Chapter 203 – NEOPLASMS OF THE LARGE INTESTINE

A person living in North America faces an average lifetime risk of 6% for developing colorectal cancer. Colorectal cancer is the second leading cause of cancer-related deaths after lung cancer and has a 5-year survival rate of approximately 55%. Cancers of the colon and rectum are the most lethal gastrointestinal malignant diseases in the Western world. Despite these grim statistics, colorectal cancer is preventable and is highly curable if detected early enough, so public health initiatives have emphasized large-scale screening and surveillance.

Major advances in understanding the genetic pathogenesis of colorectal cancer are likely to lead to the development of cell-selective chemotherapeutic agents. By far the two most common and clinically significant neoplastic lesions that appear in the large intestine are adenomatous polyps and adenocarcinomas arising from epithelial cells of the colonic or rectal mucosa. However, the large bowel is also the site of other malignant diseases including anal carcinoma (squamous or transitional cell types; Chapter 148 ), lymphoma ( Chapter 196 ), leiomyosarcoma ( Chapter 213 ), malignant carcinoid tumor ( Chapter 251 ), and Kaposi's sarcoma ( Chapters 213 and 416 ). Malignant diseases from adjacent sites such as the prostate, ovary, uterus, and stomach may also involve the colon and/or rectum by direct invasion.

 Polyps of the Colon

A polyp is defined as a grossly visible mass of cells with stroma that protrudes from the mucosal surface into the lumen of the intestine ( Fig. 203-1 ). A polyp may either be sessile or pedunculated when it is attached by a stalk of cells. Polyps are classified as either non-neoplastic or neoplastic, and they are clinically relevant by causing rectal bleeding or partial bowel obstruction (rare) or because of their potential to become malignant. 

 Large pedunculated polyp in the rectum

FIGURE 203-1  Large pedunculated polyp in the rectum. The stalk (S) itself is benign, with the head (H) containing the adenomatous tissue. The polyp was removed safely in a one-step endoscopic procedure.  (Courtesy of Pankaj Jay Pasricha.)

   Nonadenomatous Polyps

Nonadenomatous polyps, which account for approximately 90% of all mucosal polyps detected in the large bowel, can be found in more than 50% of people older than 60 years of age. These polyps, which are also termed non-neoplastic polyps, can be further subcategorized into hyperplastic, inflammatory, lymphoid, and juvenile polyps. Most non-neoplastic polyps are hyperplastic polyps, which arise as a result of abnormal maturation of the mucosal epithelial cells; these polyps are usually small in diameter and are found predominantly in the distal sigmoid colon and rectum. Hyperplastic polyps are not malignant and are not thought to be associated with any measurable increase in malignant potential, although the cancer-causing genes in some cells in some subsets of hyperplastic polyps can undergo aberrant methylation. Inflammatory polyps, which arise in the setting of chronic ulcerative colitis and are composed of regions of inflamed mucosa surrounded by areas of ulceration, are associated with an increased risk of cancer. Lymphoid polyps are regions of the mucosa that contain exaggerated intramucosal lymphoid tissue. Juvenile polyps usually develop in the rectum of children younger than 5 years of age and are termed hamartomatous because they are focal malformations that resemble tumors but are caused by abnormal development of the lamina propria; these polyps require no therapy unless they cause symptoms such as obstruction or severe bleeding.

   Adenomatous Polyps Definition

Adenomatous polyps (or adenomas), which are neoplastic polyps with malignant potential, are more common in the distal colon and rectum, where their anatomic distribution parallels that of colorectal adenocarcinoma. Adenomatous polyps manifest in a range of sizes; smaller lesions are usually pedunculated, whereas larger polyps can be sessile. Convincing evidence that adenomatous polyps are the precursor lesion to colorectal adenocarcinoma comes from persons with the hereditary polyposis syndromes and from animal studies in which adenomas are induced by either carcinogens or genetic manipulation. Correlative evidence includes the observations that the epidemiology is similar for adenomas and carcinomas, that both lesions are more common in the same anatomic locations, and that adenomatous tissue can often be found in small adenocarcinomas. Intervention studies have shown that removal of adenomatous polyps leads to a significant decrease in risk for colorectal cancer.

