The term intestinal polyp is used to describe any projection arising from a flat mucosa into the intestinal lumen. Polyps can be pedunculated (see first image below) or sessile (see second image below).
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Endoscopic view of a pedunculated polyp.
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Endoscopic view of a sessile polyp.
See Benign or Malignant: Can You Identify These Colonic Lesions?, a Critical Images slideshow, to help identify the features of benign lesions as well as those with malignant potential.
Colonic polyps are usually classified as nonneoplastic, hamartomatous, neoplastic (adenomas and carcinomas), serrated (which can be neoplastic or nonneoplastic), or submucosal (which can be neoplastic or nonneoplastic). Adenomas account for approximately 65% of all colonic polyps, and serrated lesions account for the remaining 35%.[1] Approximately two thirds of all colorectal carcinomas are believed to arise from adenomas, a finding that underscores the importance of treatment and surveillance of adenomas of the gastrointestinal tract. The focus of this article is adenomatous colonic polyps, as shown in the images below.
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Villous adenoma, low-power view. Courtesy of George H. Warren, MD.
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High-power view of adenomatous polyp with low-grade dysplasia. Courtesy of George H. Warren, MD.
In the United States, colorectal cancer (CRC) is the third most common cause of cancer and the second leading cause of cancer-related death.[2] Screening for premalignant adenomatous polyps has the potential of preventing CRC. Colorectal adenomatous polyps are therefore targets for intervention and they may also represent biomarkers for CRC risk.
Colonoscopic screening for adenomatous polyps and their removal results in a decreased risk of colon cancer. The National Polyp Study[3] demonstrated that removal of all colonic adenomas resulted in a 76% to 90% reduction in colon cancer incidence and a 53% reduction in mortality from colon cancer over long-term follow-up compared with historic controls.
A more recent concern is that colonoscopy does not necessarily protect against colon cancers proximal to the splenic flexure (right-sided colon cancers).[4, 5, 6] This is likely due to a combination of reasons, including technical issues, such as poorer bowel preparation in the right side of the colon and higher rates of missed or incompletely resected polyps in the right side of the colon (that tend to be more flat and more difficult to identify and remove). In addition, it is possible that right-sided polyps have different biologic characteristics that may make them more elusive to detection and more aggressive in their progression.
Despite these potential limitations, physicians should advise patients regarding available options for colorectal polyp and cancer screening. Consensus guidelines on the early detection and surveillance of colorectal cancer and polyps from the United States Preventive Services Task Force (USPSTF)[7] were most recently published in 2008 and guidelines from the US Multi-Society Task Force (MSTF) on Colorectal Cancer[8] were updated in 2012.
The colonic mucosa is a self-renewing epithelium that is structured is a very tightly regulated balance between cell proliferation at the base of a crypt, maturation as colonocytes, migrate up the crypt, and extrusion of senescent and/or apoptotic cells from the upper crypt into the lumen. This entire process takes approximately 3-6 days.
Adenomatous cells are characterized by a loss of normal growth control. They continue to proliferate as they reach the top of the crypt, and they are not extruded into the lumen. Instead, they multiply and eventually fold back into the surrounding normal mucosa, inducing a response in the mesenchymal tissue that helps shape the microscopic architecture of the adenoma. The rate of growth and progression of adenomas to cancer is variable, but typically occurs in 10-15 years.[9] Patients with heritable forms of the disease, such Lynch syndrome, otherwise known as hereditary nonpolyposis colorectal cancer (HNPCC), have a significantly more rapid rate of adenoma formation and progression to cancer.[10]
The conventional adenoma-carcinoma sequence is thought to be a genetically driven process characterized by the occurrence over time of successive cycles of somatic mutation and clonal expansion of cells that have acquired a survival advantage. The first mutation in this process often involves inactivating mutations of the adenomatous polyposis coli (APC) tumor suppressor gene (inherited mutations in the APC gene cause familial adenomatous polyposis [FAP], and somatic mutations in the APC gene occur in about 80% of sporadic adenomas).
Additional progressive mutations occur in cells of the adenoma, including activating mutations of the oncogenes (Ki-ras), and inactivating mutations of additional tumor suppressor genes (ie, TP53). Some of these individual mutations lead to clones of cells that have acquired a survival advantage over surrounding cells, leading to a clone of mutant cells. Subsequent cycles of mutation and clonal expansion ultimately lead to adenoma growth, increased severity of dysplasia, and ultimately, acquisition of the invasive and metastatic characteristics of an adenocarcinoma.
Lynch syndrome colorectal cancers (CRCs) also arise from or within conventional adenomas, but the process is driven by a germline mutation in one of the DNA mismatch repair genes (ie, MSH2, MLH1, MSH6, PMS2); when focal somatic or the remaining wild-type allele occurs in the colon, it leads to loss of DNA mismatch repair, an increased mutation rate, microsatellite instability, and a rapid progression to CRC.
An epigenetic pathway to CRC has been described that is thought to arise through a serrated polyp pathway (hyperplastic polyp, sessile serrated adenomas, traditional serrated adenomas) rather than via conventional adenomas. In this pathway, silencing of DNA mismatch repair genes (MLH1) or other DNA repair genes (MGMT) by methylation results in failure of DNA repair and a resultant increased mutation rate that can result in progression to CRC.[9]
Another study suggests that activation of HuR, an RNA-binding protein implicated in immune homeostasis and various cancers, including CRC, is an early event in FAP-adenoma but not inflammatory bowel disease dysplasia and that HuR inhibition may potentially be an effective FAP chemoprevention.[11]
Up to 5% of all colorectal cancers are thought to arise from well-characterized inherited mutations.[12] Adenomatous polyps occur at a younger age and at a higher frequency in patients who carry these genetic predispositions.
