Neurofibroma
Encyclopedia
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
.. 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.
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
. This gene codes for neurofibromin which is a large 220-250 KDa cytoplasm
ic 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. 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. 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.
(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.”
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.
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.
.
s in the skin
, plexiform neurofibromas can grow from nerve
s 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. In addition, about 10% of plexiform neurofibromas undergo malignant transformation. This transformation turns the plexiform neurofibroma into a malignant peripheral nerve sheath tumor (MPNST).
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.”
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. These examples serve to illustrate that plexiform neurofibromas can form anywhere and can make surgical resection difficult.
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.
Erlotinib
The combination of Erlotinib
with Sirolimus
is being studied to treat low-grade glioma
s.
Imatinib
Early research has shown potential for using the c-kit tyrosine kinase blocking properties of Imatinib
to treat plexiform neurofibromas.
Pegylated Interferon
Peginterferon alfa-2b
is being studied to treat plexiform neurofibromas.
Sirolimus
Sirolimus
is an antibiotic developed as an antifungal agent. It inhibits mTOR signalling. It is being studied to treat plexiform neurofibromas.
Sorafenib
Sorafenib
is being studied for treatment of unresectable plexiform neurofibroma and low-grade astrocytoma
s.
Tranilast
In vitro
, Tranilast
, inhibits growth of neurofibroma cells.
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.
In a letter to the editor of the Annals of Surgical Oncology by Dr. Hamid Namazi in 2008, ACE inhibitor
s 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.
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.
Gene therapy
for the neurofibromin 1
gene represents the ultimate solution to preventing the cluster of maladies which are enabled by the mutation.
As of 2006, therapy for NF1 tumors had not been tested due to the lack of an appropriate NF1 tumor model.
, 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.
Nerve sheath tumor
A nerve sheath tumor is a type of tumor of the nervous system which is made up primarily of the myelin surrounding nerves.A peripheral nerve sheath tumor is a nerve sheath tumor in the peripheral nervous system....
in the peripheral nervous system. Usually found in individuals with neurofibromatosis type I
Neurofibromatosis type I
Neurofibromatosis type I , formerly known as von Recklinghausen disease after the researcher who first documented the disorder, is a human genetic disorder. It is possibly the most common inherited disorder caused by a single gene...
(NF1), an autosomal dominant genetically-inherited disease
Genetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....
, 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
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
of the NF1 gene that codes for the protein neurofibromin
Neurofibromin 1
Neurofibromin 1 also known as neurofibromatosis-related protein NF-1 is a protein that in humans is encoded by the NF1 gene. Mutations in the NF1 gene are associated with neurofibromatosis type I .- Function :NF1 encodes the protein neurofibromin, which appears to be a negative regulator of the...
.. This protein is responsible for regulating the RAS-mediated cell growth pathway. In contrast to schwannomas
Schwannomas
A schwannoma is a benign nerve sheath tumor composed of Schwann cells, which normally produce the insulating myelin sheath covering peripheral nerves....
, 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.
Genetics and Intracellular Signaling
Neurofibromin
Neurofibromin can refer to one of two different proteins:* Neurofibromin 1* Neurofibromin 2...
. The NF1 gene is composed of 60 exons spanning 350kb of genomic data, and maps to chromosomal region 17qll.2
CCL7
Chemokine ligand 7 is a small cytokine known as a chemokine that was previously called monocyte-specific chemokine 3 . Due to CCL7 possessing two adjacent N-terminal cysteine residues in its mature protein, it is classified among the subfamily of chemokines known as CC chemokines. CCL7...
. This gene codes for neurofibromin which is a large 220-250 KDa cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
ic protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
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
GTPase activating protein
GTPase-Activating Proteins, or GAPs, or GTPase-Accelerating Proteins are a family of regulatory proteins whose members can bind to activated G proteins and stimulate their GTPase activity, with the result of terminating the signaling event...
