Etiology
The causes of the development of colorectal carcinoma and its precursor lesion, the colonic adenoma, are multifactorial and include both genetic predisposition and environmental insults. Risk factors for colorectal carcinoma include familial polyposis syndrome, ulcerative colitis, family history of colorectal cancer, age, male gender, smoking, alcohol intake, and obesity.
Prevalence and Epidemiology
Colon cancer is the third most commonly diagnosed cancer and third most common cause of cancer-related death in both men and women. It is responsible for 10% of new cancer cases and 9% of cancer-related deaths annually in the United States, representing an estimated 146,970 new cases and 24,680 deaths each year. The lifetime risk for developing colorectal carcinoma is 5.5% in men and 5.1% in women. Winawer and associates demonstrated a marked reduction in colorectal carcinoma incidence after colonoscopic polypectomy, indicating that screening techniques are essential in the prevention and early detection of colorectal carcinoma.
Prevalence and Epidemiology
Colon cancer is the third most commonly diagnosed cancer and third most common cause of cancer-related death in both men and women. It is responsible for 10% of new cancer cases and 9% of cancer-related deaths annually in the United States, representing an estimated 146,970 new cases and 24,680 deaths each year. The lifetime risk for developing colorectal carcinoma is 5.5% in men and 5.1% in women. Winawer and associates demonstrated a marked reduction in colorectal carcinoma incidence after colonoscopic polypectomy, indicating that screening techniques are essential in the prevention and early detection of colorectal carcinoma.
Clinical Presentation
The clinical manifestation of colorectal cancer includes blood in the stool, change in bowel habits, bowel obstruction, bowel perforation, abdominal pain, diminished appetite, or systemic symptoms such as generalized fatigue and weight loss. However, colorectal carcinoma is often detected in asymptomatic patients at screening.
The late presentation of colon cancer includes symptoms related to metastatic disease. Colon cancer spreads hematogenously most commonly to the liver and lungs and via lymphatics to regional lymph nodes.
Laboratory findings can include microcytic anemia related to blood loss and elevation of the carcinoembryonic antigen tumor marker.
Pathophysiology and Pathology
Histologic Findings of Colonic Polyps
Colonic polyps are growths into the bowel lumen and can develop as isolated polyps or in the setting of polyposis syndromes. Isolated colonic polyps of all sizes are seen in approximately 37.6% of the screening population, whereas potentially clinically significant polyps 6 mm or greater have a prevalence of 14%. Polyps are histologically characterized as adenomatous, hyperplastic, and other. The “other” category includes juvenile/hamartomatous polyps, inflammatory polyps, lymphoid aggregates, mucosal tags, and submucosal lipomas.
Of all the types of polyps, only adenomatous polyps are of concern with respect to colon cancer. The adenoma is a precursor lesion that can potentially harbor dysplasia and develop into colon cancer; this prevailing view on the pathogenesis of colon cancer is called the adenoma-carcinoma sequence (see later discussion).
Adenomas are further characterized into three subtypes based on their histologic architecture: tubular, tubulovillous, and villous. Adenomas containing less than 25% villous features are classified as tubular adenomas; those with 25% to 75% villous features are tubulovillous adenomas; and those with more than 75% villous features are villous adenomas.
Adenomas also can be characterized based on the degree of cellular atypia seen on pathology (mild, moderate, or severe dysplasia), depending on the amount of nuclear changes and number of mitotic figures.
With imaging studies and/or colonoscopy as screening tools, the radiologist and gastroenterologist cannot visually distinguish among the different types of polyps (with the exception of lipomas), nor can they determine the histologic factors or degree of cellular atypia of an adenoma. Thus, generally all encountered polyps seen on colonoscopy and those meeting a certain size threshold on noninvasive studies such as computed tomography (CT) colonography are removed.
Location of Adenomas
Adenomas can develop anywhere in the colon or rectum but are seen with the greatest frequency in the sigmoid colon. In a recent colonoscopy/CT colonography series, the distribution of adenomas and carcinomas was rectal, 13.4%; sigmoid colon, 25.1%; descending colon, 10.7%; transverse colon, 18.4%; ascending colon, 19.8%; and cecum, 12.6%.
