 In terms of what some of the unmet needs are for patients with NF1 [neurofibromatosis type 1] and plexiform neurofibromas, it’s important that we find additional chemotherapy options for these patients that have symptomatic and inoperable plexiform tumors. Selumetinib is the first drug that’s been proven to have efficacy, but we need newer agents with increased efficacy and activity with reduced toxicity and more durable responses. This would mean third- and fourth-generation MEK inhibitors as well as other types of signal transduction inhibitors that can slow down tumor growth.

Neurofibromatosis affects so many aspects of life for our patients, and there are so many unmet needs, even with the advent of these drugs. The use of MEK inhibitors and selumetinib in treating plexiform neurofibromas is a huge first step, but there are a number of other symptoms that are just as important to the patient population, in terms of looking for disease-modifying therapy. In particular, cutaneous neurofibromas—which are neurofibromas on the skin—can be very disfiguring. They are not as medically harmful as the plexiform neurofibromas but have tremendous impact on patients in terms of their social lives, ability to get jobs, and have a wide array of effects on quality of life for these patients.

Additionally, problems with learning, attention, and anxiety are very common and prevalent in this population and similarly can have a large impact on the lives of our patients. There are currently no medications specifically indicated for treatment in adults or children with NF1 with behavior or learning issues. Another unmet need in this patient population is we don’t know a good way to treat malignant peripheral nerve sheath tumors [MPNSTs]. There is an increased rate of this type of sarcoma developing in patients with NF1. These tumors are highly aggressive, very difficult to treat, and don’t respond well to traditional chemotherapy or radiation. We are in desperate need of better therapies for treatment of MPNST as well as other cancer types that can be associated with NF1.

 What advice might I have for physicians treating patients with NF1 and plexiform neurofibromas? I think they need to be aware of selumetinib as an option now for these patients. Especially with symptomatic plexiform neurofibromas that cannot undergo a quality tumor resection, they now have a drug option that can actually shrink these tumors in two-thirds of cases and give symptomatic relief, especially in patients who have pain and disfigurement.

Caregivers should also be familiar with selumetinib as a viable drug option for their loved ones, and their NF [neurofibromatosis] treatment team should be aware of this drug. They need to know the symptoms and aspects of plexiform tumors. It can be helpful for this drug to be used as treatment, and they should bring this up with their team.

 NF1 is a very complex disorder, and the treatment decisions and management of these patients is dependent on familiarity with the disease and the disease population. One of my primary recommendations for clinicians taking care of adults and children with NF1 is, when possible, to refer to centers where they are treating a large number of these patients and have great familiarity with the available treatments, as well as the various signs and symptoms and management of neurofibromatosis.

Additionally, a number of guidelines have been recently published. There have been recent updated guidelines for the treatment and management of children with NF1, as well as for the first time, management guidelines for treatment of adults with NF1. These guidelines can be helpful tools for clinicians in knowing what aspects of neurofibromatosis they need to be monitoring on a regular basis and how to approach diagnosis and management of a variety of signs and symptoms associated with NF1.

One of the most difficult aspects of neurofibromatosis is the wide variety of signs and symptoms that can be associated with the disorder. For parents of children with NF1, this can be particularly challenging because it can be really hard to know what symptoms are attributable to NF1 specifically and what are things typically associated with childhood and typical childhood illnesses. For parents of children with NF1, we recommend that they seek out the care of clinicians that are really familiar with NF1 to help guide them through the entire life span of their child and knowing which symptoms to be cognizant of. This is because at every age there are different things, different aspects of this disorder that parents need to watch for.

Additionally, I’m always talking with families about the importance of educating themselves about NF1 and the different manifestations of the disorder. This is in part because frequently there are times when they will encounter clinicians or the health care system in such a way that they may be the best-educated person in the room about this disorder. They can bring knowledge and understanding of NF1 to their health care providers and be an active participant in the choices that need to be made about the health care of their children.

