Neurofibroma

Neurofibroma
Classification and external resources
Histopathologic image of cutaneous neurofibroma obtained by biopsy
ICD-10	D36.1 (ILDS D36.160)
ICD-O:	M9540/0-9550
DiseasesDB	23371
MeSH	D009455

A neurofibroma is a benign nerve sheath tumor in the peripheral nervous system. Usually found in individuals with neurofibromatosis type I (NF1), an autosomal dominant genetically-inherited disease, they can result in a range of symptoms from physical disfiguration and pain to cognitive disability. Neurofibromas arise from Schwann cells that exhibit biallelic inactivation of the NF1 gene that codes for the protein neurofibromin..^[1] This protein is responsible for regulating the RAS-mediated cell growth pathway. In contrast to schwannomas, 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.^[2]

Genetics and Intracellular Signaling

This picture illustrates the structure of the NF1 gene product, neurofibromin. This protein is 2818 amino acids long with 3 alternatively spiced 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.

Neurofibromas arise from Schwann cells that are homozygous for the inactive version of the NF1 gene, which leads to a complete loss of expression of neurofibromin. The NF1 gene is composed of 60 exons spanning 350kb of genomic data, and maps to chromosomal region 17qll.2.^[3] 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). 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. It is suspected that this increased activity of downstream RAS pathways might work together to increase cell growth and survival.^[4] 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.^[5] 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.

Origin and Development of Neurofibromas

Schwann cells are the neoplastic element in neurofibromas. 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. This conglomeration of nonmyelinating Schwann cells and axons is called a Remak bundle. 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. According to Zheng et al. in the paper Induction of Abnormal Proliferation by Nonmyelinating Schwann Cells Triggers Neurofibroma Formation, “Taken together, our data suggest that the initially expanded nonmyelinating Schwann cells are early-stage tumor cells, which are responsible for both the initiation and progression of plexiform neurofibromas.”^[6]

Once a nonmyelinating Schwann cell has suffered inactivation of its NF1 genes, through genetic mutation and DNA damage caused by environmental factors, 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. Dermal and plexiform neurofibromas do differ in later development stages, but the details are unclear at this point.^[4]

Once a plexiform neurofibroma has formed, there is a chance that it will undergo transformation into a malignant peripheral nerve sheath tumor (MPNST). The formation of malignant cancers from neurofibromas is associated with the loss of expression of the CDKN2A or TP53 gene in non-myelinating Schwann cells that also exhibit biallelic inactivation of the NF1 gene.

Subtypes of Neurofibromas

Neurofibroma of the skin in a patient suffering from von Recklinghausen's disease.

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.

Dermal Neurofibromas

Dermal neurofibromas, sometimes referred to as cutaneous neurofibromas, typically arise in the teenage years and are often associated with the onset of puberty. They continue to increase in number and size throughout adulthood, although there are limits to how big they get. They look like lumps on or under the skin. While dermal neurofibromas can lead to stinging, itching, pain and disfiguration, there is no evidence of malignant transformation.^[1]

Plexiform Neurofibromas

Plexiform neurofibromas are often congenital defects, and are the more troublesome type. They can be very large and can cause pain, disfigurement, neurological and other clinical deficits. While dermal neurofibromas originate in nerves in the skin, plexiform neurofibromas can grow from nerves in the skin or from more internal nerve bundles.

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. Plexiform neurofibromas also have the potential to cause severe clinical complications if they occur in certain areas.^[7] In addition, about 10% of plexiform neurofibromas undergo malignant transformation.^[8] This transformation turns the plexiform neurofibroma into a malignant peripheral nerve sheath tumor (MPNST).

Diagnosis

A blood test for protein melanoma inhibitory activity may be used to detect the presence of neurofibromas.^[9][10]

Treatment

According to Packer, et al. in the article titled Plexiform neurofibromas in NF1-Toward biologic-based therapy, “There are several impediments that have limited progress in designing optimal therapies for NF1-associated neurofibromas, including a more complete understanding of 1) the contribution of each cell type in a neurofibroma to its genesis and continued growth, 2) the specific consequences of absent NF1 gene function on cell growth control, and 3) the role of additional genetic and biologic factors that influence neurofibroma formation and growth.” While this article was written prior to the papers cited in the Origin and Development of Neurofibromas section, these issues have not been totally addressed. While surgery is the most common method of treating neurofibromas, there are some alternative methods as well.

Surgery

Neurofibromas are commonly treated with surgical removal. Dermal neurofibromas are not usually removed unless they are painful or disfiguring, because there are generally so many of them and they are not dangerous.

