Skip to main content
SpringerLink
Log in

Prognostic Factors and Risk Stratification

  • Chapter
  • First Online:
Neuroblastoma

  • 989 Accesses

Abstract

Neuroblastoma (NB), the third most common paediatric cancer, accounts for 7% of paediatric malignancies and 10–15% of cancer-related deaths in children. Prognosis and tailored treatments are determined by several clinical and biological risk factors. These factors have been used to create risk classifiers that predict the probability of recurrence. The estimated 5-year survival rates for patients with non-high risk and high-risk neuroblastoma are 90% and 50%, respectively. Recent clinical trials have continued to reduce therapy for patients with non-high risk neuroblastoma, including the most favourable subsets of patients, who are now often followed with observation approaches. In contrast, high-risk neuroblastoma patients are treated aggressively with chemotherapy, radiation, surgery, myeloablative and immunotherapies. Current prognostic factors used by most clinical trials cooperative groups and the International Risk Group (INRG) classification system include age, stage, histopathology, ploidy, status of MYCN and segmental chromosome aberrations (SCAs). In addition to these well-validated risk factors, research advances facilitated by large international collaborations and next generation sequencing (NGS) technologies have identified additional emerging prognostic factors at diagnosis and during treatment. These include specific genetic alterations of the ALK oncogene, aberrations of the telomerase pathway (including TERT fusions and ATRX mutations) and metastatic response. Standard prognostic factors together with these newer biomarkers will enable us to further refine risk categories as well as optimize treatment and enable precision medicine strategies.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 79.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 99.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 129.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Irwin MS, Park JR. Neuroblastoma: pediatric paradigm for precision medicine. Pediatr Clin North Am. 2015;62:225–56.

    Article  PubMed  Google Scholar 

  2. Pinto NR, et al. Advances in risk classification and treatment strategies for neuroblastoma. J Clin Oncol. 2015;33:3008–17. https://doi.org/10.1200/JCO.2014.59.4648.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Brodeur GM, et al. Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol. 1993;11:1466–77.

    Article  CAS  PubMed  Google Scholar 

  4. Cohn SL, et al. The International Neuroblastoma Risk Group (INRG) classification system: an INRG Task Force report. J Clin Oncol. 2009;27:289–97.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Cecchetto G, et al. Surgical risk factors in primary surgery for localized neuroblastoma: the LNESG1 study of the European International Society of Pediatric Oncology Neuroblastoma Group. J Clin Oncol. 2005;23:8483–9.

    Article  PubMed  Google Scholar 

  6. Monclair T, et al. The International Neuroblastoma Risk Group (INRG) staging system: an INRG Task Force report. J Clin Oncol. 2009;27:298–303.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Simon T, Hero B, Benz-Bohm G, von Schweinitz D, Berthold F. Review of image defined risk factors in localized neuroblastoma patients: results of the GPOH NB97 trial. Pediatr Blood Cancer. 2008;50:965–9. https://doi.org/10.1002/pbc.21343.

    Article  PubMed  Google Scholar 

  8. Simon T, Spitz R, Faldum A, Hero B, Berthold F. New definition of low-risk neuroblastoma using stage, age, and 1p and MYCN status. J Pediatr Hematol Oncol. 2004;26:791–6.

    PubMed  Google Scholar 

  9. Schmidt ML, et al. Biologic factors determine prognosis in infants with stage IV neuroblastoma: a prospective Children’s Cancer Group study. J Clin Oncol. 2000;18:1260–8.

    Article  CAS  PubMed  Google Scholar 

  10. George RE, et al. Hyperdiploidy plus nonamplified MYCN confers a favorable prognosis in children 12 to 18 months old with disseminated neuroblastoma: a Pediatric Oncology Group study. J Clin Oncol. 2005;23:6466–73.

    Article  CAS  PubMed  Google Scholar 

  11. London WB, et al. Evidence for an age cutoff greater than 365 days for neuroblastoma risk group stratification in the Children’s Oncology Group. J Clin Oncol. 2005;23:6459–65.

    Article  CAS  PubMed  Google Scholar 

  12. Mosse YP, et al. Neuroblastoma in older children, adolescents and young adults: a report from the International Neuroblastoma Risk Group project. Pediatr Blood Cancer. 2014;61:627–35. https://doi.org/10.1002/pbc.24777.

