Colon Cancer Screening
Teri Brentnall, M.D., Toan Nguyen, M.D., Matthew Mealiffe, M.D.,
William M. Grady, M.D., and Emily Wong, M.D.

Introduction

Colorectal cancer (CRC) is the second leading cause of cancer death in the United States. The disease is common, affecting approximately 5% of the population at some time in their lives, and the associated mortality from advanced cases is high. In 2004, more than 146,000 new cases were diagnosed and more than 56,000 people died from CRC. Survival from colorectal cancer is inversely related to the stage of cancer and early detection can prevent up to 90% of colorectal cancer deaths. Different screening tests for colorectal cancer are accurate, acceptable, and cost-effective; some also confer the potential benefit of preventing the relatively slow and predictable progression of this disease [Winawer, 1997]. Screening for colorectal cancer is desirable and has been endorsed by the American College of Gastroenterology, the American Gastroenterological Association, the American Cancer Society, and the U.S. Preventive Services Task Force. Due to the rapid evolution of the field, we would like to caution that the following discussion is based on the available data in September 2005. Different strategies are recommended for screening of people at average risk (i.e. without identifiable risk factors for colorectal cancer) from those at increased risk so these groups will be discussed separately.

Multiple methods are available for screening average risk patients for colorectal cancer. The purpose of this chapter is to review the strengths and weaknesses of different screening procedures. While some issues may seem mundane, they can have a major impact on the effectiveness and cost of screening. There are several authoritative guidelines offering similar approaches to colorectal cancer screening, however the wide latitude within these guidelines makes it incumbent for the primary care physician to understand the key issues of screening techniques.

To prepare this chapter a Medline search was performed using the MeSH headings and search terms of colon cancer, colorectal cancer, screening, adenomas, polyps, surveillance, screening, genetic testing, familial adenomatous polyposis, Gardner Syndrome, Turcot Syndrome, Cowden Syndrome, Adenomatous Polyposis Coli, Hamartomatous Polyposis, Peutz-Jegher Syndrome, Hereditary Non-Polyposis Colorectal Cancer, fecal occult blood test, and inflammatory bowel disease. The years of the search included 1970-September 2005.

1. CRC SCREENING FOR PEOPLE WITH AVERAGE RISK (I.E. NO KNOWN RISK FACTORS)

Adoption of a screening policy should fulfill the following criteria: a) the relevant disease is common and serious, b) screening tests are accurate, acceptable, and feasible, c) treatment after detection improves prognosis, and d) the potential benefits outweigh possible harm and costs. Screening for colorectal cancer (CRC) is desirable because a) in 2004, the estimated incidence of new cases of CRC is 146,000 new cases, with a mortality of 56,000, b) the different screening tests are accurate, acceptable, and feasible, c) removing polyps and detecting early cancer reduces mortality from the disease, and d) cost-effectiveness analyses have shown satisfactory results [Winawer, 1997].

1.1 SCREENING GUIDELINES

Recent guidelines for colorectal cancer (CRC) screening of average risk individuals, have been developed or updated by a) the US Preventive Services Task Force (USPSTF) in 2002, b) the Agency for Health Care Policy Research (AHCPR) in 1997 and 2003, endorsed by the American Gastroenterological Association, the American Cancer Society, the American College of Gastroenterology, the American Society of Colon and Rectal Surgeons, the American Society for Gastrointestinal Endoscopy, and the Crohn’s and Colitis Foundation of America) [Winawer, 1997], [Winawer, 2003] c) the American College of Gastroenterology (AGG) in 2000 [Rex, 2000], and d) the American Cancer Society (ACS) in 2001 [Smith, 2001]. These guidelines are summarized in Table 1.

These colorectal cancer screening guidelines have the following recommendations in common: Differences in opinion include:

1. The frequency of tests other than FOBT:

The US Preventive Services Task Force does not specify an interval for tests other than FOBT, citing insufficient evidence.

2. Double contrast barium enema and colonoscopy:

While recognizing that there is no direct evidence (i.e. randomized or non-randomized trials or case-control studies) that double-contrast barium enema reduces mortality from CRC, the AHCPR and the ACS guidelines recommend double contrast barium enema every 5 years as acceptable screening tools for CRC. The USPSTF, citing insufficient evidence, did not recommend for or against routine screening use of barium enema, stating instead that “Double-contrast barium enema offers an alternative means of whole-bowel examination, but it is less sensitive than colonoscopy, and there is no direct evidence that it is effective in reducing mortality rates.” The ACG does not recommend barium enema as a screening strategy, except in selected situations when individual radiologists with a strong interest in this technique have established a high-quality pattern, in which case barium enema may substitute for flexible sigmoidoscopy in the alternative strategy.

3. Combined flexible sigmoidoscopy and FOBT:

In addition to sigmoidoscopy or FOBT performed alone, the AHCPR guidelines also list combined sigmoidoscopy and FOBT as an option for CRC screening. However, the AHCPR recognizes that while the individual components are supported by strong evidence, the added value of combining the two tests, while theoretically present, is not well established by research evidence. The USPSTF states, “The combination of FOBT and sigmoidoscopy may detect more cancers and more large polyps than either test alone, but the additional benefits and potential harms of combining the two tests are uncertain.” The ACS prefers combined sigmoidoscopy and FOBT over either test alone, while the ACG only recommends combined sigmoidoscopy and FOBT.

4. Colonoscopy:

Both the AHCPR and the ACS guidelines include this modality in their recommended screening. The USPSTF states, more cautiously, that “it did not find direct evidence that screening colonoscopy is effective in reducing colorectal cancer mortality rates; efficacy of colonoscopy is supported by its integral role in trials of FOBT, extrapolation from sigmoidoscopy studies, limited case-control evidence, and the ability of colonoscopy to inspect the proximal colon.” Only the ACG advocates colonoscopy every 10 years as the preferred screening strategy.

The available screening modalities are discussed further below.

1.2. FECAL OCCULT BLOOD TEST (FOBT)

Fecal occult blood testing is based on the premise that polyps and cancer bleed more than normal mucosa. The amount of bleeding is related to the site of the cancer (highest blood loss from large lesions in the cecum and ascending colon) and increases with the size of the polyp and the stage of the cancer [Macrae, 1982]. This bleeding is also intermittent and unevenly distributed in the stool, necessitating multiple samplings. The generally accepted collection protocol includes two samples from each stool specimen obtained on three different days. Convenient packages for testing (3 slides with two windows each), along with detailed instructions to patients, are available. A single digital FOBT is a poor screening test for CRC, as fewer than 5% of patients with advanced neoplasia have a positive test result [Collins, 2005]; it is specifically not recommended as a screening modality by the USPSTF.

A positive result with any sample warrants examination of the whole colon, most preferably colonoscopy; a combination of flexible sigmoidoscopy and air-contrast barium enema may be offered if colonoscopy cannot be performed [Winawer, 2003], [ACP, 1997].

Of note, a recent physician survey showed that a considerable number still use single sample digital testing, alone (32%) or in combination with home testing (41%). In addition, 30% will follow-up a positive FOBT with a repeat FOBT while 22% will recommend sigmoidoscopy alone. These deviations from recommended guidelines correlate well with a patient survey showing that one third of adults who reported having FOBT had an in-office test and that nearly one third of those who reported abnormal FOBT results reported no follow-up diagnostic procedures [Nadel, 2005].

In general, none of the current FOBT methods are highly accurate, with significant rates of false positive and false negative findings. Recent reviews on this subject are available [Ahlquist, 1997], [Bond, 1997], [Bond, 2002], [Van, 1995] including the position paper of the American College of Physicians [ACP, 1997], [Ransohoff, 1997].

1.2.1. The Procedure

FOBT based on pseudoperoxidase reaction:

Most current FOBT methods are guaiac-based tests, as established more than a century ago. The pseudoperoxidase activity of heme, either as intact hemoglobin or free heme, converts colorless guaiac to a blue color in the presence of hydrogen peroxide. In 1971, Gregor popularized the notion of FOBT using guaiac-impregnated cards [Greegor, 1971]. While most convenient and practical, due to its nature, this test is neither specific for blood nor cancer, and gives no indication of the amount of blood being lost. To minimize false positives, patients should avoid aspirin and non-steroidal anti-inflammatory drugs for 1 week (to prevent potential upper gastrointestinal bleeding), red meat (to avoid cross reactivity), and raw fruits and vegetables (especially melons, cauliflower, parsnips, radishes, turnips, horseradish and broccoli, to minimize confounding sources of peroxidase). Vitamin C, an antioxidant, may produce false negative results; intake in excess of 250 mg/day should be avoided.

Typically patients are provided with three cards; each card has two windows. The patient is asked to sample two sites from three stool specimens on successive days. After specimen collection, the rate of true-positive result decreases over time; it is important that the specimen is processed within one week. The common guaiac-based FOBT are Hemoccult II, which can be developed directly or following rehydration, and Hemoccult Sensa (abbreviated as HemeSensa). Rehydration of Hemoccult II slides prior to development increases sensitivity but decreases specificity, it is not recommended in the updated AGA guidelines [Winawer, 2003].

FOBT based on immunochemical detection of hemoglobin:

Many fecal immunochemical tests (FIT) have been or are being developed, such as InSure, Instant-View, immoCARE, MonoHaem, Clearview, Flexsure OBT/Hemmocuult-ICT, Magstream 1000/Hem SP, or Bayer Detect; they are currently used in different countries such as Australia and Japan. These tests differ in methods for specimen collection and testing.

FIT are based on antibodies that detect partial sequences of antigenic sites on the globin portion of human hemoglobin; this means of detection offer many potential advantages. Hemoglobin from upper GI sources is generally degraded by bacterial and digestive enzymes before reaching the large intestine and is therefore rendered immunochemically non-reactive. Hemoglobin from lower GI sources, on the other hand, undergoes less degradation and therefore remains immunochemically reactive. FIT may thus offer improved specificity for lower GI lesions with associated bleeding. Furthermore, because they do not cross-react with myoglobin or hemoglobin from many animal species and are not affected by peroxidase, ferrous sulfate, or vitamin C, FIT do not require any dietary restriction, a feature that may enhance patient compliance. In the same vein, Insure offers a convenient technique to sample the surface of the stool in the toilet bowel water.

Comparison of available FOBT systems:

Specificity and sensitivity are the main performance characteristics of FOBT that determine their relative merit. With the low prevalence of colorectal cancer and the vast population to be screened, a small decrease in specificity will be amplified into a much larger decrease in the positive predictive value and result in a large number of negative follow-up evaluations. Many studies have directly compared the sensitivities and specificities of different FOBT.

In an urban, community-based, screening study, where 10,818 FOBT kits were returned, the positivity rates for rehydrated Hemoccult, Hemoccult Sensa, and non-hydrated Hemoccult were, respectively, 15%, 7%, and 5%, while the respective positive predictive values for neoplasia = 1 cm were 7%, 11%, and 14% [ Levin, 1997]. In another study, the sensitivities for Hemoccult, HemeSensa, and HemeSelect were 88. 8%, 93.5% and 97.2% for 107 patients with colorectal cancer and 42.2%, 60.0%, and 75.6% for 45 patients with asymptomatic adenomas = 1 cm [St. John, 1993].

Four additional studies have determined and compared the performance characteristics of the different FOBT, alone or in combination: a study from the Oakland Kaiser Permanente Medical Center involving 8,104 subjects with a two-year follow-up [Allison, 1996], a study from Israel, with 403 patients undergoing lower endoscopic examination [Rozen, 1997], an international study of 554 patients referred for colonoscopy for predetermined indications [Greenberg, 2000], and a study from Japan with 21,085 patients undergoing FIT and a simultaneous colonoscopy [Morikawa, 2005]. The results of these studies are summarized in Table 2.

Table 2 shows notable variations in the performance characteristics for each FOBT between different studies. These differences most likely reflect the different populations tested (CRC screening [Allison, 1996] vs. colonoscopy referral [Greenberg, 2000]) and the methods for identifying neoplasia (2 years follow-up [Allison, 1996], vs. colonoscopy [Greenberg, 2000], [Morikawa, 2005]), vs. colonoscopy or flexible sigmoidoscopy prior to or at the time of testing [Rozen, 1997]. Indeed, while Allison et al. and Rozen et al. report specificities for HemeSelect and Flexsure OBT that are higher than the one of HemeSensa, Greenberg et al. report lower specificities.

Common trends can however be identified from these studies: a) HemeSensa is more sensitive but less specific than Hemoccult; b) Some FIT are more sensitive than Hemoccult and about as sensitive as HemeSensa; and c) HemeSensa combined with either HemeSelect or FlexSure OBT yields the highest specificity and positive predictive value, but exhibits a lower sensitivity. Of note, the sensitivity and specificity of FIT can be adjusted depending on the threshold set for globin detection. This quantitative modulation can be used to optimize a screening program, balancing positivity rate and positive predictive value.

The low sensitivities of these one-time FOBT may be compensated by repeated annual testing, as recommended by the different guidelines. The practicality and cost of the different FOBT methods should be considered. The estimated costs are ~ $2 for Hemoccult II or Hemoccult Sensa, and ~ $20 for FIT. Hemoccult and HemeSensa, rely on color development and are simple tests to perform; FIT are more complex tests, best developed in a central laboratory. Of note, even the simple guaiac-based FOBT can be misinterpreted [Selinger, 2003] and, in a general practice, the potential advantages of certain FIT may not be realized [Ko, 2003].

1.2.2. Supporting Evidence

Four controlled randomized trials support the efficacy of FOBT in decreasing colorectal cancer mortality. These trials are summarized in Table 3. The first study included 46,551 volunteers from Minnesota, 50-80 years of age, who were randomly assigned to a control group without screening and to FOBT screening (Hemoccult/ 83% rehydrated) every year or every other year with a 13 year follow-up [Mandel, 1993]. The 13-year cumulative mortality per 1,000 volunteers for colorectal cancer was reduced from 8.83 in the control group or 8.33 in the biennially screened group to 5.88 in the annually screened group, or a 33% reduction. This reduced mortality was accompanied by improved survival in those with colorectal cancer and a shift to detection at an earlier stage of cancer.

An 18-year follow-up study further demonstrates a significant reduction in the incidence of CRC, with cumulative incidence ratios of 0.80 (C.I. of 0.70 – 0.90) for the annual screening group and of 0.83 (C.I. of 0.73 – 0.94) for the biennial screening group. Non-compliance and a hiatus of about 4 years in the screening program may also underestimate the true reduction achieved with FOBT [Mandel, 2000].

The second study involved 61,933 people, 45-75 years of age, sampled from a base population of 140,000 from Funen, Denmark, who were randomized to either biennial screening over 10 years or control without screening [Kronborg, 1996]. The compliance rate for the first screening was 67%. Over the 10-year study, there were 205 deaths attributable to colorectal carcinoma in the screened group compared to 249 in the control group, or an 18% reduction.

The third study involved 150,251 people, 45-74 years of age, from Nottingham, United Kingdom, who were randomized to biennial screening or to control without screening [Hardcastle, 1996]. The compliance rate was 60% for at least one screening. Over the median follow-up of 7.8 years, there were 360 deaths due to colorectal cancer in the screening group, compared to 420 in the control group.

The fourth study, from Burgundy, France, included 91,199 individuals age 45-74 who were allocated to FOBT screening or no screening. FOBT was performed biennially without diet restriction and was processed by a central laboratory without rehydration; positive tests were followed up by colonoscopy. After 11 years and 6 screening rounds, the reduction in CRC mortality in the screened group relative to the control group was 16%; when confined to individuals accepting screening at least once, the reduction rate was 33%. The acceptability of the test was about 53%; the positivity rate was 2.1% for the initial round and 1.4% on average for the successive rounds [Faivre, 2004].