Lynch syndrome
Lynch syndrome, otherwise known as hereditary nonpolyposis colorectal cancer (HNPCC), is an autosomal dominant syndrome caused by the inheritance of a germline mutation in one of several DNA mismatch repair genes (eg, MSH2, MLH1, MSH6, PMS2). Only a few colon adenomas develop in patients with Lynch syndrome, but those that do appear to have a very high rate of progression to colorectal cancer (CRC). Patients with Lynch syndrome develop tumors at a younger age (mean age, 44 y), have tumors more commonly in the proximal colon (60% to 70% proximal to splenic flexure), and are more likely to present with a multiplicity of cancers. Lynch syndrome accounts for up to 3% of all CRCs.[13]
Familial adenomatous polyposis
Familial adenomatous polyposis (FAP) is an autosomal dominant syndrome caused by the inheritance of a germline mutation in the APC gene. FAP is classically characterized by the appearance of hundreds to thousands of adenomas of the colon that typically begin during adolescence (average age at polyp formation is approximately 15 y) and a nearly 100% lifetime risk of colon cancer (average age at cancer development is approximately 40 y) if the colon is not removed. There is also an attenuated phenotype of FAP with which patients usually have fewer than 100 adenomas with a right-sided predominance. Attenuated FAP patients generally present later in life and have a 70% lifetime risk of developing CRC. FAP accounts for less than 1% of the total colorectal cancer risk in the United States.[14]
MUTYH-associated polyposis
MUTYH-associated polyposis (MAP) is an autosomal recessive syndrome caused by a biallelic inheritance of a mutation in the MUTYH gene, which is a part of the base-excision repair pathway involved in the repair of oxidative DNA damage. MAP has a variable phenotype, ranging from CRC without polyposis to up to 100 polyps. MAP results in a predisposition for both adenomatous and serrated polyps—both with malignant potential.[15]
Intestinal hamartomas
Multiple hamartomas of the intestine occur in the rare autosomal dominant syndromes of Peutz-Jeghers syndrome, familial juvenile polyposis, and Cowden syndrome. Adenomatous change can occur within the hamartomas and lead to adenocarcinoma, most commonly of the colon and small intestine.
Family history
Although up to 5% of all CRCs can be traced back to well-characterized genetic mutations, up to 30% of all CRCs have a familial component. Any patient with a first-degree relative who has a colorectal cancer or a large or histologically advanced adenoma when younger than 60-70 years is at a moderately increased (ie, 1.5- to 2-fold) risk for developing an adenoma.[16]
Diet and lifestyle
Initial epidemiologic studies suggested that increased dietary fiber was protective for CRC and increased dietary fat was a risk factor for CRC.[17] Subsequently, the prospective Nurses Health Study and other large cohort studies showed that dietary fiber did not significantly affect the risk for colon cancer. Although some fruits and vegetables may be protective, dietary fiber alone seems to have little impact on colon cancer risk.[18] Several cohort studies have also cast doubt on the notion that dietary fat increases the risk for colon cancer,[18, 19] although red meat may increase the risk.
The dietary Polyp Prevention Trial demonstrated that a dietary intervention promoting a low-fat, high-fiber diet had no impact on the recurrence of adenomatous polyps compared with controls, including the total number of adenomas, the number of adenomas by site, or the number of high-risk or advanced adenomas.[20] A 17-year follow-up study revealed no impact of this 4-year dietary intervention on the total adenoma rate or colon cancer risk.[21]
Abdominal obesity is associated with an increased risk of adenomas. Patients with a body mass index (BMI) of 25 or higher have a significantly higher prevalence of colorectal adenomas (odds ratio = 1.24; 95% confidence interval, 1.16-1.33; P< .01) when compared with those with a BMI of less than 25.[22] Physical activity has been consistently shown to be a protective factor for CRC and adenomas.[23]
The American Cancer Society makes the following lifestyle and nutrition recommendations for general cancer prevention[24] :
Achieve and maintain a healthy weight throughout life.
Be as lean as possible throughout life without being underweight.
Avoid excess weight gain at all ages. For those who are currently overweight or obese, losing even a small amount of weight has health benefits and is a good place to start.
Engage in regular physical activity and limit consumption of high-calorie foods and beverages as key strategies for maintaining a healthy weight.
Adopt a physically active lifestyle.
Adults should engage in at least 150 minutes of moderate-intensity or 75 minutes of vigorous-intensity activity each week, or an equivalent combination, preferably spread throughout the week.
Children and adolescents should engage in at least 1 hour of moderate or vigorous intensity activity each day, with vigorous intensity activity occurring at least 3 days each week.
Limit sedentary behavior such as sitting, lying down, watching television, or other forms of screen-based entertainment.
Doing some physical activity above usual activities, no matter what one’s level of activity, can have many health benefits.
Consume a healthy diet, with an emphasis on plant foods.
Choose foods and beverages in amounts that help achieve and maintain a healthy weight.
Limit consumption of processed meat and red meat.
Eat at least 2.5 cups of vegetables and fruits each day.
Choose whole grains instead of refined grain products.
If you drink alcoholic beverages, limit consumption.
Drink no more than 1 drink per day for women or 2 per day for men.
Long-term smoking has a detrimental effect on the risk of developing colonic adenomatous polyps, and it confers an increased risk of CRC. Those who have long-standing history of smoking may have up to a 3-fold increase in risk of adenomas[25] and an approximately 2-fold risk of CRC.[26, 27]
There may be a potential association between radiotherapy and intestinal adenomatous polyposis leading to the development of gastrointestinal carcinoma.[28]
Colonoscopic[29] and autopsy[30] series suggest an overall prevalence of adenomatous polyps of 40% to 50% by age 50-60 years and some endoscopic series suggest even higher rates. The prevalence of colonic adenomas increases with age and varies depending on the inherent risk of colorectal cancer in a given population.
