Colonic Polyps and Polyposis Syndromes

Prevalence

The prevalence of adenomatous polyps is concordant with the background rate of CRC in the population, and varies with patient age, sex, and family history. Colon adenomas occur more frequently in populations at greater risk for colon cancer. In populations at low risk for colon cancer, data from autopsy series indicate adenoma prevalence rates less than 12%, whereas in most intermediate- and high-risk populations, adenomas are found in 30% to 40% of the population. ^, In high-risk areas, up to two thirds of people older than 65 years harbor colonic adenomas. ^,

Age is the single most important independent determinant of adenoma prevalence. The prevalence rate of adenomatous polyps within the asymptomatic population has been elucidated by studies of screening colonoscopy in average-risk, healthy adults without GI symptoms. Approximately 20% to 53% of such individuals older than 50 years of age will have at least one adenoma, and 3.4% to 7.6% will have an adenoma with advanced pathology (AAP, see Malignant Potential of Adenomatous Polyps later). By comparison, similar screening studies of asymptomatic persons 40 to 49 years of age revealed prevalence rates of only 8.7% for tubular adenomas (TAs) and 3.5% for AAP or cancer. Advancing age also correlates with a greater likelihood for multiple polyps, adenomas with more severe degrees of dysplasia, and, in some studies, larger adenomas. Adenomatous polyps are also more prevalent among persons with a family history of CRC and adenomas, particularly if more than one relative is affected with CRC and if the affected relative is young.

Gender and race/ethnicity also influence adenoma prevalence. Colonoscopic series indicate that men have a 1.5-fold increased relative risk (RR) of adenomas compared with age-matched women, ^, which is consistent with earlier observations in autopsy series. ^, Men also have higher rates of AAPs than women, with an RR of approximately 1.5. A large database study collected from 67 GI practice sites in the USA found a higher rate of polyps larger than 9 mm in African Americans undergoing screening colonoscopy compared with age-matched whites, and other studies suggest higher rates of adenomas overall, and of proximal lesions in particular, among African Americans and Hispanics compared with Caucasians.

Incidence

Estimating the incidence of new adenomas requires examination of the colon at more than one point in time. Data on adenoma incidence are derived from colonoscopic surveillance studies following polypectomy (or following cancer resection) or studies of interval examinations in persons who initially had a negative colonoscopy. Estimates of adenoma incidence in both types of studies are potentially affected by the low but measurable rate of missed lesions.

The incidence of a first adenoma varies from 24% to 41%. In one study, patients underwent colonoscopy twice on the same day to clear the colon of all potentially missed adenomas, and 38% were found to have new adenomas at colonoscopy 2 years later. In the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, incident adenomas were found in 3.1% of subjects who underwent a 3-year follow-up sigmoidoscopy after an initial negative examination. Updated data from the PLCO study combined results of 3- and 5-year follow-up sigmoidoscopies and revealed an adenoma rate of 4.6%, with 1.6% of these being considered advanced (>10 mm, or displaying villous morphology or high-grade dysplasia [HGD]). In average-risk, asymptomatic persons with no adenomas at baseline colonoscopy, repeat colonoscopy within 5 years detects an adenoma in approximately 16% to 27% ^, and an AAP in approximately 1% to 2.4%. In a separate study of individuals who underwent 3 colonoscopies at roughly 3-year intervals, 10.3% had high-risk findings (≥3 adenomas or ≥1 advanced adenoma) at the third colonoscopy.

The recurrence rate of new adenomas within 3 to 5 years after removal of an index lesion(s) is estimated to be 20% to 50%. The risk of subsequent adenomas in patients with one or more adenomas removed during colonoscopy is strongly influenced by the number of adenomas initially removed (≥3) and whether any of the adenomas were larger than 10 mm, harbored HGD, or showed villous morphology. In one study of 8472 subjects with a prior history of one or more adenomas, 34.1% were found to have a new adenoma on surveillance colonoscopy. If the initial colonoscopy removed more than 3 adenomas, the odds ratio (OR) for any adenoma on follow-up exam was 1.8 (95% confidence interval [CI], 1.2 to 2.2), and the presence of advanced features in the index adenoma was associated with ORs ranging from 2.7 to 3.9.

