Vinod P. Balachandran, Resident in General Surgery, Department of Surgery, New York Presbyterian Hospital, Weill Cornell Medical College, New York, NY; Martin S. Karpeh, Chairman, Department of Surgery, Beth Israel Medical Center, New York, NY
Vinod P. Balachandran, MD
Resident in General Surgery
Department of Surgery
New York Presbyterian Hospital
Weill Cornell Medical College
New York, NY
Martin S. Karpeh, MD
Department of Surgery
Beth Israel Medical Center
New York, NY
Introduction: A malignant peripheral nerve sheath tumor (MPNST) is any tumor that arises from a peripheral nerve or shows nerve sheath differentiation, excluding those that originate from the epineurium or the peripheral nerve vasculature.1 MPNSTs are histologically classified as malignant soft-tissue sarcomas and are a rare form of cancer. They are most commonly seen in patients with neurofibromatosis 1 (NF1) and are associated with significantly high rates of morbidity and mortality.
Results and discussion: The authors report a case of MPNST in a 47-year-old man with NF1 and discuss the various diagnostic and therapeutic modalities currently available.
Conclusion: The high incidence of MPNSTs in patients with NF1 and the severity of the disease require physicians to have a thorough understanding of related diagnostic and treatment methods to ensure adequate management. The future in treating MPNSTs revolves around developing targeted molecular therapies and improving our understanding of the biologic basis of the disease.
According to the World Health Organization, the term malignant peripheral nerve sheath tumor (MPNST) refers to any malignancy arising from a peripheral nerve or demonstrating nerve sheath differentiation, excluding those tumors that originate from the epineurium or peripheral nerve vasculature.1 MPNSTs are histologically classified as malignant soft-tissue sarcomas, which encompasses several subtypes, including malignant schwannoma, neurogenic sarcoma, neurofibrosarcoma, and malignant neurilemoma.2
MPNST is a rare form of cancer, with an incidence of 0.001% in the general population, and accounts for only 3% to 10% of all soft-tissue sarcomas.3-7 Although MPNSTs are rare, approximately 50% to 60% of these lesions are found in patients who have neurofibromatosis 1 (NF1), making NF1 the greatest risk factor for developing this cancer. We report a case of MPNST in a patient with NF1 and discuss the various diagnostic modalities, surgical treatments, indications for radiation and chemotherapy, and emerging biologic therapies for patients with these tumors.
A 47-year-old man with NF1 presented to the surgical oncology service after experiencing 2 months of pain that he associated with the increasing size of a long-standing mass located in the medial aspect of his right knee. He described the pain as intermittent and throbbing, worsening with activity, and leaving him unable to jog. The patient reported no sensory or motor function deficits; no autonomic dysfunction, such as anhydrosis, coolness, or cyanosis; and no recent weight loss. He had no history of radiation exposure or trauma and experienced no systemic symptoms, such as fevers or chills, nor had he suffered similar pain in the past. His surgical history was notable for removal of a gastrointestinal stromal tumor (GIST) 3 years earlier and excision of a soft-tissue mass of unknown etiology from his neck 15 years earlier.
The patient appeared healthy with no evidence of cachexia. He was afebrile, and his vital signs were normal. Multiple caf?-au-lait macules and axillary and inguinal skin freckling were noted, consistent with his history of NF1. Inspection of the extremity revealed a large, suprapatellar mass along the medial aspect of the patient's right thigh. The overlying skin showed no evidence of erythema, discoloration, or necrosis. On palpation, the tumor was soft and without appreciable pulsation or fluctuance. The mass was freely movable along a medial-lateral axis but demonstrated minimal movement along a craniocaudal axis. There was no evidence of attachment to deeper structures or to the joint capsule. A positive Tinel's sign was appreciated on percussion of the mass. Sensory evaluation of the affected limb revealed normal responses to light touch, pinprick, two-point discrimination, vibration, and proprioception. A motor examination of the affected extremity found no difference in bulk, tone, or strength when compared with the unaffected extremity. Deep tendon reflexes were normal in the affected extremity. No inguinal lymphadenopathy was noted. Routine hematology and general chemistry were within normal limits.
