What Is a Plexiform Neurofibroma and How Is It Treated?

A plexiform neurofibroma is a benign but often debilitating nerve sheath tumor that grows along peripheral nerves, weaving through surrounding tissue in a tangled, web-like pattern. These tumors occur almost exclusively in people with neurofibromatosis type 1 (NF1), a genetic condition affecting roughly 1 in 3,000 people, and they can appear anywhere from the face and limbs to the spine and deep organs. While the tumors themselves are not cancerous, they carry a real risk of transforming into a deadly soft-tissue cancer, and even without malignant change they can cause serious pain, disfigurement, and disability.

What Drives Their Growth

The root cause is loss of function of the NF1 gene, which produces a protein called neurofibromin. Neurofibromin acts as a brake on a cell-signaling pathway called Ras. When both copies of the NF1 gene are knocked out in Schwann cells, the support cells that insulate nerves, Ras signaling becomes stuck in overdrive. Studies comparing normal and neurofibromin-deficient Schwann cells have confirmed that these cells show persistently elevated levels of active Ras.¹ That unchecked Ras activity does more than just make cells proliferate. Research has shown it disrupts the normal relationship between Schwann cells and the nerve fibers they wrap around; about half of Schwann cells with oncogenic Ras displayed abnormal axonal interaction in experimental models.² This disruption is a key early step in how these tumors take shape, because normal Schwann cells line up in orderly sheaths around axons, while tumor-forming ones pile up chaotically.

But the Schwann cells do not act alone. The tumor microenvironment is an active accomplice. Tumorigenic Schwann cells secrete a chemical signal called stem cell factor, which attracts mast cells (immune cells involved in inflammation). Once recruited, the mast cells release inflammatory molecules that stimulate the Schwann cells, surrounding fibroblasts, and blood vessels, creating a self-reinforcing loop of tumor growth. Animal experiments using bone marrow transplants have demonstrated that plexiform neurofibromas require NF1 haploinsufficiency, meaning one faulty gene copy, in the blood-cell compartment as well, underscoring that these tumors depend on a conspiracy between different cell types at the genetic level.³

How Fast They Grow, and When

Plexiform neurofibromas are often present at birth or develop in early childhood, and their growth rate varies considerably by age. Longitudinal MRI studies tracking tumor volume over time have consistently found that younger patients have the fastest-growing tumors, while growth tends to slow after adolescence. In one study, the fastest-growing tumors were found in children under five, and progressive tumors (defined as growing at least 20% per year) were unusual after adolescence.⁴

An important detail from volumetric MRI tracking is that while growth rates differ a lot between patients, they tend to stay remarkably consistent within the same patient over time. In one study, about 70% of patients showed a 20% or greater increase in tumor volume during the observation period, and these tumors grew faster than the children’s own body weight, meaning the growth was not simply proportional to the child getting bigger.⁵ The clinical takeaway is that the window of fastest, most dangerous growth is in childhood and early adolescence, making this the period when surveillance and treatment decisions carry the most weight.

Surgery does not necessarily end the story for growth, either. Post-surgical studies have confirmed the same age-dependent pattern: patients 21 and younger had the highest rate of tumor progression after surgery, and the growth rate decreased by roughly half a percentage point per year of age.⁶ Tumor site and depth also affected progression, but age was the dominant factor.

Where They Form and What They Do to the Body

Plexiform neurofibromas can develop along virtually any peripheral nerve, but certain locations are especially common and especially troublesome. Large plexiform tumors are frequently seen in the cervicothoracic region of the spine.⁷ They also commonly involve the face, orbit (eye socket), limbs, and trunk. Because these tumors grow along and within nerve bundles, they can compress or invade surrounding structures, causing a cascade of problems depending on location: airway obstruction from head and neck tumors, vision loss from orbital tumors, limb deformity and functional impairment from extremity tumors, and bowel or bladder dysfunction from pelvic or abdominal tumors.

Pain is one of the most burdensome symptoms, and it is not the ordinary ache of a lump pressing on something. The pain in plexiform neurofibromas often has neuropathic qualities, meaning it arises from nerve damage itself and can manifest as burning, tingling, or shooting sensations. Chronic pain is one of the main drivers of reduced quality of life, as we will see below.