Adenoma-Carcinoma Sequence
The currently accepted evolution of colon cancer is via the adenoma-carcinoma sequence, a name first coined by Jackman and Mayo in 1951 and further developed and refined by pathologists, including Morson, Muto, and Bussey.
The model for progression from normal epithelium to adenoma to carcinoma is a series of genetic mutations. Colonic neoplasms are thought to arise as a result of mutational activation of oncogenes ( RAS gene on chromosome 12p) coupled with the mutational inactivation or loss of tumor suppression genes (familial adenomatous polyposis gene on chromosome 5q, TP53 gene on chromosome 17p, and DCC gene on chromosome 18q). These mutations act at a number of steps in the progression from normal epithelium to hyperproliferative epithelium to early, intermediate, and late adenoma and, finally, to carcinoma.
The degree of dysplasia is highly correlated with the risk for malignancy because on a genetic and cellular level increasing atypia leads to a stepwise progression toward carcinoma. The presence of high-grade dysplasia is therefore the best predictor of which adenomas will progress to carcinomas.
There is a close relationship between the size of an adenoma and its propensity to harbor malignancy. In a colonoscopy series of a nonscreening population, the rate of carcinoma in adenomas greater than 2 cm was 19.4%, whereas that in adenomas less than 1 cm was 0.07%. In an older surgical series, the rate of carcinoma in adenomas larger than 2 cm was 46% whereas that in adenomas smaller than 1 cm was 1.3%.
Accordingly, adenoma size is correlated with the degree of cellular dysplasia. Some authors have also proposed a direct relationship between increasing the villous component seen on histologic examination and the degree of dysplasia. As a result, the degree of dysplasia, adenoma size, and histologic characteristics are used as markers for malignancy risk in removed polyps.
Advanced Adenoma
Screening studies should be targeted toward the removal of adenomas that have the highest potential for developing into colorectal carcinoma. These “advanced adenomas” have traditionally been defined by any of the following three criteria: high-grade dysplasia, size 1 cm or greater, or a substantial (>25%) villous component (i.e., tubulovillous or villous adenomas). These lesions are at high risk for developing into colorectal carcinomas compared with their less-advanced counterparts. In an asymptomatic screening population, the overall prevalence of an advanced adenoma or carcinoma (collectively termed advanced neoplasia ) is 3.3%.
Multiple Adenomas
Patients who have an adenoma, advanced or otherwise, detected on a screening study are more likely to have additional adenomas detected on the same examination (synchronous) or on future examinations (metachronous). The presence of multiple adenomas (two or more) has been shown to confer an increased risk for developing an advanced adenoma on subsequent follow-up studies. Therefore, the factors that inform our current screening guidelines include adenoma size, histologic features (i.e., presence of villous component), cellular features (i.e., degree of dysplasia), and total number.
Screening
Theory of Screening and Cost-Benefit Analysis
The goal of any cancer screening, including colon cancer screening, is to achieve a reduction in mortality by identifying disease at earlier stages and thus reducing the incidence of advanced disease.
The 5-year survival is 90% for disease confined to the wall of the bowel; however, it falls to 68% for regional disease and plummets to 10% for metastatic disease. It thus becomes clear that if cancer can be caught at earlier stages, mortality from the disease will be drastically reduced. In fact, prospective randomized trials and observational studies have demonstrated a reduction in mortality by detection of invasive disease and subsequent therapy.
The American Cancer Society first issued formal guidelines for colorectal screening in 1980, followed by guidelines from the U.S. Preventive Services Task Force, the American College of Radiology, and the U.S. Multi-Society Task Force on Colorectal Cancer. Although there are differences among the guidelines, there is growing consensus, with the latest iteration being a collaborative effort by all of these groups. The recommendations include continued support of the fecal occult blood test (FOBT) as well as the fecal immunohistochemical test (FIT) and stool DNA testing, assuming a patient is willing to undergo an invasive procedure in the instance of a positive test. The recommendations prefer tests that detect lesions earlier, including optical colonoscopy (OC) every 10 years or flexible sigmoidoscopy (FSIG), CT colonography (CTC), or double-contrast barium enema (DCBE) every 5 years.
