Eur J Cancer 33:609–615. [DOI] [PubMed] [Google Scholar]
  • 28. Giordana MT, Cavalla P, Chio A, Marino S, Soffietti R, Vigliani MC, Schiffer D (1995) Prognostic factors in adult medulloblastoma. A clinico‐pathologic study. Tumori 81:338–346. [DOI] [PubMed] [Google Scholar]
  • 29. Goldberg‐Stern H, Gadoth N, Stern S, Cohen IJ, Zaizov R, Sandbank U (1991) The prognostic significance of glial fibrillary acidic protein staining in medulloblastoma. Cancer 68:568–573. [DOI] [PubMed] [Google Scholar]
  • 30. Goodrich LV, Milenkovic L, Higgins KM, Scott MP (1997) Altered neural cell fates and medulloblastoma in mouse patched mutants. Science 277:1109–1113. [DOI] [PubMed] [Google Scholar]
  • 31. Grotzer MA, Hogarty MD, Janss AJ, Liu X, Zhao H, Eggert A, Sutton LN, Rorke LB, Brodeur GM, Phillips PC (2001) MYC messenger RNA expression predicts survival outcome in childhood primitive neuroectodermal tumor/medulloblastoma. Clin Cancer Res 7:2425–2433. [PubMed] [Google Scholar]
  • 32. Grotzer MA, Janss AJ, Phillips PC, Trojanowski JQ (2000) Neurotrophin receptor TrkC predicts good clinical outcome in medulloblastoma and other primitive neuroectodermal brain tumors. Klin Padiatr 212:196–199. [DOI] [PubMed] [Google Scholar]
  • 33. Hahn H, Wojnowski L, Zimmer AM, Hall J, Miller G, Zimmer A (1998) Rhabdomyosarcomas and radiation hypersensitivity in a mouse model of Gorlin syndrome. Nat Med 4:619–622. [DOI] [PubMed] [Google Scholar]
  • 34. Haslam RH, Lamborn KR, Becker LE, Israel MA (1998) Tumor cell apoptosis present at diagnosis may predict treatment outcome for patients with medulloblastoma. J Pediatr Hematol Oncol 20:520–527. [DOI] [PubMed] [Google Scholar]
  • 35. Helton KJ, Gajjar A, Hill DA, Boop FA, Kun LE, Langston JW (2002) Medulloblastoma metastatic to the suprasellar region at diagnosis: a report of six cases with clinicopathologic correlation. Pediatr Neurosurg 37:111–117. [DOI] [PubMed] [Google Scholar]
  • 36. Herms J, Neidt I, Luscher B, Sommer A, Schurmann P, Schroder T, Bergmann M, Wilken B, Probst‐Cousin S, Hernaiz‐Driever P, Behnke J, Hanefeld F, Pietsch T, Kretzschmar HA (2000) C‐MYC expression in medulloblastoma and its prognostic value. Int J Cancer 89:395–402. [PubMed] [Google Scholar]
  • 37. Ito S, Hoshino T, Prados MD, Edwards MS (1992) Cell kinetics of medulloblastomas. Cancer 70:671–678. [DOI] [PubMed] [Google Scholar]
  • 38. Janss AJ, Yachnis AT, Silber JH, Trojanowski JQ, Lee VM, Sutton LN, Perilongo G, Rorke LB, Phillips PC (1996) Glial differentiation predicts poor clinical outcome in primitive neuroectodermal brain tumors. Ann Neurol 39:481–489. [DOI] [PubMed] [Google Scholar]
  • 39. Jay V, Squire J, Bayani J, Alkhani AM, Rutka JT, Zielenska M (1999) Oncogene amplification in medulloblastoma: analysis of a case by comparative genomic hybridization and fluorescence in situ hybridization. Pathology 31:337–344. [DOI] [PubMed] [Google Scholar]
  • 40. Jenkin D, Shabanah MA, Shail EA, Gray A, Hassounah M, Khafaga Y, Kofide A, Mustafa M, Schultz H (2000) Prognostic factors for medulloblastoma. Int J Radiat Oncol Biol Phys 47:573–584. [DOI] [PubMed] [Google Scholar]
