Malignant peripheral nerve sheath tumors: Prognostic impact of rhabdomyoblastic differentiation (malignant triton tumors), neurofibromatosis 1 status and location

Purpose

The purpose of this study was to assess the impact of rhabdomyoblastic differentiation [malignant triton tumors (MTT)], neurofibromatosis 1 (NF1) status and location on the outcome of malignant peripheral nerve sheath tumors.

Methods

In this IRB-approved, HIPAA-compliant retrospective study medical records of 84 patients with pathologically confirmed MPNST from 1999 to 2011 were retrospectively reviewed. Patient and tumor characteristics including size, location, NF1 status, absence or presence of rhabdomyoblastic differentiation (MPNST versus MTT, respectively), recurrence and metastatic patterns and outcomes were evaluated.

Results

Of 84 patients, 62 were MPNST and 22 were MTT. MTT occurred in older patients than MPNST (50 years versus 40.7 years, p = 0.04) and were larger (12.3 cm versus 8.1 cm, p = 0.01). While there was no difference between the location, rate of recurrent or metastasis disease, and metastatic pattern between MTT and MPNST groups, MTT had shorter metastasis-free interval (median, 1 month versus 9 months, p = 0.02) and shorter survival (median, 10 months versus 43 months, p < 0.0001). NF1 status, while associated with earlier diagnosis (mean age, 35.1 years versus 46.5 years, p = 0.008), had no impact on rate of MTT or on prognosis. Patients with primary in the torso had shorter survival than those with extremity primary (median, 15 months versus 47 months, p = 0.0004). Multivariate analysis using the Cox proportional hazard regression model yielded age (p = 0.029), size (p = 0.0001), presence of rhabdomyoblastic differentiation (MTT) (p = 0.001), and location in the torso (p = 0.01) as independent predictors of survival.

Conclusions

Among patients with malignant peripheral nerve sheath tumors, rhabdomyoblastic differentiation (MTT) and location in the torso are associated with poor prognosis. NF1 status has no impact on the prognosis.     

Malignant peripheral nerve sheath tumours in NF1: improved survival in women and in recent years

Background

Malignant peripheral nerve sheath tumours (MPNST) are the main soft tissue malignancy associated with neurofibromatosis 1. These uncommon tumours are known to occur at high frequency and lead to poor survival. Our aim was to determine risk of MPNST in NF1 patients, and survival rates.

Methods

The incidence of MPNST in NF1 was identified through the NF1 genetic register and The North West Cancer Intelligence Service (NWCIS). Data were used to generate incidence and survival curves. Strict regional boundaries were adhered to avoid ascertainment bias. Kaplan-Meier curves were used to determine five and ten-year survival.

Results

Of the 1059 NF1 patients 52 developed MPNST (30 cases in females and 22 in males), 43 cases were resident within the strict regional boundary. The risk of MPNST was 10.2% in males and 12.7% in females by age 70 years (p = 0.9), with a statistically better survival in females than males (5 and 10 year survival 46% and 41.5% versus 22% and 8.2%; p = 0.05). Survival was also significantly improved for patients diagnosed in the last 14 years compared to the previous 13-year period (p = 0.03).

Conclusion

With fifteen strict regional MPNSTs in the fourteen years since our previous population study an annual incidence of above 1 per 1000 NF1 patients has now been maintained over a 27-year period. No significant increase in risk of MPNST in females compared to males was found, though the difference in survival is intriguing. Male survival is particularly poor with <10% alive at 10 years.     

巢蛋白和Ki-67在恶性外周神经鞘膜瘤中的表达及其意义

 目的　探讨恶性外周神经鞘膜瘤（MPNST）中巢蛋白和细胞增殖核抗原Ki-67的表达情况及其意义。方法　采用免疫组织化学SP法检测42例MPNST中巢蛋白和Ki-67的蛋白表达。24例外周神经良性肿瘤作为对照。结果　MPNST中巢蛋白阳性表达率为95.2 %（40／42）,其中巢蛋白强阳性表达率为40.5 %（17／42）,明显高于外周神经良性肿瘤的4.2 %（1／24）,差异有统计学意义（χ2＝8.403,P＝0.004）;MPNST中Ki-67标记指数介于1 %～70 %之间,其中＞3 %的占64.3 %（27／42）,24例外周神经良性肿瘤中Ki-67标记指数均＜3 %,两者比较差异有统计学意义（χ2＝23.518,P＝0.000）。结论　联合检测巢蛋白和Ki-67免疫标志物有助于MPNST的诊断。     

