Hereditary nonpolyposis colorectal cancer pathophysiology: Difference between revisions

Jump to navigation Jump to search
VisualWikitext
No edit summary
 
(46 intermediate revisions by 6 users not shown)
Line 1: Line 1:
__NOTOC__
__NOTOC__
{{Hereditary nonpolyposis colorectal cancer}}
{{Hereditary nonpolyposis colorectal cancer}}
{{CMG}}{{AE}}{{MV}}
{{CMG}}{{AE}}{{MV}} {{Akram}}


==Overview==
==Overview==
 
Hereditary nonpolyposis colorectal cancer is an [[autosomal dominant]] [[genetic]] [[disease]] characterized by an early onset of [[colon cancer]], [[endometrial cancer]], and other [[malignant]] [[tumors]]. Development of hereditary nonpolyposis colorectal cancer is the result of multiple [[genetic mutation]]s. The [[Gene|genes]] involved in the [[pathogenesis]] of hereditary nonpolyposis colorectal cancer include: [[MSH2|MSH-2]], [[MLH1|MLH-1]], [[MSH6|MSH-6]], [[PMS2|PMS-2]] , [[PMS1|PMS-1]], [[TGFBR2|TGF-BR2]], and [[MLH3|MLH-3]]. This [[syndrome]] occurs most commonly in the [[proximal]] [[colon]] (60% to 80%). [[Endometrial cancer]] is the most common [[Sentinel event|sentinel]] [[cancer]] among [[female]] [[patients]] with hereditary nonpolyposis colorectal cancer.
HNPCC is an autosomal dominant genetic disease characterized by the early onset of [[colon cancer]], [[endometrial cancer]] and other tumors caused by a genetic mutation within [[DNA]] mismatch repair (MMR) genes.<ref name="pmid26474631">{{cite journal |vauthors=Si JW, Wang L, Ba XJ, Zhang X, Dong Y, Zhang JX, Li WT, Li T |title=[Clinicopathological screening of Lynch syndrome: a report of 2 cases and literature review] |language=Chinese |journal=Beijing Da Xue Xue Bao |volume=47 |issue=5 |pages=858–64 |year=2015 |pmid=26474631 |doi= |url=}}</ref>


==Pathogenesis==
==Pathogenesis==
HNPCC defects in [[DNA mismatch repair]] lead to [[microsatellite instability]], also known as MSI-H, which is a hallmark of HNPCC. Three major groups of MSI-H cancers can be recognized by histopathological criteria:
*Hereditary nonpolyposis colorectal cancer results from a defect in the [[DNA mismatch repair]] mechanism that leads to [[microsatellite instability|microsatellite instability (MSI)]], which is a hallmark of the [[disease]].
* (1) right-sided poorly differentiated cancers
* Most cases result in changes in the lengths of [[Tandem repeat|dinucleotide repeats]] of the [[nucleobase]]s [[cytosine]] and [[adenine]].<ref>{{cite journal | vauthors = Oki E, Oda S, Maehara Y, Sugimachi K | title = Mutated gene-specific phenotypes of dinucleotide repeat instability in human colorectal carcinoma cell lines deficient in DNA mismatch repair | journal = Oncogene | volume = 18 | issue = 12 | pages = 2143–7 | date = Mar 1999 | pmid = 10321739 | pmc =  | doi = 10.1038/sj.onc.1202583 }}</ref>
* (2) right-sided mucinous cancers
*[[Microsatellite instability|Microsatellite instability (MSI)]] is a [[surrogate marker]] for [[DNA mismatch repair]] [[gene]] dysfunction.<ref>Lynch syndrome.Ganfyd.http://www.ganfyd.org/index.php?title=Lynch_syndrome Accessed on December 01, 2015</ref><ref name="pmid10348829">{{cite journal |vauthors=Vasen HF, Watson P, Mecklin JP, Lynch HT |title=New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC |journal=Gastroenterology |volume=116 |issue=6 |pages=1453–6 |year=1999 |pmid=10348829 |doi= |url=}}</ref>
* (3) [[adenocarcinomas]] in any location showing any measurable level of [[intraepithelial lymphocyte]] (TIL)
*In hereditary nonpolyposis colorectal cancer, [[Colon (anatomy)|colon]] [[Cancer|malignancies]] usually occur from a single or multiple [[Adenoma|adenomas]], and mostly in the [[Anatomical terms of location|proximal]] [[Colon (anatomy)|colon]].
 
