Neurofibroma pathophysiology: Difference between revisions

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{{Neurofibroma}}
{{Neurofibroma}}
{{CMG}}; {{AE}} {{SC}}
{{CMG}}; {{AE}}{{S.M.}}{{SC}}
==Overview==
==Overview==
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]].<ref name="pmid15486243">{{cite journal |vauthors=Wilkinson LM, Manson D, Smith CR |title=Best cases from the AFIP: plexiform neurofibroma of the bladder |journal=[[Radiographics : a Review Publication of the Radiological Society of North America, Inc]] |volume=24 Suppl 1 |issue= |pages=S237–42 |year=2004 |pmid=15486243 |doi=10.1148/rg.24si035170 |url=http://pubs.rsna.org/doi/10.1148/rg.24si035170?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed |issn= |accessdate=2015-11-13}}</ref> On microscopic histopathological analysis, [[spindle cell]]s with wavy [[nuclei]] without pleomorphism, wire-like [[collagen]], moderate increase of cellularity vis-a-vis normal [[dermis]], and [[mast cells]] are characteristic findings of neurofibroma.<ref name=pmid24216989>{{Cite journal  | last1 = Bernthal | first1 = NM. | last2 = Jones | first2 = KB. | last3 = Monument | first3 = MJ. | last4 = Liu | first4 = T. | last5 = Viskochil | first5 = D. | last6 = Randall | first6 = RL. | title = Lost in translation: ambiguity in nerve sheath tumor nomenclature and its resultant treatment effect. | journal = Cancers (Basel) | volume = 5 | issue = 2 | pages = 519-28 | month =  | year = 2013 | doi = 10.3390/cancers5020519 | PMID = 24216989 }}</ref><ref name=pmid20233971>{{Cite journal  | last1 = Staser | first1 = K. | last2 = Yang | first2 = FC. | last3 = Clapp | first3 = DW. | title = Mast cells and the neurofibroma microenvironment. | journal = Blood | volume = 116 | issue = 2 | pages = 157-64 | month = Jul | year = 2010 | doi = 10.1182/blood-2009-09-242875 | PMID = 20233971 }}</ref>
[[Neurofibroma|Neurofibromas]] arise from the nonmyelinating-type [[Schwann cells]] and can occur anywhere in the [[body]]. [[Gene]] involved in the [[pathogenesis]] of [[plexiform neurofibroma]] is ''[[Neurofibromatosis type I|NF1]]'' which [[Code|codes]] for [[neurofibromin]] that leads to loss of ''[[RAS]]'' [[control]] causing increased [[Activity (chemistry)|activity]] of [[Downstream (molecular biology)|downstream]] [[RAS]] pathways involved in increased [[Cell (biology)|cell]] [[growth]] and [[Survival rate|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 cell]]s with wavy [[nuclei]] without [[pleomorphism]], shredded carrot [[collagen]], moderate increase of cellularity vis-a-vis normal [[dermis]], [[blood vessels]], [[mast cells]], pseudomeissnerian [[Body|bodies]], and varying [[Degree (angle)|degrees]] of myxoid [[degeneration]] are characteristic findings of [[neurofibroma]]. However, [[plexiform neurofibroma]] shows a characteristic target [[Sign (medicine)|sign]] on [[Histopathology|histopathology,]] representing a [[central]] [[Core (anatomy)|core]] of [[collagenous]] and [[Fibril|fibrillary]] [[Tissue (biology)|tissue]] with [[Periphery|peripheral]] less [[Dense|densely]] [[cellular]] myxoid [[Tissue (biology)|tissue]]. [[Electron microscopy]] of [[Neurofibroma|neurofibromas]] shows [[Schwann cells]] enclosing [[axons]] in plasmalemmal [[Invagination|invaginations]] (mesaxons).