Expression and significance of EGFR in malignant peripheral nerve sheath tumor

Malignant peripheral nerve sheath tumor (MPNST) is an aggressive sarcoma. Epidermal growth factor receptor (EGFR) may play a putative role in its pathogenesis, and be targeted for therapeutic purposes. The study was aimed at investigating the expression and prognostic influence of EGFR in MPNST. Primary and metastatic MPNSTs were immunostained with antibodies to EGFR. The total EGFR expression (membranous and cytoplasmic) was analyzed by morphometry, grade of positivity and the intensity (score 0–3). An EGFR composite score (range 0–300) was calculated by multiplying the intensity by the grade. A composite score >10 was considered as EGFR overexpression. Score was correlated with clinical behavior. Forty-three percentage of 46 patients with MPNST overexpressed EGFR in the primary tumor, and had a higher prevalence of advanced-stage tumors (≥IIc, 46% vs. 80%, P = 0.011). Patients without overexpression had a higher prevalence of tumors with a low mitotic rate (31% vs. 0%, P = 0.049). Neurofibromatosis was more prevalent in patients with EGFR overexpression (75% vs. 42%, P = 0.007). Five year disease free survival (mean 30.1 vs. 17.4 months, P = 0.048), time to progression (mean 9.2 vs. 5.2 months, P = 0.005) and 5 year survival (52% vs. 25%, P = 0.041, mean 54 vs. 43 months) were significantly higher among patients without overexpression. EGFR appeared to play a role in MPNST progression. EGFR overexpression was correlated with worse prognostic variables and course. Clinical trials of targeting EGFR in MPNST are warranted. An erratum to this article can be found at     

Genetics of neurofibromatosis 1-associated peripheral nerve sheath tumors

Neurofibromatosis 1, an inherited disorder that affects 1/3500 individuals worldwide, predisposes to the development of benign and malignant peripheral nerve sheath tumors. The disorder results from inactivation of one of the NFI genes. The second NFI gene is typically inactivated in Schwann cells during tumor formation. This article reviews the different types of genetic alterations in NFI in both constitutional and tumor tissues and genetic alterations of other genes that may affect tumorigenesis. These studies have provided insight into the genetic basis of both the variable expression of the disorder and of benign and malignant peripheral nerve sheath tumorigenesis.     

Epidermal growth factor receptor expression and mutational analysis in synovial sarcomas and malignant peripheral nerve sheath tumors

BACKGROUND: Synovial sarcomas (SnSrcs) and malignant peripheral nerve sheath tumors (MPNSTs) are rare mesenchymal tumors of adolescence and young adulthood. Previous work from our laboratory has demonstrated that SnSrcs express epidermal growth factor receptor (EGFR) and human EGFR (HER)-2/neu. The present study extends that work to examine the expression of EGFR in MPNSTs and the characterization of potential targets of the EGFR tyrosine kinase domain. METHODS: Tissue microarrays containing 48 cases of SnSrc and 32 cases of MPNST were stained for EGFR, EGFRvIII, and activated EGFR (pY1068-EGFR). Tumor DNA was extracted from fresh and formalin-fixed, paraffin-embedded tissue blocks and sequenced for exons 17-21 of EGFR and exon 2 of K-ras and b-raf. RESULTS: Immunohistochemistry (IHC) demonstrated that EGFR is expressed in a majority of SnSrcs and MPNSTs (71% and 62.5%, respectively). EGFRvIII immunoreactivity was negative. IHC was weakly immunopositive for activated EGFR (18.7% and 3.1%, respectively). Sequence analysis of the EGFR genomic DNA did not demonstrate mutations in exons 17-21. No K-ras or b-raf mutations were observed in either tumor type. CONCLUSIONS: Expression of EGFR in SnSrcs and MPNSTs with an intact EGFR/mitogen-activated protein kinase pathway has been hypothesized to contribute to the malignant potential of these tumors. Our study reveals the absence of known activating mutations in EGFR, which suggests that trials of small-molecule inhibitors would be of little clinical benefit. A clinical study of treatment with cetuximab is ongoing and may help elucidate whether blockade of EGFR with antibodies is likely to be more active.     