  • 41. Kleihuis P, Cavenee W (2000): Tumors of the Nervous System. Lyon , France : IARC press. [Google Scholar]
  • 42. Kopelson G, Linggood RM, Kleinman GM (1983) Medulloblastoma. The identification of prognostic subgroups and implications for multimodality management. Cancer 51:312–319. [DOI] [PubMed] [Google Scholar]
  • 43. Korshunov A, Golanov A, Ozerov S, Sycheva R (1999) Prognostic value of tumor‐associated antigens immunoreactivity and apoptosis in medulloblastomas. An analysis of 73 cases. Brain Tumor Pathol 16:37–44. [DOI] [PubMed] [Google Scholar]
  • 44. Korshunov A, Savostikova M, Ozerov S (2002) Immunohistochemical markers for prognosis of average‐risk pediatric medulloblastomas. The effect of apoptotic index, TrkC, and c‐myc expression. J Neurooncol 58:271–279. [DOI] [PubMed] [Google Scholar]
  • 45. Leonard JR, Cai DX, Rivet DJ, Kaufman BA, Park TS, Levy BK, Perry A (2001) Large cell/anaplastic medulloblastomas and medullomyoblastomas: clinicopathological and genetic features. J Neurosurg 95:82–88. [DOI] [PubMed] [Google Scholar]
  • 46. MacDonald TJ, Brown KM, LaFleur B, Peterson K, Lawlor C, Chen Y, Packer RJ, Cogen P, Stephan DA (2001) Expression profiling of medulloblastoma: PDGFRA and the RAS/MAPK pathway as therapeutic targets for metastatic disease. Nat Genet 29:143–152. [DOI] [PubMed] [Google Scholar]
  • 47. Packer RJ, Sutton LN, Rorke LB, Littman PA, Sposto R, Rosenstock JG, Bruce DA, Schut L (1984) Prognostic importance of cellular differentiation in medulloblastoma of childhood. J Neurosurg 61:296–301. [DOI] [PubMed] [Google Scholar]
  • 48. Pearl GS, Takei Y (1981) Cerebellar “neuroblastoma”: nosology as it relates to medulloblastoma. Cancer 47:772–779. [DOI] [PubMed] [Google Scholar]
  • 49. Perry A (2002) Medulloblastomas with favorable versus unfavorable histology: how many small blue cell tumor types are there in the brain Adv Anat Pathol 9:345–350. [DOI] [PubMed] [Google Scholar]
  • 50. Pietsch T, Waha A, Koch A, Kraus J, Albrecht S, Tonn J, Sorensen N, Berthold F, Henk B, Schmandt N, Wolf HK, von Deimling A, Wainwright B, Chenevix‐Trench G, Wiestler OD, Wicking C (1997) Medulloblastomas of the desmoplastic variant carry mutations of the human homologue of Drosophila patched. Cancer Res 57:2085–2088. [PubMed] [Google Scholar]
  • 51. Pomeroy SL, Tamayo P, Gaasenbeek M, Sturla LM, Angelo M, McLaughlin ME, Kim JY, Goumnerova LC, Black PM, Lau C, Allen JC, Zagzag D, Olson JM, Curran T, Wetmore C, Biegel JA, Poggio T, Mukherjee S, Rifkin R, Califano A, Stolovitzky G, Louis DN, Mesirov JP, Lander ES, Golub TR (2002) Prediction of central nervous system embryonal tumour outcome based on gene expression. Nature 415:436–442. [DOI] [PubMed] [Google Scholar]
  • 52. Reardon DA, Jenkins JJ, Sublett JE, Burger PC, Kun LK (2000) Multiple genomic alterations including N‐myc amplification in a primary large cell medulloblastoma. Pediatr Neurosurg 32:187–191. [DOI] [PubMed] [Google Scholar]