==Pathogenesis==
==Pathogenesis==
* Neurofibromas arise from nonmyelinating-type [[Schwann cells]].<ref name="pmid11159187">{{cite journal |author=Muir D, Neubauer D, Lim IT, Yachnis AT, Wallace MR. |title=Tumorigenic properties of neurofibromin-deficient neurofibroma Schwann cells. |journal= American Journal of Pathology |volume=158 |issue=2 |pages=501–13 |year=2003 |pmid=11159187 |doi= 10.1016/S0002-9440(10)63992-2|pmc=1850316}}</ref>  
* [[Neurofibroma|Neurofibromas]] arise from the non[[Myelin|myelinating]]-type [[Schwann cells]].<ref name="pmid11159187">{{cite journal |author=Muir D, Neubauer D, Lim IT, Yachnis AT, Wallace MR. |title=Tumorigenic properties of neurofibromin-deficient neurofibroma Schwann cells. |journal= American Journal of Pathology |volume=158 |issue=2 |pages=501–13 |year=2003 |pmid=11159187 |doi= 10.1016/S0002-9440(10)63992-2|pmc=1850316}}</ref><ref name="pmid24216989">{{Cite journal  | last1 = Bernthal | first1 = NM. | last2 = Jones | first2 = KB. | last3 = Monument | first3 = MJ. | last4 = Liu | first4 = T. | last5 = Viskochil | first5 = D. | last6 = Randall | first6 = RL. | title = Lost in translation: ambiguity in nerve sheath tumor nomenclature and its resultant treatment effect. | journal = Cancers (Basel) | volume = 5 | issue = 2 | pages = 519-28 | month =  | year = 2013 | doi = 10.3390/cancers5020519 | PMID = 24216989 }}</ref><ref name="pmid20233971">{{Cite journal  | last1 = Staser | first1 = K. | last2 = Yang | first2 = FC. | last3 = Clapp | first3 = DW. | title = Mast cells and the neurofibroma microenvironment. | journal = Blood | volume = 116 | issue = 2 | pages = 157-64 | month = Jul | year = 2010 | doi = 10.1182/blood-2009-09-242875 | PMID = 20233971 }}</ref>
* [[Plexiform neurofibroma]]s can grow from [[nerve]]s in the [[skin]] or from more internal nerve bundles, and can be very large.<ref>Neurofibroma. Wikipedia 2015. https://en.wikipedia.org/wiki/Neurofibroma#cite_note-Yamashiroya2002-3</ref>
* [[Plexiform neurofibroma]]s can [[Growth|grow]] from [[nerve]]s in the [[skin]] or from more [[internal]] [[nerve]] bundles, and can be very large.
* About 10% of [[plexiform neurofibroma]]s undergo [[transformation]] into a [[malignant peripheral nerve sheath tumor]] (MPNST).<ref name="pmid12898075">{{cite journal |author=Mautner VF, Friedrich RE, von Deimling A, Hagel C, Korf B, Knöfel MT, Wenzel R, Fünsterer C. |title=Malignant peripheral nerve sheath tumours in neurofibromatosis type 1: MRI supports the diagnosis of malignant plexiform neurofibroma. |journal=American Journal of Pathology |volume=45 |issue=9 |pages=618–25 |year=2003 |pmid=12898075 |doi=10.1007/s00234-003-0964-6}}</ref>
* About 10% of [[plexiform neurofibroma]]s undergo [[transformation]] into a [[malignant peripheral nerve sheath tumor]] ([[MPNST]]).<ref name="pmid12898075">{{cite journal |author=Mautner VF, Friedrich RE, von Deimling A, Hagel C, Korf B, Knöfel MT, Wenzel R, Fünsterer C. |title=Malignant peripheral nerve sheath tumours in neurofibromatosis type 1: MRI supports the diagnosis of malignant plexiform neurofibroma. |journal=American Journal of Pathology |volume=45 |issue=9 |pages=618–25 |year=2003 |pmid=12898075 |doi=10.1007/s00234-003-0964-6}}</ref>
* In 2006, Yang et al demonstrated a [[Critical Care|critical]] [[neurofibroma]] microenvironment [[interaction]] that includes [[SCF complex|SCF]]-[[Stimulated emission|stimulated]] [[NF1|Nf1]]+/− [[mast cells]] potentiating [[NF-1|Nf1]]+/− [[fibroblast]] [[Function (biology)|functions]].<ref>http://www.bloodjournal.org/content/116/2/157?sso-checked=true</ref>
* Nearly one-half of the dry [[tumor]] [[weight]] is made up of [[collagen]] [[Secrete|secreted]] by [[fibroblasts]], which comprise the major [[cellular]] [[Portion control (dieting)|portion]] of [[neurofibroma]].
* [[Fibroblasts]] migrate, [[proliferate]], and [[synthesize]] [[collagen]] in [[Response rate|response]] to [[Transforming growth factor β|transforming growth factor β (TGF-β)]].
* [[Fibroblast]] bioactivity is [[TGF beta|TGF-β]] [[Dependent variable|dependent]].
* [[NF1|Nf1]]+/− [[mast cell]] is the critical [[Effector (biology)|effector]] in the [[paracrine]] [[Induction (biology)|induction]] of [[neurofibroma]] [[pathogenesis]].
* [[TGF-β]]–[[Dependent variable|dependent]] [[NF1|Nf1]]+/− [[fibroblast]] [[hyperactivity]] is a result of increased [[kinase]] [[Activity (chemistry)|activity]] of c-abl secondary to increased [[Ras]]-[[GTPBP1|GTP]].


