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'''Colorectal tumours''', especially '''colorectal carcinomas''', are very common.  They are the bread and butter of GI pathology.  Non-tumour colon is dealt with in the ''[[colon]]'' article.
'''Colorectal tumours''', especially '''colorectal carcinomas''', are very common.  They are the bread and butter of GI pathology.  Non-tumour colon is dealt with in the ''[[colon]]'' article.


An introduction to gastrointestinal pathology is in the ''[[gastrointestinal pathology]]'' article.  The precursor lesion of colorectal carcinoma (CRC) is, typical, an [[adenomatous polyp]].  Polyps are discussed in the ''[[intestinal polyps]]'' article.  
''Colonic tumours'' and ''rectal tumours'' redirect here.


==Classification==
An introduction to gastrointestinal pathology is in the ''[[gastrointestinal pathology]]'' article.  The precursor lesion of colorectal carcinoma (CRC) is, typically, an [[adenomatous polyps|adenomatous polyp]].  Polyps are discussed in the ''[[intestinal polyps]]'' article.
 
=Classification=
===Most common===
===Most common===
*Colon & rectum - most common = [[adenocarcinoma]].<ref name=Ref_PBoD864>{{Ref PBoD|864}}</ref>
*Colon & rectum - most common = [[colorectal adenocarcinoma|adenocarinoma]].<ref name=Ref_PBoD864>{{Ref PBoD|864}}</ref>


===Others===
===Others===
Other tumours - many (incomplete list):<ref name=Ref_WMSP198>{{Ref WMSP|198}}</ref>
Other tumours - many (incomplete list):<ref name=Ref_WMSP198>{{Ref WMSP|198}}</ref>
*Mucinous carcinoma.
*[[Mucinous carcinoma]].
**Need > 50% mucinous component.<ref name=pmid17679024 >{{cite journal |author=Tozawa E, Ajioka Y, Watanabe H, ''et al.'' |title=Mucin expression, p53 overexpression, and peritumoral lymphocytic infiltration of advanced colorectal carcinoma with mucus component: is mucinous carcinoma a distinct histological entity? |journal=Pathol. Res. Pract. |volume=203 |issue=8 |pages=567–74 |year=2007 |pmid=17679024 |doi=10.1016/j.prp.2007.04.013 |url=}}</ref>
**Need > 50% mucinous component.<ref name=pmid17679024 >{{cite journal |author=Tozawa E, Ajioka Y, Watanabe H, ''et al.'' |title=Mucin expression, p53 overexpression, and peritumoral lymphocytic infiltration of advanced colorectal carcinoma with mucus component: is mucinous carcinoma a distinct histological entity? |journal=Pathol. Res. Pract. |volume=203 |issue=8 |pages=567–74 |year=2007 |pmid=17679024 |doi=10.1016/j.prp.2007.04.013 |url=}}</ref>
*Adenosquamous carcinoma.
*[[Adenosquamous carcinoma]].
*Signet-ring carcinoma.
*Signet-ring carcinoma.
*Squamous carcinoma.
*Squamous carcinoma.
*Neuroendocrine neoplasms (carcinoid tumours).
*[[Neuroendocrine neoplasm]]s (carcinoid tumours).
*[[Lipoma]].
*[[Lipoma]].
*[[Leiomyoma]].
*[[Leiomyoma]].
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Notes:
Notes:
*Mucinous carcinoma - percentage required to call varies by site:
*[[Mucinous carcinoma]] - percentage required to call varies by site:
**Colon/rectum: > 50%.<ref name=pmid17679024 >{{cite journal |author=Tozawa E, Ajioka Y, Watanabe H, ''et al.'' |title=Mucin expression, p53 overexpression, and peritumoral lymphocytic infiltration of advanced colorectal carcinoma with mucus component: is mucinous carcinoma a distinct histological entity? |journal=Pathol. Res. Pract. |volume=203 |issue=8 |pages=567–74 |year=2007 |pmid=17679024 |doi=10.1016/j.prp.2007.04.013 |url=}}</ref>
 