Anatomic Distribution

In autopsy series, adenomas are distributed uniformly throughout the colorectum; this even distribution is consistent with more recent colonoscopic series of asymptomatic subjects. ^,

Anatomically, polyps are considered proximal if they are located in the portions of colon proximal to the junction of the splenic flexure and descending colon. ^, Polyps generally are described as right-sided if found proximal to the splenic flexure, whereas left-sided lesions are distal to the splenic flexure. Large adenomas have a distal predominance, in the region where most colon cancers arise, thereby supporting the adenoma-carcinoma sequence hypothesis. Adenomas detected in surgical and colonoscopic studies of symptomatic patients also display a left-sided predominance, likely reflecting the fact that distal adenomas are more likely to come to clinical attention because of bleeding or colon obstruction. Studies of endoscopy and pathology databases show consistent trends toward advancing age and the proportion of adenomas located in the proximal colon, and some studies suggest that African Americans and Hispanics have a greater proportion of proximal adenomas compared with whites, especially in persons older than 60 years. ^,

Multiple Adenomas and Carcinomas

The term multiple adenomas (or carcinoma) refers simply to the presence of 2 or more neoplasms. An adenoma or carcinoma that is diagnosed at the same time as an index colorectal neoplasm is called a synchronous lesion , whereas one that is diagnosed at least 6 months later (an arbitrary limit) is considered metachronous.

The adenomatous polyp itself commonly is regarded as a marker of a neoplasm-prone colon. Indeed, 30% to 50% of colons with one adenoma contain at least one other synchronous adenoma, especially in older age groups. ^{, ,} Risks of colon cancer and of HGD both increase with the number of adenomas present ( Table 126.3 ) and approach 100% in people with FAP.

A synchronous adenoma can be identified in 30% of colons that harbor a carcinoma ^, and in 50% to 85% of those that harbor 2 or more synchronous cancers. ^, If the synchronous adenoma is diagnosed preoperatively and is distant from the carcinoma, the surgical approach might have to be adapted to the particular circumstances. For this reason, before surgical resection of any CRC, a thorough examination of the colon by preoperative colonoscopy or CT colonography (CTC) is strongly recommended. Moreover, the presence of a synchronous adenoma in a patient with a colonic adenoma or colon cancer increases the risk for developing metachronous polyps and cancer. ^,

Malignant Potential of Adenomatous Polyps

The 3 principal features that correlate with malignant potential for an adenomatous polyp are size, histologic type, and degree of dysplasia (see Table 126.2 ). Although higher rates of malignant transformation are found when the source of the pathologic material is mainly from surgical polypectomies rather than colonoscopic polypectomies, the malignant potential is correlated directly with larger adenoma size, more villous histology, and higher degrees of dysplasia. These 3 histopathologic criteria usually are interdependent. For example, although only 1.3% of all adenomas less than 1 cm in diameter harbor a cancer, if these small lesions have a predominant villous component or contain a focus of severe dysplasia, the cancer rate rises to 10% or 27%, respectively. A small (<1 cm), tubular, mildly dysplastic adenoma is highly unlikely to harbor a focus of invasive cancer. Nonetheless, although this type of lesion, once removed, is innocuous in itself, it often is considered a marker of risk for developing a recurrent adenoma (discussed later). Adenomas are considered advanced on the basis of size alone if they are more than 1 cm in diameter, or if less than 1 cm, they contain at least 25% villous architecture, or any evidence of HGD or carcinoma.

Diminutive Polyps

Diminutive polyps measure 1 to 5 mm. In a prospective study of 451 colorectal polyps, it was reported that 90% of polyps encountered during routine colonoscopy are subcentimeter and, of these, 90% are less than 5 mm in diameter. Diminutive polyps thus represent the vast majority of polyps encountered during colonoscopy, and a better understanding of the natural history and potential for advanced histology in these small polyps has important clinical implications for treatment and recommendations for follow-up.

