Neurofibroma pathophysiology: Difference between revisions

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==Overview==
==Overview==
Neurofibromas arise from the nonmyelinating-type [[Schwann cells]]. Gene involved in the pathogenesis of [[plexiform neurofibroma]] is ''[[Neurofibromatosis type I|NF1]]''. 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, [[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.
[[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 the 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><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 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 Accessed on November 17, 2015</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 neurofibroma microenvironment interaction that includes SCF-stimulated Nf1+/− mast cells potentiating Nf1+/− fibroblast functions<ref>http://www.bloodjournal.org/content/116/2/157?sso-checked=true</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 secreted by fibroblasts, which comprise the major cellular portion of neurofibroma
* 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 to transforming growth factor β (TGF-β)
* [[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-β dependent  
* [[Fibroblast]] bioactivity is [[TGF beta|TGF-β]] [[Dependent variable|dependent]].
*Nf1+/− mast cell is the critical effector in the paracrine induction of neurofibroma pathogenesis
* [[NF1|Nf1]]+/− [[mast cell]] is the critical [[Effector (biology)|effector]] in the [[paracrine]] [[Induction (biology)|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
* [[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]].
 
{|
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[[File:Fibroblast nf.jpg|thumb|500px|none|Mast cells and the neurofibroma microenvironment. Potential cellular interactions in the plexiform neurofibroma microenvironment. NGF indicates nerve growth factor; and MMP, matrix metalloproteinase. [http://www.bloodjournal.org/content/116/2/157?sso-checked=true Source: Staser Karl. et al]]]
|}


==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. Accessed on November 17, 2015 </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 ''[[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, [[MAPK]], [[SCF-complex|SCF]]/[[c-kit]]'' 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==
* [[Neurofibroma|Neurofibromas]] can occur anywhere in [[body]]. [[Gross]] [[Features (pattern recognition)|features]] of different types of [[Neurofibroma|neurofibromas]] include the following:
'''Localised neurofibroma and Diffuse neurofibroma'''
'''Localised neurofibroma and Diffuse neurofibroma'''
* Superficial [[mass]]<ref name="radio">Neurofibroma. Dr Bruno Di Muzio and Dr Maxime St-Amant et al. Radiopaedia.org 2015. http://radiopaedia.org/articles/neurofibroma Accessed on November 17, 2015 </ref>
* [[Superficial (human anatomy)|Superficial]] [[mass]]
* Not encapsulated
* Not encapsulated
'''Soft tissue neurofibroma'''
'''Soft tissue neurofibroma'''
*Not encapsulated, softer (more gelatinous) than schwannoma
* Not encapsulated, [[Soft tissue|softer]] (more gelatinous) than [[schwannoma]].
*Superficial tumors are small, pedunculated nodules protruding from skin (molluscum pendulum)
* [[Superficial]] [[tumors]] are small, [[pedunculated]] [[nodules]] protruding from [[skin]] ([[molluscum]] pendulum).
*Deeper tumors are larger, may cause tortuous enlargement of peripheral nerves (plexiform neurofibromas)
* Deeper [[tumors]] are larger, may cause [[tortuous]] enlargement of [[peripheral nerves]] ([[Plexiform neurofibroma|plexiform neurofibromas]]).
 
'''Plexiform neurofibroma'''
'''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><ref>Neurofibroma. Libre Pathology 2015. http://librepathology.org/wiki/index.php/Neurofibroma#cite_note-pmid15486243-2 Accessed on November 17, 2015 </ref><ref>Neurofibroma. Libre Pathology 2015. http://librepathology.org/wiki/index.php/Neurofibroma#cite_note-pmid15486243-2 Accessed on November 17, 2015 </ref>
* "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 grossly enlarged and tortuous nerves
* Associated with [[Gross|grossly]] enlarged and [[tortuous]] [[nerves]]
*Deep tumors are often large
* Deep [[tumors]] are often large
*Highly vascularized and locally invasive
* Highly [[Vascular|vascularized]] and [[Local|locally]] [[invasive]]
 