MSI is identifiable in [[cancer]] specimens in the [[pathology]] laboratory. In hereditary nonpolyposis colorectal cancer, colon malignancies usually occur from a single or a few adenomas, and mostly occurs in the proximal colon.


==Genetics==
==Genetics==
HNPCC is known to be associated with mutations in [[gene]]s involved in the [[DNA mismatch repair]] pathway
*Hereditary nonpolyposis colorectal cancer is inherited in an [[autosomal dominant]] manner.
*Development of hereditary nonpolyposis colorectal cancer is the result of multiple [[genetic mutation]]s.<ref name="pmid26474631">{{cite journal |vauthors=Si JW, Wang L, Ba XJ, Zhang X, Dong Y, Zhang JX, Li WT, Li T |title=[Clinicopathological screening of Lynch syndrome: a report of 2 cases and literature review] |language=Chinese |journal=Beijing Da Xue Xue Bao |volume=47 |issue=5 |pages=858–64 |year=2015 |pmid=26474631 |doi= |url=}}</ref>
* Most [[Mutation|mutations]] (90%) that cause hereditary nonpolyposis colorectal cancer are found in the [[MLH1]] or [[MSH2]] [[genes]].<ref>Lynch Syndrome. Canadian Cancer Society http://www.cancer.ca/en/cancer-information/cancer-101/what-is-a-risk-factor/genetic-risk/lynch-syndrome/?region=ab#ixzz3t69IQ9M7 Accessed on December 01 2015 </ref>
*[[MSH6]] and [[PMS2]] account for the other 10% of mutations.<ref>Lynch Syndrome. Canadian Cancer Society http://www.cancer.ca/en/cancer-information/cancer-101/what-is-a-risk-factor/genetic-risk/lynch-syndrome/?region=ab#ixzz3t69IQ9M7 Accessed on December 01 2015 </ref>
*[[Endometrial cancer]] is the most common distant [[cancer]] among female [[Patient|patients]] with hereditary nonpolyposis colorectal cancer.
*[[MSH2]] [[Mutation|mutations]] have an increased risk of [[Transitional cell carcinoma|urothelial carcinoma]] relative to [[MLH1]] and [[MSH6]] [[Mutation|mutations]].<ref name="pmid20591884">{{Cite journal  | last1 = van der Post | first1 = RS. | last2 = Kiemeney | first2 = LA. | last3 = Ligtenberg | first3 = MJ. | last4 = Witjes | first4 = JA. | last5 = Hulsbergen-van de Kaa | first5 = CA. | last6 = Bodmer | first6 = D. | last7 = Schaap | first7 = L. | last8 = Kets | first8 = CM. | last9 = van Krieken | first9 = JH. | title = Risk of urothelial bladder cancer in Lynch syndrome is increased, in particular among MSH2 mutation carriers. | journal = J Med Genet | volume = 47 | issue = 7 | pages = 464-70 | month = Jul | year = 2010 | doi = 10.1136/jmg.2010.076992 | PMID = 20591884 }}</ref>


