Malignant Peripheral Nerve Sheath Tumors
by Claire Cambron
July 2018

Claire Cambron

The 2017-2018 Rein in Sarcoma Scholars are each writing a detailed article about a particular sarcoma cancer sub-type. Claire Cambron is a studying at the Mayo Clinic School of Medicine. She is originally from Phoenix, Arizona and completed her undergrad at Arizona State University. Before coming to medical school, she taught English at an elementary school in Cheongju, South Korea for a year. At this point in her medical education, she is most interested in a career in pediatric hematology/oncology. Her involvements at Mayo include PreMed Insight, a student-run initiative that helps pre-medical students of minority and disadvantaged backgrounds explore the medical field, as well as Oncology Interest Group. She also leads the program "My Story", an initiative created by the Student Life and Wellness Committee that encourages Mayo medical students and faculty to share experiences of overcoming challenges in their medical careers in order to promote resiliency and wellness.

Introduction

Sarcoma is a rare type of cancer confined to the connective tissue of the body. Connective tissue encompasses bone and soft tissue, the latter of which includes supporting structures such as muscles, tendons, and ligaments, nerves, fat, blood vessels and deep skin tissue9. The classification of the tumor typically depends on the type of tissue from which the sarcoma originates. However, some classifications are based on misconceptions regarding the tumor cell’s origin; for instance, while synovial sarcoma was believed to have originated from synovium, the tumor cell origin is unknown.

Malignant schwannoma, also known as a malignant peripheral nerve sheath tumor (MPNST), is a type of soft tissue sarcoma that originates in the lining (sheath) of peripheral nerves that emerge from the spinal cord. Nerve bundles in the proximal extremities, specifically the sciatic nerve, are most often affected2. This rare tumor comprises approximately 2% of the roughly 13,040 new soft tissue sarcoma diagnoses made each year2, 4. Studies suggest that MPNSTs do not demonstrate a gender predilection and can arise at any age. However, the etiology of the tumor can influence the age of presentation. For example, about 50% of the time, MPNSTs are associated with a genetic syndrome called neurofibromatosis type 1 (NF1)2. The median age of patients with NF1 who develop malignant peripheral nerve sheath tumors (MPNST) is between 20 – 40 years, versus a median age of 30 – 60 years in patient with sporadic MPNSTs2.

Clinical presentation

In patients with neurofibromatosis type 1, malignant peripheral nerve sheath tumors may arise from pre-existing plexiform neurofibromas, a subset of the benign nerve sheath tumors known as neurofibromas. Plexiform neurofibromas typically form larger masses than cutaneous or spinal neurofibromas and are more likely to transform into a malignancy than the latter two subsets6. Plexiform neurofibromas can be found in many different areas of the body including the eye socket, face, extremities, back, chest, and abdomen6. MPNSTs developing on the trunk may have a worse prognosis10.

A malignant transformation of a benign plexiform neurofibroma may first present as new, intensifying or persistent pain localized to the pre-existing mass2. In a patient without NF1, a malignant nerve sheath tumor may manifest as pain arising from an entirely new, rapidly enlarging mass2. As a result of the tumor’s mass effect in either etiology, local neurological symptoms of weakness or paresthesia may also develop.

The most common sites of malignant peripheral nerve sheath tumors include the nerve roots in the proximal extremities and pelvis, especially in the sciatic nerve2.

Causes of Malignant Peripheral Nerve Sheath Tumors

Half of all malignant peripheral nerve sheath tumors develop secondary to neurofibromatosis type 1, a genetic syndrome caused by an autosomal dominant “loss of function” mutation in the tumor suppressor gene neurofibromin. NF1 affects 1 in 3000 live births, and approximately 8-13% of those affected will develop MPNSTs over their lifetime2. The syndrome demonstrates variable expressivity, meaning that the disease may manifest as many different phenotypes. Associated signs and symptoms include café-au-lait spots, neurofibromas, Lisch nodules in the eye, seizures, and malignant peripheral nervous sheath tumors. Due to variable expressivity, it can be difficult to predict and track MPNSTs in a patient with NF1.

Neurofibromas are not always associated with NF1. In fact, a majority of the time, they are sporadic tumors. Therefore, MPNSTs do not always arise due to an inherited condition; they can also develop from a stand-alone, benign neurofibroma.

Another risk factor for MPNST is previous radiation therapy1. While the prevalence of MPNSTs in the general population is only 0.001%, the risk of developing a MPNST as a secondary malignancy due to prior radiotherapy is 0.06%11. A MPNST may develop in a radiation-treated area within 10-20 years of receiving treatment. This etiology is often linked with radiation treatment for childhood cancer. Up to 10% of MPNSTs are attributed to prior radiation treatment3.

Diagnosis

Biopsy is required for diagnosing a malignant peripheral nerve sheath tumor. In terms of imaging, magnetic resonance imaging is often used to characterize MPNSTs; however, MRI does not always prove a reliable method of differentiating benign neurofibromas from MPNSTs. It can, however, prove useful in guiding surgical excision, as it can help determine whether the mass involves adjacent structures3. Fluorodeoxyglucose positron emission tomography (FDG-PET scan) can be used to differentiate MPNSTs from benign neurofibromas3.