Magnetic resonance imaging (MRI) was performed on the patient's lower extremities. T1- and T2-weighted MRIs with and without contrast revealed numerous bilateral soft-tissue masses in subcutaneous and intramuscular locations. The largest mass was oval and measured 9.1 x 5.6 x 5.2 cm (Figure 1). It was located in the right thigh, lateral to the saphenous nerve and superficial femoral artery, displacing the sartorius muscle laterally. No evidence of involvement of underlying bony or adjacent neurovascular structures was observed. An additional oval mass, measuring 8.3 x 7.0 x 6.1 cm, was visible in the posterior medial compartment of the right thigh, posterior to the vastus medialis muscle. All masses revealed isointense T1 signal and heterogeneously hyperintense T2 signal with heterogeneous enhancement, consistent with the diagnosis of neurofibroma. This was confirmed with T1- and T2-weighted MRI studies with fat suppression sequences. A computed tomography (CT) scan of the chest was negative for metastatic lesions.
The patient's clinical presentation made suspicion for malignancy high. A biopsy was not performed because the patient elected to have the painful knee masses surgically removed regardless of malignancy. The masses were approached through a longitudinal incision, parallel to the long axis of the lower extremity. The masses appeared to originate from the saphenous nerve in the Hunter's canal. Care was taken to excise the masses completely while sparing the superficial femoral artery and nearby muscles. Frozen-section analysis of the larger mass revealed an atypical spindle-cell tumor, suggestive of sarcoma (Figure 2), and the smaller mass demonstrated features of neurofibroma. Margins were negative for the presence of tumor, with the closest margin being 3 mm.
Pathologic examination of the larger tumor revealed a large, well-circumscribed, encapsulated, white-to-tan, firm nodule measuring 7.0 x 5.8 x 5.8 cm (Figure 3), demonstrating areas of low- and high-grade MPNST (Figure 4). The high-grade malignant areas were noted to be far from the surgical margins. Immunohistochemical staining for c-kit demonstrated approximately 10% staining of tumor cells. The tumor was diagnosed as a high-grade MPNST arising in a neurofibroma. The smaller lesion contained three white-to-tan elongated nodules, ranging from 1.5 x 0.6 x 0.6 cm to 0.7 x 0.4 x 0.4 cm, that exhibited features consistent with neurofibroma (Figure 5). Based on pathologic findings, the tumor was classified as stage IIIb, G3 T2 N0 M0, placing the patient at high risk for local recurrence and distant metastatic spread.
The patient was discharged on postoperative day 1 with a Hemovac drain in his right thigh. Postoperative radiotherapy was recommended with follow-up.
Although MPNSTs are rare, they are among the most common malignancies found in NF1 patients and are associated with significant rates of morbidity and mortality. A thorough understanding of the various diagnostic and therapeutic options for MPNSTs is imperative to ensure adequate management.
NF1, also called von Recklinghausen's disease, is an autosomal-dominant neurocutaneous disorder. The NF1 gene is located on chromosome 17q and generates the intracellular protein neurofibromin. Neurofibromin acts as a tumor suppressor, catalyzing inactivation of the proto-oncogene p21-ras, a protein that plays a vital role in mitogenic intracellular signaling pathways.3,8,9 NF1 results when gene mutations alter its protein product, neurofibromin, leading to overexpression of p21-ras.2,3,8 Approximately 30% to 50% of cases involve de novo germline mutations, meaning the absence of a positive family history does not exclude someone from developing the disease.3,10,11
NF1 has an estimated birth incidence between 1 in 2,500 to 1 in 3,000 and a disease prevalence between 1 in 4,000 to 1 in 5,000, making it the most common human cancer predisposition syndrome.2,3,8 Clinical features of NF1 include pigment manifestations, such as caf?-au-lait spots, axillary or inguinal freckling, and iris hamartomas (Lisch nodules); osseous dysplasia; optic gliomas; and an increased risk of developing benign and malignant tumors, especially MPNSTs.2,8
MPNSTs are a rare form of cancer, accounting for 0.001% of cancers in the general population and for 3% to 10% of all soft-tissue sarcomas.3-7 MPNSTs are most commonly seen in NF1 patients, with approximately 50% to 60% of all lesions found in patients with this neurocutaneous disorder.3,4,7,12-14 The incidence of MPNSTs in patients with NF1 has been estimated at 2% to 5%, with a cumulative lifetime risk as high as 10%; thus, NF1 is the greatest risk factor for developing this cancer.8 Radiation exposure is also a risk factor, with nearly 10% of MPNSTs occurring in patients who have undergone irradiation; the reported average lag time is 15 years.1,3,4,7,12-16
De novo lesions are the second most common type of MPNSTs. In rare cases, MPNSTs can arise from malignant degeneration within a schwannoma, ganglioneuroma, or pheochromocytoma.3,17-20 MPNSTs typically arise in preexisting plexiform neurofibromas and are very aggressive, with frequent local recurrence and distant metastasis.
