Colon Cancer and Screening Strategies

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.

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.