These four studies, from different locations and using different designs, came to the same conclusion that FOBT can be used as a screening tool to decrease CRC mortality. However, these studies differ in the reported efficacy for reduction of CRC mortality: 33 % for the Minnesota study, 18 % for the Danish study, 16% for the French study, and 14 % for the British study. It is unclear whether the nearly double mortality reduction in the Minnesota trial is due to the participation of volunteers, who may be more health-conscious and compliant, or the use of annual rehydrated Hemoccult slides. In this study, the overall test positivity rate increased more than fourfold with slide rehydration (from 2% to 10%) and the sensitivity increased from 80% to 92%. However, as discussed above, as the positivity rate increases, the resultant number, risk, and costs of additional colonoscopies should also be taken into account. Indeed, the Minnesota study had a 31% colonoscopy rate in 13 years, compared to 4% in 10 years for the Danish and British studies.

1.2.3 Discussion

Based on the current data, annual FOBT is an acceptable modality for CRC screening. Of the different FOBT, HemeSensa offers the optimal compromise between sensitivity and specificity. The role of FIT remains to be clarified and optimized through additional ongoing studies.

1.3 FLEXIBLE SIGMOIDOSCOPY

Endoscopy allows direct visualization of the colonic lumen, thus ensuring high diagnostic sensitivity and specificity. In addition to detection, endoscopy also allows CRC prevention through removal of adenomas that may become cancers over time. Flexible sigmoidoscopy allows examination of distal colon (rectum, sigmoid, +/- descending colon) and will be discussed here. For additional information, readers are directed to a recent review [Levin, 2002].

1.3.1 The Procedure

Description:

The sensitivity of the sigmoidoscopic examination is directly related to the distance examined. For example, in a recent study of screening colonoscopy, 53% of patients with advanced neoplasia had lesions in the rectum and sigmoid (the area typically visualized during sigmoidoscopy) [Lieberman, 2001]. Whenever possible, the 60 cm flexible sigmoidoscope should be the preferred instrument (rather than a rigid or shorter sigmoidoscope) because it allows better visualization of a longer segment of the colon and is more comfortable, increasing compliance. In addition, it is important, within the constraints of patient tolerance and preparation, to complete an exam, or otherwise to consider it a limited screening procedure.

Polyps:

The current approach to polyps is based on the size. If a polyp is greater than 1cm, it is likely to be adenomatous;
a biopsy is not necessary and a follow-up colonoscopy is required to allow polyp removal and evaluation of synchronous lesions. If the polyp is smaller than 1 cm, it should be biopsied to determine whether it is adenomatous or hyperplastic. If it is adenomatous, a full colonoscopy is required to allow polypectomy and to exclude synchronous lesions in the remaining portion of the colon.

If the polyp is hyperplastic, no further follow-up beyond routine screening is needed since distal hyperplastic polyps, unlike those with distal adenomas, do not exhibit an increased risk for proximal neoplasia compared to those with no distal polyps [Lin, 2005]. Additional variations of this approach are being currently evaluated (e.g. removal of all polyps irrespective of size and stratification of colonoscopy indication according to tumor histology and patient age and sex).

1.3.2 Supporting Evidence

Three case-control studies support the utility of sigmoidoscopy in decreasing mortality from CRC. The first study compared the history of previous screening sigmoidoscopy (66% flexible) in 66 patients who died of large-bowel cancer from 1979 to 1988 at the Greater Marshfield Community Health Plan, Wisconsin. They were compared with 196 control members of the same health plan who were of similar gender, age, and enrollment duration [Newcomb, 1992]. The history of screening sigmoidoscopy was much less common among case subjects (10%) than among control subjects (30%). The risk of death from colorectal cancer was reduced among individuals having had a single examination by screening sigmoidoscopy with an odds ration of 0.21 (95% confidence interval = 0.08 - 0.52). Because this reduction in risk appeared to be limited to tumors in the rectum and distal colon, confounding factors were not significant in the analysis.

The second study compared 261 members of the Kaiser Permanente Program who died of cancer of the rectum or distal colon from 1971 to 1988 with 868 control subjects matched with the case subjects for age and sex [Selby, 1992]. Only 8.8% of the case subjects had undergone screening by sigmoidoscopy, compared to 24.2 % of controls. The corresponding odds ratio was 0.3 (95% confidence interval: 0.19 - 0.48). After adjustment for confounding factors such as history of colorectal cancer or polyps or a family history of colorectal cancer, this ratio was 0.41 (95% confidence interval 0.25 - 0.69), suggesting a protective effect gained from sigmoidoscopy. This protective effect lasted as much as 9 to 10 years. The specificity for the screening intervention was verified by a lack of a protection when 268 patients with fatal colon cancer above the reach of the sigmoidoscope were compared with 268 controls (odds ratio of 0.96 with 95% confidence interval 0.61 - 1.50).

A third study compared the data files of 4,337 VA patients dying of colorectal cancer between 1988 and 1992 and 16,531 living patients and 16,199 dead control patients matched for age, sex, and race. Diagnostic procedures of the large bowel reduced mortality from colorectal cancer, the odds ratio being 0.41 (95% confidence interval 0.33 - 0.50) when compared with living control subjects and 0.44 (confidence interval 0.36 - 0.53) when compared with dead control subjects. These procedures were protective for 5 years or longer against death from cancer of the colon and rectum. The specificity of the protective action was suggested by the observation that, even though all procedures exerted a significantly protective influence, removal of tissue from the colon or rectum (biopsy, fulguration, and polypectomy) was the most effective procedure. The specificity was further strengthened by the fact that colorectal procedures reduced death from colorectal cancer selectively, but did not influence mortality in general (comparison with dead controls) [Muller, 1995].

Large clinical trials studying screening flexible sigmoidoscopy are in progress. The recruitment and screening phases of a British trial are now complete and the corresponding information for neoplasia detection, acceptability, safety, and feasibility recently published [Atkins, 2002]. Of 368,142 eligible people, 40,674 underwent screening flexible sigmoidoscopy while 113,178 served as controls. These sigmoidoscopies used carbon dioxide insufflation, normally reached the junction of the sigmoid and descending colon, and lasted less than 5 min. All small polyps were removed and patients were referred for colonoscopy for high-risk lesions (= 3 adenomas, polyp = 1 cm, tubulovillous or villous histology, severe dysplasia, malignancy, or = 20 hyperplastic polyps). Distal polyps were found in 25% of screened patients, with adenomas or cancer in 12%, high-risk lesions in 4.7 %, and cancer in 0.3%. There was one perforation and 12 hospital admissions for bleeding. Acceptability was high; eighty percent of patients reported no or only mild pain and 97% were glad they had the test and would recommend it to a friend.

Of note, in a cooperative study of screening colonoscopy at 13 VA medical centers, discussed in detail in the section on colonoscopy, while patients with adenomas in the distal colon were more likely to have advanced proximal neoplasia, 52% of patients with advanced proximal neoplasia had no distal adenomas and 2.7% of patients with no distal adenomas had advanced proximal lesions. The authors estimated that if a screening flexible sigmoidoscopy were performed to the splenic flexure, followed by a full colonoscopy if an adenoma of any size is discovered, only 80% of advanced neoplasia would be detected. The corresponding value for a flexible sigmoidoscopy limited to sigmoid and rectum is 32% [Lieberman, 2000]. In another study of screening colonoscopy, 46% of patients with advanced proximal neoplasms (villous features, high-grade dysplasia, or cancer) had no distal hyperplastic or adenomatous polyps [Imperiale, 2000].

1.3.3 Discussion

While the results from large clinical trials are still pending, case-control studies of flexible sigmoidoscopy suggest that this modality reduces CRC mortality by 30-50%, an effect limited to lesions within the reach of the sigmoidoscope. In addition, this protective effect lasts 5-10 years. Thus, screening with flexible sigmoidoscopy every 5 years is certainly justifiable.

Flexible sigmoidoscopy allows direct examination and polyp removal of the distal colon. Its main drawback is that it can only clear a portion of the colon. Indeed as discussed below (1.4.2), if a flexible sigmoidoscopy was performed to the splenic flexure, followed by a full colonoscopy if an adenoma of any size was detected, only 70% of the advanced neoplasia would have been detected. Combining this strategy with one-time FOBT allows a small and statistically insignificant increase to 76%. Compared to colonoscopy, sigmoidoscopy has several potential advantages: it is inexpensive and easier to perform, requires a simpler bowel preparation and is usually completed without sedation. Whether these perceived advantages outweigh the completeness of a colonoscopic examination is currently a matter of debate. In addition, the criteria whereby a distal polyp necessitates a follow-up colonoscopy are being refined.

Practical economic considerations may also affect the use of flexible sigmoidoscopies in screening programs: indeed, in the US, this procedure may be reimbursed at a rate that is too low to justify the required equipment, staff time, and dedicated space [Ransohoff, 2005].

1.4 COLONOSCOPY

Excellent reviews of the technical aspects and effectiveness of screening colonoscopy are available [Nelson, 2002], [Rex, 2002]. The main points are addressed below.

1.4.1 The Procedure

Colonoscopy is a relatively complex procedure that requires complete bowel preparation and is performed under conscious sedation by skilled endoscopists (usually gastroenterologists). Similar to flexible sigmoidoscopy, colonoscopy allows both detection and prevention of CRC. Indeed, the National Polyp Study demonstrated that colonoscopic polypectomy reduced the incidence of CRC by 76 - 90% (p < 0.001) [Winawer, 1993]. The main advantage of colonoscopy over flexible sigmoidoscopy is the greater extent of the examination, i.e. visualization of the entire colon. In two recent studies of screening colonoscopy [Imperiale, 2000], [Lieberman, 2000] the cecum was reached in ~ 97% of instances. Other studies also showed a completion rate of > 95%, with women with a low body mass index or with a history of hysterectomy at higher risk for a more difficult colonoscopy.

In these recent studies, the safety of the procedure was also assessed and the complication rates were low. In one study, the incidence of serious complications during or immediately after colonoscopy was 0.3% (bleeding, myocardial infarction, cerebrovascular accident, Fornier’s gangrene, and thrombophlebitis), and there was no perforation or death directly related to the procedure [Lieberman, 2000]. In the other study, out of 1,994 colonoscopies, there was one perforation, three significant bleeding episodes, and no death related to the procedure [Imperiale, 2000]. We should caution, however, that well-trained endoscopists performed these exams in the context of a clinical trial. These performance characteristics may be not be duplicated if the increased number of screening colonoscopies necessitates their performance under less optimal conditions.

The accuracy of colonoscopy has also been examined. In a study of 183 patients subject to two consecutive colonoscopies, the miss rate for adenomas was 24%. As expected, this rate was dependent on the size of the polyp: it was 27% for adenomas = 5 mm, 13% for adenomas 6-9 mm, and 6% for adenomas = 1 cm [Rex, 1997]. In another study of 90 patients subjected to tandem colonoscopy by two alternating examiners, similar missed rates were observed: no missed lesions for polyps = 10 mm, 12.3 % for polyps 6-9 mm, and 16% for diminutive polyps = 5 mm [Hixson, 1990]. However, a limitation of these studies was that colonoscopy was used as its own internal standard; virtual colonoscopy allows a separate reference standard. In a prospective, multicenter screening trial involving 3 medical centers and 1,233 asymptomatic adults who underwent same-day virtual colonoscopy followed by optical colonoscopy with segmental unblinding to correlate findings, the miss rate for adenomas = 6 mm, 8mm, and 10 mm were, respectively, 11.9%, 10.5%, and 11.8%. Of the missed adenomas that were = 10 mm, nonrectal neoplasms accounted for 71%; 93% of these were located on a fold and 71% on the proximal side of the fold. Of the rectal missed lesions, 83.3% were located within 10 cm of the anal verge [Pickhardt, 2004]. Again, these reported rates may still underestimate the true miss rate since neither virtual colonscopy nor optical colonscopy are infallible, especially with lesions of smaller size.

1.4.2 Supporting Evidence

While there is no direct evidence that screening colonoscopy decreases CRC mortality, two recent studies have addressed the utility of screening colonoscopy for detection of advanced neoplasia. In a cooperative study at 13 VA medical centers, 3,121 asymptomatic subjects (mostly men, some with family history of CRC), aged 50-75 years, underwent complete colonoscopy between1994 to 1997 [Lieberman, 2000]. Of the subjects tested, 37.5% showed one or more neoplastic lesions, 7.9% had a villous adenoma or an adenoma = 1cm, 1.6% showed adenoma with high-grade dysplasia, and 1% showed invasive cancer. Patients with adenomas distal to the splenic flexure were more likely to have advanced proximal neoplasia (adenoma = 10 mm, presence of villous features, high-grade dysplasia, or cancer) than those without. However, 52% of patients with advanced proximal neoplasia had no distal adenomas and 2.7% of patients with no distal adenomas had advanced proximal lesions. In other words, if a screening flexible sigmoidoscopy were performed to the splenic flexure, followed by a full colonoscopy if an adenoma of any size is discovered, only 80% of advanced neoplasia would be detected. The corresponding value for a flexible sigmoidoscopy limited to sigmoid and rectum is 32%.

A follow-up analysis correlated the colonoscopy findings with one-time FOBT (rehydrated Hemoccult II) in the 2,885 colonoscopy patients in whom both tests were obtained. The FOBT positivity rate was 8.3%, and the sensitivity was 23.9% for advanced neoplasia and 35.6% for cancer and high-grade dysplasia. The positive and negative predictive values for advanced neoplasia were, respectively, 39.7% and 87.8%. Left-sided detection rate (equivalent to a flexible sigmoidoscopy) for advanced neoplasia was 70.3% in this analysis; combined with a positive FOBT, it increased slightly to 76% (not statistically significant) [Lieberman, 2001]. Of note, this one-time FOBT may not have the same performance characteristics as the recommended repeated annual FOBT.

In another study, 1,994 asymptomatic subjects older than 50 underwent screening colonoscopy between 1995 and 1998. Of those, 5.6% had advanced neoplastic lesions (3.1% distal and 2.5% proximal). Similar to the VA study, 46% of patients with advanced proximal neoplasms (villous features, high-grade dysplasia, or cancer) had no distal hyperplastic or adenomatous polyps. The prevalence of advanced proximal neoplasia among patients with no distal polyp, with distal tubular adenomas, and with advanced distal neoplasia was respectively, 1.5%, 7.1%, and 11.5% [Imperiale, 2000].

In a tandem project for the VA Cooperative study, complete colonoscopy was achieved in 1,463 asymptomatic women (15.7% with family history of colon cancer). Colonoscopy revealed advanced neoplasia in 4.9%; if flexible sigmoidoscopy alone had been performed, advanced neoplasia would have been detected in 1.7% and missed in 3.2%. In other words, only 35.2% of women would have had their lesions identified if they had undergone FS alone, as compared with 66.3% of matched men in the VA Coop study. There were no clinically significant complications. It was therefore concluded that colonoscopy is the preferred method of screening for colorectal cancer in women and that FS is an inadequate method of predicting advanced neoplasia in the proximal colon in women (vs. men) [Schoenfeld, 2005].

