Primary Malignant Peripheral Nerve Sheath Tumours Research Articles

Low-grade malignant peripheral nerve sheath tumour presenting as retroperitoneal spindle cell neoplasm.

Retroperitoneal spindle cell neoplasms are diagnostically challenging. Malignant peripheral nerve sheath tumours (MPNSTs) can sometimes present as sporadic primary retroperitoneal tumours. MPNSTs are usually high-grade and highly aggressive tumours and are associated with a poor prognosis. Low-grade MPNSTs are very rarely described. This current case report describes a case of sporadic primary low-grade MPNST presenting as retroperitoneal spindle cell neoplasm. The diagnosis, imaging and immunohistopathological findings, as well as its successful surgical management, are presented.

Malignant peripheral nerve sheath tumours in magnetic resonance imaging: primary and recurrent tumour appearance, post-treatment changes, and metastases.

PurposeTo analyse the appearance of primary and recurrent malignant peripheral nerve sheath tumours (MPNSTs) in magnetic resonance imaging (MRI) with a focus on configuration, and to assess the occurrence of loco-regional post-treatment changes and metastases during post-treatment follow-up.Material and methodsTwenty patients with histologically proven MPNST underwent post-treatment 1.5 T MRI. Primary and recurrent MPNSTs were examined for configuration, contrast enhancement, extent, and signal intensity in MRI. Loco-regional post-treatment changes and information on metastases were extracted from the follow-up.ResultsMPNSTs occurred most often in the extremities (p = 0.006). Twenty per cent (n = 4) of the patients developed recurrences, with a total of 24 lesions. Recurrent MPNSTs were significantly smaller than primary MPNSTs (p = 0.003). Primary MPNSTs mostly occurred unifocally as multilobulated or ovoid and heterogeneous lesions with mostly well-defined borders. Recurrent MPNSTs purely occurred multifocally as mostly nodular (p < 0.001), multilobulated, or ovoid lesions. 80%, 65% and 30% of the patients showed post-treatment subcutaneous oedema (p = 0.002 to 0.03), muscle oedema (p = 0.02), and seroma, respectively. Twenty-five per cent (n = 5) of patients presented metastases during follow-up. The relative risk in patients with recurrences to develop lung or lymph node metastases is eightfold (p = 0.056).ConclusionsWhile primary MPNSTs mostly appear unifocally as multilobulated or ovoid lesions, recurrent MPNSTs purely occur multifocally as mostly nodular lesions. Subcutaneous and muscle oedema are very common loco-regional post-treatment changes. Patients with recurrences have a higher risk for lung and lymph node metastases.

A nationwide cohort study on treatment and survival in patients with malignant peripheral nerve sheath tumours

BackgroundDespite curative intents of treatment in localized malignant peripheral nerve sheath tumours (MPNSTs), prognosis remains poor. This study investigated survival and prognostic factors for overall survival in non-retroperitoneal and retroperitoneal MPNSTs in the Netherlands. MethodsData were obtained from the Netherlands Cancer Registry and the Dutch Pathology Database. All primary MPNSTs were collected. Paediatric cases (age ≤18 years) and synchronous metastases were excluded from analyses. Separate Cox proportional hazard models were made for retroperitoneal and non-retroperitoneal MPNSTs. ResultsA total of 629 localized adult MPNSTs (35 retroperitoneal cases, 5.5%) were included for analysis. In surgically resected patients (88.1%), radiotherapy and chemotherapy were administered in 44.2% and 6.7%, respectively. In retroperitoneal cases, significantly less radiotherapy and more chemotherapy were applied. In non-retroperitoneal MPNSTs, older age (60+), presence of NF1, size >5 cm, and deep-seated tumours were independently associated with worse survival. In retroperitoneal MPNSTs, male sex and age of 60+ years were independently associated with worse survival. Survival of R1 and that of R0 resections were similar for any location, whereas R2 resections were associated with worse outcomes. Radiotherapy and chemotherapy administrations were not associated with survival. ConclusionIn localized MPNSTs, risk stratification for survival can be done using several patient- and tumour-specific characteristics. Resectability is the most important predictor for survival in MPNSTs. No difference is present between R1 and R0 resections in both retroperitoneal and non-retroperitoneal MPNSTs. The added value of radiotherapy and chemotherapy is unclear.