==Genetics==
==Genetics==
* Gene involved in the pathogenesis of [[plexiform neurofibroma]] is [[Neurofibromatosis type I|NF1]].<ref name=radio> Neurofibroma. Dr Bruno Di Muzio and Dr Maxime St-Amant et al. Radiopaedia.org 2015. http://radiopaedia.org/articles/neurofibroma </ref>
* [[Gene]] involved in the [[pathogenesis]] of [[plexiform neurofibroma]] is ''[[Neurofibromatosis type I|NF1]]''.
* The [[Neurofibromin 1|NF1]] gene is composed of 60 [[exons]] spanning 350kb of genomic data, and maps to chromosomal region [[CCL7|17q11.2]].<ref name="pmid8825042">{{cite journal |author=MH Shen, PS Harper, M Upadhyaya. |title=Molecular genetics of neurofibromatosis type 1 (NF1) |journal=Journal of Medical Genetics |volume=33 |issue=1 |pages=2–17 |year=1996 |pmid= 8825042|doi=10.1136/jmg.33.1.2 |pmc=1051805}}</ref> 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) in the encoding gene.  The functional part of neurofibromin is a [[GTPase activating protein|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 [[c-Raf|RAF]], [[Extracellular signal-regulated kinases|ERK1/2]], [[Phosphoinositide 3-kinase|PI3K]], PAK and [[Mammalian target of rapamycin|mTOR-S6 kinase]]. It is suspected that this increased activity of downstream RAS pathways might work together to increase cell growth and survival.<ref name="pmid16069817">{{cite journal |author=Rubin JB, Gutmann DH. |title= Neurofibromatosis type 1 - a model for nervous system tumour formation? |journal=Nature Reviews Cancer |volume=5 |issue=7 |pages=557–64 |year=2005 |pmid=16069817|doi=10.1038/nrc1653}}</ref><ref name="pmid8516298">{{cite journal |author=Johnson MR, Look AT, DeClue JE, Valentine MB, Lowy DR. |title= Inactivation of the NF1 gene in human melanoma and neuroblastoma cell lines without impaired regulation of GTP.Ras. |journal=Proceedings of the National Academy of Sciences of the USA |volume=90 |issue=12 |pages=5539–43 |year=1993 |pmid=8516298|doi=10.1073/pnas.90.12.5539 |pmc=46756}}</ref>
* The ''[[Neurofibromin 1|NF1]]'' [[gene]] is composed of 60 [[exons]] spanning 350kb of [[genomic]] [[data]], and maps to [[Chromosome|chromosomal]] region [[CCL7|17q11.2]].<ref name="pmid8825042">{{cite journal |author=MH Shen, PS Harper, M Upadhyaya. |title=Molecular genetics of neurofibromatosis type 1 (NF1) |journal=Journal of Medical Genetics |volume=33 |issue=1 |pages=2–17 |year=1996 |pmid= 8825042|doi=10.1136/jmg.33.1.2 |pmc=1051805}}</ref>
*This [[gene]] [[Code|codes]] for [[neurofibromin]] which is a large 220-250 KDa [[cytoplasm]]ic [[protein]] that is composed of 2,818 [[amino acids]] with three alternatively [[Splice|spliced]] [[exons]] (9a, 23a, and 48a) in the [[Encoding (memory)|encoding]] [[gene]].   
*The functional part of [[neurofibromin]] is ''[[GTPase activating protein|GAP]]'', or [[GTPase activating protein|GTPase-activating protein]].
*''[[GAPVD1|GAP]]'' accelerates the [[Conversion (logic)|conversion]] of the active [[GTPBP1|GTP]]-bound [[RAS]] to its inactive GDP-bound form, inactivating ''[[RAS]]'' and reducing [[RAS]]-mediated [[growth]] [[Signaling pathway|signaling]].  
*Loss of ''[[RAS]]'' [[control]] leads to increased [[Activity (chemistry)|activity]] of other [[Signaling pathway|signaling pathways]] including ''[[c-Raf|RAF]]'', ''[[Extracellular signal-regulated kinases|ERK1/2]]'', ''[[Phosphoinositide 3-kinase|PI3K]]'', ''[[PAK1|PAK]], [[MAPK]], [[SCF-complex|SCF]]/[[c-kit]]'' and ''[[Mammalian target of rapamycin|mTOR-S6 kinase]]''. It is suspected that this increased [[Activity (chemistry)|activity]] of [[Downstream (molecular biology)|downstream]] [[RAS]] pathways might work together to increase [[Cell (biology)|cell]] [[growth]] and [[Survival rate|survival]].<ref name="pmid16069817">{{cite journal |author=Rubin JB, Gutmann DH. |title= Neurofibromatosis type 1 - a model for nervous system tumour formation? |journal=Nature Reviews Cancer |volume=5 |issue=7 |pages=557–64 |year=2005 |pmid=16069817|doi=10.1038/nrc1653}}</ref><ref name="pmid8516298">{{cite journal |author=Johnson MR, Look AT, DeClue JE, Valentine MB, Lowy DR. |title= Inactivation of the NF1 gene in human melanoma and neuroblastoma cell lines without impaired regulation of GTP.Ras. |journal=Proceedings of the National Academy of Sciences of the USA |volume=90 |issue=12 |pages=5539–43 |year=1993 |pmid=8516298|doi=10.1073/pnas.90.12.5539 |pmc=46756}}</ref>