International statistics
Significant geographic variation occurs throughout the world. For example, 2 different ethnic groups from genetically homogeneous regions in Japan have as much as a 20% difference in the prevalence of adenomas in people aged 50 years.
Race-related demographics
Although substantial variations in adenoma risk occur among different populations, race itself does not appear to be an independent determinant of risk. Dietary and environmental factors may have a role in explaining some of the differences observed throughout the world; for instance, a larger waist circumference in Japanese women and metabolic syndrome in Japanese men was associated with a higher risk of advanced neoplasia.[31] Similarly, blacks in New Orleans have a high risk for adenomas, while South African rural blacks are at low risk for developing adenomas.
The Veterans Administration Colonoscopy Screening study[32] found that African Americans had a higher risk of polyps larger than 9 mm (8% vs 6% among whites). This difference was especially pronounced in African American women compared with white women. African Americans older than 60 years are also more likely to have proximal colon adenomas, more likely to develop colorectal cancer (CRC) at a younger age, and may have a higher CRC-associated mortality rate.
Sex-related demographics
A meta-analysis of 17 studies including over 900,000 patients showed a pooled relative risk for advanced colonic neoplasia of 1.83 (95% confidence interval, 1.69-1.97) for men compared with women. The positive association between sex and advanced neoplasia was significant across all age groups from 40 years to older than 70 years.[33]
Age-related demographics
The prevalence of adenomas increases progressively with age. Adenomas are uncommon in people younger than 30 years unless associated with a significant family history or familial syndrome. Most studies suggest that sporadic adenoma prevalence begins to increase substantially in people aged 40-50 years and continues to increase through age 80 years.[30]
Almost all cases of colorectal cancer (CRC) arise from an adenoma; excision of adenomas reduces the incidence of CRC. Adherence to guidelines for screening and surveillance of adenomas is expected to substantially reduce the risk of developing colon cancer.
Mortality/Morbidity
Except for the rare adenoma that causes a clinically significant hemorrhage or obstruction, morbidity and mortality are primarily related to the carcinoma that can arise from an adenoma.
Complications
The primary complication associated with adenomas is the potential development of colorectal cancer. Less than 5% of all adenomas progress to cancer. The risk of progression to cancer rises with increasing size, villous component, and degree of dysplasia.
Complications of colonoscopy include perforation, bleeding and sedation-related complications. A diagnostic colonoscopy carries a complication risk of about 0.1%; polypectomy substantially increases the risk of complications to up to 0.2% for perforation and 1% for bleeding.
A sustained public awareness campaign emphasizing the importance of early detection of adenomas in the prevention of CRC has been supported by all major gastroenterology associations.
The patient must be aware that there is a 6% to 12% miss rate for adenomas that are 1 cm or larger; the miss rate for smaller adenomas is up to 25%. It is wise to include this information in the informed consent process.
Most adenomas are asymptomatic and are identified primarily by colorectal cancer (CRC) screening tests or by colonic imaging tests ordered for unrelated reasons.
The most common symptoms and signs, usually occurring from large adenomas, include the following:
Rectal bleeding, overt and occult
Change in bowel habits
Abdominal pain
Rectal prolapse
Occasional bowel obstruction from a large adenoma
Intussusception
A large villous adenoma causing profuse watery diarrhea (rare)
Most patients have no symptoms and adenomas are found during routine colon cancer screening.
Rarely, patients, primarily Ashkenazi Jews, may have hereditary mixed polyposis syndrome, in which duplication of a noncoding sequence near the gremlin 1, DAN family BMP antagonist gene (GREM1) occurs.[34] Clinical features include the presence of extracolonic tumors, onset of polyps in adolescence, and the rapid progression of some polyps to advanced adenomas.[34]
Physical examination
Physical examination findings are usually benign. A large rectal polyp or a flat adenoma can sometimes be detected on digital rectal examination.
2015 ACG guidelines on genetic testing and management of hereditary gastrointestinal cancer syndromes
The American College of Gastroenterology (ACG) released the following recommendations for the management of patients with hereditary gastrointestinal cancer syndromes—and they specifically discuss genetic testing and management of Lynch syndrome, familial adenomatous polyposis (FAP), attenuated familial adenomatous polyposis (AFAP), MUTYH-associated polyposis (MAP), Peutz-Jeghers syndrome, juvenile polyposis syndrome, Cowden syndrome, serrated (hyperplastic) polyposis syndrome, hereditary pancreatic cancer, and hereditary gastric cancer[35] :
The initial assessment is the collection of a family history of cancers and premalignant gastrointestinal conditions and should provide enough information to develop a preliminary determination of the risk of a familial predisposition to cancer.
Age at diagnosis and lineage (maternal and/or paternal) should be documented for all diagnoses, especially in first- and second-degree relatives.
When indicated, genetic testing for a germline mutation should be done on the most informative candidate(s) identified through the family history evaluation and/or tumor analysis to confirm a diagnosis and allow for predictive testing of at-risk relatives.
Genetic testing should be conducted in the context of pre- and post-test genetic counseling to ensure the patient's informed decision making.
Patients who meet clinical criteria for a syndrome as well as those with identified pathogenic germline mutations should receive appropriate surveillance measures in order to minimize their overall risk of developing syndrome-specific cancers.
Complete blood cell (CBC) count may be helpful because patients with an adenoma occasionally can present with a microcytic (iron deficiency) anemia due to chronic occult blood loss.
