Neurofibroma
Neurofibroma of the skin in a person withneurofibromatosis type I
Specialty	Neuro-oncology

Aneurofibroma is a benignnerve-sheath tumor in theperipheral nervous system. In 90% of cases, they are found as stand-alone tumors (solitary neurofibroma,solitary nerve sheath tumor^[1] orsporadic neurofibroma^[1]), while the remainder are found in persons withneurofibromatosis type I (NF1), anautosomal-dominantgenetically inherited disease. They can result in a range of symptoms from physical disfiguration and pain to cognitive disability.

Neurofibromas arise from nonmyelinating-typeSchwann cells that exhibitbiallelic inactivation of theNF1 gene that codes for the proteinneurofibromin.^[2] This protein is responsible for regulating theRAS-mediatedcell growthsignaling pathway. In contrast toschwannomas, another type of tumor arising from Schwann cells, neurofibromas incorporate many additional types of cells and structural elements in addition to Schwann cells, making it difficult to identify and understand all the mechanisms through which they originate and develop.^[3]

Neurofibromas have been subdivided into two broad categories: dermal and plexiform. Dermal neurofibromas are associated with a single peripheral nerve, while plexiform neurofibromas are associated with multiple nerve bundles. According to the World Health Organization classification system, dermal and plexiform neurofibromas aregrade I tumors. Plexiform neurofibroma are more difficult to treat and can transform into malignant tumors. Dermal neurofibroma do not become malignant.^{[citation needed]}

Dermal neurofibromas (sometimes referred to as cutaneous neurofibromas) originate innerves in theskin. Three kinds are distinguished:^[4]

• Discrete cutaneous neurofibromas: Sessile or pedunculated masses on the skin, which are fleshy and non-tender, and can vary in size.
• Discrete subcutaneous neurofibromas: Lie below and look like bumps on the skin, which can sometimes be tender.
• Deep nodular neurofibromas: Involving tissues and organs underneath thedermis, but otherwise resembling cutaneous and subcutaneous neurofibromas.

Dermal neurofibromas typically arise in the teenage years and are often associated with the onset of puberty. In people with neurofibromatosis type I, they tend to continue to increase in number and size throughout adulthood, although limits exist as to how big they get, and cases progress at highly variable rates.^{[citation needed]}

Dermal neurofibromas can lead to stinging, itching, pain, and disfigurement.^{[citation needed]}

No evidence ofmalignant transformation has been found.^[2]

Plexiform neurofibromas can grow fromnerves in theskin or from more internal nerve bundles, and can be very large (with mass in the tens of kilograms).^[5] Internal plexiform neurofibromas are very difficult to remove completely because they extend through multiple layers of tissue and the attempt would damage healthy tissue or organs.^{[citation needed]}

Plexiform neurofibromas occur earlier in life and are thought to be congenital defects.^[4]

Plexiform neurofibroma can cause disfigurement, neurological, and other clinical deficits.^{[citation needed]}

Plexiform neurofibromas have the potential to cause severe clinical complications if they occur in certain areas.^[6]

About 10% of plexiform neurofibromas undergo transformation into amalignant peripheral nerve sheath tumor.^[7] Plexiform neurofibroma is a known precursor for MPNST in NF1 patients.^[8] The formation of malignant cancers from neurofibromas is associated with the loss of expression of theCDKN2A orTP53 gene in nonmyelinating Schwann cells that also exhibit biallelic inactivation of the NF1 gene.

This section discusses thetumorigenesis of neurofibroma in terms ofgenetics,cell signaling,histology and thecell cycle.

