Neurofibroma

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Neurofibroma
Neurofibroma02.jpg
Neurofibroma of the skin in a person with neurofibromatosis type I
Specialty Oncology Edit this on Wikidata
A neurofibroma is a benign nerve-sheath tumor in the peripheral nervous system. In
90% of cases, they are found as stand-alone tumors, 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 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 signaling 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]

Contents
1 Types
1.1 Dermal neurofibroma
1.2 Plexiform neurofibroma
2 Cause
2.1 Neurofibromin 1 gene
2.2 Schwann cells
2.3 Loss of tumor suppressor function
3 Diagnosis
4 Treatments
4.1 Dermal neurofibroma
4.2 Plexiform neurofibroma
4.3 Medications
4.4 No effect
5 Research
6 See also
7 References
8 External links
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.

Dermal neurofibroma
Anatomy
Dermal neurofibromas (sometimes referred to as cutaneous neurofibromas) originate
in nerves in the skin. Three kinds are distinguished:[3]

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. They continue to increase in number and size throughout
adulthood, although limits exist as to how big they get.

Medical complications
Dermal neurofibromas can lead to stinging, itching, pain, and disfiguration.

No evidence of malignant transformation has been found.[1]

Dermal neurofibroma in a person whose lesions first appeared when he was a teenager
Plexiform neurofibroma
Anatomy
Plexiform neurofibromas can grow from nerves in the skin or from more internal
nerve bundles, and can be very large. 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.

Age of onset

Image of neurofibroma showing myxoid appearance

Plexiform neurofibromas occur earlier in life and are thought to be congenital
defects.[3]

Medical complications
Plexiform neurofibroma can cause disfigurement, neurological, and other clinical
deficits.

Plexiform neurofibromas have the potential to cause severe clinical complications

if they occur in certain areas.[4]

About 10% of plexiform neurofibromas undergo transformation into a malignant

peripheral nerve sheath tumor.[5] 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.

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

Neurofibromin 1 gene

This picture illustrates the structure of the NF1 gene product, neurofibromin 1.
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.
The NF1 gene is composed of 60 exons spanning 350kb of genomic data, and maps to
chromosomal region 17qll.2.[6] 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.[7] 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.[8]

Schwann cells
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.

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.[9]

Loss of tumor suppressor function

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.

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.

Dermal and plexiform neurofibromas differ in later development stages, but the
details are unclear at this point.[7]

Diagnosis

Histopathologic image of cutaneous neurofibroma obtained by biopsy

A blood test for protein melanoma inhibitory activity may be used to detect the
presence of neurofibromas.[10][11]

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.� [12]

Plexiform neurofibroma
Surgery
As of 2002, the primary treatment option for plexiform neurofibroma was surgery.
[13]

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.�
[14]
A neurofibroma on the left ventricle. The neurofibroma was removed and the
patient�s mitral valve had to be replaced.[15]
A 14-year-old girl with NF1 was diagnosed with a neurofibroma involving her
bladder, a rare location.[16]
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.[17]

Medications
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.[18]

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.[19] [20]

Research
The many drug therapies under study for neurofibromas[21][22] are in various stages
of research; more time will be required to determine if these are viable options
for the treatment of neurofibromas.
The combination of erlotinib with sirolimus is being studied to treat low-grade
gliomas.[23]

Early research has shown potential for using the c-kit tyrosine kinase blocking
properties of imatinib to treat plexiform neurofibromas.[24][25] [26]

Peginterferon alfa-2b is being studied to treat plexiform neurofibromas.[27][28]

[29][30][31]

Sirolimus is an antibiotic developed as an antifungal agent. It inhibits mTOR

signalling. It is being studied to treat plexiform neurofibromas.[32][33]

Sorafenib is being studied for treatment of unresectable plexiform neurofibroma and

low-grade astrocytomas.[34][35][36][37]

In vitro, tranilast, inhibits growth of neurofibroma cells.[38]

Gene therapy for the neurofibromin 1 gene represents the ultimate solution to
preventing the cluster of maladies which are enabled by the mutation.[39][40] As of
2006, therapy for NF1 tumors had not been tested due to the lack of an appropriate
NF1 tumor model.[41]

See also
Malignant peripheral nerve sheath tumor
Neurofibromatosis
Neurofibromin
Genetic disorder
Watson syndrome
Proteus syndrome
RASopathy
Palisaded encapsulated neuroma