Mesothelioma pathophysiology: Difference between revisions

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{{Mesothelioma}}
{{Mesothelioma}}
{{CMG}}{{AE}}{{PSD}}, {{SR}}
{{CMG}}; {{AE}}{{FT}},{{SR}}


==Overview==
==Overview==
[[Asbestos]] causes DNA damage directly by mechanically interfering with the segregation of [[chromosomes]] during [[mitosis]] and indirectly by inducing [[mesothelial cells]] and [[macrophages]], to release mutagenic [[reactive oxygen]] and nitrogen species. Asbestos fibres have been shown to alter the function and secretory properties of [[macrophages]], ultimately creating conditions which favor the development of mesothelioma. Following asbestos [[phagocytosis]], macrophages generate increased amounts of hydroxyl radicals, which are normal by-products of cellular anaerobic metabolism. However, these free radicals are also known clastogenic and membrane-active agents thought to promote asbestos carcinogenicity. These oxidants can participate in the oncogenic process by directly and indirectly interacting with DNA, modifying membrane-associated cellular events, including oncogene activation and perturbation of cellular antioxidant defences. Genes involved in the pathogenesis of mesothelioma include ''[[BAP1]]'', ''[[CDKN2A]]'', ''[[WT1]]'', ''[[NF2 gene|NF2]]'', and ''[[TP53]]''. On gross pathology, pleural mesothelioma is characterized by discrete plaques and nodules that coalesce to produce a sheet-like tumor, with the pleural surface seeding of malignant mesothelioma cells. Based on the histology, mesothelioma may be classified into 3 subtypes: epithelial, sarcomatoid, and biphagic. Mesothelioma is demonstrated by positivity to [[tumor marker]]s, such as [[calretinin]], epithelial membrane antigen, [[cytokeratin]], and [[mesothelin]].


==Pathogenesis==
==Pathogenesis==
*[[Asbestos]] causes DNA damage directly by mechanically interfering with the segregation of [[chromosomes]] during [[mitosis]] and indirectly by inducing [[mesothelial cells]] and [[macrophages]], to release mutagenic [[reactive oxygen]] and nitrogen species.<ref name="ThomasChen2015">{{cite journal|last1=Thomas|first1=Anish|last2=Chen|first2=Yuanbin|last3=Yu|first3=Tinghui|last4=Gill|first4=Ammara|last5=Prasad|first5=Vinay|title=Distinctive clinical characteristics of malignant mesothelioma in young patients|journal=Oncotarget|volume=6|issue=18|year=2015|pages=16766–16773|issn=1949-2553|doi=10.18632/oncotarget.4414}}</ref>
The pathogenesis of mesothelioma is influenced by the following factors:<ref name="pmid7448712">{{cite journal| author=Selikoff IJ, Hammond EC, Seidman H| title=Latency of asbestos disease among insulation workers in the United States and Canada. | journal=Cancer | year= 1980 | volume= 46 | issue= 12 | pages= 2736-40 | pmid=7448712 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7448712  }} </ref><ref name="pmid20068227">{{cite journal| author=Heintz NH, Janssen-Heininger YM, Mossman BT| title=Asbestos, lung cancers, and mesotheliomas: from molecular approaches to targeting tumor survival pathways. | journal=Am J Respir Cell Mol Biol | year= 2010 | volume= 42 | issue= 2 | pages= 133-9 | pmid=20068227 | doi=10.1165/rcmb.2009-0206TR | pmc=2822975 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20068227  }} </ref><ref name="ThomasChen2015">{{cite journal|last1=Thomas|first1=Anish|last2=Chen|first2=Yuanbin|last3=Yu|first3=Tinghui|last4=Gill|first4=Ammara|last5=Prasad|first5=Vinay|title=Distinctive clinical characteristics of malignant mesothelioma in young patients|journal=Oncotarget|volume=6|issue=18|year=2015|pages=16766–16773|issn=1949-2553|doi=10.18632/oncotarget.4414}}</ref><ref name="pmid12706492">{{cite journal| author=Shukla A, Gulumian M, Hei TK, Kamp D, Rahman Q, Mossman BT| title=Multiple roles of oxidants in the pathogenesis of asbestos-induced diseases. | journal=Free Radic Biol Med | year= 2003 | volume= 34 | issue= 9 | pages= 1117-29 | pmid=12706492 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12706492  }} </ref>
*The [[mesothelium]] consists of a single layer of flattened to cuboidal cells forming the [[epithelium|epithelial]] lining of the serous cavities of the body including the [[peritoneum|peritoneal]], [[pericardium|pericardial]] and [[pleura]]l cavities.  Deposition of asbestos fibres in the parenchyma of the lung may result in the penetration of the visceral pleura from where the fibre can then be carried to the pleural surface, thus leading to the development of malignant mesothelial plaques.  The processes leading to the development of peritoneal mesothelioma remain unresolved, although it has been proposed that asbestos fibres from the lung are transported to the abdomen and associated organs via the [[lymphatic system]].  Additionally, asbestos fibres may be deposited in the gut after ingestion of sputum contaminated with asbestos fibres.
*Asbestos fibres
*[[Radiation therapy|Radiation]] therapy
*[[Smoking]]
===Types of Asbestos fibres===
There are two types of asbestos fibers:
* [[Amphibole]] (sharp, rod-like)
* Serpentine


