Regressive Subtype

Four observations suggest the potential of spontaneous regression in neuroblastoma:

1. The slow, but continuous disappearance of all tumor lesions in most patients with stage-4S neu-roblastoma (Pepper type; Pepper 1901; Berthold et al. 1990; Nickerson et al. 2000)

2. The >90 % event-free and overall survival rates in patients with stage 1 that are treated with surgery only in spite of residual microscopic tumor (Brodeur et al. 1993; Berthold et al. 1994; Kushner et al. 1996)

3. The two- to threefold "overdiagnosis" of patients with neuroblastoma in areas where screening programs are performed compared with areas without neuroblastoma screening (Schilling et al. 2002; Woods et al. 2002) (see Chap. 2).

4. The observation of partial or complete disappearance of stage-2 and stage-3 neuroblastoma without cytotoxic therapy in particular during, but not limited to, infancy (Yamamoto et al. 1998; Berthold et al. 1998). The time span from diagnosis to the beginning of regression is considerable (1.5-18 months, «=24; Hero et al. 2000) and could be preceded by a period of progression before regression.

Expression of unfavorable molecular markers, such as MYCN amplification, 1p and 11q deletion, DNA diploidy are typically associated with advanced-stage disease, while the absence of the unfavorable factors and the presence of triploidy are typically found in infants with the regressive subtype of neuroblastoma (Lastowska et al. 2001; Brodeur et al. 1997; Mathew et al. 2001; Spitz et al. 2002, 2003a,b; Maris et al. 2001; White et al. 1995; Hallstensson et al. 1997;Vandesom-pele et al. 1998; Guo et al. 1999; Plantaz et al. 2001; Bown et al. 1999; Abel et al. 1999; Look et al. 1991; Ladenstein et al. 2001; Kramer et al. 1997; Combaret et al. 1996,1997; Terpe et al. 1994; Norris et al. 1996); however, the molecular mechanisms underlying the phenomenon of spontaneous regression remain

Figure 7.3 a,b

Event free survival (EFS) and overall survival (S) in 2779 consecutive patients with neuroblastoma stratified by stage*. a EFS:Stage 1-3 n=1428,5-year-EFS 79.5 ± 1.1 %, Stage 4 n=1077,5-year-EFS 26.4 ± 1.4%,Stage 4S n=274,5-year-EFS 74.8 ± 2.7%. b S: Stage 1-3 n=1428,5-year-OS 88.7 ± 0.9%, Stage 4 n=1077,5-year-OS 33.3 ±1.6%, Stage 4S n=274,5-year-OS 83.7 ± 2.3%.

* 1979-1990 by the Evans'; 1990-2003 by the INSS staging system.The stages I-III (Evans') and 1-3 (INSS), Stages IVS and 4S, IV and 4 have been combined for this analysis unclear and objective and reproducible criteria that discriminate between the regressive and the progressive subtypes have not been identified. To date, the frequency and profile of regressing stage-2 and stage-3 tumors in the different age groups remain incompletely defined. This uncertainty may result in the over-treatment of patients whose tumor would have regressed without any medical intervention (for details see Chap. 11).

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