Malignant Peripheral Nerve Sheath Tumor (MPNST)

What MPNST is

Peripheral nerves are wrapped in protective layers made of Schwann cells and connective tissue (the nerve sheath). Benign nerve sheath tumors, such as neurofibromas and schwannomas, are common. In MPNST, cells in the sheath become malignant, grow rapidly, invade surrounding tissue and can spread to the lungs and other organs.

MPNST makes up roughly 5 to 10% of soft tissue sarcomas. It most often affects the large nerves of the trunk, thighs, buttocks, upper arms, and the nerves of the neck and pelvis, such as the sciatic nerve and brachial plexus.

Risk factors

• Neurofibromatosis type 1: the biggest risk factor. People with NF1 develop MPNST at a younger age, typically in their 20s to 40s, compared with 40s to 60s in others.
• Plexiform neurofibromas: large, diffuse neurofibromas present in many people with NF1. MPNST often develops within them, sometimes through an intermediate "atypical neurofibroma" stage.
• Previous radiation therapy: MPNST can develop in the radiation field 10 or more years later.
• Sporadic cases with no known risk factor.

Symptoms

• A lump or swelling, often deep, that grows over weeks to months
• Pain, which may be constant, worse at night, or a change from a previously painless neurofibroma
• Numbness, tingling or burning along the nerve
• Weakness of muscles supplied by the affected nerve
• Symptoms of spread, such as cough or breathlessness if it reaches the lungs

In NF1, distinguishing an MPNST from a benign neurofibroma is challenging, so any rapid change or new pain should be assessed promptly.

Diagnosis

1. MRI: shows size, location and relationship to nerves and vessels. Features such as rapid growth, irregular edges, internal necrosis and loss of the normal "target sign" raise suspicion.
2. FDG PET-CT: MPNSTs typically show higher metabolic activity than benign neurofibromas, helping identify suspicious areas and guide biopsy.
3. Biopsy: a core needle biopsy, planned by the sarcoma team so the biopsy track can be removed during surgery. Pathologists look for features such as loss of the H3K27me3 marker, which supports the diagnosis.
4. Staging: chest CT to look for lung spread.

Treatment

Care should be at a specialist sarcoma center with experience in nerve tumors.

Surgery

The main treatment is wide surgical excision, removing the tumor with a margin of healthy tissue. Because the tumor grows from a nerve, this may require sacrificing part of that nerve, with resulting weakness or numbness. Reconstruction and nerve or tendon transfers can restore some function. Amputation is rarely needed today.

Radiation therapy

Radiation before or after surgery reduces the risk of the tumor returning locally, especially for large, high-grade tumors or when margins are close.

Chemotherapy

Chemotherapy (for example, doxorubicin and ifosfamide) may be used before surgery to shrink large tumors, or for tumors that have spread. MPNST responds less well to chemotherapy than some other sarcomas.

Clinical trials

Targeted therapies and new approaches are being studied, and clinical trials are often recommended for advanced disease.

Outlook

MPNST is an aggressive cancer. Outcomes are best when the tumor is small, located in a limb, low grade, and completely removed. Five-year survival across all cases is roughly 35 to 60%, and it is lower for large, high-grade or metastatic tumors, and historically for NF1-associated tumors. Regular follow-up with imaging is needed because local recurrence and lung spread can occur.

Monitoring in NF1

People with NF1 benefit from:

• knowing the location and size of their plexiform neurofibromas, often with baseline whole-body or targeted MRI
• reporting any new pain, rapid growth, hardening or nerve symptoms promptly
• regular review at an NF1 clinic

MEK inhibitors, such as selumetinib, can shrink plexiform neurofibromas, but do not treat MPNST.

Frequently asked questions

What is a malignant peripheral nerve sheath tumor?

It is a rare, aggressive soft tissue sarcoma that grows from the protective sheath around peripheral nerves. It often develops in people with neurofibromatosis type 1, sometimes from a pre-existing plexiform neurofibroma, and can spread to the lungs.

What are the symptoms of MPNST?

Common symptoms are a growing lump, new or worsening pain (often at night), and numbness, tingling or weakness along the affected nerve. In people with NF1, a sudden change in an existing neurofibroma is an important warning sign.

How is MPNST related to NF1?

About half of MPNSTs occur in people with NF1, who have a lifetime risk of roughly 8 to 13%. The tumor usually develops within a plexiform neurofibroma. People with NF1 tend to develop MPNST at a younger age.

How is MPNST treated?

The main treatment is complete surgical removal with a margin of healthy tissue, often combined with radiation therapy. Chemotherapy may be used for large or spreading tumors. Treatment is best provided at a specialist sarcoma center.

What is the prognosis for MPNST?

The outlook depends on tumor size, grade, location and whether it can be completely removed. Small, completely removed limb tumors have the best outcomes. Across all cases, 5-year survival is roughly 35 to 60%, and it is lower for metastatic disease.