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{{Colon cancer}}
{{Colon cancer}}
To view the pathophysiology of familial adenomatous polyposis (FAP), click [[Familial adenomatous polyposis pathophysiology|'''here''']]<br>
To view the pathophysiology of hereditary nonpolyposis colorectal cancer (HNPCC), click [[Hereditary nonpolyposis colorectal cancer pathophysiology|'''here''']]<br><br>
{{CMG}} {{AE}} Saarah T. Alkhairy, M.D., Elliot B. Tapper, M.D.
{{CMG}} {{AE}} Saarah T. Alkhairy, M.D., Elliot B. Tapper, M.D.



Revision as of 19:15, 13 July 2015

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To view the pathophysiology of familial adenomatous polyposis (FAP), click here
To view the pathophysiology of hereditary nonpolyposis colorectal cancer (HNPCC), click here

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Saarah T. Alkhairy, M.D., Elliot B. Tapper, M.D.

Overview

The pathogenesis of colorectal carcinoma (CRC) involves genetic instability, epigenetic alteration, chronic inflammation, oxidative stress, and intestinal microbiota. Some examples of the types of colorectal carcinoma that can be linked to genetics are hereditary nonpolyposis colon cancer (HNPCC), familial adenomatous polyposis (FAP), and MUTYH-associated polyposis (MAP). Right-sided and left-sided tumors differ in their gross pathology. Depending on glandular architecture, cellular pleomorphism, and mucosecretion of the predominant pattern, adenocarcinoma may present in three degrees of differentiation: well, moderately, and poorly differentiated.

Pathogenesis

At a microbiological level, the development of the colorectal cancers (CRC) can be linked to defects within the cell cycle[1]. Although its is poorly understood, the following five factors are recognized to be responsible for its neoplastic changes[2]:

Genetic instability

  • Aneuploidy is demonstrated in about 50%-90% of cancers
  • A loss of adenomatous polyposis (APC) function is common in sporadic CRC
  • A loss of P53 function is common in colitis-associated CRC
  • The following are two types of genomic instability
  • Chromosomal instability (CIN) occurs when either whole chromosomes or parts of chromosomes are duplicated or deleted; it has a 85% frequency
  • Microsatellite instability (MSI) is the condition of genetic hypermutability that results from impaired DNA mismatch repair; it a 15% frequency

Epigenetic alteration

  • Sporadic CRC can develop from dysplasia in 1 or 2 foci of the colon
  • Colitis-associated CRC can develop from multifocal dysplasia
  • This indicates a field change effect where large areas of cells within the colon are affected by carcinogenic alterations

Chronic inflammation

Oxidative stress

  • Oxidative stress results from inflammatory reactions which include inflammatory cells, activated neutrophils, and macrophages
  • Macrophages produce large amounts of reactive oxygen and nitrogen species (RONS)
  • RONs can interact with key genes involved in carcinogenic pathways such as P53 and DNA mismatch repair genes

Intestinal microbiota

  • The mechanism is still unclear

Genetics

CRC can be grouped into three categories from a genetic perspective[3]:

  • Sporadic (75% of cases) - no apparent indications of a hereditary component
  • Familial (20% of cases) - multifactorial hereditary factors or common exposures to non-genetic risk factors or both
  • Hereditary (10% of cases)
  • Hereditary nonpolyposis colon cancer (HNPCC) also known as Lynch Syndrome results from mutations in hMLH1, hMSH2, hMSH6, and PMS2
  • Familial adenomatous polyposis (FAP) results from mutations in the APC gene located on chromosome 5p22.2
  • MUTYH-associated polyposis (MAP) results from biallelic mutation of the MutY, E. Coli, Homolog gene which functions to remove adenine residues mispaired with 8-hydroxyguanine in DNA

Gross Pathology

  • Right-sided tumors (ascending colon and cecum) tends to grow outwards from one location in the bowel wall (exophytic)
  • Left-sided tumours tend to be circumferential
Appearance of the inside of the colon showing one invasive colorectal carcinoma (the crater-like, reddish, irregularly shaped tumor).

Microscopic Pathology

  • Tumor cells form irregular tubular structures, harboring pleuristratification, multiple lumens, and reduced stroma
  • Sometimes, tumor cells are discohesive and secrete mucus, which invades the interstitium producing large pools of mucus/colloid (optically "empty" spaces)
  • If the mucus remains inside the tumor cell, it pushes the nucleus at the periphery (signet-ring cell)
  • Depending on glandular architecture, cellular pleomorphism, and mucosecretion of the predominant pattern, adenocarcinoma may present in three degrees of differentiation: well, moderately, and poorly differentiated<refPathology atlas (in Romanian)</ref>
Histopathologic image of colonic carcinoid stained by hematoxylin and eosin.


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References

  1. Scully R (2010). "The spindle-assembly checkpoint, aneuploidy, and gastrointestinal cancer". The New England Journal of Medicine. 363 (27): 2665–6. doi:10.1056/NEJMe1008017. PMID 21190461. Retrieved 2011-12-12. Unknown parameter |month= ignored (help)
  2. Kim, Eun Ran (2014). "Colorectal cancer in inflammatory bowel disease: The risk, pathogenesis, prevention and diagnosis". World Journal of Gastroenterology. 20 (29): 9872. doi:10.3748/wjg.v20.i29.9872. ISSN 1007-9327.
  3. Schlussel AT, Gagliano RA, Seto-Donlon S, Eggerding F, Donlon T, Berenberg J; et al. (2014). "The evolution of colorectal cancer genetics-Part 1: from discovery to practice". J Gastrointest Oncol. 5 (5): 326–35. doi:10.3978/j.issn.2078-6891.2014.069. PMC 4173047. PMID 25276405.


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