Removal of plexiform neurofibromas can be more difficult because they can be larger and cross tissue boundaries. However, besides pain, plexiform neurofibromas are sometimes removed due to the possibility of malignant transformation. One example of this can be found in the case study titled A case of isolated giant plexiform neurofibroma involving all branches of the common peroneal nerve, which discusses the removal of a large plexiform neurofibroma in the leg of a 6-year old male. The authors state (dr.cebesoy): “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.” In layman’s terms, they decided to remove the neurofibroma because it was causing the boy pain and numbness in his leg, and because there was a possibility that it was undergoing a malignant transformation as his family noticed an increase in the tumor's size. The authors also note, “However, complete resection is quite difficult due to invasion of the tumor into the surrounding soft tissues.” ^[11]

Sometimes plexiform neurofibromas form in locations that make them especially hard to access. One specific example of this can be found in a paper titled Surgical Treatment of a Left Ventricular Neurofibroma which chronicles the resection (partial removal) of a neurofibroma on the left ventricle. The neurofibroma was removed and the patient’s mitral valve had to be replaced. Another example of a neurofibroma in an unusual location is recorded in a paper titled Pelvic plexiform neurofibroma involving the urinary bladder. A 14-year-old girl with NF1 was diagnosed with a neurofibroma involving her bladder, a rare location.^[12] These examples serve to illustrate that plexiform neurofibromas can form anywhere and can make surgical resection difficult.

Radiation

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.^[13]

CO2 Laser

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.” ^[14]

Drug therapies

There are many drug therapies under study for neurofibromas.^[15][16] These are in various stages of research; more time will be required to determine if these are viable options for the treatment of neurofibromas.

Drug studies currently active

Erlotinib (Tarceva) with Sirolimus

The combination of Erlotinib with Sirolimus is being studied to treat low-grade gliomas.^[17]

Imatinib (Gleevec)

Early research has shown potential for using the c-kit tyrosine kinase blocking properties of Imatinib to treat plexiform neurofibromas.^{[18][19] [20]}

Pegylated Interferon (Peg-Intron)

Peginterferon alfa-2b is being studied to treat plexiform neurofibromas.^{[21][22] [23][24][25]}

Sirolimus (Rapamycin)

Sirolimus is an antibiotic developed as an antifungal agent. It inhibits mTOR signalling. It is being studied to treat plexiform neurofibromas.^[26][27][28]

Sorafenib (Nexavar)

Sorafenib is being studied for treatment of unresectable plexiform neurofibroma and low-grade astrocytomas.^{[29][30][31][32]}

Tranilast (Rizaben)

In vitro, Tranilast, inhibits growth of neurofibroma cells.^[33]

Drug studies which demonstrated no effect

Pirfenidone

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

Tipifarnib

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.^{[34] [35]}

Drug treatment hypothetical strategies

Use ACE inhibitors (status as of 2008)

In a letter to the editor of the Annals of Surgical Oncology by Dr. Hamid Namazi in 2008, ACE inhibitors were 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.^[36]

Stabilize axon-Schwann cell interaction and reduce mast cell infiltration (status as of 2008)

Based on the recent discovery that the nonmyelinating Schwann cells that make up Remak bundles are the origin of neurofibromas, it has been proposed that therapies for prevention and treatment be based on stabilizing the axon-Schwann cell interactions and reducing mast cell infiltration. As it appears that these elements are needed for neurofibroma formation, prevention or reduction could prove an effective treatment.^[6]

Gene therapy (status as of 2006)

Gene therapy for the neurofibromin 1 gene represents the ultimate solution to preventing the cluster of maladies which are enabled by the mutation.^[37][38]

As of 2006, therapy for NF1 tumors had not been tested due to the lack of an appropriate NF1 tumor model.^[39]

Notable Cases

Joseph Merrick, also known as the Elephant Man, lived in the 19th century and suffered severe facial deformities. In 1971, Ashley Montagu suggested in his book The Elephant Man: A Study in Human Dignity that Merrick suffered Neurofibromatosis type 1, and this has continued to be reported. Although, careful research has shown that Merrick actually suffered from Proteus syndrome not Neurofibromatosis as had been previously reported.

See also

• Malignant peripheral nerve sheath tumor
• Neurofibromatosis
• Neurofibromin
• Genetic disorder
• Watson syndrome

