Enrico Martin

277 General discussion and future perspectives The cover of this thesis is a satellite photo of the Great Bahama Bank. During the ice age, when sea levels were 120 meters lower than presently, the Banks were dry land. Ever since, currents have sculpted the underwater sediments in shallow waters into wavy patterns. The dark and deep water is an area known as the Tongue of the Ocean with depths of up to 4000 meters. The image may stand symbolic for our understanding of malignant peripheral nerve sheath tumors (MPNSTs). Over the last decades, many researchers have tried to understand this rare tumor and through their efforts we are increasingly seeing patterns. The deep and dark water in turn represents yet to be elucidated knowledge on tumor biology and ideal treatment of MPNSTs. The reader of this thesis, you, can be seen as the satellite that took the picture, observing what is known and what has yet to be brought to light. The overall aim of this thesis was to enhance our understanding of both oncological and functional outcomes in MPNSTs. By investigating both types of outcomes one could improve treatment considerations. In this chapter the main findings of this thesis are discussed and suggestions are made for future research efforts. Getting the diagnosis right, on time Timely diagnosis of MPNST is crucial as their prognosis remains relatively poor. Numerous studies, including Chapter 2 and 3 , have repeatedly shown large tumor size to be of negative influence on survival. 1–3 Accurate diagnosis unfortunately seems difficult, especially in the neurofibromatosis type 1 (NF1) patient population. Even though NF1 patients are commonly under surveillance, they still commonly present with larger tumors than sporadic patients. Initial diagnosis is difficult as both clinical symptoms and radiological findings are overlapping with benign counterparts. 4,5 Additionally, intratumoral heterogeneity can cause sampling errors further delaying correct diagnosis. Contrarily, repeated biopsies are cumbersome, painful, and possibly damaging and therefore ideally avoided in benign lesions. Magnetic resonance imaging (MRI) should be used to characterize any lesion in case of newly formed pain, growing mass, or neurological symptoms and fortunately Chapter 5 demonstrated that almost all surgeons utilize MRI. Chapter 6 has shown that any lesion that presents with a target sign is highly unlikely to be an MPNST and therefore generally requires no further diagnostics. Conversely, not every lesion that lacks a target sign should undergo biopsy. Additional features including perilesional edema or ill-defined margins are highly suspect for malignancy. Alas, a significant proportion of MPNSTs do not show these characteristics and more features should be taken into account which complicates the identification of ‘high-risk’ lesions to minimize the need for biopsies. In NF1 patients, positron emission tomography (PET) in combination with computed tomography (CT) or MRI can result in higher accuracies for MPNST detection. The maximum standardized uptake volume (SUVmax) of ≥3.5 currently seems to yield highest accuracy across several populations, but lacks solid validation in a PET-scanner 12