Pediatric Hematology and Oncology
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Malignant peripheral nerve sheath tumor in children: A single-institute retrospective analysis Hong Yul An, Kyung Taek Hong, Hyoung Jin Kang, Jung Yoon Choi, CheRy Hong, Hyun-young Kim, Tae Hyun Choi, Chang Hyun Kang, Han-Soo Kim, Jung-Eun Cheon, Sung-Hye Park, June Dong Park, Kyung Duk Park & Hee Young Shin To cite this article: Hong Yul An, Kyung Taek Hong, Hyoung Jin Kang, Jung Yoon Choi, CheRy Hong, Hyun-young Kim, Tae Hyun Choi, Chang Hyun Kang, Han-Soo Kim, Jung-Eun Cheon, Sung-Hye Park, June Dong Park, Kyung Duk Park & Hee Young Shin (2017) Malignant peripheral nerve sheath tumor in children: A single-institute retrospective analysis, Pediatric Hematology and Oncology, 34:8, 468-477, DOI: 10.1080/08880018.2017.1408730 To link to this article: https://doi.org/10.1080/08880018.2017.1408730
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PEDIATRIC HEMATOLOGY AND ONCOLOGY , VOL. , NO. , – https://doi.org/./..
Malignant peripheral nerve sheath tumor in children: A single-institute retrospective analysis Hong Yul An, M.D.a,b , Kyung Taek Hong, M.D.a , Hyoung Jin Kang, M.D, Ph.D. a , Jung Yoon Choi, M.D.a,b , CheRy Hong, M.D.a , Hyun-young Kim, M.D, Ph.Dc , Tae Hyun Choi, M.D.,Ph.D.d , Chang Hyun Kang, M.D., Ph.De , Han-Soo Kim, M.D., Ph.D.f , Jung-Eun Cheon, M.D., Ph.D.g , Sung-Hye Park, M.D.,Ph.D.h , June Dong Park, M.D., Ph.D.a , Kyung Duk Park, M.D., Ph.D.a , and Hee Young Shin, M.D., Ph.D.a a Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea; b Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea; c Department of Surgery, Seoul National University College of Medicine, Seoul, Korea; d Department of Plastic and Reconstructive Surgery, Seoul National University College of Medicine, Seoul, Korea; e Department of Thoracic and Cardiovascular Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea; f Department of Orthopedic Surgery, Seoul National University College of Medicine, Seoul, Korea; g Department of Radiology, Seoul National University College of Medicine, Seoul National University Children’s Hospital, Seoul, Korea; h Department of Pathology, Seoul National University, College of Medicine, Seoul, Korea
ABSTRACT
ARTICLE HISTORY
Malignant peripheral nerve sheath tumors are rare tumors that originate from Schwann cells. Patients with neurofibromatosis type 1 are prone to develop these tumors. Due to their rarity and lack of established treatment, the prognosis of malignant peripheral nerve sheath tumors is poor. A retrospective study was conducted on children treated for malignant peripheral nerve sheath tumors at the Seoul National University Children’s Hospital between 2007 and 2016. Eleven patients were diagnosed with malignant nerve sheath tumors at a median age of 12 years, eight of whom had neurofibromatosis type 1. All the patients underwent chemotherapy and received surgical resection, and 5 patients relapsed. The 2-year overall survival rate was 72.7%, and the 2-year event-free survival rate was 58.2%. Univariate analysis was performed to assess the correlations between the clinical factors. There was no statistically significant difference in the overall survival rate according to the patients’ clinical factors. However, there was a decreasing trend in the relationship between the event-free survival rate and the prevalence of neurofibromatosis type 1. Regular follow up of neurofibromatosis type 1. Regular follow-up of neurofibromatosis type 1 patients may identify detection of early relapse of malignant peripheral nerve sheath tumors. Genetic studies of these patients and tumors may identify opportunities for targeted therapy.
