Metastatic malignant peripheral nerve sheath tumour in a patient with neurofibromatosis 1 and review of contemporary systemic treatments

Abstract

Malignant peripheral nerve sheath tumours are rare soft tissue sarcomas commonly seen in patients with neurofibromatosis type 1. They typically manifest in the fibrous sheaths of major nerve trunks in the extremities or in an axial location. Presenting symptoms are generally non-specific, including pain and weakness, and survival is dependent on size and location of the tumour. Surgical resection is the primary treatment modality followed by radiotherapy or chemotherapy; however, prognosis is poor. Medications such as tyrosine kinase inhibitors and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway inhibitors are increasingly being recognised as potentially effective therapy for these malignancies. We report a case of a patient with neurofibromatosis type 1 presenting with a malignant peripheral nerve sheath tumour along the tibial nerve that was initially diagnosed as a muscle strain. We discuss the utility of diagnostic imaging and pathology in correctly identifying this aggressive tumour as well as review the drugs used in her care.

Background

Malignant peripheral nerve sheath tumours (MPNST) are an aggressive sarcoma that originate in the protective fibrous sheath of peripheral nerves.¹ They are exceedingly uncommon, comprising 2% of all sarcomas.² Moreover, roughly 50% of presenting cases occur in patients with neurofibromatosis type 1 (NF1), a multisystem genetic disorder commonly characterised by neurocutaneous findings, including benign tumours of the skin (neurofibroma) and nerves (plexiform neurofibroma).³ MPNST can arise de novo or via transformation from benign nerve sheath tumours; most MPNST in patients with NF1 arise from plexiform neurofibromas.⁴ The most common presenting features are a rapidly enlarging painful mass accompanied by weakness or paraesthesia, most often in the distribution of the sciatic nerve.^{3 5} In adults with MPNST, tumour location, grade and number of primary tumours are most predictive of mortality.⁶ The median age of onset for MPNST in patients with NF1 is between 20 and 40 years. Five-year survival of the disease is 39% and overall median survival is 32 months in duration.^{7 8} Treatment is typically surgical resection with or without chemotherapy and radiation therapy.⁹ While traditional regimens employed in treatment of MPNST include ifosfamide and anthracycline-based chemotherapies, novel inhibitors have demonstrated significant efficacy, particularly when targeting the rat sarcoma (RAS)/rapidly accelerated fibrosarcoma (RAF)/mitogen-activated protein kinase kinase (MEK)/extracellular signal regulated-kinase (ERK) pathway. We report a case of MPNST in a patient with NF1 whose management included adjuvant therapy with a tyrosine kinase inhibitor and an mitogen-activated protein kinase (MAPK)/ERK pathway inhibitor in which overall survival was 45 months.

Case presentation

An African American woman in her 40s with a history of NF 1 presented to clinic due to persistent right lower extremity pain. For over 1 month, she experienced progressive, sharp burning pain in her right ankle that radiated along the leg. Three weeks prior to presentation, the pain began to impact ambulation, prompting a visit to the emergency department. No discernible aetiology of her symptoms was evident, including no cutaneous findings in the area, and she was discharged with the diagnosis of muscle strain. On arrival, the patient endorsed pain worsened by extended periods of knee flexion and walking long distances that was only relieved with rest. Use of gabapentin had no appreciable effect. She also reported unintentional weight loss of 14 pounds over a 1-month period but denied weakness in her foot, fevers, chills or night sweats.

The patient was afebrile with a blood pressure of 104/61 mm Hg, heart rate of 72 bpm and oxygen saturation of 99% on room air. Physical examination demonstrated a palpable posterior distal thigh mass that was tender to palpation. There was no discernible skin breakdown. Knee range of motion was 0–90° bilaterally. Tinel’s sign was positive over the thigh mass, eliciting shooting pain down the lateral surface of the right leg. Ankle and toe strength was 5/5 bilaterally with preserved dorsiflexion and plantarflexion. Sensation was intact to light touch in the superficial fibular, deep fibular, tibial, saphenous and sural distributions. Initial considerations of the palpable mass included plexiform neurofibroma, MPNST or other malignancies. A follow-up incisional biopsy was scheduled along with additional imaging studies.

