Neurofibroma

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sara Mohsin, M.D.[2], Kiran Singh, M.D. [3], Shanshan Cen, M.D. [4]

Synonyms and keywords: Endoneural fibroma, Myxofibroma of nerve sheath, Neurofibromyxoma, Perineural fibroblastoma, Perineural fibroma

Overview

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sara Mohsin, M.D.[2], Shanshan Cen, M.D. [3]

Overview

Neurofibromas are benign nerve sheath tumors of neural origin in peripheral nervous system, comprising all elements of the peripheral nerve (i.e. axons, Schwann cells and fibroblasts) and can occur anywhere in the body. Neurofibromas may occur as part of the syndrome of neurofibromatosis (most common), solitary neurofibromas, or multiple neurofibromas without von Recklinghausen’s disease (NF-1). Neurofibroma may be classified into further subtypes such as localized, cutaneous, subcutaneous, intraneural, intramuscular, diffuse, pigmented, and plexiform neurofibroma. However, plexiform neurofibroma can be further subclassified into diffuse, and nodular plexiform neurofibroma. Gene involved in the pathogenesis of plexiform neurofibroma is NF1 which codes for neurofibromin that leads to loss of RAS control causing increased activity of downstream RAS pathways involved in increased cell growth and survival. On gross pathology, a non-encapsulated superficial mass is the characteristic finding of localized or diffuse neurofibroma; whereas the “bag of worms” appearance is the characteristic finding of plexiform neurofibroma. On microscopic histopathological analysis, nerve fibers, schwann cells, spindle cells with wavy nuclei without pleomorphism, shredded carrot collagen, moderate increase of cellularity vis-a-vis normal dermis, blood vessels, mast cells, pseudomeissnerian bodies, and varying degrees of myxoid degeneration are characteristic findings of neurofibroma. However, plexiform neurofibroma shows a characteristic target sign on histopathology. It usually affects both men and women equally between the age of 20-40 years. Common symptoms of neurofibroma include soft masses, transient itching, and transient pain with rest of the symptoms depending upon the involved site. There is no single diagnostic study of choice for neurofibroma, instead, it is diagnosed on the basis of medical history, physical examination, and imaging studies such as CT or MRI. The predominant therapy for neurofibroma is surgical resection. Adjunctive chemotherapy and medications such as ACE inhibitors may be required. Prognosis of neurofibroma is generally excellent. If left untreated, 10% of patients with plexiform neurofibromas may progress to develop malignant peripheral nerve sheath tumor (MPNST). Local recurrence occurs rarely.

Historical Perspective

NF1-like cutaneous tumor syndromes appeared in the literature in 1880s, when Friedrich von Recklinghausen published seminal observations detailing cutaneous tumors comprised of both neuronal and fibroblastic tissue finally termed as neurofibromas. In 2006, Yang et al demonstrated a critical neurofibroma microenvironment interaction that includes SCF–stimulated Nf1+/− mast cells potentiating Nf1+/− fibroblast functions.

Classification

Neurofibroma may be classified into 5 subtypes: cutaneous/dermal/localized, localized intraneural, subcutaneous, diffuse, intramuscular, plexiform and pigmented neurofibroma. Plexiform neurofibromas may be further sub-classified into diffuse and nodular plexiform.

Pathophysiology

Neurofibromas arise from the nonmyelinating-type Schwann cells. Gene involved in the pathogenesis of plexiform neurofibroma is NF1 which codes for neurofibromin that leads to loss of RAS control causing increased activity of downstream RAS pathways involved in increased cell growth and survival. Neurofibromas can occur anywhere in body. On gross pathology, a nonencapsulated superficial mass is the characteristic finding of localised or diffuse neurofibroma; whereas the “bag of worms” appearance is the characteristic finding of plexiform neurofibroma. On microscopic histopathological analysis, nerve fibers, schwann cells, spindle cells with wavy nuclei without pleomorphism, shredded carrot collagen, moderate increase of cellularity vis-a-vis normal dermis, blood vessels, mast cells, pseudomeissnerian bodies, and varying degrees of myxoid degeneration are characteristic findings of neurofibroma. However, plexiform neurofibroma shows a characteristic target sign on histopathology, representing a central core of collagenous and fibrillary tissue with peripheral less densely cellular myxoid tissue. Electron microscopy of neurofibromas shows Schwann cells enclosing axons in plasmalemmal invaginations (mesaxons).

Causes

Plexiform neurofibroma may be caused by the bi-allelic inactivation of the neurofibromatosis type I tumor suppressor gene.

Differential Diagnosis

Neurofibroma must be differentiated from schwannoma, dermatofibrosarcoma protuberans (DFSP), ganglioneuroma, dermal neurotized melanocytic nevus, myxoid liposarcoma, solitary circumscribed neuroma, traumatic neuroma, superficial angiomyxoma, nerve sheath myxoma, malignant peripheral nerve sheath tumor, spindle cell lipoma, leiomyoma, inflammatory myofibroblastic tumor, and fibroepithelial polyp.

Epidemiology and Demographics

Neurofibroma usually occurs between 20-40 years of age, and affects men and women equally. However, plexiform neurofibromas are thought to be congenital defects, hence, they occur earlier in life.

Risk Factors

Neurofibromatosis 1 and Neurofibromatosis 2 are the most common risk factors for development of neurofibromas.

Screening

According to the the U.S. Preventive Service Task Force (USPSTF), there is insufficient evidence to recommend routine screening for neurofibroma.

Natural History, Complications and Prognosis

Prognosis of neurofibroma is generally excellent. If left untreated, 10% of patients with plexiform neurofibromas may progress to develop malignant peripheral nerve sheath tumor (MPNST). Local recurrence occurs rarely.

Diagnosis

Diagnostic Study of Choice

There is no single diagnostic study of choice for neurofibroma, instead, it is diagnosed on the basis of medical history, physical examination, and imaging studiessuch as CT or MRI.

Staging

There is no established system for the staging of neurofibroma.

X Ray

There are no X-ray findings associated with neurofibroma.

CT Scan

CT scan may be helpful in the diagnosis of neurofibroma. Findings on CT scan suggestive of neurofibroma include a well-defined, round or oval hypodense, fusiform mass representing the nerve entering and exiting the tumor. Low attenuation is attributed to high lipid or water content within the mucinous matrix, entrapment of perineural adipose tissue and cystic degeneration.

MRI

MRI may be helpful in the diagnosis of neurofibroma. It appears as a hypointense, homogeneous low signal intensity lesion with center demonstrating a higher signal intensity than the periphery on T1. T2 weighted images show hyperintense, homogeneous lesion with positive target sign and fascicular sign. Moreover, neurofibromas have heterogeneous enhancement on T1 C+ (Gd) (with gadolinium contrast).

Ultrasound

There are no ultrasound findings associated with neurofibroma.

Other Imaging Findings

There are no other imaging findings associated with neurofibroma.

Other Diagnostic Studies

There are no other diagnostic study findings associated with neurofibroma.

Biopsy

Biopsy is helpful in the diagnosis of neurofibroma.

Treatment

Medical Therapy

The predominant therapy for neurofibroma is surgical resection. Adjunctive chemotherapy and medications such as ACE inhibitors may be required.

Surgery

Surgery is the mainstay of treatment for neurofibroma. Localized and diffuse lesions are usually treated surgically. Neurofibromas that infiltrate between nerve fascicles are unable to be separated from the parent nerve, therefore, deep-seated lesions are often managed conservatively. Local recurrence after excision is uncommon .and malignant transformation occurs rarely.

Primary Prevention

There is no established method for primary prevention of neurofibroma.

Secondary Prevention

There are no secondary preventive measures available for neurofibroma.

References

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Historical Perspective

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sara Mohsin, M.D.[2]

Overview

NF1-like cutaneous tumor syndromes appeared in the literature in 1880s, when Friedrich von Recklinghausen published seminal observations detailing cutaneous tumors comprised of both neuronal and fibroblastic tissue finally termed as neurofibromas. In 2006, Yang et al demonstrated a critical neurofibroma microenvironment interaction that includes SCF–stimulated Nf1+/− mast cells potentiating Nf1+/− fibroblast functions.

Historical Perspective

In 18th century, NF1-like cutaneous tumor syndromes appeared in the literature.^[1]
In 1880s, Friedrich von Recklinghausen published seminal observations detailing cutaneous tumors comprised of both neuronal and fibroblastic tissue finally termed as neurofibromas.
In 2006, Yang et al demonstrated a critical neurofibroma microenvironment interaction that includes SCF–stimulated Nf1+/− mast cells potentiating Nf1+/− fibroblast functions.^[2]

References

↑ Morse RP (1999). “Neurofibromatosis type 1”. Arch Neurol. 56 (3): 364–5. PMID 10190829.
↑ Staser, Karl; Yang, Feng-Chun; Clapp, D. Wade (2010). “Mast cells and the neurofibroma microenvironment”. Blood. 116 (2): 157–164. doi:10.1182/blood-2009-09-242875. ISSN 0006-4971.

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Classification

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sara Mohsin, M.D.[2]

Overview

Neurofibroma may be classified into 5 subtypes: cutaneous/dermal/localized, localized intraneural, subcutaneous, diffuse, intramuscular, plexiform and pigmented neurofibroma. Plexiform neurofibromas may be further sub-classified into diffuse and nodular plexiform.