{| class="wikitable"
====== The table below lists the [[Gene|genes]] involved in the [[pathogenesis]] of hereditary nonpolyposis colorectal cancer: ======
![[OMIM]] name
{| style="border: 0px; font-size: 90%; margin: 3px; width: 800px" align="center"
!Genes implicated in HNPCC
| valign="top" |
!Frequency of mutations in HNPCC families
|+
!Locus
! style="background: #4479BA; width: 50px;" |{{fontcolor|#FFF|Genes implicated in hereditary nonpolyposis colorectal cancer}}
!First publication
! style="background: #4479BA; width: 100px;" |{{fontcolor|#FFF|Frequency of mutations in hereditary nonpolyposis colorectal cancer families}}
! style="background: #4479BA; width: 50px;" |{{fontcolor|#FFF|Locus}}
|-
|-
|HNPCC1 ({{OMIM2|120435}})
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold; text-align:center;" |[[MSH2]]
|[[MSH2]]
| style="padding: 5px 5px; background: #F5F5F5;" |Approximately 60%
| approximately 60%
| style="padding: 5px 5px; background: #F5F5F5;" |2p22
| 2p22
|Fishel 1993<ref>{{cite journal | vauthors = Fishel R, Lescoe MK, Rao MR, Copeland NG, Jenkins NA, Garber J, Kane M, Kolodner R | title = The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer | journal = Cell | volume = 75 | issue = 5 | pages = 1027–38 | date = Dec 1993 | pmid = 8252616 | doi = 10.1016/0092-8674(93)90546-3 }}</ref>
|-
|-
| HNPCC2 ({{OMIM2|609310}})
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold; text-align:center;" |[[MLH1]]
|[[MLH1]]
| style="padding: 5px 5px; background: #F5F5F5;" | Approximately 30%
| approximately 30%
| style="padding: 5px 5px; background: #F5F5F5;" |3p21
| 3p21
|Papadopoulos 1994<ref>{{cite journal | vauthors = Papadopoulos N, Nicolaides NC, Wei YF, Ruben SM, Carter KC, Rosen CA, Haseltine WA, Fleischmann RD, Fraser CM, Adams MD | title = Mutation of a mutL homolog in hereditary colon cancer | journal = Science | volume = 263 | issue = 5153 | pages = 1625–9 | date = Mar 1994 | pmid = 8128251 | doi = 10.1126/science.8128251 }}</ref>
|-
|-
|HNPCC5
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold; text-align:center;" |[[MSH6]]
|[[MSH6]]
| style="padding: 5px 5px; background: #F5F5F5;" | 7 - 10%
| 7-10%
| style="padding: 5px 5px; background: #F5F5F5;" |2p16
| 2p16
|Miyaki 1997<ref>{{cite journal | vauthors = Miyaki M, Konishi M, Tanaka K, Kikuchi-Yanoshita R, Muraoka M, Yasuno M, Igari T, Koike M, Chiba M, Mori T | title = Germline mutation of MSH6 as the cause of hereditary nonpolyposis colorectal cancer | journal = Nature Genetics | volume = 17 | issue = 3 | pages = 271–2 | date = Nov 1997 | pmid = 9354786 | doi = 10.1038/ng1197-271 }}</ref>
|-
|-
|HNPCC4
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold; text-align:center;" |[[PMS2]]
|[[PMS2]]
| style="padding: 5px 5px; background: #F5F5F5;" |Relatively infrequent
| relatively infrequent
| style="padding: 5px 5px; background: #F5F5F5;" |7p22
|7p22 <ref>{{cite journal | vauthors = Nicolaides NC, Papadopoulos N, Liu B, Wei YF, Carter KC, Ruben SM, Rosen CA, Haseltine WA, Fleischmann RD, Fraser CM | title = Mutations of two PMS homologues in hereditary nonpolyposis colon cancer | journal = Nature | volume = 371 | issue = 6492 | pages = 75–80 | date = Sep 1994 | pmid = 8072530 | doi = 10.1038/371075a0 }}</ref>
| Nicolaides 1994
|-
|-
|HNPCC3
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold; text-align:center;" |[[PMS1]]
|[[PMS1]]
| style="padding: 5px 5px; background: #F5F5F5;" |Case report
| case report<ref name="pmid8072530">{{cite journal | vauthors = Nicolaides NC, Papadopoulos N, Liu B, Wei YF, Carter KC, Ruben SM, Rosen CA, Haseltine WA, Fleischmann RD, Fraser CM | title = Mutations of two PMS homologues in hereditary nonpolyposis colon cancer | journal = Nature | volume = 371 | issue = 6492 | pages = 75–80 | date = Sep 1994 | pmid = 8072530 | doi = 10.1038/371075a0 }}</ref>
| style="padding: 5px 5px; background: #F5F5F5;" |2q31-q33
| 2q31-q33
| Nicolaides 1994
|-
|-
|HNPCC6
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold; text-align:center;" |[[TGFBR2]]
|[[TGFBR2]]
| style="padding: 5px 5px; background: #F5F5F5;" |Case report
| case report<ref name="pmid9590282">{{cite journal | vauthors = Lu SL, Kawabata M, Imamura T, Akiyama Y, Nomizu T, Miyazono K, Yuasa Y | title = HNPCC associated with germline mutation in the TGF-beta type II receptor gene | journal = Nature Genetics | volume = 19 | issue = 1 | pages = 17–8 | date = May 1998 | pmid = 9590282 | doi = 10.1038/ng0598-17 }}</ref>
| style="padding: 5px 5px; background: #F5F5F5;" |3p22  
| 3p22
|-
|-
|HNPCC7
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold; text-align:center;" |[[MLH3]]
|[[MLH3]]
| style="padding: 5px 5px; background: #F5F5F5;" |Disputed
| disputed<ref name="pmid19156873">{{cite journal | vauthors = Ou J, Rasmussen M, Westers H, Andersen SD, Jager PO, Kooi KA, Niessen RC, Eggen BJ, Nielsen FC, Kleibeuker JH, Sijmons RH, Rasmussen LJ, Hofstra RM | title = Biochemical characterization of MLH3 missense mutations does not reveal an apparent role of MLH3 in Lynch syndrome | journal = Genes, Chromosomes & Cancer | volume = 48 | issue = 4 | pages = 340–50 | date = Apr 2009 | pmid = 19156873 | doi = 10.1002/gcc.20644 }}</ref>
| style="padding: 5px 5px; background: #F5F5F5;" |14q24.3
| 14q24.3
|-
|-
|}
|}
Up to 39% of families with mutations in an HNPCC gene do not meet the [[Amsterdam criteria]]. Therefore, families found to have a deleterious mutation in an HNPCC gene should be considered to have HNPCC regardless of the extent of the family history.  This also means that the Amsterdam criteria fail to identify many patients at risk for Lynch syndrome.  Improving the criteria for screening is an active area of research, as detailed in the Screening Strategies section of this article.
[[Image:Autosomal Dominant Pedigree Chart.svg|thumb|center|250px| HNPCC is inherited in an [[autosomal dominant]] fashion.]]
HNPCC is inherited in an [[autosomal dominant]] manner.  Most people with HNPCC inherit the condition from a parent. However, due to incomplete penetrance, variable age of cancer diagnosis, cancer risk reduction, or early death, not all patients with an HNPCC gene mutation have a parent who had cancer.  Some patients develop HNPCC de-novo in a new generation, without inheriting the gene.  These patients are often only identified after developing an early-life colon cancer.  Parents with HNPCC have a 50% chance to pass the gene on to each child.