The Risk of Becoming Cancer

The most feared complication of a plexiform neurofibroma is malignant transformation into a malignant peripheral nerve sheath tumor (MPNST). Estimates of lifetime risk for people with NF1 vary across studies, but the figure most commonly cited is around 8 to 13%. MPNSTs are aggressive, often resistant to chemotherapy, and carry high mortality rates.

Molecular studies of tumors caught mid-transformation have offered a window into how this progression happens. In one case study, researchers examined three distinct regions of a single tumor mass: one that looked benign, one that appeared transitional, and one that was fully malignant. The degree of NF1 gene loss increased dramatically across these regions, from 9% in the benign area to 42% in the transitional zone to 97% in the malignant region. Additional genetic losses in the tumor-suppressor genes TP53, RB1, and CDKN2A, along with other cell-cycle genes, appeared only in the malignant portion.⁸ In other words, NF1 loss alone starts the process, but it takes a pileup of further mutations to push a tumor over the edge into cancer.

Pathologists have tried to identify the in-between stage. A consensus panel proposed the term “atypical neurofibromatous neoplasms of uncertain biologic potential” (ANNUBP) for lesions that show worrisome features, such as a combination of nuclear atypia, loss of normal neurofibroma architecture, high cellularity, and low-level mitotic activity, but do not quite meet the bar for malignancy.⁹ Recognizing these pre-malignant lesions matters because they represent the population of tumors most likely to progress, and catching them early could save lives.

Imaging and Surveillance

MRI with volumetric analysis is the backbone of plexiform neurofibroma surveillance. By measuring total tumor volume at regular intervals, clinicians can track growth rate and flag tumors that are accelerating. When a nodular, well-defined lesion within or near a plexiform neurofibroma grows rapidly, becomes painful, or arises in a patient with prior MPNST, further evaluation is needed to rule out malignancy.¹⁰

PET scanning using the radioactive glucose tracer FDG has proven useful here. Because malignant tumors have higher metabolic activity than benign neurofibromas, FDG-PET can light up suspicious lesions. The technique is sensitive for detecting MPNSTs in NF1 patients, and adding a second tracer (carbon-11 methionine) can increase specificity in borderline cases. PET also improves preoperative staging by detecting metastases or second primary tumors that are sometimes present in patients with NF1.¹¹

An emerging complement to imaging is liquid biopsy. Researchers have developed methods to analyze cell-free DNA fragments circulating in the blood, and these fragmentomic approaches can distinguish between benign plexiform neurofibromas, pre-malignant atypical neurofibromas, and MPNSTs. One study achieved about 86% accuracy in telling MPNST from plexiform neurofibromas using plasma cell-free DNA.¹² More refined fragmentomic methods have gone further, correctly identifying atypical neurofibromas and distinguishing them from both benign and malignant tumors.¹³ If validated in larger studies, liquid biopsy could replace some of the anxiety-producing “watch and wait” approach by giving clinicians a blood-based early warning of transformation, while also sparing patients the risk of nerve injury from surgical biopsy.

Treatment With MEK Inhibitors

For decades, surgery was essentially the only option for plexiform neurofibromas, and for many tumors surgery is not feasible because the growths infiltrate critical nerves and surrounding tissue too extensively to be safely removed. That changed with selumetinib, a drug that blocks a protein called MEK, which sits downstream of the overactive Ras pathway described above. In a landmark phase 2 trial of children with inoperable plexiform neurofibromas, 70% had a confirmed partial response, meaning their tumors shrank substantially. Most of those responses lasted a year or more. Beyond tumor size, patients experienced clinically meaningful reductions in pain, along with improvements in strength, range of motion, and overall quality of life as reported by both children and their parents.¹⁴ That trial led to selumetinib becoming the first drug approved specifically for symptomatic, inoperable plexiform neurofibromas in children with NF1.