Classification

Neurofibroma may be classified into following subtypes:^[1]^[2]


Types of neurofibromas	Characteristics/Description
Cutaneous/Dermal/Localized/Sporadic neurofibroma (90%)	Most common type Circumscribed but not encapsulated Permeative growth in nerve quickly proceeds to diffuse infiltration of surrounding soft tissue Occurs as lumps or bumps on skin Painless Slowly growing Often in dermis and subcutaneous ≤2-5 cm in diameter Arise from small cutaneous nerves Overrun axons may be identified within May contain fat Starts in teenage years or young adults and rarely starts in childhood Increases in size and number over the years Clearly defined borders hence, can be removed if necessary Number of skin tumors in each patient varies tremendously Mostly solitary and sporadic, not associated with NF1 Malignant transformation very rare
Localized Intraneural neurofibroma	Second-most common type Segmental, fusiform nerve enlargement Residual axons traverse through lesion Neurofilament immunohistochemistry and Bielshowsky stain show axons within center of lesion Often contains coarse, refractile collagen Malignant change infrequent
Subcutaneous neurofibroma	Common Present underneath the skin Can be single tumors or chains They are often a form of plexiform neurofibromas
Diffuse neurofibroma (superficial)	Superficial Uncommon Feels soft and squishy Most common in head (scalp) and neck region or trunk (often protruding out, like a “love handle”) Ill defined margins, can’t tell where tumor stops Runs through the full skin thickness (from the surface all the way down to the base of the skin (subcutaneous fascia/fat) Doesn’t go deeper than fascia Nondestructive, envelops normal structures (e.g., fat cells and adenexal structures) Uniform matrix of fine, fibrillary collagen Shorter, rounder Schwann cells Clusters of pseudo-meissnerian body-like structures may be seen Usually seen in early childhood and young adults Usually associated with diffuse hyperpigmentation, so looks like a very large squishy café au lait spot Solitary lesions and not related to any inherited condition (rarely associated with NF1) Rare malignant change
Intramuscular neurofibroma	Common Usually isolated tumors in the muscle Growths along very small nerves Causes pain sometimes Can be removed (leaves a scar behind) Sometimes can occur as plexiform neurofibromas in form of chains or networks
Plexiform neurofibroma (deep)	Deep Associated with NF1 Diffuse involvement along a large nerve and its branches Mostly internal/ intraneural Can also involve small nerves and superficial skin Have more connective tissue/extracellular matrix than cutaneous neurofibromas, that separates the nerve fibers Gross enlargement of the nerve with nodular tumor development results in the gross pathologic appearance referred to as “bag of worms” Generally believed to be present at birth (congenital) Disfiguring Affects function due to sheer size as well as neurovascular compromise Upto 5% risk of malignant transformation Plexiform neurofibroma exhibits following features on T2-weighted MRI: Target sign (low signal intensity centrally with a ring of high signal intensity peripherally) Fascicular sign May appear as a larger and more infiltrating mass with lobulated borders with inhomogeneous enhancement
Pigmented neurofibroma	Neurofibroma with melanin-bearing pigmented cells, usually only appreciated microscopically Not considered a true subtype No increased risk of malignant transformation

Plexiform neurofibromas can be further subclassified into following:


Types of neurofibromas	Characteristics/Description
Diffuse Plexiform neurofibroma	It extends through the skin into fascia and muscle Lacks clear margins Has “little fingers” that invade muscle or other tissue May not be easy to see in infants May have a large café au lait spot “above” it
Nodular Plexiform neurofibroma	Usually involves nerves coming off the spinal cord or off of larger nerves (such as sciatic nerve) Usually enlarges or thickens the nerve Looks like little clusters of tumors along the nerve

References

↑ Wilkinson, Lana M.; Manson, David; Smith, Charles R. (2004). “Best Cases from the AFIP”. RadioGraphics. 24 (suppl_1): S237–S242. doi:10.1148/rg.24si035170. ISSN 0271-5333.
↑ https://pubs.rsna.org/doi/10.1148/rg.24si035170#REF8

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Pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sara Mohsin, M.D.[2]Shanshan Cen, M.D. [3]

Overview

Neurofibromas arise from the nonmyelinating-type Schwann cells and can occur anywhere in the body. Gene involved in the pathogenesis of plexiform neurofibroma is NF1 which codes for neurofibromin that leads to loss of RAS control causing increased activity of downstream RAS pathways involved in increased cell growth and survival. Plexiform neurofibroma may be caused by the bi-allelic inactivation of the neurofibromatosis type I tumor suppressor gene. On gross pathology, a nonencapsulated superficial mass is the characteristic finding of localised or diffuse neurofibroma; whereas the “bag of worms” appearance is the characteristic finding of plexiform neurofibroma. On microscopic histopathological analysis, nerve fibers, schwann cells, spindle cells with wavy nuclei without pleomorphism, shredded carrot collagen, moderate increase of cellularity vis-a-vis normal dermis, blood vessels, mast cells, pseudomeissnerian bodies, and varying degrees of myxoid degeneration are characteristic findings of neurofibroma. However, plexiform neurofibroma shows a characteristic target sign on histopathology, representing a central core of collagenous and fibrillary tissue with peripheral less densely cellular myxoid tissue. Electron microscopy of neurofibromas shows Schwann cells enclosing axons in plasmalemmal invaginations (mesaxons).

Pathogenesis

Neurofibromas arise from the nonmyelinating-type Schwann cells.^[1]^[2]^[3]
Plexiform neurofibromas can grow from nerves in the skin or from more internal nerve bundles, and can be very large.
About 10% of plexiform neurofibromas undergo transformation into a malignant peripheral nerve sheath tumor (MPNST).^[4]
In 2006, Yang et al demonstrated a critical neurofibroma microenvironment interaction that includes SCF–stimulated Nf1+/− mast cells potentiating Nf1+/− fibroblast functions.^[5]
Nearly one-half of the dry tumor weight is made up of collagen secreted by fibroblasts, which comprise the major cellular portion of neurofibroma.
Fibroblasts migrate, proliferate, and synthesize collagen in response to transforming growth factor β (TGF-β).
Fibroblast bioactivity is TGF-β dependent.
Nf1+/− mast cell is the critical effector in the paracrine induction of neurofibroma pathogenesis.
TGF-β–dependent Nf1+/− fibroblast hyperactivity is a result of increased kinase activity of c-abl secondary to increased Ras–GTP.

Genetics

Gene involved in the pathogenesis of plexiform neurofibroma is NF1.
The NF1 gene is composed of 60 exons spanning 350kb of genomic data, and maps to chromosomal region 17q11.2.^[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 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, MAPK, SCF/c-kit and mTOR-S6 kinase. It is suspected that this increased activity of downstream RAS pathways might work together to increase cell growth and survival.^[7]^[8]

Gross Pathology

Neurofibromas can occur anywhere in body. Gross features of different types of neurofibromas include the following:

Localised neurofibroma and Diffuse neurofibroma

Superficial mass
Not encapsulated

Soft tissue neurofibroma

Not encapsulated, softer (more gelatinous) than schwannoma.
Superficial tumors are small, pedunculated nodules protruding from skin (molluscum pendulum).
Deeper tumors are larger, may cause tortuous enlargement of peripheral nerves (plexiform neurofibromas).

Plexiform neurofibroma

“Bag of worms” appearance^[9]
Associated with grossly enlarged and tortuous nerves
Deep tumors are often large
Highly vascularized and locally invasive

Microscopic Pathology

Made of nerve fibers, schwann cells (cells that cover the nerve fibers), blood vessels, inflammatory white blood cells (mast cells), and connective tissue (fibroblasts and loose material called extracellular matrix)
Multiple enlarged fascicles of randomly oriented thin spindled nerve sheath cells are embeded in a stromal mucin and wire-like collageneous matrix within fibrous connective tissue^[2]
Spindle cells have hyperchromatic, elongated, wavy, buckled, small and bland nuclei with indistinct scant cytoplasm
No pleomorphism
Tactile-like bodies are also detected
Varying degrees of myxoid degeneration
Unencapsulated
Moderate increase of cellularity vis-a-vis normal dermis
Uniphasic, low to moderate cellularity (generally hypocellular)
Occasional mast cells, and lymphocytes, rare foam cells.^[3]
Thin and thick collagen strands (“shredded carrot collagen”)
Nerve fibers run through a neurofibroma (making excision more difficult with increased likelihood of nerve damage)
Nerve frequently not grossly identifiable
Features of specific differentiation (e.g. pseudomeissnerian bodies) may be present occassionally
Low mitotic index
No clear division between Antoni A and B areas within the tumor
No well formed verocy bodies
No epithelial component
No distinct lobulation
Seldom cystic
Cellularity and organization are generally insufficient to produce palisading

Neurofibroma with Degenerative Atypia (“Ancient change”)

Localized hyperchromatic atypical cells (“ancient change“) with:
- Large, pleomorphic nuclei
- Cytoplasmic intranuclear inclusions
- Smudgy chromatin
- Inconspicuous nucleoli
Absent or very low mitotic activity
Low to moderate cellularity
Often large, long standing lesions

Soft tissue neurofibromas

Proliferation of all elements of peripheral nerves.
Schwann cells with wire like collagen fibrils (wavy serpentine nuclei, pointed ends), stromal mucosubstances, mast cells, Wagner-Meissner corpuscles, Pacinian corpuscles, axons (highlight with silver or acetylcholinesterase stain, NSE, neurofilament), fibroblasts and collagen.
Perineurial cells in plexiform types, mitotic figures are rare.
Less of a fascicular pattern than fibromatosis.
May be infiltrative, have myxoid areas, contain melanin pigment, have epitheloid morphology.
Rarely has skeletal differentiation (neuromuscular hamartoma).
No Verocay bodies
No nuclear palisading
No hyalinized thickening of vessel walls

Plexiform neurofibromas

Nodular or diffuse
Diffuse cases are also known as elephantiasis neurofibromatosa; characterized by an overgrowth of epidermal and subcutaneous tissue.
Hypocellular with myxoid background; contains Schwann cells, fibroblasts and mast cells
Occasional nuclear palisading
Rarely is pigmented due to melanocytes
No biphasic pattern of schwannoma
Target sign on histopathology represents a central core made up of collagenous and fibrillary tissue with peripheral less densely cellular myxoid tissue.^[10]

Electron microscopy

Schwann cells enclose axons in plasmalemmal invaginations (mesaxons).

