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Hindawi Sarcoma Volume 2021, Article ID 9386823, 6 pages https://doi.org/10.1155/2021/9386823 Research Article Survival andNF1 Analysis in a Cohort of Orthopedics Patients with Malignant Peripheral Nerve Sheath Tumors 1 2,3 4 2 Daniel K. Knewitz, Colin J. Anderson, William T. Presley, MaryBeth Horodyski, 2,5 4,5,6 Mark T. Scarborough, and Margaret R. Wallace University of Florida College of Medicine, MS3, Gainesville, FL, USA Department of Orthopaedics and Rehabilitation, University of Florida College of Medicine, Gainesville, FL, USA Department of Orthopedic Surgery, Levine Cancer Institute and Musculoskeletal Institute, Carolinas Medical Center–Atrium Health, Charlotte, NC, USA Department of Molecular Genetics & Microbiology, University of Florida College of Medicine, Gainesville, FL, USA University of Florida Health Cancer Center, Gainesville, FL, USA University of Florida Genetics Institute, Gainesville, FL, USA Correspondence should be addressed to Margaret R. Wallace; peggyw@uﬂ.edu Received 6 April 2021; Accepted 18 September 2021; Published 4 October 2021 Academic Editor: Kanya Honoki Copyright © 2021 Daniel K. Knewitz et al. ,is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Neuroﬁbromatosis type 1 (NF1) is an autosomal dominant tumor syndrome in which benign plexiform neuroﬁbromas are at risk of transforming into malignant peripheral nerve sheath tumors (MPNSTs), a very rare soft-tissue sarcoma. ,e prognosis of patients with MPNSTs is poor, with most studies reporting <50% survival at ﬁve years. However, studies evaluating MPNSTs are limited and report heterogeneous results. Because no MPNST-speciﬁc evidence-based treatment guideline exists, individual institutional experiences are very informative to the ﬁeld. ,e main objective of this study was to investigate and report MPNST prognostic clinical and genetic biomarkers from our institution’s Orthopedics service experience treating 20 cases from 1992 to 2017. Most patients were treated with resection and adjuvant radiation. Extended follow-up, averaging 11.4 years (ranging 1.1 to 25.1), revealed excellent ﬁve-year survival rates: 70% for overall and 60% for metastatic disease. An S100 B immunonegative tumor phenotype was associated with a signiﬁcantly worse outcome than MPNSTs with positive S100 B stain. In addition, NF1 gene mutation analysis was performed on 27 families with NF1 in which at least one aﬀected family member developed MPNSTs. Of the 27NF1 germline mutations, ﬁve were large deletions spanning (or nearly spanning) the gene (18.5%), substantially more than such deletions in NF1 in general, consistent with increased risk of MPNSTs in such cases. of neuroﬁbromas in their lifetimes. Neuroﬁbromas are 1. Introduction classiﬁed as “cutaneous” when they are superﬁcial, involving Neuroﬁbromatosis type 1 (NF1) is an incurable progressive nerve endings in the skin; larger and usually deeper autosomal dominant disease. Despite an NF1 incidence of 1 “plexiform neuroﬁbromas” involve peripheral nerves . in 3000 people, the ﬁrst eﬀective systemic therapy with the Plexiform neuroﬁbromas are thought to be congenital in MEK inhibitor selumetinib was only recently FDA ap- origin and occur in about 50% of patients . Plexiform proved, in 2020 . NF1 is caused by heterozygous germline neuroﬁbromas can grow quite large and are estimated to mutations in the NF1 gene, of which over 5000 have been have a 10–30% risk of malignant transformation into a identiﬁed spanning the large locus. ,e clinical hallmark of malignant peripheral nerve sheath tumor—a rare type of NF1 is the neuroﬁbroma, a benign peripheral nerve sheath soft-tissue sarcoma—particularly if they have a nodular Schwann-cell tumor. Patients can develop few to thousands phenotype . MPNSTs are rare, aﬀecting only 1.4 in 2 Sarcoma 100,000 people, with half of such cases occurring in NF1 therapeutic history, immunohistochemical S100 B data from patients . MPNSTs are not reported to show a predilection a pathology service, and survival status. toward a speciﬁc anatomical region of the body. Cutaneous cases of MPNSTs have been described, but they do not 2.2.NF1GeneMutationAnalysis. NF1 mutation analysis was typically occur in NF1 patients . Overall, the lifetime risk performed on DNA samples from the IRB-approved Wal- of MPNSTs in NF1 patients is estimated at 12–15% . In lace Genetics Bank from 27 NF1 families bearing at least one reported studies, the MPNST 5-year survival rate is usually MPNST occurrence. Previously existing data included some reported as less than 50%  and thus the prognosis is NF1 cDNA Sanger sequencing, while current testing in- generally considered