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New Frontiers in Therapy of Peripheral Nerve Sheath Tumors In ANTICANCER RESEARCH 40 : 1817-1831 (2020) doi:10.21873/anticanres.14136 Review New Frontiers in Therapy of Peripheral Nerve Sheath Tumors in Patients With Neurofibromatosis Type 1: Latest Evidence and Clinical Implications AGATA MARJANSKA 1, PRZEMYSLAW GALAZKA 2, MARIUSZ WYSOCKI 1 and JAN STYCZYNSKI 1 1Department of Pediatric Hematology and Oncology, Nicolaus Copernicus University Torun, Jurasz University Hospital, Collegium Medicum, Bydgoszcz, Poland; 2Department of General and Oncological Pediatric Surgery, Nicolaus Copernicus University Torun, Jurasz University Hospital, Collegium Medicum, Bydgoszcz, Poland Abstract. Almost all individuals with neurofibromatosis gliomas. The disorder is typified by the presence of type 1 (NF1) develop peripheral nerve sheath tumors multisystem tumors, which carries a high risk of malignant (PNSTs), mainly benign neurofibromas, however about 10% transformation (2, 3). Nearly 100% of individuals with NF1 of PNSTs will undergo transformation to malignant develop benign peripheral nerve sheath tumors (BPNSTs) peripheral nerve sheath tumors (MPNSTs). Surgical and in approximately 30-50% of them atypical and plexiform treatment of PNSTs has traditionally been regarded as a neurofibromas (PNFs) are found. In about 10% of NF1 standard approach. The availability of new agents that target patients, neurofibromas may undergo transformation to specific molecular pathways involved in the pathogenesis of malignant peripheral nerve sheath tumors (MPNSTs), which PNST has led to a number of clinical trials, which resulted are highly aggressive. The differentiation between atypical in increased chances for better survival and quality of life. neurofibroma and low grade MPNST is probably the most This review presents the latest evidence and clinical challenging issue in the pathology of peripheral nerve sheath implications for new therapies of PNSTs in patients with NF1 tumors (PNSTs), particularly in NF1 patients. Clinically, emphasizing the potential benefit from the use of Ras/MAPK atypical tumors often develop as extensive, slowly growing pathway inhibitors, immunotherapy, chemotherapy or neoplasms, and pain can be a characteristic feature (4, 5). radiation therapy. We present evaluation of current The poor response to currently available therapies underlines knowledge on available treatment modalities. the need for more effective, targeted treatment methods for NF1-associated PNSTs (6, 7). In this review, we analyzed the Neurofibromatosis type 1 (NF1) is an autosomal dominant latest evidence and clinical implications of new therapies of neurocutaneous disease affecting about 1 in 3500 people PNSTs in patients with NF1 emphasizing the importance of worldwide (1). The hallmark clinical features of NF1 include patient risk stratification to identify those who are likely to multiple café-au-lait macules, neurofibromas, intertriginous benefit from the use of Ras/MAPK pathway inhibitors, freckling, osseous lesions, Lisch nodules and optic pathway immunotherapy, chemotherapy or radiotherapy. We also analyzed the limitations of administering these therapies to all individuals with NF1-associated PNSTs together with future perspectives. This article is freely accessible online. Methodology Correspondence to: Agata Marjanska, MD, Department of Pediatric Hematology and Oncology, Collegium Medicum, Nicolaus PubMed searches were performed to identify potentially Copernicus University, Antoni Jurasz University Hospital No. 1, ul. clinically relevant English-language studies published in the last Sklodowskiej-Curie 9, 85-094 Bydgoszcz, Poland. Tel: +48 525854860, Fax: +48 525854087, e-mail: [email protected] 15 years. The searches were based on a combination of indexed terms and free text terms ("peripheral nerve sheath tumors", Key Words: Peripheral nerve sheath tumor, plexiform neurofibroma, "plexiform neurofibromas", "MPNST", "neurofibromatosis type MPNST, neurofibromatosis type 1, NF1, MEK inhibitors, review. 1", "NF1") AND ("treatment", "therapy", "resection", "surgical 1817 ANTICANCER RESEARCH 40 : 1817-1831 (2020) treatment", "MEK inhibitors", "kinase inhibitors", "mTOR regulator p16, characterizes early steps in the malignant inhibitors", "immunotherapy", "anti-PD1", "chemotherapy", transformation of neurofibromas. Complete loss of nuclear "radiotherapy"). We analyzed all potentially relevant full p16 is a frequent finding in MPNSTs and may be detected papers, and paid particular attention to patient population and in ordinary and atypical neurofibromas indicating that it applied treatment. We analyzed all publications where the can be an early modification in malignant progression, but variety of therapies for aggressive PNSTs in pediatric and by itself is not