References

↑ 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.
↑ ^2.0 ^2.1 Bernthal, NM.; Jones, KB.; Monument, MJ.; Liu, T.; Viskochil, D.; Randall, RL. (2013). “Lost in translation: ambiguity in nerve sheath tumor nomenclature and its resultant treatment effect”. Cancers (Basel). 5 (2): 519–28. doi:10.3390/cancers5020519. PMID 24216989.
↑ ^3.0 ^3.1 Staser, K.; Yang, FC.; Clapp, DW. (2010). “Mast cells and the neurofibroma microenvironment”. Blood. 116 (2): 157–64. doi:10.1182/blood-2009-09-242875. PMID 20233971. Unknown parameter |month= ignored (help)
↑ 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.
↑ http://www.bloodjournal.org/content/116/2/157?sso-checked=true
↑ 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.
↑ 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.
↑ 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.
↑ Wilkinson LM, Manson D, Smith CR (2004). “Best cases from the AFIP: plexiform neurofibroma of the bladder”. Radiographics : a Review Publication of the Radiological Society of North America, Inc. 24 Suppl 1: S237–42. doi:10.1148/rg.24si035170. PMID 15486243. Retrieved 2015-11-13.
↑ https://pubs.rsna.org/doi/10.1148/rg.24si035170#REF8

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Causes

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sara Mohsin, M.D.[2] Shanshan Cen, M.D. [3]

Overview

Plexiform neurofibroma may be caused by the bi-allelic inactivation of the neurofibromatosis type I tumor suppressor gene.

Causes

Plexiform neurofibroma may be caused by the bi-allelic inactivation of the neurofibromatosis type I tumor suppressor gene.^[1]

References

↑ Colman SD, Williams CA, Wallace MR (1995). “Benign neurofibromas in type 1 neurofibromatosis (NF1) show somatic deletions of the NF1 gene”. Nature Genetics. 11 (1): 90–2. doi:10.1038/ng0995-90. PMID 7550323. Retrieved 2015-11-16.

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Differentiating Neurofibroma from other Diseases

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sara Mohsin, M.D.[2]

Overview

Neurofibroma must be differentiated from schwannoma, dermatofibrosarcoma protuberans (DFSP), ganglioneuroma, dermal neurotized melanocytic nevus, myxoid liposarcoma, solitary circumscribed neuroma, traumatic neuroma, superficial angiomyxoma, nerve sheath myxoma, malignant peripheral nerve sheath tumor, spindle cell lipoma, leiomyoma, inflammatory myofibroblastic tumor, and fibroepithelial polyp.

Differential Diagnosis

Neurofibroma must be differentiated from:

Schwannoma
Dermatofibrosarcoma protuberans (DFSP)
Ganglioneuroma
Dermal neurotized melanocytic nevus
Myxoid liposarcoma
Solitary circumscribed neuroma/palisaded encapsulated neuroma
Traumatic neuroma
Superficial angiomyxoma
Nerve sheath myxoma
Malignant peripheral nerve sheath tumor (MPNST)/malignant schwannoma
Spindle cell lipoma
Leiomyoma
Inflammatory myofibroblastic tumor
Fibroepithelial polyp/acrochordon (aka skin tag or soft fibroma)