, 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
C-Raf
RAF proto-oncogene serine/threonine-protein kinase also known as proto-oncogene c-RAF or simply c-Raf is an enzyme that in humans is encoded by the RAF1 gene. The c-Raf protein functions in the MAPK/ERK signal transduction pathway as part of a protein kinase cascade...
, ERK1/2
Extracellular signal-regulated kinases
In molecular biology, extracellular-signal-regulated kinases or classical MAP kinases are widely expressed protein kinase intracellular signalling molecules that are involved in functions including the regulation of meiosis, mitosis, and postmitotic functions in differentiated cells...
, PI3K
Phosphoinositide 3-kinase
Phosphatidylinositol 3-kinases are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer. In response to lipopolysaccharide, PI3K phosphorylates p65, inducing...
, PAK
PAK1
Serine/threonine-protein kinase PAK 1 is an enzyme that in humans is encoded by the PAK1 gene.-Interactions:PAK1 has been shown to interact with C-Raf, NCK1, LIMK1, RAC1, ARHGEF2, BMX, ARPC1B, DYNLL1, Cyclin-dependent kinase 5, PAK1IP1 and CDC42....
and mTOR-S6 kinase
Mammalian target of rapamycin
The mammalian target of rapamycin also known as mechanistic target of rapamycin or FK506 binding protein 12-rapamycin associated protein 1 is a protein which in humans is encoded by the FRAP1 gene...
. It is suspected that this increased activity of downstream RAS pathways might work together to increase cell growth and survival. Genes that code for proteins that regulate cell growth, such as NF1
Neurofibromin 1
Neurofibromin 1 also known as neurofibromatosis-related protein NF-1 is a protein that in humans is encoded by the NF1 gene. Mutations in the NF1 gene are associated with neurofibromatosis type I .- Function :NF1 encodes the protein neurofibromin, which appears to be a negative regulator of the...
and TP53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
, 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. While one defective allele may be inherited, loss of heterozygosity
Loss of heterozygosity
Loss of heterozygosity in a cell is the loss of normal function of one allele of a gene in which the other allele was already inactivated. This term is mostly used in the context of oncogenesis; after an inactivating mutation in one allele of a tumor suppressor gene occurs in the parent's germline...
(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 systemPeripheral nervous system
The peripheral nervous system consists of the nerves and ganglia outside of the brain and spinal cord. The main function of the PNS is to connect the central nervous system to the limbs and organs. Unlike the CNS, the PNS is not protected by the bone of spine and skull, or by the blood–brain...
(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
Group C nerve fiber
-Location:C fibers are found in the peripheral nerves of the somatic sensory system. They are afferent fibers, conveying input signals from the periphery to the central nervous system.-Structure:...
. 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.”
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
Hyperplasia
Hyperplasia means increase in number of cells/proliferation of cells. It may result in the gross enlargement of an organ and the term is sometimes mixed with benign neoplasia/ benign tumor....
, 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
Stem cell factor
Stem Cell Factor is a cytokine that binds to the c-Kit receptor . SCF can exist both as a transmembrane protein and a soluble protein...
, and angiogenic factors such as the heparin-binding growth factor midkine
Midkine
Midkine also known as neurite growth-promoting factor 2 is a protein that in humans is encoded by the MDK gene....
. 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
Nerve growth factor
Nerve growth factor is a small secreted protein that is important for the growth, maintenance, and survival of certain target neurons . It also functions as a signaling molecule. It is perhaps the prototypical growth factor, in that it is one of the first to be described...
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.
Once a plexiform neurofibroma has formed, there is a chance that it will undergo transformation into a malignant peripheral nerve sheath tumor
Malignant peripheral nerve sheath tumor
A malignant peripheral nerve sheath tumor is a form of cancer of the connective tissue surrounding nerves. Given its origin and behavior it is classified as a sarcoma...
(MPNST). The formation of malignant cancers from neurofibromas is associated with the loss of expression of the CDKN2A
CDKN2A
CDKN2A can refer to:* P16 * p14arf...
or TP53 gene in non-myelinating Schwann cells that also exhibit biallelic inactivation of the NF1 gene.