Iron studies may be needed because low serum iron and ferritin and an increased total iron-binding capacity (TIBC) can occasionally be observed as a result of blood loss in some patients with colonic adenomas and carcinomas.
Stool-based testing
Guaiac-based fecal occult blood testing (FOBT)
A small proportion of large adenomas may bleed intermittently. Depending on the age of the patients tested, 10% to 40% of asymptomatic patients with a positive result on a fecal occult blood test have an advanced adenoma. Three fresh, separate, nonhydrated stool specimens are used. FOBT screening programs are intended for the early detection of colorectal cancer (CRC) and have demonstrated decreased cancer-related and all-cause mortality.[36, 37, 38, 39]
Fecal immunochemical test (FIT)
Immunochemical testing for human globin has higher sensitivity for CRC and adenomas than traditional FOBT and is increasingly replacing guaiac-based tests as the recommended FOBT for CRC screening. In one study using 3 consecutive samples and a hemoglobin threshold of 75 ng/mL, sensitivity was 94.1% and specificity was 87.5% for cancer. Using the same testing parameters, sensitivity and specificity were 67% and 91.4%, respectively, for clinically significant neoplasia (advanced adenoma [defined as adenoma >1 cm or with villous features or high-grade dysplasia] and cancer).[40]
Many of the clinically available FITs recommend using only 1 test and a hemoglobin threshold of 100 ng/mL. This approach has been shown to still have a greater than 50% sensitivity for CRC and is associated with higher compliance than the 3-day guaiac-based testing regimens. Several issues should be considered when choosing a FIT regimen.
It is important to establish the relationship between a given quantity of hemoglobin detected in the stools and the pathology detected on colonoscopy in those with positive tests.
In CRC screening, different positivity thresholds need to be established for the immunochemical-based screening strategies. Depending on the threshold in terms of the amount of blood detected, the rates of adenoma and CRC detection vary. The positivity threshold influences the number needed to scope (NNS) to find a CRC or advanced adenoma by colonoscopy in an individual with positive FIT results.
Large differences exist in the diagnostic performance among various FITs, and the different test variances need to be carefully evaluated.
FITs increase the detection rates of advanced adenoma and CRC without generating an unacceptable number of false-positive results, which would lead to unnecessary colonoscopies.
A large, Dutch, population-based, randomized controlled trial has shown that FITs detected 2.5 times as many advanced adenomas and CRC compared with the guaiac-based FOBT, despite similar colonoscopy rates for positive screening tests. Thus, FITs appear to be superior to guaiac-based FOBTs for CRC screening.
Quantitative testing of stool for blood
This has been tried, but it does not appear to have a role for screening or diagnosis of colonic adenomas at this time.
Stool testing for genetic alterations
The analysis of fecal DNA represents an emerging area for early detection, and studies have reported 62% to 91% sensitivity for CRC and 26% to 73% sensitivity for adenomas, with a specificity ranging from 93% to 100%.[41, 42] The major drawback of current fecal DNA testing is the high cost and limited availability.
Fecal calprotectin and tumor M2-PK protein detection in stool
This test may also have better performance characteristics than guaiac-based FOBTs, but these newer tests also have low sensitivity and poor specificity.
Other biomarkers
Biomarkers in blood or urine for the detection of CRC and advanced neoplasia, such as measurement of septin 9 levels in blood and the urinary metabolite of prostaglandin E2, are being developed but are not yet ready for routine use.
Barium enema (BE) imaging can detect polyps and colorectal cancer (CRC). Air-contrast BE is more sensitive than the single-contrast technique for the detection of polyps. BE is included as an acceptable screening or surveillance test for colorectal cancer in the recommendations of the American Cancer Society and other organizations, but prospective controlled studies of its use in a screening program are lacking.
BE is generally regarded as less sensitive than colonoscopy in detecting adenomas smaller than 1 cm, and some studies indicate that it is not as accurate as colonoscopy for even larger lesions. As a result, BE is usually considered an alternative to colonoscopy for the evaluation of the entire colon.
The US Multi-Society Task Force (MSTF) offers double-contrast BE as an acceptable CRC screening tool; however, the US Preventive Services Task Force (USPSTF) does not.
This has emerged as a promising modality for the detection of adenomas and carcinomas of the colon. Thus far, computed tomography (CT) colonography has lower sensitivity than optical colonoscopy for small (<1 cm) adenomas, but the technology is improving rapidly. The advantages of virtual colonoscopy include the lack of need for sedation, the short commitment of time for the test, and its noninvasive nature. A positive test would need to be followed by a standard colonoscopy.
Most protocols still require cathartic bowel preparation, but CT colonography without bowel preparation may be possible in the future. The main disadvantages include cost, exposure to radiation, uncertainty in how to deal with extracolonic findings, and operator dependence.
The 2008 USPSTF guidelines state that there is insufficient evidence to support the use of CT colonography in routine polyp and CRC screening; however, the MSTF states CT colonography is an acceptable option.
Flexible sigmoidoscopy (FS) can be used to visualize the left colon, where over half of all colonic adenomas and cancers are located. If an adenoma is detected, a colonoscopy should then be performed. If no adenomas are detected, a repeat examination is not required for 5 years.
FS screening for average-risk patients is endorsed by all major society guidelines, including those by the US Multi-Society Task Force (MSTF) and the US Preventive Services Task Force (USPSTF). The Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial demonstrated a 26% reduction in overall colorectal cancer (CRC)–related mortality and a 21% reduction in CRC incidence with FS screening compared with standard care.[43]
The main advantages to FS include that is more widely available and less expensive than colonoscopy, has a lower risk than colonoscopy, does not require sedation, and requires a less rigorous bowel preparation (usually enema preparation alone is recommended).