**Prostate gland:  > 25%.<ref name=pmid14976541>{{cite journal |author=Grignon DJ |title=Unusual subtypes of prostate cancer |journal=Mod. Pathol. |volume=17 |issue=3 |pages=316–27 |year=2004 |month=March |pmid=14976541 |doi=10.1038/modpathol.3800052 |url=}}</ref>
**Breast: > 50%.<ref name=pmid20191033>{{cite journal |author=Park S, Koo J, Kim JH, Yang WI, Park BW, Lee KS |title=Clinicopathological characteristics of mucinous carcinoma of the breast in Korea: comparison with invasive ductal carcinoma-not otherwise specified |journal=J. Korean Med. Sci. |volume=25 |issue=3 |pages=361–8 |year=2010 |month=March |pmid=20191033 |pmc=2826751 |doi=10.3346/jkms.2010.25.3.361 |url=}}</ref>
====Squamous carcinoma====
====Squamous carcinoma====
{{Main|Squamous carcinoma}}
*Rare.
*Rare.
**In the context of a rectal tumour, retrograde growth from the [[anus]] should be considered.
**In the context of a rectal tumour, retrograde growth from the [[anus]] should be considered.
Ref.: [http://www.pathconsultddx.com/pathCon/diagnosis?pii=S1559-8675%2806%2970532-0 SCC (pathconsultddx.com)].
==Grading==
*"Adenocarcinoma in situ" and "high-grade dysplasia" is used interchangeably by many in the colon and rectum.
**Splitting hairs - ''adenocarcinoma in situ'' is ''invasion into the lamina propria'', high-grade dysplasia does not have lamina propria invasion. Ergo, the difference (in my opinion) amounts to seeing a [[desmoplastic stroma]] (adenocarcinoma) or not seeing one (dysplasia).
Grading of tumours:
*Tis - in situ (intramucosal).
*T1 - into submucosa (through mucularis mucosae).
**This is '''different than elsewhere''', e.g. in the ''small bowel'' tumour cells in the ''lamina propria'' is defined as T1.  The rationale for the ''T1'' definition in CRC is that no lymphatics are present in the mucosa, ergo no risk of distant spread.
*T2 - into muscularis propria.
*T3 - into fat beyond musclaris propria.
*T4 - into something else.
Nodes:
*N0 - no positive nodes.
*N1 - 1-3 positive nodes.
*N2 - 4+ positive nodes.
Notes:
*Memory device for N2 = 4+ +ve LNs: the number ''four'' in chinese sounds like ''death''.<ref>URL: [http://en.wikipedia.org/wiki/Numbers_in_Chinese_culture#Four http://en.wikipedia.org/wiki/Numbers_in_Chinese_culture#Four]. Accessed on: 28 June 2011.</ref>


==Staging of colorectal cancer==
==Staging of colorectal cancer==
===Simple version===
{{Main|Colorectal cancer staging}}
Tumour/node grade for stage:<ref>TN 2006 GS27.</ref>
*Stage I - '''T1 or T2''' N0 M0.
*Stage II - '''T3 or T4''' N0 M0.
*Stage III - Tx '''N1 or N2''' M0.
*Stage IV - Tx Nx '''M1'''.


===Complex version===
==Pathogenesis of colorectal carcinoma==
Detailed tumour/node grade for stage:<ref>[http://www.cancer.org/docroot/CRI/content/CRI_2_4_3X_How_is_colon_and_rectum_cancer_staged.asp http://www.cancer.org/docroot/CRI/content/CRI_2_4_3X_How_is_colon_and_rectum_cancer_staged.asp]</ref>
*Stage I - T1 or T2.
*Stage IIA - T3.
*Stage IIB - T4.
*Stage IIIA - T1 N1 or T2 N1.
*Stage IIIB - T3 N1 or T4 N1.
*Stage IIIC - Tx N2.
*Stage IV - Tx Nx M1.
 
