Colorectal cancer (CRC)

Dr. Mohamed Shekhani.

MBChB-CABM-FRCP.

CRC : Key points• CRC results from the accumulation of genetic mutations that lead

to the progression from normal mucosa to dysplastic adenoma to carcinoma.

• Tumor suppressor genes, oncogenes& mismatch repair genes differentially contribute to carcinogenesis in familial& sporadic colorectal cancers.

• Evaluation of patients with a suspected familial CRC syndrome should be performed under the guidance of a genetic counselor.

• Patients with hereditary CRC syndromes as FAP& HNPCRC have a very high risk of developing CRC& extracolonic malignancy& require aggressive screening /surveillance strategies.

• In addition to CRC, patients with FAP are at risk for cancers of the small bowel, thyroid, stomach, CNS& biliary system.

• HNPCRC should be suspected clinically in persons who have multiple family members with CRC, endometrium,ovaries, small bowel, ureter, renal pelvis&pancreaticobiliary system.

CRC : Key points• Clinical diagnostic criteria for HNPCRC include the 3-2-1 rule: • 3 relatives with an associated cancer• 2 generations affected; and • 1 person diagnosed before age 50 years. • Medical conditions that increase the risk for CRC:• Inflammatory bowel disease• Acromegaly• H/O radiation injury to the colon• Urinary diversion with implantation of ureters into the colon.

CRC : Key points• CRC screening is well tolerated, cost-effective& saves lives. • Screening for CR is feasible because of the 10-15 years that are

needed for a polyp to develop into cancer, a good time to detect & remove an adenoma.

• Fecal occult blood testing, flexible sigmoidoscopy, colonoscopy are appropriate options for screening for colorectal cancer in average-risk patients.

CRC : pathophysiology• The transformation of a normal colonocyte into cancer is the

result of a series of molecular changes. • The biologic roles of the genes involved in sporadic& familial

CRC have been elucidated. • Various environmental /dietary factors affect the risk for CRC. • 2-hit hypothesis of carcinogenesis;two mutations (or “hits”)

required for carcinogenesis, is most evident in the familial CRC syndromes.

• In hereditary cancer syndromes, the first hit is an inherited mutation that is present in the zygote ; the second hit is a somatic mutation, cancer develops in a high proportion at an early age.

• In sporadic cancers both hits are somatic mutations in a single cell, a much less likely event, that occurs in nearly 5% of the population.

CRC : Genetics• A series of genetic abnormalities resulting in progression from

normal mucosa to dysplastic adenoma to carcinoma.• The progression from normal mucosa to adenoma to cancer takes

approximately 15 years.

CRC : Genetics• Tumor suppressor genes:• In most sporadic cancers& some familial syndromes, mutations

occur in the APC gene. • It is the cause of most cases of the FAP syndrome. • Mutations in the tumor suppressor gene p53 occur in 70% of

colon cancers. The p53 gene facilitates cell repair& initiates apoptosis

• Mutations in the p53 gene often occur late in the transformation from dysplasia to carcinoma.

CRC : Genetics• Oncogenes:• Promote cell growth & replication& their normal suppression in

the healthy cell prevents cancer. • Mutations of the ras oncogene occur in half of the cases of

sporadic colon cancer but not hereditary cancers.

Gene Function Affected Gene Clinical Manifestation

Tumor supp genes APC FAP, AFAP

p53 Sporadic colon cancer

DCC Non-syndromic FCRC

Oncogenes myc Sporadic CRC

ras

src

erbB2

Mismatch repair genes MLH1 HNPCC

MLH3 Sporadic CRC

Base excision repair genes MYH FAP, AFAP—aut resisive

CRC : Genetics

• Mismatch&Base Excision Repair Genes• Mutations of mismatch repair genes are implicated as the

primary aberration in HNPCRC & 15% of sporadic CRC. • Mutations of base excision repair genes play a role in FAP that is

inherited in an autosomal recessive pattern.