This is a very exciting time to be involved in the care of people who have neurofibromatosis type 1, and we’re really on the cusp of a totally different world for these patients. We’ve never had a disease-modifying therapy available, and I think the availability of these types of medications is going to transform how we take care of adults and children with neurofibromatosis. They give us more options for treatment but also impact how we screen patients to look for tumors. They impact where we want to be taking care of these patients, so that they can have availability for the best and latest treatment, as well as appropriate monitoring for the adverse effects for treatment. I also think it will change how parents and families with family members with neurofibromatosis need to be educated about the disorder, so they can let their care providers know about the availability of new treatments, because that may not be generally known amongst clinicians. While there is still a lot to be learned about how to use these medications, they are going to be transformative in how we treat people with NF1.

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Unmet Needs in the Management of NF1 With PNs

 In patients with neurofibromatosis type 1 [NF1] being treated for the plexiform neurofibromas with MEK inhibitors and selumetinib, in addition to reduction in the size of tumors, we’re often seeing pain relief that’s starting quite soon after initiation of treatment. We’re also seeing changes and improvement in neurological function, such as strength, gait, and other things that might have been impacted by the plexiform neurofibroma.

The recent positive results of the clinical trials using MEK inhibitors and selumetinib are changing the way we think about treating neurofibromatosis. In the past, there have not been any disease-modifying therapies for NF1. With the availability of MEK inhibitors and selumetinib—along with the data from the clinical trials suggesting that the majority of patients show some benefit—we are starting to treat many more patients medically prior to thinking about surgical treatment. We are able to give our patients options about how to approach treatment of their tumors. It also offers the possibility of treating tumors that we wouldn’t have had any options for before when they were not surgically approachable.

For the approval of selumetinib for the use of treatment of plexiform neurofibromas, the specific indication will be for children aged 3 to 18 with NF1 and an inoperable symptomatic plexiform neurofibroma. That will probably be the first population of patients that will be treated with selumetinib. There are thoughts that selumetinib and other MEK inhibitors may have the potential for additional therapeutic uses outside that age window; for instance, adults with plexiform neurofibromas or children under age 3. Additionally, patients who are experiencing pain because of plexiform neurofibromas, even if it is operable, might also be considered for a treatment with these medications.

There are also thoughts that these medications may be helpful for other symptoms associated with neurofibromatosis type 1, and there are a number of clinical trials being considered to look at the use of selumetinib as well as other MEK inhibitors for the treatment of things such as cutaneous neurofibromas. There already are clinical trials for optic pathway gliomas and possibly future clinical trials for cognitive impairment in neurofibromatosis. The potential use for these drugs can be quite broad, though the initial indication will be more limited.

At this point, it remains to be seen who are the optimal patients to offer treatment with MEK inhibitors and what the right timing is, to be honest. We are still in the process of determining whether being proactive and treating tumors while they are small and presymptomatic is better than waiting until they are larger and causing neurological impairment, functional impairment, or other symptoms. It will take some time using these medications in a variety of patients before we fully understand how to stratify patients in terms of which ones undergo therapy and which ones wait.

Why would we treat with MEK inhibitors or selumetinib rather than just treat symptoms? Our hope in using these medications is that we actually modify the course of the disease, reducing the growth of tumors, reducing the potential threat these tumors might cause to surrounding structures, in addition to treating the symptoms.

The approval of a medication that is specifically indicated for patients with neurofibromatosis and plexiform neurofibromas is having a tremendous impact on the patient population as well as clinicians caring for these patients. I’ve been taking care of patients with NF1 for about 20 years, and the approval of these medications is already totally changing the conversations I have with families about the disease, the future, and what to hope for. In the past, we have been limited to treating symptoms or recommending surgery. To have a medication that can slow, stop, or even reduce tumor growth in these patients, I think the impact is unlimited in many ways. The hope that it brings to the families we take care of is tremendous.

NF1 With PNs: Future of Treatment With MEK Inhibitors

 There has been a drug recently FDA approved for treatment of symptomatic plexiform neurofibromas called selumetinib. It goes by the brand name Koselugo. This was FDA approved in April 2020, and this was published by Andrea Gross in the 

. Based on this publication, this drug is now available. The SPRINT trial is a phase 2 open-label, single-arm, multicenter study, coordinated by the National Cancer Institute as well as 3 other sites, to evaluate the efficacy of selumetinib in pediatric patients with NF1 [neurofibromatosis type 1] with symptomatic inoperable plexiform neurofibromas. There were 50 patients in the study. The mean age was 10.2 years, and 60% of them were male. The selumetinib was dosed at 25 mg/m2 orally twice daily, and the target tumor evaluation was measured using volumetric MRI [magnetic resonance imaging] at baseline every 4 cycles on drug for 2 years and then every 6 cycles.

