Neuroblastoma: morphological pattern, molecular genetic features, and prognostic factors

Neuroblastoma, the most common extracranial tumor of childhood, arises from the developing neurons of the sympathetic nervous system (neural cress stem cells) and has various biological and clinical characteristics. The mean age at disease onset is 18 months. Neuroblastoma has a number of unique characteristics: a capacity for spontaneous regression in babies younger than 12 months even in the presence of distant metastases, for differentiation (maturation into ganglioneuroma) in infants after the first year of life, and for swift aggressive development and rapid metastasis. There are 2 clinical classifications of neuroblastoma: the International neuroblastoma staging system that is based on surgical results and the International Neuroblastoma Risk Group Staging System. One of the fundamentally important problems for the clinical picture of neuroblastoma is difficulties making its prognosis. Along with clinical parameters (a patient’s age, tumor extent and site), some histological, molecular biochemical (ploidy) and genetic (chromosomal aberrations, MYCN gene status, deletion of the locus 1p36 and 11q, the longer arm of chromosome 17, etc.) characteristics of tumor cells are of considerable promise. MYCN gene amplification is observed in 20–30 % of primary neuroblastomas and it is one of the major indicators of disease aggressiveness, early chemotherapy resistance, and a poor prognosis. There are 2 types of MYCN gene amplification: extrachromosomal (double acentric chromosomes) and intrachromosomal (homogenically painted regions). Examination of double acentric chromosomes revealed an interesting fact that it may be eliminated (removed) from the nucleus through the formation of micronuclei. MYCN oncogene amplification is accompanied frequently by 1p36 locus deletion and longer 17q arm and less frequently by 11q23 deletion; these are poor prognostic factors for the disease. The paper considers in detail the specific, unique characteristics of the biological behavior of neuroblastoma, which are untypical of other tumors; histological structure; determinants of the prognosis of the disease, including MYCN gene status; and mechanisms for formation of the amplification and elimination of amplified sequences from the nucleus.

neuroblastoma, history of study, histological pattern, classification, MYCN gene amplification, amplification heterogeneity, prognostic factors, amplification of sequences, chromosomal aberrations

1. Cushing H., Wolbach S.B. The transformat ion of a malignant paravertebral sympathicoblastoma into a benign ganglioneuroma. Am J Pathol 1927;3(3):203–16.

2. Everson T.C., Cole W.H. Spontaneous regression of neuroblastoma: Spontaneous Regression of Cancer. Philadelphia, Pa: WB Saunders, 1966.

3. Ambros I.M., Zellner A., Roald B. et al. Tyrrole of ploidy, chromosome 1p, and Schwann cells in the maturation of neuroblastoma. N Engl J Med 1996;334(23):1505–11.

4. Beckwith J.B., Perrin E.V. In situ neuroblastomas: a contribution to the natural history of neural crest tumors. Am J Pathol 1963;43(6):1089–104.

5. Brodeur G.M., Bagatell R. Mechanisms of neuroblastoma regression. Nat Rev Clin Oncol 2014;11(12):704–13.

6. Matsunaga T., Shirasawa H., Hishiki T. et al. Enhanced expression of N-myc messenger RNA in neuroblastomas found by mass screening. Clin Cancer Res 2000;6(8):3199–204.

7. Maris J.M. Recent Advances in neuroblastoma. N Engl J Med 2010;362(23):2202–11.

8. Mosse Y.P., Laudenslager M., Longo L. et al. Identification of ALK as the major familial neuroblastoma predisposition gene. Nature 2008;455(7215):930–5.

9. Gustafson W.C., Weiss W.A. Myc proteins as therapeutic targets. Oncogene 2010;29(9):1249–59.

10. Cohn S.L., Pearson A.D., London W.B. et al. The International Neuroblastoma Risk Group (INRG) classification system: an INRG task force report. J Clin Oncol 2009;27(2):289–97.