    Article  PubMed  Google Scholar 

  13. Schmidt ML, et al. Favorable prognosis for patients 12 to 18 months of age with stage 4 nonamplified MYCN neuroblastoma: a Children’s Cancer Group study. J Clin Oncol. 2005;23:6474–80.

    Article  CAS  PubMed  Google Scholar 

  14. Schleiermacher G, et al. Segmental chromosomal alterations lead to a higher risk of relapse in infants with MYCN-non-amplified localised unresectable/disseminated neuroblastoma (a SIOPEN collaborative study). Br J Cancer. 2011;105:1940–8. https://doi.org/10.1038/bjc.2011.472.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Brodeur GM, Seeger RC, Schwab M, Varmus HE, Bishop JM. Amplification of N-myc in untreated human neuroblastomas correlates with advanced disease stage. Science. 1984;224:1121–4.

    Article  CAS  PubMed  Google Scholar 

  16. Seeger RC, et al. Association of multiple copies of the N-myc oncogene with rapid progression of neuroblastomas. N Engl J Med. 1985;313:1111–6.

    Article  CAS  PubMed  Google Scholar 

  17. Moreau LA, et al. Does MYCN amplification manifested as homogeneously staining regions at diagnosis predict a worse outcome in children with neuroblastoma? A Children’s Oncology Group study. Clin Cancer Res. 2006;12:5693–7.

    Article  CAS  PubMed  Google Scholar 

  18. Ambros PF, et al. International consensus for neuroblastoma molecular diagnostics: report from the international Neuroblastoma Risk Group (INRG) Biology Committee. Br J Cancer. 2009;100:1471–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Campbell K, et al. Association of MYCN copy number with clinical features, tumor biology, and outcomes in neuroblastoma: a report from the Children’s Oncology Group. Cancer. 2017;123:4224–35. https://doi.org/10.1002/cncr.30873.

    Article  CAS  PubMed  Google Scholar 

  20. Berbegall AP, et al. Comparative genetic study of intratumoral heterogenous MYCN amplified neuroblastoma versus aggressive genetic profile neuroblastic tumors. Oncogene. 2016;35:1423–32. https://doi.org/10.1038/onc.2015.200.

    Article  CAS  PubMed  Google Scholar 

  21. Marrano P, Irwin MS, Thorner PS. Heterogeneity of MYCN amplification in neuroblastoma at diagnosis, treatment, relapse, and metastasis. Genes Chromosomes Cancer. 2017;56:28–41. https://doi.org/10.1002/gcc.22398.

    Article  CAS  PubMed  Google Scholar 

  22. Huang M, Weiss WA. Neuroblastoma and MYCN. Cold Spring Harb Perspect Med. 2013;3:a014415. https://doi.org/10.1101/cshperspect.a014415.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ruiz-Perez MV, Henley AB, Arsenian-Henriksson M. The MYCN protein in health and disease. Genes (Basel). 2017;8 https://doi.org/10.3390/genes8040113.

    Article  PubMed Central  Google Scholar 

  24. Weiss WA, Aldape K, Mohapatra G, Feuerstein BG, Bishop JM. Targeted expression of MYCN causes neuroblastoma in transgenic mice. EMBO J. 1997;16:2985–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zhu S, et al. Activated ALK collaborates with MYCN in neuroblastoma pathogenesis. Cancer Cell. 2012;21:362–73. https://doi.org/10.1016/j.ccr.2012.02.010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Berry T, et al. The ALK(F1174L) mutation potentiates the oncogenic activity of MYCN in neuroblastoma. Cancer Cell. 2012;22:117–30. https://doi.org/10.1016/j.ccr.2012.06.001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Valentijn LJ, et al. Functional MYCN signature predicts outcome of neuroblastoma irrespective of MYCN amplification. Proc Natl Acad Sci U S A. 2012;109:19190–5. https://doi.org/10.1073/pnas.1208215109.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Puissant A, et al. Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013;3:308–23. https://doi.org/10.1158/2159-8290.CD-12-0418.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Gustafson WC, et al. Drugging MYCN through an allosteric transition in Aurora Kinase A. Cancer Cell. 2014;26:414–27. https://doi.org/10.1016/j.ccr.2014.07.015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Brockmann M, et al. Small molecule inhibitors of Aurora-A induce proteasomal degradation of N-Myc in childhood neuroblastoma. Cancer Cell. 2013;24:75–89. https://doi.org/10.1016/j.ccr.2013.05.005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. DuBois SG, et al. Phase I study of the Aurora A kinase inhibitor alisertib in combination with irinotecan and temozolomide for patients with relapsed or refractory neuroblastoma: a NANT (new approaches to neuroblastoma therapy) trial. J Clin Oncol. 2016;34:1368–75. https://doi.org/10.1200/JCO.2015.65.4889.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wang LL, et al. Neuroblastoma of undifferentiated subtype, prognostic significance of prominent nucleolar formation, and MYC/MYCN protein expression: a report from the Children’s Oncology Group. Cancer. 2013;119:3718–26. https://doi.org/10.1002/cncr.28251.