1.4.3 Discussion

Screening colonoscopy, while not supported by direct evidence, is a logical screening modality advocated with increasing fervor. Indeed, the ACG guidelines recommend colonoscopy as the preferred strategy, which is now reimbursed by Medicare for eligible patients. While a complete examination of the colon and the ability to prevent CRC are intuitively appealing the following reservations should be considered before advocating colonoscopy as the best CRC screening modality [Allison, 2005], [Ransohoff, 2005]:

a. Although colonoscopy may be the best diagnostic test at any one time, it may not be the most effective when programs include repeated testing over time and the end point is CRC mortality . Indeed, a less sensitive test, such as FOBT, applied repeatedly could have multiple chances to detect an existing lesion resulting in a higher overall sensitivity of the program. Furthermore, cancers that are more likely to be fatal because they develop and grow rapidly may be detected through annual screening, but not necessarily through testing at the 10-year interval suggested for colonoscopy. Indeed, in the National Polyp Study, the surveillance program for prior polyps reduced, but did not abolish, the incidence of colorectal cancer at three, six, and seven years (estimated respective reductions of 90, 88, and 76%). Increasing the frequency of colonoscopy to address this limitation will incur a higher rate of complication as well as additional use of resources.

b. Colonoscopy misses lesions. When it was used as its own standard in tandem studies, miss rates up to 6% for adenomas = 1 cm were observed. Combined virtual and optical colonoscopies demonstrated that the miss rate may reach 12%. Reports from Japan originally raised the possibility that a particular type of colorectal neoplasm, the flat and depressed lesions, may exhibit a higher potential for malignancy and invasion [Tsuda, 2002]. Recent studies suggest that these lesions may not be limited to the Far East. In American adults, a study reported that a third of the polypoid lesions were of the flat and depressed type with 82% and 4% respective incidence of adenoma or cancer. These lesions may be missed with routine colonoscopy; indeed 62% of these lesions were only detected using indigo carmine dye [Saitoh, 2001].

c. Availability: cost and manpower. A major concern with screening colonoscopy is the availability of resources, particularly endsocopists. A survey of 1,235 primary care physicians, 349 gastroenterologists, and 316 general surgeons, estimated that 4 million colonoscopic procedures were performed in the US in 2000, including 1.6 million screening examinations. In the same report, a primary colonoscopy screening program, with very conservative estimates and criteria (average risk patients between 50 and 80 years of age, 70% compliance, test positivity of 2%, only routine screening following adenoma = 5 mm, 5 years surveillance interval for polyp > 5 mm), will require 4.8 million screening and surveillance colonoscopies a year [Brown, 2003]. Thus a colonoscopy screening program by itself will require a capacity that is 20% larger than what is currently available.

A recent market analysis for CRC screening with endoscopy suggests that factors affecting demand are the size of the population to be screened, income and health insurance status of subjects, time and travel costs, price of alternative screening modalities, personal preferences, and perceived quality of care. Factors affecting supply side include the availbility of providers, efficiency in performing the procedure, procedure costs, reimbursement rates, and technical progress [Tangka, 2005]. Performing this procedure only according to accepted guidelines might also increase colonoscopic capacity. For example, in a survey of 349 gastroenterologists and 316 surgeons, 24% of gastroenterologists and 54% of surgeons recommended surveillance for a hyperplastic polyp while more than half recommended a surveillance interval of 3 years or less for a single adenoma smaller than 1 cm [Mysliwiec, 2004]. In addition, risk stratification, for example using age, sex, and BMI may further help us select subjects that would benefit the most from colonoscopic screening [Betes, 2003]. Increased training of endoscopists, including physician extenders is also being debated.

1.5 BARIUM ENEMA

1.5.1 Double Contrast Barium Enema

Double contrast barium enema is another modality that allows evaluation of the entire colon and has been recommended for CRC screening. However, the sensitivity of this technique has been of primary concern. The relative sensitivities of barium enema and colonoscopy for detection of adenoma and CRC were compared in a study of 20 community hospitals in Central Indiana [Rex, 1997]. A review was performed of the medical records of 2,193 consecutive colorectal cases and all associated procedures within 3 years of diagnosis. The sensitivity of colonoscopy for colorectal cancer (95%) was greater than that for barium enema (82.9%), with an odds ratio of 3.93 for a missed cancer by barium enema compared with colonoscopy. Of interest, barium enema performed no better in the right than the left colon. Cancers detected by colonoscopy were more likely to be Dukes' class A than cancers detected by barium enema, and colonoscopies performed by gastroenterologists were more sensitive than colonoscopies by non-gastroenterologists (97% vs. 87%, odds ratio of 5.36).

The suboptimal sensitivity of barium enema was again observed in a follow-up analysis of the National Polyp Study, involving 580 patients who underwent 862 paired colonoscopies and barium enemas for surveillance of adenomatous polyps. Using colonoscopy as the gold standard, the detection rate of adenomatous polyps by barium enema was related to the size of the adenomas: 32% for adenomas = 0.5 cm, 53% for adenomas 0.6 – 1.0 cm, and 48% for adenomas > 1 cm. Of 139 positive barium enemas and negative colonoscopies, colonoscopic reexamination revealed an additional 19 polyps (12 adenomas) [Winawer, 2000].

This low sensitivity implies that barium enema should only be used when colonoscopy is not available or contraindicated.

1.5.2 Virutal colonoscopy

A new technique that may replace barium enema in the future is virtual colonoscopy (up-to-date review [Hawes, 2002]. This new imaging technique uses thin-section helical CT to generate high-resolution two-dimensional axial images that are then reconstructed through additional software into three-dimensional images that simulate those obtained by colonoscopy. Most studies to date have used a bowel preparation (like colonoscopy and barium enema) and the colon is insufflated; newer techniques have focused on performing virtual colonoscopy without prior bowel preparation in order to improve patient acceptance. At a rate of 5-30 frames/sec, the reconstruction is represented as a fly-through, thus the name of virtual colonoscopy. In a report comparing the performance of virtual colonoscopy and endoscopic colonoscopy in 100 patients at high risk for colorectal neoplasia, the sensitivity of virtual colonoscopy was related to the size of the polyp: 55% for polyps = 5 mm, 82% for polyps 6-9 mm, and 91% for polyps = 10 mm. Limited image resolution accounted for the low detection rate of small polyps while misinterpretation (identification as stool or folds) or inadequate visualization (from retained intraluminal fluid or poor colonic distention) accounted for the missed large polyps [Fenlon, 1999].

Virtual colonoscopy offers rapid and complete examination of the colon at a negligible risk and without requirement for sedation; it also yields information about structures outside of the colon. However, the sensitivity is still suboptimal, especially for small and flat lesions, it still requires a full colon cleansing, and no therapeutic intervention is possible. On the other hand, this developing technique is being continually improved. Innovations, such as a virtual preparation (intermixing of contrast with stool obviating the need for bowel cleansing), may enhance the appeal of this modality in the future.

1.6 NEW MODALITIES BEING DEVELOPED

1.6.1 Virtual Colonoscopy

1.6.2 Stool Testing

Two approaches to stool testing have been proposed:

a. Fecal DNA: 85% of CRC result from progressive and sequential accumulation of chromosomal instability in the adenomatous polyposis coli (PAC)) gene, the p53 tumor-suppressor gene, and the K-ras oncogene; the remaining 15% of CRC arise from the loss of genes involved in DNA-mismatch repair. Colorectal cancer may therefore be detected through the use of appropriate DNA markers in neoplastic colonic cells shed into the stool. While DNA is quite stable, the challenge has been to separate the abnormal human DNA from both bacterial DNA and normal human DNA in the stool and to amplifyi it to test for genetic abnormalities.

A recent large trial compared the test characteristics of FOBT and fecal DNA, using a panel of 21 DNA mutations (3 in K-ras gene, 10 in APC gene, 8 in p53, BAT26, and a marker of long DNA) in 4,404 subjects who also underwent colonoscopy. Although only 18% of advanced neoplasia were detected by fecal DNA (vs. 11% with FOBT), fecal DNA detected 52% of invasive cancer while FOBT detected 13%. Specificities were 94.4% for fecal DNA and 95.2% for FOBT [Imperiale, 2004]. The major limitation in the use of fecal DNA will be its cost, as the first commercially available test, PreGenPlus, has a list price of $795. The source of false-positive DNA tests is also unknown; it may signal cancers in other parts of the digestive system and could be cause for concern [Ouyang, 2005].

b. Rectal Mucus: The disaccharide, D-galactose-N-acetyl-D-galactosamine (GaNAc), is differentially expressed in the mucin of CRC and precancerous cells as well as mucin of normal mucosa distant from the site of cancer. Testing rectal mucus may therefore predict cancers both near and far from the site of sampling. The galactose oxidase Schiff test (GOS) is a simple, inexpensive test in which a digital swab of rectal mucus is treated with D-galactose oxidase and Schiff’s reagent, allowing GalNAc to yield a magenta or purple coloration. In the largest study for its use, ColorectAlert (a GOS test designed by International Medical Innovations) exhibited a specificity of 85% and a sensitivity of 49% for all CRC and 54% for Dukes’ A or B CRC. While this test offers the advantage of not requiring any dietary restriction and can be performed using a sample obtained from a digital rectal exam, it remains unclear whether additional determination of its performance characteristics using larger population of average risk patients would justify its use in mass screening [Ouyang, 2005].

1.6.3 Colonoscopic Enhancement

New endoscopic techniques may greatly increase the sensitivity, specificity, and yield of colonoscopy [Regueiro, 2005]:

a. High-magnification chromoscopic colonoscopy: This technique combines image magnification (up to 1125-fold) and the use of colorizing agents to enhance visualization of the colonic mucosa. Enhancing dyes consist of contrast dyes, such as indigo carmine or cresyl violet, which pool in grooves and highlight surface irregularities, and staining dyes, such as Lugol’s solution, methylene blue, or toluidine blue, which color the convex or protuberant portions of a lesion. This technique is aimed at detecting subtle changes of the mucosa such as pallor or ertythema, changes in vascular pattern, or abnormal surface pit patterns, such aberrant crypt foci. Indeed, aberrant crypt foci have gained increasing attention as important precursors of cancer. Flat and depressed adenomas are also another target of hign magnification chromoscopic colonoscopy. As discussed previously, these lesions may have greater potential for malignancy and invasion compared to the typical polypoid lesions; they may be more common in Western populations than previously realized.

b. Spectroscopy: Light scattering spectroscopy, based on the principle that light absorption and scattering is related to the composition of the tissue being examined, can be used to probe the colonic mucosa to a greater depth than with conventional microscopy. It relies on a low-power laser light to induce auto-fluorescence of endogenous chemicals in colonic tissue; changes between normal, precancerous, and cancerous tissues will be reflected in alterations of the emitted spectra. Finally, confocal colonoscopy combines traditional endoscopy with confocal laser microscopy, added to the distal tip of a traditional video endoscope, to provide submucosal histology.

c. Optical coherence tomography: This technique uses light waves to probe the subsurface of the mucosa and allows visualization of the layers of the colonic wall, in a manner analogous to endoscopic ultrasonography.

1.7 CONCLUSION

The cost effectiveness of the different modalities [Table 4] included in the guidelines has been demonstrated in the original analysis of the Office of Technology Assessment of the US Congress. FOBT, flexible sigmoidoscopy, double contrast barium enema, and colonoscopy, individually and in combination, starting at age 50 and stopping at age 85 all cost less than $ 20,000 per year life saved and are within the acceptable range of cost-effectiveness by US health standards. However, screening sigmoidoscopy alone (at any interval) is less effective than the other screening strategies. Otherwise the cost-effectiveness of the other strategies for most screening intervals is comparable. For several strategies, there is a steep increase in cost, with only small increases in effectiveness, with shorter intervals between screening examinations [Winawer, 1997]. The cost effectiveness of fecal occult blood testing and colonoscopy was again recently verified for Australia and New Zealand [Graves, 2005]. Because each modality has its own advantages and shortcomings, it is now the consensus that our effort should be focused on increasing CRC screening compliance rather than on determining an overall marginal superiority of one modality versus another.

Indeed, while the goal of the Healthy People 2010 campaign by the US Department of Health and Human Services is a modest 50% compliance rate, it is estimated from communitiy surveys that only 37% (range from 13 – 55%) of the US population obtained screening within the recommended time frames. Overall, positive attitudes towards screening and physician recommendation are the key factors. Fear of finding cancer and the belief that cancer is not curable are barriers to adherence with screening guidelines. Adherence is also positively correlated with education, medical insurance, and differs with age (those in the 70’s are generally more compliant than those younger or older). On the other hand it is not possible to conclude that adherence is a function of any modality [Subramanian, 2004].

2.0 COLORECTAL CANCER SCREENING AND SURVEILLANCE IN PATIENTS WITH RISK FACTORS

Introduction

Assessment of the individual patient’s risk of colorectal cancer (CRC) is essential for guiding appropriate screening and surveillance. The risk of developing colon cancer is primarily dependent on three key factors: the age of the patient, the patient’s personal history of colon cancer or colon adenomas, and the family history of the patient [Winawer, 1997], [Johns, 2001], [Winawer, 2003]; [Section 3.2]. Most cases of CRC are sporadic, but inherited factors are thought to play a role in approximately 35% of cases (95% CI: 10-48%; [Lichtenstein, 2000]). This section will focus on the latter group: patients who generally can be identified by having one or more family members with colorectal cancer or adenomatous polyps. The detection of individuals harboring familial colon cancer syndromes is also very important not only because surveillance programs are crucial for preventing colon cancer in these families, but also because of the implications for the patient’s family members’ risk for cancer.

2.1 THE PRINCIPLES OF RISK ASSESSMENT: POSITIVE FAMILY HISTORY, EXCLUSIVE OF SYNDROMES

A combination of the number of family members affected with colorectal cancer or colon polyps and the ages at which they developed the polyps or cancer can help define the risk for a hereditary susceptibility syndrome. Sporadic colon cancer usually occurs in patientsage 50 and older, and its incidence increases as individuals get older. In contrast, inherited forms of colon cancer usually occur earlier, often in the fourth decade or earlier.

2.1.1 Asymptomatic Screening: Patients with One Family Member Affected (Table 1)

Most patients have an average lifetime risk of 5% for the development of sporadic colorectal cancer. A metaanalysis suggests that the relative risk of development of colorectal cancer in an individual with a first-degree relative with CRC is 2.25 (95% CI: 2.00-2.53; [Johns, 2001]). This risk can probably be stratified according to the age at diagnosis. The same study suggests a relative risk of 3.87 (95% CI: 2.40-6.22) if the first-degree relative is diagnosed with CRC before age 45 [Johns, 2001]. The corresponding relative risks for individuals with first-degree relatives diagnosed between 45 and 59 and 60 or older are 2.25 (95% CI: 1.85-2.72) and 1.82 (95% CI: 1.47-2.25).

The risk of colorectal cancer is elevated not only for relatives of patients with colon cancer, but also for relatives of patients with adenomas. First-degree relatives of patients with colorectal adenomas have a relative risk of 1.99 (95% CI: 1.55-2.55) of developing CRC [Johns, 2001]. Furthermore, robust evidence from two studies [Winawer, 1996], [Ahsan, 1998] demonstrates that the CRC risk for family members increases with decreasing age at adenoma diagnosis in the index case. For relatives of index cases diagnosed with adenoma at 50yo or younger, as compared to at 60yo or older, the relative risk was 4.36 (95% CI: 2.24-8.81; [Ahsan, 1998]). This finding supports the conclusions of Winawer et al who found a 2.6-fold increased risk (95% CI: 1.46-4.58) for CRC among siblings of individuals with adenomas diagnosed at 60yo or younger as compared to older than 60yo [Winawer, 1996].

Although there continues to be controversy regarding ideal screening modalities in individuals at average risk, current AGA guidelines recommend colonoscopy (and not sigmoidoscopy and/or barium enema) for screening individuals with a family history of adenoma or CRC as delineated in Table 1 [Winawer, 2003]. Colonoscopy has the advantage of therapeutic intervention if polyps or masses are discovered at screening.

Details regarding the modality and age to start screening for colorectal cancer are an area of controversy, but general guidelines are available (Table 1), (Table 3). Screened patients are significantly less likely to develop or die of colorectal cancer. Colonoscopy is considered by many to be the gold standard for screening because it has both diagnostic and therapeutic capability. However endoscopic screening is costly and invasive. The screening regimen may be tailored to the likelihood of finding pathology on the basis of patient's age and family history. For example, current recommendations from the AGA are for colon cancer screening with colonoscopy on an every 5 year basis starting at age that is 10 years younger than the youngest affected family member for individuals with a first degree relative with colon cancer or colon polyp <60 years of age or 2 first degree relatives with colon cancer [Winawer, 2003].

2.1.2. Asymptomatic Screening: Two or more affected family members (Table 1).

The first consideration in evaluating patients with two or more family members with colorectal cancer is to rule out an inherited familial cancer syndrome. Some inherited syndromes have a distinctive phenotype, such as the polyposis syndromes. Other inherited disorders have to be suspected on the basis of the family history alone, such as Hereditary Non-polyposis Colon Cancer or attenuated forms of familial adenomatous polyposis.