References

1. ^ ^{a b} Muir D, Neubauer D, Lim IT, Yachnis AT, Wallace MR. (2003). "Tumorigenic properties of neurofibromin-deficient neurofibroma Schwann cells.". American Journal of Pathology 158 (2): 501–13. doi:10.1016/S0002-9440(10)63992-2. PMC 1850316. PMID 11159187. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1850316. 
2. ^ Miller RT (October 2004). "Immunohistochemistry in the differential diagnosis of schwannoma and neurofibroma" (PDF). Propath. http://www.ihcworld.com/_newsletter/2004/2004-10_NF_vs_schwannoma_v1.pdf. 
3. ^ MH Shen, PS Harper, M Upadhyaya. (1996). "Molecular genetics of neurofibromatosis type 1 (NF1)". Journal of Medical Genetics 33 (1): 2–17. doi:10.1136/jmg.33.1.2. PMC 1051805. PMID 8825042. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1051805. 
4. ^ ^{a b} Rubin JB, Gutmann DH. (2005). "Neurofibromatosis type 1 - a model for nervous system tumour formation?". Nature Reviews Cancer 5 (7): 557–64. doi:10.1038/nrc1653. PMID 16069817. 
5. ^ Johnson MR, Look AT, DeClue JE, Valentine MB, Lowy DR. (1993). "Inactivation of the NF1 gene in human melanoma and neuroblastoma cell lines without impaired regulation of GTP.Ras.". Proceedings of the National Academy of Sciences of the USA 90 (12): 5539–43. doi:10.1073/pnas.90.12.5539. PMC 46756. PMID 8516298. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=46756. 
6. ^ ^{a b} Zheng H, Chang L, Patel N, Yang J, Lowe L, Burns DK, Zhu Y. (2008). "Induction of Abnormal Proliferation by Nonmyelinating Schwann Cells Triggers Neurofibroma Formation". Cancer Cell 13 (2): 117–28. doi:10.1016/j.ccr.2008.01.002. PMID 18242512. 
7. ^ Kluwe L, Hagel C, Mautner V (April 2007). "Neurofibroma". http://atlasgeneticsoncology.org/Tumors/NeurofibromaID5098.html. 
8. ^ Mautner VF, Friedrich RE, von Deimling A, Hagel C, Korf B, Knöfel MT, Wenzel R, Fünsterer C. (2003). "Malignant peripheral nerve sheath tumours in neurofibromatosis type 1: MRI supports the diagnosis of malignant plexiform neurofibroma.". American Journal of Pathology 45 (9): 618–25. doi:10.1007/s00234-003-0964-6. PMID 12898075. 
9. ^ "Rare genetic condition tracked down with potential new biomarker". CORDIS News. 4 July 2011. http://cordis.europa.eu/fetch?CALLER=FP6_NEWS&ACTION=D&DOC=1&CAT=NEWS&QUERY=0130f530e1e4:d4e6:512511ce&RCN=33582. 
10. ^ Kolanczyk M, Mautner V, Kossler N, et al. (2011). "MIA is a potential biomarker for tumour load in neurofibromatosis type 1". BMC Med 9: 82. doi:10.1186/1741-7015-9-82. PMID 21726432. http://www.biomedcentral.com/1741-7015/9/82. 
11. ^ Cebesoy O, Tutar E, Isik M, Arpacioglu O. (2007). "A case of isolated giant plexiform neurofibroma involving all branches of the common peroneal nerve". Archives of Orthopaedic and Trauma Surgery 127 (8): 709–12. doi:10.1007/s00402-007-0303-1. PMID 17377797. 
12. ^ Meesa IR, Junewick JJ. (2008). "Pelvic plexiform neurofibroma involving the urinary bladder". Clinical Image 38 (8): 916. doi:10.1007/s00247-008-0865-2. PMID 18458838. 
13. ^ Isler MH, Fogaça MF, Mankin HJ. (1996). "Radiation induced malignant schwannoma arising in a neurofibroma". Clinical Orthopaedics and Related Research 325 (325): 251–5. doi:10.1097/00003086-199604000-00031. PMID 8998885. 
14. ^ Ostertag JU, Theunissen CC, Neumann HA. (2002). "Hypertrophic scars after therapy with CO₂ laser for treatment of multiple cutaneous neurofibromas". Clinical Orthopaedics and Related Research 28 (3): 296–8. PMID 11896787. 
15. ^ Viskochil, David (2010). "Neurofibromatosis 1: Current Issues in Diagnosis, Therapy, and Patient Management" (PDF). Denver: Mountain States Genetic Foundation. http://www.mostgene.org/2010_conference/neurofibro_Viskochil.pdf. 
16. ^ Klesse, Laura (2010). "Current Therapies for Neurofibromatosis Type 1" (PDF). Denver: Mountain States Genetic Foundation. http://www.mostgene.org/2010_conference/current_ther_neuro_klesse.pdf. 
17. ^ ["Tarceva/Rapamycin for Children With Low-Grade Gliomas With or Without Neurofibromatosis Type 1 (NF1" Children's Research Institute study NCT00901849