Subtypes of Neurofibromas
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 transformationMalignant transformation
Malignant transformation is the process by which cells acquire the properties of cancer. This may occur as a primary process in normal tissue, or secondarily as malignant degeneration of a previously existing benign tumor....
.
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 nerveNerve
A peripheral nerve, or simply nerve, is an enclosed, cable-like bundle of peripheral axons . A nerve provides a common pathway for the electrochemical nerve impulses that are transmitted along each of the axons. Nerves are found only in the peripheral nervous system...
s in the skin
Skin
-Dermis:The dermis is the layer of skin beneath the epidermis that consists of connective tissue and cushions the body from stress and strain. The dermis is tightly connected to the epidermis by a basement membrane. It also harbors many Mechanoreceptors that provide the sense of touch and heat...
, plexiform neurofibromas can grow from nerve
Nerve
A peripheral nerve, or simply nerve, is an enclosed, cable-like bundle of peripheral axons . A nerve provides a common pathway for the electrochemical nerve impulses that are transmitted along each of the axons. Nerves are found only in the peripheral nervous system...
s in the skin
Skin
-Dermis:The dermis is the layer of skin beneath the epidermis that consists of connective tissue and cushions the body from stress and strain. The dermis is tightly connected to the epidermis by a basement membrane. It also harbors many Mechanoreceptors that provide the sense of touch and heat...
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. In addition, about 10% of plexiform neurofibromas undergo malignant transformation. 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.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 surgicalSurgery
Surgery is an ancient medical specialty that uses operative manual and instrumental techniques on a patient to investigate and/or treat a pathological condition such as disease or injury, or to help improve bodily function or appearance.An act of performing surgery may be called a 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
Malignant transformation
Malignant transformation is the process by which cells acquire the properties of cancer. This may occur as a primary process in normal tissue, or secondarily as malignant degeneration of a previously existing benign tumor....
. 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.”
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
Segmental resection
Segmental resection is a surgical procedure to remove part of an organ or gland. It may also be used to remove a tumor and normal tissue around it. In lung cancer surgery, segmental resection refers to removing a section of a lobe of the lung.- External links :* entry in the public domain NCI...
(partial removal) of a neurofibroma on the left ventricle
Left ventricle
The left ventricle is one of four chambers in the human heart. It receives oxygenated blood from the left atrium via the mitral valve, and pumps it into the aorta via the aortic valve.-Shape:...
. The neurofibroma was removed and the patient’s mitral valve
Mitral valve
The mitral valve is a dual-flap valve in the heart that lies between the left atrium and the left ventricle...
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. 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 chemotherapyChemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
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.
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.”Drug therapies
There are many drug therapies under study for neurofibromas. These are in various stages of research; more time will be required to determine if these are viable options for the treatment of neurofibromas.ErlotinibErlotinibErlotinib hydrochloride is a drug used to treat non-small cell lung cancer, pancreatic cancer and several other types of cancer. It is a reversible tyrosine kinase inhibitor, which acts on the epidermal growth factor receptor . It is marketed in the United States by Genentech and OSI...
(Tarceva) with SirolimusSirolimusSirolimus , also known as rapamycin, is an immunosuppressant drug used to prevent rejection in organ transplantation; it is especially useful in kidney transplants. A macrolide, sirolimus was first discovered as a product of the bacterium Streptomyces hygroscopicus in a soil sample from Easter...
The combination of Erlotinib
Erlotinib
Erlotinib hydrochloride is a drug used to treat non-small cell lung cancer, pancreatic cancer and several other types of cancer. It is a reversible tyrosine kinase inhibitor, which acts on the epidermal growth factor receptor . It is marketed in the United States by Genentech and OSI...
with Sirolimus
Sirolimus
Sirolimus , also known as rapamycin, is an immunosuppressant drug used to prevent rejection in organ transplantation; it is especially useful in kidney transplants. A macrolide, sirolimus was first discovered as a product of the bacterium Streptomyces hygroscopicus in a soil sample from Easter...
is being studied to treat low-grade glioma
Glioma
A glioma is a type of tumor that starts in the brain or spine. It is called a glioma because it arises from glial cells. The most common site of gliomas is the brain.-By type of cell:...
s.