11. Acosta S., Lavarino C., Paris R. et al. Comprehensive characterization of neuroblastoma cell line subtypes reveals bilineage potential similar to neural crest stem cells. BMC Dev Biol 2009;9:12.

12. Papac R.J. Spontaneous regression of cancer. Cancer Treat Rev 1996;22(6): 395–423.

13. Cole W.H., Everson T.C. Spontaneous regression of cancer: preliminary report. Ann Surg 1956;144(3):366–83.

14. Wilson L.M., Draper G.J. Neuroblastoma, its natural history and prognosis: a study of 487 cases. Br Med J 1974;3(3):301–7.

15. Georg R.E., London W.B., Cohn S.L. 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(27):6466–73.

16. Jeison M., Ash S., Halevy-Berko G. et al. 2p24 Gain region harboring MYCN gene compared with MYCN amplified and non amplified neuroblastoma. Am J Pathol 2010;176(6):2616–25.

17. Villamón E., Piqueras M., Mackintosh C. et al. Comparison of different techniques for the detection of genetic risk-identifying chromosomal gains and losses in neuroblastoma. Virchows Arch 2008;453:47–55.

18. Iehara T., Hiyama E., Tajiri T. et al. Is the prognosis of stage 4s neuroblastoma in patients 12 months of age and older really excellent? Eur J Cancer 2012;48(11): 1707–12.

19. Monclair T., Brodeur G.M., Ambros P.F. et al. The International Neuroblastoma Risk Group (INRG) staging system: An INRG Task Force Report. J Clin Oncol 2009;27(2):298–303.

20. Shimada H., Ambros I.M., Dehner L.P. et al. The International Neuroblastoma Pathology Classification (the Shimada system). Cancer 1999;86(2):364–72.

21. Suganuma R., Wang L.L., Sano H. et al. Peripheral neuroblastic tumors with genotype-phenotype discordance: a report from the Children’s Oncology Group and the International Neuroblastoma Pathology Committee. Pediatr Blood Cancer 2013;60(3):363–70.

22. London W.B., Castleberry R.P., Matthay K.K. 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(27):6459–65.

23. El-Sayed M.I., Ali A.M., Sayed H.A. et al. Treatment results and prognostic factors of pediatric neuroblastoma: a retrospective study. Int Arch Med 2010;3:37.

24. Teshiba R., Kawano S., Wang L.L. et al. Age-dependent prognostic effect by MitosisKaryorrhexis Insex in neuroblastoma: a report from the Children’s Oncology Group. Pediatr Dev Pathol 2014;17(6):441–9.

25. Look A.T., Hayes F.A., Shuster J.J. 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(4):581–91.

26. Ladenstein R., Ambros I.M., Pötschger U. et al. Prognostic significance of DNA di-tetraploidy in neuroblastoma. Med Pediatr Oncol 2001;36(1):83–92.

27. Attiyeh E.F., London W.B., Mosse Y.P. et al. Chromosome 1p and 11q deletions and outcome in neuroblastoma. N Engl J Med 2005;353(21):2243–53.

28. Nakazawa A., Haga C., Ohira M. et al. Correlation between the International Neuroblastoma Pathology Classification and genomic signature in neuroblastoma. Cancer Sci 2015;106(6):766–71.

29. Cetinkaya C., Martinsson T., Sandgren J. et al. Age dependence of tumor genetics in unfavorable neuroblastoma: arrayCGH profiles of 34 consecutive cases, using a Swedish 25-year neuroblastoma cohort for validation. BMC Cancer 2013;13:231.

30. Shapiro D.N., Valentine M.B., Rowe S.T. et al. Detection of N-myc gene amplification by fluorescence in situ hybridization. Am J Pathol 1993;142(5):1339–46.

31. Valent A., Benard J., Clausse B. et al. In vivo elimination of acentric double minutes containing amplified MYCN from neuroblastoma tumor cells through the formation of micronuclei. Am J Pathol 2001;158(5):1579–1584.