The disadvantages of FS are that it does not visualize the entire colon, it can be more uncomfortable for patients since they are not sedated, and it is 2-step procedure (requires subsequent colonoscopy) if adenomas are found.
Despite its efficacy in decreasing CRC incidence and mortality, FS is diminishing as a screening tool in the United States. Critics liken FS to undertaking mammography on only one breast.
Colonoscopy
Although there are several polyp and CRC screening options, colonoscopic screening has emerged as the dominant screening strategy in the United States for average-risk patients.
Colonoscopy is the recommended screening modality for high-risk individuals, such as those with first-degree relatives with colorectal cancer/advanced adenomas, those with a hereditary colorectal cancer syndrome, and for surveillance of those with a personal history of adenomas or CRC.
Colonoscopy carries the conceptual advantage of being a 1-time test that can both visualize the entire colon and remove any adenomas in a single session. A colonoscopy can be performed at longer (10-year) intervals if no adenomas are found, and there is minimal patient discomfort since the patient is sedated during the examination.
Endoscopically, polyps can be classified as pedunculated (mucosal stalk interposed between the polyp and the colonic wall), sessile (entire base is attached to the colonic wall), flat (polyp height less than one half the diameter of the polyp) or depressed (polyps with depression into the colonic mucosal wall. See the following images.
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Endoscopic view of a pedunculated polyp.
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Endoscopic view of a sessile polyp.
Disadvantages
Disadvantages of colonoscopy are that it is an invasive examination with higher risk of complications than the other screening options (although low overall); it requires sedation; thus, patients would need to take time off work and would require a driver to and from the test. It requires a full bowel preparation and it is expensive. It is operator-dependent, and the quality of colonoscopy in the United States is highly variable. The procedure also can be time consuming. Furthermore, there is concern that the United States does not have enough trained endoscopists for all CRC screening-eligible patients to undergo high-quality colonoscopy as the primary screening tool. Complications associated with colonoscopy include perforation, bleeding, cardiopulmonary events related to sedation, and, rarely death.
Perforation rates vary depending on whether an intervention takes place (eg, polypectomy). Large database studies suggest rates ranging from 0.01% to 0.3%.[44] Risk factors for perforation during diagnostic colonoscopy include advanced age, presence of diverticulosis, female sex, and a history of pelvic/abdominal surgery.
Bleeding rates range from 0.1% to 0.6%.[44] Rates significantly depend on whether an intervention takes place (3.7 in 1000 for procedures without polypectomy and 8.7 in 1000 for procedures with polypectomy).
There is a 0.9% risk of a cardiopulmonary complication,[44] usually associated with sedation.
The complication of death is extremely low, ranging from 0.007% to 0.03%.[44]
Important considerations
No prospective randomized controlled trials available to date have demonstrated a beneficial effect of colonoscopy screening on CRC incidence or mortality. Despite this, colonoscopy is endorsed by all major society guidelines in the United States for CRC screening. The main support for the efficacy of colonoscopy lies in the conceptual advantage of visualizing the entire colon (compared to FS) and indirect evidence such as data from the National Polyp Study[3] that showed a 76% to 90% reduction in CRC incidence after polypectomy compared with historic controls. Efficacy can also be extrapolated from randomized trials examining other screening modalities such as FOBT, since a positive test triggered a subsequent colonoscopy.
More recent studies have called into question the efficacy of colonoscopy efficacy. Several large retrospective studies from Canada[5, 45] and the United States[46] have quantified the occurrence of CRC 6-36 months after reportedly a “negative” colonoscopy, ranging from 7.2% to 9% of all CRCs. In all of these studies, a significantly higher rate of postcolonoscopy CRC was seen in the right-sided compared with the left-sided colon (9.9% to 12.4% vs 4.5% to 6.8%). A German study reported that previous colonoscopy was associated with a 67% reduction in advanced neoplasia in the left-sided colon, but no risk reduction in the right-sided colon.[6] Multiple studies (tandem colonoscopy, CT colonography studies) have demonstrated considerable miss rates of colonoscopy ranging from 2% to 12% for large adenomas. These data have highlighted the importance of colonoscopy quality.
Even at centers of excellence, there is wide variability (3- to 5-fold) in adenoma detection rates between providers.[47] Colonoscopy quality measures have emerged, although they are not uniformly tracked. All of these measures are geared towards adequate examination of the colon.[48]
Colonoscopists or their institutions should develop a continuous quality improvement process to document quality assurance (eg, percentage of cases reaching the cecum, withdrawal time, polyp detection rate, adenoma detection rate, quality of bowel preparation).
A good bowel preparation is essential for adequate visualization of the colonic mucosa. A split-dosed bowel preparation (half of the volume the evening prior to the procedure, half of the volume on the morning of the procedure) is the preferred method of bowel cleansing and results in improved visualization of the colon during colonoscopy.
Withdrawal time is a widely accepted surrogate for colonoscopy quality and should be a minimum of 6 minutes according the American Society for Gastrointestinal Endoscopy. Colonoscopy reports should identify landmarks of the cecum as well as the colonoscopy withdrawal time.
The adenoma detection rate should be at least 25% among male patients and 15% among female patients undergoing screening colonoscopy. It is widely recognized, however, that these rates are likely well under the true adenoma prevalence rate and that higher thresholds may be considered in the future.
Three randomized controlled trials are currently under way to directly examine the efficacy of colonoscopy. The VA Colonoscopy Versus Fecal Immunochemical Test in Reducing Mortality From Colorectal Cancer (CONFIRM) trial and a Spanish trial are comparing colonoscopy with FIT, and the Nordic-European Initiative on Colorectal Cancer trial will compare colonoscopy with no screening.
