David Cohen, M.D.·Published 20 January 2008·15 min read
Key points
A striking feature of colonic cancer is its geographic variation in incidence.
Laboratory findings that suggest the presence of colonic neoplasm include hypoalbuminemia, iron deficiency anemia, and occult blood in the stool.
The rationale for this approach is based on evidence that reduction in colorectal cancer mortality can be achieved through detection and surgical removal of early stage cancer, and by the removal of adenomatous polyps.
The presenting symptoms vary according to the location of the neoplasm in the colon.
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.
Written and revised by
David Cohen, M.D.
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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.
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Laboratory and Other Diagnostic Tests
Laboratory findings that suggest the presence of colonic neoplasm include hypoalbuminemia, iron deficiency anemia, and occult blood in the stool. Elevated alkaline phosphatase concentration suggests colonic cancer metastatic to liver or bone. In liver metastases, bilirubin concentration remains normal until late in the course, and transaminase levels are usually normal or only slightly elevated.
Radiography and endoscopy are the primary means of establishing the diagnosis of large bowel cancer. Radiologists can detect fine mucosal details and small lesions with the air-contrast barium enema technique. It is a useful procedure for the identification of small polypoid lesions, although colonoscopy seems to be more sensitive.
Colonoscopy is used instead of barium enema or to confirm the presence of possibly cancerous lesions seen on barium enema and to document their nature by biopsy. With this information, appropriate therapy can be carried out with more assurance. Flexible sigmoidoscopes, essentially short colonoscopes, can be used with similar purpose for rectosigmoid lesions. For the most part, however, a full colon examination is preferred. Synchronous colonic carcinomas that are not evident on barium enema examination can be detected by colonoscopy; they occur in 1% to 5% of patients with colonic carcinoma. In addition, up to 40% to 50% of patients have synchronous adenomatous polyps.
Digital examination of the rectum may reveal a mass lesion. The digital rectal examination is an important part of the complete physical examination for many reasons and generally should not be omitted without reason. Abdominal mass lesions may be palpable at times. If there is metastatic spread to the liver, hepatomegaly may be noted, and the liver may feel hard and nodular and be slightly tender. Peritoneal metastases may cause ascites.
Endoscopic ultrasonography has been used to stage colorectal cancer, particularly rectal cancer. Locoregional staging with endoscopic ultrasound (EUS) for depth of tumor invasion and regional lymph node metastases has proved more accurate than pelvic computed tomography (CT) for rectal cancer staging. CT is still the best modality for the evaluation of distant metastases, such as to the liver.
Screening for Colorectal Cancer
The rationale for this approach is based on evidence that reduction in colorectal cancer mortality can be achieved through detection and surgical removal of early stage cancer, and by the removal of adenomatous polyps. Widely endorsed guidelines for colorectal cancer screening have been developed based on the division of the population into average risk and increased risk groups (Fig. 343-1 [Electronic Rights Not Granted]). Those at increased risk include patients with first-degree relatives (parents, siblings, children) who have had colorectal cancer or adenomatous polyps, with a family history of familial adenomatous polyposis (FAP) or HNPCC, or with a personal history of adenomas or colorectal cancer. The screening tests used include fecal occult blood tests, flexible sigmoidoscopy, barium enema, and colonoscopy at varying onsets and intervals depending on the assessment of risk.
Genetic testing of populations for the APC gene is not feasible, since many different mutations of the gene have been found in different families. It is useful to screen family members within an affected kindred, but the significance of a negative test is uncertain. Similarly, the genetic mutations related to HNPCC are not useful in population screening but may have value in genetic identification within families at risk.
There has been recent interest in searching for mutated oncogenes in fecal DNA as a screening test for colonic neoplasia. Improved fecal occult blood tests are also under development, as is "virtual colonoscopy," an examination of the colon from images obtained during helical CT scanning. These tests have promise but have not reached a point of proven clinical utility.