In a study of 13,992 subjects undergoing colonoscopy, 3744 had a polyp no larger than 5 mm; of these, approximately half were conventional adenomas (48.5% tubular, 1.2% tubulovillous), and 1.7% had advanced histology including 1 polyp with HGD and 1 cancer. The frequency of adenomatous changes in diminutive polyps in this study was similar to several earlier studies. ^, Although estimates of the prevalence of HGD in diminutive polyps has varied, and been reported between 0.5% and 10%, studies suggest that the risk of HGD and carcinoma are low. A systematic review of 4 studies comprising over 20,000 patients who underwent screening colonoscopy found that the majority of polyps encountered were diminutive (up to 64%) and the frequency of advanced adenomas and cancers found in these diminutive-only polyps was very low at 0.9% and 0.04%, respectively.

In addition to low rates of advanced neoplasia and cancer, diminutive adenomas manifest little, if any, appreciable growth over time. A population-based study that involved fulgurating small polyps (even those up to 1 cm) without obtaining initial histologic identification reported that the subsequent risk for CRC and overall survival was no worse than in the general population. Taken together, these observations indicate that diminutive polyps, even when they prove to be adenomas, have little biologic or clinical significance. Based on this view of diminutive polyps, there is a growing interest in a “resect and discard” strategy for diminutive polyps in order to reduce pathology costs associated with polyp removal. ^, This is not standard practice currently, however, and ongoing areas of investigation in the resect and discard paradigm include the role of advanced imaging techniques such narrow band imaging (NBI), the applicability to specific patient populations, and patient ^, and provider acceptance of the strategy. An important exception to the rule of the innocuous nature of diminutive adenomas is in the setting of Lynch syndrome, in which even small adenomas can display advanced pathologic features such as villous histology or HGD (discussed later).

Flat Adenomas

A subset of adenomas, termed flat adenomas by Muto and coworkers, has received increasing attention as potentially important lesions. Macroscopically, a flat adenoma is either completely flat or slightly raised, and may contain a central depression. By definition of the Japanese Society for Cancer of the Colon and Rectum, the diameter of this polyp is more than twice its thickness. Typically less than 1 cm in diameter, these lesions can be easily missed at endoscopy. This potential risk has prompted investigators, particularly in Japan, to adapt better methods of detection that involve dye-spraying (chromoendoscopy) to generate a contrast relief-map image of the mucosa, or magnification colonoscopy, for enhanced visualization. In studies without such specialized endoscopic techniques, flat adenomas accounted for 8.5% to 12% of all adenomas and were multiple in up to 50% of patients.

Prospective studies of Western populations aided by the use of chromoendoscopy found that 6.8% to 36% of all detected adenomas were flat. Compared with lesions that were polypoid, these flat polyps tended to be smaller and to have increased rates of HGD and early cancer. A large study of more than 1800 veterans undergoing colonoscopy found a prevalence for flat or non-polypoid neoplasms of 9.4%. These lesions were 10 times more likely to harbor a carcinoma, although the rate of carcinoma was quite low. Indeed, it has been suggested that flat adenomas can have distinct biologic and chromosomal profiles. ^, In contrast, re-evaluation of adenomas removed during the National Polyp Study found no increased risk of HGD in polyps classified as flat, based on histologic features. A more recent Austrian database study of over 17,000 colonoscopies found that the presence of HGD was more closely related to polyp size rather than to morphology. Future studies might help define whether broader acceptance of advanced endoscopic techniques such as chromoendoscopy or NBI by endoscopists in Western countries will result in higher detection rates of flat adenomas, lower CRC incidence, or both following colonoscopy.

The natural history of flat adenomas is not known; it is possible that they give rise to typical polypoid adenomas. Alternatively, the facts that residual flat adenoma tissue can be found adjacent to flat carcinomas, that some studies have observed a substantial incidence of HGD in these small lesions, and that flat adenomas have a lower incidence of K-ras mutations compared with polypoid adenomas, suggest that malignant progression from flat adenomas might not necessarily involve a polypoid phase. Indeed, a recent study has shown that flat adenomas have lower rates of adenomatous polyposis coli (APC) mutations than polypoid adenomas.

Cellular Growth

The colonic epithelium is comprised of a single-cell layer of colonocytes that undergo continuous cycles of division, proliferation, differentiation, and shedding into the lumen. This process, which drives the complete renewal of colonic epithelium approximately every 5 days, requires multiple proliferative checkpoints to preserve cellular integrity, although this orderly progression can be interrupted by genomic alterations alone or through complex interactions with multiple mutagenic environmental factors.

