neurofibroma

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 are grade I tumors. Plexiform neurofibroma are more difficult to treat and can transform into malignant tumors. Dermal neurofibroma do not become malignant.{{cn|date=February 2024}}

Dermal neurofibromas (sometimes referred to as cutaneous neurofibromas) originate in nerves in the skin. Three kinds are distinguished:

• 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 the dermis, but otherwise resembling cutaneous and subcutaneous neurofibromas.

File:Dermal Neurofibroma.jpg

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.{{cn|date=February 2024}}

Dermal neurofibromas can lead to stinging, itching, pain, and disfigurement.{{cn|date=February 2024}}

No evidence of malignant transformation has been found.

File:Gould Pyle 253.jpg

Plexiform neurofibromas can grow from nerves in the skin or from more internal nerve bundles, and can be very large (with mass in the tens of kilograms).{{cite journal | vauthors = Mikami T, Honma-Koretsune Y, Tsunoda Y, Kagimoto S, Yabuki Y, Maegawa J, Terauchi T, Nawata S, Kamide H, Ishiwata Y, Kino T, Sugano T | display-authors = 6 | title = Cardiac overload resolved by resection of a large plexiform neurofibroma on both the buttocks and upper posterior thighs in a patient with neurofibromatosis type I: a case report | journal = BMC Surgery | volume = 20 | issue = 1 | pages = 106 | date = May 2020 | pmid = 32423401 | pmc = 7236506 | doi = 10.1186/s12893-020-00761-4 | doi-access = free }} 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.{{cn|date=February 2024}}

File:Neurofibroma -1.jpg

Plexiform neurofibromas occur earlier in life and are thought to be congenital defects.{{cite book | chapter-url = http://www.hawaii.edu/medicine/pediatrics/pedtext/s18c11.html | title = Case Based Pediatrics For Medical Students and Residents | chapter = Chapter XVIII.11. Neurofibromatosis | vauthors = Yamashiroya VK | date = August 2002 | location = Honolulu, HI | publisher = Department of Pediatrics, University of Hawaii, John A. Burns School of Medicine }}

Plexiform neurofibroma can cause disfigurement, neurological, and other clinical deficits.{{cn|date=February 2024}}

Plexiform neurofibromas have the potential to cause severe clinical complications if they occur in certain areas.{{cite web |vauthors=Kluwe L, Hagel C, Mautner V |title=Neurofibroma |date=April 2007 |url=http://atlasgeneticsoncology.org/Tumors/NeurofibromaID5098.html | work = Atlas Genet Cytogenet Oncol Haematol. }}

About 10% of plexiform neurofibromas undergo transformation into a malignant peripheral nerve sheath tumor.{{cite journal | vauthors = Mautner VF, Friedrich RE, von Deimling A, Hagel C, Korf B, Knöfel MT, Wenzel R, Fünsterer C | display-authors = 6 | title = Malignant peripheral nerve sheath tumours in neurofibromatosis type 1: MRI supports the diagnosis of malignant plexiform neurofibroma | journal = Neuroradiology | volume = 45 | issue = 9 | pages = 618–625 | date = September 2003 | pmid = 12898075 | doi = 10.1007/s00234-003-0964-6 | s2cid = 24072091 }} Plexiform neurofibroma is a known precursor for MPNST in NF1 patients.McCarron KF, Goldblum JR. Plexiform neurofibroma with and without associated malignant peripheral nerve sheath tumor: a clinicopathologic and immunohistochemical analysis of 54 cases. Mod Pathol. 1998; 11:612–617. [PubMed: 9688181] The formation of malignant cancers from neurofibromas is associated with the loss of expression of the CDKN2A or TP53 gene in nonmyelinating Schwann cells that also exhibit biallelic inactivation of the NF1 gene.

This section discusses the tumorigenesis of neurofibroma in terms of genetics, cell signaling, histology and the cell cycle.

Image:Neurofibroma.png. This protein is 2818 amino acids long with 3 alternatively spliced exons, 9a, 23a, and 48a. The IRA domains are hypothesized to function as negative regulators of RAS, along with the GRD domain in between them.]]