ImatinibImatinibImatinib is a drug used to treat certain types of cancer. It is currently marketed by Novartis as Gleevec or Glivec as its mesylate salt, imatinib mesilate . It is used in treating chronic myelogenous leukemia , gastrointestinal stromal tumors and some other diseases...
(Gleevec)
Early research has shown potential for using the c-kit tyrosine kinase blocking properties of Imatinib
Imatinib
Imatinib is a drug used to treat certain types of cancer. It is currently marketed by Novartis as Gleevec or Glivec as its mesylate salt, imatinib mesilate . It is used in treating chronic myelogenous leukemia , gastrointestinal stromal tumors and some other diseases...
to treat plexiform neurofibromas.
Pegylated InterferonInterferonInterferons are proteins made and released by host cells in response to the presence of pathogens—such as viruses, bacteria, or parasites—or tumor cells. They allow communication between cells to trigger the protective defenses of the immune system that eradicate pathogens or tumors.IFNs belong to...
(Peg-Intron)
Peginterferon alfa-2b
Peginterferon alfa-2b
Pegylated interferon alfa-2b is a treatment for hepatitis C developed by Schering-Plough, brand name is PegIntron.It was approved in January 2001....
is being studied to treat plexiform neurofibromas.
SirolimusSirolimusSirolimus , also known as rapamycin, is an immunosuppressant drug used to prevent rejection in organ transplantation; it is especially useful in kidney transplants. A macrolide, sirolimus was first discovered as a product of the bacterium Streptomyces hygroscopicus in a soil sample from Easter...
(Rapamycin)
Sirolimus
Sirolimus
Sirolimus , also known as rapamycin, is an immunosuppressant drug used to prevent rejection in organ transplantation; it is especially useful in kidney transplants. A macrolide, sirolimus was first discovered as a product of the bacterium Streptomyces hygroscopicus in a soil sample from Easter...
is an antibiotic developed as an antifungal agent. It inhibits mTOR signalling. It is being studied to treat plexiform neurofibromas.
SorafenibSorafenibSorafenib , is a drug approved for the treatment of primary kidney cancer and advanced primary liver cancer ....
(Nexavar)
Sorafenib
Sorafenib
Sorafenib , is a drug approved for the treatment of primary kidney cancer and advanced primary liver cancer ....
is being studied for treatment of unresectable plexiform neurofibroma and low-grade astrocytoma
Astrocytoma
Astrocytomas are a type of neoplasm of the brain. They originate in a particular kind of glial-cells, star-shaped brain cells in the cerebrum called astrocytes. This type of tumor does not usually spread outside the brain and spinal cord and it does not usually affect other organs...
s.
TranilastTranilastTranilast is an antiallergic drug. It was developed by Kissei Pharmaceuticals and was approved in 1982 for use in Japan and South Korea for bronchial asthma...
(Rizaben)
In vitro
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
, Tranilast
Tranilast
Tranilast is an antiallergic drug. It was developed by Kissei Pharmaceuticals and was approved in 1982 for use in Japan and South Korea for bronchial asthma...
, inhibits growth of neurofibroma cells.
PirfenidonePirfenidonePirfenidone is a drug developed by InterMune Inc. for the treatment of idiopathic pulmonary fibrosis. In 2011 it was approved for use in Europe for idiopathic pulmonary fibrosis under the trade name Esbriet. The proposed trade name in the US is also Esbriet.In Japan it is marketed as Pirespa by...