CRC : Epidemiology/RFs

• 1/20 in the US will develop CRC in their lifetime. • It is the third most common cancer diagnosis in both men (behind

prostate &lung)& women (behind breast & lung).• Colon cancer is also the third most common cause of cancer

death in both sexes despite. • 40% of patients diagnosed will die of the disease. • CRC affects men &women equally • Occurs in all ethnic groups, greater in black Americans, who have

more advanced clinical stage at diagnosis&a worse overall prognosis.

CRC : Epidemiology/RFs

• Environmental factors:• Diets rich in fruits, vegetables, dietary fiber& low in fat/ red meat

associated with fewer colon cancers. • High intake of calcium, folate, selenium has also been associated

with a decreased overall risk. • Trials designed to reduce CRC risk through dietary modification

have yielded disappointing results. • Obesity &a sedentary lifestyle have been associated with the

development of adenomas& an increased risk. • Obesity also reduces survival in patients diagnosed with colon

cancer. • Smoking / alcohol use have both been consistently found to be

associated with the development of colon adenomas / cancer& adversely affect survival.

Factors Associated with the Development of CRCRisk Factors Protective 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 Europe Diet high in fruits and vegetables*

Diet high in red meat, sucrose, fat Regular aerobic exercise

Physical inactivity Calcium and folate supplementation

Lack of dietary calcium and folate

Obesity

Smoking

Excessive alcohol intake

Cholecystectomy

Hereditary CRC Syndromes• FAP:• < 1% of all cases of CRC are due to FAP, transmitted in an AD

fashion • Characterized by the presence of hundreds to thousands of

adenomatous polyps &the inevitable development of CRC. • Most often due to a germline mutation in the APC gene. • Less commonly, polyposis results from biallelic mutations of the

MYH gene with a recessive pattern of transmission.• Mutations are detectable in 70%.• Polyps typically develop during the teenage years• Cancer develops between age 30-50 years. • Various benign &malignant extracolonic manifestations occur in

affected kindreds. • The next most common site of cancer in these patients is the

periampullary region of the duodenum& screening protocols include evaluation of the upper & lower GIT.

Hereditary CRC Syndromes• Attenuated FAP:• 10-100 adenomas develop• The polyps &cancer develop about 10 years later than in the

classic FAP. • It is most commonly is the result of mutations in the 3' or 5' end

of the APC gene, although biallelic MYH mutations also result in this phenotype.

• The extracolonic manifestations of the classic form also occur in patients with the attenuated form& present in those with both APC & MYH mutations.

Hereditary CRC Syndromes• HNPCC:• Lynch syndrome: AD syndrome,carries an 80% risk for CRC.• It is the most common of the hereditary CRC syndromes, accounting

for 2-3% of all colorectal adenocarcinomas. • Mutations in MLH1/MSH2 mismatch repair genes are the most

commonly detected genetic abnormality. • HNPCC-associated cancer generally becomes clinically apparent in

patients with fewer than 10 adenomas& although cancer may occur at an early age, it generally develops after age 50 years.

• The cancers tend to occur in the right side of the colon& have a mucinous histopathology with infiltrating lymphocytes.

• The pathophysiology: accelerated adenoma-to-carcinoma sequence, with cancer often occurring within a few years of a colonoscopy during which all polyps were removed.

• HNPCC-associated extracolonic cancers include uterine (40-60% lifetime risk), ovarian(10-12% lifetime risk).

• Cancers of the small bowel, stomach, pancreas, renal pelvis, ureter also occur & may occur in affected kindreds without CRC.

Hereditary CRC Syndromes• PJS:• The Peutz-Jeghers syndrome is a rare AR hereditary condition

that consists of polyposis of the colon & small bowel. • The polyps are predominantly hamartomas, although they may

undergo malignant transformation& affected persons have an 80-fold increased risk for CRC over the general population.

• The genetic abnormality occurs as a germline mutation in the STK11 gene.

• Patients may be readily identified by the classic perioral pigmentation, although the typical presentation consists of bleeding &abdominal pain from large polyps.

• Extracolonic tumors of the breast, pancreas, ovaries, lung occur at an increased rate.

Hereditary CRC Syndromes• JPS:• Juvenile polyposis syndrome is AD with hamartomatous polyps

occurring most often in the distal colon, accompanied by congenital malformations of the GIT, GU& heart.