The target plexiform tumor locations included the neck and trunk in 24% of patients, the trunk and extremity in 24%, along with the head, neck, and trunk extremities. The plexiform tumor status was progressive in 42% and nonprogressive in 30%. In terms of the target plexiform tumor-related morbidities, among the most common things seen was disfigurement in 88% of the patients, motor dysfunction in 66%, and pain in 52%, along with airway dysfunction, visual impairment, as well as bowel and bladder dysfunction. The number of plexiform tumor-related morbidities was a median of 3. Again, these were very symptomatic patients from their target tumors. Also, 40% of them had had previous surgeries for their plexiform tumors in the past.

Selumetinib is a MEK inhibitor, and this is a class of drugs that inhibit MEK1 and MEK2, which are single transduction proteins in the RAS/RAF/MEK/ERK pathway that leads from tyrosine kinase receptors at the surface of tumor cells and then activates cell proliferation and promotes survival. After inhibition of MEK, there is reduced phosphorylation of ERK. It begins to reduce promotion of cell proliferation and cell survival. This pathway is known to be activated in NF1 plexiform neurofibroma tumors since the loss of neurofibroma leads to overactive RAS GTP activity and excessive activation of the RAF/MEK/ERK pathway, again leading to excessive cell proliferation and plexiform tumor formation. There’s actually been a study by Eva Dombi, also published in the 

 in 2016, looking at a mouse model for NF1-related plexiform tumors. In that model, selumetinib was able to inhibit ERK phosphorylation as well as reduce plexiform tumor formation, volume, and proliferation.

In the SPRINT study, inoperable tumors were defined as a plexiform neurofibroma that could not be fully resected with high risk for substantial morbidity because of encasement of or close proximity to vital structures, tumor invasiveness, or tumors with high vascularity. In the study, the primary end points were overall response rate using 3-dimensional MRI and the REiNS [Response Evaluation in Neurofibromatosis and Schwannomatosis] response criteria. This included percentage of complete responses or confirmed partial responses that were greater than or equal to 20% reduction in target tumor volume with confirmed subsequent MRI in 3 to 6 months.

There were also secondary end points in the SPRINT trial, including duration of response and safety profile. There was also an exploratory end point. Those included pain-intensity ratings of the affected children. In terms of efficacy of the drug in this trial, 66% of the cohort—roughly 33 patients—achieved a confirmed partial response. There weren’t any actual complete responses, but those PRs [partial responses] were seen in two-thirds of people. About 82% of those patients with PRs remained a response after 12 months of follow-up. The median best percentage change in target tumor volume from baseline was –27.85%, which is again a significant tumor reduction in what’s supposed to be a slow-growing benign tumor. The median time to onset of response was 7.2 months. In terms of the duration of response, by 12 months or more, 82% of the patients were still responding with their PR. In 16 months, 67% of patients were still responding with their partial response.

In terms of the exploratory end point of pain intensity rating, there were 24 patients that were able to give pain-intensity rating responses, and 50% of those noted improvement of pain of 2 points or more by prior to cycle 13. In terms of common adverse reactions in the study, in terms of the most common things seen across all grades, the most common things noted were vomiting, abdominal pain, diarrhea, nausea, stomatitis, rash, and paronychia. In terms of reactions at grade 3 or grade 4, they were limited to vomiting, diarrhea, rash, and pyrexia.

In terms of the clinical significance of the SPRINT trial, it’s important to note that in a natural history study of NF1-related plexiform neurofibromas, they were noted to have a strong tendency to grow over time and are often very symptomatic. They almost never spontaneously resolve or improve on their own. It’s now important that we have an FDA-approved chemotherapy option for these inoperable tumors with improvement benefit in terms of tumor shrinkage and possibly improving patient symptoms. I feel that selumetinib should be considered for any patient who has NF1 with a plexiform tumor that is symptomatic and inoperable, especially tumors that are large and cause significant pain, weakness, or disfigurement.

