Mutation of the tumor suppressor adenomatous polyposis coli AP is the earliest step in adenoma - to - carcinoma sequence .
> 300 APC gene mutations described.
Mutations in the APC gene are responsible for the development of familial adenomatous polyposis ( FAP ) & 85% of sporadic CRC.
Single germline mutation leads to the phenotypic expression of hundreds of polyps throughout the colon in FAP .
Development of a sporadic adenomatous polyp in average - risk persons occurs only after mutation of both copies of the gene or, more commonly, after mutation of one gene& loss of the other allele ( loss of heterozygosity ) & over many years, which is why sporadic adenomatous polyps develop in older persons .
A series of subsequent mutations must take place before cancer develops which explains why only 5% of adenomatous polyps ever progress to cancer.
A The remaining 15% of sporadic CRC & virtually all cancers associated with the hereditary nonpolyposis colorectal cancer ( HNPCC ) syndrome are due to abnormalities in DNA MMR genes . Either both copies of the gene are deactivated or the promoter regions of the gene are methylated, causing gene “silencing . ” A germline mutation of an MMR gene leads to the development of HNPCC, which results in tumors with replication errors µsatellite instability ( abn repetitive DNA sequences ).
HNPCC - associated adenomas appear to progress more rapidly to adenocarcinoma than do other types of adenomas .
Colorectal cancer in patients with chronic IBD is associated with a similar sequence of accumulated mutations . However, the p53 mutations occur earlier & the APC mutations develop later in these patients than in those with sporadic adenomas, which explains why cancer develops from flat dysplastic mucosa rather than from adenomatous polyps
An attenuated form of FAP arises from mutations at the terminal end of the APC gene characterized by a lifetime cumulative number of 20 or more adenomas compared with hundreds of adenomas in patients with the classic form of FAP.
Patients with HNPCC have fewer polyps than those with FAP& polyps also tend to be larger & located in the proximal colon.
Patients with HNPCC have an 80% risk of developing colorectal cancer, usually after 50 years of age.
They also have a markedly increased risk of developing extracolonic tumors, especially of the female reproductive tract, but also of the kidneys, small intestine, biliary tract, pancreas.
Genetic tests are available to diagnose FAP & HNPCC. However, these tests should only be done in conjunction with counseling.
Persons with a family history of colorectal cancer or adenomas that do not meet the criteria for HNPCC or FAP also have an increased risk of colorectal cancer.
Having a single first-degree relative with colorectal cancer or adenomas doubles the risk.
The risk increases significantly (relative risk = 3.0 to 4.0) if the first-degree relative is younger than 50 years of age at diagnosis or if more than one family member is affected.
The risk is also increased in persons with a family history of adenomatous polyps in relatives younger than 60 years of age.
Patients with juvenile polyposis coli & the Peutz-Jeghers syndrome (hamartomatous polyps) are also at increased risk for developing colorectal cancer.
Stratification of Colorectal Cancer Risk 5%–6% >50 years of age Average ( negative family history ) 10%–20% Familial : First - degree relative with colorectal cancer 20% Presence of chronic colitis due to ulcerative colitis or Crohn's colitis Moderate 80% Presence of hereditary nonpolyposis colorectal cancer 100% Presence of familial adenomatous polyposis High Lifetime Risk Risk Level
Patients with chronic ulcerative colitis & most likely Crohn's colitis have an increased risk of developing colorectal cancer.
The risk in patients with ulcerative colitis is increased according to the duration of disease, extent of colonic involvement, early age of onset, and presence of primary sclerosing cholangitis.
The prevalence of colorectal cancer in patients with ulcerative colitis is 3.6% but increases to 5.6% if the entire colon is involved (pancolitis).
In patients with pancolitis for 8 to 10 years or left-sided colitis for 12 to 15 years, the risk of developing cancer increases by 0.5- 1% / year.
Factors Associated with the Development of CRC Cholecystectomy Excessive alcohol intake Smoking Obesity Lack of dietary calcium and folate Calcium and folate supplementation Physical inactivity Regular aerobic exercise Diet high in red meat, sucrose, fat Diet high in fruits and vegetables * Birth in North America or Northern Europe Birth in Asia or Africa Personal history of inflammatory bowel disease No family history of colorectal cancer or an inherited colorectal cancer syndrome Family history of colorectal cancer or an inherited colorectal cancer syndrome Protective Factors Risk Factors
The most effective is screening for & removal of adenoma polyps .