Received August Revised November Accepted November KEYWORDS
Neurofibromatosis type ; pediatric oncology; sarcoma; soft tissue
CONTACT Hyoung Jin Kang MD, PhD
[email protected] Division of Hematology/Oncology, Department of Pediatrics, Seoul National University Children’s Hospital and Cancer Research Institute, Seoul National University College Of Medicine, Daehak-ro, Jongno-gu, Seoul , Korea. Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/ipho. Supplemental data for this article can be accessed on the publisher’s website at https://doi.org/./. .. © Taylor & Francis Group, LLC
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Introduction Malignant peripheral nerve sheath tumors (MPNST) are tumors that originate from Schwann cells. Two patients with MPNST were reported in 1954; one was affected by neurofibromatosis, whereas the other one was not affected by neurofibromatosis type 1 (NF1). MPNST was previously known as malignant neuroma, malignant neurilemmoma, malignant schwannoma, and neurofibrosarcoma [1–3]. NF1 is the most common type of neurofibromatosis, an autosomal dominant genetic disorder with manifestations like multiple café-au-lait spots, neurofibromas, freckling in axillary or inguinal regions, optic glioma, Lisch nodules, bone abnormality, and is associated with a familial history of the disease [4–6]. NF1 patients are at a higher risk of developing sarcomas such as MPNST, Triton tumor, and Rhabdomyosarcoma [6–9]. Whether MPNST patients with NF1 have a shorter life expectancy compared with the patients without NF1 or not has been controversial [10–12]. MPNST are rare tumors with an incidence of 1/10,000 in the general population [13]. The prognosis of these tumors is dependent on tumor location, size, resection margin, metastases, and cancer stage. The prognosis of MPNST is poor, because they are rare tumors with no established treatment modalities, which vary according to each medical center’s experience. There are only a few reports of MPNST in childhood reporting their respective prognosis [14–17]. Here, we reviewed the clinical characteristics and treatment outcome of MPNST patients treated in our institute. Moreover, we reviewed a genetic finding of MPNST, which supports the development of suitable treatment strategies.
Materials and methods We retrospectively analyzed the medical records of 11 children who were treated for MPNST at the Seoul National University Children’s Hospital, between January 2007 and December 2016. The institutional review board (IRB) of the Seoul National University Hospital approved this retrospective medical study (IRB No. H 1706-115-860). All biopsies were pathologically diagnosed as MPNST with morphological and immunohistochemical analyses in accordance with the FédérationNationale des Centres de Lutte Conte le Cancer (FNCLCC) Pathologic grading system. [18] Tumors were staged based on the American Joint Committee on Cancer (AJCC) staging system [19]. All the patients were reevaluated for the combined diagnosis with NF1 by NF1 diagnostic criteria [6] examined by our institutional Neurologist, Geneticist, and Ophthalmologist. The patients were treated with multimodal therapies, including surgical resection, radiotherapy, cryotherapy, and chemotherapy. The patients were treated with 5 different chemotherapy regimens. The chemotherapy drug, dose, and timing of administration of each regimen are presented in supplementary data (Tables 1 and 2). Statistical analysis was conducted with the R project (3.3.2 GUI 1.68 Mavericks build, The R Foundation). The Kaplan–Meier method was performed for an analysis of the event-free survival (EFS) and overall survival (OS) and the log-rank test was used for subgroup comparisons. Statistical significance was determined as: p < 0.05.
Results Clinical characteristics Eleven patients (7 boys and 4 girls) were diagnosed with MPNST during a 9-year period in a single pediatric institute. These patients were diagnosed at a median age of 12 years and
∗
F
F
F
F
M
M
M
M
M
Palpable mass
Pain, residual mass
Palpable mass
Pain
Numbness, Pain, Weakness Palpable mass, pain, Weight loss Pain
Y
N
N
N
Y
Y
Y
Y
Y
Y
Pelvic cavity, retroperitoneum
Abdominal cavity th finger
Scalp
Parotid gland Pelvic cavity, retroperitoneum
Pelvic cavity, retroperitoneum Ant. Mediastinum, Pleural Lowe leg
.