The serum immunoassay for carcinoembryonic antigen (CEA) was developed to provide a means of early detection of colonic cancer. However, it is too insensitive and nonspecific to be a useful screening test. CEA concentration may also be elevated with other cancers and with benign conditions such as inflammatory bowel disease, alcoholic liver disease, and pancreatitis. The test is most useful in assessing the results of surgery. If CEA concentration is elevated preoperatively and falls to normal after curative resection, a second rise is a good indication of recurrence and may develop long before the cancer can be detected clinically. Surgical "second look" procedures have been advocated in this circumstance, but their value remains to be proved. Also, when initially high, CEA concentration has been used to gauge patient response to chemotherapy for metastatic disease.
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Differential Diagnosis
The presenting symptoms vary according to the location of the neoplasm in the colon. Cancers that occur in the more voluminous and distensible cecum and right colon, where bowel contents are liquid, usually do not cause obstruction. These cancers tend to grow to large size and ulcerate, producing a gradual chronic blood loss. In some cases enough hemoglobin is lost to produce melena. Passage of reddish maroon stool sometimes occurs, indicating the diagnosis.
Large cecal masses may involve the ileocecal valve and produce apparent small bowel obstruction. Sometimes tumors of the ascending colon partially block the lumen. If the ileocecal valve is competent, the cecum becomes painfully dilated with gas and air, creating a tender right lower quadrant mass. Patients may massage this area and find relief as they force the trapped gas past the obstruction.
Cancers in the left colon, where the lumen is narrower and less distensible and the fecal stream is solid, commonly obstruct. This causes constipation and cramping abdominal pain. Sometimes a paradoxical diarrhea develops as some colonic contents are forced past a partially obstructing cancer. Bleeding from left-sided lesions may be bright red but is generally not massive. Patients with rectal cancers in particular tend to have bright red bleeding as well as tenesmus and small-caliber stools. Colonic cancers that advance to the stage at which they invade through the bowel wall may perforate it, leading to peritonitis. Anorexia and weight loss are common in advanced colonic cancer. Anorexia is intensified by partially obstructing lesions that may cause cramping abdominal pain associated with meals.
Colonic cancers may metastasize via lymphatic or hematogenous routes or both. Metastases to regional lymph glands, with intraabdominal spread, are most common. Metastases to the liver are frequently found. Lung and bone are other sites of metastatic spread.
Several conditions must be differentiated from colonic cancer. Diverticulitis may cause an inflammatory mass and obstruction that may resemble cancer, particularly in the sigmoid colon. Barium enema may sometimes be insufficient to distinguishing between a perforated diverticulum and a perforated carcinoma. Colonoscopy with biopsy is valuable for distinguishing these disorders from one another once the infectious process has been controlled but can be difficult if muscle hypertrophy, spasm, and mucosal edema are present.
In patients with ulcerative colitis, inflammatory strictures may be difficult to distinguish from malignant strictures. Again, the colonoscope is not always able to pass through the narrowed area. Frequently, however, a stricture has a component of muscle spasm, and such areas may be evaluated although they appear on barium enema examination to be too narrow for the colonoscope to pass. A cytology brush may be passed through the narrowed area, enabling the physician to detect malignant cells. Biopsy specimens from the proximal end of the stricture may not reveal a carcinoma present in the midportion or distal end. If any doubt exists, the stricture should be considered malignant until proved otherwise.
Benign-appearing polypoid lesions of the colon must be differentiated from carcinoma if they are larger than 7 mm in diameter. Simple biopsy of polyps may be misleading because a cancerous area may be missed as a result of sampling error. Cytologic specimens from polyps are not useful in practice because they do not permit differentiation of invasive carcinoma from the presence of atypical surface cells. Thus the best way to evaluate a polyp is to remove all of it by cautery snare. If a polypoid cancer with an involved margin is removed, resection of the involved segment of bowel and mesentery is usually indicated. Polyps 7 mm or smaller are not usually malignant and may be removed by fulguration ("hot") biopsy. In this technique the polyp is destroyed by electrocoagulation while a biopsy specimen is obtained.