==Associated Conditions==
==Associated Conditions==
Line 77: Line 62:
*[[Colorectal carcinoma]]
*[[Colorectal carcinoma]]
*[[Endometrial carcinoma]]
*[[Endometrial carcinoma]]
**Non-endometrioid [[endometrial carcinoma]],<ref name=pmid20396392>{{cite journal |author=Okuda T, Sekizawa A, Purwosunu Y, ''et al.'' |title=Genetics of endometrial cancers |journal=Obstet Gynecol Int |volume=2010 |issue= |pages=984013 |year=2010 |pmid=20396392 |pmc=2852605 |doi=10.1155/2010/984013 |url=}}</ref> e.g. endometrial clear cell carcinoma.<ref name=pmid19638537>{{Cite journal  | last1 = Garg | first1 = K. | last2 = Soslow | first2 = RA. | title = Lynch syndrome (hereditary non-polyposis colorectal cancer) and endometrial carcinoma. | journal = J Clin Pathol | volume = 62 | issue = 8 | pages = 679-84 | month = Aug | year = 2009 | doi = 10.1136/jcp.2009.064949 | PMID = 19638537 | url = http://jcp.bmj.com/content/62/8/679.long }}</ref>
**Non-[[Endometrium|endometrioid]] [[endometrial carcinoma]]<ref name="pmid20396392">{{cite journal |author=Okuda T, Sekizawa A, Purwosunu Y, ''et al.'' |title=Genetics of endometrial cancers |journal=Obstet Gynecol Int |volume=2010 |issue= |pages=984013 |year=2010 |pmid=20396392 |pmc=2852605 |doi=10.1155/2010/984013 |url=}}</ref><ref name="pmid19638537">{{Cite journal  | last1 = Garg | first1 = K. | last2 = Soslow | first2 = RA. | title = Lynch syndrome (hereditary non-polyposis colorectal cancer) and endometrial carcinoma. | journal = J Clin Pathol | volume = 62 | issue = 8 | pages = 679-84 | month = Aug | year = 2009 | doi = 10.1136/jcp.2009.064949 | PMID = 19638537 | url = http://jcp.bmj.com/content/62/8/679.long }}</ref>
**Endometrioid endometrial carcinoma<ref name=pmid11873308>{{Cite journal  | last1 = Lax | first1 = SF. | title = [Dualistic model of molecular pathogenesis in endometrial carcinoma]. | journal = Zentralbl Gynakol | volume = 124 | issue = 1 | pages = 10-6 | month = Jan | year = 2002 | doi = 10.1055/s-2002-20303 | PMID = 11873308 }}</ref>
**[[Endometrium|Endometrioid]] [[Endometrial cancer|endometrial carcinoma]]<ref name="pmid11873308">{{Cite journal  | last1 = Lax | first1 = SF. | title = [Dualistic model of molecular pathogenesis in endometrial carcinoma]. | journal = Zentralbl Gynakol | volume = 124 | issue = 1 | pages = 10-6 | month = Jan | year = 2002 | doi = 10.1055/s-2002-20303 | PMID = 11873308 }}</ref>
**Suggestive features: lower uterine segment, tumor infiltrating lymphocytes.<ref name=pmid9638537>{{Cite journal  | last1 = Garg | first1 = K. | last2 = Soslow | first2 = RA. | title = Lynch syndrome (hereditary non-polyposis colorectal cancer) and endometrial carcinoma. | journal = J Clin Pathol | volume = 62 | issue = 8 | pages = 679-84 | month = Aug | year = 2009 | doi = 10.1136/jcp.2009.064949 | PMID = 19638537 }}</ref>
 
