Metastatic Malignant Peripheral Nerve Sheath Tumors Research Articles

The cytopathology of malignant peripheral nerve sheath tumor

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. 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. 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. 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.

Activated MET Is a Molecular Prognosticator and Potential Therapeutic Target for Malignant Peripheral Nerve Sheath Tumors

MET signaling has been suggested a potential role in malignant peripheral nerve sheath tumors (MPNST). Here, MET function and blockade were preclinically assessed. Expression levels of MET, its ligand hepatocyte growth factor (HGF), and phosphorylated MET (pMET) were examined in a clinically annotated MPNST tissue microarray (TMA) incorporating univariable and multivariable statistical analyses. Human MPNST cells were studied in vitro and in vivo; Western blot (WB) and ELISA were used to evaluate MET and HGF expression, activation, and downstream signaling. Cell culture assays tested the impact of HGF-induced MET activation and anti-MET-specific siRNA inhibition on cell proliferation, migration, and invasion; in vivo gel-foam assays were used to evaluate angiogenesis. Cells stably transduced with anti-MET short hairpin RNA (shRNA) constructs were tested for growth and metastasis in severe combined immunodeficient (SCID) mice. The effect of the tyrosine kinase inhibitor XL184 (Exelixis) targeting MET/VEGFR2 (vascular endothelial growth factor receptor 2) on local and metastatic MPNST growth was examined in vivo. All three markers were expressed in MPNST human samples; pMET expression was an independent prognosticator of poor patient outcome. Human MPNST cell lines expressed MET, HGF, and pMET. MET activation increased MPNST cell motility, invasion, angiogenesis, and induced matrix metalloproteinase-2 (MMP2) and VEGF expression; MET knockdown had inverse effects in vitro and markedly decreased local and metastatic growth in vivo. XL184 abrogated human MPNST xenograft growth and metastasis in SCID mice. Informative prognosticators and novel therapies are crucially needed to improve MPNST management and outcomes. We show an important role for MET in MPNST, supporting continued investigation of novel anti-MET therapies in this clinical context.

Metastatic malignant peripheral nerve sheath tumor of the cauda equina

Malignant peripheral nerve sheath tumor (MPNST) of the cauda equina is rare, with only four reported patients in the literature. We present a 70-year-old woman with a history of left sciatic nerve MPNST that had been treated by left hemipelvectomy 4 years prior. She then presented with disabling right leg weakness that progressed over 7 months. Spine imaging revealed an intradural extramedullary lesion from L5 to S1 with compression of the cauda equina. She underwent an L3–S1 laminectomy with subtotal resection of the lesion, which was diagnosed as a metastatic MPNST. At the 3-month postoperative visit, her lower extremity strength had returned to baseline. The only notable postoperative complication was a superficial wound infection that resolved with antibiotic treatment and wet-to-dry dressing changes. Thus, although uncommon, the spinal canal and cauda equina should be considered as possible locations for metastatic MPNST in the appropriate clinical scenario. To our knowledge, this is the first report of a patient with a metastatic MPNST to the cauda equina.

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 (>or=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.

Metastatic chest wall malignant schwannoma responding to sorafenib: case report and literature review

Malignant schwannomas or malignant peripheral nerve sheath tumors (MPNST) represent approximately 10% of all soft tissue sarcomas. Metastatic disease from chest wall MPNST is very rare. We present a case of a major clinical response to the tyrosine kinase inhibitor (TKI) sorafenib in a patient with metastatic MPNST. A 42-year-old female with a prior history of neurofibromas developed MPNST, which later metastasized to the lungs and brain. She was initially placed on sorafenib with significant clinical response to lung metastases. MPNST show high levels of Ras activity and hence these tumors are promising targets for TKIs. Studies are ongoing and the results are eagerly awaited regarding the responses to these medications and whether they can positively impact on the natural history of this disease.