    Article  PubMed  Google Scholar 

  33. Wang LL, et al. Augmented expression of MYC and/or MYCN protein defines highly aggressive MYC-driven neuroblastoma: a Children’s Oncology Group study. Br J Cancer. 2015;113:57–63. https://doi.org/10.1038/bjc.2015.188.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Bagatell R, et al. Significance of MYCN amplification in international neuroblastoma staging system stage 1 and 2 neuroblastoma: a report from the International Neuroblastoma Risk Group database. J Clin Oncol. 2009;27:365–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Vo KT, et al. Clinical, biological and prognostic differences based on primary tumor site in neuroblastoma: a report from the International Neuroblastoma Risk Group (INRG) project. J Clin Oncol. 2014;32(28):3169–76.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Thompson D, et al. Identification of patient subgroups with markedly disparate rates of MYCN amplification in neuroblastoma: a report from the International Neuroblastoma Risk Group project. Cancer. 2016;122:935–45. https://doi.org/10.1002/cncr.29848.

    Article  PubMed  Google Scholar 

  37. Teshiba R, et al. Age-dependent prognostic effect by Mitosis-Karyorrhexis Index in neuroblastoma: a report from the Children’s Oncology Group. Pediatr Dev Pathol. 2014;17:441–9. https://doi.org/10.2350/14-06-1505-OA.1.

    Article  PubMed  PubMed Central  Google Scholar 

  38. George RE, et al. Relationship between histopathological features, MYCN amplification, and prognosis: a UKCCSG study. United Kingdom Children Cancer Study Group. Med Pediatr Oncol. 2001;36:169–76. https://doi.org/10.1002/1096-911X(20010101)36:1<169::AID-MPO1041>3.0.CO;2-U.

    Article  CAS  PubMed  Google Scholar 

  39. Shimada H, et al. The international neuroblastoma pathology classification (the Shimada system). Cancer. 1999;86:364–72.

    Article  CAS  PubMed  Google Scholar 

  40. Shimada H, et al. Identification of subsets of neuroblastomas by combined histopathologic and N-myc analysis. J Natl Cancer Inst. 1995;87:1470–6.

    Article  CAS  PubMed  Google Scholar 

  41. Bowman LC, et al. Genetic staging of unresectable or metastatic neuroblastoma in infants: a Pediatric Oncology Group study. J Natl Cancer Inst. 1997;89:373–80.

    Article  CAS  PubMed  Google Scholar 

  42. Look AT, et al. Clinical relevance of tumor cell ploidy and N-myc gene amplification in childhood neuroblastoma: a Pediatric Oncology Group study. J Clin Oncol. 1991;9:581–91.

    Article  CAS  PubMed  Google Scholar 

  43. Oppedal BR, Storm-Mathisen I, Lie SO, Brandtzaeg P. Prognostic factors in neuroblastoma. Clinical, histopathologic, and immunohistochemical features and DNA ploidy in relation to prognosis. Cancer. 1988;62:772–80.

    Article  CAS  PubMed  Google Scholar 

  44. Janoueix-Lerosey I, et al. Overall genomic pattern is a predictor of outcome in neuroblastoma. J Clin Oncol. 2009;27:1026–33.

    Article  PubMed  Google Scholar 

  45. Attiyeh EF, et al. Chromosome 1p and 11q deletions and outcome in neuroblastoma. N Engl J Med. 2005;353:2243–53.

    Article  CAS  PubMed  Google Scholar 

  46. Brodeur GM, et al. Molecular analysis and clinical significance of N-myc amplification and chromosome 1p monosomy in human neuroblastomas. Prog Clin Biol Res. 1988;271:3–15.