头颈部恶性周围神经鞘瘤22例

[目的]探讨影响恶性周围神经路瘤的诊治和预后因素。[方法]回顾性分析22例头颈部恶性周围神经鞘瘤的临床表现及治疗结果，共复习有关文献。[结果]头颈部恶性周围神经鞘瘤的预后较差，总的5年生存率为26．3％。肿瘤＞5cm者及伴有神经纤维瘤病Ⅰ型者预后较差。扩大手术范围能改善预后。[结论]头颈部恶性周围神经鞘瘤是一种较少见治疗较困难的恶性肿瘤。早期发现，包括对神经纤维瘤病Ⅰ型患者密切随访是提高生存率的关键。     

Malignant peripheral nerve sheath tumor of proximal third tibia

A 16-year-old man had aswelling over the anterior aspect of the proximal third of the tibia for 1 year, which was peanut size initially and progressively increased to its present size of 10 cm × 8 cm. He underwent fine needle aspiration cytology (FNAC) twice during this period and reported aspindle cell sarcoma. Malignant peripheral nerve sheath tumor (MPNST) is a malignancy of the connective tissue surrounding the nerves. Previously, MPNST was also known as neurofibrosarcoma, malignant schwannoma, andneurogenic sarcoma. We are reporting this case for its rarity and peculiar mode of presentation. FNAC/core biopsy can be used as an effective tool to achievethe correct pathological diagnosis.     

Intrathoracic malignant peripheral nerve sheath tumors: imaging features and implications for management

Background

The aim of the study was to analyze the clinical and imaging characteristics of primary intrathoracic malignant peripheral nerve sheath tumors (MPNSTs).

Patients and methods.

In this institutional review board (IRB)-approved retrospective study, clinical and imaging features of 15 patients (eight men; mean age 50 years [range 18–83)] with pathologically proven malignant peripheral nerve sheath tumors seen from January 1999 to December 2011 were analyzed. Imaging features (CT in 15, MRI in 5 and PET/CT in 4) of primary tumors were evaluated by three radiologists and correlated with clinical management.

Results

Of the 15 tumors, six were located in the mediastinum (two each in anterior, middle and posterior mediastinum), four in chest wall, two were paraspinal, and three in the lung. Four patients had neurofibromatosis-1 (NF1); four tumors had heterologous rhabdomyoblastic differentiation (malignant triton tumor). Masses typically were elongated along the direction of nerves, with mean size of 11 cm. The masses were hypo- or isodense to muscles on CT, isointense on T1-weighted images, hyperintense on T2-weighted images and intensely fluorodeoxyglucose (FDG) avid (mean standardized uptake value [SUV]_max of 10.5 [range 4.4–23.6]). Necrosis and calcification was seen in four tumors each. Finding of invasion of adjacent structures on imaging led to change in management in seven patients; patients with invasion received chemoradiation.

Conclusions

Intrathoracic MPNSTs appear as large elongated masses involving mediastinum, lung or chest wall. Radiological identification of invasion of adjacent structures is crucial and alters therapy, with patients with invasion receiving neoadjuvant or adjuvant chemoradiation.     

Malignant peripheral nerve sheath tumors in childhood

Summary Malignant peripheral nerve sheath tumor (MPNST) is an uncommon sarcoma in the pediatric population; however, its presence should be considered in a child with an enlarging or painful soft-tissue mass. Diagnosis of this neoplasm depends on either the demonstration of its origin within a peripheral nerve or the association with a contiguous neurofibroma. We have identified 16 cases of MPNST involving children 16 years of age or less, which represent 12.8% of the total cases seen at the Mayo Clinic. Most of the lesions arose in children with von Recklinghausen's disease and were associated with a contiguous neurofibromatous component. The mean survival of patients who were known to have died of tumor was only 1.8 years. This sarcoma requires prompt aggressive therapy utilizing wide surgical excision. Because of the association of MPNST with von Recklinghausen's neurofibromatosis, a careful workup and family history should be obtained for the potential prognostic value and for the purpose of genetic counseling.     

The cytopathology of malignant peripheral nerve sheath tumor

BACKGROUND:

Among sarcomas, a diagnosis of malignant peripheral nerve sheath tumor (MPNST) is often one of exclusion due to the absence of unequivocally characteristic histopathology, a conclusive immunohistochemical profile, or even a unique chromosomal anomaly. Because of this, the fine‐needle aspiration (FNA) cytopathology of MPNST is extremely challenging. In the current study, the authors review their FNA experience with this neoplasm.