The NF1 gene is composed of 60 exons spanning 350kb of genomic data, and maps to chromosomal region 17qll.2.{{cite journal | vauthors = Shen MH, Harper PS, Upadhyaya M | title = Molecular genetics of neurofibromatosis type 1 (NF1) | journal = Journal of Medical Genetics | volume = 33 | issue = 1 | pages = 2–17 | date = January 1996 | pmid = 8825042 | pmc = 1051805 | doi = 10.1136/jmg.33.1.2 }} This gene codes for neurofibromin which is a large 220-250 KDa cytoplasmic protein 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 a GAP, 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 including RAF, ERK1/2, PI3K, PAK and mTOR-S6 kinase. This increased activity of downstream RAS pathways might work together to increase cell growth and survival.{{cite journal | vauthors = Rubin JB, Gutmann DH | title = Neurofibromatosis type 1 - a model for nervous system tumour formation? | journal = Nature Reviews. Cancer | volume = 5 | issue = 7 | pages = 557–564 | date = July 2005 | pmid = 16069817 | doi = 10.1038/nrc1653 | s2cid = 7909466 }} Genes that code for proteins that regulate cell growth, such as NF1 and TP53, are referred to as tumor 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.{{cite journal | vauthors = Johnson MR, Look AT, DeClue JE, Valentine MB, Lowy DR | title = Inactivation of the NF1 gene in human melanoma and neuroblastoma cell lines without impaired regulation of GTP.Ras | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 90 | issue = 12 | pages = 5539–5543 | date = June 1993 | pmid = 8516298 | pmc = 46756 | doi = 10.1073/pnas.90.12.5539 | doi-access = free }}

There are two kinds of Schwann cells, myelinating and nonmyelinating. While myelinating Schwann cells cover large diameter (>1 micrometer) peripheral nervous system (PNS) axons with myelin, nonmyelinating Schwann cells encapsulate small diameter PNS axons with their cytoplasmic processes. Nonmyelinating Schwann cells are the neoplastic element in neurofibromas. This conglomeration of nonmyelinating Schwann cells and axons is called a Remak bundle.{{cn|date=February 2024}}

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.{{cite journal | vauthors = Zheng H, Chang L, Patel N, Yang J, Lowe L, Burns DK, Zhu Y | title = Induction of abnormal proliferation by nonmyelinating schwann cells triggers neurofibroma formation | journal = Cancer Cell | volume = 13 | issue = 2 | pages = 117–128 | date = February 2008 | pmid = 18242512 | doi = 10.1016/j.ccr.2008.01.002 | doi-access = free }}

Neurofibromas arise from nonmyelinating Schwann cells that only express the inactive version of the NF1 gene, which leads to a complete loss of expression of functional neurofibromin. 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 oxidative DNA damage, that causes mutations in other cells.{{cn|date=February 2024}}

Once a nonmyelinating Schwann cell has suffered inactivation of its NF1 genes, it begins to proliferate rapidly. This condition is called hyperplasia, 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 are heterozygous for the NF1 gene must be recruited to the site. It has been hypothesized that the proliferating nonmyelinating Schwann cells secrete chemoattractants such as the KIT ligand, and angiogenic factors such as the heparin-binding growth factor midkine. These chemicals promote the migration of different kinds of cells that are heterozygous for the NF1 gene into the hyperplastic lesions created by the nonmyelinating Schwann cells. These cell types include fibroblasts, perineurial cells, endothelial cells, and mast cells. The mast cells then secrete mitogens or survival factors that alter the developing tumor microenvironment and result in neurofibroma formation.{{cn|date=February 2024}}

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

File:Histopathology of neurofibroma.jpg of neurofibroma: A spindle cell lesion composed of slender fibroblast-like cells with storiform pattern and very low amount of stroma.{{cite journal | vauthors = Rotili A, De Maria F, Di Venosa B, Ghioni M, Pizzamiglio M, Cassano E, Moratti M | title = Solitary breast neurofibroma: imaging aspects | journal = ecancermedicalscience | volume = 12 | pages = 800 | year = 2018 | pmid = 29456617 | pmc = 5813918 | doi = 10.3332/ecancer.2018.800 | doi-access = free }}
- "This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0)"]]

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".{{cite book | vauthors = James WD, Berger T, Elston D |title=Andrews' diseases of the skin : clinical dermatology. |date=2006 |publisher=Saunders Elsevier |location=Philadelphia |isbn=978-0-7216-2921-6 |edition=10th}}{{rp|619}}