Pleural contamination with asbestos or other mineral fibres has been shown to cause cancer.  Long thin asbestos fibers (blue asbestos, [[amphibole]] fibers) are more potent carcinogens than "feathery fibers" ([[chrysotile]] or white asbestos fibers).<ref name="fibertypes">"Malignant mesothelioma and occupational exposure to asbestos: a clinicopathological correlation of 1445 cases" by V. L. Roggli, A. Sharma, K. J. Butnor, T. Sporn and R. T. Vollmer in ''Ultrastruct Pathol'' (2002) volume 26 pages 55-65 {{Entrez Pubmed|12036093}}.</ref>  However, there is now evidence that smaller particles may be more dangerous than the larger fibers.[http://www.mesothel.com/pdf/Suzuki-Yuen-01-IndHealth.pdf][http://www.mesothel.com/pdf/Suzuki-Yuen-02-AnnNYAS.pdf] They remain suspended in the air where they can be inhaled, and may penetrate more easily and deeper into the lungs. "We probably will find out a lot more about the health aspects of asbestos from [the World Trade Center attack], unfortunately," said Dr. Alan Fein, chief of pulmonary and critical-care medicine at North Shore-Long Island Jewish Health System.  Dr. Fein has treated several patients for "World Trade Center syndrome" or respiratory ailments from brief exposures of only a day or two near the collapsed buildings.[http://www.prwatch.org/prwissues/2001Q4/junkman.html]
=== Role of Asbestos fibers ===
[[Asbestos]] fibers play the following role in the development of mesothelioma:
* The most common type of fibres found in US are the serpentine fibers, which are considered less [[Carcinogen|carcinogenic]] than the amphibole ones.
* Following inhalation from the environment, these fibres are trapped in the lower third zone of the [[lung]].
* They are [[Phagocytosis|phagocytosed]] by the [[Mesothelium|mesothelial]] cells and initiate an [[oncogenic]] cascade of events which include:
** Activation of c-Myc and c-Jun [[oncogene]]
** Promotion of antiapoptotic genes such as [[Bcl-xL|Bcl]]-xL
** Binding with epidermal growth factor receptor ([[EGFR]])