The question always comes up: should the treatment be started early or later on? In general, an earlier approach is better since the drug can often cause tumor shrinkage and improve symptoms. This is more likely in a smaller tumor, which has less permanent damage to surrounding nerves, structures in the region, and soft tissues. Then there’s a question about if selumetinib is better than just using symptomatic treatment. I think it is much better than that because you have a greater than 50% chance of shrinking the tumor and improving tumor-related symptoms, which were pain, disfigurement, weakness, and gait difficulty, whereas symptomatic treatment will really not help those symptoms very much.

 SPRINT Trial: NF1 With PNs

 Recently there have been a number of clinical trials in attempt to find potential treatments for plexiform neurofibromas in neurofibromatosis type 1. One of those drugs, selumetinib, is in the hands of the FDA currently and has received approval for the treatment of plexiform neurofibromas in children with neurofibromatosis type 1.

In the majority of patients treated with selumetinib, there has been a reduction in the overall volume of the plexiform neurofibromas, as well as improvement in symptoms such as pain and functional impairment.

MEK inhibitors are a class of drug that were designed for a variety of different cancers, and our understanding of the cellular pathways involved in neurofibromatosis, the RAS pathway in particular, led researchers to look at MEK inhibitors and their potential role in treating the symptoms of neurofibromatosis.

As you might guess from their name, MEK inhibitors impact and inhibit MEK. MEK is 1 of the downstream effectors of the RAS pathway. When MEK is inhibited, the increased rates of proliferation of tumors can be impacted and can decrease the growth or even reduce the size of tumors. We don’t exactly know all the mechanisms by which MEK inhibitors impact the growth and impact the reduction in the size of plexiform neurofibromas, but it is thought to act primarily along its impact on the RAS pathway.

Our understanding of the reason why patients with neurofibromatosis develop tumors, and specifically plexiform neurofibromas, is that the RAS pathway is hyperactivated in the absence of neurofibromin. Because that is underlying the growth of these tumors, inhibiting the RAS pathway is postulated to impact tumor growth and MEK inhibition as 1 strategy to impact the RAS pathway.

From what we know from previously published clinical trials of selumetinib in plexiform neurofibromas and neurofibromatosis type 1, the majority of patients with plexiform neurofibromas show reduction in the size of their tumors when treated with this drug. Additionally, there are data that suggest that symptoms such as pain or functional limitation can also be improved with treatment with selumetinib. In general, selumetinib is well tolerated. Some of the adverse effects that are commonly seen include rash. For postpubertal patients, an acneiform rash on the face is quite common, and for younger kids a more diffuse follicular rash can be seen. We also have to monitor for liver function tests as well as cardiac function. But in general, most people tolerate the medication quite well.

Clinical trials of selumetinib and other MEK inhibitors in neurofibromatosis have primarily relied on volumetric measurements of plexiform neurofibromas to assess efficacy. However, future studies and ongoing studies are also looking at functional outcomes measuring neurological impairment, cosmetic changes, and quality of life as additional outcome measures for these medications.

Treatment of NF1 With PNs: MEK Inhibition

 There are several types of symptoms that are very common in these patients. One of the most common symptoms is pain, and with these types of tumors, that’s usually a neuropathic type of pain, which means it’s nerve related, often a burning type of sensation. This is because the parent nerve where the tumor is growing is being stretched, bent, irritated, and damaged by the growing tumor. Medications that are used for that are also used for other types of neuropathic pain, and those include Tegretol [carbamazepine], gabapentin, Elavil [amitriptyline], and Lyrica [pregabalin]. Any combination of those drugs or even using them by themselves to start with is often helpful in controlling or at least minimizing the neuropathic pain from a plexiform tumor.

In terms of NF [neurofibromatosis] plexiform tumor-related weakness and motor symptoms, this can be very common depending which nerves the tumor is growing from, especially if it’s in the brachial plexus, on some of the motor nerve roots along the lower spine, or in the lumbosacral plexus. We can’t just fix this weakness, per se. We have to have the patient focus on physical therapy and occupational therapy and work on their strength, gait, balance, coordination, and fine motor skills to improve their baseline function. Some types of braces may be helpful in terms of bracing their wrists and their ankles, and the therapist will guide the physician on what types of braces the patient needs.

