Plexiform Neurofibroma - An Overview

Introduction

Plexiform neurofibromas are tumors that form in the tissue protecting the nerves. Plexiform neurofibromas can occur anywhere outside the brain and spinal cord. They can occur on the face, neck, arms, legs, back, chest, and abdomen. Large tumors can cause a nerve to thicken. As a result, it affects the nearby bone, skin, and muscles. Plexiform neurofibromas can cause severe pain, mobility issues, hearing and vision loss, and high blood pressure. They mainly occur in children with neurofibromatosis type I (NF-1).

NF-1 is a rare autosomal dominant (a parent with the mutated gene has a 50 percent chance of passing that gene to the child) genetic disorder caused due to mutations of the NF1 gene. It comprises multiple skin changes, such as café-au-lait macules (pigmented lesions), axillary freckling (dark circular freckles in the armpit region), and tumor growth along nerves (neurofibromas). The tumor growths represent bulging and deforming masses involving connective tissue and skin folds. Hence, the clinical description of lesions is “bags of worms.”

What Are the Clinical Features of Plexiform Neurofibromas?

Cutaneous (skin) neurofibromas typically grow as small nodules. On the other hand, plexiform neurofibromas are large, with diffuse growths and well-defined borders. They can appear inside or outside the body. They can be small or involve more significant portions of the body. Plexiform neurofibromas may present as a bunch of cords under the skin. Further, they have a variation in texture or appear with darker pigmentation. Plexiform neurofibromas also differ from cutaneous neurofibromas as they can be found at birth and grow irregularly during childhood.

What Is the Diagnosis of Plexiform Neurofibroma?

Plexiform neurofibromas are clinically diagnosed through the typical features. Further, histopathology (microscopic features) can exclude malignant (cancerous) transformation. Prenatal (before birth) testing can identify the NF-1 mutation. A preimplantation genetic diagnosis can be used as a screening method for NF-1 in embryos produced through in vitro fertilization (IVF). Additionally, chorionic villus sampling (CVS) or amniocentesis can be used to detect NF-1 in the fetus.

Recent research identifies four markers (epidermal growth factor receptor, interferon-γ, interleukin-6, and tumor necrosis factor-α) to distinguish between patients with NF-1 and healthy people. Also, two additional markers (insulin-like growth factor binding protein 1, IGFBP1, and regulated upon activation and normal T-cell expressed and secreted, RANTES) are early risk predictors of developing MPNST (malignant peripheral nerve sheath tumor). Studies have found higher concentrations of these markers in patients with NF-1 and MPNST than those without the conditions. These data depict their screening role in patients with plexiform neurofibromas with a high risk of malignant transformation.

What Are the Treatment Options for Plexiform Neurofibroma?

• Surgery: Surgery is the main treatment option for plexiform neurofibroma. Patients with plexiform fibromas of the head and neck can benefit from surgery if the indications: exclude malignancy in a rapidly enlarging mass, relieve pain or weakness, improve symptoms caused by airway impingement, or enhance cosmetic results in disfiguring cases. However, some plexiform neurofibromas are difficult to remove as they have nerve and blood vessels interspersed with normal tissue. Hence, surgeons can remove only a portion, called debulking procedure. The debulking procedure, or cytoreduction, decreases the amount of tumor in the body. The idea of debulking surgery is to remove multiple tumors safely. Hence, the benefits and risks of surgical intervention for plexiform neurofibromas should be considered. The remaining tumor is usually treated with chemotherapy or radiation. Unfortunately, plexiform neurofibromas can grow back after surgery. As a result, medications are being developed to treat plexiform neurofibromas.

• Mitogen-Activated Protein Kinase (MEK) Inhibitors: MEK (MEK 1 and 2) controls cell growth and survival. Blocking MEK 1 and MEK 2 (a type of targeted therapy) can stop the growth of cancer cells. MEK inhibitors can reduce the size of inoperable plexiform neurofibromas in many individuals. In 2020, Selumetinib (a MEK inhibitor) was approved by the United States Food and Drug Administration (US FDA) for the treatment of symptomatic (with symptoms) plexiform neurofibromas in children. It is considered an option for individuals who cannot have surgery.

In a recent trial of Selumetinib involving 24 children with inoperable NF-1-related plexiform neurofibromas, the authors found a 31 percent reduction in tumor volume in 17 children (71 percent). Therefore, assessing Selumetinib treatment resulting in clinical improvement is critical to gauge the benefit-risk ratio of Selumetinib in such patients.

• Interferon-Alpha: In progressive, inoperable, and symptomatic lesions, interferon-α has given good results. It has antiproliferative and antiangiogenic (halts new blood vessel formation in tumors) properties. However, the prognosis is unpredictable due to the risk of disease progression and variable expressivity.

What Are the Complications Arising From Plexiform Neurofibroma?

Plexiform neurofibroma can cause medical complications if adjacent to a vital organ. They include the following.

• Due to the presence of mast cells (cells that secrete chemicals such as histamine that can cause itching) within plexiform neurofibromas, they can cause itching.

• A few plexiform neurofibromas can be disfiguring depending on their size and location. They may alter a person’s appearance and be an aesthetic problem for some individuals. A rapid change in the size of a plexiform neurofibroma should be reported immediately.

• Plexiform neurofibromas can impair essential organs such as the lungs or esophagus and cause dysfunction. If they involve the nerves or spinal cord, they can cause pain, weakness, numbness, or bowel/bladder problems.

• Plexiform neurofibromas can be painful when manipulated. However, they should not cause severe pain. Anyone with severe and continuous pain should seek medical care immediately.

• Plexiform neurofibromas are at an increased risk of becoming malignant. When a plexiform neurofibroma becomes malignant, it is referred to as MPNST. MPNSTs are concerning tumors and are challenging to manage (treatments are surgery, radiation, and chemotherapy). The lifetime risk of developing an MPNST from a plexiform neurofibroma is about ten percent.

When Should One Be Concerned About Plexiform Neurofibroma?

Many plexiform neurofibromas do not cause medical issues. Moreover, most plexiform neurofibromas are not malignant. But, some may undergo malignant transformation. However, due to the risk of developing MPNST, it is essential to warrant further evaluation. The signs and symptoms that a plexiform neurofibroma is becoming malignant are:

• The rapid growth of the plexiform neurofibroma.

• Severe or persistent pain in the area of the plexiform neurofibroma.

• A change into a hard texture.

• New symptoms like weakness, numbness, or bowel or bladder issues.

Conclusion

It is important to consult a healthcare provider familiar with NF1 to detect the concerning symptoms linked to a peripheral neurofibroma. The treatment is mainly surgical and aims at resecting deforming masses. Moreover, these can recur in 20 percent of cases despite an appropriate approach. Some patients prefer to avoid surgery. Hence, a clinical follow-up is required every six months. Systemic therapy with interferon-α is a possible future option.