Mesothelioma development in rats has been demonstrated following intra-pleural inoculation of phosphorylated chrysotile fibres.  It has been suggested that in humans, transport of fibres to the pleura is critical to the pathogenesis of mesothelioma. This is supported by the observed recruitment of significant numbers of [[macrophage]]s and other cells of the [[immune system]] to localised lesions of accumulated asbestos fibres in the pleural and peritoneal cavities of rats.  These lesions continued to attract and accumulate macrophages as the disease progressed, and cellular changes within the lesion culminated in a morphologically malignant tumour.  
* [[Asbestos]] causes DNA damage directly by mechanically interfering with the segregation of [[chromosomes]] during [[mitosis]] and indirectly by inducing [[mesothelial cells]] and [[macrophages]], to release mutagenic [[reactive oxygen]] and nitrogen species.
*Asbestos fibres have been shown to alter the function and secretory properties of [[macrophages]], ultimately creating conditions which favor the development of mesothelioma.  
*Following asbestos [[phagocytosis]], macrophages generate increased amounts of hydroxyl radicals, which are normal by-products of cellular anaerobic metabolism.
*However, these free radicals are also known clastogenic and membrane-active agents thought to promote asbestos carcinogenicity. These oxidants can participate in the oncogenic process by directly and indirectly interacting with DNA, modifying membrane-associated cellular events, including oncogene activation and perturbation of cellular antioxidant defences.
*The [[mesothelium]] consists of a single layer of flattened to cuboidal cells forming the [[epithelium|epithelial]] lining of the serous cavities of the body including the [[peritoneum|peritoneal]], [[pericardium|pericardial]] and [[pleura]]l cavities. 
*Deposition of asbestos fibres in the parenchyma of the lung may result in the penetration of the visceral pleura from where the fibre can then be carried to the pleural surface, thus leading to the development of malignant mesothelial plaques. 
*The processes leading to the development of peritoneal mesothelioma remain unresolved, although it has been proposed that asbestos fibres from the lung are transported to the abdomen and associated organs via the [[lymphatic system]].
*Additionally, asbestos fibres may be deposited in the gut after ingestion of sputum contaminated with asbestos fibres.
*Asbestos also may possess [[immunosuppressant|immunosuppressive]] properties.  For example, chrysotile fibres have been shown to depress the in-vitro proliferation of phytohemagglutinin-stimulated peripheral blood lymphocytes, suppress natural killer cell lysis, and significantly reduce [[lymphokine-activated killer cell]] viability and recovery.
*Furthermore, genetic alterations in asbestos-activated macrophages may result in the release of potent mesothelial cell mitogens such as [[platelet-derived growth factor]] ([[PDGF]]) and [[transforming growth factor]]-β ([[TGF-β]]) which in turn, may induce the chronic stimulation and proliferation of mesothelial cells after injury by asbestos fibres.
===Radiation therapy===
Survivors of radiation therapy have been found to develop mesothelioma according to several studies. Following cancers have been studied post-radiation therapy which are seen to develop mesothelioma:<ref name="pmid16174857">{{cite journal| author=Travis LB, Fosså SD, Schonfeld SJ, McMaster ML, Lynch CF, Storm H et al.| title=Second cancers among 40,576 testicular cancer patients: focus on long-term survivors. | journal=J Natl Cancer Inst | year= 2005 | volume= 97 | issue= 18 | pages= 1354-65 | pmid=16174857 | doi=10.1093/jnci/dji278 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16174857  }} </ref><ref name="pmid14663775">{{cite journal| author=Matesich SM, Shapiro CL| title=Second cancers after breast cancer treatment. | journal=Semin Oncol | year= 2003 | volume= 30 | issue= 6 | pages= 740-8 | pmid=14663775 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14663775  }} </ref><ref name="pmid16708354">{{cite journal| author=Tward JD, Wendland MM, Shrieve DC, Szabo A, Gaffney DK| title=The risk of secondary malignancies over 30 years after the treatment of non-Hodgkin lymphoma. | journal=Cancer | year= 2006 | volume= 107 | issue= 1 | pages= 108-15 | pmid=16708354 | doi=10.1002/cncr.21971 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16708354  }} </ref>
* Non-Hodgkins lymphoma<ref name="pmid8230284">{{cite journal| author=Travis LB, Curtis RE, Glimelius B, Holowaty E, Van Leeuwen FE, Lynch CF et al.| title=Second cancers among long-term survivors of non-Hodgkin's lymphoma. | journal=J Natl Cancer Inst | year= 1993 | volume= 85 | issue= 23 | pages= 1932-7 | pmid=8230284 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8230284  }} </ref>
* Testicular cancer
* Breast cancer


Experimental evidence suggests that asbestos acts as a complete carcinogen with the development of mesothelioma occurring in sequential stages of initiation and promotion.  The molecular mechanisms underlying the malignant transformation of normal mesothelial cells by asbestos fibres remain unclear despite the demonstration of its oncogenic capabilities.  However, complete in vitro transformation of normal human mesothelial cells to malignant phenotype following exposure to asbestos fibres has not yet been achieved.  In general, asbestos fibres are thought to act through direct physical interactions with the cells of the mesothelium in conjunction with indirect effects following interaction with inflammatory cells such as macrophages.
===Smoking===
 
* Smoking has a synergistic effect on asbestos fibre inhalation in the pathogenesis of mesothelioma.
Analysis of the interactions between asbestos fibres and DNA has shown that phagocytosed fibres are able to make contact with [[chromosome]]s, often adhering to the [[chromatin]] fibres or becoming entangled within the chromosome.  This contact between the asbestos fibre and the chromosomes or structural proteins of the spindle apparatus can induce complex abnormalities. The most common abnormality is [[monosomy]] of chromosome 22. Other frequent abnormalities include structural rearrangement of 1p, 3p, 9p and 6q chromosome arms.  