In terms of psychosocial issues, as mentioned above, these are common in this patient population. Many things can be seen, including depression, anxiety, isolation, loneliness, and difficulty finding work. Oftentimes people have limited finances, and they have feelings of inadequacy and inferiority. We have many of our patients see a counselor or a psychologist. Sometimes our social worker will work with them and do sessions in the clinic. Even a psychiatrist can be helpful if the patient has severe disease and may need some medication.

Managing Symptoms of NF1

 One of the treatment options for plexiform neurofibromas is an attempt at surgical removal. There are some plexiform neurofibromas that are well encapsulated and are approachable in the sense that we think we can remove essentially the whole tumor or the majority of the tumor. In some cases, we will attempt a total resection. However, the majority of the time these tumors are so complicated, and they interact with surrounding organs as well as with the nervous system in such a way that total removal isn’t possible. In this case debulking is an option. Debulking is the process of selecting a portion of the tumor that can be resected safely with minimal risk to the patient but provides some benefit, either by alleviating some amount of pressure on surrounding tissue or by improving cosmetic appearance.

There are a number of factors that contribute to whether a tumor can be resected completely or debulked. One is location. Often these tumors can be located in areas that aren’t approachable from a surgical standpoint safely so that the entire tumor can be removed. For instance, if there’s a plexiform neurofibroma that involves the face, it may involve the facial nerve as well as the internal carotid artery. The risk to those structures is such that it isn’t feasible to resect those tumors. However, if a tumor is more discrete and isolated from other vital structures, those tumors may be easier to approach surgically. Therefore, we might approach them earlier than we would ones that are more difficult areas to reach safely.

The risk of resecting a plexiform neurofibroma is based on several factors. One is that many of these tumors have highly complex vascular systems. These tumors can have both arterial and venous components, and resection can sometimes lead to bleeding that can be difficult to manage.

In addition to the risk of bleeding, there’s also significant risk to neurologic function. These tumors grow within nerves, and the axons are often splayed out throughout the tumor. Resection of the tumor almost always necessitates sacrifice of some portion of a nerve. Depending on where the tumor is and which nerve is impacted, it can result in some amount of neurologic dysfunction. For instance, if a sciatic nerve tumor is resected, it’s possible to lose function of the leg below the sciatic nerve. For a more superficial tumor on the chest, you might lose just sensation to that area of skin. The amount of nerve injury depends both on the location, which nerve it arises from, as well as how the tumor is associated with that specific nerve.

 For enlarging, painful, and otherwise symptomatic plexiform neurofibromas, surgical resection is usually the first option for treatment in these patients. For tumors that are accessible and amenable to surgical resection, using a laser or electrocautery is at the discretion of the surgeon who’s doing the operation. Most of the time when they’re using that, they’re trying to control bleeding and close off vessels that are oozing or leaking blood around the surgical sites. It’s something the surgeon decides at the moment during the procedure, whether they need to use that type of approach to handle bleeding on site from tumor removal.

In terms of the role of radiation therapy or chemotherapy, as a general rule most specialists with NF [neurofibromatosis] would not recommend using radiation therapy as a routine treatment option. The main reason is if you use that for a plexiform neurofibroma, you have the chance of having the radiation cause a malignant transformation of that tumor in a number of years and convert it into a malignant peripheral nerve sheath tumor, which again is a dangerous sarcomatous cancer. Sometimes we would consider using radiation for treating a malignant peripheral nerve sheath tumor, but the data are not very strong for radiation even in that setting and it doesn’t seem to help prolong survival very much.

In terms of chemotherapy, prior to April of 2020, there were no FDA-approved forms of chemotherapy for plexiform neurofibromas. Until that time, chemotherapy was used once in a while for refractory, unresectable tumors. Some of the chemotherapies that have been evaluated include pegylated interferon and imatinib, in which both were found to have some limited activity. Recently some molecular drugs, including inhibitors of mTOR, such as rapamycin, everolimus, as well as MEK inhibitors—some of the first ones like trametinib—were also thought to have some activity.

 The choice to use imaging modalities to either diagnose or monitor plexiform neurofibromas is up to the clinician. There aren’t specific guidelines at the moment for how best to diagnose and monitor these tumors. There is some thought that there could be benefit to performing a whole body MRI for patients with neurofibromatosis type 1 to identify neurofibromas before they become symptomatic, but there is not yet consensus about whether that is worthwhile. For symptomatic tumors, we will definitely image when surgery is being considered or if treatment is being considered to establish a baseline and to assess the viability of surgical resection. For tumors that are less symptomatic and treatment is not being considered, we don’t typically image those tumors unless the clinical scenario changes over time. The optimal imaging for neurofibromas includes MRI of the area, specifically with STIR [short inversion time inversion-recovery] imaging. Contrast can be helpful as well.