Electrodiagnostic testing with electromyography and nerve conduction testing is helpful in directing surgery. Malignant involvement of a nerve or parts of a nerve plexus determined pre-operatively may deter the surgeon from performing the excision at all. More likely, intraoperative electrodiagnostic testing will be used to identify nonfunctional neural tissue that can be removed by the surgeon to increase access and facilitate tumor removal3.

Staging

MRI is the primary imaging modality for visualizing the primary lesion in the extremity suspicious for MPNST. The next step is biopsy. While tumor features such as a size >5 cm, heterogeneity, and ill-defined margins with invasion of surrounding fat are all highly suggestive of MPNST, biopsy is required to confirm malignancy3. PET and PET/CT are often used for staging sarcoma. PET or gallium scan may be used to differentiate benign plexiform lesion from MPNST in a patient with NF18. Once the diagnosis of MPNST is made, a CT chest is typically done to rule out metastasis to the lung.

Treatment

If the tumor is localized to an extremity, treatment involves surgical resection. Depending on the size of the tumor, the limb may be amputated proximal to the tumor in order to achieve a clear margin. In other circumstances, a joint may be disarticulated, compromising nearby nerves and soft tissue structures. Unfortunately, nerve grafts prove insufficient in this situation due to the use of adjuvant radiation therapy (RT). Radiation therapy can be given prior to resection or after to improve chance of local control3.

Limb-salvage can be achieved with preoperative radiation therapy or chemoradiotherapy. Other rare interventions applied toward limb salvage include isolated limb perfusion and infusion as well as regional hyperthermia with chemotherapy3. The role of neoadjvuant or adjuvant systemic therapy (chemotherapy) can be used in select cases, but overall, there is limited proven benefit for systemic therapy to improve overall survival compared with local treatment alone.

Prognosis

Tumor features such as size >5cm, truncal location, and local recurrence are poor prognostic factors10. In addition, an NF1-associated MPNST may have a poorer prognosis than a non-NF1-associated MPNST due to the former’s larger size at presentation. A malignant peripheral nerve sheath tumor that develops from a neurofibroma associated with NF1 is often discovered at a later stage than a sporadic MPNST3. Perhaps this is due to the NF1-associated tumor originating from a pre-existing structure or neurofibroma. It is probable that a person who notices a new mass on their body will seek medical attention earlier than their NF1 counterpart. A meta-analysis for articles dated from 1963 to 2011 reported worse survival rates in patients with MPNSTs secondary to NF1 than patients with sporadic MPNSTs (hazard ratio 1.39)5. However, analysis limited to articles published since 2001 demonstrated an insignificant hazard ratio (HR 1.19), suggesting that outcomes are becoming more equitable among patient populations5.

A single-center retrospective study of 175 cases of MPNSTs, of which one third originated from an NF1-associated neurofibroma, demonstrated a recurrence rate of 22% and five to ten-year survival rates of 60% and 45%, respectively10. Of these cases, 69% were treated surgically with local resection and a majority received adjuvant radiation therapy, chemotherapy or a combination of the two10.

Summary

Malignant nerve sheath tumors represent a rare form of soft tissue sarcoma that affects both young and old adults. Roughly half of patients affected have the genetic syndrome, neurofibromatosis type 1, which predisposes them to the development of benign nerve sheath tumors. A subset of those patients develop malignant transformation of a pre-existing plexiform neurofibroma to MPNST. Another common etiology is the malignant transformation of a stand-alone neurofibroma, unassociated with NF1. MPNSTs may also arise as a side effect of childhood cancer radiation therapy received 10-20 years prior. Depending on the etiology, MPNSTs classically present as either new pain in a pre-existing lesion or pain in an entirely new, rapidly enlarging mass, often located in the proximal extremity. Definitive diagnosis requires biopsy of the specimen. MRI and electrodiagnostic testing may be used to guide surgical excision. Treatment of MPNSTs often involves surgical excision and neo/adjuvant radiation therapy.

References

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2. Farid, Mohamad et al. “Malignant Peripheral Nerve Sheath Tumors.” The Oncologist 19.2 (2014): 193–201. PMC. Web. 12 June 2018.
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6. “Nerve Tumors.” Neurofibromatosis (NF) Center, 2018 Washington University in St. Louis, nfcenter.wustl.edu/what-is-nf/neurofibromatosis-type-1/nerve-tumors/.
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8. Ryan, Christopher W, and Janelle Meyer. “Clinical Presentation, Histopathology, Diagnostic Evaluation, and Staging of Soft Tissue Sarcoma.” UpToDate, Wolters Kluwer, 27 Apr. 2017.
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11. Yamanaka R, Hayano A. Radiation-Induced Malignant Peripheral Nerve Sheath Tumors: A Systematic Review. World neurosurgery. 2017 Sep