Concomitant Malignant Pulmonary Peripheral Nerve Sheath Tumour and Benign Cutaneous Peripheral Nerve Sheath Tumour in a Dog

Peripheral nerve sheath tumours (PNSTs) are neoplastic growths derived from Schwann cells, perineural cells or both. Malignant PNSTs (MPNSTs) are uncommon in domestic animals. This report describes the concomitant occurrence of PNSTs in a 10-year-old female cocker spaniel with a clinical history of respiratory impairment. Grossly, there was a large infiltrative mass in the caudal lobe of the right lung; smaller nodules were observed in the other lobes of the right lung. Furthermore, a small encapsulated cutaneous nodule was observed on the left hindlimb. Histopathology of the pulmonary tumours revealed the proliferation of pleomorphic spindle-shaped cells with moderate mitotic index arranged in interwoven bundles and concentric Antoni A and Antoni B patterns; invasion of the adjacent pulmonary tissue was observed. The cutaneous nodule consisted of neoplastic mesenchymal cells in interwoven bundles with concentric whorls, but without the marked anisokaryosis, binucleation and infiltrative growth seen in the pulmonary tumour. Immunohistochemistry revealed that both tumours were immunoreactive for vimentin, glial fibrillary acidic protein and S100 protein, but were negative for factor VIII. These findings are indicative of a MPNST in the lung with a concomitant benign PNST in the limb. This case represents the first report of a primary MPNST in the lung of a dog. This neoplastic growth should be included in the differential diagnosis of primary malignant pulmonary tumours of dogs.

The role of phosphorylated signal transducer and activator of transcription 3 (pSTAT3) in peripheral nerve sheath tumours.

STAT3 is a pro-oncogenic transcription factor that requires phosphorylation for transcriptional activation. The aim of this study was to evaluate the role of phosphorylated STAT3 (pSTAT3) expression in neurofibromas, schwannomas, and malignant peripheral nerve sheath tumours (MPNSTs). Twenty-six neurofibromas, 62 schwannomas and 39 MPNSTs from a formalin-fixed paraffin-embedded tissue microarray were examined. Immunohistochemical analysis was performed with an anti-pSTAT3 (Tyr705) antibody. Nuclear expression was reviewed for both intensity and percentage of tumoral labelling. Distributions of disease-specific overall survival (DSOS) and event-free survival (EFS) were estimated with the Kaplan-Meier method, and compared between two pSTAT3 groups by use of the log-rank test. MPNSTs had higher median tumoral labelling than neurofibromas (P = 0.0012) or schwannomas (P = 0.0008). Moderate to strong pSTAT3 expression (defined as at least moderate labelling in ≥50% of cells) was found more frequently in MPNSTs than in neurofibromas (P = 0.026). Among MPNSTs, pSTAT3 expression differed between primary, recurrent and metastatic disease (P = 0.063 with increased expression in recurrent and metastatic cases). pSTAT3 expression (at least moderate labelling in ≥10% of cells) in primary MPNSTs was associated with worse DSOS (P = 0.048) and trended towards being associated with worse EFS (P = 0.063). Paired specimens revealed no increase in pSTAT3 expression in the recurrences or metastases relative to the primary tumour, suggesting that pSTAT3 expression may be an early indicator of aggressive disease at disease onset. pSTAT3 is expressed in a higher proportion of MPNSTs than neurofibromas and schwannomas. Moderate to strong pSTAT3 expression in ≥10% of cells was found to be a negative prognostic factor for DSOS among primary MPNSTs, suggesting a role of pSTAT3 in the progression of these tumours.