• Germline mutations of the SMAD4 gene are implicated in this syndrome.

• The lifetime colon cancer risk is 70%.

Stratification of Colorectal Cancer Risk

Risk Level Lifetime Risk

High

Presence of familial adenomatous polyposis 100%

Presence of hereditary nonpolyposis colorectal cancer 10%

Moderate

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

20%

Familial: First-degree relative with colorectal cancer 10-20%

Average (negative family history)

>50 years of age 5-6%

Diagnosis/Management of those at Increased Risk:• Genetic testing:• Patients who may have a hereditary cancer syndrome include: • Those with > the expected number of cancers in their family, • Those with cancer at an earlier age than anticipated• Those with endoscopically detected multiple polyps. • Performed under the guidance of a genetic counselor • If a family carries a defined genetic mutation& an at-risk family

member tests negative for the mutation, it is likely that the tested person does not carry the mutation& will not develop the disease.

• If the genetic mutation in the family is unknown, the patient must be treated as if he or she remains at risk for the syndrome even if tested negative.

Diagnosis/Management of those at Increased Risk:• Adenomatous polyposis:• FAP& attenuated PAP are most commonly diagnosed after polyposis is

detected on endoscopy, performed due to a suggestive family history or because of bleeding or abdominal pain.

• Commercial testing for mutations in the APC gene is available.• If APC mutation is not detected, MYH test should be performed. • In 30%, a genetic mutation will not be detected. • Management for FAP& for at-risk persons includes annual flexible

sigmoidoscopy beginning as early as age 10-12 years. • Colectomy should be considered when polyposis is detected, although

because the mean age of the onset of cancer in these patients is 40 years, decisions may be individualized.

• In attenuated FAP, annual complete colonoscopy is required because polyps may only be present in the proximal colon.

• Many can be managed with endoscopic polypectomy rather than with surgery, but surgery is recomm ended if the polyp burden cannot be managed at colonoscopy.

• Upper endoscopy is performed initially between ages 25-30 years & at 1- to 3-year intervals thereafter.

Diagnosis/Management of those at Increased Risk:• HNPCC:• Most identified from their medical history. • The diagnosis should be suspected in persons who have multiple

family members with cancers of the colon, endometrium/ ovaries, small bowel, ureter, renal pelvis, pancreaticobiliary system.

• The Amsterdam II clinical criteria for HNPCC use the 3-2-1 rule: • 3 relatives with an HNPCC-associated cancer• 2 generations affected• 1 person diagnosed before age 50 years.

Diagnosis/Management of those at Increased Risk:• HNPCC:• Management of patients with HNPCC or those who are

considered at risk for the disease consists of :• Colonoscopy every 1-2 years beginning at age 20 -25 years or 10

years before the age at diagnosis of the youngest family member diagnosed with CRC.

• Annual colonoscopy is recommended after age 40 years. • Women better to undergo prophylactic hysterectomy& salpingo-

oophorectomy if no longer wish to bear children. • If not, should have a pelvic examination with endometrial

sampling, transvaginal U/S&measurement of serum CA-125 every 1-2 years from age 30 years.

• Screening for urinary tract cancers with urine cytology& renal U/S should also be performed every 1-2 years beginning at age 30 years.

Screening for those with Family H/O CRC or Adenomatous Polyps

Patient Category Screening Surveillance

FDR(s) with CRC <60 ys CS at 40 or 10 years <affected relative If N,repeat *3-5

FDR(s) with CRC >60 ys CS at 40 ys If N, * 10 years

FDR(s) with AdP <60 ys CS at 40 or 10 years <affected relative If N,rep *5

FDR(s) with AdP >60 ys CS at 40 ys Ind; if N, as average risk

2nd- or 3rd DR with ca or polyps CS as ARP If N, as ARP

Diagnosis/Management of those at Increased Risk:• IBD:• Patients with UC& Crohn disease have an increased risk for colon

cancer, a risk that increases with:• Increased duration of disease.• The extent of colonic involvement• The coexistence of sclerosing cholangitis.• The annual cancer risk is 1-2% /year after 8 years of disease, • Colonoscopic surveillance should be started in patients who have

had IBD for 8 years or longer. • For patients with inflammation limited to the left colon,

recommended surveillance is after 15 years' duration of disease. • If dysplasia is detected on biopsy in a patient with colitis, the risk

for colon cancer is markedly increased even at sites distant from the site of biopsy& colectomy should be considered even without preoperative cancer diagnosis.