    CAS  PubMed  Google Scholar 

  47. Maris JM, et al. Loss of heterozygosity at 1p36 independently predicts for disease progression but not decreased overall survival probability in neuroblastoma patients: a Children’s Cancer Group study. J Clin Oncol. 2000;18:1888–99.

    Article  CAS  PubMed  Google Scholar 

  48. Mosse YP, et al. Neuroblastomas have distinct genomic DNA profiles that predict clinical phenotype and regional gene expression. Genes Chromosomes Cancer. 2007;46:936–49. https://doi.org/10.1002/gcc.20477.

    Article  CAS  PubMed  Google Scholar 

  49. Guo C, et al. Allelic deletion at 11q23 is common in MYCN single copy neuroblastomas. Oncogene. 1999;18:4948–57.

    Article  CAS  PubMed  Google Scholar 

  50. Tonini GP, et al. MYCN oncogene amplification in neuroblastoma is associated with worse prognosis, except in stage 4s: the Italian experience with 295 children. J Clin Oncol. 1997;15:85–93.

    Article  CAS  PubMed  Google Scholar 

  51. De Bernardi B, et al. Excellent outcome with reduced treatment for infants with disseminated neuroblastoma without MYCN gene amplification. J Clin Oncol. 2009;27:1034–40. https://doi.org/10.1200/JCO.2008.17.5877.

    Article  PubMed  Google Scholar 

  52. Minard V, et al. Adverse outcome of infants with metastatic neuroblastoma, MYCN amplification and/or bone lesions: results of the French society of pediatric oncology. Br J Cancer. 2000;83:973–9. https://doi.org/10.1054/bjoc.2000.1412.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Katzenstein HM, et al. Prognostic significance of age, MYCN oncogene amplification, tumor cell ploidy, and histology in 110 infants with stage D(S) neuroblastoma: the pediatric oncology group experience—a pediatric oncology group study. J Clin Oncol. 1998;16:2007–17.

    Article  CAS  PubMed  Google Scholar 

  54. Baker DL, et al. Outcome after reduced chemotherapy for intermediate-risk neuroblastoma. N Engl J Med. 2010;363:1313–23. https://doi.org/10.1056/NEJMoa1001527.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Rubie H, et al. N-Myc gene amplification is a major prognostic factor in localized neuroblastoma: results of the French NBL 90 study. Neuroblastoma Study Group of the Societe Francaise d’Oncologie Pediatrique. J Clin Oncol. 1997;15:1171–82. https://doi.org/10.1200/JCO.1997.15.3.1171.

    Article  CAS  PubMed  Google Scholar 

  56. Shimada H, et al. Histopathologic prognostic factors in neuroblastic tumors: definition of subtypes of ganglioneuroblastoma and an age-linked classification of neuroblastomas. J Natl Cancer Inst. 1984;73:405–16.

    Article  CAS  PubMed  Google Scholar 

  57. Strother DR, et al. Outcome after surgery alone or with restricted use of chemotherapy for patients with low-risk neuroblastoma: results of Children’s Oncology Group study P9641. J Clin Oncol. 2012;30:1842–8. https://doi.org/10.1200/JCO.2011.37.9990.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Meany HJ, et al. Significance of clinical and biologic features in Stage 3 neuroblastoma: a report from the International Neuroblastoma Risk Group project. Pediatr Blood Cancer. 2014; https://doi.org/10.1002/pbc.25134.

    Article  CAS  Google Scholar 

  59. Look AT, Hayes FA, Nitschke R, McWilliams NB, Green AA. Cellular DNA content as a predictor of response to chemotherapy in infants with unresectable neuroblastoma. N Engl J Med. 1984;311:231–5. https://doi.org/10.1056/NEJM198407263110405.

    Article  CAS  PubMed  Google Scholar 

  60. Park JR, et al. Children’s Oncology Group’s 2013 blueprint for research: neuroblastoma. Pediatr Blood Cancer. 2013;60:985–93. https://doi.org/10.1002/pbc.24433.

    Article  PubMed  Google Scholar 

  61. Bown N, et al. Gain of chromosome arm 17q and adverse outcome in patients with neuroblastoma. N Engl J Med. 1999;340:1954–61.

    Article  CAS  PubMed  Google Scholar 

  62. Meddeb M, et al. Additional copies of a 25 Mb chromosomal region originating from 17q23.1-17qter are present in 90% of high-grade neuroblastomas. Genes Chromosomes Cancer. 1996;17:156–65. https://doi.org/10.1002/(SICI)1098-2264(199611)17:3<156::AID-GCC3>3.0.CO;2-3.