If there are two affected first-degree relatives (parents, children, siblings), annual colonoscopy is warranted every 3-5 years beginning at age 40 or 10 years younger than the earliest cancer diagnosis in the family, whichever comes first [NEW Winawer, 2003], (Table 10). If there are three or more affected first-degree relatives, or if the first-degree relative was diagnosed with colorectal cancer before the age of 35, then an inherited colon cancer syndrome should be suspected [Burt, 1992]. If HNPCC is suspected based on the family history (see section on HNPCC below), at risk family members should have annual colonoscopy starting between 20-25 years of age or beginning 5 years younger than the age of the earliest colorectal cancer diagnosis [Aarnio, 1995], [Lynch, 1992], [Lynch, 1994]. If the colon is free of polyps and other abnormalities, then colonoscopy can be repeated every 2 years through age 40 and annually thereafter.

2.2. PERSONAL HISTORY OF COLON CANCER, COLONIC ADENOMAS OR INFLAMMATORY BOWEL DISEASE

Introduction

Some patients will require lifelong colonoscopic surveillance because of a personal history of colon cancer, adenomatous polyps or inflammatory bowel disease. Patients with colon cancer only need to have surveillance colonoscopy if they have had a resection of the cancer with intention to cure. Colonoscopy is the preferred method of surveillance in patients with a history of colonic polyps or colon cancer, because of better sensitivity and therapeutic capability compared to barium studies (e.g. polyps can be removed, if detected). Flexible sigmoidoscopy, combined with double-contrast barium enema, is acceptable as an alternative for those patients who would not tolerate colonoscopy.

2.2.1 Patients With a History of Colorectal Cancer (Table 1)

As it is very important to rule out synchronous adenomas or CRC, patients with colorectal cancer that has been resected for cure should undergo a complete colonoscopic examination within 1 year of the resection if they did not undergo complete colonoscopy preoperatively [Winawer, 1997], [Byers, 1997], [Winawer, 2003]. Patients with metastatic disease do not require surveillance. The value of the colonoscopy within one year of CRC diagnosis lies in its ability to detect synchronous/metachronous adenomas, rather than to detect recurrent intraluminal CRC [Schoemaker, 1998]. If this or a complete preoperative examination is normal then subsequent surveillance should be offered after 3 years and then, if normal, every 5 years. The continued colonoscopic surveillance is justified by the relatively high rate of second primary CRCs [Green, 2002]. Double contrast barium enema, while an alternative for patients unable to tolerate colonoscopy, is suboptimal in this setting.

Patients who are under the age of 50 at the time of colorectal cancer diagnosis represent a unique subset of colon cancer patients who have an increased likelihood of having a hereditary syndrome. It is important to remember that de novo mutations in CRC predisposition genes are not uncommon, and thus, some patients will be the first to present in the family. It is very important to identify these patients, as it will affect their clinical management, not to mention having substantial implications cancer risk on other family members. Other clues that can help identify those patients who have a hereditary syndrome include: a) having more than one colonic cancer (at the same time or sequentially), b) having multiple close family members with colorectal cancer, c) having a personal or family history of other non-colonic cancers (especially ovarian, endometrial, small bowel, and stomach), or d) having a history of >10 polyps (Table 10). For example, an individual may have unrecognized Attenuated Familial Adenomatous Polyposis or Hereditary Nonpolyposis Colon Cancer (HNPCC). In the former case, the patient may present with >10 adenomas or may have family members with colon cancer and/or extracolonic manifestations of FAP. In the case of HNPCC, a consensus panel recently released new guidelines aimed at identifying individuals with CRC who deserve further evaluation to rassess for a hereditary cancer predisposition syndrome [Umar, 2004]. These Revised Bethesda Guidelines recommend molecular testing of the colon cancer for patients under the age of 50 who develop colorectal cancer and for older patients who have certain risk factors, as outlined in (Table 8). Patients who have a positive molecular test have a high likelihood of having HNPCC and should undergo genetic testing for the HNPCC mismatch repair gene mutations or undergo surveillance as if they have the syndrome, (Table 9).

2.2.2 Patients With a History of Adenomatous Polyps (Table 1)

When a polyp has been identified it should be removed for histologic examination. Concomitantly, the entire colon should be examined endoscopically to detect and remove other polyps. Large sessile polyps or numerous polyps may require additional colonoscopies. Most patients with adenomas need surveillance, in which the first follow-up colonoscopy is scheduled for 3 years after clearing the entire colon of polyps [Winawer, 1997], [Byers, 1997], [Winawer, 1995]. The current recommendations depend on the number and size of the polyps found on the index exam. If one large or histologically advanced polyp is found or if two polyps >1cm in size are found, then a 3 year follow-up interval is indicated. Otherwise, a 5 year follow-up exam is appropriate [Winawer, 2003]. If the 3-year exam is negative, subsequent exams can be performed every 5 years. Surveillance may need to be tailored according to findings in those patients who have polyps on subsequent exams. Patients who have recurrent polyps, numerous polyps, or large sessile polyps (>2 cm) may require more frequent surveillance than every 5 years. On the other hand, for patients with a single small tubular adenoma (<1cm) on the initial exam, the interval for the first follow-up colonoscopy may be extended to 5-6 years [Byers, 1997]. When colonoscopy is not feasible because of comorbid disease or patient preference, then flexible sigmoidoscopy coupled with double-contrast barium enema is an acceptable alternative.

Patients who have a) adenomas under the age of 40, b) a history of other non-colonic cancers, c) multiple close family members with colon cancer, or d) 10 or more adenomas should undergo evaluation for an inherited colon cancer syndrome (Table 10) , (Table 11).

2.2.3 Patients With Inflammatory Bowel Disease (Table 1)

Patients with ulcerative colitis (UC) and Crohn's colitis have an increased risk of colorectal cancer. The risk of neoplasia approximates 1% per year of disease duration: for example, a person with ulcerative colitis for 20 years has about a 20% risk of having neoplasia. There are 2 other risk factors for neoplasia in IBD patients besides duration of disease: 1) disease extent proximal to the sigmoid colon [Dawson, 1959], [Devroede, 1976], [MacDougal, 1964], [Morowitz, 1969], [Farmer, 1966], [Nugent, 1970]. More recently, primary sclerosing cholangitis has been suggested as and 2) concomitant diagnosis of primary sclerosing cholangitis with IBD [Brentnall, 1996], [Broome, 1992], [DHaens, 1993], [Gurbuz, 1994]. The precursor lesion for colon cancer in IBD is called dysplasia. Dysplasia is graded as negative (normal), indefinite, low grade and high grade. High grade lesions usually develop into cancer.

Colonoscopic surveillance of ulcerative colitis patients is controversial. The current standard of practice is to perform life-long annual or biannual colonoscopic biopsy surveillance in patients with extensive colitis of 8 or more years duration. Patients with left-sided colitis (distal to the splenic flexure) warrant surveillance after 12-15 years. The cost effectiveness and optimal protocol for this approach have yet to be established. The problem is further complicated by the fact that the colon is a large organ to sample and that areas of dysplasia are usually not visible at colonoscopy. One study calculated that 33 biopsy specimens are required to achieve 90% confidence that dysplasia will be detected if it is present [Rubin, 1992].

1995 guidelines from the World Health Organization recommend annual to biannual colonoscopy with biopsies taken from normal appearing mucosa at 10-12 cm intervals throughout the colon [Winawer, 1995]. Extra biopsies should be taken from areas of mucosal irregularity. If biopsies are classified as negative or indefinite for dysplasia then surveillance colonoscopy should be repeated every 1-2 years. Barium enema should not be substituted for colonoscopy in IBD patients; dysplasia is often visible only under the microscope and thus actual biopsies are required for surveillance. More recently, guidelines for cancer surveillance in IBD patients have been updated by the Crohn’s and Colitis Foundation of America [Itzkowitz, 2005]. The task force of experts recommend that 4 quadrant biopsies be taken every 10 cm from the cecum to the rectum, with additional biopsies taken from mucosal abnormalities. Crohn’s colitis patients have an elevated risk of colon cancer that is similar to that in ulcerative colitis patients, and thus they should undergo colonoscopic surveillance after 8 years of pancolits. IBD patients who have extensive inflammatory polyps which can interfere with adequate surveillance should be referred to centers of expertise for evaluation. New studies indicate that chromoendoscopy can enhance the endoscopic detection of dysplastic lesions in colitic colons [Rutter, 2004], [Kiesslich, 2003], however this methodology should only be used by appropriately trained endoscopists.

High grade dysplasia in flat mucosa and cancer are uniform indications for colectomy. The management of low grade dysplasia is controversial. Some authorities believe that any finding of low grade dysplasia in flat mucosa warrants colectomy, [Bernstein, 1994] while our unpublished data reveals that only one third of low grade dysplasia patients progress to high grade dysplasia in [Brentnall, Personal Communication]. The discrepancy between these recommendations is likely due to the number of biopsies taken at surveillance: as noted above, the risk of missing cancer/dysplasia is inversely correlated with the number of biopsies (e.g. low numbers of biopsies leads to a high risk of missing neoplasia). Thus, management of low-grade dysplasia is uncertain and a decision regarding colectomy versus continued surveillance should reflect: If dysplasia (low or high grade) is discovered in a polyp-like lesion and the lesion is completely removed endoscopically, then continued surveillance is permitted---provided that microscopic dysplasia is not discovered in the remaining surveillance biopsies [Odze, 1998], [Odze, 2004], [Rubin, 1999]. Patients who have polyp-like lesions with dysplasia should have surveillance endoscopy on an annual basis. Several studies suggest that biopsy surveillance or prophylactic colectomy increases life expectancy in patients with ulcerative colitis [Choi, 1993], [Provenzale, 1995], [Axon, 1994].

2.3 POLYPOSIS SYNDROMES

Introduction

Colonic adenomas can evolve into carcinomas; therefore, the recognition of familial polyposis syndromes is essential for the prevention of colon cancer in these family members. Furthermore, the polyposis syndromes have implications not only for the patient but also for other at-risk family members. In order to identify patients who may have an inherited syndrome, it is important for the clinician to ask some key questions:

2.3.1 Adenomatous Polyposis: Familial Adenomatous Polyposis (FAP) and Attenuated Familial Adenomatous Polyposis (AFAP) (Table 6) and (Table 1)

Familial adenomatous polyposis is among the best known inherited colorectal cancer syndromes although it is responsible for less than 1 percent of all colorectal cancers [Grady, 2003], [Solomon, 2003]. Although previous classifications have subdivided adenomatous polyposis syndromes into FAP (GI manifestations alone) and Gardner Syndrome (FAP with extra-intestinal manifestations), these divisions are less useful now that the genetic basis of FAP and Gardner syndrome has been shown to be identical (namely, mutations in the APC or MYH genes can cause either phenotype). This section will discuss classical familial adenomatous polyposis and attenuated familial adenomatous polyposis—both caused by mutations in the APC gene. See section 2.3.2 for a discussion regarding the autosomal recessive MYH-associated polyposis syndrome which is clinically quite similar to FAP and AFAP, but caused by mutations in a different gene.




Clinical Features

In FAP, hundreds to thousandsof adenomas carpet the colon, initially appearing at an average age of 16 years (range 7-36; [Petersen, 1991]). There can be marked intrafamilial and interfamilial variation in the number of polyps present even with the exact same germline mutation. Ninety-five percent (95%) of individuals from families with classic FAP will have polyps by age 35 [Solomon, 2003]. Once polyps appear, they generally increase in number rapidly. Without colectomy, the risk of development of colorectal cancer is essentially 100%. The average age of colon cancer development in untreated individuals is 39 years. Approximately 7% of untreated FAP patients develop CRC by age 21, 87% by age 45, and 93% by age 50 [Bussey, 1975], [Solomon, 2003].




Other Clinical Features

While polyp formation usually begins in the second decade of life, GI symptoms of rectal bleeding and abdominal pain usually develop in the third decade [Erbe, 1976], [Schwabe, 1980]. There are several other variable features of FAP that may or may not be present. If found, they increase the index of suspicion and should lower the threshold for referral to a tertiary center with expertise in GI cancer genetics. Gastric polyps are present in most FAP patients. They can be either hamartomatous fundic gland polyps or adenomatous and antral in location [Solomon, 2003]. The risk for gastric cancer is relatively small (0.5%). Small intestinal adenomatous polyps are found in most individuals with FAP, commonly in the second and third portions of the duodenum, and have a significant malignant potential (approximately 4% lifetime risk of duodenal adenocarcinoma) [Kadmon, 2001], [Groves, 2002], [Bulow, 2004]. Polyps in the periampullary region are of particular concern as they have a higher rate of malignant transformation and can also obstruct the pancreatic duct leading to pancreatitis.

Extraintestinal manifestations present in some individuals with FAP include: 1) osteomas (bony growths found most commonly on the mandible and skull); 2) various dental abnormalities (supernumerary teeth, congenital absence of teeth, unerupted teeth, odontomas, and dentigerous cysts) occurring in 17% of individuals with FAP as opposed to 1-2% of the general population [Solomon, 2003]; 3) congenital hypertrophy of the retinal pigment epithelium (CHRPE; discrete, flat, pigmented lesions of the retina that are clinically asymptomatic); 4) benign cutaneous lesions (fibromas, epidermoid cysts); and 5) desmoid tumors (see below for discussion of significant morbidity and mortality secondary to these tumors). It is important to note that extraintestinal manifestations frequently precede the development of polyposis. For example, many newly diagnosed individuals with FAP retrospectively note a history of osteomas or dental abnormalities.

The extraintestinal abnormalities are primarily of cosmetic importance. However, desmoid tumors are an exception to this rule, as they are a significant cause of morbidity and mortality in FAP. Present in ~10% of FAP patients [Gurbuz, 1994], [Clark, 1996], most desmoids are found within the abdomen or the abdominal wall. They frequently occur in association with surgical scars. About 5% of individuals with FAP experience significant morbidity or mortality from these locally invasive benign tumors that do not metastasize [Solomon, 2003], [Clark, 1999]. Encasement of abdominal organs or invasion of mesenteric vessels can lead to devastating complications.

Various extracolonic cancers are more frequent in individuals with FAP than in the general population. These include the following [Solomon, 2003]: duodenal or periampullary carcinoma (4-12% lifetime risk), small bowel distal to duodenum (rare), gastric adenocarcinoma (0.5%), pancreatic adenocarcinoma (~2%), papillary thyroid carcinoma (~2%), brain cancer (usually medulloblastoma; <1%), hepatoblastoma (1.6%; children age 5 or younger), biliary duct adenocarcinoma (rare, but increased), and adrenal adenocarcinoma (rare, but increased).

The association of colorectal cancer and brain tumors has been referred to as Turcot syndrome. However, it is now clear that this group of patients is molecularly heterogeneous and that Turcot syndrome can be divided into patients with APC gene mutations (who have FAP) and patients with mismatch repair gene mutations (who have Hereditary Non-Polyposis Colorectal Cancer).

Attenuated FAP, which is also caused by mutations in the APC gene, is characterized by a significantly elevated risk of colorectal cancer. However, fewer polyps are seen in AFAP (mean ~30, range 15-100) than in FAP (>100). On average, colonic polyps are found more proximally (i.e., right colon) than in classic FAP [Solomon, 2003]. The average age of colon cancer diagnosis in AFAP is ~50-55 years—which is 10-15 years later than for classic FAP [Solomon, 2003], [Spirio, 1993].

Because this variant is associated with much fewer polyps (<100), and patients may present with as few as 5-10 polyps, this topic is considered under the heading of Non-Polyposis Syndromes (Attenuated APC). Patients with this syndrome have mutations in the extreme 5' and 3' ends of the APC gene.