A blood test for protein melanoma inhibitory activity may be used to detect the presence of neurofibromas.{{cite web |title=Rare genetic condition tracked down with potential new biomarker |date=4 July 2011 |publisher=CORDIS News |url=http://cordis.europa.eu/fetch?CALLER=FP6_NEWS&ACTION=D&DOC=1&CAT=NEWS&QUERY=0130f530e1e4:d4e6:512511ce&RCN=33582}}{{cite journal | vauthors = Kolanczyk M, Mautner V, Kossler N, Nguyen R, Kühnisch J, Zemojtel T, Jamsheer A, Wegener E, Thurisch B, Tinschert S, Holtkamp N, Park SJ, Birch P, Kendler D, Harder A, Mundlos S, Kluwe L | display-authors = 6 | title = MIA is a potential biomarker for tumour load in neurofibromatosis type 1 | journal = BMC Medicine | volume = 9 | pages = 82 | date = July 2011 | pmid = 21726432 | pmc = 3224593 | doi = 10.1186/1741-7015-9-82 | doi-access = free }} {{open access}}

A biopsy can be used for histopathology diagnosis.

File:Neurofibroma, Right Upper Back.jpg|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 titled Hypertrophic 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."{{cite journal | vauthors = Ostertag JU, Theunissen CC, Neumann HA | title = Hypertrophic scars after therapy with CO2 laser for treatment of multiple cutaneous neurofibromas | journal = Dermatologic Surgery | volume = 28 | issue = 3 | pages = 296–298 | date = March 2002 | pmid = 11896787 | doi = 10.1046/j.1524-4725.2002.01145.x | hdl-access = free | s2cid = 656654 | hdl = 1765/54189 | url = https://pure.eur.nl/en/publications/2f640f5d-8ac8-4b2a-8cc2-4037baeffbc6 }}

As of 2002, the primary treatment option for plexiform neurofibroma was surgery.{{cite journal | vauthors = Packer RJ, Gutmann DH, Rubenstein A, Viskochil D, Zimmerman RA, Vezina G, Small J, Korf B | display-authors = 6 | title = Plexiform neurofibromas in NF1: toward biologic-based therapy | journal = Neurology | volume = 58 | issue = 10 | pages = 1461–1470 | date = May 2002 | pmid = 12041525 | doi = 10.1212/wnl.58.10.1461 }}

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 of malignant 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."{{cite journal | vauthors = Cebesoy O, Tutar E, Isik M, Arpacioglu O | title = A case of isolated giant plexiform neurofibroma involving all branches of the common peroneal nerve | journal = Archives of Orthopaedic and Trauma Surgery | volume = 127 | issue = 8 | pages = 709–712 | date = October 2007 | pmid = 17377797 | doi = 10.1007/s00402-007-0303-1 | s2cid = 22638321 }}
• A neurofibroma on the left ventricle. The neurofibroma was removed and the patient's mitral valve had to be replaced.{{cite journal | vauthors = Iino K, Matsumoto Y, Endo M, Kawakami K, Kasashima F, Sasaki H, Kawashima A | title = Surgical treatment of a left ventricular neurofibroma | journal = Journal of Cardiac Surgery | volume = 21 | issue = 3 | pages = 278–280 | year = 2006 | pmid = 16684061 | doi = 10.1111/j.1540-8191.2005.00135.x | s2cid = 7247742 | doi-access = free }}
• A 14-year-old girl with NF1 was diagnosed with a neurofibroma involving her bladder, a rare location.{{cite journal | vauthors = Meesa IR, Junewick JJ | title = Pelvic plexiform neurofibroma involving the urinary bladder | journal = Pediatric Radiology | volume = 38 | issue = 8 | pages = 916 | date = August 2008 | pmid = 18458838 | doi = 10.1007/s00247-008-0865-2 | s2cid = 11649262 }}

Once a plexiform neurofibroma has undergone malignant transformation, radiation and chemotherapy 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.{{cite journal | vauthors = Isler MH, Fogaça MF, Mankin HJ | title = Radiation induced malignant schwannoma arising in a neurofibroma | journal = Clinical Orthopaedics and Related Research | volume = 325 | issue = 325 | pages = 251–255 | date = April 1996 | pmid = 8998885 | doi = 10.1097/00003086-199604000-00031 }}

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 regulating TGF-beta, which is a growth factor that has been shown to influence the development of tumors.{{cite journal | vauthors = Namazi H | title = ACE inhibitors: a novel treatment for neurofibroma | journal = Annals of Surgical Oncology | volume = 15 | issue = 5 | pages = 1538–1539 | date = May 2008 | pmid = 18157575 | doi = 10.1245/s10434-007-9737-5 | s2cid = 9603376 }}

Pirfenidone inhibits fibroblast growth. Studies showed no improvement over controls.