METHODS:

The authors searched their combined departmental cytology files for all lesions signed out as MPNST or suspicious for MPNST, as well as their own surgical pathology files for any cases of MPNST that had corresponding cytology. FNA was performed using standard techniques.

RESULTS:

A total of 55 cases of MPNST, all with tissue confirmation, and 1 misdiagnosed example of melanoma were retrieved from 52 patients (M:F ratio of 1.5:1; average age, 46 years), 26 of whom had a history of neurofibromatosis type 1 (NF‐1). Aspirates were from primary (27 cases), locally recurrent (14 cases), or metastatic (10 cases) MPNST; 4 primary tumor aspirates were of ex vivo specimens. Sites included the extremities (22 cases), trunk/pelvis (22 cases), head and neck (6 cases), and deep‐seated masses (6 cases). FNA diagnoses were MPNST (24 patients); consistent with MPNST (5 patients); sarcoma, not otherwise specified (10 patients); atypical (3 patients); spindle cell neoplasm (6 patients); malignant neoplasm (1 patient); and nondiagnostic (3 patients). A definitive diagnosis of either MPNST or consistent with MPNST was issued in 30%, 93%, and 70%, respectively, of primary, locally recurrent, and metastatic lesions.

CONCLUSIONS:

FNA cytopathology is limited as a diagnostic instrument for the initial diagnosis of MPNST, but is exceedingly accurate and valuable in the recognition of metastatic and locally recurrent MPNST. Cancer (Cancer Cytopathol) 2012. © 2012 American Cancer Society.     

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.     

Genomic and molecular aberrations in malignant peripheral nerve sheath tumor and their roles in personalized target therapy

Malignant peripheral nerve sheath tumors (MPNSTs) are malignant tumors with a high rate of local recurrence and a significant tendency to metastasize. Its dismal outcome points to the urgent need to establish better therapeutic strategies for patients harboring MPNSTs. The investigations of genomic and molecular aberrations in MPNSTs which detect many chromosomal aberrations, pathway abnormalities, and specific molecular aberrant events would supply multiple potential therapy targets and contribute to achievement of personalized medicine. The involved genes in the significant gains aberrations include BIRC5, CCNE2, DAB2, DDX15, EGFR, DAB2, MSH2, CDK6, HGF, ITGB4, KCNK12, LAMA3, LOXL2, MET, and PDGFRA. The involved genes in the significant deletion aberrations include CDH1, GLTSCR2, EGR1, CTSB, GATA3, SULT2A1, GLTSCR2, HMMR/RHAMM, LICAM2, MMP13, p16/INK4a, RASSF2, NM-23H1, and TP53. These genetic aberrations involve in several important signaling pathways such as TFF, EGFR, ARF, IGF1R signaling pathways. The genomic and molecular aberrations of EGFR, IGF1R, SOX9, EYA4, TOP2A, ETV4, and BIRC5 exhibit great promise as personalized therapeutic targets for MPNST patients.     

Current status of sporadic and neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors

Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive soft tissue sarcomas that rarely occur in the general population but have a lifetime incidence of 8% to 13% in those with neurofibromatosis type 1 (NF1). Complete surgical resection is the standard treatment for MPNSTs. Unresectable MPNSTs carry a poor prognosis, and survival appears to be worse in NF1-associated tumors than in sporadic tumors. The response rate of MPNSTs to standard chemotherapeutic agents used to treat pediatric and adult soft tissue sarcomas is unknown and is currently undergoing evaluation in a multi-institutional clinical trial. With an increasing understanding of the molecular pathogenesis of MPNSTs, clinical trials with targeted agents have become available and have established that histology-specific trials in this rare malignancy are feasible. This knowledge, coupled with the availability of preclinical MPNST models, likely will accelerate the development of effective treatments for this malignancy.     

