Neurofibroma
Neurofibroma | |
---|---|
Neurofibroma of the skin in a person with neurofibromatosis type I | |
Specialty | Neuro-oncology |
A neurofibroma is a benign nerve-sheath tumor in the peripheral nervous system. In 90% of cases, they are found as stand-alone tumors (solitary neurofibroma, solitary nerve sheath tumor[1] or sporadic neurofibroma[1]), while the remainder are found in persons 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 nonmyelinating-type
Types
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.[citation needed]
Dermal neurofibroma
Anatomy
Dermal neurofibromas (sometimes referred to as cutaneous neurofibromas) originate in nerves in the skin. 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 the dermis, but otherwise resembling cutaneous and subcutaneous neurofibromas.
Age of onset
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]
Medical complications
Dermal neurofibromas can lead to stinging, itching, pain, and disfigurement.[citation needed]
No evidence of malignant transformation has been found.[2]
Plexiform neurofibroma
Anatomy
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).[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]
Age of onset
Medical complications
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 a
Cause
This section discusses the
.Neurofibromin 1 gene
The NF1 gene is composed of 60
Schwann cells
There are two kinds of
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]
Loss of tumor suppressor function
Neurofibromas arise from nonmyelinating
Once a nonmyelinating Schwann cell has suffered inactivation of its NF1 genes, it begins to proliferate rapidly. This condition is called
Dermal and plexiform neurofibromas differ in later development stages, but the details are unclear at this point.[10]
Diagnosis
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 protein melanoma inhibitory activity may be used to detect the presence of neurofibromas.[15][16]
A biopsy can be used for histopathology diagnosis.
-
Neurofibroma marked for biopsy, right upper back
Treatments
Dermal neurofibroma
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."[17]
Plexiform neurofibroma
Surgery
As of 2002, the primary treatment option for plexiform neurofibroma was surgery.[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 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."[19]
- A neurofibroma on the left ventricle. The neurofibroma was removed and the patient's mitral 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]
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.[22]
Medications
No effect
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.[24] [25]
Research
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 inhibits mTOR signalling, is being studied to treat plexiform neurofibromas.[28][29]
The combination of erlotinib with sirolimus was studied to treat low-grade gliomas.[30]
Early research has shown potential for using the c-kit tyrosine kinase blocking properties of imatinib 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-grade astrocytomas.[38][39][40]
In vitro, tranilast, inhibits growth of neurofibroma cells.[41]
Gene therapy for the neurofibromin 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]
See also
- Malignant peripheral nerve sheath tumor
- Neurofibromatosis
- Neurofibromin
- Genetic disorder
- Watson syndrome
- Proteus syndrome
- RASopathy
- Palisaded encapsulated neuroma
- Skin lesion
- List of cutaneous conditions
References
- ^ ISBN 978-1-4160-2999-1.
- ^ PMID 11159187.
- ^ Miller RT (October 2004). "Immunohistochemistry in the differential diagnosis of schwannoma and neurofibroma" (PDF). Propath.
- ^ a b Yamashiroya VK (August 2002). "Chapter XVIII.11. Neurofibromatosis". Case Based Pediatrics For Medical Students and Residents. Honolulu, HI: Department of Pediatrics, University of Hawaii, John A. Burns School of Medicine.
- PMID 32423401.
- ^ Kluwe L, Hagel C, Mautner V (April 2007). "Neurofibroma". Atlas Genet Cytogenet Oncol Haematol.
- S2CID 24072091.
- ^ 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]
- PMID 8825042.
- ^ S2CID 7909466.
- PMID 8516298.
- PMID 18242512.
- PMID 29456617.)"
- "This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0 - ISBN 978-0-7216-2921-6.
- CORDISNews. 4 July 2011.
- PMID 21726432.
- S2CID 656654.
- PMID 12041525.
- S2CID 22638321.
- S2CID 7247742.
- S2CID 11649262.
- PMID 8998885.
- S2CID 9603376.
- ^ Clinical trial number NCT00025454 for "R115777 in Treating Patients With Advanced Solid Tumors" at ClinicalTrials.gov
- ^ "R115777 to Treat Children With Neurofibromatosis Type 1 and Progressive Plexiform Neurofibromas"
- ^ Viskochil D (2010). "Neurofibromatosis 1: Current Issues in Diagnosis, Therapy, and Patient Management" (PDF). Denver: Mountain States Genetic Foundation.
- ^ Klesse L (2010). "Current Therapies for Neurofibromatosis Type 1" (PDF). Denver: Mountain States Genetic Foundation. Archived from the original (PDF) on 2012-03-09. Retrieved 2011-05-15.
- ^ Clinical trial number NCT00652990 for "Sirolimus to Treat Plexiform Neurofibromas in Patients With Neurofibromatosis Type I" at ClinicalTrials.gov
- ^ Clinical trial number NCT00634270 for "A Phase II Study of the mTOR Inhibitor Sirolimus in Neurofibromatosis Type 1 Related Plexiform Neurofibromas (Protocol 102)" at ClinicalTrials.gov
- ^ Clinical trial number NCT00901849 for "Tarceva/Rapamycin for Children With Low-Grade Gliomas With or Without Neurofibromatosis Type 1 (NF1)" at ClinicalTrials.gov
- PMID 18984156.
- Science Daily, October 31, 2008
- ^ "Phase II Study of Gleevec/Imatinib Mesylate (STI-571, NSC 716051) in Neurofibromatosis (NF1) Patients with Plexiform Neurofibromas" Archived 2012-04-20 at the Wayback Machine
- ^ Clinical trial number NCT00678951 for "Pegintron to Treat Plexiform Neurofibromas in Children and Young Adults" at ClinicalTrials.gov
- ^ Clinical trial number NCT00396019 for "Study of PEG-Intron for Plexiform Neurofibromas" at ClinicalTrials.gov
- ^ Clinical trial number NCT00846430 for "Medical Treatment of "High-Risk" Neurofibromas" at ClinicalTrials.gov
- ^ "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
- ^ Clinical trial number NCT00727233 for "Sorafenib in Treating Young Patients With Neurofibromatosis Type 1 and Plexiform Neurofibromas That Cannot Be Removed by Surgery" at ClinicalTrials.gov
- PMID 18413802.
- PMID 21319287.
- PMID 19282654.
- PMID 20814256.
- PMID 20043723.
- ^ Muir DF (April 2006). "Angiogenesis and Therapeutic Approaches to NF1 Tumors". University of Florida Gainesville. Archived from the original on March 27, 2012. also available here
External links
- DermAtlas 67
- "Neurofibroma" at Dorland's Medical Dictionary
- Ferner RE, O'Doherty MJ (December 2002). "Neurofibroma and schwannoma". Current Opinion in Neurology. 15 (6): 679–684. S2CID 23782923.