==Genetics==
==Genetics==
*Development of mesothelioma is the result of multiple [[mutation|genetic mutations]].
*Development of mesothelioma is the result of multiple [[mutation|genetic mutations]].
*Genes involved in the pathogenesis of mesothelioma include:<ref name="ThomasChen2015">{{cite journal|last1=Thomas|first1=Anish|last2=Chen|first2=Yuanbin|last3=Yu|first3=Tinghui|last4=Gill|first4=Ammara|last5=Prasad|first5=Vinay|title=Distinctive clinical characteristics of malignant mesothelioma in young patients|journal=Oncotarget|volume=6|issue=18|year=2015|pages=16766–16773|issn=1949-2553|doi=10.18632/oncotarget.4414}}</ref><ref name="pmid15950811">{{cite journal| author=Ladanyi M| title=Implications of P16/CDKN2A deletion in pleural mesotheliomas. | journal=Lung Cancer | year= 2005 | volume= 49 Suppl 1 | issue= | pages= S95-8 | pmid=15950811 | doi=10.1016/j.lungcan.2005.03.017 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15950811 }} </ref>
*Genes involved in the pathogenesis of mesothelioma include:<ref name="pmid15950811">{{cite journal| author=Ladanyi M| title=Implications of P16/CDKN2A deletion in pleural mesotheliomas. | journal=Lung Cancer | year= 2005 | volume= 49 Suppl 1 | issue= | pages= S95-8 | pmid=15950811 | doi=10.1016/j.lungcan.2005.03.017 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15950811  }} </ref><ref name="pmid9072005">{{cite journal| author=Kumar-Singh S, Segers K, Rodeck U, Backhovens H, Bogers J, Weyler J et al.| title=WT1 mutation in malignant mesothelioma and WT1 immunoreactivity in relation to p53 and growth factor receptor expression, cell-type transition, and prognosis. | journal=J Pathol | year= 1997 | volume= 181 | issue= 1 | pages= 67-74 | pmid=9072005 | doi=10.1002/(SICI)1096-9896(199701)181:1<67::AID-PATH723>3.0.CO;2-Z | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9072005  }} </ref><ref name="pmid22825583">{{cite journal| author=Ladanyi M, Zauderer MG, Krug LM, Ito T, McMillan R, Bott M et al.| title=New strategies in pleural mesothelioma: BAP1 and NF2 as novel targets for therapeutic development and risk assessment. | journal=Clin Cancer Res | year= 2012 | volume= 18 | issue= 17 | pages= 4485-90 | pmid=22825583 | doi=10.1158/1078-0432.CCR-11-2375 | pmc=PMC3432735 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22825583  }} </ref><ref name="pmid23435014">{{cite journal| author=Andujar P, Pairon JC, Renier A, Descatha A, Hysi I, Abd-Alsamad I et al.| title=Differential mutation profiles and similar intronic TP53 polymorphisms in asbestos-related lung cancer and pleural mesothelioma. | journal=Mutagenesis | year= 2013 | volume= 28 | issue= 3 | pages= 323-31 | pmid=23435014 | doi=10.1093/mutage/get008 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23435014  }} </ref><ref name="pmid18248818">{{cite journal| author=Opitz I, Soltermann A, Abaecherli M, Hinterberger M, Probst-Hensch N, Stahel R et al.| title=PTEN expression is a strong predictor of survival in mesothelioma patients. | journal=Eur J Cardiothorac Surg | year= 2008 | volume= 33 | issue= 3 | pages= 502-6 | pmid=18248818 | doi=10.1016/j.ejcts.2007.09.045 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18248818  }} </ref><ref name="pmid21245096">{{cite journal| author=Murakami H, Mizuno T, Taniguchi T, Fujii M, Ishiguro F, Fukui T et al.| title=LATS2 is a tumor suppressor gene of malignant mesothelioma. | journal=Cancer Res | year= 2011 | volume= 71 | issue= 3 | pages= 873-83 | pmid=21245096 | doi=10.1158/0008-5472.CAN-10-2164 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21245096 }} </ref>
:*''[[BAP1]]''
:*''[[BAP1]]''
:*''[[CDKN2A]]''
:*''[[CDKN2A]]''
:*''[[WT1]]''
:*''[[NF2 gene|NF2]]''
:*''[[TP53]]''
:*''[[PTEN]]''
:*''MSLN''
:*''[[LATS2]]''
*[[Asbestos]] has also been shown to mediate the entry of foreign DNA into target cells.  Incorporation of this foreign DNA may lead to [[mutation]]s and [[oncogenesis]], by several possible mechanisms:
:*Inactivation of [[tumor suppressor gene]]s
:*Activation of [[oncogene]]s
:*Activation of [[oncogene#proto-oncogene|proto-oncogenes]] due to incorporation of foreign DNA containing a [[promoter]] region
:*Activation of DNA repair enzymes, which may be prone to error
:*Activation of [[telomerase]]
:*Prevention of [[apoptosis]]