Investigations

An X-ray of the right femur demonstrated a large soft tissue mass centred on the distal femoral segment of the tibial nerve. MRI reaffirmed a heterogeneously T2 hyperintense soft tissue mass centred on the distal segment of the femoral course of the tibial nerve measuring 61×62×123 mm in size (figure 1). There was also a smaller, similar lesion along the dermis and superficial subcutaneous adipose of the lateral aspect of the distal right thigh that was most consistent with a neurofibroma. Imaging also noted scattered regions of spontaneous hyperintensity on precontrast T1-weighted sequences with heterogeneous postcontrast enhancement and local air–fluid levels suggestive of secondary aneurysmal bone cyst. An incisional biopsy of the right leg nerve mass was performed 1 week later. Pathology demonstrated a high-grade spindle cell sarcoma consisting of cells with a high nuclear-to-cytoplasmic ratio and brisk mitoses (figure 2). Immunohistochemical stains showed tumour cells strongly positive for CD34 and cytokeratin AE1/AE3 and weakly positive for Sox-10 (figure 3). Cells were negative for S-100, ERG, STAT-6, desmin and smooth muscle actin. A fluorescent in situ hybridisation study for SS18 gene locus rearrangement was ordered to exclude intraneural synovial sarcoma and found to be negative. In consideration of the patient’s history of NF 1, clinical presentation and pathologic findings as well as results from imaging studies and biopsy, she was diagnosed with stage III T2bN0M0 grade 3 MPNST of the tibial nerve.

Figure 1.

Axial MRI of right thigh demonstrating large heterogeneously T2 hyperintense soft tissue mass centred on the distal segment of the femoral course of the tibial nerve.

Figure 2.

H&E stain of hepatic parenchyma of right thigh mass showing sheet-like proliferation of spindle and ovoid cells with a vague fascicular growth pattern at (A) 40× magnification, (B) 20× magnification and (C) 20×magnification.

Figure 3.

Immunohistochemical staining of sarcomatous mass for (A) CD34, (B) cytokeratin AE1/AE3 and (C) SOX-10.

Differential diagnosis

Differential diagnosis of the mass following imaging, prior to surgical intervention and pathologic evaluation, included plexiform neurofibroma, MPNST and schwannoma, in the context of a patient with NF-1.

Treatment

The patient received neoadjuvant radiation therapy for 21 days (total dose of 50.4 Gy) followed by radical resection of thigh sarcoma, neuroplasty and exploration with arteriolysis of the popliteal artery. After 6 months of routine monitoring, a CT of the chest demonstrated diffuse, numerous large pulmonary nodules concerning for pulmonary metastatic disease. She received a unilateral lung lower lobe wedge diaphragmatic excision 1 month later; however, surveillance at a 2-month follow-up showed progression of lung disease. The patient was started on pazopanib 800 mg/day, which was transitioned to trametinib 2 mg/day after 6 months due to continued progression. She was then referred to thoracic surgery for en bloc resection of intrathoracic mass, including right lung middle and lower lobe, en bloc resection of extrathoracic mass that involved the chest wall, primary repair of diaphragmatic defect and cryoablation of unilateral third-ninth intercostal spaces. The patient remained stable for 7 months until a worsening maculopapular rash and progressive anaemia prompted reduction of trametinib therapy to 1 mg/day.

The patient returned 6 months following dose reduction with progressive chest wall pain revealed to be evidence of further metastasis, for which she underwent chest wall radiation therapy. Recovery was complicated by spinal cord compression and pathologic fracture of the femur; subsequent imaging showed pelvic and lumbosacral metastases. The neurosurgery team indicated that surgical intervention for the sacral mass was not feasible. Meanwhile, trametinib was discontinued after 13 months of total therapy. The patient was then treated with liposomal doxorubicin for 1 month, and then gemcitabine and docetaxel. Unfortunately, metastatic disease continued to progress.

Outcome and follow-up

Despite multiple therapies, this young woman passed away 45 months after her initial diagnosis of MPNST at the age of 47.

Discussion

MPNST remains a highly aggressive sarcoma with a poor prognosis, even with routine cytotoxic chemotherapy. Significant negative prognostic factors include increasing tumour size and axial location of the neoplasm.¹⁰ Interestingly, a history of NF1 has not been shown to directly impact survival time; however, MPNST in this population tends to be larger and faster growing, indicating a need for meticulous surveillance. Currently, surgical resection with extensive negative margins remains the gold standard for initial treatment. Based on treatment of other soft tissue sarcomas, chemotherapy has been shown to improve outcomes in advanced sarcoma with recurrence or metastases, although overall response rates remain low.¹¹ The combination of ifosfamide and doxorubicin has been routinely employed in treatment of advanced soft tissue sarcoma; additionally, liposomal doxorubicin has demonstrated equivalent response rates with more favourable toxicity profiles.¹² However, the median progression-free survival with doxorubicin-based chemotherapy is 4.3 months. Therapy with gemcitabine and docetaxel has shown similarly low response rates, although prolonged duration of survival may be seen in a subset of the population.¹³ Overall response and survival are further reduced in relapsed or metastatic MPNST, emphasising the need for novel therapy.

