Difference between revisions of "Colorectal tumours"

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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.
''Colonic tumours'' and ''rectal tumours'' redirect here.


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.  
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.  
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*[[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.
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*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.
==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===
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 of colorectal carcinoma==
==Pathogenesis of colorectal carcinoma==
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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]].


===Crohn's-like lymphoid reaction===
==Microsatellite instability cancers==
*Finding associated with improved survival.<ref name=pmid7821914 >{{Cite journal  | last1 = Harrison | first1 = JC. | last2 = Dean | first2 = PJ. | last3 = el-Zeky | first3 = F. | last4 = Vander Zwaag | first4 = R. | title = Impact of the Crohn's-like lymphoid reaction on staging of right-sided colon cancer: results of multivariate analysis. | journal = Hum Pathol | volume = 26 | issue = 1 | pages = 31-8 | month = Jan | year = 1995 | doi =  | PMID = 7821914 }}</ref>
*Abbreviated ''MSI cancers''.
 
{{Main|Microsatellite instability in colorectal cancer}}
Criteria:<ref>{{Cite journal  | last1 = Graham | first1 = DM. | last2 = Appelman | first2 = HD. | title = Crohn's-like lymphoid reaction and colorectal carcinoma: a potential histologic prognosticator. | journal = Mod Pathol | volume = 3 | issue = 3 | pages = 332-5 | month = May | year = 1990 | doi =  | PMID = 2362940 }}</ref>
*Peritumoral:
*#Lymphoid aggregates with germinal centres focally.
*#Stellate fibrosis.
*#No previous clinical and pathologic evidence of [[Crohn's disease]].
 
Note:
*Should '''not''' be confused with intratumoural lymphocytes.
**Intratumoural lymphocytes are associated with MSI-H cancers.
 
==MSI cancers==
===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>
*Prognosis: slightly better than other CRC without MSI.
*Treatment implication: different response to chemotherapy.
 
====MSI classification====
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>
*MSI-H >= 30% of loci have abnormality.
*MSI-L <30% of loci have abnormality.
 
Note:
*In the context of '''''no''''' chemotherapy, individuals with MSI-H tumours have a superior outcome to those with MSI-L tumours.<ref name=pmid12867608>{{Cite journal  | last1 = Ribic | first1 = CM. | last2 = Sargent | first2 = DJ. | last3 = Moore | first3 = MJ. | last4 = Thibodeau | first4 = SN. | last5 = French | first5 = AJ. | last6 = Goldberg | first6 = RM. | last7 = Hamilton | first7 = SR. | last8 = Laurent-Puig | first8 = P. | last9 = Gryfe | first9 = R. | title = Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. | journal = N Engl J Med | volume = 349 | issue = 3 | pages = 247-57 | month = Jul | year = 2003 | doi = 10.1056/NEJMoa022289 | PMID = 12867608 }}</ref>
**With chemotherapy the outcomes are similar.
 
===Gross===
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>
*Location: proximal colon, i.e. right-sided, predominance.
 
===Microscopic===
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>
*Lymphocytic infiltrate.
*Pushing border.<ref>AP. 18 October 2010.</ref>
*Histomorphology:
**Poorly differentiated.
**Mucinous.
**Signet ring.
**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>


=Specific entities=
=Specific entities=
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*[[AKA]] ''colorectal adenocarcinoma not otherwise specified''.
*[[AKA]] ''colorectal adenocarcinoma not otherwise specified''.
*[[AKA]] ''colorectal carcinoma'', abbreviated ''CRC''.
*[[AKA]] ''colorectal carcinoma'', abbreviated ''CRC''.
{{Main|Colorectal adenocarcinoma}}
==Secondary colorectal cancer==
===General===
===General===
*Very common.
*Uncommon.
*Rectum and sigmoid > proximal large bowel.
*May be suspected.
 
Presentation:
*Bright red blood per rectum (BRBPR).
*Constipation.
*Symptoms of bowel obstruction - nausea, vomiting.
 
Pathogenesis - see ''[[Colorectal_tumours#Pathogenesis_of_colorectal_carcinoma|pathogenesis of colorectal carcinoma]]''.
 
===Gross===
Often circumferential or near circumferential:
*These are referred to as "apple core lesion" ''or'' "napkin-ring" lesion.
 
Mucosa:
*Granular appearance.
*Raised (exophytic) ''or'' heaped edges with ulceration.
 
Note:
*''Total mesorectal excisions'' should be assessed for completeness.
 
Image:
*[http://commons.wikimedia.org/wiki/File:Colon_cancer_2.jpg CRC - gross (WC)].


===Microscopic===
===Microscopic===
Features:
Features:
*Nuclear atypia:
*Normal colorectal mucosa.
**Nuclear pseudostratification.
*Atypical cells in the lamina propria or submucosa.
**Nuclear hyperchromasia.
**Chromatin clearing or granularity.
*+/-Necrosis.
*Architecture - important for grading:
**Glands.
**Sheets.
 
Images:
*[http://www.flickr.com/photos/euthman/2480926690/in/set-72057594114099781 Colorectal adenocarcinoma (flickr.com/euthman)].
*[http://commons.wikimedia.org/wiki/File:Adenocarcinoma_coli.jpg Colorectal adenocarcinoma (WC)].
 
====Grading====
Based on component composed of glands:
*>=50% of tumour = low-grade (''well-differentiated'' and ''moderately differentiated'').
*<50% of tumour = high-grade (''poorly-differentiated'' and ''undifferentiated'').
 
===IHC===
*CK7 -ve.
*CK20 +ve.
*CEA +ve.
*CDX2 +ve.


===Molecular===
DDx:
*KRAS mutation analysis.
*Colorectal neuroendocrine tumour.
**Mutation present ~ 40% of [[CRC]].
**Mutations in codons 12 or 13 associated with failure of anti-EGFR therapy (e.g. ''cetuximab'', ''panitumumab'').<ref name=pmid19792050>{{Cite journal  | last1 = Monzon | first1 = FA. | last2 = Ogino | first2 = S. | last3 = Hammond | first3 = ME. | last4 = Halling | first4 = KC. | last5 = Bloom | first5 = KJ. | last6 = Nikiforova | first6 = MN. | title = The role of KRAS mutation testing in the management of patients with metastatic colorectal cancer. | journal = Arch Pathol Lab Med | volume = 133 | issue = 10 | pages = 1600-6 | month = Oct | year = 2009 | doi = 10.1043/1543-2165-133.10.1600 | PMID = 19792050 }}</ref>
*BRAF mutation analysis.
**''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>


Note:
===Images===
*KRAS mutations and BRAF mutations are considered mutually exclusive as they occur in the same pathway.
<gallery>
Image:Prostate carcinoma in rectum -- very low mag.jpg | Pca in rectum - very low mag. (WC)
Image:Prostate carcinoma in rectum -- low mag.jpg | Pca in rectum - low mag. (WC)
Image:Prostate carcinoma in rectum -- intermed mag.jpg | Pca in rectum - intermed. mag. (WC)
Image:Prostate carcinoma in rectum -- high mag.jpg | Pca in rectum - high mag. (WC)
</gallery>
<gallery>
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=
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*[[Colon]].
*[[Colon]].
*[[Gastrointestinal pathology]].
*[[Gastrointestinal pathology]].
*[[Tumour budding]].
*[[Tumour perforation in colorectal cancer]].
*[[Transanal minimally invasive surgery]].


=References=
=References=
Michael
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