Relevant Physiology and Pathophysiology

Epidemiology and Incidence. A striking feature of colonic cancer is its geographic variation in incidence. The disease seems to occur primarily in industrialized Western countries. In the United States, about 134,000 new cases of colorectal cancer were diagnosed in 1996. Studies of migrant populations have shown fascinating changes in the incidence of colonic carcinoma. For example, in Japan the incidence of colonic cancer is increasing but remains relatively low. In Japanese families who have emigrated to the United States, however, within one generation colonic cancer occurs at a rate similar to that in the general American population.

Carcinogenesis and Its Inhibition. Diets high in fat and refined carbohydrate and low in plant fiber, more typical in the industrialized West, have been implicated in higher colonic cancer rates. There is some data to suggest that low-dose aspirin and other nonsteroidal antiinflammatory drugs may decrease colon cancer risk. At least 20 different classes of chemicals, some of which occur naturally in food (e.g., calcium), seem to have a protective effect against colon cancer in laboratory models.

Although the effects of environment continue to be studied and debated, genetic susceptibility to colonic cancer has become better defined. In certain groups hereditary colonic cancer risk has been clearly established. In the hereditary polyposis syndromes, particularly in familial adenomatous polyposis and in Gardner’s syndrome, the risk is very high. These diseases, accounting for about 1% of colorectal cancer cases, are inherited as autosomal dominants with high penetrance.

Familial polyposis coli is characterized by the growth of numerous adenomatous polyps in the colon, most markedly in the distal colon. The polyps frequently begin in childhood and increase in number with the patient’s age. The colon may become carpeted with adenomas. Gardner’s syndrome is characterized by multiple soft tissue tumors, fibromas, and osteomas, as well as colonic adenomas. In every patient with familial polyposis coli or Gardner’s syndrome a colonic carcinoma will develop, with risk increasing as the patient becomes older. Other syndromes involving colonic polyposis and increased cancer risk include Turcot’s syndrome, in which patients may have gliomas and medulloblastomas, and Oldfield’s syndrome, in which patients have multiple sebaceous cysts. In the Peutz-Jeghers syndrome, characterized by abnormal pigmentation of the skin and mucous membranes and gastrointestinal hamartomas, there is a small increased risk of colonic adenocarcinoma.

Families have been identified with a marked hereditary increased risk of colonic carcinoma without florid polyposis, which has been called hereditary nonpolyposis colorectal cancer (HNPCC). HNPCC accounts for about 5% of new colorectal cancer cases. Two groups have been recognized. In Lynch syndrome I, cancers occur at an earlier age on average than sporadic colon cancers and are site specific to the colon. In Lynch syndrome II, patients have an additional susceptibility to other forms of cancer, particularly of the endometrium and ovaries. These syndromes are dominantly inherited and are characterized by the occurrence of small “flat adenomas” in the ascending colon. The “Amsterdam criteria” set the strictest standard for diagnosis of HNPCC: (1) three or more relatives with colorectal cancer; (2) at least one a first-degree relative of the other two; (3) diagnosis in one or more relatives before age 50; and (4) colorectal cancer involving at least two generations.

The actual gene responsible for familial adenomatous polyposis and variants including Gardner’s syndrome and Turcot’s syndrome has been identified on the long arm of chromosome 5 and sequenced (APC gene). In HNPCC, mutations in four genes on chromosomes 2, 3, and 7 are associated with 70% to 80% of cases.

Premalignant States. Patients with adenomatous polyps, especially villous adenomas, are considered at higher risk for colonic cancer. Evidence is mounting that there is a common sequence from adenoma to carcinoma. Invasive cancer has frequently been found in adenomatous tissue. Adenomas in patients with familial polyposis are similar to those in patients with single polyps. Several cases have been reported in which patients refused surgery for polyps that were subsequently observed over a period of years to become malignant. About one third of operative specimens from patients with colonic cancer also contain one or more adenomas.

A prior adenoma or colorectal cancer puts an individual at higher risk for subsequent colorectal neoplasia. On the other hand, colon adenomas are common, occurring in about 25% of patients over 50 years and increasing with age. Few adenomas progress to cancer, with an estimated incidence of only 2.5 polyps per 1000 per year. Progression from normal mucosa to adenoma seems related to a series of genetic abnormalities acquired after birth. Further abnormalities in both oncogenes and tumor suppressor genes result in further degeneration to carcinoma. A diminutive polyp takes an estimated average of 10 years to develop into an invasive carcinoma. About 75% of new cases of colorectal cancer occur in individuals with no known predisposing factors.

With increasing size, polyps tend to show increasing villous change and increasing dysplasia. An exception are some small colorectal flat adenomas reported most often from Japan, which seem to develop dysplasia and carcinoma in spite of their small size. Precancerous dysplastic changes have been described in the colonic mucosa of patients with long-standing ulcerative colitis and Crohn’s disease, who have an increased risk of colonic cancer.

In patients with colonic adenomas and carcinomas the zone of cell proliferation at the base of the colonic crypts has been shown to expand upward. Cells continue to show evidence of deoxyribonucleic acid (DNA) synthesis and other evidence of immature cellular structure and function at the mucosal surface. Such changes have also been found in patients with inflammatory bowel disease.

The incidence of colonic carcinoma is nearly the same in men and women, although incidence of rectal cancer is slightly higher in men and overall incidence is slightly higher in women. Colonic cancer before age 40 is uncommon and suggests possible familial disease. The mean age at diagnosis is about 65 years.

The location of cancers in the colon appears to be changing. Two decades ago about two thirds of colonic cancers were reported to occur in the distal 25 cm of the rectosigmoid. More recently this proportion has decreased to one half or less of colonic cancers.

Most colonic adenocarcinomas form hard, nodular areas that grow irregularly. They may be polypoid and fungate and ulcerate, producing exophytic, bulky masses, or they may infiltrate around the bowel lumen, causing the classic “napkin-ring” lesion. Histologically, colonic cancers may vary from well-differentiated cells that appear normal (grade I) to highly anaplastic cells (grade IV) and may contain a variable amount of mucin. Colonic cancers, which produce intracellular mucin (signet-ring type), tend to be particularly aggressive. The pathologic staging of colonic cancer is based on depth of invasion and absence or presence of lymph node or distant metastases. The Dukes’ staging system is most widely used, but there is increasing acceptance of the TNM (tumor, node, metastasis) system proposed by the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC).

Only about 1% of colon malignancies are not adenocarcinomas. The most common of these are the lymphomas, primarily the diffuse histiocytic type. More common in immunosuppressed patients, such as those with HIV disease, these usually occur in either the cecal or the rectal areas. If polypoid, lymphomas may be impossible to distinguish grossly from adenocarcinomas. They may also infiltrate diffusely, producing a nodular, thickened bowel wall with ulcerations. Although less common, sarcomas may occur in the wall of the colon and resemble in behavior those found in the stomach and small intestine.