Evaluation of magnetic resonance imaging-based radiomics characteristics for differentiation of benign and malignant peripheral nerve sheath tumors in neurofibromatosis type 1

BackgroundPatients with neurofibromatosis type 1 (NF1) develop benign (BPNST), premalignant atypical (ANF), and malignant (MPNST) peripheral nerve sheath tumors. Radiological differentiation of these entities is challenging. Therefore, we aimed to evaluate the value of a magnetic resonance imaging (MRI)-based radiomics machine-learning (ML) classifier for differentiation of these three entities of internal peripheral nerve sheath tumors in NF1 patients.MethodsMRI was performed at 3T in 36 NF1 patients (20 male; age: 31 ± 11 years). Segmentation of 117 BPNSTs, 17 MPNSTs, and 8 ANFs was manually performed using T2w spectral attenuated inversion recovery sequences. One hundred seven features per lesion were extracted using PyRadiomics and applied for BPNST versus MPNST differentiation. A 5-feature radiomics signature was defined based on the most important features and tested for signature-based BPNST versus MPNST classification (random forest [RF] classification, leave-one-patient-out evaluation). In a second step, signature feature expressions for BPNSTs, ANFs, and MPNSTs were evaluated for radiomics-based classification for these three entities.ResultsThe mean area under the receiver operator characteristic curve (AUC) for the radiomics-based BPNST versus MPNST differentiation was 0.94, corresponding to correct classification of on average 16/17 MPNSTs and 114/117 BPNSTs (sensitivity: 94%, specificity: 97%). Exploratory analysis with the eight ANFs revealed intermediate radiomic feature characteristics in-between BPNST and MPNST tumor feature expression.ConclusionIn this proof-of-principle study, ML using MRI-based radiomics characteristics allows sensitive and specific differentiation of BPNSTs and MPNSTs in NF1 patients. Feature expression of premalignant atypical tumors was distributed in-between benign and malignant tumor feature expressions, which illustrates biological plausibility of the considered radiomics characteristics.     

Quantitative F18‐fluorodeoxyglucose positron emission tomography accurately characterizes peripheral nerve sheath tumors as malignant or benign

BACKGROUND:

Correct pretreatment classification is critical for optimizing diagnosis and treatment of patients with peripheral nerve sheath tumors (PNSTs). The aim of this study was to evaluate whether F18‐fluorodeoxyglucose positron emission tomography (FDG PET) can differentiate malignant (MPNST) from benign PNSTs.

METHODS:

Thirty‐four adult patients presenting with PNST who underwent a presurgical FDG PET/computed tomography (CT) scan between February 2005 and November 2008 were included in the study. Tumors were characterized histologically, by FDG maximum standardized uptake value (SUV_max [g/mL]), and by CT size (tumor maximal diameter [cm]). The accuracy of FDG PET for differentiating MPNSTs from benign PNSTs (neurofibroma and schwannoma) was evaluated by receiver operating characteristic (ROC) curve analysis.

RESULTS:

SUV_max was measured in 34 patients with 40 tumors (MPNSTs: n = 17; neurofibromas: n = 9; schwannomas: n = 14). SUV_max was significantly higher in MPNST compared with benign PNST (12.0 ± 7.1 vs 3.4 ± 1.8; P < .001). An SUV_max cutoff point of ≥6.1 separated MPNSTs from BPSNTs with a sensitivity of 94% and a specificity of 91% (P < .001). By ROC curve analysis, SUV_max reliably differentiated between benign and malignant PNSTs (area under the ROC curve of 0.97). Interestingly, the difference between MPNSTs and schwannomas was less prominent than that between MPNSTs and neurofibromas.

CONCLUSIONS:

Quantitative FDG PET imaging distinguished between MPNSTs and neurofibromas with high accuracy. In contrast, MPNSTs and schwannomas were less reliably distinguished. Given the difficulties in clinically evaluating PNST and in distinguishing benign PNST from MPNST, FDG PET imaging should be used for diagnostic intervention planning and for optimizing treatment strategies. Cancer 2010. © 2010 American Cancer Society.     

Telomere maintenance mechanisms in malignant peripheral nerve sheath tumors: expression and prognostic relevance