*[[Stomach carcinoma]],<ref name=OMIM120435>{{OMIM|120435}}</ref> intestinal-type.<ref name=pmid3581033>{{Cite journal  | last1 = Cristofaro | first1 = G. | last2 = Lynch | first2 = HT. | last3 = Caruso | first3 = ML. | last4 = Attolini | first4 = A. | last5 = DiMatteo | first5 = G. | last6 = Giorgio | first6 = P. | last7 = Senatore | first7 = S. | last8 = Argentieri | first8 = A. | last9 = Sbano | first9 = E. | title = New phenotypic aspects in a family with Lynch syndrome II. | journal = Cancer | volume = 60 | issue = 1 | pages = 51-8 | month = Jul | year = 1987 | doi =  | PMID = 3581033 }}</ref>
*[[Stomach carcinoma|Stomach carcinoma (intestinal type)]]<ref name="OMIM120435">{{OMIM|120435}}</ref><ref name="pmid3581033">{{Cite journal  | last1 = Cristofaro | first1 = G. | last2 = Lynch | first2 = HT. | last3 = Caruso | first3 = ML. | last4 = Attolini | first4 = A. | last5 = DiMatteo | first5 = G. | last6 = Giorgio | first6 = P. | last7 = Senatore | first7 = S. | last8 = Argentieri | first8 = A. | last9 = Sbano | first9 = E. | title = New phenotypic aspects in a family with Lynch syndrome II. | journal = Cancer | volume = 60 | issue = 1 | pages = 51-8 | month = Jul | year = 1987 | doi =  | PMID = 3581033 }}</ref>
**Significantly more common in males<ref name=pmid19215248>{{Cite journal  | last1 = Barrow | first1 = E. | last2 = Robinson | first2 = L. | last3 = Alduaij | first3 = W. | last4 = Shenton | first4 = A. | last5 = Clancy | first5 = T. | last6 = Lalloo | first6 = F. | last7 = Hill | first7 = J. | last8 = Evans | first8 = DG. | title = Cumulative lifetime incidence of extracolonic cancers in Lynch syndrome: a report of 121 families with proven mutations. | journal = Clin Genet | volume = 75 | issue = 2 | pages = 141-9 | month = Feb | year = 2009 | doi = 10.1111/j.1399-0004.2008.01125.x | PMID = 19215248 }}</ref>
*[[Cholangiocarcinoma|Biliary tree carcinoma]]<ref name="OMIM120435">{{OMIM|120435}}</ref>
<ref name=pmid12059060>{{Cite journal  | last1 = Renkonen-Sinisalo | first1 = L. | last2 = Sipponen | first2 = P. | last3 = Aarnio | first3 = M. | last4 = Julkunen | first4 = R. | last5 = Aaltonen | first5 = LA. | last6 = Sarna | first6 = S. | last7 = Järvinen | first7 = HJ. | last8 = Mecklin | first8 = JP. | title = No support for endoscopic surveillance for gastric cancer in hereditary non-polyposis colorectal cancer. | journal = Scand J Gastroenterol | volume = 37 | issue = 5 | pages = 574-7 | month = May | year = 2002 | doi =  | PMID = 12059060 }}</ref>
*[[Pancreatic cancer|Pancreatic carcinoma]]
*Biliary tree carcinoma<ref name=OMIM120435>{{OMIM|120435}}</ref>
*[[Urinary system]] [[carcinoma]]
*Pancreatic carcinoma<ref name=OMIM120435>{{OMIM|120435}}</ref>
*Urinary system carcinoma<ref name=OMIM120435>{{OMIM|120435}}</ref>
**More common in the [[ureter]] than in sporadic cancers<ref name=pmid21419447>{{Cite journal  | last1 = Crockett | first1 = DG. | last2 = Wagner | first2 = DG. | last3 = Holmäng | first3 = S. | last4 = Johansson | first4 = SL. | last5 = Lynch | first5 = HT. | title = Upper urinary tract carcinoma in Lynch syndrome cases. | journal = J Urol | volume = 185 | issue = 5 | pages = 1627-30 | month = May | year = 2011 | doi = 10.1016/j.juro.2010.12.102 | PMID = 21419447 }}</ref>
**Papillary lesions > flat lesions<ref name=pmid12673555>{{Cite journal  | last1 = Hartmann | first1 = A. | last2 = Dietmaier | first2 = W. | last3 = Hofstädter | first3 = F. | last4 = Burgart | first4 = LJ. | last5 = Cheville | first5 = JC. | last6 = Blaszyk | first6 = H. | title = Urothelial carcinoma of the upper urinary tract: inverted growth pattern is predictive of microsatellite instability. | journal = Hum Pathol | volume = 34 | issue = 3 | pages = 222-7 | month = Mar | year = 2003 | doi = 10.1053/hupa.2003.22 | PMID = 12673555 }}</ref>
**Extensive inverted growth pattern suggestive of MSI<ref name=pmid12673555/>
**MSH2 mutations have an increased risk of urothelial carcinoma relative to MLH1 and MSH6 mutations<ref name=pmid20591884>{{Cite journal  | last1 = van der Post | first1 = RS. | last2 = Kiemeney | first2 = LA. | last3 = Ligtenberg | first3 = MJ. | last4 = Witjes | first4 = JA. | last5 = Hulsbergen-van de Kaa | first5 = CA. | last6 = Bodmer | first6 = D. | last7 = Schaap | first7 = L. | last8 = Kets | first8 = CM. | last9 = van Krieken | first9 = JH. | title = Risk of urothelial bladder cancer in Lynch syndrome is increased, in particular among MSH2 mutation carriers. | journal = J Med Genet | volume = 47 | issue = 7 | pages = 464-70 | month = Jul | year = 2010 | doi = 10.1136/jmg.2010.076992 | PMID = 20591884 }}</ref>