Therapeutic Options for NF1 With PNs

 How do we identify the symptoms of plexiform neurofibromas? This can happen in a number of ways. First a patient will come to us and tell us what symptoms they’re experiencing. Pain is a common symptom associated with plexiform neurofibromas, or change in neurologic function, such as gait. Patients will also come to attention because of cosmetic issues or disfigurement caused by these tumors. Additionally, upon neurologic examination we can sometimes find evidence of focal neurologic dysfunction, which then leads us to look for a previously undiagnosed plexiform neurofibroma. So a regular and careful neurologic examination for adults and kids with NF1 [neurofibromatosis type 1] is really essential.

Plexiform neurofibromas can have many different symptoms, pain being one of the most important. Pain is important for plexiform neurofibromas for a couple of reasons. One is that the tumors themselves can be painful through direct impact on the associated nerves or nearby organs. But they can also cause impairment of function, which then can lead to a cascade of muscle tightness, gait changes, or functional impairments that then lead to compensation and can lead to musculoskeletal pain as a result. Additionally, pain in plexiform neurofibromas can be a signal of the possibility of malignant transformation. There’s a percentage of these tumors that can become a malignant peripheral nerve sheath tumor, and severe pain that wakes patients up at night can be a red flag that there is a possibility of malignant transformation.

In addition to physical pain, plexiform neurofibromas can cause psychological pain as well. These tumors are often very disfiguring and can be limiting in terms of function, which can be very distressing to the patient.

 There’s actually a very high psychological and emotional impact on many patients with NF1. Depending on the severity of their phenotype, they can often have issues including pain, weakness, disfigurement, and other severe symptoms. Some of these can impact the patient quite severely. Many of them are depressed or anxious, feel different from other children or adults, often feel inadequate or inferior, and often have a chronic level of frustration from dealing with their disease.

Especially in children with NF1, there can be quite a few learning and behavioral issues. Neurocognitive deficits are highly prevalent in this group. Learning difficulties can include visual spatial and visual motor deficits, language disorders, as well as fine and gross motor deficiencies. Also attention deficit hyperactivity disorder, autism spectrum disorder, behavioral abnormalities, and psychological issues are very prevalent in this population, especially in the pediatric patients.

In terms of the impact of NF1 and plexiform neurofibromas on quality of life, it depends on how severe a person’s disease is, but in the average patient with a symptomatic plexiform tumor, they have many symptoms that can affect quality of life. In particular, pain is very common. Some patients can have large tumors that disfigure their neck, their face, or their body, which could be a problem. Weakness and other motor deficits can be an issue. Then again, we also see cognitive impairment, depression, and anxiety, which is very common.

The impact on caregivers for patients with NF1, especially for the mothers and parents of children with this disease, can be significant. As with other severe chronic diseases like cancer and Alzheimer disease, the caregiver has a lot on their shoulders, and again, this typically falls on the mother or the parents of a child with NF. They also tend to suffer from anxiety, depression, frustration, and stress due to the impact of the disease on their loved one, as well as frustration with how much of their own time, and energy, and resources are spent taking care of that loved one.

In terms of options for support for caregivers, there are many local and regional chapters related to the Neurofibromatosis Foundation. There’s also the national Neurofibromatosis Network in Chicago, Illinois, which is a national level resource. There are also a lot of social media groups focused on NF and being a caretaker, especially on Facebook and those types of media. Then there are many large tertiary medical centers like our own at AdventHealth that have dedicated NF clinics that also have social workers that could help out with the support for the caregivers.

Disease Burden of NF1 with PNs

 The prevalence of plexiform neurofibromas in patients with NF1 [neurofibromatosis type 1] is that they arise in around 30% to 50% of patients with this disease. They’re very variable in terms of their overall size, invasiveness, depth within tissues, and involvement with surrounding structures.

