Colorectal cancer (CRC):

Dr.Mohammad Shaikhani.

MBChB/CABM/FRCP.

CRC:PRECURSORS• Most develop from polyps via adenoma-carcinoma sequence • 30-50% of adults develop adenomatous polyps during their

lifetime, although only 1 / 20 polyps will progress to cancer.

CRC:PRECURSORS• This transformation to cancer results from an accumulation of

genetic mutations occuring over a decade or more&involve:• Tumor suppressor genes: (e.g.,APC gene, p53 gene) regulate

&control cell growth& when both copies of a gene are abnormal, uncontrolled growth can occur.

• Oncogenes: Oncogenes (e.g. K-ras oncogene) stimulate controlled cell growth but, when mutated, result in unregulated cell proliferation.

• DNA repair mechanisms:(MMR genes) correct errors that occur during replication&its loss can cause mutations, resulting in progression of an adenoma to carcinoma.

CRC:APC mutation• 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.

CRC: MMR Mutations • 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 &microsatellite instability (abn repetitive DNA sequences).

• HNPCC-associated adenomas appear to progress more rapidly to adenocarcinoma than do other types of adenomas.

CRC:IBD-associated mutations• 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

Key points:• 1/ 20 adenomatous polyps will progress to colorectal cancer.

• The progression of adenomatous polyps to colorectal cancer results from an accumulation of genetic mutations.

• The major hereditary colorectal cancer syndromes are familial adenomatous polyposis & hereditary nonpolyposis CRC.

Epidemiology/risk factors• Colorectal cancer is the most common GIT malignancy. • It is the third most common malignancy& the second most

common cause of cancer deaths accounting for 10% of all cancer deaths.

• Only smoking-related cancers have a higher mortality rate. • The lifetime risk of developing CRC is 5.6%& 2% of patients will

die of this disease. • Men are affected slightly more than women, blacks have slightly

higher incidence / mortality rates. • CRC is uncommon before 50 years, but the incidence increases

sharply thereafter, nearly doubling every 7 years • Patients with one of the hereditary CRC syndromes (especially

familial adenomatous polyposis & hereditary nonpolyposis colorectal cancer) & IBD are at increased risk for developing CRC.

Epidemiology/RFs: Key points

• Patients with a hereditary CRC syndrome or IBD are at increased risk for developing CRC.

• Genetic testing for hereditary CRC syndromes should only be done in conjunction with counseling.

Hereditary CRC Syndromes:• Familial adenomatous polyposis (FAP) & hereditary nonpolyposis

colorectal cancer (HNPCC) are the best understood of the hereditary CRC syndromes.

• Both are autosomal dominant, although one third of patients are found to have APC genetic mutations or DNA MMR genetic abnormalities.

• Patients with FAP develop hundreds of adenomatous colon polyps during adolescence & have a 100% risk of developing CRC by a mean age of 40 years.

• Tumors of the UGIT, as fundic gland polyps & duodenal adenomas, also occur in patients with FAP& adenocarcinoma of the ampulla of Vater is the second most common malignant tumor in these patients.

• Extraintestinal manifestations of FAP include desmoid tumors, osteomas of the mandible, soft-tissue tumors& congenital hypertrophy of the retinal pigment epithelium.

Hereditary CRC Syndromes:

• 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.

Hereditary CRC Syndromes:

• 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

Risk LevelLifetime Risk

High

Presence of familial adenomatous polyposis100%

Presence of hereditary nonpolyposis colorectal cancer80%

Moderate

Presence of chronic colitis due to ulcerative colitis or Crohn's colitis20%

Familial: First-degree relative with colorectal cancer10%–20%

Average (negative family history)

>50 years of age5%–6%

IBD:

• 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 CRCRisk FactorsProtective Factors

Family history of colorectal cancer or an inherited colorectal cancer syndrome

No family history of colorectal cancer or an inherited colorectal cancer syndrome

Personal history of inflammatory bowel disease

Birth in Asia or Africa

Birth in North America or Northern EuropeDiet high in fruits and vegetables*

Diet high in red meat, sucrose, fatRegular aerobic exercise

Physical inactivityCalcium and folate supplementation

Lack of dietary calcium and folate

Obesity

Smoking

Excessive alcohol intake

Cholecystectomy

Primary prevention& screening:• 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

Patient selection for screening:

• 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.