==Gross Pathology==
==Gross Pathology==
 
*On [[gross pathology]], there are no characteristic findings of hereditary nonpolyposis colorectal cancer.<ref name="pmid26474631">{{cite journal |vauthors=Si JW, Wang L, Ba XJ, Zhang X, Dong Y, Zhang JX, Li WT, Li T |title=[Clinicopathological screening of Lynch syndrome: a report of 2 cases and literature review] |language=Chinese |journal=Beijing Da Xue Xue Bao |volume=47 |issue=5 |pages=858–64 |year=2015 |pmid=26474631 |doi= |url=}}</ref>
On gross pathology, there are no characteristic findings of HNPCC.  


==Microscopic Pathology==
==Microscopic Pathology==
 
*On [[microscopic]] [[Histopathology|histopathological]] [[analysis]], hereditary nonpolyposis colorectal cancer is more likely to be poorly differentiated, abundant in [[extracellular]] [[mucin]], and distinguished by a [[Lymphocyte|lymphoid]] (peritumoral [[Lymphocyte|lymphocytes]]) host response to the [[tumor]].<ref name="pmid26474631">{{cite journal |vauthors=Si JW, Wang L, Ba XJ, Zhang X, Dong Y, Zhang JX, Li WT, Li T |title=[Clinicopathological screening of Lynch syndrome: a report of 2 cases and literature review] |language=Chinese |journal=Beijing Da Xue Xue Bao |volume=47 |issue=5 |pages=858–64 |year=2015 |pmid=26474631 |doi= |url=}}</ref>
On microscopic histopathological analysis, HNPCC is more likely to be poorly differentiated, abundant in extracellular mucin, and distinguished by a lymphoid (peritumoral lymphocytes) host response to the tumor.
* Three major groups of MSI-H [[Cancer|cancers]] can be recognized by [[Histopathology|histopathological]] criteria, which include:<ref name="pmid19659756">{{cite journal| author=Lynch HT, Lynch PM, Lanspa SJ, Snyder CL, Lynch JF, Boland CR| title=Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications. | journal=Clin Genet | year= 2009 | volume= 76 | issue= 1 | pages= 1-18 | pmid=19659756 | doi=10.1111/j.1399-0004.2009.01230.x | pmc=2846640 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19659756  }} </ref><ref name="pmid29169633">{{cite journal| author=Ma H, Brosens LAA, Offerhaus GJA, Giardiello FM, de Leng WWJ, Montgomery EA| title=Pathology and genetics of hereditary colorectal cancer. | journal=Pathology | year= 2018 | volume= 50 | issue= 1 | pages= 49-59 | pmid=29169633 | doi=10.1016/j.pathol.2017.09.004 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29169633  }} </ref>  
 