Fecal occult blood test, flexible sigmoidoscopy, colonoscopy, barium enema, CT colonography ( virtual colonoscopy ) are screening tests for the diagnosis of aden polyps .
CT colonography,involves computer - enhanced spiral CT scanning of a prepped / insufflated colon, does not require sedation & allows complete evaluation of the colonic mucosa,but patients are exposed to radiation (similar to a barium enema) & must undergo colonoscopy if a suspicious polyp is found.
No compelling evidence to choose one screening test over another based on cost-effectiveness alone. However, colonoscopy has become an increasingly popular choice for screening and is recommended as the preferred test by the American College of Gastroenterology.
Colonoscopy allows both diagnosis & removal of adeno polyps.
Genetic counseling / testing should be considered for patients with a family history of familial adenomatous polyposis or hereditary nonpolyposis colorectal cancer .
Algorithm for screening symptomatic persons for CRC
Patients with an adenoma in the distal colon have a 20% to 30% risk of having a synchronous ( concomitant ) adenoma in the proximal colon .
Surveillance colonoscopy should be performed in all patients with known adenomatous polyps&Colonoscopy should be repeated every 3 years for patients with a single large polyp, several small polyps, or a polyp with features such as villous architecture or high-grade dysplasia. Patients with one or two small adenomas should undergo surveillance colonoscopy in 5 years. After a subsequent negative examination, surveillance should be repeated every 5 years.
In all patients with CRC who underwent resection for cure where the site should be re - examined in 3 to 6 months .
Patients with longstanding IBD& primary sclerosing cholangitis have a cancer risk 5 times greater than patients with IBD but without primary sclerosing cholangitis .
The most common presenting symptoms of colorectal cancer are abdominal pain (44%), change in bowel habits (43%), hematochezia or melena (40%), weakness (20%), anemia (11%), , weight loss (6%)& patients may have more than one symptom.
Patients with symptomatic colorectal cancer have a slightly worse prognosis than those with asymptomatic disease.
Patients with left-sided colon cancer more often have changes in bowel habits or hematochezia& those with proximal colon cancer often develop occult GIB.
Men or postmenopausal women with IDA should be evaluated for CRC.
Diagnostic studies are indicated for patients with symptoms of or positive screening tests for colorectal cancer.
Colonoscopy should be performed because this procedure allows visualization of the entire colon and provides the ability to perform biopsies.
Complications of diagnostic colonoscopy range from 0.03% to 0.6% and include perforation, bleeding, and cardiorespiratory complications due to sedation.
Complications of therapeutic colonoscopy range from 0.07% to 2.7%.
If colonoscopy cannot be performed or completed, double-contrast barium enema examination or possibly CT colonography should be done because synchronous cancers occur in 3% to 5% of patients with colorectal cancer.
Endoscopic procedures can be used for palliation of patients with colorectal cancer who are not surgical candidates.
Laser or argon plasma coagulation can be used to control bleeding.
Expandable metal stents can be placed to prevent or treat obstruction or put preoperatively in a patient with an obstructing lesion to improve bowel cleansing& allow performance of a single-stage surgical procedure in order to avoid the need for two-stage surgery& a temporary colostomy.
Patients with advanced stages of colon cancer& rectal cancer may benefit from chemoradiation therapy.
The prognosis in patients with CRC is based on the pathologic stage of the cancer at diagnosis.
The majority of metachronous lesions in patients who have undergone surgical resection for CRC recur within 2 ys postop
Patients who have undergone surgical resection for CRC should have serum CEA every 3- 6 months for 2-3 years postop.
Patients with CRC should undergo complete colonoscopy before surgical resection (or after resection if preoperative evaluation is not possible) to detect synchronous lesions & colonoscopy at 3 years postop to detect metachronous lesions&If no lesions are found, colonoscopy should be repeated every 5 years.
At the time of diagnosis, 40% have local disease without regional or distant metastases, 35% have regional spread (stages II & III), & 16% have distant metastases.
The 5-year survival rate is 95% for patients with local disease, 64% for those with regional spread, 7% for distant metastases.
Management of patients who have undergone surgical resection for colorectal cancer is directed towards detecting recurrent disease or metachronous (new) polyps.