Colorectal cancer (CRC) is the third leading cause of cancer in the United States. It accounts for 9% of all new cancer diagnoses (130,000 new cases annually) and 11% of all cancer deaths (over 56,000 annually). Not all individuals are of equal risk. A person with a first-degree relative with CRC has an 8% lifetime CRC risk, but with two first-degree relatives the risk increases to 17%. Various racial and geographic factors also contribute to the risk. For example, the CRC incidence for men (per 100,000 per year) is 8 for Miyagi, Japan, 10-17 for Europeans, 28 for Caucasians in New Orleans, and 34 for Hawaiians of Japanese decent.

Many lines of data have led to the widespread acceptance of the hypotheses that most cancers develop from colonic adenomasthe "adenoma-to-carcinoma" sequence. Removal of adenomas has been demonstrated to be associated with a 76 to 90% reduction in the number of expected CRC cases. If detected early, CRC is a very curable disease. The expected 5 year cancer-free survival for a Dukes-Turnbull Class "A" patient is 95-100%. However, currently over half of the patients in America have their cancer first detected at the late Class C or D stage, with a correspondingly poor prognosis. This exemplifies the need for screening to detect these cancers earlier. Unfortunately, only about 30 % of all Americans have ever had CRC screening.

Recent studies have shown that colonoscopy is the most cost effective CRC screening strategy available. As of July 1, 2001, Medicare has approved payment for screening colonoscopy for high and average risk individuals. This review presents the screening tests that are available currently and describes the latest US national guidelines. Screen your patients for CRC "by the book", and turn tears into triumph for this dreaded disease

back to the top

Current Screening Tests

The easiest and least intrusive test, fecal occult blood testing has been shown in three randomized trials to reduce CRC mortality from 15 to 33% in the general population. Unfortunately, on each cycle of testing only 33 to 50% of the CRC will be detected. Additionally, compliance for repeat testing is poor in every study and early adenomas are rarely detected by this testing. Furthermore, any positive hemoccult is an indication for a colonoscopy, as bleeding from CRC is intermittent.

Flexible Sigmoidoscopy (FxS) can reach as high as 60 cm and can survey the entire left colon. The detection of a polyp at FxS mandates that a full colonoscopy be performed to remove this index polyp and to seek polyps in the proximal colon that cannot be reached by FxS. A recent study revealed that only about 35% of patients with a proximal CRC (right side of the colon) had an index adenoma in the left colon, and therefore these right-sided lesions would not have been detected by screening FxS. Studies have demonstrated that Primary Care Physicians, nurse practitioners, and physician assistants can be trained to do a successful FxS. Medicare will pay for a screening FxS every 4 years (as an alternative to colonoscopy).

Air Contrast Barium Enema (BE) is not advised as a primary screening procedure. However, it has value in cases when: 1. a complete colonoscopy could not be obtained; 2. areas can't be adequately evaluated ("blind turns", etc) or 3. patients refuse colonoscopy but have indications for a colonic imaging. The National Polyp Study suggested that BEs find fewer than 50% of the polyps detected by colonoscopy and that specificity of BE is poor with 18% false-positives.

Virtual Colonoscopy (VC) is a promising new tool. It uses either a helical CT Scanner or an MRI with a special software package to construct an image of the colon. Current VC machines fail to detect nearly 10% of polyps measuring 10mm or less in diameter, and miss about 5% for those greater than 10 mm. Additionally, Medicare and other carriers will not reimburse for this procedure. VC should not be recommended if colonoscopy can be performed but some experts believe VC is an acceptable alternative to barium enema for patients for whom colonoscopy does not reach the cecum. Further information is found in Dr. Etzkorn's article in this issue of Jacksonville Medicine.

While Colonoscopy with appropriate biopsy and polypectomy is the current gold standard for CRC screening, it is important to review its shortcomings. The bowel clean out procedure is somewhat difficult for many patients but is critical to the accuracy of the exam. Oral iron, aspirin, Coumadin and other anticoagulants, and NSAIDS must be withheld for a week before the exam. The procedure to reaches the cecum in more that 95% of patients, though in one series physicians failed to reach the cecum in 15% of cases. The reported miss rate for polyps varies with the size of the polyp. For example, for those less than 5 mm, the miss rate can be as high as 16-27%; for 6-9 mm polyps, 12-13% will be missed; and for those greater than 10mm, the miss rate is 0-6%. Complications of colonoscopy are unusual but can include perforation (0.14 0.25%), bleeding (0.7 2.5%), and death (less than 0.02%).