Multiple screening options are available for colorectal polyps and colorectal cancer (CRC) in the average-risk patient, including stool-based tests (fecal occult blood test [FOBT], fecal immunochemical test [FIT]), imaging tests (barium enema [BE] imaging of the colon, computed tomography [CT] colonography), and endoscopic tests (flexible sigmoidoscopy [FS], colonoscopy).
FOBT and FS have been shown to decrease CRC-related mortality, but colonoscopy has emerged as the dominant screening modality in the United States because of its multiple conceptual advantages. Trials investigating colonoscopic screening are underway.
High-risk patients should undergo colonoscopic screening and surveillance.
Although colonoscopy is considered to be the criterion standard for screening for CRC by looking for adenomatous polyps, it is recognized that the miss rate for advanced adenomas and CRC with colonoscopy is sufficiently high to be of concern.
Average-risk individuals should begin screening at age 50 years.
Those at high risk have specific recommendations based on risk, such as the following:
Among persons with no colorectal neoplasia on initial screening colonoscopy, repeat screening is recommended in 10 years.
For those with 1-2 small adenomas (≤9 mm), repeat colonoscopy is recommended in 5-10 years.
For those with an adenoma larger than 1 cm, 3 or more adenomas of any size, or any adenoma with advanced histology (villous features, high-grade dysplasia), colonoscopy should be repeated in 3 years.
Adenomas are classified based on their size, architecture, and degree of dysplasia. Large size, villous content, and high-grade dysplasia in colorectal adenomas are all associated with a higher rate of finding a focus of colorectal cancer (CRC) within the adenoma. The term advanced adenoma is used for adenomas that are 1 cm or larger in diameter or have tubulovillous or villous histologic features or high-grade dysplasia.
Size
Most adenomas are small (1 cm) tend to have more severe dysplasia, more worrisome architecture, and increased risk of malignant potential. However, small (6-10 mm) and diminutive adenomas (≤5 mm) may have advanced histology or carcinoma, in up to 10.1% and 1.7%, respectively.
Architecture
Traditionally, adenomas are described as tubular, tubulovillous, or villous, primarily based on the overall percentage of villous component. Risk of malignancy increases with increased villous composition of the polyp.
Tubular adenomas are variously defined as those that contain 0% to 25% villous tissue. About 70% to 85% of all adenomas are tubular; they tend to be smaller than villous adenomas. See the image below.
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Tubular adenoma, low-power view. Courtesy of George H. Warren, MD.
Tubulovillous adenomas contain approximately 25% to 75% villous tissue. These adenomas represent 10% to 25% of all adenomas; they tend to be intermediate in size.
Villous adenomas contain more than 75% villous tissue. These adenomas represent 5% of all adenomas; they tend to be larger and have the greatest malignancy potential.
Dysplasia
Dysplasia is a neoplastic change in histology. All adenomas are dysplastic; they display varying degrees of hyperchromasia, nucleolar prominence, nuclear pleomorphism, and increased mitoses.
Dysplasia is classified as either low-grade or high-grade. High-grade dysplasia is associated with an increased risk of malignancy. Invasive carcinoma is distinguished from high-grade dysplasia by invasion of neoplastic tissue beyond the muscularis mucosa.
The histologic criteria used to differentiate low- and high-grade dysplasia are as follows:
Low-grade: Basal or stratified nuclei, crowded glands, less goblet cells and mucin (See the following image.)
High-grade: Loss of glandular architecture, increased mitoses (includes previously termed carcinoma in situ and intramucosal carcinoma) (See the image below.)
Excision and complete removal of adenomatous tissue during colonoscopy is considered the treatment of choice, and the goal of therapy is to decrease the risk for the development of colorectal cancer (CRC). Several techniques for polyp removal are used, including biopsy forceps and snare excision (with and without electrocautery), as well as simple fulguration and piecemeal excision of large polyps.
Chemoprevention—with sulindac, a nonsteroidal anti-inflammatory drug (NSAID)—has been shown to significantly reduce the number and size of adenomas in patients with familial adenomatous polyposis (FAP).[49, 50] The selective cyclooxygenase-2 (COX-2) inhibitor celecoxib has also been shown to cause modest regression of colonic adenomas in patients with FAP.[51] Although widely used, neither of these drugs is approved by the US Food and Drug Administration (FDA) for polyp prevention in FAP.
There has been a case report of chemoprevention with curcumin followed by silibinin significantly reducing the number of recurrent polyps in a middle-aged patient with multiple colorectal adenomatous polyps but without germline adenomatous polyposis coli (APC) or MYH gene mutations.[52] Another case report indicated a possible chemopreventive role for tacrolimus and mycophenolate mofetil; investigators noted complete reversion of FAP in a teenager carrier with a germline mutation in the APC gene who received a kidney transplant, followed by treatment with tacrolimus and mycophenolate mofetil.[53]
Several case-control and cohort studies indicate that the regular use of aspirin or other NSAIDs is associated with a lower rate of CRC and mortality. Several controlled trials have shown that aspirin and selective COX-2 inhibitors can decrease the rate of metachronous adenomas.[54] Owing to concerns about their adverse effects, NSAIDs are not currently recommended for either treatment or prevention of sporadic colonic adenomas in average-risk patients.
Flexible sigmoidoscopy and colonoscopy generally are outpatient procedures. Inpatient care rarely is required for the diagnosis and treatment of adenomas.