Differentiating neurofibroma from other diseases
Disease entity	Etiology (Genetic or others)	Histopathological findings	Immunohistochemical staining	Risk factors	Common site of involvement	Clinical manifestations	Other associated features
Neurofibroma^[1]^[2]^[3]^[4]^[5]^[6]^[7]^[4]^[8]^[9]^[10]^[11]	Can be sporadic or as a part of Neurofibromatosis 1 and 2 NF1 gene located at chromosomal region 17q11.2, codes forneurofibromin Functional part of neurofibromin GAP (or GTPase-activating protein) accelerates the conversion of the active GTP-bound RAS to its inactive GDP-bound form Loss of RAS controlleads to increased activity of other signaling pathwaysincluding RAF, ERK1/2, PI3K, PAK, MAPK, SCF/c-kit and mTOR-S6 kinase	Uniphasic, low to moderate cellularity No peripheral perineural capsule Random pattern, only rare palisading No well formed verocy bodies Hypocellular with abundant mucinous/myxoid matrix without hypercellular areas Frequent mast cells Contains neural fibroblasts and fibrillary or shredded carrot collagen Random proliferation of Schwann cells and scattered admixed axons No nevoid cells No epithelial component Diffuse growth pattern Scant cytoplasm Wavy spindle cells with buckled nuclei Pseudomeissnerian bodies representing specific differentiation may be present Lacks storiform pattern Neurofibroma with degenerative atypia (“ancient change“) has following microscopic features: Localized cells with large pleomorphic nuclei, cytoplasmic nuclear inclusions, smudgy chromatin, and inconspicuous nuclei Absent or very low mitotic activity Low to moderate cellularity	Positive for: S100 (weaker) SOX10 Neurofilament (and Bielshowsky) GFAP CD34 (stronger) Factor XIIIa Calretinin (focal) MBP (myelin–basic protein) Negative for: EMA (except in plexiform neurofibromas)	Neurofibromatosis 1 Neurofibromatosis 2(multiple neurofibromas, meningiomas of the brainor spinal cord, and ependymomas of the spinal cord)	Can occur anywhere Diffuse neurofibromas commonly involve scalp	Soft masses/bumps on or under skin (internal or superficial) Transient itching (mast cells release histamine) Transient pain Numbness and tingling in the affected area Severe bleeding (sign of tumor growth) Physical disfiguration Cognitive disability Stinging Neurological deficits Changes in movement (clumsiness in hands, trouble walking) Bowel incontinence Scoliosis (an abnormal curvature of the spine, if the tumor creates muscular imbalance or erodes bones of the spine) Following symptoms may occur with genitourinary tract involvement (rarely): Urinary tract infection (most common clinical manifestation) Urinary retention Urinary frequency Urgency Hematuria Pelvic mass Hydronephrosis Urinary incontinence (decreased bladder capacity or compliance) Appears as a focal mass or diffuse bladder wall thickening in case of a plexiform neurofibroma	Nerve often not identified, incorporates nerve, axons often present in lesion Seldom cystic Frequently multiple Widespread soft tissue infiltration Tends to displace adnexa <2cm in diameter Lacks distinct lobulation Lacks fat Affects individuals between 20-40 years of age Men and women are equally affected Plexiform neurofibroma are thought to be congenital and occur earlier in life
Schwannoma^[12]^[13]^[14]^[15]^[16]	Loss of function of the tumor suppressor gene merlin (schwannomin) Direct genetic change involving the NF2 gene on chromosome 22 Can occur spontaneously Mutations and biallelic inactivation of SMARCB1 (spinal schwannomas)	Encapsulated Aggregates of spindled cells with indistinct cytoplasm and elongated nuclei with blunt pointed ends Ancient changes may show nuclear pleomorphism and occasionally nuclear inclusions as well Infrequent extracellular collagen Biphasic: majority entirely, and compactly hypercellular Antoni A & myxoid hypocellular Antoni B areas (may be absent in small tumors) Nuclear palisading evident around fibrillary process (Verocay bodies) in cellular areas Large, irregularly spaced vessels prominent in Antoni B areas Narrow, elongated and wavy cells with tapered ends, interspersed with collagen fibers Tumor cells with ill defined cytoplasm, dense chromatin Often displays degenerative nuclear atypia (ancient change) Rare mitotic figures Blood vessels may show gaping tortuous lumina having thickened hyalinized walls; may have thrombi Dilated vessels surrounded/invested by hemorrhage Foamy macrophages Lymphoid aggregates Amianthoid fibers or collagenous spherules: large nodular masses of collagen with radiating edges No axons except where nerve is attached Malignant transformation may have malignant epithelioid cells and rarely shows divergent differentiation as angiosarcoma-like areas	Positive for: S-100 SOX10 CD56 Podoplanin CD34 (weak) Neurofilament (and Bielshowsky) Factor XIIIa (focal) Calretinin GFAP EMA (capsule) highlights the perineural fibroblasts Laminin Type IV collagen Vimentin CD68 Negative for: Cytokeratin Desmin SMA	NF-2 associated Schwannomatosis Carney complex	Upper limbs Head and neck area (oral cavity, orbit and salivary glands) Deeply seated tumors are mainly in: Posterior mediastinum Retroperitoneum Posterior spinal roots Bone Gastrointestinal tract Pancreas Liver Thyroid Adrenal glands Lymph nodes Penis (rarely) Vulva (rarely)	Symptoms of schwannoma depend on the location of the tumor: Intracranial schwannoma: Acoustic neuroma (most common): Sensorineural hearing loss Vertigo Tinnitus Facial weakness Facial numbness and tingling Headaches Dizziness Difficulty swallowing and hoarseness Taste changes Confusion Trigeminal schwannoma: Trigeminal nerve dysfunction Facial nerve schwannoma: Facial nerve dysfunction Jugular foramen schwannoma: Hearing loss Tinnitus Dysphagia Ataxia Hoarseness Hypoglossal schwannomas: Hypoglossal nerve dysfunction Spinal schwannoma: Back pain Urinary incontinence Urinary retention Clumsiness Weakness Paresthesias Intercostal nerve schwannoma: Usually asymptomatic Intramuscular schwannoma: Painless mass	Nerve often identifiable Eccentric to nerve, axons generally absent within lesion Occasionally cystic Can cause other neoplasms including: Meningioma Mesothelioma Glioma multiforme Breast cancer Colorectal cancer Kidney (clear cell type) carcinoma Hepatocellular carcinoma Prostatic cancer Dermal cancer Affects individuals between 20-50 years of age Men and women are equally affected
Palisaded encapsulated neuroma (PEN) /solitary circumscribed neuroma^[17]	Spontaneous development RET proto-oncogene genetic mutations (inherited PEN)	Solitary dermal or subcutaneous tumor Encapsulated by perineurium Club-like extension in the subcutaneous tissue Moderately cellular lesion with proliferation of schwann cells and axons Nuclear palisading may be present Rare mast cells Silver stains show the axons traversing the Schwann cells	Positive for: EMA S100 (schwann cells) Neurofilament (axons) Collagen type IV EMA (perineurium) Neuron-specific Enolase CD57 (Leu-7) Myelin basic proteins Negative for: GFAP	Positive family history of tumor occurrence Multiple mucosal neuroma syndrome Multiple endocrine neoplasia syndrome (MEN 2B)	90% lesions affect the face involving: Eyelid Nose Oral mucosa Remaining 10% can occur anywhere in body involving: Shoulder Arm Hand Foot Glans of penis	Small, solitary, raised, dome-shaped, firm, flesh-colored painless nodule on skin Cosmetic issues due to facial involvement Scar after surgery	Benign tumor of the nerve fibers Affects middle aged people (40-60 years) No known familial association Affects females more frequently than males
Traumatic neuroma^[18]^[19]^[20]^[21]	Tangle of neural fibers and connective tissue that develops following a peripheral nerve injury Interruption in continuity of nerve causing wallerian degeneration (loss of axons in proximal stump and retraction of axons in distal segment), followed by exuberant regeneration of nerve and formation of mass of Schwann cells, axons and fibrous cells	Numerous well formed small nerve twigs Limited soft tissue infiltration Contains axons in haphazardly arranged nerves within mature collagenous scar with entrapped smooth muscle	Positive for: S100	History of trauma to a nerve (especially during a surgery) Cone biopsy (rare complication) 55% of hysterectomy patients have microneuromas, associated with childbirth	Most common oral locations are: Tongue Near mental foramen of mouth Rarely involves: Head Neck	Firm, oval, whitish, slowly growing, palpable nodule on skin (no discoloration of skin on the top of nodule) </=2cm in size Traumatic neuropathic pain with the presence of a typical trigger point in the area of a neuroma (especially with the pressure application) causing the patient to feel burning, stabbing, raw, gnawing or sickening sensations Paresthesia over the injured area Dysesthesia (painful hypersensitivity to normal light tactile stimuli) Functional impairment Psychological distress (severely decreasing the quality of life)	Also known as: Amputation neuroma Pseudoneuroma
Neurotized melanocytic nevus^[22]^[23]^[24]^[25]	Melan-A (Mart-1) gene Defect in embryologic development causing fast proliferation rate of melanocytes (during first twelve weeks of pregnancy)	Neurotized Nevus is a type of mole in which melanocytes are in the dermis with accompanying fibrosis Biphasic consisting of malignant melanoma and mature appearing neural component Superficial classic nevoid melanocytes (i.e. melanocytes appear like spindle cells resembling a nerve; and hence, called a neurotized nevus) Congenital and nested growth patterns More abundant cytoplasm Tends to surround adnexa Scattered nests of type A or B nevus cells, surrounded by basement membrane, present in the papillary dermis of lesions (otherwise indistinguishable from neurofibromas)	Positive for: S-100 MelanA (MART-1) Negative for: Factor XIIIa Leu-7 GFAP MBP	Sun exposure (ultraviolet light) Hormonal changes during: Pregnancy Diabetes Fair-skinned individuals (Caucasians of America and Europe) Positive family history of mole	Can occur anywhere in body, mostly involving following areas: Head Neck	Slowly growing, benign, oval or round, well-circumscribed macule, papule or nodule Color varies from skin color to light brown to black Cosmetic concerns	_