[[File:Plexi gross gif.gif|thumb|200px|none|Plexiform neurofibroma of the submandibular gland in patient with von Recklinghausen's disease Photograph showed left ankle cutaneous neurofibroma (A), right forearm cutaneous neurofibroma (B), and Cafè -au-lait spots found on the body of the patient (C).[https://openi.nlm.nih.gov/detailedresult?img=PMC3070454_rt-2011-1-e4-g001&query=&req=4Source: Bisher HA. et al, Department of Surgery, Abington Memorial Hospital, Abington, Pennsylvania, USA.]]]
{|
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[[File:Gross neurofb.jpeg|thumb|300px|none|Plexiform Neurofibroma of the Bladder. Horizontally oriented cross section of the tumor shows the bladder mucosa (M) surrounded by masses of nodules. Arrows = locations of the ureteric orifices. (Scale is in centimeters.)[https://pubs.rsna.org/doi/10.1148/rg.24si035170#F1A Source: Wilkinson LM. et al, From the Department of Medical Imaging, Hospital for Sick Children, Toronto, Ontario, Canada.]]]
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[[File:GB nb.jpg|thumb|300px|none|Gallbladder neurofibroma presenting as chronic epigastric pain - Case report and review of the literature. Intact gallbladder specimen following the operation. Neurofibroma extended along the inferior wall of the gallbladder from the cystic duct to the fundus, protruding extraluminally.[https://openi.nlm.nih.gov/detailedresult?img=PMC3339114_NAJMS-2-496-g001&query=&req=4 Source: Sucandy I. et al, Department of Surgery, Abington Memorial Hospital, Abington, Pennsylvania, USA.]]]
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[[File:Gb open gross.jpg|thumb|300px|none|Gallbladder neurofibroma presenting as chronic epigastric pain - Case report and review of the literature. Opened gallbladder specimen showing mural nodules and normal mucosa. Gallbladder appeared to be normal without signs of inflammation. Silk sutures were used to ligate the cystic duct prior to division.[https://openi.nlm.nih.gov/detailedresult?img=PMC3339114_NAJMS-2-496-g002&query=&req=4 Source: Sucandy I. et al, Department of Surgery, Abington Memorial Hospital, Abington, Pennsylvania, USA.]]]
|-
|}


==Microscopic Pathology==
==Microscopic Pathology==
*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]])
* 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]])
*Multiple enlarged fasicles of nerve sheath<nowiki/> cells with elongated nuclei and scant cytoplasm are embeded in a stromal mucin and collageneous matrix within fibrous connective tissue  
* 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" />
*Tactile-like bodies are also detected
* [[Spindle cell]]s have hyperchromatic, elongat<nowiki/>ed, wavy, buckled, small and bland [[nuclei]] with indistinct scant [[cytoplasm]]
*<nowiki/>Varying degrees of myxoid degeneration
* No [[pleomorphism]]
*<nowiki/>Unencapsulated
* [[Tactile]]-like [[Body|bodies]] are also detected
*No clear division betwee<nowiki/>n Antoni A and B a<nowiki/>reas within the tumor
* <nowiki/>Varying [[Degree (angle)|degrees]] of myxoid [[degeneration]]
*[[Spindle cell]]s with wavy [[nuclei]] without pleomorphism
* <nowiki/><nowiki/><nowiki/><nowiki/>Unencapsulated
*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>
* <nowiki/>Moderate increase of cellularity vis-a-vis normal [[dermis]]
*Moderate increase of cellularity vis-a-vis normal [[dermis]]
* Uniphasic, low to moderate cellularity (generally hypocellular)
*[[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><ref>Neurofibroma. Libre Pathology 2015. http://librepathology.org/wiki/index.php/Neurofibroma#cite_note-pmid15486243-2 Accessed on November 17, 2015 </ref>
* Occasional [[Mast cells|mast cells,]] and [[lymphocytes]], [[rare]] [[foam cells]].<ref name="pmid20233971" />
*Target sign on histopathology represents a central core made up of collagenous and fibrillary tissue with peripheral less densely cellular myxoid tissue<ref>https://pubs.rsna.org/doi/10.1148/rg.24si035170#REF8</ref>
* 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]] [[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===
===Soft tissue neurofibromas===
* Proliferation of all elements of peripheral nerves
* [[Proliferation]] of all [[Element|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
* [[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 in plexiform types, mitotic figures are rare
* Perineurial [[Cells (biology)|cells]] in [[Plexiform neurofibroma|plexiform]] types, [[mitotic]] figures are [[rare]].
* Less of a fascicular pattern than fibromatosis
* Less of a [[Fasciculus|fascicular]] [[pattern]] than [[fibromatosis]].
* May be infiltrative, have myxoid areas, contain melanin pigment, have epitheloid morphology
* May be [[Infiltration (medical)|infiltrative]], have myxoid [[Area|areas]], contain [[melanin]] [[pigment]], have epitheloid [[morphology]].
* Rarely has skeletal differentiation (neuromuscular hamartoma)
* [[Rare|Rarely]] has [[skeletal]] [[differentiation]] ([[neuromuscular]] [[hamartoma]]).
* No Verocay bodies
* No Verocay [[Body|bodies]]
* No nuclear palisading
* No [[nuclear]] palisading
* No hyalinized thickening of vessel walls
* No [[Hyaline|hyalinized]] thickening of [[Vessel wall|vessel walls]]
 