The initial aberration arises within individual colonic crypts when the proliferative compartment expands beyond the crypt base resulting in a unicryptal adenoma. Colonocyte proliferation eventually outpaces the rate of surface epithelial cells sloughing and the crypt accommodates by expanding in a downward infolding manner, interposing itself between adjacent normal crypts. New adenomatous glands then are created either by further infolding or by branching. Thus, the unicryptal adenoma is believed to arise from a monoclonal expansion of an abnormal cell, and as the adenoma enlarges, the adenomatous cell population becomes polyclonal through acquisition of additional mutations. Evidence for this concept comes from studying intestinal tissues from a patient with familial adenomatous polyposis (FAP) who was an XO/XY mosaic. Analysis of Y chromosome expression in the intestinal mucosa of this patient revealed that normal crypts of the small and large intestine and even unicryptal adenomas were monoclonal (either XO or XY), whereas at least 76% of very small microadenomas were polyclonal.

Molecular Pathogenesis

Conventional adenomas and a subset of sessile serrated adenomas (SSAs) (discussed later) develop according to 2 major pathways: chromosomal instability (CIN) or microsatellite instability (MSI). The major drivers in both pathways are somatic mutations in a core set of approximately 30 genes, most commonly the tumor suppressors APC and TP53, and the oncogenes KRAS, PI3KCA, BRAF, and NRAS. Approximately 85% of sporadic colon cancers arise from conventional adenomas through the classic adenoma-carcinoma sequence, which involves a median of 60 additional mutations beyond the core driver mutations primarily in the CIN pathway (see Chapter 127 ).

The progression from adenoma to carcinoma results from an accumulation of molecular genetic alterations involving, among other changes, activation of oncogenes, and inactivation of tumor suppressor genes ( Fig. 126.3 ). Tumor suppressor genes that normally function to suppress tumor development commonly are inactivated in colorectal neoplasms by mutation or allelic deletion, thereby promoting tumorigenesis. The APC gene on the long arm of chromosome 5 is considered the “gatekeeper” for the process of colon carcinogenesis. It is believed that most, if not all, adenomas arise from an initial loss of APC gene function, and for that to happen, an epithelial cell must lose the function of both APC alleles (2 “hits”). In patients with FAP, one APC allele is inherited in a mutated form (germline mutation) from the affected parent. Adenomas can arise when the second, normal copy of the APC gene from the unaffected parent either is lost or mutated (somatic mutation). Because persons with FAP are born with the first hit, they develop polyps at a much younger age and in much greater number than does the general population. In the general population, sporadic adenomas arise as a consequence of 2 acquired somatic mutations of the APC gene within the same cell. Because 2 acquired hits are statistically less likely than one acquired hit, sporadic adenomas tend to occur later in life and to be fewer in number than in patients with FAP.

In addition to APC inactivation, the “chromosomal instability (CIN)” pathway is further promoted by activating point mutations at particular sites within the KRAS oncogene. KRAS activation appears to be important for adenoma growth and the intermediate stages of tumorigenesis. Less than 10% of small adenomas exhibit KRAS gene mutations, compared with 58% of adenomas larger than 1 cm, and 47% of colon cancers. KRAS activation in the absence of APC mutations generally does not lead to adenomas and malignancy, whereas a large number of adenomas and cancers do not have KRAS gene mutations, highlighting both the primary importance of APC gene mutations as the inciting molecular event in colon carcinogenesis as well as the contributions of multiple additional genes.

The loss of function of additional tumor suppressor genes including deleted in colorectal cancer (DCC) and TP53 contribute to the intermediate and later stages of the conventional adenoma-carcinoma sequence. Allelic deletion at the DCC locus occurs in 11% to 13% of small TAs or tubulovillous adenomas, but increases to 47% of adenomas with foci of cancer and 73% of frank colon cancers. Allelic deletion of chromosome 17p, at the locus that contains the TP53 gene, is the most common region of allelic loss in CRCs. Because adenomas seldom manifest 17p deletion, this alteration probably occurs as a late step in the adenoma-carcinoma progression.