.
.
.
.
.
.
Y
N
N
N
N
N
N
N
Y
Y
Y
Size (Long Dia. cm) Metastasis
IV
IIA
IIB
IIA
III
III
IIB
III
IV
III
IV
AJCC stage
Upfront (At Dx)
Upfront (At Dx) Upfront (At Dx) Upfront (At Dx)
Upfront (At Dx) Delayed (After Dx) Upfront (At Dx)
Upfront (At Dx)
Upfront (At Dx)
Upfront (At Dx)
Upfront (At Dx)
R
R
R
R
R
R
R
R
R
R
R
Event/ Status
Outcome
Not done
CPMVCRDTICAD R#
Not done
CPMVCRDTICAD Not done R# CPMVCRDTICAD fx, . Gy R# POG-ICE # CPMVCRDTICAD Not done R# POG-ICE# CarboVCRCCGP # CPMVCRDTICADR Not done # CPMVCRDTICADR Not done # CPMVCRDTICADR Not done #
CPMVCRD TICADR#
Not done
Not done
Not done
Not done
Not done
Not done
Not done
Not done
On chemotherapy On chemotherapy
Off therapy
Off therapy
f/u (. mo)
f/u (. mo)
f/u (. mo)
f/u (. mo)
On f/u (. mo) chemotherapy Relapse f/u (. mo) (. mo) Relapse Death (. mo) (. mo) Relapse Death (. mo) (. mo)
POG-ICE # fx, Gy Cryotherapy Relapse f/u loss (. mo) CPMVCRDTI(. mo) CADR# CPMVCRDTICA Not done Not done Relapse f/u loss (. mo) DR# POG-ICE # (. mo) mCCG-ICE # CarboplatinP# Not done Not done Progression Discharge to hospice (. mo) (. mo)
Surgical Residual Other resection mass Chemotherapy Radiotherapy treatment
Abbreviations: Pt, patient; No, number; Dx, diagnosis; NF, neurofibromatosis type; Dia, diameter; AJCC, American Ioint Committee on Cancer; POG-ICE, Ifosfamide + Carboplatin+Etoposide; CPMVCRDTICADR, Cyclophosphamide+Vincristine+Dacarbazine+Adriamycin; mCCG-ICE, ifosfamide+carboplatin+etoposide; Carboplatin P, carboplatin+etoposide+adriamycin+cyclophosphamide; CarboVCRCCGP, carboplatin+adriamycin+cyclophosphamide+vincristine; fx, fraction; Gy, Grays; mo, months; f/u, follow up.
. Poor oral intake, pain, weight loss
. Poor oral intake, diarrhea . Palpable mass
.
.
.
.
.
.
.
Psoas muscle
M
Y
Inguinal mass
Palpable mass
M
.
Primary Site
Age at Predisposing NF Pt No Sex Dx(Yr) symptom Combine
Table . Clinical characteristics and treatment outcome of total study population.
470 H. YUL AN ET AL.
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Table . Clinical characteristics of MPNST patients with and without NF.
Patient number Median age Median size Metastasis Residual mass after operation Event (relapse + death) Death ∗.
Diagnosed with NF
Not diagnosed with NF
. yr (.–.) . cm (.–.)
. yr (.–.) . cm (.–)
p < . p = . p = . p= p = . p = .
Abbreviations: NF, Neurofibromatosis type ; yr, year.