Patient selection for screening:

• Patients with longstanding IBD (pancolitis for > 8 to 10 years; left-sided colitis for > 12 to 15 years) should also undergo surveillance colonoscopy .

• Biopsy samples for dysplasia are obtained. • Patients who are found to have any degree of dysplasia should be

referred for surgical consultation. • Patients with inflammatory bowel disease and primary sclerosing

cholangitis have a cancer risk 5 times that of patients with this disease but without primary sclerosing cholangitis.

• Surveillance in these patients should begin at the time of diagnosis and be continued annually.

Clinical Manifestations / Diagnosis of CRC:

• 15-20% of patients with CRC have distant metastases at the time of presentation.

• Spread can be via the lymphatic system or hematogenous. • The most common metastatic sites are local lymph nodes, the

liver, lungs, peritoneum. • The liver is the most common site of hematogenous spread of

cancer from the colon. • Because the venous drainage of the distal rectum is into the IVC,

cancer of that area will initially metastasize to the lung. • An elevated serum carcinoembryonic antigen value suggests a

poor prognosis for a patient with CRC.• Patients with adenomas of the colon are usually asymptomatic&

those with colorectal cancer may occasionally have no initial symptoms.

Clinical Manifestations / Diagnosis of CRC:

• 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.

Clinical Manifestations / Diagnosis of 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.

Clinical Manifestations / Diagnosis of CRC:

• Once the diagnosis is confirmed, staging is indicated• The stage of the lesion is closely associated with prognosis &will

direct therapy. • The two staging systems frequently used are Duke's classification

&the now preferred tumor, node, metastasis (TNM) system. • Staging requires both imaging & histologic studies. • Preoperative staging should include a general physical exam to

identify signs of possible distant metastases ( as LNs, ascites, or hepatomegaly), a CT scan of the abdomen, a chest radiograph.

• Although liver chemistry tests are often obtained, values may be normal despite the presence of liver metastasis.

• If the patient has obvious distant metastasis, further staging exams are not necessary.

• MRI provides information similar to that obtained with CT scanning but may also identify more hepatic lesions & can better detect local lymphadenopathy in patients with rectal cancer.

Clinical Manifestations / Diagnosis of CRC:

• Positron emission tomography can add complementary information & may also detect 20% more metastatic disease not found by routine CT.

• Endoscopic ultrasonography is especially helpful for staging rectal cancer& predict the tumor stage in 80-95% compared with 65-75% for CT scanning & 75-85% for MRI.

• Fine-needle aspiration tissue sampling of local lymph nodes adds to the accuracy of EUS for staging .

• Several tumor markers are associated with colorectal cancer, but these are not helpful in screening.

• An elevated serum CEA (>5 ng/mL) suggests a poorer prognosis, & an elevated value that does not return to normal following resection may indicate persistent disease.

• The presence of microsatellite instability in the lesion predicts fewer metastases & improved prognosis.

Treatment of CRC:

• Most patients with colorectal cancer undergo surgery for curative intent or palliation& involves debulking of the tumor to treat bleeding or prevent obstruction.

• The portion of the colon to be resected is based upon the anatomic location of the cancer & the vascular & lymphatic drainage in the area.

• Preoperative radiation therapy is often administered for patients with rectal cancers.

• Laparoscopic resection is being evaluated to see how this procedure compares with traditional open surgical resection.

• Endoscopic removal of pedunculated polyps with carcinoma limited to the mucosa is curative if a free stalk margin is present & there is no vascular or lymphatic invasion.

• Surgical resection is the treatment of choice for lesions with an uncertain margin (e.g., sessile polyps) or with possible vascular or lymphatic invasion.

Treatment of CRC:

• 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.

Treatment of CRC: key point

• Management of most patients with colorectal cancer involves surgery for curative intent or palliation.

• Endoscopic procedures can be used for palliation of patients with colorectal cancer who are not surgical candidates.

Prognosis of CRC:• 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.