    Article  CAS  PubMed  Google Scholar 

  63. Caron H, et al. Allelic loss of chromosome 1p as a predictor of unfavorable outcome in patients with neuroblastoma. N Engl J Med. 1996;334:225–30.

    Article  CAS  PubMed  Google Scholar 

  64. Riley RD, et al. A systematic review of molecular and biological tumor markers in neuroblastoma. Clin Cancer Res. 2004;10:4–12.

    Article  CAS  PubMed  Google Scholar 

  65. Spitz R, Hero B, Simon T, Berthold F. Loss in chromosome 11q identifies tumors with increased risk for metastatic relapses in localized and 4S neuroblastoma. Clin Cancer Res. 2006;12:3368–73. https://doi.org/10.1158/1078-0432.CCR-05-2495.

    Article  CAS  PubMed  Google Scholar 

  66. Schleiermacher G, et al. Segmental chromosomal alterations have prognostic impact in neuroblastoma: a report from the INRG project. Br J Cancer. 2012;107:1418–22. https://doi.org/10.1038/bjc.2012.375.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Defferrari R, et al. Influence of segmental chromosome abnormalities on survival in children over the age of 12 months with unresectable localised peripheral neuroblastic tumours without MYCN amplification. Br J Cancer. 2015;112:290–5. https://doi.org/10.1038/bjc.2014.557.

    Article  CAS  PubMed  Google Scholar 

  68. Chicard M, et al. Genomic copy number profiling using circulating free tumor DNA highlights heterogeneity in neuroblastoma. Clin Cancer Res. 2016;22:5564–73. https://doi.org/10.1158/1078-0432.CCR-16-0500.

    Article  CAS  PubMed  Google Scholar 

  69. Van Roy N, et al. Shallow whole genome sequencing on circulating cell-free DNA allows reliable noninvasive copy-number profiling in neuroblastoma patients. Clin Cancer Res. 2017;23:6305–14. https://doi.org/10.1158/1078-0432.CCR-17-0675.

    Article  CAS  PubMed  Google Scholar 

  70. Campbell BB, et al. Comprehensive analysis of hypermutation in human cancer. Cell. 2017;171:1042–1056 e1010. https://doi.org/10.1016/j.cell.2017.09.048.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Pugh TJ, et al. The genetic landscape of high-risk neuroblastoma. Nat Genet. 2013; https://doi.org/10.1038/ng.2529.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Molenaar JJ, et al. Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes. Nature. 2012;483:589–93. https://doi.org/10.1038/nature10910.

    Article  CAS  PubMed  Google Scholar 

  73. Sausen M, et al. Integrated genomic analyses identify ARID1A and ARID1B alterations in the childhood cancer neuroblastoma. Nat Genet. 2013;45:12–7. https://doi.org/10.1038/ng.2493.

    Article  CAS  PubMed  Google Scholar 

  74. Bresler SC, et al. ALK mutations confer differential oncogenic activation and sensitivity to ALK inhibition therapy in neuroblastoma. Cancer Cell. 2014;26:682–94. https://doi.org/10.1016/j.ccell.2014.09.019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Suzuki M, et al. Treatment and outcome of adult-onset neuroblastoma. Int J Cancer. 2018; https://doi.org/10.1002/ijc.31399.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Cheung NK, et al. Association of age at diagnosis and genetic mutations in patients with neuroblastoma. JAMA. 2012;307:1062–71. https://doi.org/10.1001/jama.2012.228.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Bellini A, et al. Deep sequencing reveals occurrence of subclonal ALK mutations in neuroblastoma at diagnosis. Clin Cancer Res. 2015;21:4913–21. https://doi.org/10.1158/1078-0432.CCR-15-0423.

    Article  CAS  PubMed  Google Scholar 

  78. Schleiermacher G, et al. Emergence of new ALK mutations at relapse of neuroblastoma. J Clin Oncol. 2014; https://doi.org/10.1200/JCO.2013.54.0674.

    Article  CAS  PubMed  Google Scholar 

  79. Eleveld TF, et al. Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations. Nat Genet. 2015;47:864–71. https://doi.org/10.1038/ng.3333.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Padovan-Merhar OM, et al. Enrichment of targetable mutations in the relapsed neuroblastoma genome. PLoS Genet. 2016;12:e1006501. https://doi.org/10.1371/journal.pgen.1006501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Schulte JH, et al. High ALK receptor tyrosine kinase expression supersedes ALK mutation as a determining factor of an unfavorable phenotype in primary neuroblastoma. Clin Cancer Res. 2011;17:5082–92. https://doi.org/10.1158/1078-0432.CCR-10-2809.