Current techniques for CRC screening are suboptimal because of inaccuracies, invasiveness, cost, and patient and/or physician reluctance. Recent studies of stool with DNA target assays for K-ras, p53, APC, BAT-26, and "highly-amplifiable or long" DNA resulted in a sensitivity of 91% for cancer, 82% for polyps, and a specificity of 93%. Excluding K-ras from the panel led to an increasing specificity of 100% with no change in sensitivity for cancer and a minimal decrease in sensitivity for adenomas to 73%. Large population-based testing will be needed to determine whether any of these tests will be useful screening tools in the future.

back to the top

Today's Screening Guidelines

Death from Colorectal Cancer is one of the most preventable in America. Asymptomatic individuals with no risk factors for colon cancer should undergo colonoscopy starting at age 50 years and every 10 years thereafter. For those found to have adenomas, especially adenomas 10mm or larger in size, follow-up colonoscopy should be performed every 3 years. For those with villous polyps, colonoscopy is advised every 2 years. For those found to have CRC, colonoscopy is advised one year after the initial cancer is removed, and then every 2 years until year 5, after which colonoscopy is performed every 3 years.

High-risk individuals are those with one of the known genetic syndromes (see below) or those with a known family or personal history of colon polyps; with a family history of colon cancer, breast cancer or female pelvic cancer; or with a history of inflammatory bowel disease of the colon. Those individuals with a positive family history of colon cancer should start colonoscopy at age 40 years (or 10 years younger than the earliest case noted in first degree relatives). These individuals should have colonoscopy every 5 years thereafter. The specifics for the various other high risk individuals are described below and in the tables.

Alternative screening options are available and have been found to prevent death from colon cancer but are not as sensitive as colonoscopy for detecting adenomas or early cancers. These options include yearly digital rectal exams, yearly stool tests to detect the presence of blood (the Hemoccult test), and a flexible Sigmoidoscopy every 3-5 years.

back to the top

"In the Family Way"

Approximately 25-30% of CRC is "familial" or associated with known genetic syndromes. The remainder are said to be "sporadic". The proven genetic syndromes are: Familial Adenomatous Polyposis (FAP), Hereditary Nonpolyposis Colorectal Cancer (HNPCC), Peutz-Jeghers Syndrome (P-J), and juvenile Polyposis (JP). Genetic testing should be considered for: 1. confirmation of a suspected diagnosis of an inherited syndrome and 2. determining a gene carrier status in a family where a mutation has been identified. In the first case, once confirmed, screening can then be based on genetic testing with colonoscopy targeted on those testing positive for the known mutation. DNA is almost always derived from white blood cells from a standard blood draw. Informed consent and genetic counseling must be part of any genetic testing. However, the sensitivity of these assays is well below 100% so the inability to find a mutation does not rule out a familial syndrome. Therefore, it is advised that if a genetic syndrome is reasonably certain on clinical grounds, then the index case and family members should be screened with colonoscopy and managed as if they had the syndrome.

HNPCC is the most common hereditary form of CRC and is responsible for 3-5% of all cases of CRC. The risk of CRC in HNPCC approaches 80% by age 65 years. Between 60-70% of the cancers are proximal in location. The average age of onset of CRC is 44 years. Originally, the diagnostic standards used for HNPCC were the Amsterdam Criteria (Table 1).

Table 1: The Amsterdam Criteria For HNPCC

Classic or Amsterdam I Criteria There should be at least 3 relatives with colorectal cancer; all the following criteria should be present: One should be a first-degree relative of the other two At least 2 successive generations should be affected At least 1 colorectal cancer should be diagnosed before age 50 Familial adenomatous polyposis should be excluded Tumors should be verified by pathological examination

Amsterdam II Criteria There should be at least 3 relatives with an HNPCC-associated cancer (colorectal cancer, cancer of the endometrium, small bowel, ureter, or renal pelvis) One should be a first-degree relative of the other 2 At least 2 successive generations should be affected At least 1 should be diagnosed before age 50 Familial adenomatous polyposis should be excluded in the colorectal cancer case(s) if any are found Tumors should be verified by pathological examination

Currently, the Bethesda Criteria are the accepted standards for diagnosing HNPCC (Table 2).