Tipifarnib (also known as drug R115777) inhibits the activation of RAS. This drug is a Farnesyltransferase 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.{{ClinicalTrialsGov|NCT00025454|R115777 in Treating Patients With Advanced Solid Tumors}}

[http://clinicaltrials.gov/ct2/show/NCT00029354?term=NCT00029354&rank=1 "R115777 to Treat Children With Neurofibromatosis Type 1 and Progressive Plexiform Neurofibromas"]

The many drug therapies under study for neurofibromas{{cite web | vauthors = Viskochil D | title=Neurofibromatosis 1: Current Issues in Diagnosis, Therapy, and Patient Management |year=2010 |publisher=Mountain States Genetic Foundation |url=http://www.mostgene.org/2010_conference/neurofibro_Viskochil.pdf |location=Denver }}{{cite web | vauthors = Klesse L |title=Current Therapies for Neurofibromatosis Type 1 |year=2010 |publisher=Mountain States Genetic Foundation |url=http://www.mostgene.org/2010_conference/current_ther_neuro_klesse.pdf |location=Denver |access-date=2011-05-15 |archive-url=https://web.archive.org/web/20120309091045/http://www.mostgene.org/2010_conference/current_ther_neuro_klesse.pdf |archive-date=2012-03-09 |url-status=dead }} 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 inhibits mTOR signalling, is being studied to treat plexiform neurofibromas.{{ClinicalTrialsGov|NCT00652990|Sirolimus to Treat Plexiform Neurofibromas in Patients With Neurofibromatosis Type I}}{{ClinicalTrialsGov|NCT00634270|A Phase II Study of the mTOR Inhibitor Sirolimus in Neurofibromatosis Type 1 Related Plexiform Neurofibromas (Protocol 102)}}

The combination of erlotinib with sirolimus was studied to treat low-grade gliomas.{{ClinicalTrialsGov|NCT00901849|Tarceva/Rapamycin for Children With Low-Grade Gliomas With or Without Neurofibromatosis Type 1 (NF1)}}

Early research has shown potential for using the c-kit tyrosine kinase blocking properties of imatinib to treat plexiform neurofibromas.{{cite journal | vauthors = Yang FC, Ingram DA, Chen S, Zhu Y, Yuan J, Li X, Yang X, Knowles S, Horn W, Li Y, Zhang S, Yang Y, Vakili ST, Yu M, Burns D, Robertson K, Hutchins G, Parada LF, Clapp DW | display-authors = 6 | title = Nf1-dependent tumors require a microenvironment containing Nf1+/-- and c-kit-dependent bone marrow | journal = Cell | volume = 135 | issue = 3 | pages = 437–448 | date = October 2008 | pmid = 18984156 | pmc = 2788814 | doi = 10.1016/j.cell.2008.08.041 }}[https://www.sciencedaily.com/releases/2008/10/081030123837.htm "Gleevec Holds Potential As First Drug To Successfully Treat Neurofibromatosis, Scientists Report"], Science Daily, October 31, 2008[http://www.nfcure.org/newnf1trial/gleevecnf1trial.html "Phase II Study of Gleevec/Imatinib Mesylate (STI-571, NSC 716051) in Neurofibromatosis (NF1) Patients with Plexiform Neurofibromas"] {{webarchive|url=https://web.archive.org/web/20120420015449/http://nfcure.org/newnf1trial/gleevecnf1trial.html |date=2012-04-20 }}

Peginterferon alfa-2b is being studied to treat plexiform neurofibromas.{{ClinicalTrialsGov|NCT00678951|Pegintron to Treat Plexiform Neurofibromas in Children and Young Adults}}{{ClinicalTrialsGov|NCT00396019|Study of PEG-Intron for Plexiform Neurofibromas}}{{ClinicalTrialsGov|NCT00846430|Medical Treatment of "High-Risk" Neurofibromas}}[http://clinicalstudies.info.nih.gov/detail/A_2008-C-0130.html "A Phase II Trial of Peginterferon Alpha-2b (Pegintron) for Neurofibromatosis Type 1 Related Unresectable, Symptomatic or Life-Threatening Plexiform Neurofibromas"], National Institutes of Health study 08-C-0130