    Article  CAS  PubMed  Google Scholar 

  82. De Brouwer S, et al. Meta-analysis of neuroblastomas reveals a skewed ALK mutation spectrum in tumors with MYCN amplification. Clin Cancer Res. 2010;16:4353–62. https://doi.org/10.1158/1078-0432.CCR-09-2660.

    Article  CAS  PubMed  Google Scholar 

  83. Duijkers FA, et al. High anaplastic lymphoma kinase immunohistochemical staining in neuroblastoma and ganglioneuroblastoma is an independent predictor of poor outcome. Am J Pathol. 2012;180:1223–31. https://doi.org/10.1016/j.ajpath.2011.12.003.

    Article  PubMed  Google Scholar 

  84. Bresler SC, et al. Differential inhibitor sensitivity of anaplastic lymphoma kinase variants found in neuroblastoma. Sci Transl Med. 2011;3:108ra114. https://doi.org/10.1126/scitranslmed.3002950.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Infarinato NR, et al. The ALK/ROS1 inhibitor PF-06463922 overcomes primary resistance to crizotinib in ALK-driven neuroblastoma. Cancer Discov. 2016;6:96–107. https://doi.org/10.1158/2159-8290.CD-15-1056.

    Article  CAS  PubMed  Google Scholar 

  86. Peifer M, et al. Telomerase activation by genomic rearrangements in high-risk neuroblastoma. Nature. 2015;526:700–4. https://doi.org/10.1038/nature14980.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Valentijn LJ, et al. TERT rearrangements are frequent in neuroblastoma and identify aggressive tumors. Nat Genet. 2015;47:1411–4. https://doi.org/10.1038/ng.3438.

    Article  CAS  PubMed  Google Scholar 

  88. Hertwig F, Peifer M, Fischer M. Telomere maintenance is pivotal for high-risk neuroblastoma. Cell Cycle. 2016;15:311–2. https://doi.org/10.1080/15384101.2015.1125243.

    Article  CAS  PubMed  Google Scholar 

  89. Henson JD, et al. The C-Circle Assay for alternative-lengthening-of-telomeres activity. Methods. 2017;114:74–84. https://doi.org/10.1016/j.ymeth.2016.08.016.

    Article  CAS  PubMed  Google Scholar 

  90. Mender I, Gryaznov S, Dikmen ZG, Wright WE, Shay JW. Induction of telomere dysfunction mediated by the telomerase substrate precursor 6-thio-2′-deoxyguanosine. Cancer Discov. 2015;5:82–95. https://doi.org/10.1158/2159-8290.CD-14-0609.

    Article  CAS  PubMed  Google Scholar 

  91. Flynn RL, et al. Alternative lengthening of telomeres renders cancer cells hypersensitive to ATR inhibitors. Science. 2015;347:273–7. https://doi.org/10.1126/science.1257216.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Vermeulen J, De Preter K, Laureys G, Speleman F, Vandesompele J. 59-Gene prognostic signature sub-stratifies high-risk neuroblastoma patients. Lancet Oncol. 2009;10:1030. https://doi.org/10.1016/S1470-2045(09)70325-0, S1470-2045(09)70325-0 [pii].

    Article  PubMed  Google Scholar 

  93. De Preter K, et al. Accurate outcome prediction in neuroblastoma across independent data sets using a multigene signature. Clin Cancer Res. 2010;16:1532–41.

    Article  PubMed  Google Scholar 

  94. Oberthuer A, et al. Customized oligonucleotide microarray gene expression-based classification of neuroblastoma patients outperforms current clinical risk stratification. J Clin Oncol. 2006;24:5070–8.

    Article  CAS  PubMed  Google Scholar 

  95. Oberthuer A, et al. Prognostic impact of gene expression-based classification for neuroblastoma. J Clin Oncol. 2010;28:3506–15. https://doi.org/10.1200/JCO.2009.27.3367, JCO.2009.27.3367 [pii].