Table 2: The Bethesda Criteria For HNPCC

Individuals with cancer in families that meet the Amsterdam criteria Individuals with two HNPCC-related cancers, including synchronous and metachronous colorectal cancers or associated extracolonic cancers* Individuals with colorectal cancer and a first-degree relative with colorectal cancer and/or HNPCC-related extracolonic cancer and/or colorectal adenoma: one of the cancers diagnosed at under the age of 45, and the adenoma diagnosed at under the age of 40. Individuals with colorectal cancer or endometrial cancer diagnosed under the age of 45. Individuals with right-sided colorectal cancer with an undifferentiated pattern (solid/cribriform) on histopathology diagnosed under the age of 45. Individuals with signet-ring-cell-type colorectal cancer diagnosed under the age of 45. Individuals with adenomas diagnosed under the age of 40.

back to the top

The risk of uterine cancer in HNPCC is about 40 %; ovarian, urologic, gastric and biliary cancer rates run around 10-20%; and there is a 1-5% risk of small bowel, CNS, and renal cancer. The Muir-Torre Syndrome arises from a mutation of the MSH2 gene and includes sebaceous adenomas and an increase in hepatobiliary and breast cancer.

HNPCC arises from mutations in one of five mismatch repair genes (MMR). These genes direct the production of certain proteins that participate in a nuclear process of DNA repair. When one of the MMR genes is mutated, the DNA replication errors persist in daughter cells and may lead to cancer development. This process usually leads to multiple replication errors. Tumors with these multiple errors are said to have micro-satellite instability (MSI), which is detected by a test performed on tumor specimens. MSI is found in over 90% of HNPCC cancers but in only about 15% of sporadic cancers.

Over 95% of all HNPCC cancers are found to have mutations in either the MLH1 or MSH2 genes. In theory the lymphocytes of individuals could be used to screen for these mutations. However, more than 100 mutations of these genes have been identified, making screening highly expensive. One strategy for optimizing genetic testing for HNPCC would be to test the tumor in question for MSI, which is less costly than the tests for MLH1 and MSH2. A negative MSI test makes the diagnosis of HNPCC very unlikely. A positive test confirms the diagnosis and may justify specific testing for mutations.

Colonoscopy in those with HNPCC should begin at age 25 years or 10 years younger than the youngest CRC diagnosed in the family (which ever comes first). It should be done every one to two years thereafter. If no mutation is found and/or MSI testing is negative in high risk families not meeting the HNPCC Criteria, then the family members should undergo colonoscopy every 3-5 years starting at age 40 years or 10 years younger than the earliest case in the family.

FAP is characterized by the development of hundreds to thousands of adenomas between puberty and the mid age 30's, with 100% of the affected untreated individuals developing colon cancer by an average age of 39 years. FAP affects one in every 8000-10,000 persons and arises from a mutation of the Adenomatous Polyposis Coli (APC) gene. Gardner's Syndrome is a variant of FAP which includes also osteomas, dental abnormalities, epidermoid cysts, desmoid tumors, and/or congenital hypertrophy of the retinal epithelium. FAP patients with meduloblastomas have Turcot's Syndrome. Interestingly, HNPCC with glioblastomas also is called Turcot's Syndrome. Additionally, the majority of FAP patients have gastric polyps and about half will have premalignant polyps at the Ampulla of Vater in the duodenum. Gastric cancer will be noted in about 0.5% and duodenal cancer will be found in 5-10% of these patients.

In suspected FAP, genetic testing should be done by age 10-12 years. Carriers will then undergo sigmoidoscopy every 1-2 years until adenomas are found. If genetic testing is indeterminate, then all family members will need sigmoidoscopy every 1-2 years. If the index case has "attenuated FAP", then screening should be with a colonoscope as these patients have primarily proximal colonic lesions (and often a decade later than in traditional FAP). Traditional treatment is either a colectomy with ileorectal or ileoanal anastamosis or total proctocolectomy with ileostomy. If the rectum is left in place, then surveillance will be needed every 6-12 months with ablation of any adenomas found. Regression for these polyps has been observed with some users of some NSAID's, including the COX2 inhibitors, but not with all NSAID's.

The hamartomateus polposis syndromes are confirmed by genetic testing in about 50% of the cases. The Peutz-Jeghers (P-JS) Syndrome arises from mutations of the STK11 (also called LKR1) gene on chromosome 19. Perioral and buccal melanin spots are the hallmark of P-JS. These are seen in over 95% of all cases. The hamartomas may cause bleeding and obstruction but, after the third decade of life, malignant complications predominate. By age 65 years, cumulative incidence of all colonic cancers could reach 93%.

The diagnosis of Juvenile Polyposis is made by the presence of 10 or more juvenile polyps in the GI tract. About half of the affected families will be found to have a mutation of the SMAD4 (or the DPC4) gene on chromosome 18. Colon cancer is greatly increased (perhaps as high as 50%) with 34 years being the average age of onset. Colonoscopy is advised every 3 years for these individuals.