poor. cluded PCR and sequencing of 13 exons (4, 5, 11, 13, 14, 16, Because of its rarity, there have been few clinical trials 18, 20, 22, 26, 28, 32, 40, and 46) of the 57 exons in the locus speciﬁcally for patients with MPNSTs and information about (NCBI gene sequence: NG_009018.1) (methods described in natural history and response to therapies in the literature is [16, 17]). In addition, all samples were screened for large sparse. Typically, MPNSTs are managed with treatment deletions using four TaqMan NF1 copy-number assays protocols for soft-tissue sarcomas, as protocols speciﬁc to across the gene (,ermoFisher; Hs05477010, Hs06413401, MPNSTs have not been established . Early surgery has Hs05512625, and Hs03960106) (Center for Pharmacoge- been shown to be an eﬀective treatment  with a goal of nomics Core, UF Clinical and Translational Institute). resecting the tumor with wide or negative margins. Adjuvant radiation or chemotherapy regimens have also been used at diﬀerent institutions to reduce the risk of local recurrence or 2.3. Statistical Analysis. All data were analyzed using sta- to treat systemic disease . Although recent trials with tistical software (SPSS 25, IBM Co. Armonk, NY). ,e novel targeted therapies have so far proven ineﬀective, re- signiﬁcance level for analyses was set a priori at p< 0.05. current gene mutations that have been associated with more Descriptive statistics were computed for demographic and aggressive tumors in patients with NF1, such as the poly- clinical variables. Kaplan–Meier survival curves were gen- comb repressive complex 2 (PRC2) core components, em- erated to assess the overall survival of the study population bryonic ectoderm development protein (EED), and and compare between demographic, clinical, survival, and suppressor of zeste 12 homolog (SUZ12), may serve as future pathological variables. treatment targets [9–12]. ,ere is some controversy in the literature regarding germlineNF1 mutation eﬀect on the risk 3. Results of developing an MPNST. Some studies reported a higher incidence of deletions spanning the entire NF1 locus and A total of twenty subjects (14 males and 6 females) qualiﬁed surrounding genes in NF1 patients who develop an MPNST for this study’s retrospective chart review. Demographic than the NF1 population overall , while other reports did characteristics are provided in Table 1. not ﬁnd such a trend . With respect to race, 12, 6, and 1 subject(s) were ,ere are a limited number of publications reporting Caucasian, black, and Hispanic, respectively. Race was not MPNSTsurvival, most with small case numbers and variable identiﬁed in the medical record of one subject. ,e mean outcomes, not unexpected for such a rare tumor. ,us, total length of follow-up was 136.9 months. ,e survival rate experience from institutions managing patients with for the entire study population was approximately 70% MPNSTs is important to add to the ﬁeld’s knowledge . (Figure 1). ,e purpose of our study was to evaluate both clinical and Two subjects had local recurrence, and ﬁve had subse- NF1 mutation data from the MPNST population at our quent metastasis. ,e mean time to local recurrence and institution to identify prognostic factors. time to metastasis were 134.9 and 113.6 months, respec- tively. Both subjects with local recurrence received radiation therapy. At the last follow-up for all subjects, 14 were alive 2. Materials and Methods and 6 were deceased. Two of the ﬁve subjects who developed 2.1. Clinical and Demographic Data Collection. As approved subsequent metastasis were alive at the last follow-up (2018) by the University of Florida Institutional Review Board, a and survived an average of 197.9 months (range 85.7 to retrospective medical chart review of 1992 to 2017 was 309.8) after diagnosis of metastasis. Four of these metastases performed from 1992 to 2017 to gather data on our insti- targeted the lung, and one subject developed metastasis in tution’s Division of Orthopedic Oncology’s experience of the brain. ,e ﬁve-year survival rate of patients with met- treating patients with MPNSTs. ,e data were extracted astatic disease was 60%. ,e female gender was associated with better cumulative from an EPIC electronic medical record service and from the Enneking/Anspach Research Center database in the De- survival outcomes, and the diﬀerence was not signiﬁcant partment of Orthopedics and Rehabilitation. Inclusion (p � 0.45). Black subjects were found to have better cu- criteria were (1) diagnosis of MPNSTs, (2) deﬁnitive treat- mulative survival outcomes than Caucasian and Hispanic ment performed at our institution, and (3) at least 12 months subjects; however, the diﬀerence was not signiﬁcant of