NF1 patients with MPNSTs tend to present in their second and third decades of life, which is nearly a decade earlier than MPNST patients without this genetic abnormality.3-5,8,21 When evaluating a patient for a possible MPNST, obtaining a detailed medical history and conducting a thorough physical examination are the first steps. Patients with peripheral nerve tumors often present with few symptoms, but the most common ones include the presence of an asymptomatic or symptomatic mass, sensory or motor function loss, pain, visceral symptoms, weakness, and autonomic dysfunction.22 Finding a mobile mass perpendicular (but not parallel) to the axis of a known peripheral nerve in combination with a positive Tinel's sign on tapping suggests a soft-tissue mass of peripheral nerve origin.22 Symptoms such as progressive pain, early onset sensory or motor deficit, and rapid growth indicate a malignant lesion such as MPNST.6
When MPNST is suspected, clinicians should look for characteristics of NF1. A history of radiation exposure may also suggest MPNST. The size of peripheral nerve tumors varies widely and has been noted not to correlate with malignancy, although MPNSTs tend to have more irregular borders.3 A lesion that is hard on palpation also suggests malignancy, especially when there is evidence of local infiltration into surrounding tissue, which is a late feature of MPNSTs.23
MRI remains one of the most useful and sensitive modalities in facilitating the diagnosis of peripheral nerve tumors, including MPNSTs. If a peripheral nerve tumor is suspected, pre- and post-contrast MRI should be conducted. Fat suppression sequences may better indicate the nerve in question.23 MRI typically shows an oval or fusiform mass that has low signal intensity on T1-weighted sequences and high signal intensity on T2-weighted sequences, with marked enhancement on post-contrast images; however, these features also are common to benign neurofibromas. Regions of inhomogeneous enhancement, representing areas of central necrosis and hemorrhage, further suggest MPNST but are also seen with benign schwannomas and neurofibromas.3 MRI cannot indicate conclusively whether a peripheral nerve tumor is benign or malignant. One small study showed positive gallium scans as specific for MPNSTs, but this has yet to be corroborated by larger, follow-up studies.24
MRI can also help diagnose complex situations such as schwannomatosis. If further resolution of nearby soft-tissue structures is required, magnetic resonance neurography offers greater visualization and definition of peripheral nerve masses and demonstrates greater differentiation from nearby tissue. In situations where the vascular nature of the mass requires further analysis, magnetic resonance angiography, time-of-flight sequences, and traditional angiography can be helpful.
Positron emission tomography (PET) scanning with 18-fluoro-2-deoxy-D-glucose (FDG) allows visualization and quantification of glucose metabolism in cells; malignant tumors metabolize glucose faster.9 Studies have shown that FDG-PET scanning is useful in detecting MPNSTs that arise in benign plexiform neurofibromas.8,25 In addition to performing an initial MRI evaluation of the mass, CT scanning of the chest has been recommended as part of the metastatic work-up before surgery.
Following radiologic evaluation, biopsy of the specimen is undertaken. Biopsy is typically done only after the MRI evaluation to ensure proper visualization of vital structures at the biopsy site. Biopsies performed before conducting MRI could adversely affect anatomic detail on the scans.
Biopsy options include fine-needle aspiration (FNA), Tru-Cut needle biopsy, open incisional biopsy, and excisional biopsy. FNA has been deemed inadequate for allowing accurate assessment of tumor type and grade, because dissociated tumor cells are obtained with loss of their architectural relationships.8 Tru-Cut needle biopsy has been recommended when management is undertaken in a multidisciplinary, team setting.8 Both FNA and Tru-Cut biopsy have been associated with intense neuropathic pain, and some researchers advocate incisional biopsy for pathologic diagnosis instead.3 Incisional biopsy's advantages are that it allows a wider sampling of the intrinsically heterogeneous tumor and allows determination of the nerve of origin, which can help anticipate possible deficits should oncologic surgery with nerve sacrifice be required.3 Care must be taken to ensure that the biopsy sample is not limited to one site and includes areas suspected of harboring malignancy.
It has been suggested that combining Tru-Cut and open incisional biopsy can remedy the likelihood of inadequate tissue sampling.8 It is recommended that excisional biopsy be reserved for small, superficially located tumors that can be resected with clear margins.8 Intraoperative biopsy specimens can be analyzed rapidly using frozen-section analysis, but permanent-section analysis is needed to obtain a definitive pathologic diagnosis.