Surgical intervention is usually not required in the management of adenomatous polyps. Rarely, a large (>2 cm) sessile adenoma may not be amenable to endoscopic resection and may require surgery. Large rectal adenomas can be removed via intraoperative transanal resection. More proximal lesions may require laparoscopy or laparotomy with segmental colonic resection and evaluation of lymph nodes. For these lesions, it is important that the endoscopist mark the location of the polyp with a tattoo during colonoscopy prior to surgery.
In a retrospective study (2000-2014) that used data from the Healthcare Cost and Utilization Project National Inpatient Sample to evaluate rates of surgical resection for nonmalignant colorectal polyps in the age of endoscopy, Peery et al found an increased incidence from 5.9 per 100,000 adults in 2000 to 9.4 per 100,000 adults in 2014, in men and women across all races and ethnicities aged 20-79 years.[55] However, over the same period, the incidence of surgery for colorectal cancer decreased significantly (31.5 to 24.7 surgeries per 100,000 adults).
Most colonoscopy and polyp treatment is performed by gastroenterologists or colorectal surgeons who work closely with primary care physicians and pathologists to coordinate the diagnosis, treatment, and follow-up of adenomas.
Observational studies have suggested a link between dietary measures such as avoidance of red meat and alcohol or diets high in fruits and vegetables as measures to protect against the development of colorectal adenomas. These measures, however, have not been shown to prevent new adenomas in prospective randomized trials. The US Preventive Services Task Force (USPSTF) guidelines[7] acknowledge these data and do not recommend specific dietary measures for the prevention of colorectal adenomas. In contrast, the American Cancer Society has prudent lifestyle and dietary recommendations for cancer prevention.
The American Cancer Society (ACS) makes the following lifestyle and nutrition recommendations for general cancer prevention[24] :
Achieve and maintain a healthy weight throughout life.
Be as lean as possible throughout life without being underweight.
Avoid excess weight gain at all ages. For those who are currently overweight or obese, losing even a small amount of weight has health benefits and is a good place to start.
Engage in regular physical activity and limit the consumption of high-calorie foods and beverages as key strategies for maintaining a healthy weight.
Adopt a physically active lifestyle.
Adults should engage in at least 150 minutes of moderate-intensity or 75 minutes of vigorous-intensity activity each week, or an equivalent combination, preferably spread throughout the week.
Children and adolescents should engage in at least 1 hour of moderate or vigorous intensity activity each day, with vigorous intensity activity occurring at least 3 days each week.
Limit sedentary behavior such as sitting, lying down, watching television, or other forms of screen-based entertainment.
Doing some physical activity above the usual activities, no matter what one’s level of activity, can have many health benefits.
Consume a healthy diet, with an emphasis on plant foods.
Choose foods and beverages in amounts that help achieve and maintain a healthy weight.
Limit consumption of processed meat and red meat.
Eat at least 2.5 cups of vegetables and fruits each day.
Choose whole grains instead of refined grain products.
If you drink alcoholic beverages, limit consumption.
Drink no more than 1 drink per day for women or 2 per day for men.
Multiple epidemiologic studies suggest that obesity increases and regular physical activity decreases colorectal cancer (CRC) risk. No intervention studies have yet directly evaluated the relationship between obesity, physical activity, and adenoma or carcinoma risk, but avoiding obesity and maintaining regular physical activity are prudent recommendations for good health and they may affect CRC risk.
Observational epidemiologic studies have implicated several dietary factors as potentially modulating the prevalence of adenomas. Red meat has been associated with an increased risk, whereas consumption of fruits/vegetables and diets high in fiber has been associated with a decreased risk in some observational studies. These dietary factors have not been shown to alter the risk of adenomas in prospective studies. Thus, at this time, the US Preventive Services Task Force (USPSTF) does not recommend specific dietary measures in the prevention of colorectal adenomas, but prudent lifestyle and dietary recommendations have been made by the American Cancer Society (ACS) (see Diet).
Antioxidant supplements do not have a significant beneficial effect on the primary or secondary prevention of adenoma.
Growing evidence suggests a protective role for aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) against the development of colorectal cancer; however, there is ongoing concern about the risk of these medications. At this time, chemoprevention is not recommended for individuals without hereditary cancer syndromes. There is a role for the use of sulindac and celecoxib in the management of familial adenomatous polyposis (FAP).
Smoking tobacco increases the risk of adenomatous polyps and colorectal cancer (CRC). Patients should be encouraged to quit smoking.
The interval between colonoscopy depends on the size, number, and histological type of polyp, as well as the patient's family history. Polyp recurrence rates are approximately 20% at 5 years and around 50% at 15 years, with even higher recurrence rates in patients with multiple index polyps. Polyps may be missed at the index colonoscopy, and the presence of a polyp when colonoscopy is repeated at 1 year is about 33%.
For those with no adenomas on colonoscopy, repeat screening is recommended in 10 years. For those with 1-2 small adenomas (≤9 mm), repeat colonoscopy is recommended in 5-10 years. For those with an adenoma larger than 1 cm, 3 or more adenomas of any size, or an adenoma with advanced histology (villous features, high-grade dysplasia), colonoscopy should be repeated in 3 years.
In a multicenter, longitudinal, observational study in 15 colorectal cancer (CRC) high-risk clinics in Spain, investigators studied the risk of developing CRC or the need for surgery during endoscopic surveillance in a cohort of patients with multiple (10-100) colorectal polyps. A total of 265 patients were followed for a median of 3.8 years, and patients underwent a median of 5 colonoscopies. More than 10% of patients required colorectal surgery within 4 years, more than half of which was for incident CRC.[56]
Colonoscopy should be repeated within 6 months if the mucosa was not adequately visualized (poor bowel preparation, incomplete colonoscopy) or if a high-risk lesion was removed (large polyp, piecemeal resection) to ensure that the entire polyp has been removed.
