Enrico Martin

72 Chapter 4 Introduction Malignant peripheral nerve sheath tumors (MPNSTs) are rare and aggressive soft tissue sarcomas (STS), accounting for 2% of all STS. 1 A significant amount of MPNSTs occur in neurofibromatosis type 1 (NF1) patients, others occur sporadically, and in adults some are induced by radiation. 2,3 Despite the rare nature of MPNSTs, these sarcomas are among the most common non-rhabdomyosarcomatous STS (NRSTS) in pediatric patients, encompassing approximately 10% of all NRSTS. 4–6 Besides clinically diverse presentations of MPNSTs based on tumor location, tumors will also present with different histological aspects. MPNSTs can arise within a neurofibroma as a malignant transformation, which is especially troublesome in the NF1 population. 7,8 Rarely, MPNSTs may also present with rhabdomyoblastic differentiation, so-called Triton tumors, which have been reported to be associated with poorer survival. 9,10 To date, surgery remains the key to improve survival in any localized MPNST. 3,11 However, MPNSTs have been reported unresectable in 17-53%, which is higher than other NRSTS. 6,12–15 Also, when unresectable, clinical response to neoadjuvant chemotherapy is lowest in MPNSTs compared to other NRSTS, especially in NF1 patients. 15,16 As in other STS, radiotherapy is commonly administered in order to improve local control, but no effect has been shown on survival. 3,17,18 However, long-term morbidity of radiotherapy in a pediatric population needs particular attention. Despite the curative intent of treatment in localized MPNST, local recurrences and distant metastases are very common and survival remains poor. 2,3,11 Overall survival in MPNSTs is also poorer compared to other NRSTS. 19 Additionally, factors influencing survival are not evident yet in pediatric MPNSTs. Recently, the influence of NF1 on survival has been subject of debate as studies report conflicting results. 11,15,20,21 As pediatric NRSTS are rare they have historically been treated as rhabdomyosarcomas, yet the low chemosensitivity and aggressive nature of MPNSTs pose difficulties in selecting ideal treatment regimens. More needs to be learned on prognostic factors of survival in pediatric MPNSTs particularly, as it may help tailoring clinical decision- making. This study aims to investigate differences in clinical presentation between adult and pediatric MPNST patients. It also aims to evaluate overall survival, treatment modalities used, and factors associated with survival in pediatric MPNSTs only using a Dutch nationwide cohort of patients.