A second major molecular pathway in colon carcinogenesis is characterized by BRAF mutations and hypermethylation of genes involved in mismatch repair (MMR) leading to a high frequency of MSI. The MSI pathway is the major pathway for the formation of “MSI-high” tumors in Lynch syndrome. The primary function of the MMR proteins MLH1, MSH2, MSH6, and PMS2 is to correct DNA mismatch errors that occur during replication of microsatellite sequences. Inactivation of MMR genes through either germline mutation or promoter hypermethylation results in the accumulation of mutations in target genes with microsatellite DNA, including transforming growth factor-β receptor 2 and insulin-like growth factor 2 receptor. ^, Approximately 15% of sporadic colon cancers and 85% of Lynch syndrome colon cancers are associated with MSI. The numbers of adenomas that occur in patients with Lynch syndrome are similar to those in the general population but Lynch syndrome is marked by accelerated tumor progression, and polyps often manifest advanced pathology (villous features, HGD) and MSI even at small sizes early in their development.

A third major pathway important for adenoma development involves the aberrant hypermethylation of CpG (“p” indicates that “C” [cytosine] and “G” [guanosine] are connected by a phosphodiester bond) dinucleotide-rich DNA islands (CpG island methylator phenotype, CIMP). CIMP-associated epigenetic changes may affect a large number of genes, including tumor suppressors (CDKN2A ) and DNA repair genes (MGMT ^, ) and are found in up to half of sporadic colon cancers. Due to the large number of genes potentially affected, the CIMP pathway overlaps to some extent with both the CIN and MSI pathways, and contributes to both MSI and non-MSI tumors. It also is recognized to play a key role in the development and progression of SSAs (discussed later).

Inherited Susceptibility

Epidemiologic studies have revealed a 2- to 3-fold increased risk for adenomas and colon cancer in probands who have a first-degree relative affected by colonic cancer or adenoma. Data from the National Polyp Study indicate that siblings and parents of patients with adenomatous polyps are at an increased risk for colon cancer, particularly when the adenoma proband was younger than age 60 at diagnosis. There is even a suggestion that adenomas in patients with a family history of CRC have faster growth rates.

It is now estimated that as many as 10% to 30% of colon cancers are familial, implying the possibility of susceptibility genes that give rise to common colon cancers not associated with autosomal dominant syndromes such as FAP and Lynch syndrome. Despite epidemiologic data to suggest an increased risk in patients with family members who have colon cancer or adenomas, however, it has been difficult to fully elucidate the causative genetic basis. Several genes have been identified that can contribute to common familial risk; these include a germline mutation in the APC gene at codon 1307 (I1307K) that appears to predispose Ashkenazi Jewish populations to colon cancer; mutations of the DNA MMR gene hMSH6 ; a type I transforming growth factor-β receptor allele TbR-I(6A); and polymorphisms of certain genes involved in the metabolism of nutrients and environmental agents (e.g., methylenetetrahydrofolate reductase, N -acetyltransferase-1 and -2). ^, A specific mutation in methylenetetrahydrofolate reductase also has been found to be protective against colon cancer risk. The identification of such low-penetrance genes responsible for common susceptibility to colonic adenoma and carcinoma is an area of considerable research.

Diet and Lifestyle

Dietary and lifestyle factors also play an important role in colorectal carcinogenesis. It is estimated that as much as a third to a half of colon cancer risk and a fourth to a third of distal colon adenoma risk might be avoidable by modification of dietary and lifestyle habits. Dietary factors that correlate with a predisposition to colon cancer are also associated with a risk for colonic adenomas, and include cigarette smoking, excess alcohol intake, excess dietary fat, and obesity.

