Neurofibroma pathophysiology: Difference between revisions

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==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]]''.<ref name=radio> Neurofibroma. Dr Bruno Di Muzio and Dr Maxime St-Amant et al. Radiopaedia.org 2015. http://radiopaedia.org/articles/neurofibroma </ref>
* 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 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>


==Gross Pathology==
==Gross Pathology==

Revision as of 19:15, 17 December 2015

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

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.[1] On microscopic histopathological analysis, spindle cells 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.[2][3]

Pathogenesis

Genetics

  • Gene involved in the pathogenesis of plexiform neurofibroma is NF1.[7]
  • The NF1 gene is composed of 60 exons spanning 350kb of genomic data, and maps to chromosomal region 17q11.2.[8] This gene codes for neurofibromin which is a large 220-250 KDa cytoplasmic protein that is composed of 2,818 amino acids with three alternatively spliced exons (9a, 23a, and 48a) in the encoding gene. The functional part of neurofibromin is a GAP, or GTPase-activating protein. GAP accelerates the conversion of the active GTP-bound RAS to its inactive GDP-bound form, inactivating RAS and reducing RAS-mediated growth signaling. Loss of RAS control leads to increased activity of other signaling pathways including RAF, ERK1/2, PI3K, PAK and mTOR-S6 kinase. It is suspected that this increased activity of downstream RAS pathways might work together to increase cell growth and survival.[9][10]

Gross Pathology

Localised neurofibroma and Diffuse neurofibroma[7]

  • Superficial mass
  • Not encapsulated

Plexiform neurofibroma[1]

  • "Bag of worms" appearance

Gallery

  • Macroscopical specimen of a Neurofibroma in a Neurofibromatosis type I patient. Such lesions can attain a considerable size.[11]

    Macroscopical specimen of a Neurofibroma in a Neurofibromatosis type I patient. Such lesions can attain a considerable size.[11]

  • Neurofibroma: Nodular mass with whitish glistening cut surface.[12]

    Neurofibroma: Nodular mass with whitish glistening cut surface.[12]

Microscopic Pathology

Gallery

  • Histopathologic image of cutanous neurofibroma obtained by biopsy. Photographed by CCD camera through Olympus microscope, then modified by auto-contrast function in Adobe software.[13]

    Histopathologic image of cutanous neurofibroma obtained by biopsy. Photographed by CCD camera through Olympus microscope, then modified by auto-contrast function in Adobe software.[13]

References

  1. ↑ 1.0 1.1 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.
  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. ↑ 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.
  5. ↑ Neurofibroma. Wikipedia 2015. https://en.wikipedia.org/wiki/Neurofibroma#cite_note-Yamashiroya2002-3
  6. ↑ 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.
  7. ↑ 7.0 7.1 Neurofibroma. Dr Bruno Di Muzio and Dr Maxime St-Amant et al. Radiopaedia.org 2015. http://radiopaedia.org/articles/neurofibroma
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ Neurofibroma. Libre Pathology 2015. http://librepathology.org/wiki/index.php/Neurofibroma#cite_note-pmid15486243-2
  12. ↑ Neurofibroma. Libre Pathology 2015. http://librepathology.org/wiki/index.php/Neurofibroma#cite_note-pmid15486243-2
  13. ↑ Neurofibroma. Libre Pathology 2015. http://librepathology.org/wiki/index.php/Neurofibroma#cite_note-pmid15486243-2


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