Diagnosis and Referral Guidelines

Diagnosis of FAP relies on clinical findings and may be made in any individual who has: 1) >100 colon adenomas OR 2) multiple colon adenomas and is a first-degree relative of an individual with known FAP. For individuals with questionable diagnoses, molecular genetic testing of the APC gene can be used to confirm the diagnosis. However, genetic testing is more frequently useful in identifying the specific disease-causing mutation in an affected family member, so that at-risk family members can be tested to rule-in or rule-out inheritance of risk. The differential diagnosis of FAP includes the MYH-associated polyposis syndrome ([Sieber, 2003]; see Section 2.3.2), which is inherited in an autosomal recessive manner (as opposed to the autosomal dominant nature of APC-gene associated FAP). This distinction has important implications for risk to various family members. Consultation with a GI cancer genetics professional is therefore warranted.

Diagnosis of attenuated FAP is more difficult as there is clinical overlap with both the MYH-associated polyposis syndrome and HNPCC. AFAP should be considered in individuals with many (more than 20 adenomas during the lifetime of the patient) colonic adenomatous polyps OR a family history of colon cancer in persons less than age 60 with multiple adenomatous polyps [Solomon, 2003].

Genetic Testing

Genetic testing is commercially available for FAP/AFAP. There are two categories of individuals who may benefit from genetic testing for APC gene mutations [Grady, 2003], [Solomon, 2003]:

First, individuals with a clinical diagnosis or clinical suspicion of FAP/AFAP may wish to be tested. In equivocal cases, the finding of a deleterious APC gene mutation may be helpful in making the diagnosis. Furthermore, the identification of a mutation in a clearly affected individual allows other asymptomatic family members to potentially be tested for inheritance or lack of inheritance of the mutation.

Second, relatives of individuals with known APC gene mutations may be tested presymptomatically. It is reasonable to refer for testing first-degree relatives of people with known APC mutations regardless of polyps. In addition, it would be reasonable to refer any individual with multiple polyps who is a relative of a patient with a known APC mutation [Grady, 2003].

In general, if consideration is being given to genetic testing for FAP/AFAP, consultation with a GI cancer genetics specialist is always appropriate and is strongly recommended [Grady, 2003]. Such specialists are most frequently found in the medical genetics and gastroenterology divisions of regional academic medical centers. They may also be identified through the list of genetics professionals located on the GeneTests website.

Genetic testing is available for the APC gene that is located on chromosome 5q [Bodmer, 1987], [Leppert, 1987], [Groden, 1995], [Nishisho, 1991]. Current assays detect approximately 82% of cases tested [Nugent, 1996]. Testing for potential APC families should always start with analysis of an affected family member first, to identify the mutation responsible for the disease in that family. Importantly, 20-30% of newly diagnosed adenomatous polyposis patients have de novo mutations, e.g. these patients are the first in the family to present with colonic polyposis.

A specific APC mutation (I1307K) has been found in 28% of Ashkenazi Jews with a family history of colon cancer and in 6% of those with a negative family history of colorectal cancer. The I1307K mutation does not significantly alter the APC gene product, but rather, makes the APC gene prone to subsequent mutations in other regions of the gene [Laken, 1997]. Patients with the I1307K mutation have a 1.5-2 fold increased risk of colorectal cancer compared with the general population and warrant regular colonoscopic screening. For mutation carriers who have a positive family history of colorectal cancer the lifetime risk may approach 50%. Ashkenazi Jews with a family history of colon cancer may benefit from genetic testing for I1307K, and if positive for the mutation would warrant colonoscopy every 2 years beginning at age 35 (personal communication, R. Jacoby) (Table 6). The general population (e.g. non-Jewish patients), has an extremely low carrier rate of this mutation, and thus probably do not warrant screening for it [Lynch, 1997]. Genetic testing for the I1307K variant is available (Table 12).

Screening and Surveillance: Familial Adenomatous Polyposis (Table 6):

Colon:

First degree relatives at risk, who are not known to have polyps, should undergo flexible sigmoidoscopy starting at age 12 – 15 depending on family genotype and pheontype, or sooner if symptomatic [Rustgi, 1994], [Erbe, 1976], [Schwabe, 1980], [Petersen, 1994], [http://www.nccn.org]. Sigmoidoscopy should be repeated annually to age 24 and then every 2 years to age 35. Colonoscopy should be considered by age 20 - 25 and again in 10 years to evaluate for right sided polyps. Because classical FAP is 100% penetrant, virtually all affected members will exhibit polyps by age 35.

Proctocolectomy is the treatment of choice in adult FAP patients with adenomas [Vasen, 2001] and should be considered at the time of diagnosis in teenagers. The timing of proctocolectomy may be individualized in teenagers depending on genotype, phenotype and personal considerations. In teenagers with adenomas who delay surgery, yearly colonoscopy surveillance is indicated, and proctocolectomy is recommended by age 19, or when there are signs of advancing polyposis, including more than 100 polyps, multiple polyps >0.5 - 1cm in size, villous histology or high-grade dysplasia, whichever occurs first [Burt, Personal Communication]. Colectomy is not indicated in FAP prior to the appearance of the polyps. Following proctocolectomy, adenomas can form in the ileal-anal pouch, but infrequently progress to cancer . Thus some experts recommend periodic endoscopic surveillance of the pouch.

Genetic counseling and testing of probands with FAP is recommended to faciliate screening of family members. After a causative APC mutation is identified in an index case, other family members can be tested for the same mutation. Testing should be offered in adolescence or early teens prior to initiation of screening. Those who test negative for the APC mutation that causes disease in their family are considered to be unaffected by FAP and do not require specialized screening (Table 12).

Patients who undergo total abdominal colectomy with ileorectal anastomosis are at nearly 1% per year risk of developing rectal cancer and at greater than 50% risk of requiring subsequent proctectomy [Bulow, 2000]. Risk of death from rectal cancer may remain as high as 12% by age 65 even for patients under surveillance [Vasen, 2001]. Surveillance of the retained rectum with endoscopy and polypectomy is recommended at 6 – 12 months intervals. Consideration for proctectomy is indicated for patients with dense rectal polyposis and/or advanced histology.

Duodenal Surveillance:

Patients with the classical FAP phenotype are at risk for duodenal cancer with a cumulative lifetime risk of 5 – 10% and mean age in the late 50’s. The accuracy of this estimate is limited by the paucity of cohorts over age 50 years who have been followed post colectomy. Duodenal cancer is rare under age 30 years, and uncommon under age 40 years, but risk increases significantly after age 50 years. Hence, it is recommended to initiate side viewing duodenoscopy at age 25 – 30. In patients without duodenal adenomas, duodenoscopy is repeated at approximately 4 year intervals to age 50 and then every 2 – 3 years [http://www.nccn.org].

Surveillance intervals are based on expert assessment and staging of duodenal polyposis as well as on the endoscopic management plan (Table 6). Spigelman’s classification, based on the number, size and histology of duodenal polyps, serves as the standard for staging. In addition, expert qualitative assessment of adenoma density is important because duodenal adenomas are manifest in a wide range of lesions, including minimal mucosal irregularities, plaques of varying thickness, thickened folds, and sessile polyps. Risk of cancer rises significantly in patients with advanced, stage IV, disease. The risk of developing stage IV polyposis has been recently estimated to be about 40% at age 60, and 50% by age 70 [Groves, 2002], [Bulow, 2004], [Saurin, 2004].

It is recommended that all significant lesions be biopsied at the time of duodenoscopy. Mucosectomy or ampullectomy is considered for large or thick lesions which are amenable to such treatment, especially in the presence of villous histology. Another option is to prophylactically remove or ablate smaller adenomas, especially those near the ampulla, though there is paucity of outcomes data on the potential benefits and risks of this approach. Surgery is generally reserved for advanced lesions that cannot be managed endoscopically, and for HGD and carcinoma [Groves, 2002], [Bulow, 2004], [Saurin, 2004].

Stomach:

Fundic gland polyps (FGP) occur in the majority of FAP patients, classical and attenuated, and often are too numerous to count [Offerhaus, 1992], [Kurtz, 1987], [Jarvinen, 1983], [Burt, 2003]. In FAP, FGPs usually display biallelic inactivation of the APC gene, and contain dysplasia or microadenomas of the foveolar epithelium in over 25% of patients. However, FGP’s are not associated with significant risk for cancer. Gastric cancer is uncommon in FAP in the western world at this time, with a lifetime risk of 0.5% - 0.7% [Wallace, 1998], [Burt, 2003]. Endoscopic biopsies of FGP are not routinely recommended. However, the stomach should be inspected for polyps that stand out because they appear irregular in shape or texture or large in size, suggesting adenomatous change. Gastric adenomas develop in approximately 10% of patients and are predominantly in the antrum. Hence, it is recommended that polyps in or near the antrum should be removed or biopsied if possible.

Because sporadic gastric cancer of the intestinal type, occurs in the setting of intestinal metaplasia, gastric atrophy, and longstanding H. pylori infection, it is also reasonable to intensify screening and biopsy in FAP patients with these findings and to treat H. pylori infection.

Thyroid:

Patients with FAP are at risk for thyroid cancer with a lifetime risk of under 2%, median age in the third decade, and female predominance (>95%). The majority of tumors show papillary differentiation, are multifocal, and carry a good prognosis [Bulow, 1997], [Giardiello, 1993]. Yearly thyroid physical examination is recommended.

Hepatoblastoma:

Hepatoblastoma occurs in less than 0.5% of patients with FAP, predominantly in boys under the age of 5 [Hughes, 1992], [Giardiello, 1996]. Early diagnosis can be curative, but the efficacy of screening as well as the associated risks are undefined. Potential screening options include physical examination, serum alpha-fetoprotein, and/ or hepatic unltrasound at 6 – 12 months intervals. Multidisciplinary evaluation of positive screening results are recommended to minimize the need for invasive procedures.

Screening and Surveillance: Attenuated Familial Adenomatous Polyposis (Table 6):

Colon:

AFAP, in comparison to classical FAP, is characterized by later onset of colorectal adenomas and cancer, and right sided predominance with frequent rectal sparing. Cancer is rare under age 25. Hence, patients with AFAP lacking a family history of dense polyposis or early onset cancer are screened with colonoscopy beginning at age 15 – 18 years. In patients without adenomas, screening colonoscopy is repeated at 2 – 3 year intervals and continued throughout life. Intervals can be increased to 3 – 5 years with advancing age in those who are not known to be gene carriers. Young patients with a limited number of adenomas that are manageable by endoscopy are usually surveilled with colonoscopy and polypectomy at 1 – 2 year intervals, and attempt is made to remove all the polyps. Surgical consultation and counseling is recommended at the onset of adenomas, and the surgical option is strongly considered with advancing age, especially after age 40 – 50 years, even in patients with few adenomas. Surgery is indicated in patients with residual polyps that are not manageable by polypectomy. Abdominal colectomy with ileorectal anastomosis is the procedure of choice in patients with few or no rectal adenomas.

Extra-colonic cancer screening (AFAP):

Duodenal screening and surveillance recommendations for patients with AFAP are the same as for classical FAP, though the risk of cancer is somewhat lower. Yearly thyroid examination is recommended. Risk of childhood hepatoblastoma is undefined but low and screening is not routinely recommended [http://www.nccn.org].

Chemoprevention, using a nonsteroidal anti-inflammatory drug, sulindac, has been associated with a regression of polyps in patients with FAP. In a randomized, double blind, placebo-controlled study, sulindac was found to reduce the number and size of colonic adenomas, but the effect was incomplete. The role of sulindac in prevention upper gastrointestinal adenomas is unclear. Celecoxib, a COX-2 inhibitor, has also been shown to decrease the formation of rectal adenomas and duodenal adenomas, but, as with sulindac, the effect is not complete and the long-term effects of this medication on either colon or duodenal cancer are not known [Steinbach, 2000], [Phillips, 2002]. Chemoprevention has not replaced the role of screening or need for colectomy in affected individuals [Giardiello, 1993].

Screening and surveillance of extracolonic tumors can be performed by yearly physical exam and laboratory testing [Rustgi, 1994], [Burt, 1988]. Desmoid tumors occur in 10% of FAP families and can be lethal as they encase and constrict abdominal organs and vessels.



Desmoids appear to cluster in families, occur more frequently in women, and are provoked by surgery and childbirth. Sulindac, tamoxifen, chemotherapy, and occasionally surgery are options for treatment.

Eye examinations should be performed to evaluate for congenital hypertrophy of the retinal pigment epithelium (CHRPE) in the index case with FAP. If the index case has CHRPE, then this may be a useful clinical marker of FAP in other first-degree relatives; when present it has 100% predictive value. The absence of CHRPE in the proband or the first-degree relatives has no predictive value [Traboulsi, 1990]. When screening first degree relatives of a patient with FAP, the absence of extra-intestinal manifestations, such as bone and skin tumors, does not rule out FAP.

2.3.2 Adenomatous Polyposis: MYH-Associated Polyposis Syndrome (MAP)

Recently it has been demonstrated that a subset of patients who appear to have a classical FAP or attenuated FAP phenotype have biallelic mutations in the hMYH gene. Although it is perhaps premature to conclude what proportion of North American cases of FAP or AFAP are due to hMYH mutations, it needs to be considered in the differential diagnosis with APC gene mutations. Population-based colorectal cancer studies in Europe suggest that MAP could be responsible for as much as 1% of all colorectal cancer cases. Molecular genetic testing of the MYH gene is clinically available. Current recommendations are to manage these patients as though they have germline mutations in the APC gene. Importantly, because this is an autosomal recessive trait, these individuals may appear to be de novo cases of FAP, until a more thorough family history is obtained.

2.3.3 Hamartomatous Polyposis: Juvenile Polyposis, Cowden, and Peutz-Jegher Syndromes.

Hamartomatous Polyposis:

Hamartomas are non-malignant masses comprised of tissues that normally make up the organ in question. Colonic hamartomatous polyposis syndromes are often marked by a characteristic histopathology that allows the diagnosis of particular familial syndromes. Hamartomatous polyps may occur sporadically in individuals. Alternatively, when occurring in greater numbers or with other suggestive features, they may be part of a cancer predisposition syndrome.

Juvenile Polyposis Syndrome (JPS):

JPS is a rare hamartomatous polyposis syndrome that is associated with an increase in colorectal cancer risk and is inherited in an autosomal dominant fashion [OMIM], [GeneReviews]. Incidence estimates for JPS range from ~1 in 16,000 to 1 in 100,000 [Burt, 1990], [Haidle, 2004], [Chevrel, 1975]. Because of the disorder’s relative rarity, more reliable estimates of incidence from population-based registries are lacking.



JPS: Diagnosis

It is critical to distinguish JPS from the solitary juvenile polyps that occur sporadically in approximately 2% of children. Sporadically occurring juvenile polyps are diagnosed at an average age of 3-5 years old; they typically are sloughed into the stool and do not recur. They do not indicate any risk for cancer in the affected individual or his/her family [Howe, 2002].

In contrast, the clinical diagnosis of JPS is made in individuals meeting any of the following criteria: 1) More than 5 colorectal juvenile polyps; 2) Multiple juvenile polyps throughout the gastrointestinal tract; OR 3) One or more juvenile polyps found in a patient with a family history of JPS [Jass, 1988].

As juvenile polyps may be seen in PTEN Hamartoma Tumor Syndrome (Cowden Syndrome and Bannayan-Riley- Ruvalcaba Syndrome) and also Basal Cell Nevus Syndrome (Gorlin Syndrome), exclusion of these diagnoses by a medical geneticist or other physician familiar with their clinical manifestations is important prior to arriving at a diagnosis of JPS [Woodford-Richens, 2000], [Haidle, 2004]. Hereditary Mixed Polyposis Syndrome (see below) also must be considered in the differential diagnosis of syndromic causes of juvenile polyps.

JPS: Histopathology

Juvenile polyps have a very distinct histology characterized by normal epithelium, dense stroma, an inflammatory infiltrate, and dilated mucus-filled cysts in the lamina propria. Juvenile polyps lack both muscle fibers and the proliferative characteristics of adenomas.

JPS: Typical Presentations

Bleeding +/- anemia may result from sloughing of the polyp or its epithelium. Other affected individuals may present with obstruction due to a large polyp or intussusception [O'Riordain, 1991]. The polyps can be either sessile or pedunculated but have the characteristic histology noted above. Some affected individuals may have only five polyps over their lifetimes, while others in the same family may have a hundred or more. This marked intrafamilial heterogeneity is called variable expressivity.