Phase II study of gemcitabine/vinorelbine (GV) as first or second line chemotherapy in patients with metastatic soft tissue sarcoma (STS)

9009 Background: Both single agent gemcitabine and vinorelbine have efficacy for treatment of STS. Combination GV is active therapy for metastatic carcinoma, with acceptable toxicity. This single institution phase II trial has been undertaken to determine response rates and toxicity of combination GV for treatment of metastatic STS. Methods: Pts with PS 0–2, unresectable or metastatic STS, adequate end organ function, and no more than 1 prior regimen were eligible. Gemcitabine at 800mg/m2 was infused over 90 minutes on days 1 and 8 of a 21 day cycle, following vinorelbine at 25mg/m2. Pts with grade 3 or 4 toxicity were subsequently treated at the same doses on days 1 and 15 of a 28 day cycle. Results: An initial 18 pts have been accrued, following standard two-stage design by the method of Simon. Histology was uterine or extremity leiomyosarcoma (LMS) in 9, high grade pleomorphic sarcoma in 2, and 1 each with carcinosarcoma, pleomorphic liposarcoma, malignant peripheral nerve sheath tumor (MPNST), desmoplastic small round cell tumor, rhabdomyosarcoma, and small round cell sarcoma. As expected, toxicity has been moderate. 57 cycles have been administered. No treatment related deaths have occurred. Only 3 grade 4 toxicities have been noted, all hematologic. Of 19 episodes of grade 3 toxicity, 10 have been hematologic. Of the remaining 9, 4 have been treatment related, including cough, nausea, vomiting, and SGPT elevation. 3 pts have experienced clinical benefit defined as partial response (PR) or stable disease for greater than 4 months. There have been two confirmed PRs, one high grade uterine LMS progressing after single agent doxorubicin, and one small round cell tumor recurring within 6 months of completion of a 5 drug Ewing's regimen. One metastatic MPNST has exhibited stable disease for greater than 4 months. Median time to progression has been 4.2 months and median survival 6.25 months. Conclusions: GV appears to be a well-tolerated and potentially effective regimen for first or second line treatment of metastatic STS. Further accrual to this Phase II study is warranted. No significant financial relationships to disclose.

Phase II study of gemcitabine/vinorelbine (GV) as first or second line chemotherapy in patients with metastatic soft tissue sarcoma (STS)

9009 Background: Both single agent gemcitabine and vinorelbine have efficacy for treatment of STS. Combination GV is active therapy for metastatic carcinoma, with acceptable toxicity. This single institution phase II trial has been undertaken to determine response rates and toxicity of combination GV for treatment of metastatic STS. Methods: Pts with PS 0–2, unresectable or metastatic STS, adequate end organ function, and no more than 1 prior regimen were eligible. Gemcitabine at 800mg/m2 was infused over 90 minutes on days 1 and 8 of a 21 day cycle, following vinorelbine at 25mg/m2. Pts with grade 3 or 4 toxicity were subsequently treated at the same doses on days 1 and 15 of a 28 day cycle. Results: An initial 18 pts have been accrued, following standard two-stage design by the method of Simon. Histology was uterine or extremity leiomyosarcoma (LMS) in 9, high grade pleomorphic sarcoma in 2, and 1 each with carcinosarcoma, pleomorphic liposarcoma, malignant peripheral nerve sheath tumor (MPNST), desmoplastic small round cell tumor, rhabdomyosarcoma, and small round cell sarcoma. As expected, toxicity has been moderate. 57 cycles have been administered. No treatment related deaths have occurred. Only 3 grade 4 toxicities have been noted, all hematologic. Of 19 episodes of grade 3 toxicity, 10 have been hematologic. Of the remaining 9, 4 have been treatment related, including cough, nausea, vomiting, and SGPT elevation. 3 pts have experienced clinical benefit defined as partial response (PR) or stable disease for greater than 4 months. There have been two confirmed PRs, one high grade uterine LMS progressing after single agent doxorubicin, and one small round cell tumor recurring within 6 months of completion of a 5 drug Ewing's regimen. One metastatic MPNST has exhibited stable disease for greater than 4 months. Median time to progression has been 4.2 months and median survival 6.25 months. Conclusions: GV appears to be a well-tolerated and potentially effective regimen for first or second line treatment of metastatic STS. Further accrual to this Phase II study is warranted. No significant financial relationships to disclose.