Biopsy is typically done only after the MRI evaluation to ensure proper visualization of vital structures at the biopsy site.
Histological examination should include staining with conventional tinctorial stains, such as reticulin and hematoxylin and eosin. Microscopically, MPNSTs demonstrate a highly cellular spindle-cell tumor arranged in fascicles. Although immunohistochemical staining for S100 protein, skeletal muscle markers desmin and myogen, and proliferation marker MIB-1 have been advocated, there is no single immunohistochemical marker specific for these tumors.8 The recommended staining for S100 protein expressed by Schwann cells is lost in as many as 50% of all MPNSTs.3 The other recommended immunohistochemical markers, such as desmin and myogenin, smooth muscle actin, epithelial membrane antigen, and CD34 and CD68 are primarily used to help exclude other spindle-cell tumors.8
Electron microscopy is another modality that may be helpful in making a final pathologic diagnosis. It shows transformed cells with ultrastructural characteristics that are consistent with Schwann cells or of peripheral nerve origin and lack the features of muscle or other soft-tissue sarcomas.8
Pathologic criteria for malignancy include invasion of surrounding tissues by tumor cells, vascular invasion, marked nuclear pleomorphism, necrosis, and the presence of mitoses.3,8 The presence of even a single mitotic figure may be significant, especially in the context of hypercellularity and nuclear atypia. Mitosis itself is not sufficient for diagnosis, however, because a limited number of mitoses (less than five per high-power field) are associated with atypical but benign schwannoma variants.3,8
Grossly, MPNSTs have a fusiform or globoid appearance associated with a peripheral nerve.
Determining the histologic grade of an MPNST is paramount, because higher grade tumors are associated with increased rates of local recurrence and metastatic spread. Histologic grade is an important prognostic indicator and is incorporated into the tumor, node, metastases (TNM) classification, resulting in a modified grading TNM (GTNM) system. Grading schemes for MPNSTs are the same as those used for the more common soft-tissue sarcomas and are based on standard mitotic rates and histologic features.3,7,26 A significant number of tumors fall into the category of "atypical neurofibromas," and do not fit any defined grading scheme. They may be locally aggressive but less likely to undergo distant metastasis.8 Molecular techniques to determine profiles of gene expression may aid pathologists in more accurately predicting the behavior of these tumors.
The primary treatment for these lesions is complete surgical excision with tumor-free margins. Following a negative metastatic screen, wide-excision surgery is performed, leaving tumor-free margins of at least 2 cm in all directions. Larger tumors should be excised as widely as possible (>e;10 cm) to avoid centripetal spread. Grossly, MPNSTs have a fusiform or globoid appearance associated with a peripheral nerve. They may show evidence of necrosis, pseudocystic change, or hemorrhage.
In the past, surgical therapy often involved limb amputation and disarticulation. Evidence has shown that wide resection in conjunction with neoadjuvant radiation, adjuvant radiation, or chemotherapy can achieve the same goals without limb sacrifice.3,27,28 Nerve reconstruction for brachial and lumbosacral plexus lesions is not advocated because it does not restore useful function and may compromise the adequacy of the surgical excision.8 Amputation may be indicated for extensive tumors and for MPNSTs that recur even after seemingly adequate excision.
Adjuvant radiotherapy is indicated for intermediate-to high-grade lesions and low-grade MPNSTs following a marginal excision. Radiotherapy provides local control and may delay the onset of local recurrence, although it has little demonstrated effect on long-
term survival. Doses for soft-tissue sarcomas range from 60 Gy or higher, delivered to 5-cm margins for optimum control. Preoperative radiation versus postoperative radiation is another treatment consideration. Proponents of preoperative radiation suggest that it makes it easier to achieve tumor-free margins and may be more effective in killing tumor cells because the vasculature has not been disturbed. Arguments against preoperative radiation focus on its negative effects on postoperative wound healing. Results from preliminary studies indicate no clear difference in outcome with respect to the timing of radiation, and postoperative radiation remains current practice.3
Postoperative brachytherapy is another method of delivering postoperative radiation. The primary advantage of brachytherapy is its significantly shorter period of initiation and therapy duration. External beam radiation usually takes 6 weeks, starting approximately 1 month after surgery, whereas brachytherapy generally starts within 1 week postoperatively and is completed in 4 or 5 days. Brachytherapy is more technically challenging and requires the presence of an experienced radiation oncologist during the procedure. Brachytherapy and external beam radiation appear to be equally effective when properly administered.
