Difference between revisions of "Colorectal tumours"

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==Microsatellite instability cancers==
==Microsatellite instability cancers==
*Abbreviated ''MSI cancers''.
*Abbreviated ''MSI cancers''.
===General===
{{Main|Microsatellite instability in colorectal cancer}}
*Can be sporadic, i.e. non-syndromic.<ref name=pmid24199172>{{Cite journal  | last1 = Heinimann | first1 = K. | title = Toward a Molecular Classification of Colorectal Cancer: The Role of Microsatellite Instability Status. | journal = Front Oncol | volume = 3 | issue =  | pages = 272 | month =  | year = 2013 | doi = 10.3389/fonc.2013.00272 | PMID = 24199172 }}</ref>
*Strong association with [[Lynch syndrome]].<ref>{{Cite journal  | last1 = Mensenkamp | first1 = AR. | last2 = Vogelaar | first2 = IP. | last3 = van Zelst-Stams | first3 = WA. | last4 = Goossens | first4 = M. | last5 = Ouchene | first5 = H. | last6 = Hendriks-Cornelissen | first6 = SJ. | last7 = Kwint | first7 = MP. | last8 = Hoogerbrugge | first8 = N. | last9 = Nagtegaal | first9 = ID. | title = Somatic mutations in MLH1 and MSH2 are a Frequent Cause of Mismatch-repair Deficiency in Lynch Syndrome-like Tumors. | journal = Gastroenterology | volume =  | issue =  | pages =  | month = Dec | year = 2013 | doi = 10.1053/j.gastro.2013.12.002 | PMID = 24333619 }}</ref><ref name=pmid24199172/>
 
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.
 
====When to test====
*National Comprehensive Cancer Network (NCCN) in the USA recommends testing all individual with colorectal cancer that are under the age of 70 years.<ref>URL: [http://www.medscape.com/viewarticle/821981 http://www.medscape.com/viewarticle/821981]. Accessed on: 12 January 2016.</ref> 
*A draft document (written in 2015) from CAP, ASCO and others suggests testing all colorectal cancer cases for MSI.<ref>URL: [http://www.amp.org/committees/clinical_practice/documents/20150327CRCMMDraftRecommendationsforOCP-UPDATEDfinaldraft_001.pdf http://www.amp.org/committees/clinical_practice/documents/20150327CRCMMDraftRecommendationsforOCP-UPDATEDfinaldraft_001.pdf]. Accessed on: 12 January 2016.</ref>
*In Canada, the guidelines vary by the province.<ref>URL: [http://www.ncbi.nlm.nih.gov/books/NBK321468/ http://www.ncbi.nlm.nih.gov/books/NBK321468/]. Accessed on: 12 January 2016.</ref> Some use the Bethesda criteria (see below) and others have their own set of criteria.
 
=====Bethesda criteria of 2004 for MSI testing=====
MSI testing should be done if any of the following apply:<ref name=pmid14970275>{{Cite journal  | last1 = Umar | first1 = A. | last2 = Boland | first2 = CR. | last3 = Terdiman | first3 = JP. | last4 = Syngal | first4 = S. | last5 = de la Chapelle | first5 = A. | last6 = Rüschoff | first6 = J. | last7 = Fishel | first7 = R. | last8 = Lindor | first8 = NM. | last9 = Burgart | first9 = LJ. | title = Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. | journal = J Natl Cancer Inst | volume = 96 | issue = 4 | pages = 261-8 | month = Feb | year = 2004 | doi =  | PMID = 14970275 }}</ref>
*Colorectal cancer in patient <50 years old.
*Colorectal cancer with MSI-H histology <60 years old.
**MSI-H histology (any of the following): mucinous differentiation, signet ring differentiation, medullary growth pattern, [[TILs]], [[Crohn's like reaction]].
*Regardless of age - any of the following:
**HNPCC-associated tumours.†
**Synchronous colorectal cancer.
**Metachronous colorectal cancer.
*Colorectal cancer in an individual with:
**One or more first degree relatives with a HNPCC-related tumour diagnosed when <50 years old.
**Two or more first- or second degree relatives with HNPCC-related tumours (diagnosed at any age).
 
Notes:
*Formally known as ''Revised Bethesda Guidelines for Hereditary Nonpolyposis Colorectal Cancer (Lynch Syndrome) and Microsatellite Instability''.
* †Includes: colorectum, endometrium, stomach, ovary, pancreas, ureter and renal pelvis, biliary tract and brain (usu. glioblastoma), [[sebaceous adenoma|sebaceous gland adenoma]]s and [[keratoacanthoma]] in [[Muir-Torre syndrome]] and small bowel carcinoma.<ref name=pmid14970275/>
 
====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 - see ''[[intratumoural lymphocytic response]]''.
*Large peritumoural collections of lymphocytes - see ''[[peritumoural lymphocytic response]]''.
*Pushing border.<ref>Pollet, A. 18 October 2010.</ref>
*Histomorphology:
**Poorly differentiated.
**Mucinous.
**[[Signet ring cell carcinoma|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>
 
===Molecular===
Commonly associated abnormalities in the genes:
#MLH1.
#PMS2.
#MSH2.
#MSH6.
Less common abnormalities:
#PMS1.
#MLH3.
#MSH3.
 
