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Originally published as JCO Early Release 10.1200/JCO.2004.12.939 on February 17 2004 © 2004 American Society of Clinical Oncology.
Biologic Risk Stratification of Medulloblastoma: The Real Time Is Now
Stanford University, Palo Alto, CA Many of us remember medulloblastoma as the prototype malignant childhood brain tumor we learned about in medical school [1]. Typically, a child aged approximately 5 years presents with several weeks to months of nausea, vomiting, headaches, ataxia, and sometimes a turned-in eye or abducens nerve paresis. Subsequent head computed tomography or magnetic resonance imaging reveals a somewhat circumscribed cerebellar tumor and obstructive hydrocephalus. Histologically, the WHO defines this small, round, blue-cell tumor with hyperchromatic nuclei and scant cytoplasm as a grade 4 neoplasm [2]. Because of its tendency to disseminate through the subarachnoid spaces and to form microscopic or bulky metastases in about a third of patients, craniospinal radiotherapy to a dosage of 36 Gy, with an additional radiation boost to the posterior fossa, had been the mainstay of adjuvant therapy following tumor resection. Five-year survival exceeded 50% by the late 1970s, for "better-risk" patients, using this approach [3]. However, much has changed in the classification and treatment of medulloblastoma during the past two decades. As articles by Gajjar et al [4] and Fernandez-Teijeiro et al [5] in the current issue of the Journal of Clinical Oncology make clear, in this era of molecular medicine, we must grapple with a new risk stratification for this disease, incorporating clinical features, histopathological subtype, and expression of specific genes and proteins. Use of chemotherapy was a major advance in the treatment of medulloblastoma. In the 1980s, the debilitating cognitive and endocrinologic sequelae of craniospinal radiotherapy, with the poor survival for children with residual tumor following surgery, led to successive randomized cooperative trials by the International Society of Pediatric Oncology (SIOP) [6], Children's Cancer Group (CCG 942) [7], and Pediatric Oncology Group (POG 7909) [8], which introduced chemotherapy to improve survival and, later, reduce radiation dosage. At first, an increase in overall survival from chemotherapy was not apparent for all children, but only those who had bulky residual tumor or metastatic disease. Subsequently, in the 1990s, for children aged 3 to 10 years, without residual tumor or metastases, the single-arm study CCG 9892 was performed, and used 23.4 Gy craniospinal irradiation rather than the standard 36 Gy, followed by eight courses of lomustine, cisplatin, and vincristine. This study attained a remarkable 5-year event-free survival of 78% [9]. While it accrued just 65 eligible patients, it demonstrated that chemotherapy can be substituted for at least some amount of craniospinal irradiation in children with "favorable" or average-risk medulloblastoma. We await the final results of a much larger North American Children's Oncology Group trial (COG A9961) to replicate this success with reduced dose irradiation. Through all these medulloblastoma trials, the risk classification for relapse and selection of treatment has remained strictly clinical. Since the mid-1990s in the COG, children aged 3 years and older have been stratified into two groups, based on resection extent and Chang metastasis staging [10]. In this classification, average-risk includes children with less than 1.5 cm2 of residual tumor, and no metastasis. High-risk is defined by more than 1.5 cm2 of residual disease, or any metastatic disease. The extent of tumor spread at diagnosis has always been the most robust predictor of outcome. However, the impact of only microscopic tumor cells in lumbar CSF on survival remains debatable. In both CCG 921 and the German trial HIT '91, overall survival was not significantly different in children who were staged as having no metastasis or microscopic metastasis [11,12]. Children younger than 3 years are always considered to be at high-risk because of their well-established higher rates of recurrence [13]. Finally, brainstem invasion (described as Chang stage T3b), previously considered an indicator of high-risk, is now thought not to affect prognosis [11]. Pathologic correlates are gaining acceptance as a way to establish risk in this tumor, homogeneously classified as WHO grade 4. The variant desmoplastic medulloblastoma has long been considered to behave less aggressively [14]. Large-cell anaplastic (LCA) medulloblastoma, which is characterized by pleomorphic, large, round to irregular nuclei with prominent nucleoli, along with numerous mitoses and a high apoptotic rate, was first thought to connote a poor prognosis [15]. More recently, a large retrospective study in 330 POG medulloblastoma patients confirmed shorter survival in the 24% with moderate or severe anaplasia [16]. Interestingly, metastatic stage did not predict outcome for those children in whom these data were available. A similar SIOP study of 273 nondesmoplastic medulloblastomas reported decreased survival in 47 children with the LCA variant [17]. Molecular prognostic markers have also advanced during the last decade. Amplification and overexpression of the proto-oncogene MYCC has been linked to a poor prognosis [18-20]. MYCC amplification is associated with 17p loss and the LCA medulloblastoma subtype [21-23]. Loss of heterozygosity of chromosome 17p, frequently noted in conjunction with