Cutaneous myxoma (Superficial angiomyxoma)^[26]^[27]^[28]^[29]	Sporadic Associated with: Carney’s syndrome (autosomal dominant condition associated with abnormalities in chromosomes 2p and 17q, especially mutation in the PRKAR1α gene on the chromosome 17q22–q24 locus) NAME syndrome LAMB syndrome	Predominantly involves dermis and subcutis Multilobulated, poorly circumscribed Alcian blue positive, and hyaluronidase sensitive myxoid stroma/acellular mucin pools forming cleft-like spaces Scattered bland stellate to spindled cells with multiple oval nuclei Rarely, pleomorphism, and mitotic figures seen Occasional intranuclear pseudoinclusions Many thin-walled small blood vessels Frequent neutrophils Entrapped epithelial component in 20-30% of cases: Keratinous cyst Thin strands of squamous epithelium Basaloid buds	Positive for: CD34 Smooth muscle actin (90%) Muscle specific actin (67%) Factor XIIIa (60%) Vimentin S-100 (rarely, 40%) Factor VIIIa (variable) Negative for: Cytokeratin Desmin GFAP ER PR	Associated with Carney’s complex/syndrome which includes following: Myxomas: Cutaneous External ear Heart Breast myxoid fibroadenoma Cutaneous melanocytic lesions: Lentigines Blue nevus Endocrine hyperplasia and neoplasia: Pituitary Thyroid Adrenal cortex Testis large cell calcifying Sertoli cell tumor Psammomatous melanotic schwannoma May be associated with NAME or LAMB syndrome	Trunk Limbs Head/face (eyelids and external ear canal in Carney’s syndrome) Neck Perineal Nipples Buttocks	Solitary or multiple flesh-colored nodules 1-5cm in diameter	Sometimes, may be the earliest manifestation of Carney complex Affects men more frequently than women Involves mostly middle-aged population
Nerve sheath myxoma^[30]^[31]^[32]^[33]^[34]^[35]	Unknown etiology	Tumors involve the dermis and/or subcutis Distinct multinodular/multilobular masses Markedly hypocellular with abundant myxoid stroma Peripheral fibrous border made up of collagen IV Schwann cells may show the following different features: Cytoplasmic–nuclear invaginations Small epithelioid Schwann cells in corded, nested, and/or syncytial-like aggregates Schwann cells with a ring-like appearance Scattered spindled and stellate-shaped Schwann cells	Positive for: S-100 Glial fibrillary acidic protein Neuron specific enolase CD57 Epithelial membrane antigen CD34	_	Can occur anywhere in body: Most commonly involves extremities especially: Fingers Knees Rarely involves: Scalp/head Trunk	Painless skin mass or nodule Occasionally painful to touch Skin over the nodule is pink, soft, and usually intact (no ulceration) 0.5-2 cm in size Cosmetic issue (when present in head and neck region)	First described by Harkin and Reed in 1969 Peak incidence in the fourth decade of life Strong predilection for the extremities Also known as: Classical Nerve Sheath Myxoma Cutaneous Lobular Neuro Myxoma Myxomatous Perineuroma
Malignant peripheral nerve sheath tumor (MPNST)/malignant schwannoma^[36]^[37]^[38]^[39]^[40]^[41]	50% arise denovo 50% associated with neurofibromatosis (loss of heterozygosity of p53 on 17p chromosome)	Generalized atypia Increased mitotic activity Diffuse hypercellularity Infiltrative growth Pleomorphic nuclei Areas of geographic necrosis may show divergent differentiation, with tumor palisading at edges, resembling glioblastoma multiforme Monomorphic serpentine cells, large gaping vascular spaces, perivascular plump tumor cells May have bizarre cells 15% have metaplastic cartilage, bone, and muscle May have glandular differentiation, if so, presume malignant May have melanin in tumor cells, particularly if arise from spinal nerve roots (overlaps with primary melanoma of nerves) Some have no discernable Schwannian features at any level Electron microscopy shows: Cell membrane infoldings with lamellar configuration, discontinuous basal lamina, conspicuous intercellular junctions, and occasional dense–core granules	Positive for: CD99/O13 (86%) S-100 (patchy in 62% cases) CD57 (55%) Collagen IV p53 Leu7/CD57 (in neurofibroma-like areas) Protein gene product 9.5 (more sensitive than S100 but not specific) In case of glandular differentiation (malignant), positive for: Keratin EMA CEA Chromogranin Negative for: CD19	Associated with: NF1 May be associated with: Radiations Ganglioneuroma (rarely)	Bulky deep-seated tumor usually arising from major nerves in: Neck Forearm Lower leg Buttock	Painless swelling in extremities (arms or legs, aka peripheral edema) Difficulty moving the extremity with tumor (limping) Localized soreness in tumor area Neurological symptoms Pain or discomfort: numbness, burning, or tingling (pins and needles) Dizziness Loss of balance	Most common frequent soft tissue sarcoma in the pediatrics population
Dermatofibrosarcoma protuberans (DFSP)	t(17,22)(q21;q13) (collagen type 1 alpha 1(COL1A1) gene and platelet derived growth factor (PDGF) beta chain gene), resulting fusion protein is processed into mature platelet-derived growth factor which is a potent growth factor Supernumerary ring chromosomes derived from t(17;22)	Usually forms a mass Non circumscribed, highly cellular, tight storiform pattern (cells radiating in spokes at right angles around a central point that often contains a vessel) deeply infiltrating into subcutaneous tissue and entraping fat cells leading to characteristic honeycomb pattern Areas of fascicular growth (some tumors) Distinct storiform pattern may be absent in early plaque stage Monomorphic, thin and spindly cells with scant eosinophilic cytoplasm and hyperchromatic nuclei (resembling neurofibroma) Numerous mitotic figures (not atypical ones) Non-polarizable and thin collagen Only mild pleomorphism and focal atypia May coexist with giant cell fibroblastoma Usually no significant pleomorphism, no / rare histiocytes, no histiocyte-like cells, no foam cells, no giant cells or other inflammatory cells Variants: Atrophic (depressed lesion), collagenous (with central thick collagen bundles), granular cell, myxoid, palisading, pigmented, and sclerosing	Positive for: CD34 (strong in 95%) Vimentin Actin (focal) ApoD Bcl2 NKI-C3 CD99 Negative for: S-100 Factor XIIIa (usually) Keratin EMA S100 HMB45 Desmin CD117	_	Head Deep soft tissue of (posterior) neck Trunk Arms Legs Doesn’t involve hands and feet	Begins as a minor firm area of skin 1 to 5 cm in diameter Resembles a bruise, birthmark, or pimple Can become a raised nodule after growth May cause redness, open up or bleed	Also called intermediate (borderline) fibrous histiocytoma More common in blacks in US Involves adults of 20 – 40 years of age
Spindle cell lipoma	16q abnormalities (usually)	Delicate encapsulation Floret cell formation No degenerative atypia Mixture of mature adipocytes and mildly pleomorphic bland spindle cells (pale eosinophilic cytoplasm with uniform wavy nuclei similar to neurofibroma) in mucinous / myxoid or fibrous background with thick collagen bundles Spindle cells arranged in short fascicles with occasional nuclear palisading Hemangiopericytic or angiomatous vascular pattern may be seen Minimal or no fat Variable mast cells and lymphocytes No storiform pattern, no lipoblasts, no/rare mitotic activity	Positive for: CD34 (strongly, spindle cells) Androgen receptors in men and usually women (spindle cells) S-100(stains only adipocytes) Spindle cells are negative for: S100 Desmin	_	Neck Posterior upper back Shoulder	Multiple well-circumscribed painless nodules involving several body parts	_
Ganglioneuroma^[42]^[43]	Genes involved in the pathogenesis of ganglioneuroma include: MYCN oncogene Chromosome 1p36 Activating RET protooncogene mutation (adrenal ganglioneuromas)	Derived from the primordial neural crest cells (undifferentiated cells of the sympathetic nervous system) Admixture of ganglion cells, schwann cells, and fibrous tissue Doesn’t contain neuroblasts, intermediate cells, or mitotic figures Characterized by spindle-shaped cells with cell borders in a fibrillar matrix containing ganglion cells with large round nuclei, prominent nucleoli, and abundant eosinophilic cytoplasm No significant atypia, necrosis or mitotic activity is present Well differentiated neuronal tumors that do not contain immature elements Ganglion cells are mature to mildly dysmorphic: Mature: compact, eosinophilic cytoplasm with distinct cell borders, single eccentric nucleus, prominent nucleolus Dysmorphic: single or multiple pyknotic nuclei Vary in distribution and number, may be quite sparse May contain finely granular, gold to brown pigment (lipofuscin or neuromelanin) Schwann cells: Ensheath neuritic processes Arranged in small intersecting fascicles, separated by loose myxoid stroma Two histologic subtypes: Mature = every ganglion cell is mature Maturing = minor component of scattered collections of differentiating neuroblasts or maturing ganglion cells (unlike intermixed subtype of ganglioneuroblastoma, these immature foci do not form distinct microscopic nests) Background may include lobules of mature adipose tissue (especially at periphery of lesion), mast cells, chronic inflammation, dense collagenized stroma Mild variation in cellularity may be present Masculinizing ganglioneuroma is an admixture of ganglioneuroma and Leydig cells with crystalloids of Reinke or strands/clusters of cells resembling adrenal cortical cells Electron microscopy: Mixture of neural bundles and normal appearing ganglion cells with eccentric nuclei and large numbers of cytoplasmic organelles	Positive for: Schwann cells/stroma: S100 Synaptophysin Neurofilament (NF) protein Ganglion cells: S100 Synaptophysin Chromogranin A NF protein Glial fibrillary acidic protein (GFAP) PGP 9.5 Type IV collagen Vasoactive intestinal peptide (VIP) Negative for: EMA Cytokeratin HMB45 WT1 CD99 CD45 Desmin Myogenic markers (myogenin, MyoD1)	Ganglioneuromas may be associated with: Multiple endocrine neoplasia type IIb (mucosal ganglioneuromas) Turner syndrome Neurofibromatosis type 1	Located along distribution of sympathetic nervous system: Posterior paraspinal mediastinum (most common) Adrenal gland (~20-30% of cases) Paraspinal retroperitoneum (especially presacral space) Cervical and parapharyngeal area in neck Urinary bladder Prostate Bone Pancreas Skin Orbit Paratesticular area Appendix Gastrointestinal tract	Symptoms of ganglioneuroma vary depending on the location of tumor, and include the following: Mediastinum: Dyspnea Chest pain Trachea compression Retroperitoneum: Abdominal pain Bloating Spinal cord: Paresis Pain and numbness/loss of sensation in limbs Patients with ganglioneuroma may also have paraneoplastic syndrome, which may manifest with: Diarrhea Diaphoresis Hirsutism Enlarged clitoris (in females) High blood pressure Sweating	Ganglioneuromas are included in the neuroblastic tumors group, which includes: Ganglioneuroma (benign) Ganglioneuroblastoma (intermediate) Neuroblastoma (aggressive)