**Right-sided poorly differentiated [[Cancer|cancers]]
 
**Right-sided [[Mucin|mucinous]] [[Cancer|cancers]]
==Gallery==
**[[Adenocarcinomas]] in any location showing any measurable level of [[intraepithelial lymphocyte]]
 
<gallery>
Image:<gallery>
Image:Muir-torre micropathology.jpg|<sub> [[Micrograph]] of a sebaceous adenoma, as may be seen in Muir-Torre syndrome.</sub>
</gallery>


==References==
==References==
Line 116: Line 89:
{{WikiDoc Help Menu}}
{{WikiDoc Help Menu}}
{{WikiDoc Sources}}
{{WikiDoc Sources}}
[[Category:Up-To-Date]]
[[Category:Oncology]]
[[Category:Medicine]]
[[Category:Gastroenterology]]
[[Category:Surgery]]

Latest revision as of 14:38, 29 April 2019

Hereditary Nonpolyposis Colorectal Cancer Microchapters

Home

Patient Information

Overview

Historical Perspective

Classification

Pathophysiology

Causes

Differentiating Hereditary Nonpolyposis Colorectal Cancer from other Diseases

Epidemiology and Demographics

Risk Factors

Screening

Natural History, Complications and Prognosis

Diagnosis

Diagnostic Study of Choice

History and Symptoms

Physical Examination

Laboratory Findings

Electrocardiogram

X-ray

Echocardiography and Ultrasound

CT scan

MRI

Other Imaging Findings

Other Diagnostic Studies

Treatment

Medical Therapy

Surgery

Primary Prevention

Secondary Prevention

Cost-Effectiveness of Therapy

Future or Investigational Therapies

Case Studies

Case #1

Hereditary nonpolyposis colorectal cancer pathophysiology On the Web

Most recent articles

Most cited articles

Review articles

CME Programs

Powerpoint slides

Images

American Roentgen Ray Society Images of Hereditary nonpolyposis colorectal cancer pathophysiology

All Images
X-rays
Echo & Ultrasound
CT Images
MRI

Ongoing Trials at Clinical Trials.gov

US National Guidelines Clearinghouse

NICE Guidance

FDA on Hereditary nonpolyposis colorectal cancer pathophysiology

CDC on Hereditary nonpolyposis colorectal cancer pathophysiology

Hereditary nonpolyposis colorectal cancer pathophysiology in the news

Blogs on Hereditary nonpolyposis colorectal cancer pathophysiology

Directions to Hospitals Treating Hereditary nonpolyposis colorectal cancer

Risk calculators and risk factors for Hereditary nonpolyposis colorectal cancer pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Maria Fernanda Villarreal, M.D. [2] Ali Akram, M.B.B.S.[3]

Overview

Hereditary nonpolyposis colorectal cancer is an autosomal dominant genetic disease characterized by an early onset of colon cancer, endometrial cancer, and other malignant tumors. Development of hereditary nonpolyposis colorectal cancer is the result of multiple genetic mutations. The genes involved in the pathogenesis of hereditary nonpolyposis colorectal cancer include: MSH-2, MLH-1, MSH-6, PMS-2 , PMS-1, TGF-BR2, and MLH-3. This syndrome occurs most commonly in the proximal colon (60% to 80%). Endometrial cancer is the most common sentinel cancer among female patients with hereditary nonpolyposis colorectal cancer.