Patients with chronic colonic inflammatory bowel disease (IBD), especially juvenile onset patients with involvement proximal to the splenic flexure, are at increased risk for the development of CRC. A retrospective study of referred patients in New York revealed a 10% incidence of colon cancer. Patients with pancolitis (ulcerative colitis involving the entire colon) had a 13% rate of malignancy, with a 5% rate for those with only left-sided disease. The incidence rate for CRC was less than 1% in the first decade of colitis, 7% in the second decade, 16% in the third decade and 53% in the fourth decade of pancolitis. Screening colonoscopy with biopsies for dysplasia is advised every 2 years for those with 8-10 years of IBD and every year after 20 years of disease.

back to the top

References

1. AGA Technical Review on Hereditary Colorectal Cancer and Genetic Testing, American Gastroenterological Association, Gastroenterology 2001; 121:198-213.
2. American Gastroenterological Association Medical Position Statement: Hereditary Colorectal Cancer and Genetic Testing, Gastroenterology 2001; 121:195-197.
3. Binder, Henry J., M.D. et al, Virtual Colonoscopy, Gastroenterology 2001; 121: 221-226.
4. Boland, C. Richard, Malignant Tumors of the Colon, Textbook of Gastroenterology Vol. 2, 1995; Chap. 87:1967-2026.
5. Boland, C. Richard, Identifying and Managing Risk for Hereditary Nonpolyposis Endometrial Cancer (HNPCC), A Continuing Medical Educational Program from the American Medical Association and American Gastroenterological Association (CME Publication), May 2001.
6. Bond, John H., M.D., Polyp Guideline: Diagnosis, Treatment and Surveillance for Patients with Nonfamilial Colorectal Polyps, Annals of Internal Medicine 1993; 277:915-922.
7. Burke, Wylie, M.D., PhD. Et al, Recommendations for Follow-up Care of Individuals with an Inherited Predisposition to Cancer: I. Hereditary Nonpolyposis Colon Cancer, JAMA 1997; 277:915-922.
8. Burt, Randell W., Colon Cancer Screening, Gastroenterology 2000; 119:837-853.
9. Guardiello, Francis M., M.D. et al, Phenotypic Expression of Disease in Families That Have Mutations in the 5' Region of the Adenomatous Polyposis Coli Gene, Annals of Internal Medicine 1997; 126:514-523.
10. Grodstein, Francine, ScD et al, Postmenopausal Hormone Use and Risk for Colorectal Cancer and Adenoma, Annals of Internal Medicine 1998; 128:705-720.
11. Leiberman, David, M.D., Colon Cancer Screening: Role of Endoscopy, ASGE: Clinical Update, July 2000; Vol. 8.
12. Luk, Gordon D., Colonic Polyps: Benign and Premalignant Neoplasm of the Colon, Textbook of Gastroenterology Vol. 2, 1995; Chap 85: 1911-1943.
13. Mandel, J. S. et al, The Effect of Fecal Occult-Blood Screening on the Incidence of Colorectal Cancer, New England Journal of Medicine 2000; 343:952-957.
14. Pappalardo, Guiseppe et al, Magnetic Resonance Colonography Versus Conventional Colonoscopy for Detection of Colonic Endoluminal Lesions, Gastroenterology 2000; 119:300-304.
15. Rex, Douglas K., M.D. et al, Colonoscopic Miss Rates of Adenomas Determined by Back-To-Back Colonoscopies, Gastroenterology 1997; 112:24-28.
16. Rex, Douglas K., M.D. et al, Medical-Legal Risks of Incident Cancers After Clearing Colonoscopy, The American Journal of Gastroenterology 2001, 96:952-957.
17. Rex, Douglas K., M.D. et al, Relative Sensitivity of Colonoscopy and Barium Enemas for Detection of Colorectal Cancer in Clinical Practice, Gastroenterology 1997; 112:17-23.
18. Scheitel, Sidna M., M.D. et al, Colorectal Cancer Screening: A Community Case- Control Study of Proctosigmoidoscopy, Barium Enema Radiography, and Fecal Occult Blood Test Efficacy, Mayo Clinical Prospectus 1999; 74:1207-1213.
19. Thompson, Jon S., M.D., What's New in GI, The American Journal of Gastroenterology 2001; 96:644-646.
20. Vasen, Hans F. A., New Clinical Criteria for Hereditary Nonpolyposis Colorectal Cancer (HNPCC, Lynch Syndrome) Proposed by the International Collaborative Group on HNPCC, Gastroenterology 1999; 116:1453-1456.