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Management
The only known curative treatment for colonic adenocarcinoma is surgical resection. The prognosis for recurrence after resection depends on the degree of bowel wall invasion by the cancer and the presence of lymph node or distant metastases. If resection is adequate, in the Dukes' A group only 5% to 10% of patients will have recurrent cancer in contrast to 20% to 30% in the Dukes' B group and to 50% in the Dukes' C group with cancer in the colon and 70% with cancer in the rectum.
The incidence and mortality of colorectal cancer has slightly decreased in the United States during the past decade. These observed declines may be due to better diets, removal of premalignant polyps, earlier diagnosis, and improved therapy in varying degrees and contributions.
Cancers in the right colon and left colon require right and left hemicolectomy, respectively. A wide margin should be taken with adequate resection of the mesentery and lymph nodes. Lesions in the rectosigmoid more than 6 to 8 cm from the anal verge may be treated by anterior resection, whereas sizeable cancers below this level require combined abdominal-perineal resection with colostomy. Small low rectal cancers may sometimes be curatively removed by wide local excision. Full-thickness excision, with perirectal lymph nodes if possible, is preferable to electrofulguration for local treatment because it allows pathologic analysis. In unresectable rectal cancer, electrocautery or laser treatment or stent insertion may provide palliation, sometimes precluding the need for colostomy. Resection of colon cancer using laparoscopic "minimally invasive" technique has proved feasible on a trial basis but requires additional follow-up studies.
Irradiation before surgery has been used in treating advanced rectal cancer. An unresectable lesion occasionally becomes resectable after treatment with 2000 to 3000 rad. Some physicians have advocated the routine use of preoperative radiotherapy for rectal lesions, but the results of studies have been conflicting. Postoperative irradiation for patients with rectal cancer at risk for residual disease has been advocated, and some radiation therapists advise a "sandwich" technique combining preoperative and postoperative treatment. In patients with advanced colorectal cancer, after resection of all gross disease, adjuvant therapy with a combination of 5-fluorouracil and levamisole has shown a significantly higher survival rate than in control subjects.
In patients with unresectable colonic cancer, both radiation therapy and chemotherapy have been widely used. Irradiation is usually employed for palliation and shrinkage of tumor masses in the pelvis. Chemotherapy remains unsatisfactory and experimental. 5-Fluorouracil has been the most widely used single agent; only about 15% to 20% of patients respond, most temporarily. Combination chemotherapy and modulation of 5-fluorouracil metabolism has not yet provided a noteworthy advance in colonic carcinoma treatment, although multiple-drug trials are in progress. A combination of radiation therapy and chemotherapy may have some increased benefit over either modality alone.
Infusions of 5-fluorouracil into the hepatic artery or portal vein, or both, have occasionally decreased hepatic metastases when systemic chemotherapy has failed. Patients with liver metastases have been treated with hepatic artery infusion via an implanted pump. A clear advantage over systemic treatment has not been demonstrated. A 5-year survival rate of about 20% has been reported in groups of patients who underwent surgical resection of localized liver metastases.
The judicious use of analgesics, sedatives, antidepressants, blood products, and nutritional supplements by a sympathetic physician can do much to enhance the quality of life for patients with metastatic colonic cancer.
Author: Charles J. Lightdale
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Harris AG, Redfern JS: Octreotide treatment of carcinoid syndrome: analysis of published dose-titration data, Aliment Pharmacol Ther 9:387, 1995.
Moertel BC et al: Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma, N Engl J Med 322:352, 1990.
Rex DK, Rahmani EY, Haseman JH et al: Relative sensitivity of colonoscopy and barium enema for detection of colorectal cancer in clinical practice, Gastroenterology 112:17, 1997.
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