The majority of cohort and case-control studies have demonstrated an association between alcohol intake and risk of advanced adenomas. A pooled analysis of 8 cohort studies revealed a RR of 1.41 (95% CI 1.16 to 1.72) for subjects who consumed three or more alcoholic drinks per day, and the effects of alcohol intake appear to synergize with tobacco to increase adenoma risk. Dietary fat intake and obesity are other important risk factors for adenomas. In a large cohort study, men in the highest quintile of saturated fat intake had a RR of 2.0 (95% CI 1.2 to 3.2) for colorectal adenomas when compared with men who had the lowest fat intake after controlling for total caloric intake. A linear association between BMI and adenoma risk also has been confirmed in several high-quality studies, including a comprehensive review of 36 publications, which described a 19% increase in adenoma risk for each 5-unit increase in BMI. ^, In obese patients, a central distribution of obesity and increased visceral fat confers a higher risk of colorectal adenomas. Patients with higher levels of insulin and C peptide also have been found to have an increased risk of adenomas. Factors that have shown the most consistent protective effect against adenomas in epidemiologic studies include dietary fiber and plant foods. Patients with the highest fiber intake in the prospective PLCO trial had a 27% lower risk of adenomas compared with those who had the lowest fiber intake. Other protective measures include increased physical activity, increased intake of calcium, and high intake of folate. An analysis of an asymptomatic, predominantly male veteran population undergoing screening colonoscopy found that smoking and moderate to heavy alcohol use increased risk, whereas cereal fiber intake, vitamin D intake, and use of NSAIDs decreased risk for advanced colonic neoplasia (AAPs and colon cancer).

Despite evidence of dietary associations with risk of polyp formation, prospective interventional studies have been negative. Dietary changes maintained over 2 to 4 years have failed to significantly reduce recurrent or incident adenomas in several studies that tested reductions in fat with increases in fiber, fruits, and vegetables; combinations of low-fat with wheat bran or β-carotene supplements, or both; supplements of wheat bran fiber with vitamins C and E; and a complex supplement of calcium, vitamin C, vitamin E, and selenium.

Unlike these null studies, 4 classes of chemopreventive compounds have shown protective effects against colon adenomas or cancers: NSAIDs, calcium, hormone replacement therapy (HRT), and selenium; of these, NSAIDs, including aspirin, are most well established. Over 90% of the more than 110 studies of various animal models and over 35 epidemiologic studies confirm a significant reduction in colorectal adenomas, cancers, and cancer-associated mortality among users of aspirin or NSAIDs. For example, the Nurses’ Health Study, a prospective cohort study of 27,077 nurses, found that regular use of aspirin was associated with a 25% reduction in risk of developing colorectal adenomas.

Three prospective randomized trials that investigated the use of aspirin to prevent colorectal adenomas have shown decreased rates of adenoma recurrence in the study groups compared with the placebo group. In one trial, which was terminated early because of significant results, 635 patients with a history of curative resection of CRC and randomized to 325 mg/day of aspirin or placebo, were found to have a significant 35% reduction in incident adenomas after a mean of 12.8 months. Another trial of patients with prior colorectal adenomas compared 81 mg/day or 325 mg/day of aspirin with placebo and found that the 81-mg dose reduced the RR of developing adenomas and advanced adenomas by 19% and 41%, respectively, with a similar, but not significant, trend found with the higher dose. The 1-year results of a trial comparing 2 doses of lysine acetylsalicylate with placebo found a significant reduction in recurrence of adenomas larger than 5 mm in both treatment groups, but a greater effect with the higher dose. In contrast, in the Physicians’ Health Study, administration of aspirin 325 mg every other day over 5 years showed no reduction compared with placebo in advanced adenomas or colon cancers. A meta-analysis pooled data on more than 2900 patients with a history of an adenoma from 4 randomized trials to compare aspirin at doses of 81 to 325 mg daily with placebo. At a median follow-up of 33 months, the rate of recurrent adenoma was 37% in the placebo group and 33% in the aspirin group. The absolute risk reduction with aspirin use was 6.7%.

NSAIDs act by inhibiting COX-1 and COX-2 enzymes, which thereby reduces cellular proliferation, enhances apoptosis, and reduces angiogenesis; other COX-independent effects also are operative. Based on these observations as well as studies that show selective COX-2 inhibition reduces the number of adenomas in patients with FAP (discussed later), 3 large-scale prospective studies of COX-2 inhibitors (celecoxib and rofecoxib) have been undertaken. The APPROVe, APC, and PreSap trials randomized more than 5000 patients with a history of adenomas to treatment with celecoxib or rofecoxib or placebo. In all 3 studies, celecoxib or rofecoxib was superior to placebo in preventing recurrent adenomas and, specifically, AAPs. Enthusiasm for these agents, however, was tempered by the finding of increased cardiovascular adverse effects (AEs) in the COX-2 arms. The APPROVe study was terminated early and rofecoxib was withdrawn from the market, but the studies illustrated proof of principle that COX-2 inhibition leads to decreased polyp burden.