This study investigated the prevalence and the prognostic relevance of the 2 known telomere maintenance mechanisms (TMMs), telomerase activity (TA) and alternative lengthening of telomeres (ALT), in malignant peripheral nerve sheath tumors (MPNST). In 57 specimens from 49 patients with MPNST (35 sporadic, 14 neurofibromatosis type 1-related), TA was determined using the telomeric repeat amplification protocol, and ALT was detected by assaying ALT-associated promyelocytic leukemia bodies (APB) and terminal restriction fragment (TRF) length distribution. TA or ALT (defined on the basis of APB) alone was found in 24.6% or 26.3% of the lesions, respectively, whereas 6 cases (10.5%) were TA+/ALT+. A concordance between APB and TRF results in defining the ALT status was observed in 44 of 57 cases (77.2%; P < .0001). TA was more frequently expressed in samples from patients with neurofibromatosis type 1 than in those with sporadic disease (60% vs 29.4%, P = 0.087). In the overall series, TA proved to be prognostic for 5-year disease-specific death (hazard ratio, 3.78; 95% confidence interval [CI], 1.60-8.95; P = .002), even when adjusted for the presence of neurofibromatosis type 1 (hazard ratio, 4.22; 95% CI, 1.804-9.874; P = .001) and margin status after surgery (hazard ratio, 5.78; 95% CI, 2.19-15.26; P < .001). Conversely, ALT did not significantly affect clinical outcome of MPNST using either APB expression (hazard ratio, 1.25; 95% CI 0.54-2.89; P = 0.605) or TRF distribution (hazard ratio, 0.57; 95% CI, 0.17-1.96; P = .375) as the detection approach. Our results indicate for the first time that both TMMs, TA and ALT, are present in MPNST and differentially affect patient prognosis.     

恶性外周神经鞘膜瘤中 TBX2 基因突变及相关蛋白 表达的临床意义

  目的  检测恶性外周神经鞘膜瘤基因组异常并探讨TBX2、CHK2和p53在恶性外周神经鞘膜瘤中的表达及其临床意义。  方法  收集天津医科大学肿瘤医院骨与软组织肿瘤科1991年1月至2011年12月手术切除并经病理证实的恶性外周神经鞘膜瘤组织标本63例。从中选取新鲜且DNA质量合格的肿瘤样本12例,采用第二代测序(next-generation sequencing,NGS) 方法,检测人恶性外周神经鞘膜瘤组织样本基因组异常情况。应用免疫组织化学方法检测63例恶性外周神经鞘膜瘤组织样本中TBX2、CHK2和p53的表达情况。  结果  12例恶性外周神经鞘膜瘤组织样本中,有1例TBX2基因突变。63例恶性外周神经鞘膜瘤组织样本中,TBX2、CHK2和p53的高表达率分别为60.3%(38/63) 、47.6%(30/63) 及30.2%(19/63) 。TBX2的高表达与AJCC分期、复发和转移有显著相关性(P＜0.05) ;TBX2的表达与CHK2的表达呈正相关(r=0.254,P=0.045) ,CHK2的表达与p53的表达呈正相关(r=0.343,P=0.006) 。高表达TBX2、CHK2和p53的无病生存时间及总生存时间均显著低于低表达组(P＜0.05) ,且TBX2、CHK2和p53均为恶性外周神经鞘膜瘤的独立预后因素。  结论  TBX2及其相关蛋白的表达可能在恶性外周神经鞘膜瘤发生发展过程中起重要作用,检测其表达有望为MPNST预后提供理论依据。       

The pan erbB inhibitor PD168393 enhances lysosomal dysfunction-induced apoptotic death in malignant peripheral nerve sheath tumor cells

Malignant peripheral nerve sheath tumors (MPNSTs) are rapidly progressive Schwann cell neoplasms. The erbB family of membrane tyrosine kinases has been implicated in MPNST mitogenesis and invasion and, thus, is a potential therapeutic target. However, tyrosine kinase inhibitors (TKIs) used alone have limited tumoricidal activity. Manipulating the autophagy lysosomal pathway in cells treated with cytostatic agents can promote apoptotic cell death in some cases. The goal of this study was to establish a mechanistic basis for formulating drug combinations to effectively trigger death in MPNST cells. We assessed the effects of the pan erbB inhibitor PD168393 on MPNST cell survival, caspase activation, and autophagy. PD168393 induced a cytostatic but not a cytotoxic response in MPNST cells that was accompanied by suppression of Akt and mTOR activation and increased autophagic activity. The effects of autophagy modulation on MPNST survival were then assessed following the induction of chloroquine (CQ)-induced lysosomal stress. In CQ-treated cells, suppression of autophagy was accompanied by increased caspase activation. In contrast, increased autophagy induction by inhibition of mTOR did not trigger cytotoxicity, possibly because of Akt activation. We thus hypothesized that dual targeting of mTOR and Akt by PD168393 would significantly increase cytotoxicity in cells exposed to lysosomal stress. We found that PD168393 and CQ in combination significantly increased cytotoxicity. We conclude that combinatorial therapies with erbB inhibitors and agents inducing lysosomal dysfunction may be an effective means of treating MPNSTs.