Plexiform Neurofibroma

What a plexiform neurofibroma is

Neurofibromas are tumors made of Schwann cells (which wrap nerves), fibroblasts and other cells. The common cutaneous neurofibromas of NF1 are small, soft bumps in the skin. Plexiform neurofibromas are different: they grow along the length of a nerve and its branches, like a "bag of worms," can be very large, and may involve deep structures such as the spine, chest, abdomen, pelvis or face.

They are caused by loss of function of the NF1 gene, which normally controls the RAS/MAPK growth pathway. That is why MEK inhibitors, which block this pathway, can shrink them.

Symptoms

Symptoms depend on location and size:

• a soft, irregular swelling under the skin, sometimes with overlying darker skin or excess hair
• overgrowth of skin and soft tissue, and enlargement of a limb or part of the face
• pain, often the most troublesome symptom
• weakness, numbness or tingling
• reduced movement of joints
• airway, vision or hearing problems for head and neck tumors
• bladder or bowel problems for pelvic tumors
• spinal cord compression for paraspinal tumors
• bone changes, including scoliosis and bowing of long bones

Many PNs are deep and not visible, found only on MRI.

Neurofibromatosis type 1

Neurofibromatosis type 1 is a genetic condition affecting about 1 in 3,000 people. Other features include cafe-au-lait macules, freckling in the armpits and groin, cutaneous neurofibromas, Lisch nodules in the iris, optic pathway gliomas, learning difficulties and bone abnormalities. About half of cases are inherited; the rest arise from new gene changes.

Malignant transformation

People with NF1 have a lifetime risk of roughly 8 to 15% of developing a malignant peripheral nerve sheath tumor (MPNST), most often arising within a plexiform neurofibroma. Warning signs include:

• rapid growth
• a change from soft to hard
• new, persistent or night pain
• new neurological deficits

Atypical neurofibromas (also called ANNUBP) are intermediate lesions that may precede MPNST. PET-CT and MRI help identify suspicious areas, and biopsy confirms.

Diagnosis

• Clinical exam with measurement and photographs
• MRI: the standard imaging; whole-body MRI to assess the overall tumor burden
• Volumetric MRI to track growth and treatment response
• FDG PET-CT if malignant change is suspected
• Biopsy of suspicious areas
• Genetic testing for NF1 if not already confirmed

Treatment

Many PNs are watched if they cause no symptoms. Treatment is considered for pain, functional problems, disfigurement or threat to vital structures.

MEK inhibitors

• Selumetinib: approved for children 2 years and older with symptomatic, inoperable PNs. About two thirds of children have meaningful tumor shrinkage, with improvement in pain and function for many.
• Mirdametinib: approved for adults and children 2 years and older with symptomatic PNs not amenable to complete removal.

Common side effects include acne-like rash, skin dryness, nail infections, stomach upset and raised muscle enzymes; eye and heart checks are recommended. Tumors may regrow if treatment stops.

Surgery

Complete removal is often difficult because PNs intertwine with nerves and are very vascular. Partial removal (debulking) can relieve symptoms or improve appearance, particularly for superficial tumors. Regrowth is common, especially in young children.

Supportive care

• pain management, including medicines for nerve pain
• physical and occupational therapy
• orthopedic care for bone involvement
• psychological support for body image and quality of life

Outlook

PNs tend to grow fastest in early childhood and more slowly in adulthood. With MEK inhibitors, outcomes have improved substantially. Lifelong monitoring in a specialist NF clinic allows early detection of growth or malignant change.

Frequently asked questions

What is a plexiform neurofibroma?

It is a benign tumor that grows along multiple branches of a nerve, forming a soft, sometimes large mass. It almost always occurs in people with neurofibromatosis type 1 and can cause pain, disfigurement and problems with nearby organs.

Are plexiform neurofibromas cancerous?

They are benign, but they can occasionally transform into a cancer called a malignant peripheral nerve sheath tumor. Rapid growth, hardening, new or night pain and new weakness are warning signs that need prompt evaluation.

How are plexiform neurofibromas treated?

Options include observation, MEK inhibitor medicines such as selumetinib and mirdametinib that can shrink tumors, and surgery to remove or debulk tumors when feasible. Pain management and therapy support daily function.

What percentage of people with NF1 have plexiform neurofibromas?

About 30 to 50% of people with NF1 have at least one plexiform neurofibroma, though many are deep and found only on MRI. Many do not cause symptoms.

Can plexiform neurofibromas grow back after surgery?

Yes. Because they are hard to remove completely, regrowth after surgery is common, especially in young children. MEK inhibitors may be used before or after surgery, or as an alternative, depending on the tumor.