There are also numerous case reports of individuals or families affected with both JPS and Hereditary Hemorrhagic Telangiectasia, an autosomal dominant syndrome of multiple arteriovenous malformations that can affect multiple organ systems (OMIM 187300; more information may be found at www.genetests.org). Recent data demonstrates that individuals with mutations in MADH4—in some cases—may have physical findings consistent with HHT in addition to having JPS (see below) [Gallione, 2004].



JPS: Molecular Diagnosis and Inheritance

JPS is inherited in an autosomal dominant manner. Approximately 75% of JPS patients have an affected parent; 25% of JPS patients have no affected relatives and may be affected due to de novo gene mutations.

Mutations in two different genes are known to cause JPS [Haidle, 2004]. Approximately 20-25% of patients with JPS have mutations in the BMPR1A (Bone morphogenetic protein receptor type IA; OMIM 601299; chromosomal locus 10q22.3) gene. About 15-20% of JPS patients have mutations in the MADH4 (Mothers against decapentaplegic homolog 4 [previously SMAD4]; OMIM 600993; chromosomal locus 18q21.1) gene. Clinical testing (in CLIA-certified laboratories) for mutations in these genes is available and best pursued through referral to a GI cancer genetics professional in the gastroenterology and/or medical genetics division of a regional tertiary care academic medical center. Nevertheless, despite the availability of DNA sequencing of MADH4 and BMPR1A, causative mutations are currently found in only 40-50% of individuals meeting diagnostic criteria for JPS [Haidle, 2004], [Grady, 2003].

In individuals with clinical findings consistent with JPS and Hereditary Hemorrhagic Telangiectasia, initial testing should be directed at MADH4. (Interestingly, HHT without JPS is caused by mutations in Endoglin or ACVRL1 which, like BMPR1A and MADH4, are components of the TGF-β signaling pathway [Guttmacher, 2004]).



JPS: Cancer Risk

Most juvenile polyps are benign, but individuals with JPS are clearly at increased risk for GI malignancies. GI cancer risk estimates in JPS range from ~9-50% [Haidle, 2004]. Elevated lifetime colon cancer risks of ~10-38% are probably due to cancers arising from adenomatous components found in a subset of juvenile polyps [Grady, 2003], [Howe, 1998], [Desai, 1998]. Lifetime risks of gastric and duodenal cancer are thought to be ~15-20% due to juvenile polyps located in the upper GI tract [Grady, 2003], [Howe, 1998], [Scott-Conner, 1995].

JPS: Genotype-Phenotype Correlations

1) Individuals with MADH4 mutations appear more likely to develop—and have a family history of—upper gastrointestinal polyps [Friedl, 2002], [Sayed, 2002]. 2) JPS patients with either MADH4 or BMPR1A mutations are more likely to have >10 lower GI polyps and a family history of cancer than JPS patients without mutations identified in these genes [Burger, 2002], [Friedl, 2002], [Sayed, 2002].

There is insufficient evidence to support the utilization of testing for germline mutations in MADH4 or BMPR1A to predict age of onset, severity of disease, or progression rates in presymptomatic individuals [Grady, 2003]. Nevertheless, the identification of a germline mutation in a family may be helpful in determining which family members should receive increased screening and surveillance measures.

Screening and Surveillance: Juvenile Polyposis (Table 7)

The increased cancer risk for individuals with JPS have led to recommendations for increased screening and surveillance in those at risk. Individuals with JPS and family members at risk for JPS should be encouraged to report any rectal bleeding, symptoms consistent with anemia, abdominal pain, constipation, diarrhea, or change in stool size, shape or color promptly to their physician (as these symptoms may warrant additional screening). Increased screening and surveillance seems quite appropriate, yet there is currently no clinical evidence proving a mortality benefit.

Reasonable surveillance guidelines include the following (adapted from [Haidle, 2004]):

For individuals with MADH4 or BMPR1A mutations identified by molecular genetic testing, individuals with a clinical diagnosis of JPS, or individuals with a family history of JPS who have not yet undergone molecular genetic testing or whose molecular genetic test results are uninformative [Haidle, 2004]: Lastly, it has been suggested that JPS patients with MADH4 (not BMPR1A) mutations should be screened for the visceral arteriovenous malformations associated with Hereditary Hemorrhagic Telangiectasia. As these AVM’s can be associated with catastrophic complications, referral to a medical geneticist or a HHT-focused clinic at a tertiary academic medical center should be considered [Gallione, 2004] see [Guttmacher, 2004] for more information about HHT. Conversely, consideration of JPS should occur when patients present with HHT—particularly in those found not to have ENG or ACVRL1 mutations on molecular testing.

Cowden Syndrome and Bannayan-Riley-Ruvalcaba Syndrome (PTEN Hamartoma Tumor Syndrome)

The PTEN hamartoma tumor syndrome (PTHS) includes both Cowden syndrome (CS; OMIM 158350) and Bannayan-Riley-Ruvalcaba syndrome (BRRS; OMIM 153480). Although the majority of the manifestations of these disorders are outside of the GI tract, they are included here as they should be included in the differential diagnosis of hamartomatous gastrointestinal polyposis. In CS, hamartomas of multiple tissues are seen and there is an elevated risk of both benign and malignant neoplasms of the breast, endometrium,thyroid, and possibly colon [Pilarski, 2004]. The prevalence of CS has been estimated at 1 in 200,000 [Nelen, 1997], [Nelen, 1999]; however, this is likely a substantial underestimate as the diagnosis can be difficult to establish due to sometimes subtle manifestations. BRRS is a congenital disorder characterized by macrocephaly, lipomas, pigmented macules of the penis, and gastrointestinal polyposis [Pilarski, 2004].



CS: Diagnosis

The diagnosis of PHTS is only made when a germline mutation in the PTEN gene is identified. Clinical diagnostic criteria for Cowden syndrome are somewhat complicated, but are summarized here (see [Pilarski, 2004] for further details). Criteria for clinical diagnosis are divided into several categories:

Pathognomonic Criteria Major Criteria Minor Criteria An operational diagnosis of Cowden syndrome may be made if an individual meets any one of the following criteria [Pilarski, 2004]: In a family in which one individual meets the diagnostic criteria for Cowden syndrome listed above, other relatives are considered to have a diagnosis of CS if they meet any of the following criteria: BRRS: Diagnosis

Diagnosis of BRRS is based upon the characteristic features of macrocephaly, hamartomatous polyposis, pigmented macules of the glans penis, and lipomas [Pilarski, 2004], [Gorlin, 1992].

PTHS: Gastrointestinal Polyposis

Although extra-gastrointestinal manifestations predominate in BRRS and particularly CS, hamartomatous polyposis is seen in these disorders. Approximately 45% of individuals with BRRS have intestinal hamartomatous polyposis; juvenile polyposis-like polyps can also be seen in CS [Kurose, 1999], [Pilarski, 2004]. Although colon cancer has been observed in Cowden syndrome families, it is not currently considered to be a significant part of the syndrome [Pilarski, 2004]. Individuals with BRRS and PTEN gene mutations are thought to have the same cancer risks as individuals with CS. The intestinal polyposis in BRRS can lead to rectal bleeding and intussusception.



PTHS: Molecular Diagnosis and Inheritance

Molecular genetic testing for PTEN mutations is available on a clinical basis (see [Pilarski, 2004] for more information). Because of the elevated risks of cancer in multiple organ systems, if the diagnosis of CS or BRRS is being entertained, referral to a medical geneticist or other physician experienced in the evaluation of patients for CS/BRRS is recommended. Approximately 80% of individuals meeting CS diagnostic criteria and ~60% of individuals with a clinical diagnosis of BRRS have a detectable PTEN mutation upon clinical testing [Marsh, 1998], [Marsh, 1999].

Screening and Surveillance: Cowden Syndrome (Table 7)

There appears to be no elevated risk of GI cancers in Cowden syndrome despite the fact the polyps can bepresent throughout the GI tract [Marra, 1994]. Polyps are usually hamartomatous and frequently can resemble Juvenile polyps, but 17% of polyps can be other histologic types, usually hyperplastic. Endoscopic surveillance does not appear to be necessary. However, the elevated lifetime risks of breast cancer (~25-50% for affected females), thyroid cancer (~10%), and endometrial cancer (5-10%) merit special surveillance in affected individuals (see [Pilarski, 2004] for recently updated peer-reviewed guidelines).



Peutz-Jegher Syndrome (PJS)



PJS is a relatively rare autosomal dominant gastrointestinal hamartomatous polyposis syndrome with associated characteristic mucocutaneous pigmentary alterations [Rustgi, 1994], [Giardiello, 1987], [Foley, 1988], [Aaltonen, 2002], [Amos, 2004], [OMIM, 175200], [GeneReviews, 2004]. Birth prevalence is not well defined, but has been estimated to be somewhere between 1 in 25,000 to 1 in 280,000.

PJS: Diagnosis

The diagnosis of PJS is based upon clinical findings. The key to early identification can be the detection of the pigmentations, which are melanin deposits around the nose, lips, buccal mucosa, external genitalia, perianal region, hands and feet [Hand, 2003].

The pigmentations appear to look like freckles, but can be distinguished by the fact that freckles are absent at birth, usually do not occur on the lips, and never appear on the buccal mucosa. Ninety-five percent of Peutz-Jegher patients will have pigmentations around the lips, however these can fade at puberty so it is important to examine the buccal mucosa where they do not fade as much. The average age of diagnosis of PJS is in the mid-20's, when the patient may present with small bowel intussusception, obstruction and/or bleeding due to hamartomatous polyps.

Some controversy exists over diagnostic criteria for PJS. A definite PJS diagnosis requires the presence of the following [Giardiello, 1987], [Amos, 2004]: **Some controversy exists in the literature regarding the application of the diagnostic criteria to mucocutaneous hyperpigmentation. Some authorities feel that characteristic hyperpigmentation of the lips/buccal mucosa should be included in the above diagnostic criteria [Tomlinson, 1997]; others have limited the characteristic hyperpigmentation to that of the digits and the external genitalia (see [Amos, 2004]), perhaps because of some observations that similar melanin spots may be seen in a significant proportion of normals around the lips (see [Aaltonen, 2002] for further discussion).

A probable diagnosis of PJS may be made based on the presence of 2 out of the 3 clinical criteria, in the absence of histopathology confirming hamartomatous polyps [Giardiello, 1987]. However, for confirmation of diagnosis, histopathology is particularly important for those without a family history of the disorder [Tomlinson, 1997]. Lastly, for individuals who have a first-degree relative with known PJS, mucocutaneous hyperpigmentation is generally sufficient for presumptive diagnosis [Amos, 2004].

PJS: Histopathology

Histopathology is important in the differential diagnosis of hamartomatous polyposis syndromes. PJS polyps have a very characteristic appearance with interdigitating bundles of smooth muscle in the lamina propria that have a tree-like or arborizing appearance [McGarrity, 2000].

PJS: Typical Presentations and Cancer Risk

PJS polyps are most common in the small intestine, but occur in many affected individuals in the large bowel and stomach, as well. Chronic bleeding and anemia are common and in many cases, the polyps can lead to recurrent obstruction and/or intussusception requiring laparotomies. Importantly, adenomas also appear more frequently in the GI tract in this syndrome. There is significant interfamilial variability in the age at which polyps are first observed. Symptoms can occur within the first few years of life. Studies have suggested mean/median ages of first GI symptoms between 10 and 13 years old [Amos, 2004].

While polyp-induced obstruction and bleeding are the common causes of death before the age of 30; after the age of 30 malignancy becomes the most common cause of death. Patients develop hamartomatous polyps in the entire luminal GI tract and approximately 5% of these polyps will undergo neoplastic change.

Females with PJS can present with hyperestrogenism due to benign ovarian neoplasms, specifically sex cord tumors with annular tubules (SCTAT) [Young, 1982]. Presenting symptoms in these cases include precocious puberty, or more commonly, irregular or heavy menses. Similarly, males with PJS can develop calcifying Sertoli cell tumors of the testis; as these also can secrete estrogen, these patients can present with gynecomastia [Young, 1995].

Patients with PJS have a substantially increased lifetime cancer risk: both intestinal and extra-intestinal. Giardiello et al. reported a 93% cumulative lifetime risk of cancer [Giardiello, 2000]; however, others suggest that ascertainment biases in this study may overestimate lifetime risks [Amos, 2004]. Other studies suggest that the relative risk for all cancers combined is approximately 10-fold elevated [Boardman, 1998], [Lim, 2003]. Risks are particularly high for GI cancers (which can include colorectal, gastric, esophageal, small bowel, and pancreatic) and for breast cancer. The age of onset has been noted to be relatively young for cancers in PJS. Females can also present with an unusual and rare adenocarcinoma called adenoma malignum of the cervix (see [Amos, 2004] for more information about cancer risks in PJS).

PJS: Molecular Diagnosis and Inheritance

PJS is inherited in an autosomal dominant manner. Molecular genetic testing of the STK11 gene (also called LKB1) reveals disease-causing mutations in roughly 40-70% of individuals with a positive family history and between 20 and 70% of individuals without a family history. STK11 molecular genetic testing is available clinically. Consultation with a clinic experienced in the evaluation and management of individuals with PJS and other inherited GI cancer predisposition syndromes is recommended prior to undertaking molecular genetic studies.

PJS: Genotype-Phenotype Correlations

Individuals with PJS without an identifiable STK11 mutation may be at increased risk for proximal biliary cancer [Olschwang, 2001]. Another group has reported that PJS patients with missense mutations in STK11—as opposed to “truncating” mutations or undetectable mutations—tend to have later onset of symptoms [Amos, 2004]. However, neither of these findings should change management at this point for individuals with PJS.

Screening and Surveillance: Peutz-Jegher Syndrome (Table 7)

Management and surveillance regimens in this syndrome are primarily based on expert opinion rather than evidence regarding impact on morbidity and mortality from clinical trials at this point [Grady, 2003], [Amos, 2004]. However, there is some evidence demonstrating improved polyp clearance and decreased laparotomy frequency with routine endoscopic and intraoperative enteroscopy [Pennazio, 2000], [Edwards, 2003]. Because numerous organ systems are at risk for neoplasia, extensive surveillance programs are necessary.

The following surveillance guidelines for PJS are adapted from several references [McGarrity, 2000], [Boardman, 2002], [Grady, 2003]; (see [Amos, 2004] for regularly updated suggested management guidelines):





Screening of the first-degree relatives consists of colonoscopy and upper gastrointestinal series with small bowel follow-through [Rustgi, 1994]. Large polyps should be removed, if polyps >1.5 cm can not be removed endoscopically then they should be removed surgically. Affected individuals should also have annual physical exams (Table 12).

2.4 NON-POLYPOSIS SYNDROMES

The non-polyposis syndromes account for approximately 1-2% of all CRC. The identification of of hereditary colon cancer syndromes is very important not only because of the implications for identifying the optimal surveillance regimens for these people, but also because of the implications for colon cancer risk in current and future family members.

