Porth's Essentials of Pathophysiology, 4e

720

Gastrointestinal and Hepatobiliary Function

U N I T 8

Benign colonic neoplasms

Tubular adenoma

Villous adenoma

Progressive proliferative abnormality

Normal

Initial proliferative abnormality

Colonic crypt

5%

40%

Invasive adenocarcinoma

Invasive adenocarcinoma

FIGURE 29-13. The histogenesis of adenomatous polyps of the colon.The initial proliferative abnormality of the colonic mucosa, the extension of the mitotic zone in the crypts, leads to accumulation of mucosal cells.The formation of adenomas may reflect epithelial–mesenchymal interactions. (From Rubin R.The gastrointestinal tract. In: Rubin R, Strayer DS, eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine. 6th ed. Philadelphia, PA: Wolters Kluwer Health | Lippincott Williams &Wilkins; 2012:663.)

thirds of the crypts, after which they mature, migrate to the surface, and become senescent. They then become apoptotic and are shed from the surface. 7 Adenomas arise from a disruption in this sequence, such that the epithelial cells retain their proliferative ability through- out the entire length of the crypt. Aberrations in cell differentiation can lead to dysplasia and progress to the development of invasive adenocarcinoma. Colorectal Cancer Adenocarcinoma of the colon is the most common malig- nancy of the gastrointestinal tract and is the major cause of morbidity and mortality worldwide. 6,7,58–60 It affects approximately 150,000 Americans annually, approxi- mately one third of whom die. 58 It affects approximately 250,000 persons annually in Europe and approximately 1 million persons worldwide. Epidemiology. The incidence of colorectal cancer peaks at 60 to 70 years of age, and fewer than 20% of cases occur before age 50. 7 Its incidence is increased among persons with a family history of cancer, persons with Crohn disease or ulcerative colitis, and those with familial adenomatous polyposis of the colon. Persons with a familial risk—those who have two or more first- or second-degree relatives (or both) with colorec- tal cancer—make up approximately 20% of all persons with colorectal cancer. 61 Familial adenomatous polyposis is a rare autosomal dominant trait linked to a mutation in the long arm of chromosome 5. Persons with the disor- der develop multiple adenomatous polyps of the colon at an early age. 7 Carcinoma of the colon is inevitable, often by 40 years of age, unless a total colectomy is performed. Diet also is thought to play a role. 7 Attention has focused on dietary fat intake, refined sugar intake, fiber intake, and the adequacy of such protective

micronutrients as vitamins A, C, and E in the diet. It has been hypothesized that a high level of fat in the diet increases the synthesis of bile acids in the liver, which may be converted to potential carcinogens by the bacte- rial flora in the colon. The proliferation of colonic bacte- ria is enhanced by a high dietary level of refined sugars. Dietary fiber is thought to increase stool bulk and thereby dilute and remove potential carcinogens. Refined diets often contain reduced amounts of vitamins A, C, and E, which may act as oxygen free radical scavengers. In addition to dietary modification, pharmacologic chemoprevention has become an area of great interest. Several studies indicate that aspirin or other NSAIDs may protect against colorectal cancer. 62 An analysis of the incidence of colorectal cancer in the Nurses’ Health Study showed a decreased incidence of colorectal cancer among women who took four to six aspirins per week. Although the mechanism of aspirin’s action is unknown, it may be related to its effect on the synthesis of pros- taglandins, one or more of which may be involved in signal systems that influence cell proliferation or tumor growth. Aspirin inhibits cyclooxygenase, the enzyme that catalyzes the conversion of arachidonic acid in cell membranes to prostaglandins. One form of cyclooxy- genase, COX-2, promotes inflammation and cell pro- liferation, and colorectal cancers often overexpress this enzyme. Clinical Manifestations. Cancer of the colon is usu- ally present for a long period of time before it produces symptoms. 58,59 Bleeding is a highly significant early symptom and usually is the one that causes persons to seek medical care. Other symptoms include a change in bowel habits, diarrhea or constipation, and sometimes a sense of urgency or incomplete emptying of the bowel. Pain usually is a late symptom.