bleeding manifesting as hematochezia may occur with larger polyps, which may be evident when the

polyps are located distally in the rectum. Adenomas typically lose less than 1 mL of blood daily unless

they are 2 cm or larger in size. Although colorectal polyps are the most common lesions detected in

patients without symptoms undergoing colonoscopy because of the presence of fecal occult blood, the

polyps are probably not responsible for the bleeding. Very large colonic polyps may be associated with

obstructive symptoms, such as lower abdominal cramping or alterations in bowel habits, but this is

unusual. Secretory diarrhea with accompanying hypokalemia and hypochlorhydria has been associated

with very large villous adenomas of the distal colon and rectum. This is a rare syndrome, and the search

for secretagogues such as vasoactive intestinal polypeptide or prostaglandins in patients with polyps and

diarrhea, is infrequently productive.

Adenomas Associated with Lynch Syndrome and Its Variants

Lynch syndrome is a disease of autosomal dominant inheritance in which cancers arise in discrete

adenomas, but polyposis (i.e., dozens or hundreds of polyps) does not occur. Lynch syndrome patients

can get adenomas, HPs, and sessile serrated polyps (SSPs), but adenoma is the lesion that leads to

cancer. The loss of DNA MMR activity usually occurs after the appearance of a small adenoma, and

typically occurs after the adenoma is 8 mm or greater in diameter.16 The mean cumulative number (plus

2 standard deviations) of adenomas in mutation carriers undergoing annual screening colonoscopy is 3

by age 30 and 6 by age 50.17 However, there are outliers with larger numbers. Currently, the diagnosis

of Lynch syndrome is made by finding a germline mutation in the DNA MMR gene, not by clinical

criteria.18 The frequency of Lynch syndrome in the general population is difficult to determine, but

Lynch syndrome accounts for about 3% to 4% of all colorectal cancer cases; this suggests that Lynch

syndrome may occur in about 2 to 5 per 1,000 of the population.

Turcot syndrome is a term of historical significance, in which there is a concurrence of primary brain

tumors and multiple colorectal adenomas or cancer in young people. With the advent of accurate

genetic characterization, these families may be categorized as either FAP or Lynch syndrome, as brain

tumors are an occasional complication of both diseases, more often a medulloblastoma in FAP, and

glioblastomas in Lynch syndrome.19

Diagnosis

Most colorectal adenomas are asymptomatic and often are detected in the setting of an evaluation for

unrelated colonic symptoms or occult blood in the stool. Similarly, adenomatous polyps frequently are

detected when patients without symptoms are screened for colorectal neoplasia. Nevertheless, data

strongly suggest that the detection and removal of adenomatous polyps are important in reducing

colorectal cancer–related mortality.

In 2008, a joint guideline on screening and surveillance for early detection of colorectal cancer and

adenomatous polyps was issued by the American Cancer Society (ACS), the U.S. Multi-Society Task

Force on Colorectal Cancer (USMTF), and the American College of Radiology (ACR).20 This update of

previous guidelines is notable in that it grouped screening tests into those that primarily detect cancer

(annual fecal occult blood tests [FOBTs] including those that are guaiac-based or immunochemical, and

stool DNA tests, interval not specified) and those that can detect early cancer and adenomatous polyps

(flexible sigmoidoscopy every 5 years, colonoscopy every 10 years, double-contrast barium enema

every 5 years, or computed tomography [CT] colonography every 5 years). In November 2008, the U.S.

Preventative Services Task Force (USPSTF) also issued updated guidelines (Table 67-2).21 Based on a

targeted evidence-based review and a decision-analytic modeling analysis, the USPSTF recommended

screening of average-risk individuals age 50 to 75 years with high-sensitivity FOBTs annually,

sigmoidoscopy every 5 years plus FOBTs every 3 years, or colonoscopy every 10 years. Notably, the

USPSTF indicated that while the benefits of screening outweigh the potential harms for 50 to 75 year

olds, the likelihood that detection and early intervention will yield a mortality benefit declines after age

75 because of the long average time between adenoma development and cancer diagnosis. Routine

screening was therefore not recommended for adults aged 76 to 85 years, and screening was not

recommended at all in adults older than 85. These guidelines also indicated that for all populations

there is insufficient evidence to assess the benefits and harms of screening with CT colonography or

fecal DNA testing.