2.4.1 Hereditary Nonpolyposis Colorectal Cancer (HNPCC)

HNPCC is a highly penetrant autosomal dominant colon cancer syndrome with an 60-90% probability of colorectal cancer developing in gene mutation carriers [Lynch, 1994], [Rustgi, 1994], [Parc, 2003]. The genes involved in this syndrome are members of the mutation mismatch repair genes (MMR), which include MLH1, MSH2, MSH6, PMS1, and PMS2. One or several adenomas, the precursors of the cancers, are often present in the colon but there is no polyposis. The cancer is characterized by early onset (mean age 4-48 years, compared to 64 years for sporadic colon cancer), proximal location (>60% of cancers are in the right colon), synchronous and metachronous tumors (30-70% of cases), and tumors that are mucinous and diploid [DeFrancisco, 2003]. Clinicians may make reference to two HNPCC syndromes: inherited colon cancer only (Lynch I), and a cancer family syndrome including, in order of decreasing frequency, cancers of the colon, endometrium, ovary, stomach, urinary tract, brain, biliary tract, small bowel, and possibly breast (Lynch II). It is now appreciated that both Lynch I and II syndrome result from germline mutations in the MMR genes



[Rustgi, 1994], [Burt, 1988], [Lynch, 1995]. No mandatory number of extra-colonic cancers characterizes Lynch II. The prevalence of the disease is controversial with estimates ranging from 1-15% of individuals with colorectal cancer [Ponz de Leon, 2004]. Because the Lynch I and II are genetically indistinguishable, most specialists no longer subdivide the syndrome. However, it is of note that the specific MMR gene that is mutated in a family can influence the risk of developing both colonic and extracolonic cancer. Germline MSH6 mutation carriers are at a lower risk of developing colon cancer, but a higher risk of endometrial cancer than are MLH1 or MSH2 germline mutation carriers [Berends, 2002], [Hendriks, 2004].

The diagnosis of HNPCC can be very difficult to make without a careful and thorough family history. The clinical diagnosis of HNPCC is based on meeting criteria from one of four different sets of guidelines, which include the Amsterdam criteria, the Amsterdam II critera, Bethesda guidelines, or Revised Bethesda guidelines. The most stringent clinical diagnosis of HNPCC is established by meeting all three of the Amsterdam criteria (the rule of 3-2-1): three or more relatives must have histologically verified colorectal cancer (one is a first degree relative of the other two); the disease must span two generations; one cancer must be diagnosed before the age of 50 [Hixson, 1990]. The Amsterdam criteria remain the most strict basis for the diagnosis of HNPCC, but will miss some families that carry germline mutations in one of the MMR genes. This is a consequence of the fact that the Amsterdam criteria do not account for small kindreds, nor for extracolonic cancers such as ovarian or uterine cancer that may predominate in a particular kindred. For kindreds who are suspect, but do not fit the Amsterdam criteria for HNPCC, the Bethesda Guidelines were drawn up in 1997 followed by the Amsterdam II criteria (1999) and the Revised Bethesda Guidelines in 2004 (Table 8). These guidelines make use of the molecular and histopathologic traits of the HNPCC tumors to help identify HNPCC kindreds that fall short of the Amsterdam criteria.

Colonic cancers associated with HNPCC have characteristic pathologic features that are suggestive of, but not specific for, HNPCC [Rodriguez-Bigas, 1997]. An HNPCC patient may have multiple primary colon cancers, either synchronous (occurring at the same time) or metachronous (occurring at a different time). The colonic tumors are more often poorly differentiated, mucin producing, or of the signet ring cell type. Very often there is a dense lymphocytic infiltrate and a "Crohn’s like" reaction. Other typical pathological features include a cribriforming pattern, medullary-type pattern, sponge-like mucinous growth, and a pushing invasive margin [Alexander, 2001].

From a molecular standpoint, HNPCC tumors differ from most sporadic tumors in that HNPCC tumors tend to have a high accumulation of random mutations throughout the genome. This property is referred to as genomic instability and it is caused by an underlying defect in DNA mismatch repair genes. The genes that proofread DNA are defective and genetic errors accumulate and are copied into daughter cells. This proofreading defect is the basis for tumor formation in HNPCC and it can be exploited as a molecular marker to identify HNPCC tumors. The repair defect can be detected by testing the tumor tissue for mutations, or instability, in simple repetitive sequences of DNA, called microsatellites. Microsatellite instability is a very common, but not completely unique feature, of HNPCC tumors. Using microsatellite instability as a genetic marker for HNPCC, it may be possible to identify patients who carry an HNPCC germline mutation but do not fit the Amsterdam criteria. Not all patients who have colon cancer warrant this molecular evaluation, however (Table 8) outlines those patients who may have HNPCC and thus whose tumors might benefit from microsatellite instability testing. Patients who fit the Bethesda Criteria and who have tumors that are microsatellite instability positive should have genetic testing to look for a constitutional mutation in the DNA mismatch repair genes, or should undergo colonoscopic surveillance as if they have HNPCC.

Variants of Hereditary Nonpolyposis Colorectal Cancer:

Turcot Syndrome



Turcot Syndeome is the combination of brain tumors (usually glioblastomas) and hereditary nonpolyposis colorectal cancer. Turcot Syndrome formerly represented a heterogeneous group of patients who inherit colorectal cancer and brain tumors, but this has recently been divided into those patients who have mutations in the APC gene (Crail Syndrome) and those who have mutations in the DNA repair genes (Turcot Syndrome) [Giardiello, Personal Communication], [Turcot, 1959], [Groden, 1995], [Hamilton, 1995].

Muir-Torre Syndrome



The Muir-Torre syndrome is characterized by autosomal inheritance of skin lesions (sebaceous adenomas, sebaceous carcinomas, and multiple keratoacanthomas) in tandem with the cancer phenotype of hereditary nonpolyposis colorectal cancer [Johnson, 1998]. These rare syndromes are caused by mutations in the same mismatch repair genes that cause HNPCC.

Screening and Surveillance: Hereditary Nonpolyposis Colorectal Cancer (Table 9)

Management of at risk family members and gene carriers includes genetic counseling, genetic testing, and cancer screening. Not all families will choose genetic testing and not all testing identifies a mutated gene responsible for HNPCC (Table 12) [Peltomaki, 1994]. Thus many patients will require colonoscopic screening and surveillance, as the lifetime risk for colorectal cancer is 68-75% [Burke, 1997], [Aarnio, 1995]. Recommendations for surveillance are based on retrospective observational studies and on the clinical experience of experts. There are no randomized controlled trials and thus recommendations are provisional. However, the observational studies have demonstrated a 62% reduction in the screened group of HNPCC family members compared to those who elected not to have screening (colonoscopy every 2 years) [Jarvinen, 2000].

The 65-80% lifetime risk of CRC and increased risk for extra-colonic cancer in HNPCC patients has led to intense efforts to identify screening strategies that will decrease this cancer risk [Vasen, 1995], [Vasen, 1996]. Despite these efforts and because of the relatively small number of people affected by this condition, there have been no clinical trials of prospectively validated screening protocols completed to date. Nonetheless, screening guidelines for HNPCC patients, with or without an identified germline mutation, have been developed based on expert opinion and observational studies [Burke, 1997], [Giardiello, 2000]. In general, this level of support has led to the recommendation to perform colonoscopy-based colon cancer screening for HNPCC family members. The best evidence that colonoscopic screening is beneficial for preventing colon cancer in HNPCC patients has come from observational studies of 22 HNPCC families that were followed for fifteen years. One hundred and thirty three family members were voluntarily screened every three years and 119 declined colonoscopic surveillance during the study period. CRC was reduced by 62% in the screened group versus the unscreened group. The reduction was ascribed to polypectomies in the intervention group. No CRC related deaths occurred in the group that underwent regular colonoscopic screening compared to a 36% CRC related mortality rate in the unscreened group [Jarvinen, 2000], [Jarvinen, 1995]. These results are consistent with a clinical benefit from frequent colonoscopic exams with polypectomies in the at-risk subjects with HNPCC as has already been shown for average risk patients [Winawer, 1993]. A cost-effectiveness study by Vasen et al demonstrated that colon cancer surveillance is more cost-effective than not performing surveillance [Vasen, 1998]. In addition, Syngal et al examined the effect of endoscopic surveillance on life expectancy and quality adjusted life expectancy benefits and found substantial gains in both [Syngal, 1999].

In regards to specific guidelines for colon cancer screening, these recommendations have arisen from observational studies but are also influenced by our current understanding of colon cancer formation in the setting of HNPCC. As previously mentioned, colon cancers that occur in HNPCC patients are believed to arise from adenomas, however, these adenomatous polyps likely have a shortened adenoma-carcinoma progression sequence compared to the general population. Thus, for a known MLH1 or MSH2 germline mutation carrier, full colonoscopy every one to two years beginning at ages 20-25 or 5 years prior to the first diagnosed CRC in the family is recommended. After the age of 35-40, colonoscopy should be performed annually [Dunlop, 2002], [Jarvinen, 2000], [Burke, 1997], [Vasen, 1995], [Thorson, 1999], [Mecklin, 1986], [Vasen, 1993] For individuals with an unknown mutation status, the recommendations are similar. Those people are recommended to undergo complete colonoscopy every 1 to 2 years starting between the ages of 20 to 30, or 5 years younger than the youngest affected family member, then annually after age 40 [Winawer, 1997], [Brewer, 1994]. In those individuals with HNPCC who have had a subtotal colectomy, flexible sigmoidoscopy should be performed every one to two years. In a retrospective study of 71 patients with HNPCC who underwent colectomy, the risk of cancer in the retained rectum was found to be 3% every three years for the first twelve years [Rodriguez-Bigas, 1997]. There is disagreement about whether to continue lifelong screening or to stop between ages of 65 and 75 [Aarnio, 1995], [Vasen, 1993]. In light of the paucity of data about this issue, it seems reasonable to consider the patient’s overall state of health, co-morbidities, and personal preference when deciding when to terminate the surveillance regimen. As recommended for any individual, incomplete colonoscopy should be followed by a barium enema. If a suspicious area is found on barium enema, repeat colonoscopy should be performed. Flexible sigmoidoscopy plus barium enema could also be used with as-needed follow-up colonoscopy if potential polyps are identified. There are no prospective randomized controlled trial data to support these recommendations, but there is strong indirect evidence that endoscopic surveillance, either for primary or secondary prophylaxis, provides a beneficial effect on both mortality and cancer incidence [Jarvinen, 2000], [Renkonen-Sinisalo, 2000].

Importantly, in light of the advanced dysplasia present in even small adenomas, it is imperative that careful inspection of the colon be preformed in HNPCC patients undergoing surveillance colonoscopy [Ahlquist, 1995], [Jass, 1988]. Thus, the preparation for colonoscopy should be excellent in order to prevent missing small, but significant adenomas. Indeed, in a 1997, Rex et al observed a 27% miss rate of adenomas which were less than 3mm on back to back colonoscopies by skilled endoscopists underscoring the need to perform meticulous colonic inspection in HNPCC patients because of the advanced dysplasia found in the small adenomas in these patients [Rex, 1997]. Furthermore, Vasen et al identified 5 interval cancers in HNPCC patients within 3.5 years of a normal colonoscopy, which may have been missed because they arose from small polyps present at the time of the colonoscopy [Vasen, 1995]. It is also important to recognize the potential hazards of the aggressive screening regimen recommended for HNPCC family members and to appropriately inform these individuals about these risks. Estimates of adverse event frequencies for biennial colonoscopies over a 25-year time span have been extrapolated from a 15-year surveillance study. The average risks of 13 colonoscopies and 0.49 polypectomies/gene carrier are predicted to result in a 1.3% risk of perforation, 0.4% risk of bleeding and 0.1% risk of intervention related death [Jarvinen, 2000], [Dunlop, 2002]. Nonetheless, despite being higher than the lifetime risks associated with colon cancer screening regimens recommended for general population, the substantial reduction of cancer, due to frequent colonoscopic screening, outweighs these risks and should be emphasized.

Prophylactic Colectomy

There is no information from clinical studies to guide recommendations regarding the role of prophylactic colectomy in HNPCC. In general, it is felt that people with colon cancer who are from an HNPCC family or are known MMR gene mutation carriers should be educated about their treatment options and offered a surgical procedure that includes not only a treatment component but also a prophylaxis component. In light of the high rate of metachronous colon cancer, it appears reasonable to consider prophylactic resection of the uninvolved colon as well as the part of the colon with the cancer. Currently, expert opinion is that a subtotal colectomy with ileorectal anastamosis be considered in HNPCC mutation carriers with metachronous colon cancer, an initial CRC diagnosis, and even when multiple adenomas are identified at colonscopy [Burke, 1997]. A subtotal colectomy is recommended as opposed to a hemi-colectomy or a segmental resection because of the 45% risk for a metachronous colon cancer of the colon over 10 years [Vasen, 1997]. In carefully selected patients, such as those unwilling or unable to undergo periodic colonic surveillance, prophylactic subtotal colectomy can be considered as well, given the extremely high lifetime risk of CRC [Church, 1996]. Patients should be aware that they will need to continue annual flexible sigmoidoscopies to monitor the rectum because of the 3%/3 year risk for at least the first 12 years after subtotal colectomy [Rodriguez-Bigas, 1997]. Church supports the idea of prophylactic colectomy since the lifetime risk of CRC in HNPCC individuals who carry known germline mutations is so high (80-85%) [Church, 1996], [Burke, 1997]. Incidentally, this rate approaches the CRC incidence of FAP where prophylactic colectomy is a universal recommendation. However, at this time, there is insufficient information to provide recommendations for primary prophylactic colectomy [Dunlop, 2002]. Furthermore, in at-risk family members who are not proven mutation-carriers, the maximum risk of colorectal cancer appears to be 40% for men and 15-30% for women, making it less clear whether primary prophylactic colectomy would be beneficial in these individuals as opposed to regular colon cancer screening with colonoscopy [Dunlop, 2002].

Upper Gastrointestinal Tract Cancer Surveillance

The lifetime risk for gastric cancer in HNPCC family members is estimated to be 13-20% [Vasen, 1995], [Aarnio, 1995]. This increased risk has led to the use of upper GI tract surveillance techniques in an attempt to reduce the incidence of gastric cancer and death from gastric cancer in these families. Although there is insufficient clinical data to support the use of endoscopic surveillance for the prevention and/or early detection of gastric cancer, it is felt to be a prudent recommendation [Renkonen-Sinisalo, 2002]. Based on expert opinion, upper endoscopy and small bowel evaluation every 2-3 years in HNPCC families from Asia and those in which a family member has been diagnosed with gastric cancer is recommended. Gastric cancer typically occurs after age 40, although it can occur in the third decade [Vasen, 2001]. Consequently, surveillance should start between 30-50 years of age or 5 years earlier than the first gastric cancer case in the family, whichever is younger [Dunlop, 2002]. It is also recommended that HNPCC individuals who have a positive family history for gastric cancer be assessed for H. pylori infection and treated for this infection, if positive.

Upper Gastrointestinal Tract Cancer Surveillance

As stated earlier, endometrial cancer is the most common extracolonic malignancy in HNPCC. Endometrial cancer has an estimated cumulative risk, by age 70, of 20-50% and an average age of cancer of 49 years [Watson, 1994], [Marra, 1995], [Aarnio, 1995], [Vasen, 1996], [Dove-Edwin, 2002]. Therefore, most experts recommend surveillance for endometrial cancer in women in HNPCC families. Annual surveillance for endometrial cancer should begin between the ages of 25-35 years and should include pelvic examination and endometrial aspiration with or without transvaginal ultrasound [Vasen, 1993], [Vasen, 1999]. The sensitivity of a pelvic ultrasound and pipelle sampling in premenopausal women is unknown, but there is data showing 100% sensitivity and 98% specificity of office-based pipelle sampling for endometrial carcinoma in postmenopausal women with vaginal bleeding [Van den Bosch, 1995]. However, there is insufficient evidence from clinical studies to recommend for or against this approach in HNPCC family members. The results of one observational study suggest that an approach based on prompt attention to abnormal menstrual bleeding may be as effective as annual or biennial surveillance exams for the early detection of endometrial cancer [Dove-Edwin, 2002]. Thus, in addition to recommending endometrial cancer surveillance, it is prudent to recommend to women in HNPCC families to seek prompt evaluation of abnormal menstrual bleeding, regardless of their last surveillance exam results [Dove-Edwin, 2002].

In regards to ovarian cancer, approximately 3-12% of mutation carriers will develop ovarian cancer by age 70 [Lynch, 1997], [Aarnio, 1995], [Vasen, 2001]. Based on expert opinion, it is recommended that surveillance start between the ages of 25-35 years and be performed on an annual basis. The proposed surveillance method for ovarian tumors includes transvaginal ultrasound exams and serum CA-125 measurements [Burke, 1997]. Important disadvantages to endometrial cancer and ovarian cancer surveillance regimens to consider include the discomfort associated with endometrial biopsies and transvaginal ultrasound exams and the perforation risk associated with endometrial biopsies.