===Plexiform neurofibromas===
===Plexiform neurofibromas===
*Nodular or diffuse
* [[Nodular]] or [[diffuse]]
*Diffuse cases are also known as elephantiasis neurofibromatosa; characterized by an overgrowth of epidermal and subcutaneous tissue
* [[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
* Hypocellular with myxoid [[background]]; contains [[Schwann cells]], [[fibroblasts]] and [[mast cells]]
*Occasional nuclear palisading
* Occasional [[nuclear]] palisading
*Rarely is pigmented due to melanocytes
* [[Rare|Rarely]] is [[Pigmented lesions|pigmented]] due to [[melanocytes]]
*No biphasic pattern of schwannoma
* 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>
|
[[File:Nf histo.jpeg|thumb|200px|none|Plexiform Neurofibroma of the Bladder. Photomicrograph (original magnification, ×100; hematoxylin-eosin stain) shows that the oval plexiform neurofibroma (PNF) has a denser outer core with areas that have a looser configuration. It is surrounded by fibrous tissue and pushes aside elongated smooth muscle cells (SM). (b) Photomicrograph (original magnification, ×400; hematoxylin-eosin stain) shows that the plexiform neurofibroma (PNF) has variable architecture. On the right, the tumor cells have a wavy, parallel arrangement; on the left, the cells are arranged more loosely and haphazardly. There is no true capsule. The tumor pushes aside bundles of smooth muscle cells (SM).[https://pubs.rsna.org/doi/10.1148/rg.24si035170#F1A Source: Wilkinson LM. et al, From the Department of Medical Imaging, Hospital for Sick Children, Toronto, Ontario, Canada.]]]  
|
[[File:Neurofb histo.jpeg|thumb|200px|none|Plexiform Neurofibroma of the Bladder. Photomicrograph (original magnification, ×100; hematoxylin-eosin stain) shows that the oval plexiform neurofibroma (PNF) has a denser outer core with areas that have a looser configuration. It is surrounded by fibrous tissue and pushes aside elongated smooth muscle cells (SM). (b) Photomicrograph (original magnification, ×400; hematoxylin-eosin stain) shows that the plexiform neurofibroma (PNF) has variable architecture. On the right, the tumor cells have a wavy, parallel arrangement; on the left, the cells are arranged more loosely and haphazardly. There is no true capsule. The tumor pushes aside bundles of smooth muscle cells (SM).[https://pubs.rsna.org/doi/10.1148/rg.24si035170#F1A Source: Wilkinson LM. et al, From the Department of Medical Imaging, Hospital for Sick Children, Toronto, Ontario, Canada.]]]
|
[[File:GB neurofb.png|thumb|200px|none|Gallbladder neurofibroma presenting as chronic epigastric pain - Case report and review of the literature. Histologic appearance of gallbladder neurofibroma. Photomicrograph shows diffuse neurofibroma cells with short fusiform and round shapes within fine fibrillary collagen matrix.[https://openi.nlm.nih.gov/detailedresult?img=PMC3339114_NAJMS-2-496-g003&query=neurofibroma&it=xg&req=4&npos=34 Source: Sucandy I. et al, Department of Surgery, Abington Memorial Hospital, Abington, Pennsylvania, USA.]]] 
|
[[File:Plexi histo.png|thumb|200px|none|Photomicrograph of the plexiform neurofibroma, Histopathological image of the plexiform neurofibroma along with normal glandular tissue (Hematoxylin-Eosin stain) (A), Elongated, spindly cells with wavy nuclei (Hematoxylin-Eosin stain) (B), Immuno-positive staining for the S-100 protein (C).[https://openi.nlm.nih.gov/detailedresult?img=PMC3070454_rt-2011-1-e4-g004&query=neurofibroma&it=xg&req=4&npos=37 Source: Bisher HA. et al, Department of Surgery, Abington Memorial Hospital, Abington, Pennsylvania, USA.]]]   
|}


==Electron microscopy==
==Electron microscopy==
*Schwann cells enclose axons in plasmalemmal invaginations (mesaxons)
* [[Schwann cells]] enclose [[axons]] in plasmalemmal [[Invagination|invaginations]] (mesaxons).
 
==References==
==References==
{{Reflist|2}}
{{Reflist|2}}

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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