Enrico Martin

13 Introduction and thesis outline General treatment Treatment of MPNST typically follows high-grade STS guidelines. 16 Correct diagnosis before treatment is advised and generally requires the use of MRI and biopsy. However, in both sporadic and NF1 patient populations, MPNSTs originating in or near major nerves may present with similar symptoms as benign nerve sheath tumors (BPNST). 17,18 The diagnostic accuracy of MRI is furthermore doubted as BPNSTs and MPNSTs can show similar characteristics on MRI. 19,20 This is especially troublesome in the NF1 population as many patients have numerous deep-seated (plexiform) neurofibromas and repeated biopsies are cumbersome, painful, and possibly damaging. 21 The use of positron emission tomography-computed tomography (PET-CT) has gained popularity in NF1 patients as it has shown increased accuracy compared to MRI for the detection of MPNST. 22 However, the exact use and ideal thresholds for semiquantitative parameters remain unknown. Subsequent treatment of an MPNST requires complete surgical resection, as it has been the only proven therapy to increase survival in localized disease. 4,15 Radiotherapy can be administered, similar to other STS, to improve local control in case of positive margins or large tumors. 4,23,24 Neoadjuvant administration of radiotherapy is gaining popularity in STS as it decreases radiation field and dosage. 25,26 The use of radiotherapy can be questioned as it has not been shown to affect survival and can cause growth problems in a pediatric population and possibly secondary malignancies in NF1 patients. Despite the use of wide resections and radiotherapy, MPNSTs recur and metastasize commonly. The use of chemotherapy is controversial, although some studies suggest a benefit in high-grade, large, and deep MPNST. 27,28 Chemotherapy is more commonly administered in pediatric MPNST and its use is already implemented in the European Pediatric Soft Tissue Sarcoma Study Group and Children’s Oncology Group guidelines. In any metastasized MPNST cytotoxic chemotherapy regimens have unsatisfactory responses. New therapies are therefore warranted and several studies have tried to elucidate altered cellular pathways in MPNSTs that are eligible for targeted therapy. 29,30 Ideal pathways are nevertheless not yet known. Overall, there remains a lack of solid evidence for ideal treatment of MPNSTs. This is further complicated by its rareness and presentation to several surgical subspecialties possibly resulting in divergent treatment strategies. 1