10 months old (range 3 months to 15 years and 10 months). Two patients were diagnosed during infancy (18%), 3 patients during childhood (27%), and 6 patients during adolescence (45%). From the study population, eight patients also presented NF1 (73%). The most common initial symptoms were pain (55%, n = 6) and a palpable mass (45%, n = 5). The primary sites of tumor were variable. The abdominal cavity was the most frequent site (45%, n = 5), followed by the head and neck (18%, n = 2), the thorax (9%, n = 1), the upper extremities (9%, n = 1), and the lower extremities (18%, n = 2). The median size of the tumor, measured as the longer diameter, was 8.5 cm (range 0.6 cm to 18 cm). At the diagnosis, four patients (36%) had metastatic lesions. Diagnosis and pathology All the patients received surgical resection and were pathologically confirmed as MPNST patients at initial diagnosis. Only 2 patients (18%) achieved a tumor margin-free resection. The specimens of 9 patients (82%) were S-100 positive (marker for derivation from the neural crest) and the additional 2 patients (18%) were not tested for the presence of this protein. The median index of tumor mitosis on 10 high power fields was 18 (range 6 to 100). According to the FNCLCC grade system, there were 5 patients with grade 3 tumors (45%), 4 patients with grade 2 tumors (36%), and 2 specimens could not be examined. Multimodal therapies All the patients underwent chemotherapy with various combinations of cyclophosphamide (100%, n = 11), adriamycin (100%, n = 11), vincristine (91%, n = 10), dacarbazine (91%, n = 10), carboplatin (45%, n = 5), etoposide (45%, n = 5), and ifosfamide (36%, n = 4). The chemotherapy regimen used in each patient is detailed in Table 1 (see also Supplement 1). As previously mentioned, all the patients were treated with surgical resection. Five patients had more than two surgeries. One patient presented a progressive tumor (20%), 3 patients had tumor relapses (60%), and the remaining patients had shown an increase in tumor mass (20%), which was characterized as a benign plexiformneurofibroma. After the initial diagnosis, 2 patients (18%) received local radiotherapy with 28 fractions/50.4 Gy at 13.6 months, and 30 fractions/54 Gy at 3.5 months, respectively. Only one patient (No 1) was treated with cryotherapy for the pleural metastasis. Outcomes Survival All the patients showed an initial treatment response, except one patient (No 3), who showed disease progression in spite of chemotherapy and surgery, and was discharged to hospice
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Figure . Total event-free survival.
after 2.3 months. From the remaining 10 patients, 5 patients (45%) relapsed after the end of the therapy. The median relapse interval from the end of the therapy was 8.1 months (range 2.1 months to 142.6 months). From these patients, 2 patients (No 1 and 2) were transferred to local hospitals for treatment after chemotherapy, where their medical records were lost during follow-up. One patient (No. 7) did not survive due to tumor progression complications; as the initial tumor was in the abdominal cavity, it led to the development of acute renal failure and neurogenic bladder. Another patient (No. 6) died due to second malignancy, anaplastic astrocytoma, which led to central respiratory failure and central diabetes insipidus. Only one patient (No. 5) is alive and under regular follow-up after relapse. After the second surgery without chemotherapy, the patient survived in an event-free status for 1 year and 2 months, with a minor wound problem that was noticed during this period. The OS rate of the total study population was 55% (n = 6), with a median range of 18.8 months (range 2.3 months to 167.1 months) and the observed EFS rate was 45% (n = 5), with a median range of 6.2 months (range 2.3 months to 142.6 months). Among the 6 survivors in the last follow-up day, 3 patients were on chemotherapy and 3 patients had ended the therapy. Relapse All the relapse patients were patients with NF1. The relapse symptoms were increasing tumor mass, pain and swelling, falling down and limping gait, voice changes and aspiration, abdominal pain, and residual urine. The weakness, associated with falling down and limping gait, was different from the primary symptom, but had the same primary site. The voice changes and aspiration were unique symptoms compared to the initial symptoms and these symptoms had originated from the secondary malignancy (anaplastic astrocytoma). Five patients underwent relapse (45%), and only 3 patients underwent more than two operations. Among them 2 patients had the tumors analyzed by needle or excisional biopsy in the first remission status. At that time, a pathology report confirmed benign plexiformneurofibroma. The symptoms of patients became worse with time; therefore, we took the final excision mass and the pathology results indicated MPNST. Analysis In the subgroup analysis, there were 8 patients with NF1 and 3 without NF1. The OS of the MPNST patients with NF1 was 63% and their EFS rate was 25% with a median follow up duration of 14.3 months (range 2.3 months to 167.1 months) as illustrated in Figures 1 and 2. The OS rate of the MPNST patients without NF1 was 100% and the EFS was 100% with a
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Figure . Total overall survival rate.