Pirfenidone
Pirfenidone
Pirfenidone is a drug developed by InterMune Inc. for the treatment of idiopathic pulmonary fibrosis. In 2011 it was approved for use in Europe for idiopathic pulmonary fibrosis under the trade name Esbriet. The proposed trade name in the US is also Esbriet.In Japan it is marketed as Pirespa by...
inhibits fibroblast
Fibroblast
A fibroblast is a type of cell that synthesizes the extracellular matrix and collagen, the structural framework for animal tissues, and plays a critical role in wound healing...
growth. Studies showed no improvement over controls.
TipifarnibTipifarnibTipifarnib is a farnesyltransferase inhibitor that is being investigated in patients 65 years of age and older with newly diagnosed acute myeloid leukemia . It inhibits the Ras kinase in a post translational modification step before the kinase pathway becomes hyperactive...
Tipifarnib
Tipifarnib
Tipifarnib is a farnesyltransferase inhibitor that is being investigated in patients 65 years of age and older with newly diagnosed acute myeloid leukemia . It inhibits the Ras kinase in a post translational modification step before the kinase pathway becomes hyperactive...
(also known as drug R115777) inhibits the activation of RAS. This drug is a Farnesyltransferase inhibitor
Farnesyltransferase inhibitor
The farnesyltransferase inhibitors are a class of experimental cancer drugs that target protein farnesyltransferase with the downstream effect of preventing the proper functioning of the Ras , which is commonly abnormally active in cancer....
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.
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 inhibitor
ACE inhibitor
ACE inhibitors or angiotensin-converting enzyme inhibitors are a group of drugs used primarily for the treatment of hypertension and congestive heart failure...
s 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
TGF beta
Transforming growth factor beta is a protein that controls proliferation, cellular differentiation, and other functions in most cells. It plays a role in immunity, cancer, heart disease, diabetes, Marfan syndrome, and Loeys–Dietz syndrome....
, which is a growth factor that has been shown to influence the development of tumors.
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.
Gene therapy (status as of 2006)
Gene therapy
Gene therapy
Gene therapy is the insertion, alteration, or removal of genes within an individual's cells and biological tissues to treat disease. It is a technique for correcting defective genes that are responsible for disease development...
for the neurofibromin 1
Neurofibromin 1
Neurofibromin 1 also known as neurofibromatosis-related protein NF-1 is a protein that in humans is encoded by the NF1 gene. Mutations in the NF1 gene are associated with neurofibromatosis type I .- Function :NF1 encodes the protein neurofibromin, which appears to be a negative regulator of the...
gene represents the ultimate solution to preventing the cluster of maladies which are enabled by the mutation.
As of 2006, therapy for NF1 tumors had not been tested due to the lack of an appropriate NF1 tumor model.
Notable Cases
Joseph Merrick, also known as the Elephant ManJoseph Merrick
Joseph Carey Merrick , sometimes incorrectly referred to as John Merrick, was an English man with severe deformities who was exhibited as a human curiosity named the Elephant Man. He became well known in London society after he went to live at the London Hospital...
, 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
Proteus syndrome
Proteus syndrome, also known as Wiedemann's syndrome , is a congenital disorder that causes skin overgrowth and atypical bone development, often accompanied by tumors over half the body....
not Neurofibromatosis as had been previously reported.
See also
- Malignant peripheral nerve sheath tumorMalignant peripheral nerve sheath tumorA malignant peripheral nerve sheath tumor is a form of cancer of the connective tissue surrounding nerves. Given its origin and behavior it is classified as a sarcoma...
- NeurofibromatosisNeurofibromatosisNeurofibromatosis is a genetically-inherited disorder in which the nerve tissue grows tumors that may be benign or may cause serious damage by compressing nerves and other tissues...
- NeurofibrominNeurofibrominNeurofibromin can refer to one of two different proteins:* Neurofibromin 1* Neurofibromin 2...
- Genetic disorderGenetic disorderA genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....
- Watson syndromeWatson syndromeWatson syndrome is an autosomal recessive condition characterized by Lisch nodules, axillary/inguinal freckling, and neurofibromas.Watson syndrome may be allelic to NF1, the same gene associated with Neurofibromatosis type 1.- References :...