The prognosis is also variable because the phenotype in any 1 patient with NF1 can vary a lot from those who are mildly affected to those who have severe disease with large tumors that are very invasive and difficult to remove. So it depends on how severe and extensive their disease is as well as how many tumors they have and how severe those tumors are.

Malignant peripheral nerve sheath tumors are actually a type of neurofibrosarcoma. It’s a subtype of the sarcoma group of peripheral tumors. These derive from Schwann cells, and they comprise 3% to 10% of all soft tissue sarcomas. They can develop anywhere in the body, but there is an increased risk by 20-fold of them occurring in the area where there’s already an existing internal plexiform neurofibroma.

The cumulative lifetime risk of developing a malignant peripheral nerve sheath tumor in a patient who has NF [neurofibromatosis] is roughly 8% to 13%. It’s very hard for us to predict who’s going to get one and who isn’t. So we’ve got to watch for red flags in a given patient in terms of a tumor that’s growing very rapidly, has rapidly escalating pain, a change in consistency of a given tumor, going from very soft to very hard type of consistency, and then patients who are developing rapidly new neurological symptoms.

In the perfect world, we like to approach neurofibromatosis type 1 with a multidisciplinary team, and that will depend somewhat on whether you’re at an adult NF center versus a pediatric NF center. But in general, the team members we would like to see for the management of this type of disease would be a neurosurgeon, a neurooncologist or a general neurologist, an adult medical oncologist or a pediatric oncologist, an orthopedic surgeon for any spine-related issues or other bony related issues, an ophthalmologist to monitor the eyes and the vision, a physical therapist, an occupational therapist, a speech therapist, an audiologist to monitor hearing, and then a medical geneticist for advising on genetic issues.

Most patients with NF1 will be followed by either an oncologist, medical or pediatric, or a neurologist who could be a neurooncologist or a general neurologist. They will do most of the routine follow-up and visits with the patient and will do screening CTs and MRI scans. They will follow them for any increasing tumor growth or issues that need to be dealt with. Then they often bring in the other specialists when needed, whether that’s a neurosurgeon, an orthopedist, or an ophthalmologist, and they help coordinate the care.

NF1 is a genetic disease. It’s an autosomal dominant mutation in the 

 gene located on chromosome 17. This is a tumor suppressor gene, and around 50% of this patient population will have a family history of NF1. The other 50% will develop the disease through de novo or spontaneous mutations. It’s very helpful to have a genetic counselor involved to talk to the patient’s family about their risk for transmitting this disease to their offspring. The genetic counselor will go through the family history and see if they really do have a familial form of NF1 or perhaps it was more of a spontaneous mutation. Then they’re going to give them advice on how likely it is to pass the disease on to their children.

Management of Plexiform Neurofibromas in NF1

 What are plexiform neurofibromas? Plexiform neurofibromas are one of the most complex and difficult aspects of neurofibromatosis type 1. These are benign tumors that can develop anywhere in the peripheral nervous system from the spinal roots out to the periphery. They are basically hyperproliferative Schwann cells as well as infiltrating immune cells such as mast cells and fibroblasts. These tumors usually extend along long lengths of nerves or coalesce around groups of nerves, such as the brachial plexus or the lumbosacral plexus.

Where do plexiform neurofibromas develop? Plexiform neurofibromas can really develop anywhere in the peripheral nervous system, arising from paraspinal lesions on the spinal roots all the way out into the periphery. Their clinical manifestations are dependent on where the tumor develops. If they have a superficial component, there are often skin changes overlying the tumor such as thickened skin, hyperpigmentation, or increased hair growth. But tumors can also develop internally without any superficial manifestations and may be found only on the basis of feeling an underlying mass, based on clinical symptoms, or based on imaging findings.

Even though plexiform neurofibromas arise from nerves, they can impact other organ systems, often through direct impact physically on those organs and sometimes through invasion. For instance, sometimes a plexiform neurofibroma can develop intra-abdominally, and sometimes those tumors can involve the intestinal wall. They might also involve the wall of the bladder. When they grow in and around the face or the neck, they can impact blood vessels, the trachea, or the esophagus. But again, it’s primarily through a direct physical impact on those organs and vital structures as opposed to direct invasion.