median follow up duration of 24.2 months (range 6.2 months to 24.3 months). The univariate analysis was performed to assess the correlations between clinical factors that can influence survival and recurrence. The survival rate of the patients with NF1 was lower, but no statistically significant differences could be found (Fisher exact test, p value = 0.49). On the other hand, the relapse in NF1 patient has shown a decreasing trend in the EFS (75% versus 0%, p value = 0.06). Metastasis, primary tumor size, age, and residual tumor did not show any association with the OS and the EFS (Tables 1 and 2). Discussion In this study, the percentage of MPNST patients with NF1 was 72%, which is higher than the one reported in previous studies [20–23]. There are several research studies that aimed to clarify whether there is a difference in the survival rate of the MPNST patients with NF1. Previous reports had shown that patients with MPNST and NF1 had a lower survival rate [13, 24], but other studies had shown no significant difference between MPNST patient survival depending on the presence of NF1 [11]. In a recent report on adult MPNST patients in Korea, it was shown that there is no association of OS and NF1 presence in MPNST patients [23]. In this series, there was no difference in survival between patients with or without NF1, however, NF1 was associated with decreased event-free survival. In this series, MPNST patients with NF1 were diagnosed earlier and had decreased EFS compared to patients without NF1. (Table 3). This might be due to the genetic background,
Figure . Event-free survival in MPNST patients with and without NF.
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Table . Clinical characteristics of MPNST patients with NF. Pt No
Sex
Age at Dx(Yr)
NF
Features
M
.
Y
M
.
Y
F F
. .
Y Y
F
.
Y
F
.
Y
M M M M M
. . . . .
Y N N N Y
Café au lait spot, freckling, multiple neurofibromas, family history Café au lait spot, freckling, multiple neurofibromas, optic nerve gloma Café au lait spot, multiple neurofibromas Café au lait spot, freckling, multiple neurofibromas, Lisch nodule Café au lait spot, optic nerve gloma, multiple neurofibromas Café au lait spot, optic nerve gloma, multiple neurofibromas Café au lait spot, multiple neurofibromas, family history Not applicable Not applicable Not applicable Café au lait spot, multiple neurofibromas, family history
the early treatment at a relatively young age, and the regular screening after childhood. Previous studies had shown that screening at an early age and surgical treatment can be helpful [5, 25, 26]. It has been reported that PET/CT imaging may facilitate early diagnosis of MPNST in NF1 patients [27]. Therefore, we hypothesize that there might be difference in tumor characteristics dependent on age, on more susceptible somatic mutation and protein or RNA expression levels. Previous studies had shown that the survival rate of MPNST patients was very low (33 to 52%) [16, 17, 23, 28]. The survival rate in our institute was higher than that reported in the literature, with a 2-year OS rate of 72.7% (8/11), including two cases lost to followup. Recent developments in biological research have led to an explosive growth in the knowledge related with molecular mechanism of MPNST. The methylation profiling is altered in MPNST when compared to schwannoma, and there are reports showing that HDAC8 inhibitor can be used as a therapeutic agent [29, 30]. There is also another study that revealed the different genetic profiles and expression patterns of germline mutations in NF1 patients and somatic mutations in plexiformneurofibroma of the same patients by using whole exome sequencing [31]. Moreover, several genes have emerged as drivers of MPNST, and research has been actively conducted to study these genes. Overexpression of PDGFR and loss of NF1 and p53 have been reported to be involved in the pathogenesis of MPNST [32]. It is also reported in the literature that the blockade of CDK2 may induce the degradation of