Common gene abnormalities in mesothelioma cell lines include deletion of the [[tumor suppressor gene]]s:
==Gross Pathology==
 
The following features are seen on gross pathology of mesothelioma:<ref name="epidemiologymesothelioma1">Mesothelioma. CGMH.ORG 2016. https://www1.cgmh.org.tw/intr/intr5/c6700/OBGYN/f/web/Mesothelioma/index.htm. Accessed on February 15, 2016</ref>
* [[Neurofibromatosis]] type 2 at 22q12
*On gross pathology, [[Pleural cavity|pleural]] mesothelioma is characterized by discrete [[Plaque|plaques]] and nodules that coalesce to produce a sheet-like tumor, with the pleural surface seeding of [[malignant]] mesothelioma cells.
* P16<sup>INK4A</sup>
*The growth usually starts at the inferior margins of the [[pleura]] and may invade the [[diaphragm]].
* P14<sup>ARF</sup>
*The lung and interlobar [[Fissure|fissures]] may also be involved.
 
Asbestos has also been shown to mediate the entry of foreign DNA into target cells.  Incorporation of this foreign DNA may lead to mutations and oncogenesis by several possible mechanisms:
 
* Inactivation of tumor suppressor genes
* Activation of [[oncogene]]s
* Activation of [[oncogene#proto-oncogene|proto-oncogenes]] due to incorporation of foreign DNA containing a [[promoter]] region
* Activation of DNA repair enzymes, which may be prone to error
* Activation of [[telomerase]]
* Prevention of [[apoptosis]]


Asbestos fibres have been shown to alter the function and secretory properties of macrophages, ultimately creating conditions which favour the development of mesothelioma. Following asbestos phagocytosis, macrophages generate increased amounts of hydroxyl [[radical (chemistry)|radicals]], which are normal by-products of cellular anaerobic metabolism. However, these free radicals are also known [[clastogenic]] and membrane-active agents thought to promote asbestos carcinogenicity.  These oxidants can participate in the oncogenic process by directly and indirectly interacting with DNA, modifying membrane-associated cellular events, including oncogene activation and perturbation of cellular antioxidant defences.
===Gallery===
<gallery>
Image:Mesothelioma gross pathology image 1.jpg|<sub>Mesothelioma completely encasing the lung.<ref name=grosspictureofmesotheliomaimage1>Image courtesy of Dr. Yale Rosen. Radiopaedia (original file [http://radiopaedia.org/cases/mesothelioma-gross-pathology-1 here]). Creative Commons BY-SA-NC
</ref></sub></gallery>


Asbestos also may possess [[immunosuppressant|immunosuppressive]] properties. For example, chrysotile fibres have been shown to depress the in vitro proliferation of phytohemagglutinin-stimulated peripheral blood lymphocytes, suppress natural killer cell lysis and significantly reduce [[lymphokine-activated killer cell]] viability and recovery. Furthermore, genetic alterations in asbestos-activated macrophages may result in the release of potent mesothelial cell mitogens such as [[platelet-derived growth factor]] (PDGF) and [[transforming growth factor]]-β (TGF-β) which in turn, may induce the chronic stimulation and proliferation of mesothelial cells after injury by asbestos fibres.
==Microscopic Pathology==
Based on the '''histology''', mesothelioma may be classified into 3 subtypes:<ref name="mesotheliomaclass1">Mesothelioma. Dr Bruno Di Muzio and A.Prof Frank Gaillard et al. Radiopaedia 2016. http://radiopaedia.org/articles/mesothelioma. Accessed on February 8, 2016</ref>
*Epithelial
*Sarcomatoid
*Biphasic (mixed)