Plexiform neurofibromas are very complex tumors, and as a result of their complexity, they’re often very difficult to remove surgically. They are highly vascular tumors, so surgery can often result in excessive bleeding. Also, the way these tumors grow within nerves essentially necessitates sacrifice of a nerve to remove the tumor. Any nerve that the tumor is growing on will often be injured at the time of surgery and the function of that nerve lost. The way these tumors grow, they often insinuate themselves around and into adjacent structures and organs, again making surgical resection very difficult. It’s almost impossible to resect these tumors completely.

How do we determine if these tumors are inoperable? It’s a difficult issue, and we’re often weighing the risk of resection with the potential benefit to the patient. The tumors that I would consider inoperable are the ones where there is going to be risk of significant neurologic impairment worse than the symptoms that the patient is already experiencing, or tumors that put the patient at too much risk of blood loss or injury to adjacent vital structures.

Our choices around surgery with the advent of new medical therapies is certainly changing. I do think that there is a role for debulking of these tumors in certain situations, particularly where a limited surgical procedure can provide a patient immediate and safe benefit, either cosmetic or functional. I think over time, we will better be able to ascertain how much medical therapy will replace some of the surgical procedures that we’ve done in the past, but I do think that at this point there’s still a role for both.

Overview of Plexiform Neurofibromas in NF1

 Neurofibromatosis type 1, or NF1, is a genetically caused neurocutaneous disorder that results in the predisposition to the growth of multiple tumors in the central nervous system—including the brain, spinal cord, as well as the peripheral nervous system and skin.

The cause of neurofibromatosis type 1 is a mutation in the NF1 gene. It’s an autosomal dominant condition. About half the time it’s inherited from a parent, and half the time it arises as a spontaneous mutation. The gene mutation causes an abnormality in the RAS pathway which predisposes patients to develop multiple tumors and tumor types. There is tremendous variability in the types of manifestations that are a result of this mutation, which can result in tumor formation, as I mentioned, but it also can affect a variety of other organ systems. It can affect cognition and behavior, causing anxiety, and attention deficit disorder as well as learning disabilities.

It can lead to cafe au lait macules, which are brown birth marks on the skin; axillary and inguinal freckling, a very characteristic freckling pattern in the armpits and the groin area; something called Lisch nodules, which are little benign hamartomas on the iris; as well as bone abnormalities such as sphenoid wing dysplasia and tibial bowing or pseudoarthrosis, which a problem with the long bones of the leg. It can cause a variety of other manifestations as well, some of which are less common, but things like vascular abnormalities, vitamin D deficiency, growth delay, and others.

The prevalence of neurofibromatosis type 1 is estimated to be about 1 in 3000. It’s actually one of the more common rare genetic disorders, and there’s no predilection for any specific geographic location or ethnic or cultural group. All populations have about the same incidence.

NF1 is usually diagnosed in childhood. The skin manifestations, particularly the cafe au lait spots, are usually apparent at birth or in the first year of life, and then kids often come to attention through their pediatric examination where the cafe au lait spots are noticed, and the possibility of a diagnosis of NF1 is raised. Then they’re typically referred on to neurology or genetics for further evaluation. The average age of diagnosis is probably somewhere between 2 years and 5 years of age.

Neurofibromatosis type 1 is usually diagnosed based on clinical symptoms. There’s a wide range of clinical symptoms associated with neurofibromatosis type 1. The diagnostic symptoms include cafe au lait macules, which are flat, brown pigmented macules on the skin; a distinctive pattern of freckling called axillary or inguinal freckling; Lisch nodules, which are benign hamartomas of the iris; optic pathway gliomas, which are astrocytomas of the optic pathway; neurofibromas of a variety of different types, either cutaneous neurofibromas or plexiform neurofibromas; and then distinctive bone abnormalities, such as sphenoid wing dysplasia and tibial bowing.

The presence of a first-degree family member would also count as a diagnostic criterion. In addition to these clinical criteria, there are other potential clinical manifestations and signs of NF, including choroidal nodules on the retina; nevus anemicus, which are white patches on the skin; and a variety of other tumor types, including pheochromocytomas, which can manifest as hypertension. Patients can have vascular abnormalities, including carotid stenosis and moyamoya, or renal artery stenosis. They can also have short stature and can have an increased incidence of certain types of cancer.

Herbert B. Newton, MD, FAAN Advent Health Cancer Institute

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