beta-catenin and might be used as a treatment target for MPNST by induction of apoptosis [33]. Reduced expression of p53 can lead to overexpression of EGFR and affect tumorigenesis [34]. It was also reported that survin overexpression is a marker for MPNST and that molecular targets may be present [35]. Although microRNA-204 has been introduced as a possible diagnostic marker and therapeutic target, this microRNA has not reached yet a meaningful application stage [36]. A research group claims that the classic therapeutic modality, the combination therapy with IfosfamideDoxorubicin, leads to an increase in the survival rate in a more pronounced way than the Doxorubicin-based therapy [37]. Nevertheless, another research group has shown that the existing chemotherapy cannot significantly increase the survival rate, and that another type of treatment modality needs to be developed [21]. In this study, only 2 patients were treated with radiotherapy, neither with significant responses. Previous reports have shown that radiotherapy is not clinically meaningful [28], but it is reported that radiation therapy can reduce local relapse [22]. Although hematopoietic
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stem-cell transplantation is not routinely performed, there is a report showing that this procedure might be beneficial for the survival rate when performed in the complete remission status [38]. As the two-hit theory states for the RB1 gene, there are also claims that a second hit in NF1 patients may be associated with the MPNST [39, 40]. According to our data, the neurofibromas of Patient No. 5 and No. 6 were examined via needle biopsy or excisional biopsy and histological examination after first remission follow-up period. These patients eventually underwent malignant change to MPNST, and the Patient 6 died after relapse. Therefore, if MPNST occurs once, the remaining mass like the optic glioma or neurofibroma in the NF1 patient, it is a predisposing event, even after healing, for serial malignancy changes. Therefore, the patient who had this predisposition statue was aggressively treated and mass excision was done. Even if it is reported as benign in the conventional biopsy, if the size continues to grow or new symptoms such as pain occur, surgical treatment should be considered [41, 42]. To our knowledge, this report is the first retrospective study on the clinical characteristics and outcome of pediatric MPNST in Asia. Our study is limited by its small cohort size, because it is retrospective, and a single-center study. We could not perform genomic data analysis yet, but the analysis is progressing and we believe that it will provide further hints in the MPNST pathology. A prospective, multicenter collaboration study on a larger number of patients and with genomic data will enable the study of the benefits of various treatment modalities, and the identification of molecular pathways. These types of studies will thus aid in the development of more efficient treatment strategies for these aggressive tumors.
Conflicts of Interest Conflict of interest relevant to this article was not reported by the authors.
Acknowledgment This study was supported by grant no 03-2015-0040 from SNUH Research Fund.
Funding Seoul National University Hospital(grant number 03-2015-0040).
ORCID Hyoung Jin Kang
http://orcid.org/0000-0003-1009-6002
References 1. Gornak KA. Primary multiple malignant tumors of the peripheral nerves. Zh Nevropatol Psikhiatr Im S SKorsakova. 1954; 54(3):272–277. 2. D’Agostino AN, Soule EH, Miller RH. Primary malignant neoplasms of nerves (malignant neurilemomas) in patients without manifestations of multiple neurofibromatosis (von recklinghausen’s disease). Cancer. 1963; 16:1003–1014. 3. D’Agostino AN, Soule EH, Miller RH. Sarcomas of the peripheral nerves and somatic soft tissues associated with multiple neurofibromatosis (Von Recklinghausen’s Disease). Cancer. 1963; 16:1015–1027.
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H. YUL AN ET AL.
