Difference between revisions of "Colorectal tumours"

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*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>
*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>


===Bethesda criteria of 2004 for MSI testing===
=====Bethesda criteria of 2004 for MSI testing=====
MSI testing should be done if any of the following apply:<ref>{{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>
MSI testing should be done if any of the following apply:<ref>{{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 in patient <50 years old.

Revision as of 16:38, 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

  • Rare.
    • In the context of a rectal tumour, retrograde growth from the anus should be considered.

Staging of colorectal cancer

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

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

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.

General

Features:[11]

  • 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.[12]
  • A draft document (2015) from CAP, ASCO suggests testing all colorectal cancer cases for MSI.[13]
  • In Canada the guidelines vary by the province.[14]
Bethesda criteria of 2004 for MSI testing

MSI testing should be done if any of the following apply:[15]

  • Colorectal cancer in patient <50 years old.
  • Colorectal cancer with MSI-H histology <60 years old.
  • 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).

Note:

  • Formally known as Revised Bethesda Guidelines for Hereditary Nonpolyposis

Colorectal Cancer (Lynch Syndrome) and Microsatellite Instability.

MSI classification

MSI associated cancers can be classified into:[16][17]

  • 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.[18]
    • With chemotherapy the outcomes are similar.

Gross

Features:[11]

  • Location: proximal colon, i.e. right-sided, predominance.

Microscopic

Features:[11]

Molecular

Commonly associated abnormalities in the genes:

  1. MLH1.
  2. PMS2.
  3. MSH2.
  4. MSH6.

Less common abnormalities:

  1. PMS1.
  2. MLH3.
  3. 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.[citation needed]

MSI staining loss patterns:[21]

  • 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.[21]

Etiology/significance loss of staining

  • MSH2 mutations (IHC stain -ve) - often associated with a germline mutation,[22] while mutations in MLH1 are usually sporatic.[23]
  • PMS2 mutations (IHC stain -ve) - often associated with a germline mutation.[24]

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 (High Screen Pass).
  • The 2s (MSH2, PMS2) are associated with germline mutations (Four legs good two legs bad!).

Specific entities

Colorectal adenocarcinoma

  • AKA colorectal adenocarcinoma not otherwise specified.
  • AKA colorectal carcinoma, abbreviated CRC.

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.
  9. 9.0 9.1 Heinimann, K. (2013). "Toward a Molecular Classification of Colorectal Cancer: The Role of Microsatellite Instability Status.". Front Oncol 3: 272. doi:10.3389/fonc.2013.00272. PMID 24199172.
  10. Mensenkamp, AR.; Vogelaar, IP.; van Zelst-Stams, WA.; Goossens, M.; Ouchene, H.; Hendriks-Cornelissen, SJ.; Kwint, MP.; Hoogerbrugge, N. et al. (Dec 2013). "Somatic mutations in MLH1 and MSH2 are a Frequent Cause of Mismatch-repair Deficiency in Lynch Syndrome-like Tumors.". Gastroenterology. doi:10.1053/j.gastro.2013.12.002. PMID 24333619.
  11. 11.0 11.1 11.2 Boland CR, Goel A (June 2010). "Microsatellite instability in colorectal cancer". Gastroenterology 138 (6): 2073–2087.e3. doi:10.1053/j.gastro.2009.12.064. PMID 20420947.
  12. URL: http://www.medscape.com/viewarticle/821981. Accessed on: 12 January 2016.
  13. URL: http://www.amp.org/committees/clinical_practice/documents/20150327CRCMMDraftRecommendationsforOCP-UPDATEDfinaldraft_001.pdf. Accessed on: 12 January 2016.
  14. URL: http://www.ncbi.nlm.nih.gov/books/NBK321468/. Accessed on: 12 January 2016.
  15. Umar, A.; Boland, CR.; Terdiman, JP.; Syngal, S.; de la Chapelle, A.; Rüschoff, J.; Fishel, R.; Lindor, NM. et al. (Feb 2004). "Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability.". J Natl Cancer Inst 96 (4): 261-8. PMID 14970275.
  16. Lawes DA, Pearson T, Sengupta S, Boulos PB (August 2005). "The role of MLH1, MSH2 and MSH6 in the development of multiple colorectal cancers". Br. J. Cancer 93 (4): 472–7. doi:10.1038/sj.bjc.6602708. PMC 2361590. PMID 16106253. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361590/.
  17. Guidoboni M, Gafà R, Viel A, et al. (July 2001). "Microsatellite instability and high content of activated cytotoxic lymphocytes identify colon cancer patients with a favorable prognosis". Am. J. Pathol. 159 (1): 297–304. PMC 1850401. PMID 11438476. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1850401/.
  18. Ribic, CM.; Sargent, DJ.; Moore, MJ.; Thibodeau, SN.; French, AJ.; Goldberg, RM.; Hamilton, SR.; Laurent-Puig, P. et al. (Jul 2003). "Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer.". N Engl J Med 349 (3): 247-57. doi:10.1056/NEJMoa022289. PMID 12867608.
  19. Pollet, A. 18 October 2010.
  20. Truta B, Chen YY, Blanco AM, et al. (2008). "Tumor histology helps to identify Lynch syndrome among colorectal cancer patients". Fam. Cancer 7 (3): 267–74. doi:10.1007/s10689-008-9186-8. PMID 18283560.
  21. 21.0 21.1 Hall, G.; Clarkson, A.; Shi, A.; Langford, E.; Leung, H.; Eckstein, RP.; Gill, AJ. (2010). "Immunohistochemistry for PMS2 and MSH6 alone can replace a four antibody panel for mismatch repair deficiency screening in colorectal adenocarcinoma.". Pathology 42 (5): 409-13. doi:10.3109/00313025.2010.493871. PMID 20632815.
  22. Mangold E, Pagenstecher C, Friedl W, et al. (December 2005). "Tumours from MSH2 mutation carriers show loss of MSH2 expression but many tumours from MLH1 mutation carriers exhibit weak positive MLH1 staining". J. Pathol. 207 (4): 385–95. doi:10.1002/path.1858. PMID 16216036.
  23. A. Pollett. 2010.
  24. Vaughn CP, Robles J, Swensen JJ, et al. (May 2010). "Clinical analysis of PMS2: mutation detection and avoidance of pseudogenes". Hum. Mutat. 31 (5): 588–93. doi:10.1002/humu.21230. PMID 20205264.