Calcium supplements have been shown in 2 randomized placebo-controlled phase III studies to reduce adenoma recurrence by approximately 19% to 34%, with effects noticed even after one year of supplementation. ^, It has been suggested that calcium supplements might have a more pronounced effect on AAPs. The mechanism for this protective effect likely is multifactorial, because calcium has been shown to decrease proliferation of colonic epithelial cells and to inhibit mucosal injury induced by bile acids and carcinogens in the fecal stream. A follow-up randomized trial of calcium and/or vitamin D supplements, however, failed to demonstrate a protective benefit for adenoma recurrence.

In a study investigating chemoprevention of skin cancer, selenium supplements were associated with a 58% reduction in colon cancer incidence as a secondary end-point. This result has prompted additional trials to evaluate the effects of selenium on recurrent formation of adenoma. HRT has been associated in many studies with an approximately 20% reduction in colon cancer risk and a protective effect against colonic adenomas. As with NSAIDs, however, the AEs of HRT often outweigh the beneficial chemopreventive effects of these agents. A randomized placebo-controlled trial in patients with a history of adenomas found that use of ursodeoxycholic acid at a dose of 8 to 10 mg/kg for 3 years did not lead to a statistically significant decrease in recurrent adenomas; however, there was a statistically significant 39% decrease in adenomas with HGD. Initial evidence from multiple cohort studies, including the Nurses’ Health Study and Canadian National Breast Cancer Screening study, suggested a 40% lower risk of colorectal adenomas in women with the highest levels of folate intake. A randomized controlled trial of folate alone or in combination with aspirin, however, did not show a decreased risk of polyps or advanced neoplasia in the folate arms. Currently, it is unclear if folate has a true benefit in reducing polyp burden.

Other agents that continue to be examined as chemoprevention agents include Difluoromethylornithine, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, vitamin E, metformin, and mesalamine compounds. Overall, given the need for long-term therapy and the potential AEs associated with many of these agents, they are likely best studied in patients at high risk for colorectal neoplasia.

Diet and dietary supplements can affect the intestinal microbiota. Recent advances in the analysis of the microbiome are beginning to suggest an association between the microbiota and adenomas. Adenoma patients have demonstrated higher concentrations of Dorea spp. and Faecalibacterium spp., with lower concentrations of Bacteroides spp. than non-adenoma patients. Other studies have noted increased microbial richness and increased abundance of Fusobacterium in the normal rectal mucosa of individuals with adenomas, even after controlling for other adenoma risk factors. It has been postulated that an altered microbiota plays a role in colonocyte inflammation and tumorigenesis, although clear mechanisms have not yet been elucidated. It is not known if altering the intestinal microbiome by probiotics or antibiotics can affect risk of adenoma development or recurrence.

Predisposing Conditions

A variety of clinical circumstances have been associated with adenomatous polyps. Of the conditions discussed here, the predisposition to have or to develop adenomas is strongest for ureterosigmoidostomy, acromegaly, and Streptococcus gallolyticus (formerly Streptococcus bovis ) bacteremia. Patients with any of these 3 conditions should undergo a thorough colorectal examination and, in the former 2 conditions, periodic surveillance should be considered (although the frequency of such examinations is not well defined). As for the other conditions, either data are conflicting or the risk is not strong enough to recommend a policy of surveillance.

Fecal Occult Blood Testing

The actual frequency of bleeding from adenomas is difficult to determine. A significant adenoma (i.e., >1 cm or HGD) is the cause in less than 10% of people who report frank rectal bleeding. In general, polyps smaller than 1 cm do not bleed. This dictum is supported by quantitative measurements of fecal blood loss in people with known adenomas; these measurements indicate that only patients with adenomas greater than 1.5 to 2 cm lose more than the estimated normal GI tract blood loss of 0.5 to 1.5 mL/day.