==Gross Pathology==
==Gross Pathology==
'''Localised neurofibroma/Diffuse neurofibroma'''<ref name=radio> Neurofibroma. Dr Bruno Di Muzio and Dr Maxime St-Amant et al. Radiopaedia.org 2015. http://radiopaedia.org/articles/neurofibroma </ref>
* Superficial [[mass]]
* Not encapsulated


'''Plexiform neurofibroma'''<ref name="pmid15486243">{{cite journal |vauthors=Wilkinson LM, Manson D, Smith CR |title=Best cases from the AFIP: plexiform neurofibroma of the bladder |journal=[[Radiographics : a Review Publication of the Radiological Society of North America, Inc]] |volume=24 Suppl 1 |issue= |pages=S237–42 |year=2004 |pmid=15486243 |doi=10.1148/rg.24si035170 |url=http://pubs.rsna.org/doi/10.1148/rg.24si035170?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed |issn= |accessdate=2015-11-13}}</ref>
* [[Neurofibroma|Neurofibromas]] can occur anywhere in [[body]]. [[Gross]] [[Features (pattern recognition)|features]] of different types of [[Neurofibroma|neurofibromas]] include the following:  
* "Bag of worms" appearance


===Gallery===
'''Localised neurofibroma and Diffuse neurofibroma'''
<gallery>
* [[Superficial (human anatomy)|Superficial]] [[mass]]
Image:
* Not encapsulated
Neurofibroma1.jpg|Neurofibroma<ref>Neurofibroma. Libre Pathology 2015. http://librepathology.org/wiki/index.php/Neurofibroma#cite_note-pmid15486243-2 </ref>
'''Soft tissue neurofibroma'''
Neurofibroma2.jpg|Neurofibroma<ref>Neurofibroma. Libre Pathology 2015. http://librepathology.org/wiki/index.php/Neurofibroma#cite_note-pmid15486243-2 </ref>
* Not encapsulated, [[Soft tissue|softer]] (more gelatinous) than [[schwannoma]].
</gallery>
* [[Superficial]] [[tumors]] are small, [[pedunculated]] [[nodules]] protruding from [[skin]] ([[molluscum]] pendulum).
* Deeper [[tumors]] are larger, may cause [[tortuous]] enlargement of [[peripheral nerves]] ([[Plexiform neurofibroma|plexiform neurofibromas]]).
'''Plexiform neurofibroma'''
* "Bag of worms" [[appearance]]<ref name="pmid15486243">{{cite journal |vauthors=Wilkinson LM, Manson D, Smith CR |title=Best cases from the AFIP: plexiform neurofibroma of the bladder |journal=[[Radiographics : a Review Publication of the Radiological Society of North America, Inc]] |volume=24 Suppl 1 |issue= |pages=S237–42 |year=2004 |pmid=15486243 |doi=10.1148/rg.24si035170 |url=http://pubs.rsna.org/doi/10.1148/rg.24si035170?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed |issn= |accessdate=2015-11-13}}</ref>
* Associated with [[Gross|grossly]] enlarged and [[tortuous]] [[nerves]]
* Deep [[tumors]] are often large
* Highly [[Vascular|vascularized]] and [[Local|locally]] [[invasive]]