TheNF1 gene is composed of 60exons spanning 350kb of genomic data, and maps to chromosomal region17qll.2.^[9] This gene codes for neurofibromin which is a large 220-250 KDacytoplasmicprotein that is composed of 2,818 amino acids with three alternatively spliced exons (9a, 23a and 48a) in the encoding gene. The functional part of neurofibromin is aGAP, or GTPase-activating protein. GAP accelerates the conversion of the active GTP-bound RAS to its inactive GDP-bound form, inactivating RAS and reducing RAS-mediated growth signaling. Loss of RAS control leads to increased activity of other signaling pathways includingRAF,ERK1/2,PI3K,PAK andmTOR-S6 kinase. This increased activity of downstream RAS pathways might work together to increase cell growth and survival.^[10] Genes that code for proteins that regulate cell growth, such asNF1 andTP53, are referred to astumor suppressor genes. Neurofibromin has other growth-regulatory properties besides its ability to regulate RAS activity, but these other functions are poorly understood at this time.^[11]

There are two kinds ofSchwann cells, myelinating and nonmyelinating. While myelinating Schwann cells cover large diameter (>1 micrometer)peripheral nervous system (PNS) axons withmyelin, nonmyelinating Schwann cells encapsulate small diameter PNS axons with their cytoplasmic processes. Nonmyelinating Schwann cells are theneoplastic element in neurofibromas. This conglomeration of nonmyelinating Schwann cells and axons is called aRemak bundle.^{[citation needed]}

While nonmyelinating Schwann cells are the origin of neurofibromas, the mutations that make them susceptible to this transformation occur in Schwann cell precursors during early nerve development. Mutated nonmyelinating Schwann cells do not form normal Remak bundles. Instead, they fail to properly surround and segregate target axons. It is unknown at this time why, if both types of Schwann cells exhibit bilallelic inactivation of the NF1 gene, only the nonmyelinating variety give rise to neurofibromas.^[12]

Neurofibromas arise from nonmyelinatingSchwann cells that only express the inactive version of the NF1 gene, which leads to a complete loss of expression of functionalneurofibromin. While one defective allele may be inherited,loss of heterozygosity (LOH) must occur before a neurofibroma can form; this is called the 'two-hit hypothesis'. This LOH happens by the same mechanisms, such as oxidativeDNA damage, that causesmutations in other cells.^{[citation needed]}

Once a nonmyelinating Schwann cell has suffered inactivation of its NF1 genes, it begins to proliferate rapidly. This condition is calledhyperplasia, which is cell growth beyond what is normally seen. However, despite increased numbers of nonmyelinating Schwann cells, there is no neurofibroma yet. In order for the neurofibroma to develop, cells that areheterozygous for the NF1 gene must be recruited to the site. It has been hypothesized that the proliferating nonmyelinating Schwann cells secretechemoattractants such as theKIT ligand, andangiogenic factors such as the heparin-binding growth factormidkine. These chemicals promote the migration of different kinds of cells that are heterozygous for the NF1 gene into the hyperplasticlesions created by the nonmyelinating Schwann cells. These cell types includefibroblasts,perineurial cells,endothelial cells, andmast cells. The mast cells then secretemitogens orsurvival factors that alter the developing tumor microenvironment and result in neurofibroma formation.^{[citation needed]}

Dermal and plexiform neurofibromas differ in later development stages, but the details are unclear at this point.^[10]

Dermal neurofibromas may be 2 to 20 mm in diameter, is soft, flaccid, and pinkish-white, and frequently this soft small tumor can be invaginated, as if through a ring in the skin by pressure with the finger, a maneuver called "button-holing".^[14]: 619

A blood test for proteinmelanoma inhibitory activity may be used to detect the presence of neurofibromas.^[15][16]

Abiopsy can be used forhistopathology diagnosis.

• 
  Neurofibroma marked for biopsy, right upper back

Dermal neurofibromas are not usually surgically removed unless they are painful or disfiguring, because there are generally so many of them and they are not dangerous.

CO₂ lasers have been used to remove dermal neurofibromas. In a paper titledHypertrophic Scars After Therapy with CO₂ Laser for Treatment of Multiple Cutaneous Neurofibromas Ostertag et al. said this about treatment by laser: "The cosmetic disfigurement is the most important issue in the decision to treat cutaneous symptoms of neurofibromatosis. Treating patients with extensive neurofibromas with [a] CO₂ laser is still the best choice. However, it is strongly advised that a test treatment be performed to judge the effectiveness of the procedure and whether the developed scar is an acceptable trade-off."^[17]

As of 2002, the primary treatment option for plexiform neurofibroma wassurgery.^[18]

Removal of plexiform neurofibromas is difficult because they can be large and cross tissue boundaries. However, besides pain, plexiform neurofibromas are sometimes removed due to the possibility ofmalignant transformation.