==Immunohistochemistry==
==Immunohistochemistry==
*The cytological and histological diagnosis can be difficult, with mesothelial hyperplasia and metastatic adenocarcinoma appearing similar. Specific markers may be helpful in the diagnosis of mesothelioma.<ref name=pathologymesotehelioma1>Pathology of mesothelioma. Dr Bruno Di Muzio and A.Prof Frank Gaillard et al. Radiopaedia 2016. http://radiopaedia.org/articles/mesothelioma. Accessed on February 10, 2016</ref>
*The cytological and histological diagnosis can be difficult, with mesothelial hyperplasia and metastatic adenocarcinoma appearing similar. Specific markers may be helpful in the diagnosis of mesothelioma.<ref name="pathologymesotehelioma1">Pathology of mesothelioma. Dr Bruno Di Muzio and A.Prof Frank Gaillard et al. Radiopaedia 2016. http://radiopaedia.org/articles/mesothelioma. Accessed on February 10, 2016</ref>
*Mesothelioma is demonstrated by positivity to [[tumor marker]]s, such as:<ref name=pathologymesotehelioma1>Pathology of mesothelioma. Dr Bruno Di Muzio and A.Prof Frank Gaillard et al. Radiopaedia 2016. http://radiopaedia.org/articles/mesothelioma. Accessed on February 10, 2016</ref><ref name=ihcmesothelioma1>Immunohistochemistry of mesothelioma. Wikipedia 2016. https://en.wikipedia.org/wiki/Mesothelioma. Accessed on February 12, 2016</ref>
*Mesothelioma is demonstrated by positivity to [[tumor marker]]s, such as:<ref name="pathologymesotehelioma1">Pathology of mesothelioma. Dr Bruno Di Muzio and A.Prof Frank Gaillard et al. Radiopaedia 2016. http://radiopaedia.org/articles/mesothelioma. Accessed on February 10, 2016</ref><ref name="ihcmesothelioma1">Immunohistochemistry of mesothelioma. Wikipedia 2016. https://en.wikipedia.org/wiki/Mesothelioma. Accessed on February 12, 2016</ref>
:*[[Calretinin]]
:*[[Calretinin]]
:*Epithelial membrane antigen
:*Epithelial membrane antigen
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[[Category:Asbestos]]
[[Category:Asbestos]]
[[Category:Occupational diseases]]
[[Category:Occupational diseases]]
[[Category:Oncology]]
[[Category:Up-To-Date]]
[[Category:Oncology]]
[[Category:Medicine]]

Latest revision as of 19:37, 9 March 2018


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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Feham Tariq, MD [2],Sujit Routray, M.D. [3]

Overview

Asbestos causes DNA damage directly by mechanically interfering with the segregation of chromosomes during mitosis and indirectly by inducing mesothelial cells and macrophages, to release mutagenic reactive oxygen and nitrogen species. Asbestos fibres have been shown to alter the function and secretory properties of macrophages, ultimately creating conditions which favor the development of mesothelioma. Following asbestos phagocytosis, macrophages generate increased amounts of hydroxyl radicals, which are normal by-products of cellular anaerobic metabolism. However, these free radicals are also known clastogenic and membrane-active agents thought to promote asbestos carcinogenicity. These oxidants can participate in the oncogenic process by directly and indirectly interacting with DNA, modifying membrane-associated cellular events, including oncogene activation and perturbation of cellular antioxidant defences. Genes involved in the pathogenesis of mesothelioma include BAP1, CDKN2A, WT1, NF2, and TP53. On gross pathology, pleural mesothelioma is characterized by discrete plaques and nodules that coalesce to produce a sheet-like tumor, with the pleural surface seeding of malignant mesothelioma cells. Based on the histology, mesothelioma may be classified into 3 subtypes: epithelial, sarcomatoid, and biphagic. Mesothelioma is demonstrated by positivity to tumor markers, such as calretinin, epithelial membrane antigen, cytokeratin, and mesothelin.

Pathogenesis

The pathogenesis of mesothelioma is influenced by the following factors:[1][2][3][4]

Types of Asbestos fibres

There are two types of asbestos fibers:

Role of Asbestos fibers

Asbestos fibers play the following role in the development of mesothelioma:

  • The most common type of fibres found in US are the serpentine fibers, which are considered less carcinogenic than the amphibole ones.
  • Following inhalation from the environment, these fibres are trapped in the lower third zone of the lung.
  • They are phagocytosed by the mesothelial cells and initiate an oncogenic cascade of events which include:
    • Activation of c-Myc and c-Jun oncogene
    • Promotion of antiapoptotic genes such as Bcl-xL
    • Binding with epidermal growth factor receptor (EGFR)
  • Asbestos causes DNA damage directly by mechanically interfering with the segregation of chromosomes during mitosis and indirectly by inducing mesothelial cells and macrophages, to release mutagenic reactive oxygen and nitrogen species.
  • Asbestos fibres have been shown to alter the function and secretory properties of macrophages, ultimately creating conditions which favor the development of mesothelioma.
  • Following asbestos phagocytosis, macrophages generate increased amounts of hydroxyl radicals, which are normal by-products of cellular anaerobic metabolism.
  • However, these free radicals are also known clastogenic and membrane-active agents thought to promote asbestos carcinogenicity. These oxidants can participate in the oncogenic process by directly and indirectly interacting with DNA, modifying membrane-associated cellular events, including oncogene activation and perturbation of cellular antioxidant defences.
  • The mesothelium consists of a single layer of flattened to cuboidal cells forming the epithelial lining of the serous cavities of the body including the peritoneal, pericardial and pleural cavities.
  • Deposition of asbestos fibres in the parenchyma of the lung may result in the penetration of the visceral pleura from where the fibre can then be carried to the pleural surface, thus leading to the development of malignant mesothelial plaques.
  • The processes leading to the development of peritoneal mesothelioma remain unresolved, although it has been proposed that asbestos fibres from the lung are transported to the abdomen and associated organs via the lymphatic system.
  • Additionally, asbestos fibres may be deposited in the gut after ingestion of sputum contaminated with asbestos fibres.
  • Asbestos also may possess immunosuppressive properties. For example, chrysotile fibres have been shown to depress the in-vitro proliferation of phytohemagglutinin-stimulated peripheral blood lymphocytes, suppress natural killer cell lysis, and significantly reduce lymphokine-activated killer cell viability and recovery.
  • Furthermore, genetic alterations in asbestos-activated macrophages may result in the release of potent mesothelial cell mitogens such as platelet-derived growth factor (PDGF) and transforming growth factor-β (TGF-β) which in turn, may induce the chronic stimulation and proliferation of mesothelial cells after injury by asbestos fibres.

Radiation therapy

Survivors of radiation therapy have been found to develop mesothelioma according to several studies. Following cancers have been studied post-radiation therapy which are seen to develop mesothelioma:[5][6][7]

  • Non-Hodgkins lymphoma[8]
  • Testicular cancer
  • Breast cancer

Smoking

  • Smoking has a synergistic effect on asbestos fibre inhalation in the pathogenesis of mesothelioma.

Genetics

  • Asbestos has also been shown to mediate the entry of foreign DNA into target cells. Incorporation of this foreign DNA may lead to mutations and oncogenesis, by several possible mechanisms:

Gross Pathology

The following features are seen on gross pathology of mesothelioma:[15]

  • On gross pathology, pleural mesothelioma is characterized by discrete plaques and nodules that coalesce to produce a sheet-like tumor, with the pleural surface seeding of malignant mesothelioma cells.
  • The growth usually starts at the inferior margins of the pleura and may invade the diaphragm.
  • The lung and interlobar fissures may also be involved.

Gallery

  • Mesothelioma completely encasing the lung.<ref name=grosspictureofmesotheliomaimage1>Image courtesy of Dr. Yale Rosen. Radiopaedia (original file here). Creative Commons BY-SA-NC

    Mesothelioma completely encasing the lung.<ref name=grosspictureofmesotheliomaimage1>Image courtesy of Dr. Yale Rosen. Radiopaedia (original file here). Creative Commons BY-SA-NC

Microscopic Pathology

Based on the histology, mesothelioma may be classified into 3 subtypes:[16]

  • Epithelial
  • Sarcomatoid
  • Biphasic (mixed)

Immunohistochemistry

  • The cytological and histological diagnosis can be difficult, with mesothelial hyperplasia and metastatic adenocarcinoma appearing similar. Specific markers may be helpful in the diagnosis of mesothelioma.[17]
  • Mesothelioma is demonstrated by positivity to tumor markers, such as:[17][18]

