Difference between revisions of "Colorectal tumours"

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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).

Revision as of 12:11, 30 April 2014

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

  • "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).

Staging 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.[4]

Overall stage

Simple version

Tumour/node grade for stage:[5]

  • 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:[6]

  • 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

Overview

Colorectal carcinoma is thought to arise from one of two pathways:[7][8]

  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 missense mutation found in ~10% CRC.[9]
  • KRAS mutation status.

BRAF V600E mutation

Features:[9]

  • 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:[10][11]

  • 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:[14]

  • Prognosis: slightly better than other CRC without MSI.
  • Treatment implication: different response to chemotherapy.

MSI classification

MSI associated cancers can be classified into:[15][16]

  • 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.[17]
    • With chemotherapy the outcomes are similar.

Gross

Features:[14]

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

Microscopic

Features:[14]

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.

MSI staining loss patterns:[20]

  • 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.[20]

Etiology/significance loss of staining

  • MSH2 mutations (IHC stain -ve) - often associated with a germline mutation,[21] while mutations in MLH1 are usually sporatic.[22]
  • PMS2 mutations (IHC stain -ve) - often associated with a germline mutation.[23]

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.
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. ↑ URL: http://en.wikipedia.org/wiki/Numbers_in_Chinese_culture#Four. Accessed on: 28 June 2011.
  5. ↑ Shiau, Carolyn; Toren, Andrew (2006). Toronto Notes 2006: Comprehensive Medical Reference (Review for MCCQE 1 and USMLE Step 2) (22nd edition (2006) ed.). Toronto Notes for Medical Students, Inc.. pp. GS27. ISBN 978-0968592861.
  6. ↑ http://www.cancer.org/docroot/CRI/content/CRI_2_4_3X_How_is_colon_and_rectum_cancer_staged.asp
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 9.0 9.1 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.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 12.0 12.1 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.
  13. ↑ 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.
  14. ↑ 14.0 14.1 14.2 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.
  15. ↑ 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/.
  16. ↑ 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/.
  17. ↑ 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.
  18. ↑ Pollet, A. 18 October 2010.
  19. ↑ 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.
  20. ↑ 20.0 20.1 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.
  21. ↑ 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.
  22. ↑ A. Pollett. 2010.
  23. ↑ 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.
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