  • 53. Reddy AT (2001) Advances in biology and treatment of childhood brain tumors. Curr Neurol Neurosci Rep 1:137–143. [DOI] [PubMed] [Google Scholar]
  • 54. Roberts RO, Lynch CF, Jones MP, Hart MN (1991) Medulloblastoma: a population‐based study of 532 cases. J Neuropathol Exp Neurol 50:134–144. [DOI] [PubMed] [Google Scholar]
  • 55. Sarkar C, Pramanik P, Karak AK, Mukhopadhyay P, Sharma MC, Singh VP, Mehta VS (2002) Are childhood and adult medulloblastomas different? A comparative study of clinicopathological features, proliferation index and apoptotic index. J Neurooncol 59:49–61. [DOI] [PubMed] [Google Scholar]
  • 56. Scheurlen WG, Schwabe GC, Joos S, Mollenhauer J, Sorensen N, Kuhl J (1998) Molecular analysis of childhood primitive neuroectodermal tumors defines markers associated with poor outcome. J Clin Oncol 16:2478–2485. [DOI] [PubMed] [Google Scholar]
  • 57. Schiffer D, Cavalla P, Migheli A, Chio A, Giordana MT, Marino S, Attanasio A (1995) Apoptosis and cell proliferation in human neuroepithelial tumors. Neurosci Lett 195:81–84. [DOI] [PubMed] [Google Scholar]
  • 58. Segal RA, Goumnerova LC, Kwon YK, Stiles CD, Pomeroy SL (1994) Expression of the neurotrophin receptor TrkC is linked to a favorable outcome in medulloblastoma. Proc Natl Acad Sci U S A 91:12867–12871. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59. Stavrou T, Bromley CM, Nicholson HS, Byrne J, Packer RJ, Goldstein AM, Reaman GH (2001) Prognostic factors and secondary malignancies in childhood medulloblastoma. J Pediatr Hematol Oncol 23:431–436. [DOI] [PubMed] [Google Scholar]
  • 60. Sure U, Berghorn WJ, Bertalanffy H, Wakabayashi T, Yoshida J, Sugita K, Seeger W (1995) Staging, scoring and grading of medulloblastoma. A postoperative prognosis predicting system based on the cases of a single institute. Acta Neurochir 132:59–65. [DOI] [PubMed] [Google Scholar]
  • 61. Weil MD, Lamborn K, Edwards MS, Wara WM (1998) Influence of a child's sex on medulloblastoma outcome. JAMA 279:1474–1476. [DOI] [PubMed] [Google Scholar]
  • 62. Xing Fan YW, Kratz John, Dan Brat J., Robitaille Yves, Albert Moghrabi, Perlman Elizabeth J., Dang Chi V., Burger Peter C., and, Eberhart CG (2003) hTERT Gene Amplification and Increased mRNA Expression in CNS Embryonal Tumors. American Journal of Pathology (In Press). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63. Zeltzer PM, Boyett JM, Finlay JL, Albright AL, Rorke LB, Milstein JM, Allen JC, Stevens KR, Stanley P, Li H, Wisoff JH, Geyer JR, McGuire‐Cullen P, Stehbens JA, Shurin SB, Packer RJ (1999) Metastasis stage, adjuvant treatment, and residual tumor are prognostic factors for medulloblastoma in children: conclusions from the Children's Cancer Group 921 randomized phase III study. J Clin Oncol 17:832–845. [DOI] [PubMed] [Google Scholar]
  • 64. Zerbini C, Gelber RD, Weinberg D, Sallan SE, Barnes P, Kupsky W, Scott RM, Tarbell NJ (1993) Prognostic factors in medulloblastoma, including DNA ploidy. J Clin Oncol 11:616–622. [DOI] [PubMed] [Google Scholar]

Articles from Brain Pathology are provided here courtesy of Wiley

RESOURCES