Diagnosis/Management of those at Increased Risk:• Others:• Other conditions that increase the risk & should have an

accelerated surveillance program include:• A history of radiation injury to the colon• Acromegaly• Urinary diversion with implantation of the ureters into the colon.

Screening for CRC:• Assessing a person's risk is central to formulating an appropriate

screening / surveillance protocol. • Screening/ surveillance decrease the incidence of CRC. • The guidelines include various screening modalities. • Screening is cost effective , tolerated,cost-effective& saves lives. • Screening is feasible because the 10-15 years needed for a polyp to

develop into cancer are sufficient time to detect and remove an adenoma.

Screening for CRC:• Average risk persons include:• Those with no personal or family history of colon adenoma or

cancer who do not have a condition that predisposes them to cancer.

• Screening in this population should be started at age 50 years, with surveillance intervals depending upon the screening modality.

Screening for CRC:• Nonsyndromic Family History• A family history of CRC or FAP significantly increases a person“s

risk for colon cancer.• Up to 30% of those screened have such a history. • The magnitude of risk depends on whether the affected family

member is a first-degree relative (parent, sibling, child) or second-degree relative (grandparent, aunt, uncle), the number of affected family members&their age at onset of disease.

• The presence of colon cancer in a first-degree relative carries a two- to threefold increased lifetime risk over the general population; that risk is doubled again if the affected relative was diagnosed before age 45 years.

• If two first-degree relatives have colon cancer, the colon cancer risk approaches 20%.

• For persons with a family H/O CRC in 1st DR screening is initiated either at 40 years or beginning 10 years earlier than the diagnosis of the youngest affected family member .

Screening for CRC: Screening tests • FOBT• An effective screen; proper performance requires a dedicated

physician & motivated patient. • The test is inexpensive, noninvasive, generally acceptable to

patients& can detect bleeding anywhere in the colon. • Detected by either a guaiac-based test (gFOBT) or fecal

immunochemical test (FIT).• gFOBT testing detects hemoglobin by a peroxidase reaction; the

procedure requires annual testing, that two samples be collected from each of three spontaneously passed stools& diets be modified during the testing period to avoid aspirin, red meat&certain fruits / vegetables.

• It reduces CRC-related mortality by 33%. • FIT detects human globin & more specific than gFOBT.• FIT requires fewer precollection restrictions & fewer samples,

thereby improving patient compliance.

Screening for CRC:• FOBT• Recommendations:• Annual stool testing with either gFOBT or FIT.

Screening for CRC:• Flexible Sigmoidoscopy• Decreases colon cancer &CRC- mortality by 45%. • Advanced adenomas (≥1 cm, villous,HGD or cancer) are detected *3 more

often by sigmoidoscopy than by fecal occult blood testing.• Combined FOBT & sigmoidoscopy modestly increases the detection rate

from 70-76%. • Small polyps detected during sigmoidoscopy can be biopsied or removed

safely with a snare without cautery. • Cautery should be avoided in the uncleansed colon because of the

possibility of colonic rupture. • Removing large polyps needs colonic prep& snare polypectomy.• If a polyp removed & found to be an adenoma, complete colonoscopy is

required. • Factors at sigmoidoscopy associated with finding advanced adenomas on

follow-up colonoscopy include multiple adenomas, adenomas ≥1 cm, patient age >65 years&villous adenomas

• Guidelines:sigmoidoscopy every 5-year if no adenomas detected. • Sigmoidoscopy is well tolerated, not require sedation, fewer complications

than colonoscopy.