The American College of Gastroenterology (ACG) Guidelines for Colorectal Cancer Screening also

grouped options into cancer prevention tests (colonoscopy every 10 years, flexible sigmoidoscopy every

5 to 10 years, and CT colonography every 5 years) and cancer detection tests (annual FOBT with fecal

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immunochemical tests [FITs], fecal DNA testing every 3 years).22 Colonoscopy is considered the

preferred choice overall. The ACG also recommends that screening in African Americans should begin at

age 45 instead of age 50 for average-risk individuals, and that CT colonography replace double-contrast

barium enema as a radiologic option. The “European guidelines for quality assurance in colorectal

cancer screening and diagnosis” is a 386-page document authored by 90 authors from 32 countries

which provides an evidence-based review of existing data on CRC screening which stresses quality

measures and cost effectiveness.23 Numerous international CRC screening programs have been initiated

as evidence grows for an impact of CRC screening on mortality.24

Fecal Occult Blood Tests

Screening studies from both Europe and the United States indicate that a polyp is detected in about 30%

of patients without symptoms who are 50 years of age or older and undergo colonoscopy for follow-up

of a positive fecal occult blood test result. Blood loss from polyps is related to polyp size, and positive

fecal occult blood test results are related to polyp size and proximity to the rectum. In one study where

rehydrated Hemoccult slides were used (rehydration results in greater sensitivity but also increases the

number of false-positive findings), only 15% of polyps smaller than 1 cm were associated with a

positive Hemoccult test result, whereas 80% of polyps larger than 2 cm were associated with a positive

result. In another study, standard testing with Hemoccult cards detected 17% of adenomas smaller than

1 cm and 42% of adenomas larger than 1 cm. A prospective randomized study of fecal occult blood tests

in which rehydrated Hemoccult cards were used indicated that annual testing reduces colorectal cancer–

related deaths by 33% through 18 years of follow-up.25 This study, in addition to two European trials,

has also demonstrated a 15% to 21% reduction in colon cancer–related death from biennial fecal occult

blood testing.26 Thus, unless one rigorously performs the fecal occult blood test on an annual basis, the

reduction in colorectal cancer mortality will be disappointing.

Methods that may decrease the false-positive FOBT rates while maintaining or increasing sensitivity

currently are being refined and compared for efficiency with Hemoccult-type slide tests. FITs are

designed to detect human globin and are not affected by diet or drugs. A variety of FITs are now

available worldwide and FIT is likely to replace guaiac-based FOBTs. FITs have good performance

characteristics compared with standard heme-based FOBT tests, and may have superior sensitivity and

specificity for detecting colonic neoplasms.27–29 Issues which remain to be resolved regarding FIT

include the optimal number of samples to be tested, requirements for storage and shipping (effect of

temperature), and the relative benefit of quantitative (specific amount of hemoglobin per gram of stool)

versus qualitative (i.e., positive or negative) reporting, and the optimal “cut-off” for a positive test. The

quantitative immunochemical FOBT has been shown to have very good sensitivity and specificity for

detection of clinically significant neoplasia in studies of asymptomatic and symptomatic patients, but

test performance in prospective screening programs has been less well studied. Recent studies suggest

the effectiveness of FIT for programmatic screening for colorectal cancer, but adenoma detection

remains much lower than that of carcinoma.29 FITs have now been included as the preferred form of

FOBT in screening guidelines.

CLASSIFICATION

Table 67-2 Guidelines for Screening Average-Risk Individuals for Colorectal

Cancer

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Figure 67-7. CRC mortality in the National Polyp Study for adenoma and nonadenoma patients with comparison with the US

incidence-based mortality rates over up to 20 years The number of subjects at risk per years followed is given for the adenoma

(blue line) and nonadenoma (red line) cohorts. The cumulative incidence-based mortality for the average risk US Population is taken

from SEER data (black line). Among patients who had adenomas removed during participation in the study, after a median of 15.8

years, there was a 53% reduction in colorectal cancer mortality compared to expected deaths from colorectal cancer in the general

population. (Modified from Zauber AG, Winawer SJ, O’Brien MJ, et al. Colonoscopic polypectomy and long-term prevention of

colorectal-cancer deaths. N Engl J Med 2012;366:687–696.)

Results from the NPS strongly indicate that the removal of index polyps detected by fecal occult blood

testing and other methods, together with subsequent colonoscopic surveillance, results in a very

substantial reduction in colorectal cancer mortality. A recent update of this trial with median follow-up

of 15.8 years indicated that colonoscopic polypectomy is associated with a 53% reduction in mortality

from CRC compared with the expected incidence-based mortality from CRC in the general population

(Fig. 67-7).15

Sigmoidoscopy

The benefit of sigmoidoscopy in interrupting the adenoma-to-carcinoma sequence is suggested by a

number of studies. Three prospective randomized trials have now shown that programmatic screening

with flexible sigmoidoscopy can have an impact on CRC-related incidence and mortality, mostly related

to the detection and removal of adenomas.30–32 The UK Flexible Sigmoidoscopy Screening Trial is a

randomized trial which tested the hypothesis that a single flexible sigmoidoscopy screening offered at

approximately age 60 years can lower the incidence and mortality of CRC.30 In per protocol analyses,

the incidence of CRC was reduced by 33% and mortality by 43% (23% and 31%, respectively, based on

intention to treat analysis), and the incidence of cancer of the rectum and sigmoid was reduced by 50%.

The Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) enrolled 154,900 subjects

aged 55 to 74 in a prospective randomized trial that compared flexible sigmoidoscopy with repeat

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