Pathogenesis

Genetics

The table below lists the genes involved in the pathogenesis of hereditary nonpolyposis colorectal cancer:
Genes implicated in hereditary nonpolyposis colorectal cancer Frequency of mutations in hereditary nonpolyposis colorectal cancer families Locus
MSH2 Approximately 60% 2p22
MLH1 Approximately 30% 3p21
MSH6 7 - 10% 2p16
PMS2 Relatively infrequent 7p22
PMS1 Case report 2q31-q33
TGFBR2 Case report 3p22
MLH3 Disputed 14q24.3

Associated Conditions

Gross Pathology

  • On gross pathology, there are no characteristic findings of hereditary nonpolyposis colorectal cancer.[4]

Microscopic Pathology

References

  1. ↑ Oki E, Oda S, Maehara Y, Sugimachi K (Mar 1999). "Mutated gene-specific phenotypes of dinucleotide repeat instability in human colorectal carcinoma cell lines deficient in DNA mismatch repair". Oncogene. 18 (12): 2143–7. doi:10.1038/sj.onc.1202583. PMID 10321739.
  2. ↑ Lynch syndrome.Ganfyd.http://www.ganfyd.org/index.php?title=Lynch_syndrome Accessed on December 01, 2015
  3. ↑ Vasen HF, Watson P, Mecklin JP, Lynch HT (1999). "New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC". Gastroenterology. 116 (6): 1453–6. PMID 10348829.
  4. ↑ 4.0 4.1 4.2 Si JW, Wang L, Ba XJ, Zhang X, Dong Y, Zhang JX, Li WT, Li T (2015). "[Clinicopathological screening of Lynch syndrome: a report of 2 cases and literature review]". Beijing Da Xue Xue Bao (in Chinese). 47 (5): 858–64. PMID 26474631.
  5. ↑ Lynch Syndrome. Canadian Cancer Society http://www.cancer.ca/en/cancer-information/cancer-101/what-is-a-risk-factor/genetic-risk/lynch-syndrome/?region=ab#ixzz3t69IQ9M7 Accessed on December 01 2015
  6. ↑ Lynch Syndrome. Canadian Cancer Society http://www.cancer.ca/en/cancer-information/cancer-101/what-is-a-risk-factor/genetic-risk/lynch-syndrome/?region=ab#ixzz3t69IQ9M7 Accessed on December 01 2015
  7. ↑ van der Post, RS.; Kiemeney, LA.; Ligtenberg, MJ.; Witjes, JA.; Hulsbergen-van de Kaa, CA.; Bodmer, D.; Schaap, L.; Kets, CM.; van Krieken, JH. (2010). "Risk of urothelial bladder cancer in Lynch syndrome is increased, in particular among MSH2 mutation carriers". J Med Genet. 47 (7): 464–70. doi:10.1136/jmg.2010.076992. PMID 20591884. Unknown parameter |month= ignored (help)
  8. ↑ Okuda T, Sekizawa A, Purwosunu Y; et al. (2010). "Genetics of endometrial cancers". Obstet Gynecol Int. 2010: 984013. doi:10.1155/2010/984013. PMC 2852605. PMID 20396392.
  9. ↑ Garg, K.; Soslow, RA. (2009). "Lynch syndrome (hereditary non-polyposis colorectal cancer) and endometrial carcinoma". J Clin Pathol. 62 (8): 679–84. doi:10.1136/jcp.2009.064949. PMID 19638537. Unknown parameter |month= ignored (help)
  10. ↑ Lax, SF. (2002). "[Dualistic model of molecular pathogenesis in endometrial carcinoma]". Zentralbl Gynakol. 124 (1): 10–6. doi:10.1055/s-2002-20303. PMID 11873308. Unknown parameter |month= ignored (help)
  11. ↑ 11.0 11.1 Online Mendelian Inheritance in Man (OMIM) 120435
  12. ↑ Cristofaro, G.; Lynch, HT.; Caruso, ML.; Attolini, A.; DiMatteo, G.; Giorgio, P.; Senatore, S.; Argentieri, A.; Sbano, E. (1987). "New phenotypic aspects in a family with Lynch syndrome II". Cancer. 60 (1): 51–8. PMID 3581033. Unknown parameter |month= ignored (help)
  13. ↑ Lynch HT, Lynch PM, Lanspa SJ, Snyder CL, Lynch JF, Boland CR (2009). "Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications". Clin Genet. 76 (1): 1–18. doi:10.1111/j.1399-0004.2009.01230.x. PMC 2846640. PMID 19659756.
  14. ↑ Ma H, Brosens LAA, Offerhaus GJA, Giardiello FM, de Leng WWJ, Montgomery EA (2018). "Pathology and genetics of hereditary colorectal cancer". Pathology. 50 (1): 49–59. doi:10.1016/j.pathol.2017.09.004. PMID 29169633.


Template:WikiDoc Sources

Retrieved from "https://www.wikidoc.org/index.php?title=Hereditary_nonpolyposis_colorectal_cancer_pathophysiology&oldid=1565549"