==Microscopic Pathology==
==Microscopic Pathology==
*[[Spindle cell]]s with wavy [[nuclei]] without pleomorphism
* Made of [[nerve fibers]], [[schwann cells]] ([[Cells (biology)|cells]]<nowiki/> that cover the [[nerve fibers]]), [[blood vessels]], [[inflammatory]] [[white blood cells]] ([[mast cells]]), and [[connective tissue]] ([[fibroblasts]] and loose [[Material conditional|material]] called [[extracellular matrix]])
*Intermixed with wire-like [[collagen]]<ref name=pmid24216989>{{Cite journal  | last1 = Bernthal | first1 = NM. | last2 = Jones | first2 = KB. | last3 = Monument | first3 = MJ. | last4 = Liu | first4 = T. | last5 = Viskochil | first5 = D. | last6 = Randall | first6 = RL. | title = Lost in translation: ambiguity in nerve sheath tumor nomenclature and its resultant treatment effect. | journal = Cancers (Basel) | volume = 5 | issue = 2 | pages = 519-28 | month =  | year = 2013 | doi = 10.3390/cancers5020519 | PMID = 24216989 }}</ref>
* Multiple enlarged [[fascicles]] of [[Random|randomly]] or<nowiki/>iented thin [[Spindle|spindled]] [[nerve sheath]] [[Cells (biology)|cells]] are embeded in a [[stromal]] [[mucin]] and [[wire]]-like [[Collagen|collageneous]] [[matrix]] within [[fibrous]] [[connective tissue]]<ref name="pmid24216989" />
*Moderate increase of cellularity vis-a-vis normal [[dermis]]
* [[Spindle cell]]s have hyperchromatic, elongat<nowiki/>ed, wavy, buckled, small and bland [[nuclei]] with indistinct scant [[cytoplasm]]
*[[Mast cells]]<ref name=pmid20233971>{{Cite journal  | last1 = Staser | first1 = K. | last2 = Yang | first2 = FC. | last3 = Clapp | first3 = DW. | title = Mast cells and the neurofibroma microenvironment. | journal = Blood | volume = 116 | issue = 2 | pages = 157-64 | month = Jul | year = 2010 | doi = 10.1182/blood-2009-09-242875 | PMID = 20233971 }}</ref>
* No [[pleomorphism]]
 