32. Valent A., Le Roux G., Barrois M. et al. MYCN gene overrepresentation detected in primary neuroblastoma tumour cells without amplification. J Pathol 2002;198(4):495–501.

33. Fredlund E., Ringner M., Maris J.M., Påhlman S. High Myc pathway activity and low stage of neuronal differentiation associate with poor outcome in neuroblastoma. Proc Natl Acad Sci USA 2008;105(37):14094–9.

34. Aoki T., Ichimura S., Itoh A. et al. Identification of the neuroblastoma-amplified gene product as a component of the syntaxin 18 complex implicated in Golgi-toendoplasmic reticulum retrograde transport. Mol Biol Cell 2009;20:2639–49.

35. Stock C., Bozsaky E., Watzinger F. et al. Genes proximal and distal to MYCN are highly expressed in human neuroblastoma as visualized by comparative expressed sequence hybridization. Am J Pathol 2008;172(1):203–14.

36. Hiyama E., Hiyama K., Yokoyama T. et al. Correlating telomerase activity levels with human neuroblastoma outcomes. Nat Med 1995;1(3):249–55.

37. Pezzolo A., Pistorio A., Gambini C. et al. Intratumoral diversity of telomere length in individual neuroblastoma tumors. Oncotarget 2014;6(10):7493–503.

38. Ohali A., Avigad S., Ash S. et al. Telomere Length Is a Prognostic Factor in Neuroblastoma. Cancer 2006;107(6):1391–9.

39. Theissen J., Boensch M., Spitz R. et al. Heterogeneity of the MYCN oncogene in neuroblastoma. Clin Cancer Res 2009;15(6):2085–90.

40. Moreau L.A., McGrady P., London W.B. 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(19):5693–7.

41. Wahl G.M. The Importance of Circular DNA in Mammalian gene amplification. Cancer Res 1989;49:1333–40.

42. Storlazzi C.T., Lonoce A., Guastadisegni M.C. et al. Gene amplification as double minutes or homogeneously staining regions in solid tumors: origin and structure. Genome Res 2010;20(9):1198–206.

43. L’Abbate A., Macchia G., D’Addabbo P. et al. Genomic organization and evolution of double minutes/homogeneously staining regions with MYC amplification in human cancer. Nucleic Acid Res 2014;42(14):9131–45.

44. Yong M.H., Hwang W.S., Knight L.A. et al. Comparing hystopathological classification with MYCN, 1p36 and 17q status detected by fluorescence in situ hybridization from 14 untreated primary neuroblastomas in Singapore. Singapore Med J 2009;50(11):1090–4.

45. Ambros I.M., Rumpler S., Luegmayr A. et al. Neuroblastoma cells can actively eliminate supernumerary MYCN gene copies by micronucleus formation – sign of tumor cell revertance? Eur J Cancer 1997;33(12):2043–9.

46. Shimizu N., Shimura T., Tanaka T. Selective elimination of acentric double minutes from cancer cells through the extrusion of micronuclei. Mutat Res 2000;448(1):81–90.

47. Shimizu N., Itoh N., Utiyama H., Wahl G.M. Selective entrapment of extrachromosomally amplified DNA by nuclear budding and micronucleation during S phase. J Cell Biol 1998;140(6):1307–20.

48. Spitz R., Hero B., Ernestus K., Berthold F. Gain of distal chromosome arm 17q is not associated with poor prognosis in neuroblastoma. Clin Cancer Res 2003;9:4835–40.

49. Tajiri T., Tanaka S., Shono K. et al. Quick quantitative analysis of gene dosages associated with prognosis in neuroblastoma. Cancer Lett 2001;166(1):89–94.

50. Spitz R., Hero B., Simon T., Berthold F. Loss in chromosome11q identifies tumors with increased risk for metastatic relapses in localized and 4S neuroblastoma. Clin Cancer Res 2006;12(11):3368–73.