isochromosome 17q, is seen in as many as half of all medulloblastomas [24,25]. The 17p deletion may knock out as yet unidentified tumor suppressor genes, including the hypermethylated in cancer-1 (HIC-1) tumor suppressor gene [26,27]. Both 17p loss and high levels of HIC-1 methylation have been associated with shorter survival [26]. In contrast, high expression of TRKC, a neurotrophin receptor gene that promotes apoptosis in medulloblastoma, has predicted a favorable clinical outcome [28-30]. However, as discussed below, Gajjar et al did not find a significant relationship between TRKC levels and outcome, highlighting the need for larger prospective studies [4]. The platelet-derived growth factor receptor and members of the downstream RAS/mitogen-activated protein kinase signal transduction pathway are upregulated in medulloblastoma with metastases [31]. Nevertheless, all of these molecular studies have been hampered by small sample sizes of less than 100 patients. In this issue of the Journal of Clinical Oncology, Gajjar et al show that overexpression of ERBB2, a gene for class I receptor tyrosine kinases, predicts poor survival, and its absence in average-risk disease corresponds to 100% overall survival [4]. These findings suggest that the analysis of protein levels for individual oncogenes could add to or even supplant clinical markers. However, some caution must be exercised in interpreting their findings. First, 58% of patients were high-risk in this study, compared with 30% to 40% in the general population. Selection or referral bias could therefore affect results. Second, with just 49 samples for analysis of MYCC, MYCN, and TRKC, the authors report that these genes do not correlate with outcome, but their study is underpowered to exclude a type II error, or a false-negative result. Third, with just 18 LCA medulloblastomas, they show that ERBB2 and metastasis are surrogate markers of LCA medulloblastoma and portend worse outcome, yet find that histopathologic type was not associated with prognosis. Again, as they discuss, their sample size is insufficient to conclude that LCA medulloblastoma is not an important predictor. Indeed, in prior studies, this group of investigators has found not only high ERBB2 expression but also subtotal resection, metastasis, and isolated 17p loss, all to be adverse prognosticators, indicating a need for larger studies to verify results from small groups [32]. Regardless, the present findings on ERBB2 are compelling. Most importantly, Gajjar et al have shown that rapid molecular profiling of medulloblastoma in a reference laboratory is both feasible and practical, and must be done. Fernandez-Teijeiro et al also present intriguing findings in this issue of the JCO [5]. In a reanalysis of 55 patients with medulloblastoma, they retrospectively demonstrate that gene expression profiles predicted outcome, independent of other criteria [30]. Genes characteristic of cerebellar differentiation (eg, vesicle coat protein ß-NAP) and genes encoding extracellular matrix proteins (eg, PLOD lysyl hydroxylase) were found to cluster with better survival, while genes associated with cellular proliferation and metabolism (eg, MYBL2 and ribosomal protein genes) were markers of treatment failure. A trend was found toward decreased survival of patients with metastases at diagnosis and favorable gene expression profile. Again, with a subset of only 16 patients having metastases, this study lacks power to be certain that metastasis is not an independent predictor. How do all these biologic factors affect our understanding of medulloblastoma? The answer is unclear. We can conclude only that the simple lumping of all medulloblastomas as homogeneous WHO grade 4 neoplasms may be a mistake. All these studies indicate that histologic and molecular classification holds great promise for refining risk assessment in medulloblastoma. Indeed, it has become increasingly clear that molecular and microscopic factors are often associated in these embryonal neoplasms, and that specific molecular changes may drive histopathological tumor progression (for example, from classic to anaplastic medulloblastoma) [33]. For some medulloblastomas, biologic factors associated with metastasis may be present at the onset of tumorigenesis. This controverts the notion that metastasis is simply a function of duration of disease. Whether any of these factors, such as ERBB2, may also be targets for novel therapies, is uncertain. Small numbers of patients in studies thus far limit our certainty about which biologic variables are most predictive (Table 1) [34-40]. Thus, it is imperative that all future COG, SIOP, and other cooperative studies in which hundreds of children will enroll, incorporate real-time biologic risk assessment to define precisely new risk categories, and ultimately to tailor treatment. We must move quickly to achieve this, and it will not be a simple task. In our cooperative group studies of medulloblastoma, we have not yet achieved full agreement on the definition of histologic variants and we have never reached full participation in central review of neuroradiographs or assessment of neuropsychologic outcome. For many institutions to supply tissue samples for real-time histologic and molecular analyses, the logistics will be complex, and the cost high. Nevertheless, we must immediately find a way to accomplish this if we hope to make any further advances towards curing more children of this cancer and reducing its often devastating treatment sequelae. The real time is now.
Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest.
REFERENCES 1. Strother DR, Pollack IF, Fisher PG, et al: Tumors of the central nervous system, in: Pizzo PA, Poplack DG (eds): Principles and Practice of Pediatric Oncology (ed 4). Philadelphia, PA, Lippincott Williams and Wilkins, 2002, pp 751-824 2. Giangaspero F, Bigner SH, Kleihues P, et al: Medulloblastoma, in: Kleihues P, Cavenee WK (eds): World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of the Nervous System. Lyon, France, International Agency for Research on Cancer, 2000, pp 129-137 3. Gurney JG, Smith MA, Bunin GR. CNS and miscellaneous intracranial and intraspinal neoplasms, in: Ries LAG, Smith MA, Gurney JG, et al (eds): Cancer Incidence and Survival among Children and Adolescents: United States SEER Program 1975-1995. NIH Pub. No. 99-4649. Bethesda, MD, National Cancer Institute, 1999, pp 51-63
4. Gajjar A, Hernan R, Kocak M, et al: Clinical, histopathological and molecular markers of prognosis: Toward a new disease risk stratification for medulloblastoma. J Clin Oncol 22: 984-993, 2004
5. Fernandez-Teijeiro A, Betensky RA, Sturla LM, et al: Combining gene expression profiles and clinical parameters for risk stratification in medulloblastomas. J Clin Oncol 22: 994-998, 2004 6. Tait DM, Thronton-Jones H, Bollom HJG, et al: Adjuvant chemotherapy for medulloblastoma: The first multi-centre control trial of the International Society of Paediatric Oncology (SIOP I). Eur J Cancer 26:464-469, 1990 7. Evans AE, Jenkin RDT, Sposto R, et al: The treatment of medulloblastoma: Results of a prospective randomized trial of radiation therapy with and without CCNU, vincristine, and prednisone. J Neurosurg 72:572-582, 1990[Medline] 8. Krischer JP, Ragab AH, Kun L, et al: Nitrogen mustard, vincristine, procarbazine, and prednisone as adjuvant chemotherapy in the treatment of medulloblastoma. J Neurosurg 74:905-909, 1991[Medline]
9. Packer RJ, Goldwein J, Nicholson HS, et al: Treatment of children with medulloblastoma with reduced-dose craniospinal radiation therapy and adjuvant chemotherapy: A Children's Cancer Group study. J Clin Oncol 17:2127-2136, 1999 10. Chang CH, Housepian EM, Herbert C: An operative staging system and a megavoltage radiotherapeutic technic for cerebellar medulloblastoma. Radiology 93:1351-1359, 1969[Medline]
11. Zeltzer PM, Boyett JM, Finlay JL, et al: Metastasis stage, adjuvant treatment, and residual tumor are prognostic factors for medulloblastoma in children: Conclusions from the Children's Cancer Group 921 randomized phase II study. J Clin Oncol 17:832-845, 1999 12. Kortmann RD, Kuhl J, Timmerman B, et al: Postoperative neoadjuvant chemotherapy before radiotherapy as compared to immediate radiotherapy followed by maintenance chemotherapy in the treatment of medulloblastoma in childhood: Results of the German prospective randomized trial HIT '91. Int J Radiat Oncol Biol Phys 46:269-279, 2000[CrossRef][Medline] 13. McNeil DE, Cote TR, Clegg L, et al: Incidence and trends in pediatric malignancies medulloblastoma/primitive neuroectodermal tumor: A SEER update. Med Pediatr Oncol 39:190-194, 2002[CrossRef][Medline] 14. Chatty EM, Earle KM: Medulloblastoma: A report of 201 cases with emphasis on the relationship of histologic variants to survival. Cancer 28:977-983, 1971[CrossRef][Medline] 15. Giangspero F, Rigobello L, Bodily M, et al: Large-cell medullobastomas: A distinct variant with highly aggressive behavior. Am J Surg Pathol 16:687-693, 1992[Medline] 16. Eberhart CG, Kepner JL, Goldthwaite PT, et al: Histopathologic grading of medulloblastomas: A Pediatric Oncology Group study. Cancer 94:552-560, 2002[CrossRef][Medline] 17. McManamy CS, Lamont JM, Taylor RE, et al: Morphophenotypic variation predicts clinical behavior in childhood non-desmoplastic medulloblastomas. J Neuropathol Exp Neurol 62:627-632, 2003[Medline] 18. Herms J, Neidt I, Luscher B, et al: C-MYC expression in medulloblastoma and its prognostic value. Int J Cancer 89:395-402, 2000[CrossRef][Medline]