In a retrospective study (2002-2007) of outpatient screening and surveillance colonoscopies over a span of 5 years, Murphy et al compared next-day versus any other day ("non-next-day") repeat colonoscopy outcomes. They found a substantial increase in adenoma detection on follow-up, confirming the need for repeat examination after a colonoscopy with inadequate bowel preparation. Investigators found no differences in outcomes between next-day and non-next-day colonoscopy, supporting the view that inadequate colonoscopy should be repeated within 1 year as convenient for the patient and physician.[57]
In another retrospective study (1982-2014), investigators evaluated severity scoring for surveillance and treatment in 437 patients with duodenal polyposis who underwent 1912 upper gastrointestinal endoscopies and found that not only did over 20% of patients develop high-grade dysplasia after 10 years but surgical remained necessary in 12% of patients despite iterative endoscopic resections, with many occurring too late (20% who underwent surgery had developed duodenal or ampulary adenocarcinoma and 8% displayed malignancy with lymph node involvement).[58] The investigators indicated that in high-risk patients, more accurate predictive scoring by accounting for ampullary anomalies may increase compliance with closer endoscopic surveillance.
Patients diagnosed with adenomas who are not properly followed with surveillance of a repeat colonoscopy have an increased risk of developing metachronous adenomas and/or colorectal cancer. Whatever the interval recommended for repeat colonoscopy, the patient must be cautioned to report any new bowel symptoms or bleeding, because of the concern that new pathology may have developed in the interim.
Clinical Context:
Sulindac is a sulfoxide that is metabolized to the anti-inflammatory sulfide metabolite and a sulfone metabolite. Both metabolites are known to have apoptotic activity on the colonic epithelial cells, but whether this is required for the chemoregressive activity of these drugs is not known. It has multiple systemic effects, including analgesia, antipyretic, and anti-inflammatory, mostly mediated by the inhibition of prostaglandin synthesis.
Clinical Context:
Celecoxib inhibits primarily COX-2. COX-2 is considered an inducible isoenzyme, induced during pain and inflammatory stimuli. Inhibition of COX-1 may contribute to NSAID GI toxicity. At therapeutic concentrations, COX-1 isoenzyme is not inhibited, thus GI toxicity may be decreased. It has multiple systemic effects, including analgesia, antipyretic, and anti-inflammatory, mostly mediated by the selective inhibition of prostaglandin synthesis.
Growing evidence suggests a protective role for NSAIDs against the development of colorectal cancer. In addition, a significant effect in reversing adenoma growth has been illustrated with the use of sulindac and celecoxib in patients with familial adenomatous polyposis (FAP). Aspirin may also be useful to reduce the recurrence of polyps or cancer, but because of the potential for these drugs to cause damage to the upper gastrointestinal tract, they are not routinely recommended for this purpose. The mechanism of NSAID-induced polyp regression is not known, but it is thought that it is at least in part due to inhibition of cyclooxygenase 2 (COX-2) and the resultant decrease in prostaglandin synthesis, although non-COX mechanism may also contribute.
Swati G Patel, MD, MS, Clinical Lecturer of Internal Medicine, Division of Gastroenterology, University of Michigan Health System; Staff Physician, Ann Arbor VA Medical Center
Disclosure: Nothing to disclose.
Coauthor(s)
Dennis J Ahnen, MD, Professor of Medicine, Divisions of Gastroenterology/Medical Oncology, University of Colorado Health Science Center; Consulting Staff, Chief, Gastroenterology Section, Department of Medicine, Veteran's Affairs Medical Center of Denver
Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Cancer Prevention Pharmaceuticals<br/>Serve(d) as a speaker or a member of a speakers bureau for: Ambry Genetics.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Douglas M Heuman, MD, FACP, FACG, AGAF, Chief of Hepatology, Hunter Holmes McGuire Department of Veterans Affairs Medical Center; Professor, Department of Internal Medicine, Division of Gastroenterology, Virginia Commonwealth University School of Medicine
Disclosure: Received grant/research funds from Novartis for other; Received grant/research funds from Bayer for other; Received grant/research funds from Otsuka for none; Received grant/research funds from Bristol Myers Squibb for other; Received none from Scynexis for none; Received grant/research funds from Salix for other; Received grant/research funds from MannKind for other.
Chief Editor
BS Anand, MD, Professor, Department of Internal Medicine, Division of Gastroenterology, Baylor College of Medicine
Disclosure: Nothing to disclose.
Additional Contributors
Rajeev Vasudeva, MD, Clinical Professor of Medicine, Consultants in Gastroenterology, University of South Carolina School of Medicine
Disclosure: Received honoraria from Pricara for speaking and teaching; Received consulting fee from UCB for consulting.
Acknowledgements
John Riopelle, DO Fellow, Department of Medicine, Division of Gastroenterology/Hepatology, University of Colorado Health Sciences Center
Disclosure: Nothing to disclose.
Alan BR Thomson, MD Professor of Medicine, Division of Gastroenterology, University of Alberta, Canada
Alan BR Thomson, MD is a member of the following medical societies: Alberta Medical Association, American College of Gastroenterology, American Gastroenterological Association, Canadian Association of Gastroenterology, Canadian Medical Association, College of Physicians and Surgeons of Alberta, and Royal College of Physicians and Surgeons of Canada
Martinez ME, Marshall JR et al. Colorectal cancer: environmental and lifestyle issues. Kelsen DP, Daly JM, Kern SE, Levin B, Tepper JE, eds. Gastrointestinal Oncology: Principles and Practices. Philadelphia: Lippincott Williams and Wilkins; 2002. 665-83.
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