Establishment and characterization of a recurrent malignant peripheral nerve sheath tumor cell line: RsNF.

Malignant peripheral nerve sheath tumor (MPNST) is a highly aggressive and recurrent soft tissue sarcoma. It most commonly occurs secondary to neurofibromatosis type I, and it has a 5-year survival rate of only 8-13%. To better study the tumor heterogeneity of MPNST and to develop diverse treatment options, more tumor-derived cell lines are needed to obtain richer biological information. Here, we established a primary cell line of relapsed MPNST RsNF cells derived from a patient diagnosed with NF1 and detected the presence of NF1 mutations and SUZ12 somatic mutations through whole-exome sequencing(WES). Through tumor molecular marker targeted sequencing and single-cell transcriptome sequencing, it was found that chromosome 7 copy number variation (CNV) was gained in this cell line, and ZNF804B, EGFR, etc., were overexpressed on chromosome 7. Therefore, RsNF cells can be used as a useful tool in NF1-associated MPNST genomic amplification studies and to develop new therapeutic strategies.

Ovarian epithelioid malignant peripheral nerve sheath tumor with EWSR1-CREM fusion: A case report and literature review.

Epithelioid malignant peripheral nerve sheath tumor (EMPNST) is a rare soft tissue sarcoma. The authors report the first case of EMPNST arising in the ovary (OEMPNST). A 7-year-old child underwent left salpingo-oophorectomy due to tumor rupture and the pathology suggested a juvenile granulosa cell tumor (JGCT). Six cycles of bleomycin, etoposide, and carboplatin were administrated. A second surgery was applied due to relapse 4 months after the last cycle of chemotherapy, and the pathology revealed JGCT with extensive abdominopelvic seedings even after interinstitutional consultation in two hospitals. Next-generation sequencing demonstrated EWSR1 exon12-CREM exon6 fusion with neurofibromatosis-2 gene deletion, and no mutation was detected in either FOXL2 or DICER1. However, pathology consultation in two other hospitals suggested the diagnosis of OEMPNST, and additional immunohistochemical (IHC) staining revealed positive H3K27me3. Nonetheless, she was treated with nine courses of chemotherapy but experienced a second recurrence of extensive abdominal metastases approximately 3 months after ceasing chemotherapy. Neither elevated tumor makers nor abnormal sex hormones level was noted since the initial presentation. Repeated cytoreductive surgery was conducted and IHC staining showed expression of SOX10, S-100, INI-1, and α-inhibin in tumor tissue. A final diagnosis of OEMPNST with EWSR1-CREM fusion was established, indicating that the probability of OEMPNST could not be excluded when treatment for JGCT showed poor response. A comprehensive evaluation including biological characteristics, morphology, IHC staining, and molecular features is vital in the differential diagnosis between JGCT and OEMPNST.

Survival analysis of malignant peripheral nerve sheath tumor: Experience of a tertiary center in Taiwan.

BACKGROUND: This study aimed to analyze the demographic characteristics and prognostic factors of malignant peripheral nerve sheath tumor (MPNST) in a Taiwanese population. Single-center treatment outcomes were also presented. METHODS: This retrospective cohort study analyzed the medical records of 54 patients with pathological diagnoses of MPNSTs from 2005 to 2021 at a single institution. The primary endpoint was the 5-year overall survival rate of MPNST, and the secondary endpoint was recurrence-free 5-year survival. Variables including patient characteristics, metastasis status at initial diagnosis, and surgical outcomes were analyzed with competing risk analysis. RESULTS: Among all 41 eligible patients diagnosed with MPNST, female predominance was noted, and the median age at diagnosis was 44 years. The most common site of lesion was found at the trunk (46.34%), and eight patients were diagnosed with notable metastasis. Twelve patients were diagnosed with type 1 neurofibromatosis (NF1). The 5-year overall survival rate was 36.84% and the 5-year recurrence-free survival was 28.95%. Metastasis diagnosed at presentation, large lesion sizes, and recurrence were identified as significant poor prognostic factors of survival. Metastasis diagnosed at presentation was identified as the only significant risk factor of recurrence. CONCLUSION: In our series, metastasis diagnosed at presentation, large lesion sizes, and recurrence were identified as significant poor prognostic factors of survival. Metastasis was also identified as the only significant risk factor of recurrence. NF1-associated MPNSTs presented with significantly larger tumor sizes and additional treatment postoperatively did not significantly improve survival. The limitations of this study include its retrospective nature and sample size.

RRM2 as a novel prognostic and therapeutic target of NF1-associated MPNST.

BACKGROUND: Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas that typically develop in the setting of neurofibromatosis type 1 (NF1) and cause significant morbidity. Conventional therapies are often ineffective for MPNSTs. Ribonucleotide reductase subunit M2 (RRM2) is involved in DNA synthesis and repair, and is overexpressed in multiple cancers. However, its role in NF1-associated MPNSTs remains unknown. Our objective was to determine the therapeutic and prognostic potential of RRM2 in NF1-associated MPNSTs. METHODS: Identification of hub genes was performed by using NF1-associated MPNST microarray datasets. We detected RRM2 expression by immunochemical staining in an MPNST tissue microarray, and assessed the clinical and prognostic significance of RRM2 in an MPNST cohort. RRM2 knockdown and the RRM2 inhibitor Triapine were used to assess cell proliferation and apoptosis in NF1-associated MPNST cells in vitro and in vivo. The underlying mechanism of RRM2 in NF1-associated MPNST was revealed by transcriptome analysis. RESULTS: RRM2 is a key hub gene and its expression is significantly elevated in NF1-associated MPNST. We revealed that high RRM2 expression accounted for a larger proportion of NF1-associated MPNSTs and confirmed the correlation of high RRM2 expression with poor overall survival. Knockdown of RRM2 inhibited NF1-associated MPNST cell proliferation and promoted apoptosis and S-phase arrest. The RRM2 inhibitor Triapine displayed dose-dependent inhibitory effects in vitro and induced significant tumor growth reduction in vivo in NF1-associated MPNST. Analysis of transcriptomic changes induced by RRM2 knockdown revealed suppression of the AKT-mTOR signaling pathway. Overexpression of RRM2 activates the AKT pathway to promote NF1-associated MPNST cell proliferation. CONCLUSIONS: RRM2 expression is significantly elevated in NF1-associated MPNST and that high RRM2 expression correlates with poorer outcomes. RRM2 acts as an integral part in the promotion of NF1-associated MPNST cell proliferation via the AKT-mTOR signaling pathway. Inhibition of RRM2 may be a promising therapeutic strategy for NF1-associated MPNST.

Photonic hyperthermia of malignant peripheral nerve sheath tumors at the third near-infrared biowindow.

Background: Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas that typically carry a dismal prognosis. Given the insensitivity of these tumors to traditional chemotherapy and the absence of effective targeted drugs, new therapeutic strategies are urgently needed. Photothermal therapy (PTT) including near-infrared laser at the third biowindow (NIR-III) has demonstrated significant potential in cancer theranostics due to its minimally invasive nature and excellent therapeutic outcomes. However, the passive utilization of photothermal agents (PTAs) with poor target specificity and biocompatibility substantially hinders the clinical translation and application of this method. Methods: We evaluated the efficiency, safety, and underlying mechanisms of NIR-III without PTAs in the treatment of MPNSTs. The photothermal performance and tissue penetration capability of the NIR-III laser were evaluated in human MPNST cell lines using CCK-8, Calcein-AM and propidium iodide (PI) staining, and Annexin V-FITC/PI assays. The tumor xenografted mice model was used for evaluating the efficacy and biosafety of NIR-III photothermal ablation. Finally, the underlying mechanisms of NIR-III treatment, explored by whole-transcriptome sequencing, are further verified by RT-qPCR. Results: We found that although the NIR-III photothermal treatment efficiency varied among individuals, which was possibly influenced by different endoplasmic reticulum stress responses, the expected antineoplastic effect was ultimately achieved after adjustment of the power density and radiation duration. Conclusions: The present study provides an intriguing noninvasive therapy for MPNSTs that accelerates the clinical translation of PTT while avoiding the biocompatibility issues arising from PTAs. Funding: This work was supported by grants from National Natural Science Foundation of China (82102344; 82172228); Shanghai Rising Star Program supported by Science and Technology Commission of Shanghai Municipality (20QA1405600); Natural Science Foundation of Shanghai (22ZR1422300); Science and Technology Commission of Shanghai Municipality (19JC1413) ; "Chenguang Program" supported by Shanghai Education Development Foundation (SHEDF) (19CG18); Shanghai Municipal Key Clinical Specialty (shslczdzk00901); Innovative research team of high-level local universities in Shanghai (SSMU-ZDCX20180700).

Malignant peripheral nerve sheath tumor: models, biology, and translation.

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive, invasive cancer that comprise around 10% of all soft tissue sarcomas and develop in about 8-13% of patients with Neurofibromatosis Type 1. They are associated with poor prognosis and are the leading cause of mortality in NF1 patients. MPNSTs can also develop sporadically or following exposure to radiation. There is currently no effective targeted therapy to treat MPNSTs and surgical removal remains the mainstay treatment. Unfortunately, surgery is not always possible due to the size and location of the tumor, thus, a better understanding of MPNST initiation and development is required to design novel therapeutics. Here, we provide an overview of MPNST biology and genetics, discuss findings regarding the developmental origin of MPNST, and summarize the various model systems employed to study MPNST. Finally, we discuss current management strategies for MPNST, as well as recent developments in translating basic research findings into potential therapies.

Clinicopathological and prognostic significance of H3K27 methylation status in malignant peripheral nerve sheath tumor: correlation with skeletal muscle differentiation.

Malignant peripheral nerve sheath tumor (MPNST) is a very aggressive peripheral nerve sheath-derived sarcoma, which is one of the most difficult tumors to diagnose due to its wide spectrum of histological findings and lack of specific immunohistochemical markers. Recently, it has been reported that losses of expression of H3K27me3 and H3K27me2 caused by PRC2 dysfunction may be useful diagnostic markers for MPNST, but there is no consensus on their clinicopathological significance. Here, we investigated the relationship between loss of H3K27 methylation and various parameters and clarified the clinicopathological significance of such loss. We analyzed the clinicopathological and immunohistochemical features in 84 MPNST cases. Complete losses of H3K27me3 and H3K27me2 were observed in 37 (44%) and 29 (35%) cases, respectively. Losses of H3K27me3 and H3K27me2 were significantly correlated with myogenic immunopositivity (H3K27me3 vs. desmin, P = 0.0051; H3K27me3 vs. myogenin, P = 0.0009; H3K27me2 vs. myogenin, P = 0.042). Meanwhile, there were significant correlations between preservation of immunohistochemical neurogenic markers and intact H3K27me3 and H3K27me2 (H3K27me3 vs. S-100 protein, P = 0.0019; H3K27me3 vs. SOX10, P = 0.014; H3K27me2 vs. S-100 protein, P = 0.0011; H3K27me2 vs. SOX10, P = 0.0087). In multivariate analysis, local recurrence, distant metastasis, high FNCLCC grade, and loss of SOX10 expression were independent prognostic factors for overall survival. H3K27me3 and H3K27me2 expression was retained in all 26 cases of rhabdomyosarcoma non-alveolar subtype. In conclusion, we suggest that H3K27me3 and H3K27me2 immunonegativity is useful but not definitive for diagnosing MPNST. Complete loss of H3K27 methylation may be involved in aggressive transdifferentiation from neural differentiation to skeletal muscle differentiation in MPNST.

Comparison of the 7th and 8th version of the AJCC classification system for soft tissue sarcomas of extremities and trunk in patients with localised, intermediate or high-grade disease treated at European tertiary sarcoma centres.

BACKGROUND: The updated 8th version of the AJCC-staging system for soft tissue sarcomas (STS) has been criticised for omitting tumour depth as category-defining variable and eventually not improving prognostic accuracy in comparison to the 7th version. This study aimed at investigating the prognostic accuracy of both AJCC-versions in STS-patients treated at European tertiary sarcoma centres. METHODS: 1032 patients (mean age: 60.7 ± 16.3 years; 46.0% [n = 475] females; median follow-up: 38.6 months), treated at five tertiary sarcoma centres for localised, intermediate or high-grade STS of extremities and trunk were retrospectively included. Uni- and multivariate Cox-regression models and Harrell's C-indices were calculated to analyse prognostic factors for overall survival (OS) and assess prognostic accuracy. RESULTS: In univariate analysis, prognostic accuracy for OS was comparable for both AJCC-versions (C-index: 0.620 [8th] vs. 0.614 [7th]). By adding margins, age, gender, and histology to the multivariate models, prognostic accuracy of both versions could be likewise improved (C-index: 0.714 [8th] vs. 0.705 [7th]). Moreover, tumour depth did not significantly contribute to prognostic accuracy of the 8th version's multivariate model (C-index for both models: 0.714). Stratification into four main T-stages based on tumour size only, as implemented in the 8th version, significantly improved prognostic accuracy between each category. However, T-stages as defined in the 7th version had poorer discriminatory power (C-index: 0.625 [8th] vs. 0.582 [7th]). CONCLUSION: Both AJCC-versions perform equally well regarding prognostic accuracy. Yet, simplification of the 8 th version by omitting tumour depth as T-stage-defining parameter, whilst emphasizing the importance of tumour size, should be considered advantageous.

Treatment of malignant peripheral nerve sheath tumors in pediatric NF1 disease.

BACKGROUND: Malignant peripheral nerve sheath tumors (MPNSTs) are rare yet highly aggressive soft tissue sarcomas. Children with neurofibromatosis type 1 (NF1) have a 10% lifetime risk for development of MPNST. Prognosis remains poor and survival seems worse for NF1 patients. METHODS: This narrative review highlights current practices and pitfalls in the management of MPNST in pediatric NF1 patients. RESULTS: Preoperative diagnostics can be challenging, but PET scans have shown to be useful tools. More recently, functional MRI holds promise as well. Surgery remains the mainstay treatment for these patients, but careful planning is needed to minimize postoperative morbidity. Functional reconstructions can play a role in improving functional status. Radiotherapy can be administered to enhance local control in selected cases, but care should be taken to minimize radiation effects as well as reduce the risk of secondary malignancies. The exact role of chemotherapy has yet to be determined. Reports on the efficacy of chemotherapy vary as some report lower effects in NF1 populations. Promisingly, survival seems to ameliorate in the last few decades and response rates of chemotherapy may increase in NF1 populations when administering it as part of standard of care. However, in metastasized disease, response rates remain poor. New systemic therapies are therefore desperately warranted and multiple trials are currently investigating the role of drugs. Targeted drugs are nevertheless not yet included in first line treatment. CONCLUSION: Both research and clinical efforts benefit from multidisciplinary approaches with international collaborations in this rare malignancy.

Cardiac Malignant Peripheral Nerve Sheath Tumor Accessed By 18F-FDG PET/CT.

This is a case report of a patient presenting an extremely rare cardiac malignancy: malignant peripheral nerve sheath tumour. The 18F-fluorodeoxyglucosis positron emission tomography associated to computed tomography (18F-FDG PET/CT) accesses the tumour anatomy and metabolic activity, thereby making it possible to characterize a malignant neoplasm noninvasively. The diagnostic approach with 18F-FDG PET/CT spared the heart from a likely futile invasive procedure when detecting a distant metastasis and changed the biopsy site and therapeutic planning.

Giant Malignant Peripheral Nerve Sheath Tumor of the Scalp: Case Report and Review of the Literature.

BACKGROUND: Malignant peripheral nerve sheath tumors (MPNSTs) are rare nervous system tumors that rarely appear on the scalp. About half of the scalp MPNSTs described in the literature have reached giant dimensions at the time of diagnosis. The surgical treatment is the gold standard for this type of tumor. Some authors suggest adjuvant radiotherapy for local tumor control, although there is uncertainty about its advantages and its use is not without risks. CASE DESCRIPTION: We present the case of a 31-year-old man who presented with a large necrotic scalp tumor of the left frontoparietal convexity. magnetic resonance imaging showed a large extra-axial tumor, measuring 17 x 17 x 8 cm, centered on the soft tissues, with skull erosion and signs of dural invasion, although with no intradural component. The tumor was surgically removed and the osteocutaneous defect was reconstructed with a latissimus dorsi muscle free flap. The anatomopathologic diagnosis was MPNST. The patient then underwent adjuvant radiotherapy. After 7 months he developed a progressive right hemiparesis and magnetic resonance imaging showed results compatible with cerebral radiation necrosis. This motor deficit improved with corticotherapy. After 9 months the patient went back to his home country and was subsequently lost to follow-up. CONCLUSIONS: Giant MPNSTs of the scalp are highly aggressive lesions that should primarily be treated in a surgical fashion. Although adjuvant radiotherapy has been used routinely for local tumor control, there is uncertainty about its advantages.

Neurofibromatosis-associated malignant peripheral nerve sheath tumors in children have a worse prognosis: A nationwide cohort study.

BACKGROUND: Malignant peripheral nerve sheath tumors (MPNST) are rare and aggressive non-rhabdomyoblastic soft-tissue sarcomas (NRSTS) in children. This study set out to investigate clinical presentation, treatment modalities, and factors associated with survival in pediatric MPNST using Dutch nationwide databases. METHODS: Data were obtained from the Netherlands Cancer Registry (NCR) and the Dutch Pathology Database (PALGA) from 1989 to 2017. All primary MPNSTs were collected. Demographic differences were analyzed between adult and pediatric (age ≤18 years) MPNST. In children, demographic and treatment differences between neurofibromatosis type 1 (NF1) and non-NF1 were analyzed. A Cox proportional hazard model was constructed for localized pediatric MPNSTs. RESULTS: A total of 70/784 MPNST patients were children (37.1% NF1). Children did not present differently from adults. In NF1 children, tumor size was more commonly large (> 5 cm, 92.3% vs 59.1%). Localized disease was primarily resected in 90.6%, and radiotherapy was administered in 37.5%. Non-NF1 children tended to receive chemotherapy more commonly (39.5% vs 26.9%). Overall, estimated five-year survival rates of localized NF1-MPNST was 52.4% (SE: 10.1%) compared with 75.8% (SE: 7.1%) in non-NF1 patients. The multivariate model showed worse survival in NF1 patients (HR: 2.98; 95% CI, 1.17-7.60, P = 0.02) and increased survival in patients diagnosed after 2005 (HR: 0.20; 95% CI, 0.06-0.69, P = 0.01). No treatment factors were independently associated with survival. CONCLUSION: Pediatric MPNSTs have presentations similar to adult MPNSTs. In children, NF1 patients present with larger tumors, but are treated similarly to non-NF1 MPNSTs. In localized pediatric MPNST, NF1 is associated with worse survival. Promisingly, survival has increased for pediatric MPNSTs after 2005.

Cardiac malignant peripheral nerve sheath tumor on computed tomography and magnetic resonance imaging: A case report.

RATIONALE: Malignant peripheral nerve sheath tumor (MPNST) is a very rare sarcoma of the heart, and few cases have been reported. Herein, we retrospectively reviewed clinical manifestations, imaging features and management of our patient and other reported cases. PATIENT CONCERNS: A 32-year-old woman was referred to the emergency department of our institution with expiratory dyspnea, edema of face for a month. DIAGNOSIS: The patient was initially diagnosed with asthma at a local hospital based on a history of fatigue, cough and expiratory dyspnea, as well as negative electroencephalogram (ECG) and chest radiography. Based on computed tomography (CT) and cardiac magnetic resonance imaging (CMRI) in our hospital, she was found to have a malignant tumor involving right atrium. The tumor was diagnosed as MPNST according to histopathological results. INTERVENTIONS: The tumor was deemed unresectable during the surgery. Then, the patient was referred for chemotherapy and radiotherapy. OUTCOMES: The patient deteriorated and died 4 months later. LESSONS: Cardiac MPNST is very uncommon with nonspecific clinical and imaging characteristics according to limited cased reported. CMR, due to the high tissue resolution and multiple sequence imaging advantages, is useful for the detection, location and evaluation whether there is involvement of adjacent structures, and may help better clinical decision-making.

[The nerve root syndrome in small animals - A review focussing on pathophysiology and therapy in the dog]. / Das Nervenwurzelsyndrom beim Kleintier.

A large variety of etiologies is considered to be the cause of nerve root syndrome in dogs. Lateralized disc herniation, foraminal stenosis and malignant as well as benign nerve sheath tumors are some of the most important triggers described. The clinical signs of a nerve root syndrome are characterized by monoparesis in combination with progressive lameness, which may be accompanied by an elevation of the affected limb. Although the problem is well known among clinicians, there is no review article in the veterinary literature that specifically covers the subject of "nerve root syndrome in small animals". Mostly, this is merely mentioned as a symptom of its potential etiologies, as the so-called "nerve root sign" or "nerve root signature". In the pathophysiology of nerve root compression or irritation, a number of biomechanical and biochemical factors play a role. These occur individually or in combination and may lead to the same changes. The pathophysiology of the syndrome seems to focus around changes in microcirculation. These microcirculation disorders not only lead to pathomorphological changes such as edema formation, demyelination and axon death, but also initiate a cascade of reactions at the site of damage as well as in the central nervous tissue. This leads to the release of various neuropeptides, modulation of nerve excitability and impulse transmission. Different pathomechanisms therefore often lead to a uniform damage pattern, which makes it difficult to point out the original triggering factors. The body's response to these factors determines whether a nerve root syndrome actually develops or not. The treatment of the cause, if found, and an individual and multimodal pain therapy seem to be the most successful therapeutic approaches for nerve root syndrome in dogs.

[Targeted therapy for malignant peripheral nerve sheath tumor: translational research and clinical application].

Malignant peripheral nerve sheath tumor (MPNST) is a rare invasive soft tissue sarcoma that originates from peripheral nerve branches and peripheral nerve sheaths. Early radical surgery is an effective treatment for MPNST. Since it is insensitive to radiotherapy and chemotherapy, the disease manifests a rapid progression, poor prognosis and high mortality. In recent years, the translational researches on the driving factors and therapeutic targets of MPNST have been rapidly developed, including the pathways of NF1-Ras, Raf-MEK-ERK, PI3K-AKT-mTOR, Wnt signaling, and abnormal expressions of apoptotic proteins, the general loss of polycomb repressive complex 2 (PRC2), upregulation of the HDAC family, abnormal expressions of receptor tyrosine kinases, expressions of programmed cell death ligand (PD-L1), aurora kinase and various microRNAs.This review summarizes the current translational researches on potential therapeutic targets of MPNST, and the clinical trials which provide helpful information for MPNST targeted therapy.

[Treatment of malignant peripheral nerve sheath tumors: case reports and a literature review]. / Lechenie zlokachestvennykh opukholei obolochek perifericheskikh nervov: sluchai iz praktiki i obzor literatury.

Malignant peripheral nerve sheath tumors (MPNSTs) are soft tissue sarcomas that develop from peripheral nerve sheath cells (T. Hirose, B.W. Scheithauer). These tumors are characterized by aggressive growth with an unfavorable outcome and may develop de novo or through malignant transformation of schwannomas, neurofibromas, or ganglioneuromas. MPNSTs are characterized by a rapid course and a poor prognosis. In this article, we reported cases of patients with malignant peripheral nerve tumors of the brachial plexus trunks and spinal localization.

Multiple primary malignancies associated with a germline SMARCB1 pathogenic variant.

A 51-year old presented with a 6-month history of increasing pelvic/lower back pain with nocturnal waking and episodes of anorexia and vomiting. Examination revealed right torticollis and Horner's syndrome, and a large abdominal mass arising from the pelvis. Magnetic resonance and positron emission tomography imaging revealed (A) a 14 cm heterogeneous enhancing mass, abutting the left kidney with standardised uptake value max = 2.9, (B) a large heterogeneous enhancing pelvic mass (C) mesenteric adenopathy standardised uptake value max = 10.3 and (D) 6 cm right lung apex mass standardised uptake value max = 4.3. Computerised tomography-guided biopsy of lesion A was reported as neurofibroma with occasional atypia, lesion B a benign uterine leiomyoma and lesion C follicular lymphoma world health organisation Grade 2. Although she had been given the diagnosis of Neurofibromatosis Type-1 (NF1) 25-years previously following removal of an intradural extramedullary schwannoma she had no cutaneous stigmata of NF1. Genetic analysis of blood lymphocyte DNA identified a pathogenic variant in SMARCB1 confirming a diagnosis of schwannomatosis. Following 6-months chemotherapy for lymphoma, surgery was performed to remove lesion A. Histology revealed a malignant peripheral nerve sheath tumour with areas of low and high-grade change. An incidental, well-differentiated small bowel neuroendocrine carcinoma was also excised. Close surveillance continues with no recurrence after 6 years. This case study describes a novel finding of three separate synchronous primary malignancies in a patient with schwannomatosis and a proven SMARCB1 pathogenic variant.

Outcome and prognostic factors in pediatric malignant peripheral nerve sheath tumors: An analysis of the European Pediatric Soft Tissue Sarcoma Group (EpSSG) NRSTS-2005 prospective study.

BACKGROUND: Malignant peripheral nerve sheath tumors (MPNST) are rare tumors of childhood. The role of standard chemotherapy in unresectable MPNST is still unclear. We report the outcome and prognostic factors in the EpSSG risk-adapted prospective study for localized pediatric MPNST. METHODS: Patients were stratified into four treatment groups defined by surgical resection, tumor size, and tumor grade (G): (a) surgery-only group-resected tumors G1; (b) adjuvant radiotherapy group-R0/R1, G2 tumors; (c) adjuvant chemotherapy group-R0/R1, G3 tumors; and (d) neoadjuvant chemotherapy group-R2 resected tumors and/or nodal involvement. Chemotherapy consisted of four courses of ifosfamide-doxorubicin and two courses of ifosfamide concomitant with radiotherapy (50.4-54 Gy). RESULTS: Overall, the study included 51 patients. The 5-year event-free survival (EFS) and overall survival (OS) were 52.9% (95% confidence interval, 38.1-65.8) and 62.1% (46.7-74.3), respectively. The 5-year EFS was 92% (56.6-98.9) for treatment group 1 (N = 13), 33% (0.9-77.4) for treatment group 2 (N = 4), 29% (4.1-61.2) for treatment group 3 (N = 7), and 42% (23.1-60.1) for treatment group 4 (N = 27). Response rate to chemotherapy (partial response + complete response) in patients with measurable disease was 46%. The presence of neurofibromatosis type 1 (NF1; 51% of patients) was an independent poor prognostic factor for OS and EFS. CONCLUSION: The outcome for patients with resectable MPNST was excellent. Standard ifosfamide-doxorubicin for unresectable MPNST rendered the best reported outcome. Children with NF1 disease seem to have worse prognosis.