Depending on patient’s preference and, to a lesser extent, the specific MMR germline mutation present, prophylactic hysterectomy +/- bilateral salpingo-oophorectomy may be considered at the time of colorectal surgery, especially when childbearing is concluded [Watson, 1994], [Vasen, 1995]. Relevant issues to consider when entertaining prophylactic surgical resection of organs include cancer phobias, family history of extra-colonic cancers, and the likelihood of maintaining compliance with surveillance recommendations. Importantly, there is no clinical evidence demonstrating that prophylactic hysterectomy and oophorectomy affects cancer-related mortality or overall mortality. If this option is chosen, the optimal age to pursue this option is felt to be between 35 and 40 given that endometrial cancers develop at a younger age in the setting of HNPCC (average age 49, range 31-69) [Burke, 1997]. Women considering this option should also be counseled on the need for lifelong hormonal replacement therapy. A consensus panel found insufficient evidence to recommend for or against prophylactic hysterectomy and oophorectomy as a measure for reducing cancer risk in HNPCC family members [Burke, 1997].

Surveillance For Other Extracolonic Cancers

Based on expert opinion, annual urine cytology exams and renal ultrasound studies are recommended when there is a family history of transitional cell cancer of the ureter or renal pelvis. Of note, MSH2 germline mutation carriers appear to have a significantly increased risk of cancer in the urinary tract compared to MLH1 germline mutation carriers (1.3% vs. 12% by age 70) [Vasen, 2001], [Vasen, 1996], [Lynch, 1990]. Some experts recommend annual skin exams for basal cell or squamous cell carcinoma, however, there is insufficient evidence for or against this strategy to make a clear recommendation concerning this surveillance program.

3. GENETIC TESTING

Introduction

Most, but not all, hereditary colon cancer syndromes are inherited from one lost or mutated gene. Gardner syndrome, Familial adenomatous polyposis, hereditary non-polyposis colon cancer, and Peutz-Jegher syndrome are all inherited in an autosomal dominant (recode link) pattern. In these familial cancers an altered gene is inherited through the germ cells (sperm or egg), and thus the altered gene is present in every cell throughout the body. Importantly, the remaining wild type (normal) gene must acquire a mutation in order to give rise to a cancer. If the second mutation occurs in colonic mucosa then a colon cancer may form. However, other organs may acquire this "second hit" or second mutation besides the colon; this is why many syndromes have associated extra-intestinal cancers, such as ovarian or breast (e.g. hereditary non-polyposis colon cancer, where colon, breast and ovarian cancers can all be seen in one family). The concept of a germ-line mutation followed by a "second hit" is in contrast to sporadic, or non-familial colon cancer in which a person usually acquires multiple somatic gene mutations in the colonic mucosa, not in the germ cells, for a colon cancer to develop.

Indications for testing should include the following parameters: 1) the person has a strong family history of cancer or very early age of onset of disease; 2) the test can be adequately interpreted; and 3) the results will influence the medical management of the patient or family member [ASCO, 1996]. The family member who is affected should be the one first tested (e.g. one who has cancer). Because the sensitivity of mutation detection is not 100% in any colon cancer syndrome, one can avoid confusion by testing a family member who clearly manifests the phenotype of the syndrome. Once the gene mutation has been identified in an affected family member, then other relatives who wish to know if they have inherited the disease can subsequently be tested.

3.1 MODES OF INHERITANCE

An autosomal dominant pattern of inheritance is present in patients with hereditary colorectal cancer syndromes. A typical pattern would include multiple family members, both first and second-degree relatives, in two or more generations, who develop cancer. Children of an individual with an autosomal dominant trait have a 50% chance of inheriting the same genetic mutation from their affected parent. However, it is important to realize that the phenotype, or genetic expression, can vary among the individuals within a kindred (family). Occasionally, a pedigree will look as if cancer skipped a generation (e.g. a grandmother and granddaughter both developed colon cancer at the age of 40, but the mother has not by the age of 60). There can be people who inherit the gene mutation, but who do not develop clinical signs associated with the mutation, such as cancer. Such a phenomenon is called incomplete penetrance, and is suggestive that other factors such as diet, environment and other genes can influence gene expression. Many of the hereditary colorectal cancer syndromes have penetrance >90%, however occasionally family members will be present who must carry the gene mutations, but do not have the disease. Moreover, subtle disease manifestations (such as the cutaneous manifestations of Cowden syndrome or Peutz-Jegher syndrome) may be missed.

Some hereditary colorectal cancer syndromes appear to cause similar phenotypes (for example, early colorectal cancer without polyposis) but are due to mutations in different genes. An example of this would be the non-polyposis syndromes such as Attenuated Adenomatous Polyposis Coli and Hereditary Nonpolyposis Colon Cancer. These syndromes have been associated with the APC and mismatch repair genes, respectively. It is valuable for the clinician to determine the genotype (gene involved) because treatment recommendations and cancer surveillance protocols are different for Attenuated Familial Adenomatous Polyposis compared with Hereditary Nonpolyposis Colon Cancer. (Table 6) (Table 9).

The patient with a negative family history will have a very low risk of having an inherited colorectal cancer gene. A caveat exists for those individuals with negative family history that develop a colorectal cancer before the age of 45. These patients may indeed have a germline mutation resulting from incomplete penetrance in the parents, false paternity, or an actual de novo mutation occurring for the first time in this individual. The latter event is especially relevant in patients who develop colorectal cancer at 35 years of age or younger. Lui and colleagues have demonstrated that nearly one quarter of patients under 35 with colorectal cancer harbor a germline mutation for hereditary non-polyposis colorectal cancer [Liu, 1995]. This diagnosis may be of clinical value for those young "sporadic" colorectal cancer patients who have children or are planning to have children. For evaluation of patients with colorectal cancer before the age of 45 see the Bethesda Criteria for HNPCC (CODE THIS LINK). (Table 8)

3.2 RECORDING A GENETIC FAMILY HISTORY

The pedigree is a powerful, efficient and cost-effective tool for recognizing a family with a possible hereditary colon cancer. The two key factors in recognizing a pedigree suggestive of a familial colon cancer syndrome are individuals with colon cancer before the age of 45, and multiple closely related affected individuals in more than one generation. Additional clues include a family history of other cancers (particularly breast, thyroid and uterine cancers), and individuals with more than one primary cancer (Table 10).

At a minimum a three generation pedigree, which includes the consultand’s (patient) children, grandchildren, siblings, parents, grandparents, aunts and uncles, nieces and nephews, should be obtained. If a family member is identified with cancer, the pedigree should extend back as far as possible. For each person in the pedigree, information should be obtained on their age (or year of birth), age at death, cause of death, and any cancer diagnosis. Recording ethnicity is also important since some cancer susceptibility mutations may be more easily identified in certain ethnic groups (e.g. an APC mutation in someone of Jewish ancestry) [Laken, 1997]. Documentation of the cancers with pathology reports is essential since a patient’s historical reports are often inaccurate. For a complete review of standardized pedigree nomenclature see Bennett et al [Bennett, 1995]. Table 11 lists a set of screening questions to ask when taking a family health history for colon cancer.

3.3 GENETIC TESTING AND COUNSELING

Germline molecular testing is available for more and more colon cancer genetic syndromes (Table 12). The availability of this testing can be a useful tool for establishing a clinical diagnosis. An accurate diagnosis assists the clinician in predicting clinical outcomes. For example, it is important to distinguish a diagnosis of Hereditary Nonpolyposis Colon Cancer (HNPCC) from Familial Adenomatous Polyposis Coli (FAP); the management of FAP suggests prophylactic colectomy in the mid-20s, which is not the case for HNPCC. Germline testing does not indicate the presence of cancer, but it can be helpful in establishing a surveillance plan, particularly in a healthy person under the age of 50 with a family history of colorectal cancer.

The identification of presymptomatic individuals with an inherited cancer susceptibility mutation is a new phenomenon in medicine. While such information is potentially of immense value to individuals in these high risk families and their health providers, many uncertainties and potential risks are inherent in this process.

3.3.1 Counseling and Informed Consent

Genetic counseling involves discussing the psychological, medical and genetic issues associated with the occurrence or risk of a genetic disorder within a family. Genetic information carries unique personal, family, and social burdens. The individual considering genetic testing may have very different feelings about risks and burden of disease than his or her health care providers. To protect the client’s right to autonomous decision making, a non-directive, non-judgmental, client-centered approach to counseling is best.

Genetic counseling is more than identifying a familial cancer syndrome and the provision of risk information; supportive follow-up counseling concerning the implications of this information is essential. A multidisciplinary approach to providing genetic counseling and testing to high-risk individuals and their families is useful. In addition to gastroenterologists, members of the team may include masters level certified genetic counselors, medical geneticists, nurse specialists, oncologists, surgeons, radiologists, psychologists, and primary care providers. If a colorectal cancer syndrome with multiple cancers is suspected (such as in Hereditary Nonpolyposis Colon Cancer), it is useful to draw from the appropriate experts, such as specialists in screening for breast and genitourinary cancers.

There are unique psychological consequences of making a genetic diagnosis of colon cancer versus identifying a sporadic etiology. Such a diagnosis now affects multiple family members, such as parents, children and siblings. To make the diagnosis, information must be obtained on multiple family members, including deeply personal information about health and lifestyle (i.e., alcohol use in someone with liver cancer). A whole family becomes your patient. This intrusion into the patient’s privacy may extend even to the necessity to obtain blood samples and medical records on affected family members. The individual is no longer a person with colon or other cancers, but he or she is "labeled" a Hereditary Nonpolyposis Colon Cancer or Familial Adenomatous Polyposis patient. The patient’s perception of self may change to feeling that he or she is "mutant" or "flawed". It is important to avoid language such as "You have an abnormal gene" when communicating with these families.

Guilt is almost always a feeling experienced by a person diagnosed with a familial colorectal cancer syndrome. The person may feel tremendous guilt for having "passed the syndrome" to future generations even though he or she knows rationally that there is no fault. Guilt can also be seen in the form of "survivor guilt". For example, if a two out of three brothers test positive for a colon cancer susceptibility mutation, the other brother may feel "guilt" for having "escaped". This brother may also feel like he is no longer a "part of the family team". He may also feel an increased burden to be responsible for the welfare of his brothers and their families.

The importance of obtaining informed consent can not be over-emphasized. Position statements by groups such as the Institute of Medicine (99), the American Society of Clinical Oncologists [ASCO, 1996] and the National Society of Genetic Counselors [McKinnon, 1997] stress the importance of pre-test education and genetic counseling. The components of genetic assessment and pre-and post-test education should include: pedigree analysis and disclosure of risk assessment; review of the natural history of the suspected colon cancer syndrome(s)- including the role of non-genetic factors; the limits and predictive value of genetic testing; possibility of disclosing false-paternity; costs of testing; and review of medical surveillance options with or without genetic testing. The client’s psychological motivations for testing should be reviewed as well as the potential impact the test will have on extended family, friends and co-workers. The potential for insurance discrimination and confidentiality of the medical records and test results should be discussed. The health professional should inquire as to the emotional support the client has during and after testing. The patient should receive a comprehensive written summary of the counseling session(s) and test results [McKinnon, 1997].

A reasonable outcome of genetic counseling is the decision to postpone or not pursue genetic testing, even if a genetic test is available. Molecular genetic testing can be expensive, and the results of the testing may not alter the medical management of the patient or other family members, particularly in an elderly individual. Extracting DNA from the blood of an affected family member, to save in a DNA bank, is an important option in these families. Saving DNA in this manner allows for other family members to have access to this genetic information in the event of that person’s death. Often individuals who bank DNA feel that they are helping future generations without personally undergoing the expense and psychological stress of genetic testing. DNA banking is available at many commercial laboratories and university medical centers.

3.3.2 Make a Plan for the Result Session

An often overlooked component of genetic testing is planning how the results will be presented. This is usually done best in person with a support person present. The results of genetic testing have profound implications on the person being tested, regardless of the test results. The individual who is tested often has many questions about the interpretation of the test result, and the implications for other family members [McKinnon, 1997].

3.3.3 False Negatitve Results

Since the sensitivity of any of the current molecular approaches varies, it is imperative that genetic testing begin with a closely related relative known to have colorectal cancer. Molecular genetic testing for familial colon cancer is still in its infancy. A negative screening test for a specific DNA mutation does not necessarily imply that a genetic cancer syndrome is not present. The sensitivity of molecular testing varies with each syndrome. In some syndromes it approaches 80% (Adenomatous Polyposis Coli) while in other syndromes, mutations may be detected in only 60% of affected patients (Hereditary Nonpolyposis Colon Cancer). The counselor should know and explain the limitations of genetic testing. If the tested individual has a negative molecular genetic study, yet the family history is suggestive of a hereditary colon cancer syndrome, all family members should be counseled and managed accordingly.

It is often difficult for patients and their health care providers to understand that a negative genetic test may not eliminate the risk of developing colon and other cancers. A patient with a negative genetic test may feel a false sense of security and fail to participate in recommended cancer screening. A study of clinical usage of APC gene testing in patients with clinical features of familial adenomatous polyposis demonstrated the great potential for misunderstanding in using these tests [Giardiello, 1997]. In this study, 31.6% of test results were misinterpreted often because the ordering physicians did not understand the potential for a false negative result. Fewer than 19% of the study participants received any genetic counseling before testing.

3.3.4 Genetic Testing of Minor Children

The general rule has been to not perform genetic testing on children before the age when screening for a familial colorectal cancer would normally begin [Ackerman, 1996], [ASHG/ACMG, 1995]. For example, with FAP, children can begin to have colonic manifestations as early as age 5 years although prophylactic surgery usually is not done until after puberty. In contrast, an individual at risk for Hereditary Nonpolyposis Colon Cancer is unlikely to show symptoms until the early 30’s and 40’s. Testing children for this condition is probably unwarranted. Minor asymptomatic children who test positive for such gene mutations may be treated differently by parents, siblings, other relatives, peers or teachers. There is also a fear that they may be discriminated against in obtaining insurance or employment. Although laws may effectively prevent discrimination from pre-existing conditions, subtle discrimination may be hard to prove.

3.3.5 Prenatal Testing

Once a mutation for a familial colorectal cancer is identified, genetic tests can be performed on cultured cells from the unborn fetus, obtained through amniocentesis or chorionic villus sampling. This is clearly not a simple decision for most families, particularly if symptoms may not develop for many decades after birth. If the fetus has a positive test, and the pregnancy is continued, one then faces the issues of testing a presymptomatic minor. Genetic counseling by a professional familiar with the psychological stresses involved in prenatal testing is imperative for these couples.

3.4 SUMMARY
  1. Take a thorough three generation family history from patients to evaluate for cancer risk.
  2. Genetic testing is now available for many colon cancer syndromes, including Familial Adenomatous Polyposis and Hereditary Nonpolyposis Colon Cancer and their variants.
  3. Genetic testing should be accompanied by informed consent and by genetic counseling before and after the test.
  4. Genetic testing should be performed, whenever possible, on an affected individual first, to identify the specific mutation associated with the disease in a particular family.
  5. Testing does not indicate the presence of cancer, but can indicate cancer risk and provide information that may be useful for surveillance management.
  6. Some people who inherit the gene mutation do not develop clinical signs associated with the mutation, such as cancer. Such a phenomenon is called incomplete penetrance, and is suggestive that other factors such as diet and environment can influence gene expression.
  7. Hereditary Nonpolyposis Colon Cancer is associated with 75-80% penetrance, while Familial Adenomatous Polyposis has virtually 100% penetrance.
  8. Use of a DNA bank is an important option for saving DNA on an affected family member for families desiring to postpone testing. It also should be considered for affected individuals if clinical testing is not yet available.
  9. Genetic testing of asymptomatic minors should not be performed before the age that surveillance for colorectal cancer would normally begin for a considered syndrome.