Myxoid liposarcoma^[44]^[45]^[46]^[47]^[48]^[49]^[50]^[51]^[52]^[53]	Atypical lipomatous tumor/well differentiated liposarcoma and dedifferentiated liposarcoma are associated with: Presence of a large/giant marker chromosome and/or ring chromosomes at 12q13-15 region Amplification of this chromosome region rich in protooncogenes, including CHOP, CDK4, MDM2, HMGI-C, GLI, SAS, OS1, HMGA2 andOS9 Myxoid liposarcoma is associated with: t(12:16)(q13;p11) – CHOP(DDIT3) / FUSor t(12;22)(q13;q22) – CHOP(DDIT3) / EWS Pleomorphic liposarcoma is associated with: Complex karyotypicaberrations	Well-differentiated liposarcoma: Sclerosing liposarcoma (distinctive stromal cells distributed across the tissue, associated with lipoblasts filled with multiple vacuoles, and collageno us background of fibrillary appearance) Adipocytic liposarcoma (adipocytes with different cell sizes, hyperchromasia, and nuclear atypia. Fibrous sept acontaining hyperchromatic stromal cel ls surrounding adipocytes) Inflammatory liposarcoma (heavy chronic inflammatoryinfiltrate composed of different lympho-plasmacytic aggregates) Spindle cell liposarcoma(proliferation of neural-like spindle cells organized in a fibrous structurecontaining lipoblasts) De-differentiated liposarcoma: Myxoid liposarcoma ( non-homogenous appearance with cystic and soli d components) Round cell liposarcoma (small, round, or spindle cells with sparse eosinophilic and granular cytoplasmand large nuclei,scattered lipoblasts and areas of necrosis) Pleomorphic liposarcoma (pleomorphic cells with enlarged round to bizarre nuclei)	Atypical lipomatous tumor/well differentiated liposarcoma is positive for: MDM2 CDK4 p16 S100 (stains adipocytes and lipoblasts)	Chemical carcinogens Phenoxyacetic herbicides Chlorophenols Dioxin contaminations Arsenic Thorium dioxide (Thorotrast) Radiation (dose of 50 GY) Immunodeficiency(regional acquired immunodeficiency) Genetic susceptibility Li-Fraumeni syndrome Neurofibromatosis(NF1; von Recklinghausen disease) Gardner syndrome (Familial adenomatous polyposis) Retinoblastoma Werner syndrome Nevoid basal cell carcinoma (Gorlin syndrome) Viral infections	Retroperitoneum Esophagus Bowel Mediastinum	Retroperitoneal liposarcoma maybe asymptomatic or causes: Weight loss Abdominal pain Oliguria renal failure (due to ureters or kidneys‘ compression) Palpable abdominal mass Abdominal tenderness Abdominal distention Esophageal liposarcoma may cause: Dysphagia Vomiting Cough Gastrointestinal bleeding Hoarseness Bowel liposarcoma may cause: Gastrointestinal bleeding Mediastinal liposarcoma may cause: Dyspnea Cough Chest pain Weight loss	_
Leiomyoma^[54]^[55]^[56]^[57]^[58]^[59]^[60]^[61]^[55]^[58]^[62]	Loss of normal chromosome 1q (hereditary leiomyomatosis) Renal cell cancer(HLRCC) gene mutation	Prominent cellular atypia Nuclear atypia, including nuclear pleomorphism, hyperchromatism, irregularity in nucle ar membranes, high nuclear size, and prominent nucleoli Cigar-shaped nuclei Abundant mitoses, mitotic index higher than 10 or more per 10 high-power fields Areas of coagulative necrosis (tumor cell necrosis) Palisading and extensive degenerative changes in the form of hyalinization, calcification, and myxoid changes Elongated cells with eosinophilic or occasional fibrillar cytoplasm with distinct cell membranes	Positive for: HHF35 (90%) Alpha-smooth muscle actin (90%) Vimentin Desmin (75%) H-caldesmon PTAH (stains myofibrils) Keratin (30%) ER (usually in uterine and female retroperitoneal tumors) S100 (occasionally weak staining) EMA (may be focal) CD34 Negative for: CD117	Immundeficiency (HIV) Digoxin exposure Human herpes virus type-8 (HHV-8) Epstein barr virus Long term tamoxifen use History of pelvic radiations Hereditary breast carcinoma with BRCA1 mutation Hereditary nonpolyposis colorectal carcinoma with MSH2 mutation Li-Fraumeni syndrome Malignant melanoma Retinoblastoma	Uterus Abdomen Esophagus Rectum Skin / subcutis Retroperitoneum Extremities Large vessels (inferior vena cava, saphenous vein, femoral vein, pulmonary artery, femoral artery) Superficial or deep soft tissues Bone Breast Colon Epididymis Mediastinum Lungs	Asymptomatic (uterine leiomyosarcomamay be associated with: Irregular vaginal bleeding(intermenstrual or postmenopausal) New lump or a massprotruding into vaginaor growing mass in abdomen or pelvis Abdominal pain Abdominal distension Pelvic pain Urinary symptoms Esophageal leiomyosarcoma may cause: Dysphagia Hematemesis rectal leiomyosarcomamay cause: Black, tarry stools Rectal bleeding	_
Inflammatory myofibroblastic tumor(IMT)^[54]^[55]^[56]^[57]^[58]^[59]^[60]^[61]^[55]^[58]^[62]	Unknown underlying etiology, may be due to inflammatory reaction to: Infection Underlying low grade malignancy Mutations such as: ALK (anaplastic lymphoma kinase)gene mutations in the tyrosine kinase locus at band 2p23	Spindle to stellate-shaped cells Spindle cellsarranged in short fascicles with a focal storiform (whorled or cartwheel-like) architecture Spindle cells show features of fibroblastsand myofibroblasts Variably dense, chronic, mixed polymorphic infiltrateof mononuclear inflammatory cells (plasma cells and lymphocytes, histiocytes, neutrophils, and occasional eosinophils) Histiocytes have multinucleated forms with finely vacuolated cytoplasmic lipiddroplets Plasma cells with cytoplasmic Russell bodies (globular cytoplasmic inclusions of immunoglobulin) and polyclonal pattern of light chain expression Absent hyperchromasia and atypical mitoses	Positive for: IG+ (plasma cells) IL-1 IL-6 Smooth muscle actin Desmin Calponin Activin-like kinase 1 Negative for: Beta-catenin	Multiorgan disease in association with chronicpersistent Eikenella corrodens infection Epstein Barr virus infection Human herpes virus-8(HHV-8) infection(Kaposi’s sarcoma, multicentric Castleman’s disease)	Lungs Gastrointestinal system Pelvic region Bladder Uterus Retroperitoneum Skin Bone (femur, temporal bone, jaw bone) CNS Soft tissues Larynx Heart (right ventricleis most commonly involved) Pancreas (rarely)	Asymptomatic (70%) Painless asymptomatic mass/lump/swelling Pulmonary IMT presents as: Chest pain Cough Dyspnea Hemoptysis (recurrent) Fever Fatigue Weight loss Appetite loss Bone IMT presents with: Mild bone pain Easy fractures Headache Dizziness Numbness at tumorsite Bone marrowinvolvement in some cases Heart IMT presents with: Chest pain Difficulty breathing Palpitations Fainting Obstruction of blood flow in the heart (large tumors) Bladder IMT presents with: Painless hematuria Chronic pelvic pain Difficulty in urinating Presence of burning sensation CNS IMT presents with: Presence of solitary or multiple tumors at various locations in the brain Recurrent headaches Headache Nausea and vomiting Blurred vision Double vision Drooping of the eyelid Dizziness Back pain (if spineinvolved) Seizures	Also known as: Pseudo-inflammatory tumors Inflammatory pseudotumor Plasma cell granuloma Inflammatory pseudotumor Fibrous histiocytoma Fibroxanthoma Xanthogranuloma Inflammatorypseudosarcoma Atypical fibromyxoid tumor Atypical myfibroblastic tumor
Fibroepithelial polyp/Acrochordon^[63]^[64]^[65]^[66]^[67]^[68]^[69]^[70]^[71]^[72]^[73]^[74]^[75]^[76]^[77]^[78]^[79]^[80]^[81]^[82]	Associated with: HPV 6 (low risk) HPV 11	Fibrovascular cores covered by squamous epithelium Larger lesions may have a flattened epidermis Smaller lesions can have epidermal hyperplasia or seborrheic keratosis-like changes Central core composed of loose collagen with increased blood vessels In larger lesion, may have a central core of adipose tissue Pagetoid dyskeratosis is sometimes present as an incidental finding May have ischemic necrosis due to torsion	Positive for: Desmin Vimentin ER PR Negative for: Actin	Associated with: Diabetes (elevated blood sugar and insulin) Abnormal lipid profile Other components of metabolic syndrome Birt-Hogg-Dube syndrome Acromegaly Polycystic ovary syndrome May increase in number during pregnancy	Occurs usually in intertriginous areas (i.e. axilla, groin) Face Neck Eyelids Vulva Tonsils Ureter Bowel Urinary bladder Bronchi	Soft papilloma, flesh colored to dark brown, sessile to pedunculated A few millimeters to multiple centimeters in size Larger lesions often attach to skin by slender stalks	Benign skin lesions in adults, excised for cosmetic reasons Also known as: Skin tag Soft fibroma Cutaneous papilloma Cutaneous tag Fibroma pendulum Fibroma molluscum