4. Neurofibromatosis. Conference statement. National Institutes of Health Consensus Development Conference. Arch Neurol. 1988;45(5): 575–578. 5. Wolkenstein P, Freche B, Zeller J, et al. Usefulness of screening investigations in neurofibromatosis type 1. A study of 152 patients. Arch Dermatol. 1996;132(11):1333–1336. 6. Gutmann DH, Aylsworth A, Carey JC, et al. The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA. 1997;278(1):51–57. 7. Sorensen SA, Mulvihill JJ, Nielsen A. Long-term follow-up of von Recklinghausen neurofibromatosis. Survival and malignant neoplasms. N Engl J Med. 1986;314(16):1010–1015. 8. Ward BA, Gutmann DH. Neurofibromatosis 1: from lab bench to clinic. Pediatr Neurol. 2005;32(4):221–228. 9. Ferrari A, Bisogno G, Macaluso A, et al. Soft-tissue sarcomas in children and adolescents with neurofibromatosis type 1. Cancer. 2007;109(7):1406–1412. 10. Masocco M, Kodra Y, Vichi M, et al. Mortality associated with neurofibromatosis type 1: a study based on Italian death certificates (1995–2006). Orphanet J Rare Dis. 2011;6:11. 11. Kolberg M, Holand M, Agesen TH, et al. Survival meta-analysis for >1800 malignant peripheral nerve sheath tumor patients with and without neurofibromatosis type 1. NeuroOncol. 2013;15(2):135–147. 12. Evans DG, O’Hara C, Wilding A, et al. Mortality in neurofibromatosis 1: in North West England: an assessment of actuarial survival in a region of the UK since 1989. Eur J Hum Genet. 2011;19(11):1187–1191. 13. Ducatman BS, Scheithauer BW, Piepgras DG, et al. Malignant peripheral nerve sheath tumors. A clinicopathologic study of 120 cases.Cancer. 1986; 57(10):2006–2021. 14. Ducatman BS, Scheithauer BW, Piepgras DG, et al. Malignant peripheral nerve sheath tumors in childhood. J Neurooncol.1984;2(3):241–248. 15. Demir HA, Varan A, Yalcn B, et al. Malignant peripheral nerve sheath tumors in childhood: 13 cases from a single center. J Pediatr Hematol Oncol. 2012;34(3):204–207. 16. Casanova M, Ferrari A, Spreafico F, et al. Malignant peripheral nerve sheath tumors in children: a single-institution twenty-source experience. J Pediatr Hematol Oncol. 1999;21(6): 509–513. 17. deCou JM, Rao BN, Parham DM, et al. Malignant peripheral nerve sheath tumors: the St. Jude Children’s Research Hospital experience. Ann SurgOncol. 1995;2(6):524–529. 18. Deyrup AT, Weiss SW. Grading of soft tissue sarcomas: the challenge of providing precise information in an imprecise world. Histopathology.2006; 48(1):42–50. 19. Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 2010;17(6):1471–1474. 20. Evans DG, Baser ME, McGaughran J, et al. Malignant peripheral nerve sheath tumours in neurofibromatosis 1. J Med Genet.2002;39(5):311–314. 21. Zehou O. Chemotherapy for the treatment of malignant peripheral nerve sheath tumors in neurofibromatosis 1: a 10-source institutional review. Orphanet J Rare Dis. 2013;8:127. 22. Bishop AJ, Zagars GK, Torres KE, et al. Malignant peripheral nerve sheath tumors: a single institution’s experience using combined surgery and radiation therapy. Am J Clin Oncol. 2016. 23. Hwang IK, Hahn SM, Kim HS, et al. Outcomes of treatment for malignant peripheral nerve sheath tumors: different clinical features associated with neurofibromatosis type 1.Cancer Res Treat. 2017;49(3):717–726. 24. Ferner RE, Gutmann DH. International consensus statement on malignant peripheral nerve sheath tumors in neurofibromatosis. Cancer Res. 2002; 62(5):1573–1577. 25. James AW, Shurell E, Singh A, et al. Malignant peripheral nerve sheath tumor. Surg Oncol Clin N Am. 2016; 25(4):789–802. 26. Varan A, Sen H, Aydin B, et al. Neurofibromatosis type 1 and malignancy in childhood. Clin Genet. 2016;89(3):341–345. 27. Broski SM, Johnson GB, Howe BM, et al. Evaluation of (18)F-FDG PET and MRI in differentiating benign and malignant peripheral nerve sheath tumors. Skeletal Radiol.2016;45(8):1097–1105. 28. Kahn J, Gillespie A, Tsokos M, et al. Radiation therapy in management of sporadic and neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors. Front Oncol. 2014;4:324. 29. Rohrich M, Koelsche C, Schrimpf D, et al. Methylation-based classification of benign and malignant peripheral nerve sheath tumors. Acta Neuropathol. 2016;131(6):877–887.