==Pathogenesis==
===Overview===
===Overview===
Colorectal carcinoma is thought to arise from one of two pathways:<ref name=pmid16483003>{{cite journal |author=Goldstein NS |title=Serrated pathway and APC (conventional)-type colorectal polyps: molecular-morphologic correlations, genetic pathways, and implications for classification |journal=Am. J. Clin. Pathol. |volume=125 |issue=1 |pages=146–53 |year=2006 |month=January |pmid=16483003 |doi= |url=}}</ref><ref name=pmid18314605>{{cite journal |author=Rüschoff J, Aust D, Hartmann A |title=[Colorectal serrated adenoma: diagnostic criteria and clinical implications] |language=German |journal=Verh Dtsch Ges Pathol |volume=91 |issue= |pages=119–25 |year=2007 |pmid=18314605 |doi= |url=}}</ref>
Colorectal carcinoma is thought to arise from one of two pathways:<ref name=pmid16483003>{{cite journal |author=Goldstein NS |title=Serrated pathway and APC (conventional)-type colorectal polyps: molecular-morphologic correlations, genetic pathways, and implications for classification |journal=Am. J. Clin. Pathol. |volume=125 |issue=1 |pages=146–53 |year=2006 |month=January |pmid=16483003 |doi= |url=}}</ref><ref name=pmid18314605>{{cite journal |author=Rüschoff J, Aust D, Hartmann A |title=[Colorectal serrated adenoma: diagnostic criteria and clinical implications] |language=German |journal=Verh Dtsch Ges Pathol |volume=91 |issue= |pages=119–25 |year=2007 |pmid=18314605 |doi= |url=}}</ref>
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====Syndromes====
====Syndromes====
Both of the above described pathways are associated with syndromes:
Both of the above described pathways are associated with syndromes:
*''Lynch syndrome'' AKA ''[[hereditary non-polyposis colorectal cancer syndrome]]'' (HNPCC).
#''[[Familial adenomatous polyposis]]'' (FAP) or ''familial polyposis coli'' (FPC).
*''[[Familial adenomatous polyposis]]'' (FAP) or ''familial polyposis coli'' (FPC).
#''Lynch syndrome'' ([[AKA]] ''[[hereditary non-polyposis colorectal cancer syndrome]]'' (HNPCC)).
 


===Pathways===
===Pathways===
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====Mismatch repair pathway====
====Mismatch repair pathway====
*Associated with microsatellite instability (MSI).
*Associated with [[microsatellite instability]] (MSI).
*Common associated gene mutations:
*#MLH1.
*#PMS2.
*#MSH2.
*#MSH6.
*Less common gene mutations:
*#PMS1.
*#MLH3.
*#MSH3.
 
=====IHC interpretation=====
*Loss of nuclear staining in nuclei of the tumour = mutation.
**Nuclear staining = normal.
 
MSI staining loss patterns:<ref name=pmid20632815/>
*MLH1 and PMS2 are often lost together, as MLH1 loss results in PMS2 loss.
*MSH2 and MSH6 are often lost together, as MSH2 loss results in MSH6 loss.
 
Implication of MSI staining loss patterns:
*PMS2 & MSH6 can be used as a screen.<ref name=pmid20632815>{{Cite journal  | last1 = Hall | first1 = G. | last2 = Clarkson | first2 = A. | last3 = Shi | first3 = A. | last4 = Langford | first4 = E. | last5 = Leung | first5 = H. | last6 = Eckstein | first6 = RP. | last7 = Gill | first7 = AJ. | title = Immunohistochemistry for PMS2 and MSH6 alone can replace a four antibody panel for mismatch repair deficiency screening in colorectal adenocarcinoma. | journal = Pathology | volume = 42 | issue = 5 | pages = 409-13 | month =  | year = 2010 | doi = 10.3109/00313025.2010.493871 | PMID = 20632815 }}</ref>
 
======Etiology/significance loss of staining======
*MSH2 mutations (IHC stain -ve) - often associated with a germline mutation,<ref name=pmid16216036>{{cite journal |author=Mangold E, Pagenstecher C, Friedl W, ''et al.'' |title=Tumours from MSH2 mutation carriers show loss of MSH2 expression but many tumours from MLH1 mutation carriers exhibit weak positive MLH1 staining |journal=J. Pathol. |volume=207 |issue=4 |pages=385–95 |year=2005 |month=December |pmid=16216036 |doi=10.1002/path.1858 |url=}}</ref> while mutations in MLH1 are usually sporatic.<ref>A. Pollett. 2010.</ref>
*PMS2 mutations (IHC stain -ve) - often associated with a germline mutation.<ref name=pmid20205264>{{cite journal |author=Vaughn CP, Robles J, Swensen JJ, ''et al.'' |title=Clinical analysis of PMS2: mutation detection and avoidance of pseudogenes |journal=Hum. Mutat. |volume=31 |issue=5 |pages=588–93 |year=2010 |month=May |pmid=20205264 |doi=10.1002/humu.21230 |url=}}</ref>
 
 
How to remember the more important MSI stuff:
*The ''MSHs'' are paired together.
**''MSH'' (Mount Sinai Hospital) is where they started it in the city.
*''PMS'' sucks... it's with the other one (MLH).
*The higher numbers in the pairings (PMS2, MSH6) are the screening tests.
*The ''2''s (MSH2, PMS2) are associated with germline mutations (''Four legs good two legs bad.'').


