EVIDENCE OF APOPTOSIS IN NEUROBLASTOMA AT ONSET AND RELAPSE - AN ANALYSIS OF A LARGE SERIES OF TUMORS

Neuroblastoma (NB) is a tumor of pediatric age that is associated with high mortality in metastatic stages, although stage IVS patients unde rgo frequent spontaneous regression. Since apoptosis has been proposed as a possible cause of remission among cancer patients, we tested thi s hypothesis among both localized and metastatic NE and, in particular , NE metastatic stage IVS. We have assayed 36 localized and 117 metast atic neuroblastomas for evidence of internucleosomal DNA degradation a nd confirmed DNA fragmentation by the flow cytometric Terminal deoxynu cleotidyl Transferase method, which also allowed us to measure DNA con tent and cell cycle phases. These techniques provided evidence of apop tosis in 18 out of 153 samples (11.8%), that were equally distributed among all stages except IVS, i.e., 11.1% in stage I (2/18)? 11.1% in s tage II (2/18), 13.2% in stage III (5/38), 13.4% in stage IV (9/67), a nd 0% in stage IVS (0/12). Tumor tissue samples collected at onset and also at relapse for the same patients showed that apoptosis may occur at relapse. In addition, cells appear to undergo apoptosis independen tly from N-myc amplification, cell cycle phase and DNA ploidy. In conc lusion, apoptosis seems to take place with about an equal frequency fo r both favourable and unfavourable stages with an exception for IVS. S ince DNA fragmentation remained undetected in stage IVS, we suggest th at apoptosis is not a mechanism of spontaneous regression for these pa tients. A better basic understanding of the complex molecular mechanis ms and biochemical pathways that control apoptosis in neuroblastoma ap pears to be necessary.