The clinical effectiveness of screening is often assessed in terms of life-years gained. A measure of this is the incremental cost-effectiveness ratio (ICER), defined as the difference in cost among strategies divided by the difference in life expectancy among those strategies. Although controversial, an ICER threshold of $50,000 per life-year gained is often used to differentiate a relatively efficient procedure from an inefficient procedure. Pickhardt and colleagues compared CTC and OC screening strategies for a population of 100,000 and found a nonscreening cumulative loss of 29,925 life-years from colorectal cancer. Five-year CTC demonstrated a gain of 6250 life-years as a result of colorectal cancer prevention and early treatment, and 10-year OC demonstrated a gain of 6032 life years. If CTC is reduced to a 10-year interval, the life-years gained is 5518. CTC also identified aortic aneurysms, saving an additional 1536 life-years, for a total of 7786 years of life saved. Compared with no screening, 10-year screening protocols cost just over $1000 per year of life saved, yielding a remarkable cost-benefit ratio.
Screening Modalities
Fecal Occult Blood Test and Other Stool-Based Examinations
Theory.
The principle behind the FOBT and other stool-based examinations is that invasive carcinoma will cause bleeding, which can detected using methods such as guaiac staining, immunohistochemistry, and DNA. Small polyps tend not to bleed, and larger lesions tend to bleed intermittently. As a result, these tests are subject to sampling error and are more likely to detect cancer rather than precancerous lesions.
Benefit.
FOBT is supported by randomized controlled studies, which demonstrate that its use leads to cancers being detected at an earlier and more curable stage compared with no screening, leading to reductions in colorectal cancer mortality of 15% to 33%.
Limitations.
The limitations of stool testing include the necessity for annual testing, low individual test sensitivity, and the need to follow any positive test with an invasive test. Furthermore, the sensitivity is highly variable and depends on hydration status of the feces, brand and style of the test, as well as chosen target lesion (i.e., adenoma versus carcinoma). As mentioned earlier, small polyps are unlikely to bleed; thus, sensitivity for these tests is very low, and FOBT is useful only for detecting advanced adenomas and cancers, with a sensitivity ranging from 37.1% to 79.4% when used correctly. Many physicians use an in-office FOBT examination that has a sensitivity of only 4.9% for advanced adenoma and 9% for cancer.
Recommendation.
Given the limited availability of all screening modalities for the entire population, the Multi-Society Task Force continues to recommend properly performed stool testing as one alternative screening methodology.
Flexible Sigmoidoscopy
Theory.
FSIG is an optical endoscopic procedure that examines the most distal portion of the colon lumen. It is most often performed with a 60-cm endoscope but also can be performed with a variety of alternative scopes.
Benefits.
FSIG was associated with a 60% to 80% reduction in colorectal cancer mortality for the area of colon within its reach. Overall decreased incidence compared with an unscreened group also has been demonstrated. Its principal advantages over colonoscopy are that it requires a less extensive bowel preparation than a full colonic examination, and because it is less invasive than colonoscopy, sedation is not required. It also allows for concurrent sampling and/or removal of detected lesions.
Limitations.
Like colonoscopy, FSIG can be complicated by patient discomfort and, more importantly, bowel perforation. Its greatest limitation, however, is its failure to evaluate the entire colon. Defenders of FSIG note that many people who have a proximal lesion will also have a distal lesion that would be detected on FSIG; thus, the incremental benefit of colonoscopy or colonography over FSIG is less pronounced. Finally, there is substantial variation in the depth of insertion of the scope given the lack of sedation, and insufficient insertion leads to inadequate examination.
Recommendation.
The Multi-Society Task Force continues to recommend FSIG every 5 years up to a distance of 40 cm within the colon.
Double-Contrast Barium Enema
Theory.
DCBE is a fluoroscopic examination executed by coating the mucosa with barium and distending the colon with air insufflated through a tube inserted in the rectum. Multiple images are obtained both fluoroscopically as well as by overhead method.
Benefits.
