Cancer Poster Session
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Introduction
Neuroblastoma is one of the most heterogeneous cancer in terms of clinical behavior. While children with localized neuroblastoma or with clinical stage IV S can be cured by operation alone irrespective of post-operative residuum, generalized disease with bone metastases often means fatal outcome for patient despite of intensive chemotherapy including megachemotherapy followed by autologous hematopoietic progenitor cell transplantation. These phenomena can be explained by spontaneous regression and/ or maturation (Ambros I.M. et al., 1996). Stage of disease, age at diagnosis, levels of urinary catecholamine excretion, N-myc gene amplification, 1p36 deletion, DNA ploidy, and expression of CD44 or TRKA have been found to be significant prognostic factors. The aim of this study is to verify the prognostic significance of DNA ploidy, N-myc gene amplification, and 1p36 deletion (Brodeur G.M., 1995).
Materials and Methods
We investigated twenty-four fresh samples of tumors from patients with histologicaly confirmed neuroblastoma. Patients were not previously treated by chemotherapy or radiotherapy. Eighteen samples of tumors (bone marrow with cancer cells, second look biopsy) from above mentioned patients were taken during or after finishing of therapy. The N-myc amplifcation and 1p36 deletion were explored using FISH (N-myc DNA Probe Digoxigenin labeled, Oncor, Gaithesburg, USA, respectively Chromosome 1 Midisatellite (D1Z2- 1p36) Biotin labeled, Oncor, Gaithesburg, USA). DNA ploidy was determined using flow cytometry according Vindelov (Vindelov L.L., 1977).
Results
We confirmed that DNA aneuploidy in neuroblastoma is associated with lower clinical stages of the disease and younger age at the time of diagnosis. N-myc gene amplification and del 1p36 were associated with worse prognostic signs (more advanced clinical stage and higher age of patients at diagnosis).
Survival of children with DNA aneuploid neuroblastoma was better than with DNA diploid one. There was statistical significant difference between survival of children with neuroblastoma with normal number of N-myc gene copies and with amplification of this gene. DNA ploidy was changed in four patients during chemotherapy: in three patients pre-chemotherapy DNA diploid tumors changed into DNA aneuploid and in those tumors pathologist described morphological signs of maturation. In one patient was the change of DNA ploidy reverse (pre-chemotherapy DNA aneuploid changed into DNA diploid) and tumor became more anaplastic. Changes of number of N-myc copies we did not find.
We were able to find sporadic but intact cells with N-myc amplification in two samples from second look operation in which pathologist described necrotic tissue only. We detected neuroblastoma cells in bone marrow during chemotherapy with sensitivity higher than cytological examination.
Discussion and Conclusion
Our results confirmed that majority of children with neuroblastoma (3/4) may be categorized according Brodeur´s criteria into prognostic groups. The survival of children in first group is better ( 100 %) than survival of children in group two and especially group three in spite of much more intensive therapy. Our previous data showed that chemotherapy induced maturation can be associated with giving rise to DNA aneuploidy (i.e., pre-chemotherapy DNA diploid tumors changed into DNA aneuploid ). Changes of DNA ploidy during therapy in neuroblastoma may be prognostic marker (Eckschlager, T. et al., 1996). N-myc amplification seems to be more stable marker.
N-myc gene amplification detected using FISH is not only important prognostic marker, but may be also used for detection of minimal residual disease (Eckschlager T. and McClain K.L., 1996). This method may be useful especially in residual tumors which are usually necrotic and detection of cancer cells is very difficult.
Conclusions
1/ Our results confirmed that majority of children with neuroblastoma may be categorized according Brodeur´s criteria into prognostic groups.
2/ Patients with DNA aneuploid tumors have a better prognostic course and that children with neuroblastomas with more than 10 copies of N-myc and del 1p36 have a worse course.
3/ N-myc gene amplification detected using FISH may be also used for detection of minimal residual disease especially in residual tumors which are usually necrotic and detection of cancer cells is very difficult
References
1. Ambros I. M., Zellner A., Roald B., et al., (1996): Role of ploidy, chromosome 1p, and Schwann cells in the maturation of neuroblastoma .New Engl.J.Med., 334: 1501-1511
2. Brodeur G. M. (1995): Molecular basis for heterogenity in human neuroblastoma. Eur.J.Cancer, 31A: 505-510
3. T.Eckschlager T., Pilát D., Kodet R., et al., (1996): DNA ploidy in neuroblastoma. Neoplasma, 43: 23-26
4. Eckschlager T. and McClain K.L., (1996): Comparison of fluorescent in situ hybridization (FISH) and the polymerase chain reaction (PCR) for detection of residual neuroblastoma cells. Neoplasma, 43:301-303
5. Vindelov L.L., (1977): Flow microfluorometric analysis of nuclear DNA in cells from solid tumors and cell suspension. Virchows Arch. B. Cell Pathol.,24:227-242
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