18. ^ Yang FC, Ingram DA, Chen S, et al. (October 2008). "Nf1-dependent tumors require a microenvironment containing Nf1±- and c-kit-dependent bone marrow". Cell 135 (3): 437–48. doi:10.1016/j.cell.2008.08.041. PMC 2788814. PMID 18984156. http://linkinghub.elsevier.com/retrieve/pii/S0092-8674(08)01130-6. 
19. ^ "Gleevec Holds Potential As First Drug To Successfully Treat Neurofibromatosis, Scientists Report", Science Daily, October 31, 2008
20. ^ "Phase II Study of Gleevec/Imatinib Mesylate (STI-571, NSC 716051) in Neurofibromatosis (NF1) Patients with Plexiform Neurofibromas"
21. ^ ClinicalTrials.gov NCT00678951 Pegintron to Treat Plexiform Neurofibromas in Children and Young Adults National Cancer Institute
22. ^ "Peginterferon alpha-2b in Treating Young Patients with Unresectable, Sympotomatic or Life-Threatening Plexiform Neurofibromas Associated with Neurofibromatosis Type 1"
23. ^ ClinicalTrials.gov NCT00396019 Study of PEG-Intron for Plexiform Neurofibromas
24. ^ ClinicalTrials.gov NCT00846430 Medical Treatment of "High-Risk" Neurofibromas
25. ^ "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
26. ^ ClinicalTrials.gov NCT00652990 Sirolimus to Treat Plexiform Neurofibromas in Patients With Neurofibromatosis Type I
27. ^ ClinicalTrials.gov NCT00634270 A Phase II Study of the mTOR Inhibitor Sirolimus in Neurofibromatosis Type 1 Related Plexiform Neurofibromas (Protocol 102)
28. ^ "Drug Treatments on the Horizon – Clinical drug studies in NF", by Susan Toomey MS
29. ^ ClinicalTrials.gov NCT00727233 Sorafenib in Treating Young Patients With Neurofibromatosis Type 1 and Plexiform Neurofibromas That Cannot Be Removed by Surgery
30. ^ Ambrosini G, Cheema HS, Seelman S, et al. (April 2008). "Sorafenib inhibits growth and mitogen-activated protein kinase signaling in malignant peripheral nerve sheath cells". Mol. Cancer Ther. 7 (4): 890–6. doi:10.1158/1535-7163.MCT-07-0518. PMID 18413802. http://mct.aacrjournals.org/content/7/4/890.full. 
31. ^ "Sorafenib in Children and Young Adults With Recurrent or Progressive Low-Grade Astrocytomas" National Cancer Institute study NCT00727233
32. ^ Wu J, Dombi E, Jousma E, et al. (February 2011). "Preclincial testing of Sorafenib and RAD001 in the Nf(flox/flox) ;DhhCre mouse model of plexiform neurofibroma using magnetic resonance imaging". Pediatr Blood Cancer. doi:10.1002/pbc.23015. PMID 21319287. 
33. ^ Yamamoto M, Yamauchi T, Okano K, Takahashi M, Watabe S, Yamamoto Y (March 2009). "Tranilast, an anti-allergic drug, down-regulates the growth of cultured neurofibroma cells derived from neurofibromatosis type 1". Tohoku J. Exp. Med. 217 (3): 193–201. PMID 19282654. http://joi.jlc.jst.go.jp/JST.JSTAGE/tjem/217.193?lang=en&from=PubMed. 
34. ^ ClinicalTrials.gov NCT00025454 R115777 in Treating Patients With Advanced Solid Tumors
35. ^ "R115777 to Treat Children With Neurofibromatosis Type 1 and Progressive Plexiform Neurofibromas"
36. ^ Namazi H. (2008). "ACE inhibitors: a novel treatment for neurofibroma". Clinical Orthopaedics and Related Research 15 (5): 1538–9. doi:10.1245/s10434-007-9737-5. PMID 18157575. 
37. ^ Wetmore DZ, Garner CC (September 2010). "Emerging pharmacotherapies for neurodevelopmental disorders". J Dev Behav Pediatr 31 (7): 564–81. doi:10.1097/DBP.0b013e3181ee3833. PMID 20814256. http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0196-206X&volume=31&issue=7&spage=564. 
38. ^ Gottfried ON, Viskochil DH, Couldwell WT (January 2010). "Neurofibromatosis Type 1 and tumorigenesis: molecular mechanisms and therapeutic implications". Neurosurg Focus 28 (1): E8. doi:10.3171/2009.11.FOCUS09221. PMID 20043723. http://thejns.org/doi/abs/10.3171/2009.11.FOCUS09221?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed. 
39. ^ Muir, David F. (April 2006). "Angiogenesis and Therapeutic Approaches to NF1 Tumors". University of Florida Gainesville. http://oai.dtic.mil/oai/oai?verb=getRecord&metadataPrefix=html&identifier=ADA456360.  also available here

External links

• DermAtlas 67
• "Neurofibroma" at Dorland's Medical Dictionary