Sorafenib is being studied for treatment of unresectable plexiform neurofibroma and low-grade astrocytomas.{{ClinicalTrialsGov|NCT00727233|Sorafenib in Treating Young Patients With Neurofibromatosis Type 1 and Plexiform Neurofibromas That Cannot Be Removed by Surgery}}{{cite journal | vauthors = Ambrosini G, Cheema HS, Seelman S, Teed A, Sambol EB, Singer S, Schwartz GK | title = Sorafenib inhibits growth and mitogen-activated protein kinase signaling in malignant peripheral nerve sheath cells | journal = Molecular Cancer Therapeutics | volume = 7 | issue = 4 | pages = 890–896 | date = April 2008 | pmid = 18413802 | pmc = 3267321 | doi = 10.1158/1535-7163.MCT-07-0518 }}{{cite journal | vauthors = Wu J, Dombi E, Jousma E, Scott Dunn R, Lindquist D, Schnell BM, Kim MO, Kim A, Widemann BC, Cripe TP, Ratner N | display-authors = 6 | title = Preclincial testing of sorafenib and RAD001 in the Nf(flox/flox) ;DhhCre mouse model of plexiform neurofibroma using magnetic resonance imaging | journal = Pediatric Blood & Cancer | volume = 58 | issue = 2 | pages = 173–180 | date = February 2012 | pmid = 21319287 | pmc = 3128176 | doi = 10.1002/pbc.23015 }}

In vitro, tranilast, inhibits growth of neurofibroma cells.{{cite journal | vauthors = Yamamoto M, Yamauchi T, Okano K, Takahashi M, Watabe S, Yamamoto Y | title = Tranilast, an anti-allergic drug, down-regulates the growth of cultured neurofibroma cells derived from neurofibromatosis type 1 | journal = The Tohoku Journal of Experimental Medicine | volume = 217 | issue = 3 | pages = 193–201 | date = March 2009 | pmid = 19282654 | doi = 10.1620/tjem.217.193 | doi-access = free }}

Gene therapy for the neurofibromin 1 gene represents the ultimate solution to preventing the cluster of maladies which are enabled by the mutation.{{cite journal | vauthors = Wetmore DZ, Garner CC | title = Emerging pharmacotherapies for neurodevelopmental disorders | journal = Journal of Developmental and Behavioral Pediatrics | volume = 31 | issue = 7 | pages = 564–581 | date = September 2010 | pmid = 20814256 | pmc = 2967570 | doi = 10.1097/DBP.0b013e3181ee3833 }}{{cite journal | vauthors = Gottfried ON, Viskochil DH, Couldwell WT | title = Neurofibromatosis Type 1 and tumorigenesis: molecular mechanisms and therapeutic implications | journal = Neurosurgical Focus | volume = 28 | issue = 1 | pages = E8 | date = January 2010 | pmid = 20043723 | doi = 10.3171/2009.11.FOCUS09221 | doi-access = free }} As of 2006, therapy for NF1 tumors had not been tested due to the lack of an appropriate NF1 tumor model.{{cite web | vauthors = Muir DF |title=Angiogenesis and Therapeutic Approaches to NF1 Tumors |date=April 2006 |publisher=University of Florida Gainesville |url=http://oai.dtic.mil/oai/oai?verb=getRecord&metadataPrefix=html&identifier=ADA456360|archive-url=https://web.archive.org/web/20120327064857/http://oai.dtic.mil/oai/oai?verb=getRecord&metadataPrefix=html&identifier=ADA456360|url-status=dead|archive-date=March 27, 2012}} also available [http://www.stormingmedia.us/92/9254/A925424.html here]

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

{{Reflist}}

{{Medical resources

| DiseasesDB = 23371

| ICD10 = D36.1 (ILDS D36.160)

| ICD9 =

| ICDO = {{ICDO|9540|0}}-9550

| OMIM =

| MedlinePlus =

| eMedicineSubj =

| eMedicineTopic =

| MeshID = D009455

}}

• {{DermAtlas|67}}
• {{DorlandsDict|six/000071811|Neurofibroma}}
• {{cite journal | vauthors = Ferner RE, O'Doherty MJ | title = Neurofibroma and schwannoma | journal = Current Opinion in Neurology | volume = 15 | issue = 6 | pages = 679–684 | date = December 2002 | pmid = 12447105 | doi = 10.1097/00019052-200212000-00004 | s2cid = 23782923 }}

{{Diseases of the skin and appendages by morphology}}

{{Nervous tissue tumors}}

Category:PNS neoplasia

Category:Dermal and subcutaneous growths