Malignant Peripheral Nerve Sheath Tumors: Balancing oncological and functional outcomes

Abstract

Malignant peripheral nerve sheath tumors (MPNSTs) are rare soft tissue sarcomas (STS) that undergo aggressive treatment including resections with wide margins. Histotype-specific treatment and outcomes of MPNSTs have been studied infrequently. In contrast to other STS, resecting MPNSTs always requires the resection of nervous tissue making them prone to loss of function.

In Part I of this thesis we investigated current diagnostic imaging techniques, oncological treatment, and survival, as well as predictors for survival using American (SEER) and Dutch (IKNL/Palga) cancer databases. We found that in localised disease, median survival is approximately 6 years, while neurofibromatosis type 1 (NF1) patients have a worse prognosis compared to sporadic MPNST. Increasing age, large tumor size, deep-seated tumors, localisation, and incomplete surgical resections also had a negative impact on survival. Fortunately in the Netherlands, survival among pediatric patients has ameliorated in the past decade, yet this is not the case in adult patients. While macroscopically incomplete margins (R2) are associated with worse survival, microscopically positive margins (R1) were not. However, by means of an international survey it was found that treatment considerations varied among and between surgical subspecialties on ideal diagnostic work-up, surgical strategies, extent of resection, indications for radiotherapy, and indications for chemotherapy in localised disease. Imaging features of benign and malignant nerve lesions are often similar and biopsies are commonly warranted. In benign disease, biopsies can be cumbersome, especially among NF1 patients who develop numerous benign lesions, and may result in unnecessary damage. By means of multiple meta-analyses it was found that biopsies may be obviated in the presence of a target sign and absence of perilesional edema and irregular margins as these are distinctive for benign nerve sheath tumors. In NF1 patients PET-scans may be of additional value and lesions with SUVmax <3.5 are very likely to be benign. Targeted therapies have unfortunately not been proven effective to date, but some candidate targets have arisen in preclinical studies.

In Part II of this thesis research focused on functional outcomes of MPNSTs, the use of reconstructions to restore function, and current attitude of surgeons towards function preservation in these tumors. By means of an international multicenter retrospective cohort (the MONACO study) we collected data on both oncological and functional treatment and outcomes. It was found that while surgical resection is the mainstay treatment, it may lead to loss of motor function (<M3 motor score) in 27.2% of patients and loss of critical sensation (sensation of hands, feet, or buttocks) in 24.3%. Based on current literature, functional reconstructions have uncommonly been performed in any soft tissue sarcoma, but when performed could certainly restore lost function. Similar results were seen in the MONACO study in which only 4.0% of patients underwent a functional reconstruction at any point in time. While surgical oncologists and neurosurgeons operate most MPNST patients, they were least likely to consider functional reconstructions. These results warrant close collaboration between oncological and reconstructive surgeons at an early stage to optimize both oncological and functional outcomes in these patients.