Introduction
Malignant peripheral nerve sheath tumour (MPNST) constitutes about 5% of all soft tissue sarcomas [1]. Approximately 25–50% of cases accompany neurofibromatosis type 1 (NF1) – a dominant autosomal defect in which a NF1 gene product – neurofibromin – lacking RAS-GAP function, does not act as a tumour suppressor gene [2, 3]. Depending on the type of NF1 mutation, 2–29% of carriers develop MPNST in their lifetime. Sporadic MPNST cases are not linked to any specific mutations; however, numerous chromosomal aberrations including –22 (in 40% of tumours), +3, +14, –13, –17 and –18 have been described [3]. Typical molecular changes include retinoblastoma tumour suppression pathway, aberrant expression of CHFR and aberrant expression of immune system-related genes [4–6]. The tumour originates from proliferating Schwann or perineural cells, most frequently surrounding sciatic, brachial and maxillofacial nerves [2]. The most common clinical presentation is a painful, invasively growing mass with accompanying neurological deficit [7, 8]. Spontaneous bleeding has been reported in NF1 mutation carriers as a consequence of vascular abnormalities – aneurysm rupture or arteriovenous fistula [9, 10].
The aim of this paper was to present a long-term survivor of the sporadic type of MPNST – a giant thoracic tumour with an uncommon presentation of haemothorax – and to discuss different therapeutic options.Case report
AIn August 2004 a 28-year-old man was admitted to the hospital with symptoms of rapidly progressing dyspnoea, cough, weakness and chest pain. His medical history was unremarkable, except for a dull back pain lasting for several months. Physical exam revealed tachycardia, tachypnoea and left pleural effusion up to the level of the third intercostal space, confirmed by a chest X-ray. A CT-scan of the chest showed pleural effusion and a large (18 cm) tumour located in the posterior mediastinum. Transthoracic fine needle biopsy suggested sarcoma. A radical excision of the tumour, left lung, thymus, mediastinal lymph nodes and distal parts of the 4th and 5th left ribs was performed and a histopathological examination established a diagnosis of high-grade (G3) MPNST, with positive staining of S-100 and vimentin at immunohistochemistry. The patient received postoperative radiotherapy at a dose of 66 Gy in 33 fractions. Four months later he developed dyspnoea, hectic fever and fatigue and a PET CT scan revealed a recurrent tumour infiltrating the chest wall in the left pericardial region, and multiple metastases in the right lung. Six cycles of palliative chemotherapy consisting of dacarbazine and doxorubicin resulted in stabilization of the disease. Six months later, in September 2005, a CT scan showed further progression. Of note, the patient had moderate cardiac insufficiency with tachycardia and intermittent oedema of the scrotum making him incapable of further doxorubicin-based treatment. Additional immunohistochemical analysis performed at that time showed negative EGFR [11], negative VEGFR and equivocal CD117 expression. A tumour specimen was sent for sequencing of cKit (exons 9, 11, 13, and 17), PDGFR- and PDGFR- (exons 12, 14, and 18) coding genes [12, 13].
After obtaining the patients’ consent and a positive opinion from a local Ethics Committee, a 3-month empirical treatment with imatinib given orally at a daily dose of 400 mg was administered. A CT scan performed 3 months later showed a dramatic progression of the disease. Additionally, mutations of cKit and PDGFR- and PDGFR- were not confirmed in a subsequent biopsy specimen. Owing to the deterioration of the patients’ general status, second-line chemotherapy consisting of ifosfamide 3 g/m2 IV with uromitexan, for 3 consecutive days every 28 days, was applied. After completion of 6 cycles a partial remission of the pulmonary lesions was achieved. Due to anecdotal reports on the possible role of somatostatin analogues in MPNST [14], we performed an octreoscan, which showed an increased uptake of somatostatin in the regions of the main lesion, accompanied by multiple metastatic tumours. Subsequently, octreotide treatment (20 mg every 28 days) was initiated. The disease was stable for 6 months, but then a CT scan again revealed progression (Figs. 1A, B). A third-line chemotherapy including doxorubicin, dacarbazine, cisplatin and ifosfamide was attempted, with no response. Instead, palliative reirradiation decreased dysphagia, chest pain and dyspnoea. Three months later, due to progression in the right lung, retreatment with ifosfamide was started. Because of haemoptysis after 2 cycles and evident progression of right lung metastases, the patient received 2 cycles of ecteinascidin. This therapy was also unsuccessful, whereas the re-administered ifosfamide unexpectedly resulted in symptomatic and radiological improvement. The patient, in a good general status (PS 80%), returned to work despite disseminated disease. After 8 cycles, ifosfamide treatment was discontinued due to disease progression, and in January 2009 the patient died.Discussion
Malignant peripheral nerve sheath tumour belongs to the group of invasively growing soft tissue sarcomas with poor prognosis, high metastatic potential and limited radio- and chemo-sensitivity [15]. Incomplete resection, large tumour size, location (axial vs. peripheral), lymph node metastases, high-grade (G3), primary or recurrent disease and NF1 mutations are predictive for early metastatic spread [7, 16–18]. In the largest reported series of patients, only negative surgical margins (R0) and no history of irradiation remained significantly related to survival in multivariate analysis, including tumour size, grade and location, NF1 mutation, mitotic rate, necrosis and histological subtype [7]. Adjuvant radiotherapy delivered in a total dose of less than 60 Gy does not improve the outcome significantly, whereas intraoperative brachytherapy seems to increase survival [7]. The reported 5- and 10-year survival rates are, respectively, 34% and 22%, despite aggressive local treatment. The risk of recurrence is high. Optimal therapy of locally advanced or disseminated MPNST has not been established. Palliative chemotherapy induces a response in about one-third of patients and its impact on survival is unknown. According to the results of the largest analysed group of 175 MPNST patients treated in 12 different clinical trials, only PS and the use of doxorubicin and/or ifosfamide are significant with regard to overall and progression-free survival [19]. The median survival of patients with NF-1-related or axial tumours does not exceed 12 months [1, 7].
Malignant peripheral nerve sheath tumour shows expression of at least one of the five somatostatin receptors – sst4 (in 32% of cases) and sst2 (in 15% of cases) [14]. This may suggest a beneficial role of somatostatin receptor analogues in the diagnosis and treatment; however, their usefulness has not been verified. Another possible area of investigation includes PDGFRB or EGF, or cMet pathways in both NF1-related and sporadic tumours, although data on such treatment efficacy are inconclusive [1, 11].
To conclude, more effective therapies are needed in MPNST, particularly in locally advanced and disseminated disease. Despite relative chemoresistance, systemic treatment provides a good palliation to some patients. Better knowledge of the molecular features of these tumours may provide the basis for the newly targeted agents.
Authors declare no conflict of interest.References
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Address for correspondence
Renata Zaucha
Chair and Department of Oncology and Radiotherapy
Medical University of Gdansk
Dębinki 1
80-211 Gdansk, Poland
e-mail: rzaucha@gumed.edu.pl
Submitted: 30.04.2012
Accepted: 15.06.2012