References

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↑ Vestibular Schwannoma. Wikipedia(2015) https://en.wikipedia.org/wiki/Vestibular_schwannoma Accessed on October 2 2015
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↑ Misago N, Inoue T, Narisawa Y (2007). “Unusual benign myxoid nerve sheath lesion: myxoid palisaded encapsulated neuroma (PEN) or nerve sheath myxoma with PEN/PEN-like features?”. Am J Dermatopathol. 29 (2): 160–4. doi:10.1097/01.dad.0000256688.91974.09. PMID 17414438.
↑ Lee EJ, Calcaterra TC, Zuckerbraun L (1998). “Traumatic neuromas of the head and neck”. Ear Nose Throat J. 77 (8): 670–4, 676. PMID 9745184.
↑ Hanna SA, Catapano J, Borschel GH (2016). “Painful pediatric traumatic neuroma: surgical management and clinical outcomes”. Childs Nerv Syst. 32 (7): 1191–4. doi:10.1007/s00381-016-3109-z. PMID 27179535.
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↑ Yao C, Zhou X, Zhao B, Sun C, Poonit K, Yan H (2017). “Treatments of traumatic neuropathic pain: a systematic review”. Oncotarget. 8 (34): 57670–57679. doi:10.18632/oncotarget.16917. PMC 5593675. PMID 28915703.
↑ Gray MH, Smoller BR, McNutt NS, Hsu A (1990). “Neurofibromas and neurotized melanocytic nevi are immunohistochemically distinct neoplasms”. Am J Dermatopathol. 12 (3): 234–41. PMID 1693815.
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↑ Singh N, Chandrashekar L, Kar R, Sylvia MT, Thappa DM (2015). “Neurotized congenital melanocytic nevus resembling a pigmented neurofibroma”. Indian J Dermatol. 60 (1): 46–50. doi:10.4103/0019-5154.147789. PMC 4318062. PMID 25657396.
↑ Gray MH, Smoller BR, McNutt NS, Hsu A (1990). “Immunohistochemical demonstration of factor XIIIa expression in neurofibromas. A practical means of differentiating these tumors from neurotized melanocytic nevi and schwannomas”. Arch Dermatol. 126 (4): 472–6. PMID 1690969.
↑ https://www.sciencedirect.com/topics/medicine-and-dentistry/cutaneous-myxoma
↑ Alaiti, Samer; Nelson, Fern P.; Ryoo, Jei W. (2000). “Solitary cutaneous myxoma”. Journal of the American Academy of Dermatology. 43 (2): 377–379. doi:10.1067/mjd.2000.101878. ISSN 0190-9622.
↑ Carney, J. Aidan (1986). “Cutaneous Myxomas”. Archives of Dermatology. 122 (7): 790. doi:10.1001/archderm.1986.01660190068018. ISSN 0003-987X.
↑ Iida, Ken; Egi, Takeshi; Shigi, Masato; Sogabe, Yusuke; Ohashi, Hirotsugu (2019). “Cutaneous Myxoma of Multiple Lesions”. Plastic and Reconstructive Surgery – Global Open. 7 (2): e2040. doi:10.1097/GOX.0000000000002040. ISSN 2169-7574.
↑ Fetsch JF, Laskin WB, Miettinen M (2005). “Nerve sheath myxoma: a clinicopathologic and immunohistochemical analysis of 57 morphologically distinctive, S-100 protein- and GFAP-positive, myxoid peripheral nerve sheath tumors with a predilection for the extremities and a high local recurrence rate”. Am J Surg Pathol. 29 (12): 1615–24. PMID 16327434.
↑ Yadav SK, Singh S, Sarin N, Naeem R, Pruthi SK (2019). “Nerve Sheath Myxoma of Scalp: A Rare Site of Presentation”. Int J Trichology. 11 (1): 34–37. doi:10.4103/ijt.ijt_45_18. PMC 6385516. PMID 30820132.
↑ Bhat A, Narasimha A, C V, Vk S (2015). “Nerve sheath myxoma: report of a rare case”. J Clin Diagn Res. 9 (4): ED07–9. doi:10.7860/JCDR/2015/10911.5810. PMC 4437072. PMID 26023558.
↑ Avninder S, Ramesh V, Vermani S (2007). “Benign nerve sheath myxoma (myxoid neurothekeoma) in the leg”. Dermatol Online J. 13 (2): 14. PMID 17498433.
↑ Kim BW, Won CH, Chang SE, Lee MW (2014). “A case of nerve sheath myxoma on finger”. Indian J Dermatol. 59 (1): 99–101. doi:10.4103/0019-5154.123526. PMC 3884944. PMID 24470676.
↑ Pulitzer DR, Reed RJ (1985). “Nerve-sheath myxoma (perineurial myxoma)”. Am J Dermatopathol. 7 (5): 409–21. PMID 4091218.
↑ Valeyrie-Allanore, L.; Ismaili, N.; Bastuji-Garin, S.; Zeller, J.; Wechsler, J.; Revuz, J.; Wolkenstein, P. (2005). “Symptoms associated with malignancy of peripheral nerve sheath tumours: a retrospective study of 69 patients with neurofibromatosis 1”. British Journal of Dermatology. 153 (1): 79–82. doi:10.1111/j.1365-2133.2005.06558.x. ISSN 0007-0963.
↑ Evans DG, Baser ME, McGaughran J, Sharif S, Howard E, Moran A (2002). “Malignant peripheral nerve sheath tumours in neurofibromatosis 1”. J Med Genet. 39 (5): 311–4. PMC 1735122. PMID 12011145.
↑ Panigrahi S, Mishra SS, Das S, Dhir MK (2013). “Primary malignant peripheral nerve sheath tumor at unusual location”. J Neurosci Rural Pract. 4 (Suppl 1): S83–6. doi:10.4103/0976-3147.116480. PMC 3808069. PMID 24174807.
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↑ Neville H, Corpron C, Blakely ML, Andrassy R (2003). “Pediatric neurofibrosarcoma”. J Pediatr Surg. 38 (3): 343–6, discussion 343-6. doi:10.1053/jpsu.2003.50105. PMID 12632346.
↑ Zehou, Ouidad; Fabre, Elizabeth; Zelek, Laurent; Sbidian, Emilie; Ortonne, Nicolas; Banu, Eugeniu; Wolkenstein, Pierre; Valeyrie-Allanore, Laurence (2013). “Chemotherapy for the treatment of malignant peripheral nerve sheath tumors in neurofibromatosis 1: a 10-year institutional review”. Orphanet Journal of Rare Diseases. 8 (1): 127. doi:10.1186/1750-1172-8-127. ISSN 1750-1172.
↑ Vasiliadis, K.; Papavasiliou, C.; Fachiridis, D.; Pervana, S.; Michaelides, M.; Kiranou, M.; Makridis, C. (2012). “Retroperitoneal extra-adrenal ganglioneuroma involving the infrahepatic inferior vena cava, celiac axis and superior mesenteric artery: A case report”. International Journal of Surgery Case Reports. 3 (11): 541–543. doi:10.1016/j.ijscr.2012.07.008. ISSN 2210-2612.
↑ https://radiopaedia.org/articles/ganglioneuroma
↑ Khin Thway, Rashpal Flora, Chirag Shah, David Olmos & Cyril Fisher (2012). “Diagnostic utility of p16, CDK4, and MDM2 as an immunohistochemical panel in distinguishing well-differentiated and dedifferentiated liposarcomas from other adipocytic tumors”. The American journal of surgical pathology. 36 (3): 462–469. doi:10.1097/PAS.0b013e3182417330. PMID 22301498. Unknown parameter |month= ignored (help)
↑ J. Rosai, M. Akerman, P. Dal Cin, I. DeWever, C. D. Fletcher, N. Mandahl, F. Mertens, F. Mitelman, A. Rydholm, R. Sciot, G. Tallini, H. Van den Berghe, W. Van de Ven, R. Vanni & H. Willen (1996). “Combined morphologic and karyotypic study of 59 atypical lipomatous tumors. Evaluation of their relationship and differential diagnosis with other adipose tissue tumors (a report of the CHAMP Study Group)”. The American journal of surgical pathology. 20 (10): 1182–1189. PMID 8827023. Unknown parameter |month= ignored (help)
↑ Dal Cin, Paola; Kools, Patrick; Sciot, Raf; De Wever, Ivo; Van Damme, Boudewijn; Van de Ven, Wim; Van Den Berghe, Herman (1993). “Cytogenetic and fluorescence in situ hybridization investigation of ring chromosomes characterizing a specific pathologic subgroup of adipose tissue tumors”. Cancer Genetics and Cytogenetics. 68 (2): 85–90. doi:10.1016/0165-4608(93)90001-3. ISSN 0165-4608.
↑ Dei Tos, Angelo P.; Doglioni, Claudio; Piccinin, Sara; Sciot, Raf; Furlanetto, Alberto; Boiocchi, Mauro; Dal Cin, Paola; Maestro, Roberta; Fletcher, Christopher D. M.; Tallini, Giovanni (2000). “Coordinated expression and amplification of theMDM2,CDK4, andHMGI-C genes in atypical lipomatous tumours”. The Journal of Pathology. 190 (5): 531–536. doi:10.1002/(SICI)1096-9896(200004)190:5<531::AID-PATH579>3.0.CO;2-W. ISSN 0022-3417.
↑ Dei Tos, A (2000). “Liposarcoma: New entities and evolving concepts”. Annals of Diagnostic Pathology. 4 (4): 252–266. doi:10.1053/adpa.2000.8133. ISSN 1092-9134.
↑ M. D. Kraus, L. Guillou & C. D. Fletcher (1997). “Well-differentiated inflammatory liposarcoma: an uncommon and easily overlooked variant of a common sarcoma”. The American journal of surgical pathology. 21 (5): 518–527. PMID 9158675. Unknown parameter |month= ignored (help)
↑ P. Argani, F. Facchetti, G. Inghirami & J. Rosai (1997). “Lymphocyte-rich well-differentiated liposarcoma: report of nine cases”. The American journal of surgical pathology. 21 (8): 884–895. PMID 9255251. Unknown parameter |month= ignored (help)
↑ H. L. Evans (1979). “Liposarcoma: a study of 55 cases with a reassessment of its classification”. The American journal of surgical pathology. 3 (6): 507–523. PMID 534388. Unknown parameter |month= ignored (help)
↑ A. P. Dei Tos, T. Mentzel, P. L. Newman & C. D. Fletcher (1994). “Spindle cell liposarcoma, a hitherto unrecognized variant of liposarcoma. Analysis of six cases”. The American journal of surgical pathology. 18 (9): 913–921. PMID 8067512. Unknown parameter |month= ignored (help)
↑ D. C. Dahlin, K. K. Unni & T. Matsuno (1977). “Malignant (fibrous) histiocytoma of bone–fact or fancy?”. Cancer. 39 (4): 1508–1516. PMID 192432. Unknown parameter |month= ignored (help)
↑ ^54.0 ^54.1 Coffin CM, Watterson J, Priest JR, Dehner LP (1995). “Extrapulmonary inflammatory myofibroblastic tumor (inflammatory pseudotumor). A clinicopathologic and immunohistochemical study of 84 cases”. Am J Surg Pathol. 19 (8): 859–72. PMID 7611533.
↑ ^55.0 ^55.1 ^55.2 ^55.3 Wenig BM, Devaney K, Bisceglia M (1995). “Inflammatory myofibroblastic tumor of the larynx. A clinicopathologic study of eight cases simulating a malignant spindle cell neoplasm”. Cancer. 76 (11): 2217–29. PMID 8635024.
↑ ^56.0 ^56.1 Ramachandra S, Hollowood K, Bisceglia M, Fletcher CD (1995). “Inflammatory pseudotumour of soft tissues: a clinicopathological and immunohistochemical analysis of 18 cases”. Histopathology. 27 (4): 313–23. PMID 8847061.
↑ ^57.0 ^57.1 Häusler M, Schaade L, Ramaekers VT, Doenges M, Heimann G, Sellhaus B (2003). “Inflammatory pseudotumors of the central nervous system: report of 3 cases and a literature review”. Hum Pathol. 34 (3): 253–62. doi:10.1053/hupa.2003.35. PMID 12673560.
↑ ^58.0 ^58.1 ^58.2 ^58.3 Rabban JT, Zaloudek CJ, Shekitka KM, Tavassoli FA (2005). “Inflammatory myofibroblastic tumor of the uterus: a clinicopathologic study of 6 cases emphasizing distinction from aggressive mesenchymal tumors”. Am J Surg Pathol. 29 (10): 1348–55. PMID 16160478.
↑ ^59.0 ^59.1 Kovach SJ, Fischer AC, Katzman PJ, Salloum RM, Ettinghausen SE, Madeb R; et al. (2006). “Inflammatory myofibroblastic tumors”. J Surg Oncol. 94 (5): 385–91. doi:10.1002/jso.20516. PMID 16967468.
↑ ^60.0 ^60.1 Coffin CM, Dehner LP, Meis-Kindblom JM (1998). “Inflammatory myofibroblastic tumor, inflammatory fibrosarcoma, and related lesions: an historical review with differential diagnostic considerations”. Semin Diagn Pathol. 15 (2): 102–10. PMID 9606802.
↑ ^61.0 ^61.1 Berardi RS, Lee SS, Chen HP, Stines GJ (1983). “Inflammatory pseudotumors of the lung”. Surg Gynecol Obstet. 156 (1): 89–96. PMID 6336632.
↑ ^62.0 ^62.1 Coffin CM, Hornick JL, Fletcher CD (2007). “Inflammatory myofibroblastic tumor: comparison of clinicopathologic, histologic, and immunohistochemical features including ALK expression in atypical and aggressive cases”. Am J Surg Pathol. 31 (4): 509–20. doi:10.1097/01.pas.0000213393.57322.c7. PMID 17414097.
↑ Cukic O, Jovanovic MB (2019). “Large Fibroepithelial Polyp of the Palatine Tonsil”. Ear Nose Throat J: 145561319841203. doi:10.1177/0145561319841203. PMID 30997841.
↑ Vatansever M, Dinç E, Dursun Ö, Oktay ÖÖ, Arpaci R (2019). “Atypical presentation of fibroepithelial polyp: a report of two cases”. Arq Bras Oftalmol. doi:10.5935/0004-2749.20190050. PMID 30916216.
↑ Rexhepi M, Trajkovska E, Besimi F, Rufati N (2018). “Giant Fibroepithelial Polyp of Vulva: A Case Report and Review of Literature”. Pril (Makedon Akad Nauk Umet Odd Med Nauki). 39 (2–3): 127–130. doi:10.2478/prilozi-2018-0051. PMID 30864355.
↑ Jabbour J, Chappell JR, Busby M, McCubbery NW, Brown DF, Park SJK; et al. (2019). “Glottic Obstruction from Fibroepithelial Polyp”. Am J Case Rep. 20: 219–223. doi:10.12659/AJCR.914907. PMC 6388646. PMID 30778021.
↑ Hong P, Cai Y, Li Z, Fan S, Yang K, Hao H; et al. (2019). “Modified Laparoscopic Partial Ureterectomy for Adult Ureteral Fibroepithelial Polyp: Technique and Initial Experience”. Urol Int. 102 (1): 13–19. doi:10.1159/000494804. PMID 30448831.
↑ Uçar M, Baş E, Akkoç A, Topçuoğlu M (2018). “Fibroepithelial Polyp of the Ureter: A Rare Cause of Hydronephrosis”. J Endourol Case Rep. 4 (1): 166–168. doi:10.1089/cren.2018.0031. PMC 6225073. PMID 30426076.
↑ Chaker K, Rhouma SB, Daly KM, Zehani A, Bibi M, Chehida MAB; et al. (2019). “Benign fibroepithelial polyp of the ureter: A case report”. Urol Case Rep. 22: 52–53. doi:10.1016/j.eucr.2018.10.019. PMC 6226574. PMID 30425926.
↑ Hajji F, Moufid K, Ghoundale O, Touiti D (2019). “A rare case of successful endoscopic management of a fibroepithelial polyp with intussusception of the ureter and periodic prolapse into bladder”. Ann R Coll Surg Engl. 101 (2): e66–e70. doi:10.1308/rcsann.2018.0198. PMC 6351868. PMID 30421620.
↑ Lee H, Sade I, Gilani S, Zhong M, Lombardo G (2018). “A Giant Fibroepithelial Polyp of the Small Bowel Associated with High-Grade Obstruction”. Am Surg. 84 (7): e210–e211. PMID 30401014.
↑ Chaker K (2019). “Benign fibroepithelial polyp of the ureter: A case report”. Urol Case Rep. 22: 15–16. doi:10.1016/j.eucr.2018.09.021. PMC 6180234. PMID 30319938.
↑ Lozano-Peña AK, Lamadrid-Zertuche AC, Ocampo-Candiani J (2019). “Giant fibroepithelial polyp of the vulva”. Australas J Dermatol. 60 (1): 70–71. doi:10.1111/ajd.12886. PMID 30009441.
↑ Eckstein M, Agaimy A, Woenckhaus J, Winter A, Bittmann I, Janzen J; et al. (2019). “DICER1 mutation-positive giant botryoid fibroepithelial polyp of the urinary bladder mimicking embryonal rhabdomyosarcoma”. Hum Pathol. 84: 1–7. doi:10.1016/j.humpath.2018.05.015. PMID 29883781.
↑ Akdere H, Çevik G (2018). “Rare Fibroepithelial Polyp Extending Along the Ureter: A Case Report”. Balkan Med J. 35 (3): 275–277. doi:10.4274/balkanmedj.2017.1537. PMC 5981127. PMID 29843497.
↑ Ballard DH, Rove KO, Coplen DE, Chen TY, Hulett Bowling RL (2018). “Fibroepithelial polyp causing urethral obstruction: Diagnosis by cystourethrogram”. Clin Imaging. 51: 164–167. doi:10.1016/j.clinimag.2018.05.009. PMC 6404776. PMID 29800931.
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↑ Saito N, Yamasaki M, Daido W, Ishiyama S, Deguchi N, Taniwaki M (2017). “A bronchial fibroepithelial polyp with abnormal findings on auto-fluorescence imaging”. Respirol Case Rep. 5 (5): e00244. doi:10.1002/rcr2.244. PMC 5465754. PMID 28603622.