The following examples show that plexiform neurofibromas can form anywhere and can make surgical resection difficult:

• A large plexiform neurofibroma in the leg of a 6-year-old male. The authors state: "Our case was operated, as both the cutaneous and deep branches of the peroneal nerve were involved causing pain and numbness in the leg, and because there was a possibility for malignant transformation, as growth in the mass was realized by the family members of the patient." The authors also note, "However, complete resection is quite difficult due to invasion of the tumor into the surrounding soft tissues."^[19]
• A neurofibroma on theleft ventricle. The neurofibroma was removed and the patient'smitral valve had to be replaced.^[20]
• A 14-year-old girl with NF1 was diagnosed with a neurofibroma involving her bladder, a rare location.^[21]

Once a plexiform neurofibroma has undergone malignant transformation, radiation andchemotherapy can be used as treatment. However, radiation is generally not used as a treatment for plexiform neurofibromas because of concerns that this could actually promote malignant transformation. There has even been a documented case of a Schwannoma being induced from a neurofibroma due to radiation therapy.^[22]

ACE inhibitors have been proposed as a novel treatment of neurofibromas. ACE inhibitors are currently used to treat hypertension and congestive heart failure, to avert remodeling and reinfarction after myocardial infarction, and to ameliorate diabetic nephropathy and other renal diseases. ACE inhibitors work by indirectly down regulatingTGF-beta, which is a growth factor that has been shown to influence the development of tumors.^[23]

Pirfenidone inhibitsfibroblast growth. Studies showed no improvement over controls.

Tipifarnib (also known as drug R115777) inhibits the activation of RAS. This drug is aFarnesyltransferase inhibitor which inhibits the Ras kinase in a post translational modification step before the kinase pathway becomes hyperactive. It successfully passed phase one clinical trials but was suspended (NCT00029354) in phase two after showing no improvement over controls.^[24][25]

The many drug therapies under study for neurofibromas^[26][27] are in various stages of research; more time will be required to determine if these are viable options for the treatment of neurofibromas.

Sirolimus, a compound that inhibitsmTOR signalling, is being studied to treat plexiform neurofibromas.^[28][29]

The combination oferlotinib with sirolimus was studied to treat low-gradegliomas.^[30]

Early research has shown potential for using the c-kit tyrosine kinase blocking properties ofimatinib to treat plexiform neurofibromas.^[31][32][33]

Peginterferon alfa-2b is being studied to treat plexiform neurofibromas.^{[34][35][36][37]}

Sorafenib is being studied for treatment of unresectable plexiform neurofibroma and low-gradeastrocytomas.^[38][39][40]

In vitro,tranilast, inhibits growth of neurofibroma cells.^[41]

Gene therapy for theneurofibromin 1 gene represents the ultimate solution to preventing the cluster of maladies which are enabled by the mutation.^[42][43] As of 2006, therapy for NF1 tumors had not been tested due to the lack of an appropriate NF1 tumor model.^[44]

• Malignant peripheral nerve sheath tumor
• Neurofibromatosis
• Neurofibromin
• Genetic disorder
• Watson syndrome
• Proteus syndrome
• RASopathy
• Palisaded encapsulated neuroma
• Skin lesion
• List of cutaneous conditions

• DermAtlas67
• "Neurofibroma" atDorland's Medical Dictionary
• Ferner RE, O'Doherty MJ (December 2002). "Neurofibroma and schwannoma".Current Opinion in Neurology.15 (6):679–684.doi:10.1097/00019052-200212000-00004.PMID 12447105.S2CID 23782923.

• PNS neoplasia
• Dermal and subcutaneous growths

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