DCBE evaluates the entire colon and detects most cancers and the majority of significant polyps. Sensitivity for cancer has been shown to vary from 85% to 97%. In a meta-analysis, DCBE was 70% sensitive and 71% specific for polyps 10 mm or larger. When performed properly, the examination can be completed with minimal discomfort.
Limitations.
Because it is an imaging examination, DCBE does not permit tissue biopsy. No randomized controlled studies have been performed to evaluate its efficacy, and the studies that have been done are predominately retrospective. The differential in results highlights the operator dependency of the examination. With the advent of CT colonography and increased use of colonoscopy, fewer DCBE examinations are performed annually and, consequently, radiologists currently in training will have less experience with DCBE than their predecessors.
Recommendation.
Although controversy remains, DCBE every 5 years continues to be recommended by some as an acceptable screening methodology in asymptomatic, average-risk populations 50 years and older.
Colonoscopy
Theory.
Colonoscopy is an optical procedure that evaluates the entire colon. It is one of the most commonly performed medical procedures. Patients require an extensive colonic cleansing preparation, and the procedure is performed under sedation. Because it allows for direct optical visualization, biopsies are often performed.
Benefits.
The greatest advantage to colonoscopy is that usually the entire colon can be screened and suspicious lesions sampled in a single visit. The seminal paper by Winawer and colleagues demonstrated a reduction in incidence of colon cancer of 76% to 90%. Although no prospective randomized controlled trial has been performed to evaluate colonoscopy, its health benefits are undisputed. A U.S. Department of Veterans* Affairs study demonstrated a 50% reduction in mortality when colonoscopy was performed on a symptomatic population. Numerous additional cohort studies have demonstrated reductions in colorectal carcinoma incidence and mortality. Multiple additional studies by Winawer and colleagues have reinforced these benefits.
Limitations.
The limitations of colonoscopy include the need for colon cleansing and patient sedation. Because of sedation, a patient chaperone is needed. Controlled studies have shown the colonoscopy miss rate for adenomas 10 mm or larger to be 6% to 12%. The additional risks of colonoscopy related to sedation and biopsy include cardiopulmonary events such as arrhythmia and hypotension as well as postpolypectomy bleeding and perforation.
Recommendation.
Colonoscopy every 10 years beginning at age 50 is recommended as a screening option for colorectal cancer.
Computed Tomography Colonography
Theory.
CTC is a minimally invasive examination that uses CT to acquire images of the colon and two-dimensional and three-dimensional displays for interpretation. The mechanism and technique are explained in detail elsewhere in this book.
Benefits.
CTC evaluates the entire colon, including those segments that are particularly redundant and difficult to evaluate with colonoscopy. Additionally, the examination can be performed without sedation. The examination also can detect extracolonic findings. In one study, 9% of the total patients had clinically important extracolonic findings. Meta-analysis of 33 studies on nearly 6400 patients demonstrated an 85% to 93% sensitivity and 97% specificity for polyps 10 mm and larger. The 96% sensitivity of CTC for invasive cancer was comparable to that of optical colonoscopy.
Limitations.
One of the greatest limitations of CTC is its availability. Because funding is not widely available for screening CTC, the professional capacity is markedly limited. CTC requires a cathartic bowel preparation, although studies are underway to eliminate this need. The most notable limitation is that CTC is an imaging study only, and patients must be referred to optical colonoscopy for biopsy and/or removal if a significant colonic lesion is encountered. However, Pickhardt and colleagues demonstrated a coordinated approach with gastroenterology that allows for same-day colonoscopy and biopsy in instances of positive CTC findings.
Recommendation.
CTC every 5 years for patients older than 50 years of age is an acceptable screening option for colorectal cancer.
Recommendation
An overall recommendation given the multiple methodologies of screening is challenging. The U.S. Multi-Society Task Force leaned heavily toward screening tests that could prevent cancer rather than simply detect it at a later stage and thus implied a preference away from stool testing and toward direct mucosal evaluation. At this time there is insufficient capacity to screen the entire population using any one modality. Given this, and the fact that patients have shown varied preferences for the screening tests, the goal is to encourage screening using any modality with which a patient is willing to comply, with preference for those modalities that evaluate the entire colonic mucosa ( Table 33-1 ).
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