    Article  PubMed  Google Scholar 

  96. Garcia I, et al. A three-gene expression signature model for risk stratification of patients with neuroblastoma. Clin Cancer Res. 2012–2023;18:2012. https://doi.org/10.1158/1078-0432.CCR-11-2483.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Asgharzadeh S, et al. Prognostic significance of gene expression profiles of metastatic neuroblastomas lacking MYCN gene amplification. J Natl Cancer Inst. 2006;98:1193–203. https://doi.org/10.1093/jnci/djj330., 98/17/1193 [pii].

    Article  CAS  PubMed  Google Scholar 

  98. Asgharzadeh S, et al. Clinical significance of tumor-associated inflammatory cells in metastatic neuroblastoma. J Clin Oncol. 2012;30:3525–32. https://doi.org/10.1200/JCO.2011.40.9169.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Hallett RM, Seong AB, Kaplan DR, Irwin MS. Transcript signatures that predict outcome and identify targetable pathways in MYCN-amplified neuroblastoma. Mol Oncol. 2016;10:1461–72. https://doi.org/10.1016/j.molonc.2016.07.012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Oberthuer A, et al. Revised risk estimation and treatment stratification of low- and intermediate-risk neuroblastoma patients by integrating clinical and molecular prognostic markers. Clin Cancer Res. 2015;21:1904–15. https://doi.org/10.1158/1078-0432.CCR-14-0817.

    Article  PubMed  Google Scholar 

  101. Buckley PG, et al. Chromosomal and microRNA expression patterns reveal biologically distinct subgroups of 11q-neuroblastoma. Clin Cancer Res. 2010;16:2971–8. https://doi.org/10.1158/1078-0432.CCR-09-3215, 1078-0432.CCR-09-3215 [pii].

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Chen Y, Stallings RL. Differential patterns of microRNA expression in neuroblastoma are correlated with prognosis, differentiation, and apoptosis. Cancer Res. 2007;67:976–83. https://doi.org/10.1158/0008-5472.CAN-06-3667.

    Article  CAS  PubMed  Google Scholar 

  103. De Preter K, et al. miRNA expression profiling enables risk stratification in archived and fresh neuroblastoma tumor samples. Clin Cancer Res. 2011;17:7684–92. https://doi.org/10.1158/1078-0432.CCR-11-0610.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Yanik GA, et al. Semiquantitative mIBG scoring as a prognostic indicator in patients with stage 4 neuroblastoma: a report from the Children’s Oncology Group. J Nucl Med. 2013; https://doi.org/10.2967/jnumed.112.112334.

    Article  CAS  PubMed  Google Scholar 

  105. Matthay KK, et al. Correlation of early metastatic response by 123I-metaiodobenzylguanidine scintigraphy with overall response and event-free survival in stage IV neuroblastoma. J Clin Oncol. 2003;21:2486–91. https://doi.org/10.1200/JCO.2003.09.122.

    Article  PubMed  Google Scholar 

  106. Suc A, et al. Metastatic neuroblastoma in children older than one year: prognostic significance of the initial metaiodobenzylguanidine scan and proposal for a scoring system. Cancer. 1996;77:805–11.

    Article  CAS  PubMed  Google Scholar 

  107. Ady N, et al. A new 123I-MIBG whole body scan scoring method—application to the prediction of the response of metastases to induction chemotherapy in stage IV neuroblastoma. Eur J Cancer. 1995;31A:256–61.

    Article  CAS  PubMed  Google Scholar 

  108. Ladenstein R, et al. Validation of the mIBG skeletal SIOPEN scoring method in two independent high-risk neuroblastoma populations: the SIOPEN/HR-NBL1 and COG-A3973 trials. Eur J Nucl Med Mol Imaging. 2018;45:292–305. https://doi.org/10.1007/s00259-017-3829-7.

    Article  PubMed  Google Scholar 

  109. Brownhill SC, Burchill SA. PCR-based amplification of circulating RNAs as prognostic and predictive biomarkers – focus on neuroblastoma. Pract Lab Med. 2017;7:41–4. https://doi.org/10.1016/j.plabm.2016.04.003.

    Article  PubMed  Google Scholar 

  110. Viprey VF, et al. Neuroblastoma mRNAs predict outcome in children with stage 4 neuroblastoma: a European HR-NBL1/SIOPEN study. J Clin Oncol. 2014;32:1074–83. https://doi.org/10.1200/JCO.2013.53.3604.