* [[Tactile]]-like [[Body|bodies]] are also detected
===Gallery===
* <nowiki/>Varying [[Degree (angle)|degrees]] of myxoid [[degeneration]]
<gallery>
* <nowiki/><nowiki/><nowiki/><nowiki/>Unencapsulated
Image:
* <nowiki/>Moderate increase of cellularity vis-a-vis normal [[dermis]]
Neurofibroma3.jpg|Neurofibroma<ref>Neurofibroma. Libre Pathology 2015. http://librepathology.org/wiki/index.php/Neurofibroma#cite_note-pmid15486243-2 </ref>
* Uniphasic, low to moderate cellularity (generally hypocellular)
</gallery>
* Occasional [[Mast cells|mast cells,]] and [[lymphocytes]], [[rare]] [[foam cells]].<ref name="pmid20233971" />
* Thin and thick [[collagen]] strands (“shredded carrot [[collagen]]”)
* [[Nerve]] [[Fiber|fibers]] run through a [[neurofibroma]] (making [[excision]] more difficult with increased [[likelihood]] of [[nerve]] damage)
* [[Nerve]] frequently not [[Gross|grossly]] identifiable
* [[Features (pattern recognition)|Features]] of specific [[differentiation]] (e.g. pseudomeissnerian [[Body|bodies]]) may be present occassionally
* Low [[mitotic index]]
* No clear [[Division (biology)|division]] between Antoni A and B [[Area|areas]] within the [[tumor]]
* No well formed verocy [[Body|bodies]]
* No [[epithelial]] component
* No [[Distinctive feature|distinct]] [[Lobular|lobulation]]
* Seldom [[cystic]]
* Cellularity and organiza<nowiki/>tion are generally<nowiki/> insufficient to produce palisading
===Neurofibroma with Degenerative Atypia ("Ancient change")===
* Localized hyperchromatic atypical [[Cells (biology)|cells]] ("ancient [[Change detection|change]]") with:
** Large, [[pleomorphic]] [[nuclei]]
** [[Cytoplasmic]] intranuclear [[inclusions]]
** Smudgy [[chromatin]]
** Inconspicuous [[nucleoli]]
* Absent or very low [[mitotic]] [[Activity (chemistry)|activity]]
* Low to moderate cellularity
* Often large, long standing [[lesions]]
===Soft tissue neurofibromas===
* [[Proliferation]] of all [[Element|elements]] of [[peripheral nerves]].
* [[Schwann cells]] with [[wire]] like [[collagen]] [[Fibril|fibrils]] (wavy [[Serpentine receptor|serpentine]] [[nuclei]], pointed ends), [[stromal]] mucosubstances, [[mast cells]], [[Meissner's corpuscle|Wagner-Meissner corpuscles]], [[Pacinian corpuscles]], [[axons]] (highlight with [[silver]] or [[acetylcholinesterase]] [[stain]], NSE, [[neurofilament]]), [[fibroblasts]] and [[collagen]].
* Perineurial [[Cells (biology)|cells]] in [[Plexiform neurofibroma|plexiform]] types, [[mitotic]] figures are [[rare]].
* Less of a [[Fasciculus|fascicular]] [[pattern]] than [[fibromatosis]].
* May be [[Infiltration (medical)|infiltrative]], have myxoid [[Area|areas]], contain [[melanin]] [[pigment]], have epitheloid [[morphology]].
* [[Rare|Rarely]] has [[skeletal]] [[differentiation]] ([[neuromuscular]] [[hamartoma]]).
* No Verocay [[Body|bodies]]
* No [[nuclear]] palisading
* No [[Hyaline|hyalinized]] thickening of [[Vessel wall|vessel walls]]
===Plexiform neurofibromas===
* [[Nodular]] or [[diffuse]]
* [[Diffuse]] cases are also known as [[elephantiasis]] [[Neurofibromatosis|neurofibromatosa]]; characterized by an overgrowth of [[epidermal]] and [[subcutaneous tissue]].
* Hypocellular with myxoid [[background]]; contains [[Schwann cells]], [[fibroblasts]] and [[mast cells]]
* Occasional [[nuclear]] palisading
* [[Rare|Rarely]] is [[Pigmented lesions|pigmented]] due to [[melanocytes]]
* No [[biphasic]] [[pattern]] of [[schwannoma]]
* [[Target cell|Target]] [[Sign (medicine)|sign]] on [[histopathology]] represents a [[central]] [[Core (anatomy)|core]] made up of [[collagenous]] and [[Fibril|fibrillary]] [[Tissue (biology)|tissue]] with peripheral less [[Dense|densely]] [[cellular]] myxoid [[Tissue (biology)|tissue]].<ref>https://pubs.rsna.org/doi/10.1148/rg.24si035170#REF8</ref>


==Electron microscopy==
* [[Schwann cells]] enclose [[axons]] in plasmalemmal [[Invagination|invaginations]] (mesaxons).
==References==
==References==
{{Reflist|2}}
{{Reflist|2}}
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Latest revision as of 16:08, 1 November 2019

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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]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

Genetics

Gross Pathology

Localised neurofibroma and Diffuse neurofibroma

Soft tissue neurofibroma

Plexiform neurofibroma

Microscopic Pathology

Neurofibroma with Degenerative Atypia ("Ancient change")

Soft tissue neurofibromas

Plexiform neurofibromas

Electron microscopy

References

  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.
  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.
  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)
  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. ↑ http://www.bloodjournal.org/content/116/2/157?sso-checked=true
  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.
  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.
  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.
  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.
  10. ↑ https://pubs.rsna.org/doi/10.1148/rg.24si035170#REF8


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