===Other ancillary studies===
===Other ancillary studies===
*BRAF ''V600E'' missense mutation found in ~10% CRC.<ref name=pmid20635392>{{cite journal |author=Tie J, Gibbs P, Lipton L, ''et al.'' |title=Optimizing targeted therapeutic development: Analysis of a colorectal cancer patient population with the BRAF(V600E) mutation |journal=Int J Cancer |volume= |issue= |pages= |year=2010 |month=July |pmid=20635392 |doi=10.1002/ijc.25555 |url=}}</ref>
*BRAF ''V600E'' missense mutation found in ~10% CRC.<ref name=pmid20635392>{{cite journal |author=Tie J, Gibbs P, Lipton L, ''et al.'' |title=Optimizing targeted therapeutic development: Analysis of a colorectal cancer patient population with the BRAF(V600E) mutation |journal=Int J Cancer |volume= |issue= |pages= |year=2010 |month=July |pmid=20635392 |doi=10.1002/ijc.25555 |url=}}</ref>
*KRAS mutation status.
*[[KRAS mutation]] status.


====BRAF V600E mutation====
====BRAF V600E mutation====
{{Main|BRAF V600E mutation}}
Features:<ref name=pmid20635392/>
Features:<ref name=pmid20635392/>
*Independently associated with BRAF V600E:
*Independently associated with BRAF V600E:
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====KRAS mutation====
====KRAS mutation====
{{Main|KRAS mutation}}
Features:<ref name=pmid20956938>{{cite journal |author=Dunn EF, Iida M, Myers RA, ''et al.'' |title=Dasatinib sensitizes KRAS mutant colorectal tumors to cetuximab |journal=Oncogene |volume= |issue= |pages= |year=2010 |month=October |pmid=20956938 |doi=10.1038/onc.2010.430 |url=}}</ref><ref name=pmid19001320>{{cite journal |author=Di Nicolantonio F, Martini M, Molinari F, ''et al.'' |title=Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer |journal=J. Clin. Oncol. |volume=26 |issue=35 |pages=5705–12 |year=2008 |month=December |pmid=19001320 |doi=10.1200/JCO.2008.18.0786 |url=}}</ref>
Features:<ref name=pmid20956938>{{cite journal |author=Dunn EF, Iida M, Myers RA, ''et al.'' |title=Dasatinib sensitizes KRAS mutant colorectal tumors to cetuximab |journal=Oncogene |volume= |issue= |pages= |year=2010 |month=October |pmid=20956938 |doi=10.1038/onc.2010.430 |url=}}</ref><ref name=pmid19001320>{{cite journal |author=Di Nicolantonio F, Martini M, Molinari F, ''et al.'' |title=Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer |journal=J. Clin. Oncol. |volume=26 |issue=35 |pages=5705–12 |year=2008 |month=December |pmid=19001320 |doi=10.1200/JCO.2008.18.0786 |url=}}</ref>
*Patient must have ''wild type'' KRAS to get drugs; KRAS mutation predicts resistance to cetuximab (Erbitux) and panitumumab (Vectibix).
*Patient must have ''wild type'' KRAS to get drugs; KRAS mutation predicts resistance to [[cetuximab]] (Erbitux) and [[panitumumab]] (Vectibix).
**Cetuximab and panitumumab are EGFR inhibitors.
**Cetuximab and panitumumab are [[EGFR inhibitors]].


==MSI cancers==
==Microsatellite instability cancers==
*Abbreviated ''MSI cancers''.
{{Main|Microsatellite instability in colorectal cancer}}
 
=Specific entities=
==Colorectal adenocarcinoma==
*[[AKA]] ''colorectal adenocarcinoma not otherwise specified''.
*[[AKA]] ''colorectal carcinoma'', abbreviated ''CRC''.
{{Main|Colorectal adenocarcinoma}}
 
==Secondary colorectal cancer==
===General===
===General===
Features:<ref name=pmid20420947>{{cite journal |author=Boland CR, Goel A |title=Microsatellite instability in colorectal cancer |journal=Gastroenterology |volume=138 |issue=6 |pages=2073–2087.e3 |year=2010 |month=June |pmid=20420947 |doi=10.1053/j.gastro.2009.12.064 |url=}}</ref>
*Uncommon.
*Prognosis: slightly better than other CRC without MSI.
*May be suspected.
*Treatment implication: different response to chemotherapy.