Using colonoscopy as the gold standard for polyp detection, several studies have demonstrated the limited ability of detecting adenomas by fecal occult blood testing (FOBT). ^, In one large-scale cohort of 21,805 patients undergoing colonoscopy and FOBT, the sensitivity of FOBT for adenomas smaller than 9 mm was 7.0%.

Estimates of the predictive value of a positive FOBT result are also complicated by the possibility that adenomas detected after a positive test result may be coincidental and that the FOBT result is not directly attributable to bleeding from the adenoma. When asymptomatic persons older than 40 years of age undergo colon cancer screening with guaiac-based FOBTs, about 1% to 3% will have a positive result. Upon colonoscopic evaluation, less than half of these people will have a colorectal neoplasm, and among the lesions found, adenomas outnumber carcinomas by 3:1. Thus the proportions of all positive guaiac-based tests attributable to colonic neoplasms (i.e., positive predictive values) are 30% to 35% for adenomas and 8% to 12% for cancer. Despite the predominance of adenomas among lesions detected, 75% of adenomas still may be missed by guaiac testing (i.e., false-negative values) unless they are large or located in the distal portion of the colon.

Guaiac-based testing relies on a chemical peroxidase reaction; false positives can occur if the patient recently had ingested vegetable peroxidases (in turnips, radishes, melons, broccoli, carrots, cauliflower, cucumbers, grapefruit, mushrooms, and horseradish) or rare red meat (containing myoglobin), and false negatives can occur in the presence of high doses of antioxidants such as vitamin C.

Fecal Immunochemical Testing

To avoid some of the drawbacks of FOBTs, fecal immunochemical testing (FIT) uses antibody-based detection of human hemoglobin in the stool, conferring greater specificity for human blood than guaiac-based testing. FIT also does not require dietary restrictions and it can be quantitative. Two types of FIT studies have been performed: comparison studies to FOBT in which all patients received a colonoscopy, and in vitro studies to determine at what level FIT can detect blood in various samples. For a given lesion (i.e., adenoma or cancer), FIT, like FOBT, detects more cancers than adenomas because cancers are more likely to bleed. In a meta-analysis of 19 studies, the sensitivity and specificity of FIT for the detection of CRCs was 79% (95% CI, 69% to 86%) and 94% (95% CI, 92% to 95%), respectively. However, few studies have looked at the sensitivity of FIT specifically for adenomas. One prospective study compared 6 different qualitative FITs in 1319 average-risk patients who were undergoing screening colonoscopy. In this study, the overall sensitivity for detecting any adenoma ranged from 11.4% to 58.0%, and 25.4% to 71.5% for advanced adenomas. The 2 best-performing FIT assays in this study had sensitivities of 25% to 27% for advanced adenomas with a specificity of greater than 90%, allowing the detection of 25.4% to 26.9% of advanced adenomas. All immunochemical-based assays in this study were superior to guaiac-based FOBT, which had a sensitivity for any adenoma and advanced adenoma of 5.4% and 9.4%, respectively. At present, although FIT is an improvement over guaiac-based FOBT, it remains inadequate for adenoma screening and is best used as a screening test primarily for CRC.

Barium Enema

The detection of adenomas by barium enema (BE) depends on their size. In the National Polyp Study, the detection rates of adenomas smaller than 6 mm, 6 to 10 mm, and larger than 10 mm were 32%, 53%, and 48%, respectively. Common sources of error include inadequate cleansing of the colon, which contributes to the 5% to 10% false-positive rate, and diagnostic difficulty caused by the presence of diverticulosis, redundant bowel, or poor mucosal coating, which results in a 10% false-negative rate. Because of these issues, as well as the fact that BE never has been formally tested as a colon cancer screening tool, the use of BE for colon cancer screening has all but been abandoned in favor of colonoscopy or CT colonography (CTC) (discussed later).

Sigmoidoscopy

For several decades, rigid sigmoidoscopy was the mainstay of endoscopic CRC screening and detected polyps, of all histologic types, in 10% to 15% of asymptomatic persons over the age of 40. ^, In several large-scale prospective studies, screening sigmoidoscopy was associated with a 21% to 38% reduction in mortality from distal CRCs. In the USA, increasing use of colonoscopy to ensure complete visualization of the entire colon has resulted in a marked reduction in sigmoidoscopy as a primary polyp screening modality.