Malignant peripheral nerve sheath tumours in the head and neck region: retrospective analysis of clinicopathological features and treatment outcomes

Malignant peripheral nerve sheath tumours (MPNST) are rare soft tissue sarcomas. The aim of this study was to assess clinicopathological characteristics and prognostic factors in order to improve the treatment of such tumours in the head and neck region. We performed a retrospective analysis of head and neck MPNST patients in our hospital between 1996 and 2012. Clinical features and pathological findings of these cases (n=43) were summarized. In addition, prognostic variables were evaluated by univariate and multivariate analyses. The median age of the patients at presentation was 41 years. Surgery was the main treatment approach. Pertinent information regarding the presence of neurofibromatosis type 1 was found in 13 patients (30.2%). Two-thirds of these patients were admitted for a primary tumour (n=27, 62.8%), while one-third (n=16, 37.2%) were treated for recurrent neoplasms. The overall survival rate was 46.5%. Multivariable analysis identified tumour size, surgical margins, and postoperative radiotherapy to be independent prognostic factors. MPNST of the head and neck is extremely difficult to manage. Surgery with postoperative radiation may be the optimum choice of treatment for primary head and neck MPNST.

Pulmonary malignant peripheral nerve sheath tumour

Malignant peripheral nerve sheath tumours (MPNSTs) may occur in any peripheral nerve. They are often found in the chest wall and the posterior mediastinum. On the other hand, primary pulmonary MPNST is extremely rare, and surgically treated cases have been reported. Here, we present 3 cases of primary MPNST originating from the pulmonary parenchyma who underwent surgery in our institution. We discuss the possible clinical and pathological associations in the view of the literature.

Genomic imbalance ofHMMR/RHAMMregulates the sensitivity and response of malignant peripheral nerve sheath tumour cells to aurora kinase inhibition

Malignant peripheral nerve sheath tumours (MPNST) are rare, hereditary cancers associated with neurofibromatosis type I. MPNSTs lack effective treatment options as they often resist chemotherapies and have high rates of disease recurrence. Aurora kinase A (AURKA) is an emerging target in cancer and an aurora kinase inhibitor (AKI), termed MLN8237, shows promise against MPNST cell lines in vitro and in vivo. Here, we test MLN8237 against two primary human MPNST grown in vivo as xenotransplants and find that treatment results in tumour cells exiting the cell cycle and undergoing endoreduplication, which cumulates in stabilized disease. Targeted therapies can often fail in the clinic due to insufficient knowledge about factors that determine tumour susceptibilities, so we turned to three MPNST cell-lines to further study and modulate the cellular responses to AKI. We find that the sensitivity of cell-lines with amplification of AURKA depends upon the activity of the kinase, which correlates with the expression of the regulatory gene products TPX2 and HMMR/RHAMM. Silencing of HMMR/RHAMM, but not TPX2, augments AURKA activity and sensitizes MPNST cells to AKI. Furthermore, we find that AURKA activity is critical to the propagation and self-renewal of sphere-enriched MPNST cancer stem-like cells. AKI treatment significantly reduces the formation of spheroids, attenuates the self-renewal of spheroid forming cells, and promotes their differentiation. Moreover, silencing of HMMR/RHAMM is sufficient to endow MPNST cells with an ability to form and maintain sphere culture. Collectively, our data indicate that AURKA is a rationale therapeutic target for MPNST and tumour cell responses to AKI, which include differentiation, are modulated by the abundance of HMMR/RHAMM.