Given limited benefit of cytotoxic chemotherapy, targeted therapy has been exceedingly employed in the treatment of soft tissue sarcomas. Currently, over 50 in vivo studies and clinical trials involving MPNST have been conducted or are ongoing. Results, thus, far have indicated relatively modest response rates. For example, multiple kinase inhibitors of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, such as pazopanib, have demonstrated intermediate response rates in MPNST. Combined studies of monotherapy with pazopanib for treatment of soft tissue sarcomas have elicited moderate prolongation of overall survival by 8.2 months.¹⁴

Recently, MEK inhibitors, including trametinib and selumetinib, have received increasing interest for treatment of MPNST via suppression of MAPK signalling.¹⁵ The MAPK pathway is a commonly mutated oncogenic pathway in the development of cancer, with MEK being a downstream component of the pathway that has been indicated in cancer.¹⁶ The pathway remains complex and relevant to our understanding of the development and treatment of cancers, with loss of control of the pathway, leading to cancer. Zhang et al outline the pathway, which involves a protein kinase cascade that regulates cell proliferation, with downstream signalers such as MEK being targets of mutations that can lead to cancer.¹⁷ Of note, regarding the pharmacology of MEK inhibitors, all of the currently existing drugs work as allosteric MEK inhibitors.¹⁶

Numerous preclinical studies are currently investigating the use of MEK inhibitors in paediatric and adult MPNST, particularly in those with NF1, although resulting clinical data are not yet available.¹⁸ Following disease progression after 6 months of pazopanib monotherapy, our patient received trametinib monotherapy for 13 months. Overall survival was 45 months compared with a population median overall survival of 32 months. Furthermore, although data are not readily available, duration of survival in relapsed, metastatic MPNST is assuredly lower. While overall survival cannot be entirely attributed to trametinib therapy due to additional sequential inhibitor therapy and chemotherapy, the patient demonstrated 13 months of progression-free survival on trametinib monotherapy with minor adverse effects.

Timely diagnosis of MPNST is imperative. Benign and MPNST can similarly present with swelling and weakness. Imaging studies, including MRI, demonstrate a very wide range of sensitivities and specificities in successfully capturing malignant properties. The most pertinent morphologic features include border irregularity and mass heterogeneity.¹⁸ The histopathology of MPNST is equally important. S-100 and SOX-10 are common tumour markers for soft tissue neoplasms, including schwannomas and neurofibromas. Expression of such markers is variable in MPNST, with an overall sensitivity of roughly 50%.¹⁹ High-grade sarcomas are even more challenging, with some studies indicating the presence of only few, scattered S-100-positive tumour cells.^{20 21} Soft tissue sarcomas may also be focally positive for cytokeratin AE1/AE3; however, evidence shows a substantial degree of overlap between subtypes of sarcoma.²² The role of CD34, which is frequently expressed in MPNST, is controversial in its value for classification and grading due to its ubiquitous expression.²³

The diagnosis of MPNST is clearly complex. On our patient’s initial presentation, early impressions favoured muscular strain as opposed to a neoplastic process. Additionally, imaging studies demonstrated a smaller lesion more consistent with a neurofibroma, a common neurocutaneous finding that may harbour the potential to mislead diagnoses of MPNST. The manifestation of pain in the distribution of a peripheral nerve, systemic symptoms including weight loss, imaging studies indicating heterogeneity and consistent histopathologic profile motivated the diagnosis of MPNST. Unfortunately, surgical intervention and subsequent chemotherapy and tyrosine kinase inhibitor and MAPK/ERK pathway inhibitor therapy were insufficient. Medical therapies currently only exhibit poor–modest outcomes; however, numerous clinical trials are underway. As with many malignancies, early detection is of paramount importance. Thus, medical professionals should be aware of the prevalence of MPNST in those with NF1, and a high degree of suspicion and appropriate investigation are needed, especially in patients with NF1.

Learning points.

• Malignant peripheral nerve sheath tumours are aggressive sarcomas that most frequently occur in patients with neurofibromatosis type 1.

• Malignant peripheral nerve sheath tumours are currently treated with surgical resection and chemotherapy, but response rates are poor.

• Tyrosine kinase inhibitors and mitogen-activated protein kinase (MAPK)/extracellular signal regulated-kinase (ERK) pathway inhibitors show promising results in progression-free survival and overall survival for patients with malignant peripheral nerve sheath tumours.

• Contemporary studies suggest that selective targeting of the rat sarcoma (RAS)/rapidly accelerated fibrosarcoma (RAF)/mitogen-activated protein kinase kinase (MEK)/extracellular signal regulated-kinase (ERK) pathway may yield effective outcomes.

• Malignant peripheral nerve sheath tumours can present as innocuous muscle strain, and a high clinical suspicion should be maintained.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s)