19. Grotzer MA, Hogarty MD, Janss AJ, et al: MYC messenger RNA expression predicts survival outcome in childhood primitive neuroectodermal tumor/medulloblastoma. Clin Cancer Res 7:2425-2433, 2001 20. Scheurlein WG, Schwabe GC, Joos S, et al: Molecular analysis of childhood primitive neuroectodermal tumors defines markers associated with poor outcome. J Clin Oncol 16:2478-2485, 1998[Abstract] 21. Brown HG, Kepner JL, Perlman EJ, et al: "Large cell/anaplastic" medulloblastomas: A Pediatric Oncology Group study. J Neuropathol Exp Neurol 59:857-865, 2000[Medline] 22. Leonard JR, Cai DX, Rivet DJ, et al: Large cell/anaplastic medulloblastomas and medullomyoblastomas: Clinicopathological and genetic features. J Neurosurg 95:82-88, 2001[Medline] 23. Eberhart CG, Kratz JE, Schuster A, et al: Comparative genomic hybridization detects an increased number of chromosomal alterations in large cell/anaplastic medulloblastomas. Brain Pathol 12:36-44, 2002[Medline] 24. Bigner SH, Mark J, Friedman HS, et al: Structural chromosomal abnormalities in human medulloblastoma. Cancer Genet Cytogenet 30:91-101, 1988[CrossRef][Medline] 25. Biegel JA, Janss AJ, Raffel C, et al: Prognostic significance of chromosome 17p deletions in childhood primitive neuroectodermal tumors (medulloblastomas) of the central nervous system. Clin Cancer Res 3:473-478, 1997[Abstract]
26. Rood BR, Zhang H, Weitman DM, et al: Hypermethylation of HIC-1 and 17p allelic loss in medulloblastoma. Cancer Res 62:3794-3797, 2002 27. Waha A, Waha A, Koch A, et al: Epigenetic silencing of the HIC-1 gene in human medulloblastoma. J Neuropathol Exp Neurol 62:1192-1201, 2003[Medline]
28. Grotzer MA, Janss AJ, Fung KN, et al: TrkC expression predicts good clinical outcome in primitive neuroectodermal brain tumors. J Clin Oncol 18:1027-1035, 2000
29. Kim JYH, Sutton ME, Lu DJ, et al: Activation of neurotrophin-3 receptor TrkC induces apoptosis in medulloblastomas. Cancer Res 59:711-719, 1999 30. Pomeroy SL, Tamayo P, Gaasenbeek M, et al: Prediction of central nervous system embryonal tumour outcome based on gene expression. Nature 415:436-442, 2002[CrossRef][Medline] 31. MacDonald TJ, Brown KM, LaFleur B, et al: Expression profiling of medulloblastoma: PDGFRA and the RAS/MAPK pathway as therapeutic targets for metastatic disease. Nat Genet 29:143-152, 2001[CrossRef][Medline] 32. Gilbertson R, Wickramasinghe C, Hernan R, et al: Clinical and molecular stratification of disease risk in medulloblastoma. Br J Cancer 85:705-712, 2001[CrossRef][Medline] 33. Eberhart CG, Burger PC: Anaplasia and grading in medulloblastoma. Brain Pathol 13:376-385, 2003[Medline]
34. Weil MD, Lamborn K, Edwards MSB, et al: Influence of a child's sex on medulloblastoma. JAMA 279:1474-1476, 1998 35. Roberts RO, Lynch CF, Jones MP, et al: Medulloblastoma: A population-based study of 532 cases. J Neuropathol Exp Neurol 50:134-144, 1991[Medline]
36. Gajjar AJ, Heidemann RL, Douglass EC, et al: Relation of tumor-cell ploidy to survival in children with medulloblastoma. J Clin Oncol 11:2211-2217, 1993 37. Zerbini C, Gelber RD, Weinberg D, et al: Prognostic factors in medulloblastoma, including DNA ploidy. J Clin Oncol 11:616-622, 1993[Abstract] 38. Haslam RHA, Lamborn KR, Becker LE, et al: Tumor cell apoptosis present at diagnosis may predict treatment outcome for patients with medulloblastoma. J Pediatr Hematol Oncol 20:520-527, 1998[CrossRef][Medline] 39. Grotzer MA, Geoerger B, Janss AJ, et al: Prognostic significance of Ki-67 (MIB-1) proliferation index in childhood primitive neuroectodermal tumors of the central nervous system. Med Pediatr Oncol 36:268-273, 2001[CrossRef][Medline] 40. Pelc K, Vincent S, Ruchoux MM, et al: Calbindin-D28k: A marker of recurrence for medulloblastomas. Cancer 95:410-419, 2002[CrossRef][Medline]
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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