Impaired Pten Expression in Human Malignant Peripheral Nerve Sheath Tumours

Malignant peripheral nerve sheath tumours (MPNST) are aggressive sarcomas that develop in about 10% of patients with the genetic disease neurofibromatosis type 1 (NF1). Molecular alterations contributing to MPNST formation have only partially been resolved. Here we examined the role of Pten, a key regulator of the Pi3k/Akt/mTOR pathway, in human MPNST and benign neurofibromas. Immunohistochemistry showed that Pten expression was significantly lower in MPNST (n = 16) than in neurofibromas (n = 16) and normal nervous tissue. To elucidate potential mechanisms for Pten down-regulation or Akt/mTOR activation in MPNST we performed further experiments. Mutation analysis revealed absence of somatic mutations in PTEN (n = 31) and PIK3CA (n = 38). However, we found frequent PTEN promotor methylation in primary MPNST (11/26) and MPNST cell lines (7/8) but not in benign nerve sheath tumours. PTEN methylation was significantly associated with early metastasis. Moreover, we detected an inverse correlation of Pten-regulating miR-21 and Pten protein levels in MPNST cell lines. The examination of NF1−/− and NF1+/+Schwann cells and fibroblasts showed that Pten expression is not regulated by NF1. To determine the significance of Pten status for treatment with the mTOR inhibitor rapamycin we treated 5 MPNST cell lines with rapamycin. All cell lines were sensitive to rapamycin without a significant correlation to Pten levels. When rapamycin was combined with simvastatin a synergistic anti-proliferative effect was achieved. Taken together we show frequent loss/reduction of Pten expression in MPNST and provide evidence for the involvement of multiple Pten regulating mechanisms.

Evaluation of F18-deoxyglucose positron emission tomography (FDG-PET) to assess the nature of neurogenic tumours

Aims: Benign neurofibromas and malignant peripheral nerve sheath tumours (MPNST) commonly develop in patients with neurofibromatosis. Differentiation of benign from malignant tumours by conventional preoperative imaging is unreliable. FDG-PET is a non-invasive technique for biological tumour evaluation. The aim of this study was to assess the value of FDG-PET in patients with neurogenic tumours suspicious for MPNST.Methods: Benign and malignant neurogenic soft tissue tumours were prospectively evaluated by computed tomography or magnetic resonance imaging. Three-dimensional qualitative and quantitative FDG-PET was performed. Standard uptake value (SUV) was analyzed with respect to histological diagnosis and follow-up data.Results: Twenty-five neurogenic soft tissue tumours were included. FDG-PET identified all primary (n=6) and recurrent MPNST (n=7). Benign lesions (n=12) did not demonstrate high FDG uptake. The SUV was significantly higher in MPNST (median 2.9; range 1.8–12.3), than in benign tumours (median 1.1; range 0.5–1.8) (p<0.001). At a cut-off value of 1.8 SUV measured 1 h post-injection FDG-PET distinguished between MPNST and benign neurogenic tumours with 100% sensitivity and 83% specificity.Conclusions: FDG-PET allows discrimination of benign from malignant neurogenic tumours. This should be particularly useful in patients with neurofibromatosis as FDG-PET may help to avoid multiple surgical procedures for benign tumours.

Malignant peripheral nerve sheath tumours associated with von Recklinghausen's neurofibromatosis

AimsA retrospective study was conducted of patients with von Recklinghausen's neurofibromatosis who developed malignant peripheral nerve sheath tumours to determine their clinical characteristics, treatment outcome and prognostic factors.MethodsDuring the period 1987–1995, 29 patients with von Recklinghausen's neurofibromatosis (VRN) were seen at the Royal Marsden Hospital, of whom 23 had malignant peripheral nerve sheath tumours (MPNSTs).ResultsThe median age of the patients with MPNSTs was 30 years and the sex distribution was equal. The commonest site was the lower extremity, with a tendency for tumours to occur in the proximal parts. A nerve of origin was identified in 59% of the tumours and heterologous differentiation was present in 26%. Multiple primary MPNSTs occurred in four patients (17%) and other malignant tumours developed in three (13%). The overall 5-year survival was 35% with a median survival of 36 months. The incidence of local recurrence was 38% and 75% of them occurred within 2 years.ConclusionsMPNSTs which develop in association with VRN occur in a younger age group, tend to be of a higher histological grade and are associated with a very poor prognosis. Tumour size ≥10 cm (P=0.003) and high tumour grade (P=0.003) were adverse independent prognostic factors for overall survival.