The drug has also shown benefit for spinal neurofibromas, a particularly tricky subset because of the risks involved in operating near the spinal cord. In a study of patients treated with selumetinib, the majority showed improvement in spinal neurofibroma burden, with none worsening during treatment.¹⁵ Selumetinib is not without side effects, though. Common ones include skin rash, gastrointestinal symptoms, and changes in heart function, and the drug must typically be taken continuously because tumors tend to regrow if treatment stops.

Surgery and Other Drug Approaches

When a plexiform neurofibroma is surgically accessible and causing significant symptoms, surgery remains an important option. The challenge is that these tumors rarely have clean borders. They grow within and around nerves rather than sitting neatly beside them, so complete removal is often impossible without sacrificing nerve function. A study of deep-seated nodular plexiform neurofibromas found that complications occurred in about a fifth of surgically treated tumors, including new neurological deficits. Two of four patients who developed post-surgical nerve problems recovered fully within days, but two others were left with mild but permanent sensory or motor deficits.¹⁶ The decision to operate always involves weighing the tumor’s symptoms and risks (including malignant potential) against the risk of nerve damage from the surgery itself.

Beyond MEK inhibitors, other targeted drugs are being explored. Cabozantinib, which hits multiple tyrosine kinases rather than just MEK, showed promise in mouse models by reducing plexiform neurofibroma size and number and went on to a phase 2 clinical trial in adults with NF1 and progressive or symptomatic, inoperable tumors.¹⁷ Having alternatives is important because not everyone responds to selumetinib, and some patients cannot tolerate its side effects.

Living With Plexiform Neurofibromas

The burden of these tumors reaches far beyond their physical dimensions. Surveys of adults with NF1 and plexiform neurofibromas in the UK found that quality of life was substantially worse than the general population across physical, social, and emotional domains. About 40% reported moderate to extreme pain or discomfort, and more than half reported moderate to extreme anxiety or depression.¹⁸

A US-based study painted an even starker picture for employment and daily function. Only about 12% of adults with symptomatic plexiform neurofibromas were employed, with roughly half reporting disability. Among those who did work, average work productivity loss was close to 40%. Physical function scores were well below the general population, and fatigue, depression, and anxiety scores were all elevated.¹⁹ These numbers reflect the cumulative toll of chronic pain, visible disfigurement, functional limitations, and the psychological weight of living with tumors that could become malignant.

Because NF1 is a lifelong condition, and plexiform neurofibromas can continue to cause new problems at every stage of life, the transition from pediatric to adult care is a recognized weak point. Children with NF1 often receive coordinated multidisciplinary care at specialized centers, but adults frequently lose access to that level of oversight. Cognitive challenges and executive function difficulties, which are common in NF1, can further complicate managing a complex care regimen independently.

Gene Therapy and Preclinical Models

The most conceptually satisfying treatment would be to restore the missing NF1 gene function rather than just blocking one branch of the downstream signaling. Early gene therapy experiments in mouse models have shown striking results. In one approach, human NF1-deficient Schwann cells were engineered to carry a controllable copy of the NF1 gene and implanted into mouse sciatic nerves. When the gene was switched on, the vast majority of nerves showed no neurofibroma formation, while most control nerves developed tumors. A complementary experiment showed that silencing an already-active NF1 gene led to tumors, and turning it back on allowed established tumors to regress.²⁰ Perhaps most exciting, direct injection of a virus carrying the full-length NF1 gene into established tumors significantly reduced tumor burden. These are proof-of-principle results in animals, and the gap between a mouse xenograft and a human patient is enormous, but they establish that restoring neurofibromin can reverse the tumor-forming process, not just slow it.

Getting the biology right in the lab is critical to translating any of these advances. Researchers are increasingly finding that the tumor microenvironment complicates things in ways that simple cell cultures miss. A recent study of the growth factor midkine, for instance, found that while midkine promoted tumor growth in standard lab conditions, its effect was dampened in models that included neurons alongside Schwann cells, more closely mimicking the actual nerve environment.²¹ Findings like this are a reminder that what works in a dish or even a simple mouse model may not translate directly, and that the field is moving toward more physiologically realistic testing platforms to try to close that gap.