follow-up data. Demographic and clinical information (p � 0.25). ,e most common primary MPNST locations in collection included gender, self-reported ethnic group, age at this patient population were the lower extremities (n � 11) initial diagnosis, tumor stage at ﬁrst diagnosis, time to re- and the upper extremities (n � 8), followed by the neck currence, diagnosis of NF1, family history of NF1, (n � 1). Six subjects had a diagnosis of NF1. Five subjects Sarcoma 3 Table 1: Subject demographics and clinical survival information. Mean Std. dev. Range Minimum Maximum Age at diagnosis (years) 43.4 18.4 75.4 6.0 81.4 Time to local recurrence or last follow-up (months) 134.9 102.1 309.9 4.9 314.8 Time to metastasis or last follow-up (months) 113.6 100.0 284.8 4.9 289.7 Total follow-up (months) 136.9 99.8 301.1 13.7 314.8 were NF1-negative, and the NF1 status for nine subjects was Survival Function indeterminate. Although subjects with negative NF1 status 1.0 were found to have better cumulative survival outcomes, the diﬀerence was not signiﬁcant (p � 0.39). Tumor-grade classiﬁcations were low (n � 2), interme- 0.8 diate (n � 3), and high (n � 15). Low-grade tumors were found to have better cumulative survival than intermediate 0.6 and high, although the diﬀerence was not signiﬁcant (p � 0.63). AJCC 8th Education Stage classiﬁcation of the patients was as follows: IA � 2, II � 4, IIIA � 8, IIIB � 6. 0.4 Patients with stage IA and II tumors were all alive at the last follow-up. Overall comparison between stages failed to re- 0.2 veal a signiﬁcant diﬀerence in cumulative survival (p � 0.26). S100 B immunohistochemistry status was re- ported positive in 9 tumors, negative in 4, and could not be 0.0 determined in 7. Subjects with positive S100 B status were .00 100.00 200.00 300.00 400.00 shown to have a signiﬁcantly better cumulative survival Total Follow-up (months) outcome (p � 0.003) (Figure 2). Survival Function ,ree subjects were treated with resection alone (1 Censored subsequently developed metastasis), 15 were treated with resection and adjuvant radiation, and two subjects were Figure 1: Kaplan–Meier survival curve for all 20 subjects. ,e 5- treated with resection and chemotherapy. Only one of the year survival was approximately 70%. resections involved an amputation. When comparing cu- mulative survival in subjects who received chemotherapy (n � 2) against subjects who did not receive chemotherapy (n � 18), the two subjects receiving chemotherapy had a Survival Functions poorer outcome, although it was nonsigniﬁcant (p � 0.69). 1.0 When comparing estimated overall survival in subjects who received radiation (234.1 months) against those who did not (193.9 months), subjects who received radiation had better 0.8 survival, but the diﬀerence was not signiﬁcant (p � 0.89). Among banked DNAs, there were 27 NF1 cases who 0.6 developed MPNSTs and/or had a positive family history of MPNSTs. As shown in Table 2, germline NF1 mutations among these 27 families were distributed as follows: non- 0.4 sense (9), missense (4), frameshift (5), splicing (5), deletion spanning most of the gene (1), and whole-gene deletion (4). 0.2 4. Discussion 0.0 ,e purpose of this study was to evaluate clinical prognostic .00 100.00 200.00 300.00 400.00 factors and genomic biomarkers in patients with MPNSTs Follow-up (months) treated at our institution. As an academic tertiary-care in- stitution, our institution is a referral center for cancer pa- S100B Data tients, including those with MPNSTs, from throughout the undetermined undetermined-censored yes yes-censored US as well as internationally. Most similar studies have no no-censored reported less than a 50% ﬁve-year MPNST survival rate [18–30]. Our cohort had a mean follow-up time of 11.4 years Figure 2: Kaplan–Meier survival curve based on MPNST S100 B and a 70% ﬁve-year survival rate, the latter of which is status. S100B-negative MPNSTs (green line, n � 4) were associated superior to any previously reported studies (range 38.3–62.5 with a signiﬁcantly lower survival than S100B-positive tumors (red line, n � 9) (p< 0.003). years) [18, 19, 22–30]. Cum Survival Cum Survival 4 Sarcoma Table 2: MPNST-related NF1 germline mutations. respect to survival. Similar studies with larger cohorts found individual variables associated with survival, such as tumor Mutation Eﬀect Exon size [18, 19, 22, 29], margin status [18, 24–28], NF1 diag- c.499delTGTT Frameshift 5 nostic status [19, 22, 26, 29, 30], and tumor grade c.958 G> Cp.Ala320Pro Missense 9 [19, 21, 22, 28]. c.1039 C> Tp.Gln347X Nonsense 9 Our study had a number of limitations, the foremost c.1782delAG Frameshift 16 being sample size and another being lack of NF1 status