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Epidemiology and Demographics

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sara Mohsin, M.D.[2], Shanshan Cen, M.D. [3]

Overview

Neurofibroma usually occurs between 20-40 years of age, and affects men and women equally. However, plexiform neurofibromas are thought to be congenital defects, hence, they occur earlier in life.

Epidemiology and Demographics

Age

Neurofibroma usually affects individuals between 20 and 40 years of age.
Plexiform neurofibromas occur earlier in life and are thought to be congenital defects.^[1]

Gender

Neurofibroma affects men and women equally.

References

↑ “Case Based Pediatrics For Medical Students and Residents: Chapter XVIII.11. Neurofibromatosis”, by Vince K. Yamashiroya, MD. August, 2002. Department of Pediatrics, University of Hawaii John A. Burns School of Medicine.

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Risk Factors

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sara Mohsin, M.D.[2] Shanshan Cen, M.D. [3]

Overview

Neurofibromatosis 1 and Neurofibromatosis 2 are the most common risk factors for development of neurofibromas.

Risk Factors

Following are the most common risk factors for formation of neurofibromas:^[1]

Neurofibromatosis 1
Neurofibromatosis 2 (multiple neurofibromas, meningiomas of the brain or spinal cord, and ependymomas of the spinal cord)

References

↑ Colman SD, Williams CA, Wallace MR (1995). “Benign neurofibromas in type 1 neurofibromatosis (NF1) show somatic deletions of the NF1 gene”. Nature Genetics. 11 (1): 90–2. doi:10.1038/ng0995-90. PMID 7550323. Retrieved 2015-11-16.

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Screening

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sara Mohsin, M.D.[2] Shanshan Cen, M.D. [3]

Overview

According to the the U.S. Preventive Service Task Force (USPSTF), there is insufficient evidence to recommend routine screening for neurofibroma.

Screening

According to the the U.S. Preventive Service Task Force (USPSTF), there is insufficient evidence to recommend routine screening for neurofibroma.

References

Template:WikiDoc Sources

Natural History, Complications and Prognosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sara Mohsin, M.D.[2] Shanshan Cen, M.D. [3]

Overview

Prognosis of neurofibroma is generally excellent. If left untreated, 10% of patients with plexiform neurofibromas may progress to develop malignant peripheral nerve sheath tumor (MPNST). Local recurrence occurs rarely.

Natural History

If left untreated, 10% of patients with plexiform neurofibromas may progress to develop malignant peripheral nerve sheath tumor (MPNST)^[1]

Complications

Complications that can develop as a result of neurofibroma include the following:^[1]
- Malignant transformation (plexiform neurofibroma)
- Local recurrence (rare)

Prognosis

Prognosis of neurofibroma is generally excellent

References

↑ ^1.0 ^1.1 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.

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Diagnosis

Treatment

Case Studies

Case #1

Related Chapters

Neurofibromatosis type I

Template:Nervous tissue tumors

Template:WikiDoc Sources

[pmid10190829-1] Morse RP (1999). “Neurofibromatosis type 1”. Arch Neurol. 56 (3): 364–5. PMID 10190829.

[StaserYang2010-2] Staser, Karl; Yang, Feng-Chun; Clapp, D. Wade (2010). “Mast cells and the neurofibroma microenvironment”. Blood. 116 (2): 157–164. doi:10.1182/blood-2009-09-242875. ISSN 0006-4971.

[WilkinsonManson2004-1] Wilkinson, Lana M.; Manson, David; Smith, Charles R. (2004). “Best Cases from the AFIP”. RadioGraphics. 24 (suppl_1): S237–S242. doi:10.1148/rg.24si035170. ISSN 0271-5333.

[2] ttps://pubs.rsna.org/doi/10.1148/rg.24si035170#REF8

[pmid11159187-1] 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.

[pmid24216989-2] 2.0 ^2.1 Bernthal, NM.; Jones, KB.; Monument, MJ.; Liu, T.; Viskochil, D.; Randall, RL. (2013). “Lost in translation: ambiguity in nerve sheath tumor nomenclature and its resultant treatment effect”. Cancers (Basel). 5 (2): 519–28. doi:10.3390/cancers5020519. PMID 24216989.

[pmid20233971-3] 3.0 ^3.1 Staser, K.; Yang, FC.; Clapp, DW. (2010). “Mast cells and the neurofibroma microenvironment”. Blood. 116 (2): 157–64. doi:10.1182/blood-2009-09-242875. PMID 20233971. Unknown parameter |month= ignored (help)

[pmid12898075-4] 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.

[5] ttp://www.bloodjournal.org/content/116/2/157?sso-checked=true

[pmid8825042-6] 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.

[pmid16069817-7] 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.

[pmid8516298-8] 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.

[pmid15486243-9] Wilkinson LM, Manson D, Smith CR (2004). “Best cases from the AFIP: plexiform neurofibroma of the bladder”. Radiographics : a Review Publication of the Radiological Society of North America, Inc. 24 Suppl 1: S237–42. doi:10.1148/rg.24si035170. PMID 15486243. Retrieved 2015-11-13.

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Neurofibroma

Overview

Historical Perspective

Classification

Pathophysiology

Causes

Differential Diagnosis

Epidemiology and Demographics

Risk Factors

Screening

Natural History, Complications and Prognosis

Diagnosis

Diagnostic Study of Choice

Staging

History and symptoms

Physical Examination

Laboratory Findings

X Ray

CT Scan

MRI

Ultrasound

Other Imaging Findings

Other Diagnostic Studies

Biopsy

Treatment

Medical Therapy

Surgery

Primary Prevention

Secondary Prevention

References

Overview

Historical Perspective

References

Overview

Classification

References

Overview

Pathogenesis

Genetics

Gross Pathology

Microscopic Pathology

Neurofibroma with Degenerative Atypia (“Ancient change”)

Soft tissue neurofibromas

Plexiform neurofibromas

Electron microscopy

References

Overview

Causes

References

Overview

Differential Diagnosis

References

Overview

Epidemiology and Demographics

Age

Gender

References

Overview

Risk Factors

References

Overview

Screening

References

Overview

Natural History

Complications

Prognosis

References

Diagnosis

Treatment

Case Studies

Related Chapters

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