Screening for CRC:• Colonoscopy:• A preferred diagnostic &therapeutic procedure that evaluates

the entire colon&allows biopsy/or polypectomy. • It reduced the incidence of CRC by 76-90%. • Half of patients with advanced adenomas of the proximal colon

that are detectable on colonoscopy do not have polyps within the reach of a sigmoidoscope.

• If an adenoma is detected on colonoscopy, the patient is most likely to benefit from an accelerated surveillance program, otherwise ,another colonoscopic surveillance needed after 10 ys.

• It is well tolerated, the primary source of discomfort being the colon preparation.

• Colonoscopy is not acceptable to all persons, thereby decreasing adherence rates& disproportionately so in women& ethnic minors

• Complications: bleeding (0.20%), perforation (0.02%). • The miss rate for polyps >1 cm is 6-11%.

Screening for CRC:• Double-Contrast Barium Enema• Has not been shown to reduce the incidence of CRC or mortality. • Limited to the patient in whom a complete examination of the

colon is desired but cannot be performed by other methods.

Screening for CRC:• CT Colonography (virtual colonoscopy):• An emerging modality for screening • An acceptable mode of screening. • Most useful when colonoscopy is either not feasible or

contraindicate&structural colonic imaging is required. • The optimal procedure requires a bowel preparation similar to that

for colonoscopy, insertion of a rectal tube& insufflation to establish pneumocolon.

• Sensitivity for polyp detection is extremely variable. • The sensitivity of CT colonography for polyps <5 mm varies from

30-60% , for lesions ≥1 cm is 60-95%. • Concerns:• Radiation exposure, tumor 1/714 persons, increases with subsequent

examinations• The relevance of small lesions• Surveillance intervals? Every 5 years.• Incidental findings.

Screening for CRC:• Fecal DNA Testing• Requires submission of a single stool sample. • The sensitivity ranges widely. • There are no studies demonstrating a reduction in colorectal

cancer-related mortality. • Recently been endorsed as an option for screening • The surveillance interval after initial screening remains unknown.

Algorithm for screening for CRC

Colonoc neoplasia & CRC:• Colon adenomas are usually discovered incidentally. • The strongest predictor of finding an adenoma on index colonoscopy

is the presence of blood in the stool. • Adenomas are less commonly found when the indication for

colonoscopy is abdominal pain, changes in bowel function, or weight loss.

• Abdominal pain, bleeding&altered bowel habits are the most common presenting symptoms of colon cancer; less common are anemia & weight loss.

• Colon cancer may present with local invasion & fistula formation or unexplained intra-abdominal abscess, resulting in a clinical picture similar to that of complicated diverticulitis.

• Patients with diverticulitis should undergo colonoscopy after the acute inflammation resolves.

• Bacteremia from Streptococcus bovis &Clostridium septicum has been associated with CRC& should prompt colonoscopy.

• Adenocarcinoma of unknown primary site originates from the colon in 6% of cases.

Staging for CRC:• After the diagnosis staging work-up is performed; consists of a

thorough medical history & physical examination, complete evaluation of the colon& CT scan of the abdomen / pelvis.

• MRI is more sensitive for detecting liver metastases than CT, but long scanning times& availability limit the use of MRI.

• Scanning with (FDG-PET scan) is sensitive for detecting extrahepatic metastases but is not superior to CT scan for detecting spread to the liver.

• Many centers perform combined PET-CT, which offers the benefits of both tests.

• The most accurate procedure for locoregional staging for rectal cancer is ERUS, which provides high-resolution imaging& the ability to sample suspicious nodal disease.

• A preoperative measurement of serum CEA provides prognostic information& serves as a marker for recurrent disease.

Staging for CRC:• Staging most commonly follows the TNM staging.• The strongest determinant of recurrence & survival is the

pathologic staging, which correlates with prognosis & determines the need for adjuvant therapy.

• Molecular targets that can diagnose micrometastases not detected by histologic assessment will likely have a role in staging evaluation in the near future.

• At present, the 5-year survival rate for patients diagnosed with stage I disease exceeds 90%; for patients with stage IV disease, the survival rate is only 8%.

• The overall colon cancer-related mortality rate is 40%.

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.