GIT CRC 2010 Plus pictures.

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, but only 1 / 20 will progress to cancer. • 15-25% >50 ys have adenomatous polyps, males>females.• So screening for polyps in those > 50 & earlier for those with

positive family history, prevents CRC.

CRC:PRECURSORS• Adenoma transformation to cancer results from an accumulation

of genetic mutations occuring over a decade or more&involve:• 1. 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.

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

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

CRC:TSG mutations• 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,this 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 • 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• CRC in patients with chronic IBD is associated with a similar

sequence of accumulated mutations&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

CRC precursors: Key points• 1/ 20 adenomatous polyps will progress to CRC.

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

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

Epidemiology/risk factors• CCRC is the most common GIT malignancy. • It is the 3rd most common malignancy.• It the 2nd most common cause of cancer deaths: 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

FAB& HNCRC) & 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:FAP• FAP&HNPCC are the best understood of the hereditary CRC

syndromes. • Both are AD , although 1/3 are found to have APC genetic

mutations or DNA MMR genetic abnormalities. • FAP patients develop hundreds of adenomatous colon polyps

during adolescence & have a 100% risk of developing CRC by a mean age of 40 years.

• UGIT Tumors, as fundic gland polyps & duodenal adenomas, also occur in patients with FAP& adenocarcinoma of the ampulla of Vater is the 2nd most common malignant tumor in these patients.

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

Hereditary CRC Syndromes: attenuated 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.

Hereditary CRC Syndromes: HNPCC

• Have fewer polyps than those with FAP.• Polyps also tend to be larger & located in the proximal colon. • Have 80% risk of developing CRC, usually after 50 ys age.• Have a markedly increased risk of developing extracolonic

tumors, especially of the female reproductive tract, kidneys, small intestine, biliary tract, pancreas.

• Genetic tests are available to diagnose FAP & HNPCC, but should only be done in conjunction with counseling.

Hereditary CRC Syndromes: CRC family history

• Persons with a family H/O CRC or adenomas that do not meet the criteria for HNPCC or FAP also have an increased risk of CRC.

• Having a single first-degree relative with CRC or adenomas doubles the risk.

• The risk increases significantly (relative risk = 3-4) if the first-degree relative is <50 years at diagnosis or if > one family member is affected.

• The risk is also increased in persons with a family H/O adenomatous polyps in relatives < 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 cancer10%

Moderate

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

20%

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

Average (negative family history)

>50 years of age5-6%

IBD:

• Patients with chronic UC & most likely Crohn's colitis have an increased risk of developing CRC.

• The risk in patients with UC is increased according to the duration of disease, extent of colonic involvement, early age of onset& presence of PSC.

• The prevalence of CRC in patients with UC is 3.6% but increases to 5.6% with pancolitis.

• In patients with pancolitis for 8-10 years or left-sided colitis for 12 - 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. but, colonoscopy has become an increasingly popular choice for screening&is recommended as the preferred test by ACG.

• Colonoscopy allows both diagnosis & removal of adeno polyps. • Genetic counseling / testing should be considered for patients with

a family history of FAB or HNCRC.

Algorithm for screening for CRC

Patient selection for screening:• Patients with an adenoma in distal colon have a 20-30% risk of

having a synchronous (concomitant) adenoma in 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 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 exam, surveillance should be repeated every 5 years.

• In all patients with CRC who underwent resection for cure, the site should be re-examined in 3-6 months.

• Patients with longstanding IBD& PSC have a cancer risk 5 times greater than

Patient selection for screening:

• Patients with longstanding IBD (pancolitis for > 8 to 10 years; left-sided colitis for > 12-15 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 IBD&PSC: Surveillance should begin at the time of

diagnosis & be continued annually.

Clinical Manifestations of CRC:

• 15-20% 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, liver,

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

CRC. • Because the venous drainage of the distal rectum is into the IVC,

rectal cancer will initially metastasize to the lung. • An elevated serum CEA suggests a poor prognosis.• Patients with adenomas of the colon are usually asymptomatic&

those with colorectal cancer may occasionally have no initial symptoms.

Clinical Manifestations of CRC:

• The most common presenting symptoms 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 CRC 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.

Diagnosis of CRC:

• Diagnostic studies are indicated for patients with symptoms or positive screening tests for CRC.

• Colonoscopy should be performed because it allows visualization of the entire colon & biopsies could be taken.

• Complications of diagnostic colonoscopy range from 0.03%- 0.6% & include perforation, bleeding& cardiorespiratory complications due to sedation.

• Complications of therapeutic colonoscopy range from 0.07- 2.7%. • If colonoscopy cannot be performed or completed, double-

contrast barium enema or CT colonography should be done because synchronous cancers occur in 3- 5% with CRC.

Staging 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 TNM system. • Staging requires both imaging & histological 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 identify more hepatic lesions & can better detect local lymphadenopathy in patients with rectal cancer.

Staging of CRC:

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

• EUS 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.

• FNA tissue sampling of local lymph nodes adds to the accuracy of EUS for staging .

• Several tumor markers are associated with colorectal CRC, 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 absence of microsatellite instability in the lesion predicts fewer metastases & improved prognosis.

Treatment of CRC:

• Most patients with CRC undergo surgery for curative intent or palliation or 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.

• Preop radiation is often administered for rectal cancers. • Laparoscopic resection is being evaluated to compare 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 CRC 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.

Prognosis of CRC:• The prognosis in patients with CRC is based on the pathologic

stage 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.

Prognosis of CRC:• 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 is directed towards detecting recurrent disease or metachronous (new) polyps.

The Difference between a Normal Colon and a Colon with Cancer