References

  1. ↑ Selikoff IJ, Hammond EC, Seidman H (1980). "Latency of asbestos disease among insulation workers in the United States and Canada". Cancer. 46 (12): 2736–40. PMID 7448712.
  2. ↑ Heintz NH, Janssen-Heininger YM, Mossman BT (2010). "Asbestos, lung cancers, and mesotheliomas: from molecular approaches to targeting tumor survival pathways". Am J Respir Cell Mol Biol. 42 (2): 133–9. doi:10.1165/rcmb.2009-0206TR. PMC 2822975. PMID 20068227.
  3. ↑ Thomas, Anish; Chen, Yuanbin; Yu, Tinghui; Gill, Ammara; Prasad, Vinay (2015). "Distinctive clinical characteristics of malignant mesothelioma in young patients". Oncotarget. 6 (18): 16766–16773. doi:10.18632/oncotarget.4414. ISSN 1949-2553.
  4. ↑ Shukla A, Gulumian M, Hei TK, Kamp D, Rahman Q, Mossman BT (2003). "Multiple roles of oxidants in the pathogenesis of asbestos-induced diseases". Free Radic Biol Med. 34 (9): 1117–29. PMID 12706492.
  5. ↑ Travis LB, Fosså SD, Schonfeld SJ, McMaster ML, Lynch CF, Storm H; et al. (2005). "Second cancers among 40,576 testicular cancer patients: focus on long-term survivors". J Natl Cancer Inst. 97 (18): 1354–65. doi:10.1093/jnci/dji278. PMID 16174857.
  6. ↑ Matesich SM, Shapiro CL (2003). "Second cancers after breast cancer treatment". Semin Oncol. 30 (6): 740–8. PMID 14663775.
  7. ↑ Tward JD, Wendland MM, Shrieve DC, Szabo A, Gaffney DK (2006). "The risk of secondary malignancies over 30 years after the treatment of non-Hodgkin lymphoma". Cancer. 107 (1): 108–15. doi:10.1002/cncr.21971. PMID 16708354.
  8. ↑ Travis LB, Curtis RE, Glimelius B, Holowaty E, Van Leeuwen FE, Lynch CF; et al. (1993). "Second cancers among long-term survivors of non-Hodgkin's lymphoma". J Natl Cancer Inst. 85 (23): 1932–7. PMID 8230284.
  9. ↑ Ladanyi M (2005). "Implications of P16/CDKN2A deletion in pleural mesotheliomas". Lung Cancer. 49 Suppl 1: S95–8. doi:10.1016/j.lungcan.2005.03.017. PMID 15950811.
  10. ↑ Kumar-Singh S, Segers K, Rodeck U, Backhovens H, Bogers J, Weyler J; et al. (1997). "WT1 mutation in malignant mesothelioma and WT1 immunoreactivity in relation to p53 and growth factor receptor expression, cell-type transition, and prognosis". J Pathol. 181 (1): 67–74. doi:10.1002/(SICI)1096-9896(199701)181:1<67::AID-PATH723>3.0.CO;2-Z. PMID 9072005.
  11. ↑ Ladanyi M, Zauderer MG, Krug LM, Ito T, McMillan R, Bott M; et al. (2012). "New strategies in pleural mesothelioma: BAP1 and NF2 as novel targets for therapeutic development and risk assessment". Clin Cancer Res. 18 (17): 4485–90. doi:10.1158/1078-0432.CCR-11-2375. PMC 3432735. PMID 22825583.
  12. ↑ Andujar P, Pairon JC, Renier A, Descatha A, Hysi I, Abd-Alsamad I; et al. (2013). "Differential mutation profiles and similar intronic TP53 polymorphisms in asbestos-related lung cancer and pleural mesothelioma". Mutagenesis. 28 (3): 323–31. doi:10.1093/mutage/get008. PMID 23435014.
  13. ↑ Opitz I, Soltermann A, Abaecherli M, Hinterberger M, Probst-Hensch N, Stahel R; et al. (2008). "PTEN expression is a strong predictor of survival in mesothelioma patients". Eur J Cardiothorac Surg. 33 (3): 502–6. doi:10.1016/j.ejcts.2007.09.045. PMID 18248818.
  14. ↑ Murakami H, Mizuno T, Taniguchi T, Fujii M, Ishiguro F, Fukui T; et al. (2011). "LATS2 is a tumor suppressor gene of malignant mesothelioma". Cancer Res. 71 (3): 873–83. doi:10.1158/0008-5472.CAN-10-2164. PMID 21245096.
  15. ↑ Mesothelioma. CGMH.ORG 2016. https://www1.cgmh.org.tw/intr/intr5/c6700/OBGYN/f/web/Mesothelioma/index.htm. Accessed on February 15, 2016
  16. ↑ Mesothelioma. Dr Bruno Di Muzio and A.Prof Frank Gaillard et al. Radiopaedia 2016. http://radiopaedia.org/articles/mesothelioma. Accessed on February 8, 2016
  17. ↑ 17.0 17.1 Pathology of mesothelioma. Dr Bruno Di Muzio and A.Prof Frank Gaillard et al. Radiopaedia 2016. http://radiopaedia.org/articles/mesothelioma. Accessed on February 10, 2016
  18. ↑ Immunohistochemistry of mesothelioma. Wikipedia 2016. https://en.wikipedia.org/wiki/Mesothelioma. Accessed on February 12, 2016


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