Enrico Martin

114 Chapter 6 Introduction Peripheral nerve sheath tumors are relatively common and include both benign and malignant tumors. Schwannomas are the most common benign nerve sheath tumors (BPNSTs) and neurofibromas make up the largest proportion of remaining BPNSTs. 1,2 Nerve sheath tumors may arise sporadically or in association with neurofibromatoses. Malignant peripheral nerve sheath tumors (MPNSTs) may, in contrast to schwannomas, arise from neurofibromas and are rare and aggressive soft tissue sarcomas (STS), accounting for 2-3% of all STS. 3,4 Although MPNSTs are very rare in the common population, neurofibromatosis type 1 (NF1) patients have an 8-13% lifetime risk of developing an MPNST being the leading cause of mortality in these patients. 5,6 Prognosis of MPNSTs is poor with median survival ranging between 5-6 years, demanding aggressive treatment. 7,8 Adequate and timely recognition is paramount as surgical resection is key in improving survival. 7–9 However, the resection of MPNSTs commonly results in high postoperative morbidity and motor deficits. 10 This is in contrast to BPNST treatment that only requires resection in case lesions are symptomatic and which can be removed by intracapsular resections, minimizing neurologic damage. 11,12 Unfortunately, BPNSTs and MPNSTs are difficult to distinguish based on presenting symptoms. 13,14 Computed tomography and ultrasound play a limited role in the diagnostic work-up and are mainly used to guide biopsies. Magnetic resonance imaging (MRI) should be used to further characterize lesions, but several studies argue that MRI’s alone are insufficiently reliable to detect MPNSTs. 15,16 Biopsies are therefore commonly used, but standard use may be needlessly cumbersome and because of their origin in nerve tissue biopsies are often painful and may lead to persisting nerve damage. 17 Additionally, MPNSTs commonly arise within neurofibromas and harbor significant intratumoral heterogeneity making them prone to sampling errors possibly more so than other sarcomas. 18,19 Lastly, not all lesion sites are approachable for biopsy. 20 In NF1 patients the use of 18 F-fluorodeoxyglucose positron emission tomography/computed tomography ( 18 F-FDG PET-CT) has gained popularity as several researches have suggested a high sensitivity of detecting MPNSTs using maximum standardized uptake values (SUVmax) as a quantitative metabolic imaging marker. However, ideal threshold values remain unknown and suggested thresholds may yield high false positive rates leading to unnecessary biopsies or even surgeries. 21,22 It is thus far difficult to find a balance in NF1 patients between prevention and overdiagnosis. Over the past decades biomarkers have established their key role in diagnosis and treatment of numerous cancers, including prostate cancer, 23 breast cancer, 24 and lung cancer. 25 Non-invasive liquid biopsies are therefore of interest as well in the diagnosis malignant transformation in nerve sheath tumors. Percutaneous biopsies are ideally avoided, but given current uncertainties of accurately distinguishing MPNSTs and BPNSTs with non-invasive diagnostic tools, this study aimed to find diagnostic