Enrico Martin

80 Chapter 4 And although not independently associated with survival in this study, larger tumor size and non-extremity tumor site have also been associated with worse survival in pediatric MPNST. 6,27 However, the model did not improve by adding any of the two factors, and the association of NF1 status with survival was independent of both factors. In part, it may be due to lower chemosensitivity which has been suggested in NF1 patients. 6,16,32,33 However, in the EpSSG study, similar response rates were seen between NF1 and non-NF1 children. 15 The impact of NF1 status on survival in adults has been controversial as well. While a meta-analysis suggests there is no influence seen in studies published after 2000, 20 several large recent studies do find NF1 status to be independently associated with worse survival. 21,34,35 Some immunohistochemical markers have been proposed predictors of poor survival as well as they may reflect more aggressive biology of the tumor, such as loss of p53, 2,36 negative S100 staining, 37 or loss of H3K27 tri-methylation. 38 Treatment of pediatric MPNST Although this study did not find a significant difference in survival between R2 resections and biopsies only compared to complete resections, results from previous studies in adults have shown a strong benefit on survival if performed. 11,30,31,34,39,40 In pediatric MPNST, Intergroup Rhabdomyosarcoma Study (IRS) groups III/IV (translating to R2 and metastatic cases respectively) have been associated with worse survival as well, 6,26 yet this effect may partially be due to the inclusion of metastatic patients in these analyses. Also, previous studies in pediatric MPNSTs showed higher rates of IRS III/R2 patients compared to this study possibly indicating a selection bias in larger pediatric sarcoma centers. 6,24–28,41 It may also imply that the subgroup was underpowered as only seven patients had R2 resections or biopsies only. As MPNSTs are aggressive in general and surgery is the only treatment proven effective, R0/R1 resections should still be strived after. 42 While R1 resections have been associated with increased risks for local recurrence, they have not been associated with worse survival in both adult and pediatric MPNST. 3,6,17,21 This may provide an opportunity for the adoption of planned positive margins in MPNSTs as well, thus decreasing morbidity in some patients. 43,44 The role of both chemotherapy and radiotherapy is controversial in MPNST, even more so in pediatric patients. Radiotherapy is generally administered for local control, either preoperatively or after R1 resection. 3,17,18,42 Guidelines usually follow adult doses, which is generally equal to 50Gy preoperatively and 60-66Gy postoperatively. 17,42,45,46 However, in children, keeping long-term radiation complications to a minimum is important and has resulted in lower radiation dose of 50.4-54Gy in the EpSSG guidelines. Although R1 resections may decrease postoperative morbidity by avoiding resection of adjacent functional structures, close margin surgery will necessitate the use of radiotherapy, which in turn may also impair function. Careful preoperative planning including a reconstructive surgeon and shared decision making are therefore crucial. The use of chemotherapy in unresectable cases may benefit patients as some may become resectable and thus downstage the tumor, 6,32 and is