    Article  CAS  PubMed  Google Scholar 

  111. Corrias MV, et al. A novel syngeneic murine model for thoracic neuroblastoma obtained by intramediastinal injection of tumor cells. Cancer Detect Prev. 2002;26:468–75.

    Article  PubMed  Google Scholar 

  112. Kreissman SG, et al. Purged versus non-purged peripheral blood stem-cell transplantation for high-risk neuroblastoma (COG A3973): a randomised phase 3 trial. Lancet Oncol. 2013;14:999–1008. https://doi.org/10.1016/S1470-2045(13)70309-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Marachelian A, et al. Expression of five neuroblastoma genes in bone marrow or blood of patients with relapsed/refractory neuroblastoma provides a new biomarker for disease and prognosis. Clin Cancer Res. 2017;23:5374–83. https://doi.org/10.1158/1078-0432.CCR-16-2647.

    Article  CAS  PubMed  Google Scholar 

  114. Alvarado CS, et al. Natural history and biology of stage A neuroblastoma: a Pediatric Oncology Group study. J Pediatr Hematol Oncol. 2000;22:197–205.

    Article  CAS  PubMed  Google Scholar 

  115. Perez CA, et al. Biologic variables in the outcome of stages I and II neuroblastoma treated with surgery as primary therapy: a Children’s Cancer Group study. J Clin Oncol. 2000;18:18–26.

    Article  CAS  PubMed  Google Scholar 

  116. Simon T, Spitz R, Hero B, Berthold F, Faldum A. Risk estimation in localized unresectable single copy MYCN neuroblastoma by the status of chromosomes 1p and 11q. Cancer Lett. 2006;237:215–22. https://doi.org/10.1016/j.canlet.2005.06.001.

    Article  CAS  PubMed  Google Scholar 

  117. Nuchtern JG, et al. A prospective study of expectant observation as primary therapy for neuroblastoma in young infants: a Children’s Oncology Group study. Ann Surg. 2012;256:573–80. https://doi.org/10.1097/SLA.0b013e31826cbbbd.

    Article  PubMed  Google Scholar 

  118. Hero B, et al. Localized infant neuroblastomas often show spontaneous regression: results of the prospective trials NB95-S and NB97. J Clin Oncol. 2008;26:1504–10. https://doi.org/10.1200/JCO.2007.12.3349.

    Article  PubMed  Google Scholar 

  119. Kushner BH, et al. Survival from locally invasive or widespread neuroblastoma without cytotoxic therapy. J Clin Oncol. 1996;14:373–81.

    Article  CAS  PubMed  Google Scholar 

  120. Ladenstein R, et al. Busulfan and melphalan versus carboplatin, etoposide, and melphalan as high-dose chemotherapy for high-risk neuroblastoma (HR-NBL1/SIOPEN): an international, randomised, multi-arm, open-label, phase 3 trial. Lancet Oncol. 2017;18:500–14. https://doi.org/10.1016/S1470-2045(17)30070-0.

    Article  CAS  PubMed  Google Scholar 

  121. Yu A, Gilman AL, Ozkaynak MF. A phase III randomized trial of the chimeric anti-GD2 antibody ch14.18 with GMCSF and IL2 as immunotherapy following dose intensive chemotherapy for high risk neuroblsatoma: Children’s Oncology Group (COG) study ANBL0032. J Clin Oncol. 2009;27

    Google Scholar 

  122. Depuydt P, et al. Genomic amplifications and distal 6q loss: novel markers for poor survival in high-risk neuroblastoma patients. J Natl Cancer Inst. 2018; https://doi.org/10.1093/jnci/djy022.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Paediatrics, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada

    Meredith S. Irwin

Authors
  1. Meredith S. Irwin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Meredith S. Irwin .

Editor information

Editors and Affiliations

  1. Department of Pediatric Surgery, Necker - Enfants Malades Hospital, Assistance Publique Hopitaux de Paris, University of Paris, Paris, France

    Sabine Sarnacki

  2. Department of Pediatric Surgery, Necker - Enfants Malades Hospital, Assistance Publique Hopitaux de Paris, University of Paris, Paris, France

    Luca Pio

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Irwin, M.S. (2020). Prognostic Factors and Risk Stratification. In: Sarnacki, S., Pio, L. (eds) Neuroblastoma. Springer, Cham. https://doi.org/10.1007/978-3-030-18396-7_14

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-18396-7_14

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-18395-0

  • Online ISBN: 978-3-030-18396-7

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation