Survival outcomes of malignant peripheral nerve sheath tumors (MPNSTs) with and without neurofibromatosis type I (NF1): a meta-analysis.

INTRODUCTION: Malignant peripheral nerve sheath tumors (MPNSTs) are malignancies that demonstrate nerve sheath differentiation in the peripheral nervous system. They can occur sporadically or be associated with neurofibromatosis type 1 (NF1), an autosomal dominant neurocutaneous disorder, with up to 13% of patients developing MPNSTs in their lifetimes. Previous studies have suggested conflicting findings regarding the prognosis of NF1 for patients with MPNSTs. The elucidation of NF1 as an independent prognostic factor on mortality has implications for clinical management. We aim to investigate the role of NF1 status as an independent prognostic factor of overall survival (OS) and disease-specific survival (DSS) in MPNSTs. METHODS: An electronic literature search of PubMed and MEDLINE was performed on studies reporting OS or DSS outcomes of MPNSTs with and without NF1. A grey literature search by reviewing bibliographies of included studies and review articles was performed to find pertinent studies. Data was extracted and assessed in accordance with the PRISMA guidelines. A meta-analysis was performed to calculate hazard ratios (HRs) using a random-effects model. The primary and secondary outcomes were all-cause and disease-specific mortality, respectively, with NF1 as an independent prognostic factor of interest. RESULTS: A total of 59 retrospective studies involving 3602 patients fulfilled the inclusion criteria for OS analysis, and 23 studies involving 704 MPNST patients were included to evaluate DSS outcomes. There was a significant increase in the hazard of all-cause mortality (HR 1.63, 95% CI 1.45 to 1.84) and disease-specific mortality (HR 1.52, 95% CI 1.24 to 1.88) among NF1 as compared to sporadic cases. Subgroup analyses and meta-regression showed that this result was consistent regardless of the quality of the study and year of publication. CONCLUSION: NF1 is associated with a substantially higher risk of all-cause and disease-specific mortality. This finding suggests that closer surveillance is required for NF1 patients at risk of developing MPNSTs.

Outcome of Patients With Malignant Peripheral Nerve Sheath Tumors Enrolled on Sarcoma Alliance for Research Through Collaboration (SARC) Phase II Trials.

BACKGROUND: Evaluation of prior phase II trials for malignant peripheral nerve sheath tumors (MPNST) may help develop more suitable trial endpoints in future studies. METHODS: We analyzed outcomes of patients with recurrent or unresectable/metastatic MPNST enrolled on prior Sarcoma Alliance for Research through Collaboration (SARC) phase II trials and estimated the progression-free survival (PFS). PFS from SARC006 (NCT00304083), the phase II trial of upfront chemotherapy in chemotherapy naïve patients, was analyzed separately. Impact of baseline enrollment characteristics on PFS was evaluated. RESULTS: Sixty-four patients (29 male, 35 female, median age 39 years (range 15-81)) with MPNST were enrolled on 1 of 5 trials of single agent or combination therapy that were determined to be inactive. Patients had received a median of 1 (range 0-5) prior systemic therapy, and most had undergone prior surgery (77%) and radiation (61%). Seventy-three percent had metastatic disease at enrollment. Median PFS was 1.77 months (95% CI, 1.61-3.45), and the PFS rate at 4 months was 15%. Greater number of prior systemic therapies and worse performance status were associated with inferior PFS. There was no significant difference in PFS based on age at enrollment, treatment trial, response criteria, presence of metastatic disease, disease site at enrollment, and prior surgery or radiation. In comparison, on the SARC006 trial the PFS rate at 4 months was 94% in 40 patients. CONCLUSION: These data provide a historical baseline PFS that may be used as a comparator in future clinical trials for patients with MPNST.

Surgical management of craniospinal axis malignant peripheral nerve sheath tumors: a single-institution experience and literature review.

BACKGROUND: Malignant peripheral nerve sheath tumor (MPNST) is an exceedingly rare and aggressive tumor, with limited literature on its management. Herein, we present our series of surgically managed craniospinal MPNSTs, analyze their outcomes, and review the literature. METHODS: We retrospectively reviewed surgically managed primary craniospinal MPNSTs treated at our institution between January 2005 and May 2023. Patient demographics, tumor features, and treatment outcomes were assessed. Neurological function was quantified using the Frankel grade and Karnofsky performance scores. Descriptive statistics, rank-sum tests, and Kaplan-Meier survival analyses were performed. RESULTS: Eight patients satisfied the inclusion criteria (4 male, 4 female). The median age at presentation was 38 years (range 15-67). Most tumors were localized to the spine (75%), and 3 patients had neurofibromatosis type 1. The most common presenting symptoms were paresthesia (50%) and visual changes (13%). The median tumor size was 3 cm, and most tumors were oval-shaped (50%) with well-defined borders (75%). Six tumors were high grade (75%), and gross total resection was achieved in 5 patients, with subtotal resection in the remaining 3 patients. Postoperative radiotherapy and chemotherapy were performed in 6 (75%) and 4 (50%) cases, respectively. Local recurrence occurred in 5 (63%) cases, and distant metastases occurred in 2 (25%). The median overall survival was 26.7 months. Five (63%) patients died due to recurrence. CONCLUSIONS: Primary craniospinal MPNSTs are rare and have an aggressive clinical course. Early diagnosis and treatment are essential for managing these tumors. In this single-center study with a small cohort, maximal resection, low-grade pathology, young age (< 30), and adjuvant radiotherapy were associated with improved survival.

Secretome analysis of human schwann cells derived from malignant peripheral nerve sheath tumor.

Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive, nerve-associated tumors and the main cause of death amongst neurofibromatosis type I (NF1) patients. Schwann cells (SCs) are the pathogenic cell type in MPNST, however the secretome of human MPNST -derived SCs is poorly defined. In this study, a comprehensive proteomic analysis of the proteins secreted by the sNF96.2 human SC line, derived from a patient with MPNST, was performed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). A total of 17,354 unique peptides corresponding to 1538 individual proteins were identified. Among them, 995 proteins were confirmed as secreted using various bioinformatics tools including SignalP, SecretomeP, Vertebrate Secretome Database (VerSeDa), and Ingenuity Pathway Analysis (IPA). Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were conducted to assign protein localization and function, and to define enriched pathways. Protein binding was the most enriched molecular function, and the most enriched biological process was cell-cell adhesion. Metabolic pathways showed the highest levels of enrichment. In addition, 13 of the identified proteins were validated in Western blotting. This comprehensive secretome map constitutes a reference library providing a new molecular insight into MPNST.

Investigation of Ultrasound Parameters for the Differential Diagnosis of Malignant and Benign Peripheral Nerve Sheath Tumors.

OBJECTIVES: The objectives were to identify the key features of malignant and benign peripheral nerve sheath tumors (PNSTs) and determine a strategy for differentiating them using sonography. METHODS: Forty-six malignant peripheral nerve sheath tumors (MPNSTs) and 83 benign peripheral nerve sheath tumors (BPNSTs) confirmed by pathology from April 2010 to July 2021 were included. The general data and grayscale and color Doppler ultrasonic manifestations were compared between the two groups. We used single factor, multifactor, and area under the receiver operating characteristic (ROC) curve analyses to extract significant malignant risk factors and then established a scoring system with these factors. RESULTS: The significant variables identified in univariate analysis (P < .05) were maximum diameter, location, shape, boundary, encapsulation, echogenicity, texture pattern, calcification, entering or exiting nerve, and vascularity. Shape, boundary and vascularity were significant risk factors, and a scoring system was established. The area under the ROC curve (0.925) confirmed the usefulness of the scoring system for differentiating MPNSTs and BPNSTs. CONCLUSIONS: Ultrasonography is an effective method for differentiating MPNSTs from BPNSTs.

Phase II clinical trial of pazopanib for patients with unresectable or metastatic malignant peripheral nerve sheath tumors.

Malignant peripheral nerve sheath tumor (MPNST) often does not respond well to chemotherapy and develops against a background of NF1. The purpose of our study was to examine the efficacy of pazopanib against MPNST. Our study was designed as a physician-initiated phase II clinical trial in patients with advanced MPNST. Patients were registered from 11 large hospitals. The primary endpoint was set to clarify the clinical benefit rate (CBR) at 12 weeks according to response evaluation criteria in solid tumors (RECIST). Progression-free survival (PFS), overall survival (OS) and the CBR based on modified Choi evaluation at week 12 were set as secondary endpoints along with treatment-related safety. The study enrolled 12 patients. Median age was 49 years. Seven had Grade 2 and five Grade 3 according to the FNCLCC evaluation. Median follow-up period was 10.6 months. CBR at 12 weeks was both 50.0% (RECIST and Choi). The median PFS was 5.4 months for both RECIST and Choi, and the median OS was 10.6 months. Of special interest, the median PFS was 2.9 months for patients with FNCLCC Grade 2 and 10.2 months for Grade 3 (both RECIST and Choi). Grade 4 adverse events of neutropenia and lipase elevation were noted in one patient each. The results of this pazopanib therapy were generally better than those of any of the other single molecular targeted therapies reported previously. Although accumulation of more cases remains necessary, we conclude pazopanib treatment for MPNST to be a safe and promising treatment after doxorubicin-based chemotherapy.

Soft tissue sarcoma in adolescent and young adult patients: a retrospective study using a nationwide bone and soft tissue tumor registry in Japan.

OBJECTIVE: The relationship between the adolescent and young adult age groups and poor overall survival in soft tissue sarcoma and the risk factors for poor outcomes in adolescent and young adult patients with soft tissue sarcoma were analyzed. METHODS: The medical records of 7759 Japanese patients diagnosed with soft tissue sarcoma from 2006-13 were accessed from the Bone and Soft Tissue Tumor registry. The epidemiological features of adolescent and young adult patients were compared with those of other age groups. The cancer survival rates were calculated using the Kaplan-Meier method. The prognostic factors for cancer survival were analyzed with the Cox proportional hazards models. The primary endpoint for prognosis was tumor-related death. RESULTS: There were 210 children, 1467 adolescent and young adults, 2771 adults and 3311 elderly among the 7759 patients identified with soft tissue sarcoma. Compared with other age groups, the proportions of myxoid/round cell liposarcoma, synovial sarcoma, malignant peripheral nerve sheath tumor, primitive neuroectodermal tumor and rhabdomyosarcoma in adolescent and young adult patients were the highest, but none was significantly more prevalent in adolescent and young adult patients. On multivariate analysis, age was not a prognostic factor for poor cancer survival among adolescent and young adult patients with soft tissue sarcoma. The cancer survival rates of adolescent and young adult patients with malignant peripheral nerve sheath tumor were poorer than those of the other age groups; however, adolescent and young adult age was not a prognostic factor on multivariate analysis in malignant peripheral nerve sheath tumor patients. CONCLUSIONS: Our study is the first to investigate soft tissue sarcoma in adolescent and young adult patients using the nationwide Bone and Soft Tissue Tumor registry. Adolescent and young adult age is not a prognostic factor for poor cancer survival among those with soft tissue sarcoma in Japan.

Incidence and prognosis of distant metastasis in malignant peripheral nerve sheath tumors.

BACKGROUND: Malignant peripheral nerve sheath tumors (MPNSTs) are a type of soft tissue sarcomas (STS) with recurrence and metastatic potential. We aimed to investigate the risk factors for developing distant metastases (DM) and to identify the prognostic factors in patients with DM. METHODS: Based on the Surveillance, Epidemiology, and End Result (SEER) database, MPNST patients diagnosed between 2010 and 2016 were extracted in our study. The logistic regression model was performed for predicting DM development while the Cox proportional hazard regression model was conducted for revealing the prognostic factors. RESULTS: Eventually, 764 patients diagnosed with MPNSTs were included with 109 cases presenting with metastases at initial diagnosis. Larger tumor size and lymph node metastases were independent risk factors for developing DM. The median overall survival (OS) for patients with metastases was 8.0 (95% CI: 6.1-9.9) months. Multiple metastatic sites and no surgical treatment were prognostic factors for worse survival. Tumors located in non-head and neck region were related with better survival. CONCLUSIONS: The incidence of DM was 14.3% with a dismal median OS of 8.0 months for metastatic MPNSTs. More evaluation should be applied for patients with large tumor size and lymph metastases. Tumors located in head and neck region and the presence of multiple metastases predicted worse survival outcome. Surgical treatment can significantly improve the survival of MPNST patients with distant metastasis.

Recurrent malignant peripheral nerve sheath tumor of the parietal scalp.

Malignant peripheral nerve sheath tumors (MPNSTs) are a rare and aggressive subtype of sarcomas defined by their neural origin. Head and neck manifestations are particularly uncommon. Challenges exist in diagnosis, management, and recurrence. Achieving local control, particularly in the head and neck region, is difficult. We present a patient with a rapidly enlarging MPNST on the right parietal calvarium shortly after resection of a right vagus nerve MPNST. Recommendation was made for excision and reconstruction with a local advancement flap followed by radiation therapy. Local control with good aesthetic outcome was achieved by applying recommended surgical and oncologic principles.

Racial/ethnic disparities and incidence of malignant peripheral nerve sheath tumors: results from the Surveillance, Epidemiology, and End Results Program, 2000-2014.

BACKGROUND: Malignant peripheral nerve sheath tumors (MPNSTs) are rare tumors, generally high-grade, and comprise ~ 5-10% of soft tissue sarcomas. Over two-thirds of MPNSTs metastasize, and upwards of 40% clinically recur. Etiologic risk factors for MPNSTs are historically understudied. There is evidence to suggest MPNST incidence differs across racial/ethnic groups in pediatric populations. Therefore, we sought to estimate differences in MPNST incidence by race/ethnicity among all ages in the United States. METHODS: Incidence data were obtained from the Surveillance, Epidemiology, and End Results (SEER-18) Program, 2000-2014. Race/ethnicity was categorized as: White; Black; Asian; Other; and Latino/a ("Spanish-Hispanic-Latino"). Latino/a included all races, while all other categories excluded those identified as Latino/a. Age-adjusted incidence rate ratios (IRR) and 95% confidence intervals (CIs) were generated in SEER-STAT (v8.3.4). We estimated incidence rates among all ages, and among those diagnosed < 25 and ≥ 25 years. RESULTS: MPNST cases were abstracted from SEER-18 (n = 1047). Among all age groups, Blacks experienced an elevated incidence of MPNSTs compared to Whites (IRRBlacks = 1.26, 95% CI 1.04-1.50). Asian and Latinos/as experienced lower incidences compared to Whites (IRRAsians = 0.78, 95% CI 0.61-0.99; IRRLatinos/as = 0.84, 95% CI 0.69-1.02). In subgroup analyses, no statistically significant associations with MPNSTs were identified among cases diagnosed < 25 years of age, whereas the associations observed among all age groups were prominent among those diagnosed ≥ 25 years of age. CONCLUSIONS: Incidence rates of MPNSTs were highest in Blacks compared to Whites and other minority groups. This study suggests specific patterns exist in terms of race/ethnicity and age at diagnosis of MPNSTs.

Salvage rates and prognostic factors after relapse in children and adolescents with malignant peripheral nerve sheath tumors.

BACKGROUND: Malignant peripheral nerve sheath tumor (MPNST) is one of the most common nonrhabdomyosarcoma soft tissue sarcomas encountered in pediatric age, and it is generally characterized by poor outcome, particularly for relapsing patients. MATERIALS AND METHODS: This study considered 73 patients <21 years of age with relapsing MPNST observed among 120 patients enrolled in Italian pediatric protocols from 1979 to 2004. With the aim of possibly establishing a risk-adapted stratification, patients' outcome was examined using univariate and multivariate analysis based on clinical features at onset, first-line treatments, clinical findings at the time of first relapse, and second-line treatments. RESULTS: The time to relapse ranged from 1 to 204 months after first diagnosis (median 7 months). The first relapse event was mainly local. At the time of our analysis, nine patients were alive in remission. The median overall survival after first relapse was 11 months, and the survival rates were 39.2% at 1 year and 15.8% at 5 years. The factors revealing the greatest impact on prognosis were as follows: initial tumor invasiveness, time of relapse, and achievement of a secondary complete remission (which was related to the feasibility of radical surgery). CONCLUSIONS: Our study confirmed the unsatisfactory prognosis for pediatric patients with relapsing MPNST and pointed to a risk-adapted stratification model for the purposes of deciding second-line treatments. For the time being, an aggressive surgical approach seems to be the only effective salvage treatment and should be recommended. New therapeutic approaches are under evaluation with a view to improving current outcomes.

Desmoplastic melanoma may mimic a cutaneous peripheral nerve sheath tumor: Report of 3 challenging cases.

Desmoplastic melanoma (DM) and cutaneous malignant peripheral nerve sheath tumors (MPNST) reveal histological and immunohistochemical similarities, including S100 positivity and negative staining for conventional melanocytic markers. We present 3 cases of cutaneous S100-positive spindle cell tumors in elderly patients, in which first findings led to initial misdiagnoses as cutaneous MPNST and benign peripheral sheath nerve tumor (neurofibroma). The identification of adjacent atypical melanocytic hyperplasia in the overlying skin along with tumor cell proliferation, also in the superficial dermis, the neurotropic component and the absence of any relationship between the tumor and a major nerve, pre-existing neural benign tumor or the existence of stigmata suggestive of neurofibromatosis raised consideration of a DM. Careful attention should be paid to the presence of a firm dermal nodule and atypical scar lesions especially in sun-exposed areas (mainly head and neck region) in elderly patients associated with S100-positive spindle cell proliferation, solar elastosis and adjacent atypical melanocytic proliferation. In such cases, the possibility of a DM should be excluded with caution, especially if the tumor reveals a paucicellular morphology resembling various non-melanocytic neoplasms including malignant or benign peripheral sheath nerve tumors.

Wnt Signaling in Ewing Sarcoma, Osteosarcoma, and Malignant Peripheral Nerve Sheath Tumors.

PURPOSE OF REVIEW: Wnt signaling plays a central role in development and homeostasis, and its dysregulation is a common event in many types of human cancer. Here we explore in detail the contributions of Wnt signaling to the initiation and maintenance of three types of saroma: Ewing sarcoma, osteosarcoma, and malignant peripheral nerve sheath tumors. This review provides an overview of the Wnt signaling pathway and explores in detail the current knowledge about its role in the initiation or maintenance of three tumor types: Ewing sarcoma, osteosarcoma, and malignant peripheral nerve sheath tumors. RECENT FINDINGS: Recent work has assessed the role(s) of Wnt signaling within these cell types. This review provides an overview of the mechanistic insights that have been gained from a number of recent studies to set the foundation for potential therapeutic applications. Wnt signaling has emerged as a potentially critical pathway in maintaining the growth of these types of tumors. Given the fact that many new inhibitors of the pathway have recently or will soon enter Phase 1 clinical trials, it is likely that assessment of their activity in these tumor types will occur in human patients.

[Clinicopathological features and prognosis of malignant peripheral nerve sheath tumor: a retrospective study of 140 cases].

Objective: To investigate the clinicopathological features and prognosis of malignant peripheral nerve sheath tumors (MPNST). Methods: We retrospectively reviewed the clinical data of MPNST patients who were treated at Cancer Institute & Hospital, Chinese Academy of Medical Science from January 1999 to January 2016. A total of 140 patients with 66 male and 74 female with MPNST were enrolled in the study. The median age was 40 at the time of diagnosis. Survival analysis were estimated by Kaplan-Meier method and Log rank test. Multivariate analysis were estimated by Cox proportional hazards regression model. Results: The median follow-up time was 43.0 months. The 3- and 5-year overall survival (OS) rates were 56.4% and 48.6%, respectively. The 3-year local recurrence (LR) rate and distant metastasis (DM) rates were 42.9% and 49.3%, respectively. Univariate analysis showed that the tumor location, AJCC stage, S-100, radiotherapy and margin status affected 5-year OS rate (all P<0.05). The tumor location, AJCC stage, S-100, Ki-67 staining, margin status, radiotherapy and chemotherapy affected 3-year LR rate (all P<0.05). The tumor location, AJCC stage, S-100, Ki-67 staining and margin status affected 3-year DM rate (all P<0.05). Multivariate analysis showed that the tumor location, AJCC stage, S-100 were independent factors for 5-year OS rate (all P<0.05). The tumor location, Ki-67 staining and chemotherapy were independent factors for LR (all P<0.05) while the AJCC stage, margin status and Ki-67 staining were independent factors for DM (all P<0.05). Conclusions: MPSNT is an aggressive tumor with poor prognosis. Multiple factors were identified in this study. Patients with the tumor located at head and neck, advanced AJCC stage and negative S-100 usually have a low 5-year overall survival rate. Patients with the tumor located at head and neck, Ki-67 staining ≥ 20% and without chemotherapy had a higher tendency of local recurrence. Poor prognosis factors for DM were advanced AJCC stage, positive margin and Ki-67 staining ≥ 20%.

Sec6/8 regulates Bcl-2 and Mcl-1, but not Bcl-xl, in malignant peripheral nerve sheath tumor cells.

Sec6 and Sec8, which are components of the exocyst complex, has been concerned with various roles independent of its role in secretion, such as cell migration, invadopodia formation, cytokinesis, glucose uptake, and neural development. Given the vital roles of the exocyst complex in cellular and developmental processes, the disruption of its function may be closely related to various diseases such as cancer, diabetes, and neuronal disorders. Malignant peripheral nerve sheath tumors (MPNSTs) have high malignant potential and poor prognosis because of aggressive progression and metastasis. To date, no chemotherapeutic agents have been validated for MPNSTs treatment because how MPNSTs are resistant to chemotherapeutic agents remains unknown. This study demonstrates that combination of doxorubicin and sorafenib induces apoptosis in MPNST cells through downregulation of B cell lymphoma protein 2 (Bcl-2), Bcl-2-related protein long form of Bcl-x (Bcl-xl), and myeloid cell leukemia 1 (Mcl-1). Moreover, both Sec6 and Sec8 levels decreased after treatment with doxorubicin and sorafenib and were found to be associated with Bcl-2 and Mcl-1 expressions, but not Bcl-xl. Although Sec8 was found to be involved in the regulation of both Bcl-2 and Mcl-1 at the mRNA level, Sec6 regulated Bcl-2 at the mRNA level and the binding affinity of F-box and WD repeat domain containing 7 and Mcl-1, thereby controlling Mcl-1 at the protein level. Bcl-2 or Mcl-1 mRNA suppression by Sec6 or Sec8 depletion resulted in significant changes in nuclear factor-kappa B, cAMP response element, and p53 transcriptional activity. These results suggest that Sec6 and Sec8 are therapeutic target molecules in MPNST.

Neurofibromatosis type 1 and malignancy in childhood.

Neurofibromatosis type 1 (NF1) is an autosomal dominant hereditary neurocutaneous syndrome characterized by multi-system involvement and an increased incidence of both benign and malignant tumors. In this study, we evaluated the clinical presentation and prognosis of NF1 and malignancy. Between 1975 and 2013, 26 (5%) of the 473 patients with NF1 at our center developed non-neurofibroma neoplasms. The patient files of 26 subjects with tumors, other than optic glioma, were analyzed retrospectively to evaluate clinical features and treatment results. The age at diagnosis of NF1 ranged from 3 months to 16 years (median 5.5 years). The age range at tumor diagnosis was 1.5-33 years (median 8 years) in these 26 patients. The tumor histological subtypes included the following: 12 soft-tissue tumors (6 malignant peripheral nerve sheath tumors (MPNST), 5 rhabdomyosarcomas (RMS) and 1 malignant fibrous histiocytoma), 11 brain tumors (6 low-grade gliomas, 3 high-grade gliomas, and 2 medulloblastoma), 2 neuroblastomas and 1 non-Hodgkin's lymphoma. Twelve of 26 patients were alive at the time of the study. Although benign brain tumors with NF1 are more common, high-grade brain tumors also occur. Thus, careful and regular follow-up is crucial for early detection of malignancy in NF1 patients.

The coexistence of peripheral nerve sheath tumors and vitiligo: more than coincidence?

Neurocristopathies arise from abnormal migration, differentiation, or proliferation of neural crest derivatives, leading to diverse clinical and pathological features. They are classified into dysgenetic or neoplastic, and can affect single or multiple sites (simple versus complex). Examples include congenital melanocytic nevi, neuroblastoma, Hirshsprung's disease, Waardenburg's syndrome, neurofibromatosis (NF) 1 and multiple endocrine neoplasia (MEN) 2A and 2B. We report two cases of peripheral nerve sheath tumors associated with vitiligo and discuss the possible implicated embryologic, genetic and molecular mechanisms. To our knowledge, we also report the first case of de novo malignant peripheral nerve sheath tumor (MPNST) associated with vitiligo.

Peripheral nerve sheath tumors arising in salivary glands: A clinicopathologic study.

Primary salivary gland peripheral nerve sheath tumors (PNST) are uncommon. This study is a retrospective, clinicopathologic review of 9 cases of PNST (5 neurofibromas, 3 schwannomas and 1 malignant peripheral nerve sheath tumor (MPNST)) arising from the salivary glands, encountered between 1990 and 2015. All patients with neurofibromas were male (ages 1-62 years) and had a single parotid lesion of which 2 were diffuse, 2 plexiform and one mixed diffuse/plexiform. Four had a history of neurofibromatosis I. Four of 5 presented with symptoms related to mass effect including facial swelling, facial drooping, and dysphagia. All underwent de-bulking surgery and recurred due to continued growth. Of the 3 patients with schwannomas, 1 was male and 2 were female (ages 19, 44 and 56 years). One tumor each arose in the sublingual, submandibular, and parotid glands. Two of 3 presented with soreness and swelling local to the affected gland, especially while chewing. There was no recurrence of these tumors after resection. An MPNST in a male presented as a tender mass in the patient's left parotid; the tumor was resected. There was no evidence of tumor elsewhere in the body. The tumor did not recur in 12 years of follow-up. The most common tumor type in the current series was neurofibroma; most arose in the background of neurofibromatosis type I and all of which recurred after initial subtotal resection. Most PNST arose in the parotid gland.

Reconstruction of an Extensive Midfacial Defect Using Additive Manufacturing Techniques.

Malignant peripheral nerve sheath tumors are extremely rare tumors arising in peripheral nerves. Only 17 cases involving the trigeminal nerve have ever been reported. These tumors have a very poor prognosis and very high rates of recurrence and metastases. Their recommended treatment involves complete tumor resection followed by radiation. This can be problematic in the head and neck region. We present a clinical case involving a 33-year-old female patient presenting with a slow-growing, exophytic mass of the anterior maxilla. Incisional biopsy and subsequent histological examination revealed a diagnosis of a malignant peripheral nerve sheath tumor. Surgical resection involved a complete maxillectomy, rhinectomy, and resection of the upper lip and aspects of the left and right cheeks. Reconstruction of the subsequent defect incorporated the placement of four zygomatic oncology implants to aid in retention of a facial prosthesis. These implants, however, were subsequently lost; and an anatomical model of the hard tissues was manufactured via 3D printing. This model was used to design and manufacture a titanium frame (customized implant) for the patient. The frame was then fixated and secured intraoperatively with 21 cortical screws. A maxillary denture and silicone facial prosthesis were also made to fit onto this frame. This is the first known case where additive manufacturing, via the use of rapid prototyping and 3D printing, was employed to manufacture a facial prosthesis.

Translationally controlled tumor protein is a novel biological target for neurofibromatosis type 1-associated tumors.

Neurofibromatosis type 1 (NF1) is an autosomal dominant disease that predisposes individuals to develop benign neurofibromas and malignant peripheral nerve sheath tumors (MPNSTs). Due to the lack of information on the molecular mechanism of NF1-associated tumor pathogenesis or biomarkers/therapeutic targets, an effective treatment for NF1 tumors has not been established. In this study, the novel NF1-associated protein, translationally controlled tumor protein (TCTP), was identified by integrated proteomics and found to be up-regulated via activated MAPK/PI3K-AKT signaling in response to growth factors in NF1-deficient Schwann cells. Immunohistochemical analysis of NF1-associated tumors revealed that the TCTP expression level correlated with tumorigenicity. In NF1-deficient MPNST cells, TCTP protein but not mRNA was down-regulated by NF1 GTPase-activating protein-related domain or MAPK/PI3K inhibitors, and this correlated with suppression of mammalian target of rapamycin (mTOR) signaling. mTOR inhibition by rapamycin also down-regulated TCTP protein expression, whereas knockdown or overexpression of TCTP suppressed or activated mTOR signaling, respectively, and affected cell viability. These results suggest that a positive feedback loop between TCTP and mTOR contributes to NF1-associated tumor formation. Last, the anti-tumor effect of artesunate, which binds to and degrades TCTP, was evaluated. Artesunate significantly suppressed the viability of MPNST cells but not normal Schwann cells, and the TCTP level inversely correlated with artesunate sensitivity. Moreover, combinational use of artesunate and rapamycin enhanced the cytotoxic effect on MPNST cells. These findings suggest that TCTP is functionally implicated in the progression of NF1-associated tumors and could serve as a biological target for their therapy.