===IHC===
Immunostains are commonly done for:
*MLH1.
*PMS2.
*MSH2.
*MSH6.
 
IHC interpretation:
*'''Loss of nuclear staining''' in nuclei of the tumour ''implies'' a mutation.
**Nuclear staining = normal.
* Patchy MSH6 is considered normal.{{fact}}<!-- possibly PMID 21297438 -->
 
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 ('''P'''MS2, '''M'''SH6) are the screening tests ('''''H'''igh Screen '''P'''ass'').
*The ''2''s (MSH2, PMS2) are associated with germline mutations (''Four legs good two legs bad!'').


=Specific entities=
=Specific entities=

Revision as of 20:22, 12 January 2016

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, typically, an adenomatous polyp. Polyps are discussed in the intestinal polyps article.

Classification

Most common

Others

Other tumours - many (incomplete list):[2]

Notes:

Squamous carcinoma

Main article: Squamous carcinoma
  • Rare.
    • In the context of a rectal tumour, retrograde growth from the anus should be considered.

Staging of colorectal cancer

Main article: Colorectal cancer staging

Pathogenesis of colorectal carcinoma

Overview

Colorectal carcinoma is thought to arise from one of two pathways:[4][5]

  1. APC (adenomatous polyposis coli) gene mutation pathway, AKA classic adenoma-carcinoma pathway.
  2. Serrated pathway, AKA mutator pathway, mismatch repair pathway.

Syndromes

Both of the above described pathways are associated with syndromes:

  1. Familial adenomatous polyposis (FAP) or familial polyposis coli (FPC).
  2. Lynch syndrome (AKA hereditary non-polyposis colorectal cancer syndrome (HNPCC)).

Pathways

APC gene mutation pathway

Microscopic:

Mismatch repair pathway

Other ancillary studies

BRAF V600E mutation

Main article: BRAF V600E mutation

Features:[6]

  • Independently associated with BRAF V600E:
    • Usually older (>70 years old).
    • Female gender.
    • Right-sided tumour location.
  • Worse prognosis - in the context of metastatic disease.

KRAS mutation

Main article: KRAS mutation

Features:[7][8]

  • Patient must have wild type KRAS to get drugs; KRAS mutation predicts resistance to cetuximab (Erbitux) and panitumumab (Vectibix).

Microsatellite instability cancers

  • Abbreviated MSI cancers.
Main article: Microsatellite instability in colorectal cancer

Specific entities

Colorectal adenocarcinoma

  • AKA colorectal adenocarcinoma not otherwise specified.
  • AKA colorectal carcinoma, abbreviated CRC.
Main article: Colorectal adenocarcinoma

See also

References

  1. ↑ Cotran, Ramzi S.; Kumar, Vinay; Fausto, Nelson; Nelso Fausto; Robbins, Stanley L.; Abbas, Abul K. (2005). Robbins and Cotran pathologic basis of disease (7th ed.). St. Louis, Mo: Elsevier Saunders. pp. 864. ISBN 0-7216-0187-1.
  2. ↑ Humphrey, Peter A; Dehner, Louis P; Pfeifer, John D (2008). The Washington Manual of Surgical Pathology (1st ed.). Lippincott Williams & Wilkins. pp. 198. ISBN 978-0781765275.
  3. ↑ Tozawa E, Ajioka Y, Watanabe H, et al. (2007). "Mucin expression, p53 overexpression, and peritumoral lymphocytic infiltration of advanced colorectal carcinoma with mucus component: is mucinous carcinoma a distinct histological entity?". Pathol. Res. Pract. 203 (8): 567–74. doi:10.1016/j.prp.2007.04.013. PMID 17679024.
  4. ↑ Goldstein NS (January 2006). "Serrated pathway and APC (conventional)-type colorectal polyps: molecular-morphologic correlations, genetic pathways, and implications for classification". Am. J. Clin. Pathol. 125 (1): 146–53. PMID 16483003.
  5. ↑ Rüschoff J, Aust D, Hartmann A (2007). "[Colorectal serrated adenoma: diagnostic criteria and clinical implications]" (in German). Verh Dtsch Ges Pathol 91: 119–25. PMID 18314605.
  6. ↑ 6.0 6.1 Tie J, Gibbs P, Lipton L, et al. (July 2010). "Optimizing targeted therapeutic development: Analysis of a colorectal cancer patient population with the BRAF(V600E) mutation". Int J Cancer. doi:10.1002/ijc.25555. PMID 20635392.
  7. ↑ Dunn EF, Iida M, Myers RA, et al. (October 2010). "Dasatinib sensitizes KRAS mutant colorectal tumors to cetuximab". Oncogene. doi:10.1038/onc.2010.430. PMID 20956938.
  8. ↑ Di Nicolantonio F, Martini M, Molinari F, et al. (December 2008). "Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer". J. Clin. Oncol. 26 (35): 5705–12. doi:10.1200/JCO.2008.18.0786. PMID 19001320.
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