adequate to diagnose malignancy (7, 10). adult NF1 patients were presented. All types of treatment, including surgery, chemotherapy, immunotherapy, radiation Imaging Evaluation of PNSTs – Differentiation therapy, were considered. We also analyzed reports related of Benign and Malignant Lesions to atypical treatment methods, such as diet and vaccine treatment. Our database was supplemented with abstracts Magnetic resonance imaging (MRI) is the most useful from Joint Global Neurofibromatosis Conferences held in method for evaluating the anatomical extent of the lesion 2016 (Italy, Padova) and 2018 (France, Paris) and with before surgical planning (5, 11). However, the information from https://clinicaltrials.gov website. We morphological imaging features demonstrated limited focused mainly on the results of randomized clinical trials. diagnostic precision for differentiation of benign and However, most reports were based only on a relatively small malignant PNSTs with specificities of 18-82% and number of patients. This review includes a summary of all sensitivities of 18-94%. In MRI, MPNSTs present specific NF1-related PNSTs treatment methods found in available morphological properties including irregular shapes and medical literature. We described and compared results margins, heterogeneity within tumor and peritumoral obtained by the researchers and formulated conclusions, oedema (12-14). considering which method was highly effective. Each Ultrasound or computed tomography (CT) may be useful in relevant paper was analyzed by two independent some patients for image-guided biopsies and bone scintigraphy investigators. Overlapping data were excluded. In total, 68 can be helpful in assessing osseous involvement (11, 15). papers (including conference abstracts) and 21 clinical trials FDG-PET/CT-guided percutaneous biopsy is an effective were found, and qualified as possibly relevant. Finally, 29 procedure and the most dependable approach for untimely reports and 17 clinical trials were selected as relevant to the detection of NF1-associated MPNST (16, 17). Benign PNFs objective of the study. On the basis of these analyses, we demonstrate low fludeoxyglucose (FDG) uptake, whereas complemented the review with a clinical evaluation that we MPNSTs depict moderate to high FDG accumulation. graded as: positive, negative, optional. Commonly standard uptake values (SUV), the amount of FDG uptake, usually range between 1.0-3.99 in benign Nomenclature for NF1-associated PNSTs tumors and between 3.1-21.4 in malignant lesions. There is an overlap between BPNSTs and MPNSTs for SUV values PNSTs encompass a wide spectrum of benign and between 2.5 to 3.5. Therefore, it seems that the symptomatic malignant clinicopathologic entities, whose subsets are PNFs with SUV ≥3.5 should be excised and lesions with difficult to classify. The major categories of these tumors SUV 2.5-3.5 should have precise clinical evaluation. FDG- are classified as: neurofibroma, schwannoma, perineurioma, PET/CT can be useful in the diagnosis of MPNST with hybrid nerve sheath tumors, and MPNSTs (8, 9). However, specificity ranging from 72% to 95% and sensitivity ranging this classification is not appropriate for NF1, as nearly from 91% to 100% (15, 18, 19). The optimum time for 100% of individuals with NF1 will develop PNSTs mainly measuring SUV in patients with symptomatic PNFs is 240 in the form of neurofibromas and their atypical ambiguous min after injection of FDG (19). subtypes. Since PNSTs required a separate description for Whole-body hybrid PET/MRI is a viable alternative for NF1 patients, recommendations for diagnosis and evaluation of the potential occurrence of MPNSTs in NF1 classification were proposed at the meeting held at the patients, with sensitivity similar to that of PET/CT. National Institute of Health (NIH) in 2016 in Bethesda. Furthermore, X-ray dose reduction with PET/MR Characteristics of NF1-associated PNSTs are shown in approaches 50% compared to PET/CT, a vital concern in Table I (7). this patient population with tumor suppressor gene The Ki67 index may also be useful in assessing PNSTs impairment (15, 20, 21). in NF1 individuals highlighting proliferative hot spots. Diffusion-weighted MRI (DW-MRI) without administration While cutaneous, diffuse and atypical neurofibromas of intravenous contrast material improves precision compared usually have low labeling indices (<2-5%), high to morphological MRI in the differentiation of malignant and proliferation rates (>10%) can aid in the detection of benign lesions in NF1-patients. DW-MRI can be a very MPNST arising in a neurofibroma (7). Loss of the valuable complementary method, when borderline glucose CDKN2A locus at 9p21, which encodes the cell cycle metabolism of tumors is observed in PET imaging (12). 1818 Marjanska
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