in c.2325 G>A Splice error 19 earlier cases. Although a larger sample size might aid in c.2352 G> Ap.Trp784X Nonsense 20 c.2446 C> Tp.Arg816X Nonsense 21 identifying additional signiﬁcant prognostic factors, it is c.2534insG Frameshift 21 important to report individual institution experiences be- c.2540 T> Cp.Leu847Pro Missense 21 cause of the lack of evidence-based established therapeutic c.2991-1G>A Splice error 23 regimens for MPNST. Information from institutions with c.3113+1G>C Splice error 23 better outcomes may be very useful to other groups. Toward c.3456_3457insA Frameshift 26 this goal, we excluded patients who had received prior C. 3683delC Frameshift 27 MPNST treatment at outside institutions. Although this c.3826 C> Tp.Arg1276X Nonsense 28 allowed evaluation of survival outcomes based solely on care c.4255 A> Tp.Lys1419X Nonsense 32 at our institution, a more varied subject group might have c.4435 A>G Splice error 34 been more representative of the overall US MPNST patient c.4868 A> Tp.Asn1623Val Missense 37 c.5242 C> Tp.Arg1748X Nonsense 38 population experience. c.5914 C> Tp.Gln1981X Nonsense 40 c.6148 C> Tp.Gln2050X Nonsense 42 5. Conclusions c.6302 C> Gp.,r2101Arg Missense 42 c.7285 C> Tp.Arg2429X Nonsense 50 Given the rarity and lack of clinical trial data for MPNSTs, Whole-gene deletion (n � 4) Null All treatment parameters and survival data from multiple in- Large intragenic gene deletion (n � 1) Likely null 2–50 stitutions are needed to move toward improved treatment n � 27. NCBI RefSeq: NM_0000267. and prognosis. It is critical that patients with rare tumors such as MPNSTs be referred to institutions experienced with Consistent with previous reports, we noted that subjects such cancers. Our institutional experience with MPNST with S100B-positive tumors had signiﬁcantly better out- cases treated in the Orthopedics oncology service, with comes than those with S100B-negative tumors . S100 B is treatment favoring surgical resection and adjuvant radiation, a mature Schwann-cell protein, and loss of immunostaining showed an outstanding ﬁve-year survival of 70%. ,is work is consistent with poorer cell diﬀerentiation. Further in- also highlighted the potential use of S100 B immunostaining vestigation is needed to evaluate the use of this phenotype to in prognosis. In addition, our study added to the evidence stratify patient risk, along with immunostaining of other that whole-gene germline NF1 deletions are associated with markers in MPNSTs that are of recent interest such as an increased risk of MPNST. polycomb repressor complex 2 epigenetic mark H3K27me3  and HMGA2 . Data Availability ,e frequency of whole-gene deletions (14.8%) in the 27 germline NF1 mutations associated with MPNSTs was ,is study utilized data derived from patient records at our higher in our population than the 4–5% rate of such dele- institution; hence, the data are not available for public re- tions in NF1 patients in general . ,is frequency is even lease. All pertinent HIPAA-compliant data are published in greater when including samples with a deletion of most of the accompanying tables and ﬁgures. the gene, extending beyond the 3′ end for an unknown distance. Our result is consistent with previous reports Conflicts of Interest suggesting that individuals with such deletions are at a greater risk for MPNSTs [13, 34, 35]. However, this elevated ,e authors declare that there are no conﬂicts of interest risk could be related to the increased plexiform neuroﬁ- with regard to this study. broma burden of many such patients . Although a signiﬁcant diﬀerence in survival was not found based on presence of an NF1 diagnosis, patients with Acknowledgments NF1 trended toward a poorer outcome, particularly males: one was still alive at the last follow-up at 314.8 months after ,e authors thank the University of Florida College of metastasis, but three (including one with metastatic disease) Medicine’s Medical Student Research Program for DKK’s had survival under ﬁve years (52.43 months after metastasis, support while performing this work. ,e mutation analysis 13.74 months after diagnosis, and 17.23 months after di- work was supported through Neuroﬁbromatosis ,era- agnosis, respectively). ,e two NF1 female subjects are both peutic Acceleration Program (NTAP) funding to MRW. ,e still alive (108.78 months after metastasis and 256.61 months authors also thank Dr. Hua Li for technical assistance; her after diagnosis). ,is study was underpowered to detect contribution and that of MRW were in part also supported relationships between race, gender, and other factors with by a DOD grant to MRW (Award #W81XWH-20-1-0355). 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