PEDIATRIC HEMATOLOGY AND ONCOLOGY
477
30. Lopez G, Pollock RE. Evaluating the effect of HDAC8 inhibition in malignant peripheral nerve sheath tumors. Methods Mol Biol. 2017;1510:365–374. 31. Pemov A, Li H, Patidar R, et al. The primacy of NF1 loss as the driver of tumorigenesis in neurofibromatosis type 1-associated plexiformneurofibromas. Oncogene. 2017;36:3168–3177. 32. Ki DH, He S, Rodig S, et al. Overexpression of PDGFRA cooperates with loss of NF1 and p53 260 to accelerate the molecular pathogenesis of malignant peripheral nerve sheath tumors. Oncogene. 2017;36(8):1058–1068. doi:10.1038/onc.2016.269. 33. Kendall JJ, Chaney KE, Patel AV, et al. CK2 blockade causes MPNST cell apoptosis and promotes degradation of beta-catenin.Oncotarget. 2016;7(33):53191–53203. doi:10.18632/oncotarget.10668. 34. Rahrmann EP, Moriarity BS, Otto GM, et al. Trp53 haploinsufficiency modifies EGFR-driven peripheral nerve sheath tumorigenesis. Am J Pathol.2014;184(7):2082–2098. 35. Alaggio R, Turrini R, Boldrin D, et al. Survivin expression and prognostic significance in pediatric malignant peripheral nerve sheath tumors (MPNST).PLoS One.2013;8(11):e80456. 36. Gong M, Ma J, Li M, et al. MicroRNA-204 critically regulates carcinogenesis in malignant peripheral nerve sheath tumors. NeuroOncol. 2012;14(8):1007–1017. 37. Kroep JR, Ouali M, Gelderblom H, et al. First-line chemotherapy for malignant peripheral nerve sheath tumor (MPNST) versus other histological soft tissue sarcoma subtypes and as a prognostic factor for MPNST: an EORTC soft tissue and bone sarcoma group study. Ann Oncol. 2011;22(1):207–214. 38. Kasper B, Lehnert T, Bernd L, et al. High-dose chemotherapy with autologous peripheral blood stem cell transplantation for bone and soft-tissue sarcomas. Bone Marrow Transplant. 2004;34(1):37–41. 39. Knudson AG, Jr. Mutation and cancer: statistical study of retinoblastoma. Proc. Natl. Acad. Sci. U S A. 1971;68(4):820–823. 40. McPherson JR, Ong CK, Ng CC, et al. Whole-exome sequencing of breast cancer, malignant peripheral nerve sheath tumor and neurofibroma from a patient with neurofibromatosis type 1. Cancer Med. 2015;4(12):1871–1878. 41. TonsgardJH. Clinical manifestations and management of neurofibromatosis type 1. Semin Pediatr Neurol. 2006;13(1):2–7. 42. Cecen E, Ince D, Uysal KM, et al. Soft tissue sarcomas and central nervous system tumors in children with neurofibromatosis type 1.Childs Nerv. Syst. 2011;27(11):1885–1889.