====MSI classification====
===Microscopic===
MSI associated cancers can be classified into:<ref name=pmid16106253>{{cite journal |author=Lawes DA, Pearson T, Sengupta S, Boulos PB |title=The role of MLH1, MSH2 and MSH6 in the development of multiple colorectal cancers |journal=Br. J. Cancer |volume=93 |issue=4 |pages=472–7 |year=2005 |month=August |pmid=16106253 |pmc=2361590 |doi=10.1038/sj.bjc.6602708 |url=}}</ref><ref name=pmid11438476>{{cite journal |author=Guidoboni M, Gafà R, Viel A, ''et al.'' |title=Microsatellite instability and high content of activated cytotoxic lymphocytes identify colon cancer patients with a favorable prognosis |journal=Am. J. Pathol. |volume=159 |issue=1 |pages=297–304 |year=2001 |month=July |pmid=11438476 |pmc=1850401 |doi= |url=}}</ref>
Features:
*MSI-H >= 30% of loci have abnormality.
*Normal colorectal mucosa.
*MSI-L <30% of loci have abnormality.
*Atypical cells in the lamina propria or submucosa.


===Gross===
DDx:
Features:<ref name=pmid20420947>{{cite journal |author=Boland CR, Goel A |title=Microsatellite instability in colorectal cancer |journal=Gastroenterology |volume=138 |issue=6 |pages=2073–2087.e3 |year=2010 |month=June |pmid=20420947 |doi=10.1053/j.gastro.2009.12.064 |url=}}</ref>
*Colorectal neuroendocrine tumour.
*Location: proximal colon, i.e. right-sided, predominance.


===Microscopic===
===Images===
Features:<ref name=pmid20420947>{{cite journal |author=Boland CR, Goel A |title=Microsatellite instability in colorectal cancer |journal=Gastroenterology |volume=138 |issue=6 |pages=2073–2087.e3 |year=2010 |month=June |pmid=20420947 |doi=10.1053/j.gastro.2009.12.064 |url=}}</ref>
<gallery>
*Lymphocytic infiltrate.
Image:Prostate carcinoma in rectum -- very low mag.jpg | Pca in rectum - very low mag. (WC)
*Pushing border.<ref>AP. 18 October 2010.</ref>
Image:Prostate carcinoma in rectum -- low mag.jpg | Pca in rectum - low mag. (WC)
*Histomorphology:
Image:Prostate carcinoma in rectum -- intermed mag.jpg | Pca in rectum - intermed. mag. (WC)
**Poorly differentiated.
Image:Prostate carcinoma in rectum -- high mag.jpg | Pca in rectum - high mag. (WC)
**Mucinous.
</gallery>
**Signet ring.
<gallery>
**Medullary.<ref name=pmid18283560>{{cite journal |author=Truta B, Chen YY, Blanco AM, ''et al.'' |title=Tumor histology helps to identify Lynch syndrome among colorectal cancer patients |journal=Fam. Cancer |volume=7 |issue=3 |pages=267–74 |year=2008 |pmid=18283560 |doi=10.1007/s10689-008-9186-8 |url=}}</ref>
Image:Prostate carcinoma in rectum - PSAP -- intermed mag.jpg | Pca in rectum - PSAP - intermed. mag. (WC)
Image:Prostate carcinoma in rectum - PSA -- intermed mag.jpg | Pca in rectum - PSA - intermed. mag. (WC)
Image:Prostate carcinoma in rectum - CK20 -- intermed mag.jpg | Pca in rectum - CK20 - intermed. mag. (WC)
</gallery>


==See also==
=See also=
*[[Anus]] - covers anal cancer and anal intraepithelial neoplasia.
*[[Anus]] - covers anal cancer and anal intraepithelial neoplasia.
*[[Colon]].
*[[Colon]].
*[[Gastrointestinal pathology]].
*[[Gastrointestinal pathology]].
*[[Tumour budding]].
*[[Tumour perforation in colorectal cancer]].
*[[Transanal minimally invasive surgery]].


==References==
=References=
{{reflist|2}}
{{reflist|2}}


[[Category:Gastrointestinal pathology]]
[[Category:Gastrointestinal pathology]]
Michael
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