Chemotherapy for MPNSTs is usually reserved to treat metastatic disease. Current treatment regimens consist of doxorubicin or a combination of doxorubicin and ifosfamide.3,29-31 Chemotherapy is not curative but may achieve useful palliation and, in rare instances, complete and long-lasting remission. MPNSTs have intermediate chemosensitivity; they are less sensitive than synovial sarcomas but more sensitive than refractory diseases, such as alveolar sarcomas. Partial response rate with the best available chemotherapy is likely to range between 25% and 30%.17,29
Using chemotherapy as adjuvant treatment is controversial. A meta-analysis showed a significant benefit at 10 years in terms of disease-free survival, with decreases in local and distant relapse.31 The magnitude of the survival benefit remained small and was not statistically significant. In certain circumstances, chemotherapy may be used preoperatively to downstage patients who have unresectable primary lesions.
Primary prognostic indicators include tumor size (prognosis is worse if the tumor exceeds 5 cm), tumor grade (grade 1 is best, grade 3 is worst), and positive surgical margins (poor prognosis). Local invasion has also been identified as an indicator of poor prognosis. A patient who has been symptomatic for fewer than 6 months or is older than 30 years seems to have an improved prognostic outcome.3
Long-term prognosis is unclear, owing to the lack of large multi-institutional trials. Current data suggest that MPNST patients have a worse prognosis than those with other soft-tissue sarcomas. Perrin and colleagues reported a 5-year survival rate of 64%, with only 30% of patients remaining disease-free, compared with a survival rate of 72% to 78% for patients with other sarcomas.3
Currently, there is no consensus regarding the effect of NF1 on the outcome of MPNSTs, and different studies have reached different conclusions.5,32,33 One study determined that the median length of survival for patients with MPNST, with and without NF1, was 24 months.34 Other studies' estimates on length of survival range from 8 to 44 months.2,5,32,35,36
Even after surgical excision and radiation therapy for local control, patients with intermediate- or high-grade tumors are at high risk of developing metastatic disease. The spread of MPNSTs is primarily hematogenous, and metastatic disease typically occurs as pulmonary metastases. If metastatic pulmonary disease is detected, resection of isolated pulmonary metastases should be performed when feasible. Local radiation and radiation to the systemic metastases in combination with chemotherapy should also be undertaken, but these measures are primarily palliative and have no proven survival benefit.3
Most recurrences manifest within the first 2 years, but the risk continues over a 5-year period; thus, patients must be followed closely for 2 to 5 years after treatment. Patients should have a baseline CT scan or MRI 2 to 3 months after surgery, with additional imaging studies administered depending on the patient's symptoms and the nature of the primary tumor.8
The future in treating MPNSTs revolves around improving our understanding of the disease's molecular biology and developing molecular-based therapies. The success of receptor tyrosine kinase inhibitor ST1571 (imatinib) in causing GISTs to regress by inhibiting c-kit, along with early in vitro data showing MPNST growth inhibition in cell cultures, suggest tyrosine kinase inhibitors may be effective in treating MPNSTs.37 Studies are underway to develop biologic therapies for treating MPNSTs and have focused on finding inhibitors against the epidermal and platelet-derived growth factor receptors, creating farnesyl-transferase inhibitors that target the p21-Ras-Raf-MAPK pathways, and developing anti-angiogenic agents such as thalidomide and others that work against vascular endothelial growth factor. Advances in molecular techniques may offer prognostic improvement for MPNST patients.
Although MPNSTs are rare, they remain a common and serious disease among patients with NF1. Due to the aggressive nature of these tumors, a thorough understanding of related diagnostic and treatment methods is critical to ensuring adequate management. Following initial radiographic evaluation using MRI, biopsies are recommended to aid in pathologic diagnosis. Wide surgical excision with tumor-free margins remains the mainstay of treatment, followed by adjuvant radiotherapy for intermediate- to high-grade tumors or for low-grade tumors with marginal excision. Adjuvant chemotherapy continues to be controversial and should be reserved for patients with metastatic disease. Recurrences typically occur within 5 years, and patients should be monitored with imaging studies during this time frame. Isolated pulmonary recurrences can be treated with surgical excision. Biologic therapies remain on the horizon, and it is hoped that recent advances in molecular techniques can be translated into prognostic improvements for patients.
The authors have no relationship with any commercial entity that might represent a conflict of interest with the content of this article and attest that the data meet the requirements for informed consent and for the Institutional Review Boards.