Epidemiology

Adenomatous polyps are relatively common, particularly in elderly populations; the prevalence is 20 to 30% in persons in the United States who are less than 40 years old and 40 to 50% in individuals who are more than 60 years old. The prevalence of adenomas tends to be high in regions of the world where colorectal cancer is common, and most autopsy studies indicate a 30% higher prevalence in men. The importance of genetic risk factors is clear in the hereditary polyposis syndromes (see Inherited Colorectal Cancer Syndromes), and sporadic adenomas have a familial component; for example, individuals with a positive first-degree family history are at a four-fold greater risk of developing adenomatous polyps.

Pathobiology

The layer of epithelial cells lining the surface of the normal large bowel undergoes continuous self-renewal with a turnover period of 3 to 8 days. Undifferentiated stem cells located at the base of invaginated crypts give rise to cells that migrate toward the lumen as they differentiate further into specialized enterocytes; these cells are subsequently removed by apoptosis, by extrusion, or by phagocytes underlying the epithelial layer. The development of adenomatous polyps is associated with a sequence-specific accumulation of genetic lesions that cause an imbalance between epithelial cell proliferation and cell death. As a result, cells accumulate at the luminal surface, where they remain undifferentiated and continue to undergo cell division, thus eventually leading to the abnormal development of a mass of adenomatous tissue.

Adenomas are classified into three main histologic subtypes: (1) tubular adenomas, (2) villous adenomas, and (3) tubulovillous adenomas. Tubular adenomas, which are the most common type of adenoma, account for 70 to 85% of all adenomas removed at colonoscopy. They are often small and pedunculated, and they consist of dysplastic, tubular glands that divide and branch out from the mucosal surface. In contrast, villous adenomas are much rarer (<5% of all adenomas), are generally large and sessile, and are composed of strands of dysplastic epithelium that project, finger-like, into the lumen of the gut. Tubulovillous adenomas (10 to 25% of all adenomas) have a mixture of tubular and villous architecture. Small tubular adenomas generally have low malignant potential, whereas approximately 40% of large sessile adenomatous polyps develop into cancer.

Clinical Manifestations

Patients with adenomatous polyps generally remain asymptomatic but may present with an asymptomatic positive stool occult blood test or with evident hematochezia. The lifetime incidence of additional adenomas in a patient with one known adenoma is 30 to 50%. Less than 5% of all adenomas eventually develop into carcinomas. Two critical factors that determine the likelihood that an adenoma will eventually develop into an invasive lesion are the size of the polyp and the grade of dysplasia. For polyps less than 1 cm in size, the risk for carcinoma is 1 to 3%; polyps between 1 and 2 cm have a 10% risk of becoming cancerous; and more than 40% of polyps that are greater than 2 cm progress to an invasive lesion. All adenomatous polyps contain some degree of dysplasia but can be further categorized as low or high grade to indicate the degree of dysplasia and corresponding risk for invasive carcinoma. High-grade dysplasia is associated with a 27% rate for eventual transformation into carcinoma.

Diagnosis

Adenomatous polyps in the colon and rectum can be diagnosed by endoscopy ( Chapter 136 ) or barium radiography ( Chapter 135 ), but multiple studies indicate that colonoscopy is the most accurate tool for diagnosing colorectal polyps. For example, the National Polyp Study reported that barium enema missed 52% of polyps greater than or equal to 1 cm in size. Colonoscopy is thus the preferred method for diagnosing adenomas based on this higher rate of accuracy and because the technique allows for immediate biopsy and resection of most polyps; current evidence supports the use of colonoscopy as a screening tool for the general population older than 50 years of age ( Chapter 13 ). Flexible sigmoidoscopy, which is often used to screen asymptomatic persons at average risk for colorectal adenocarcinoma, detects 50 to 60% of all polyps and cancers. Generally, patients who have polyps detected by barium radiography or flexible sigmoidoscopy should undergo colonoscopy to remove the lesion and to search for additional polyps. However, colonoscopy may not be adequately performed in patients who have advanced diverticulosis or who have had previous pelvic surgery. In these instances, a combination of double-contrast barium radiography and flexible sigmoidoscopy may be an acceptable alternative. Computed tomographic (CT) colonography or virtual colonoscopy was reported to be equivalent in accuracy to conventional colonoscopy for the detection of polyps 6 mm or larger in one large study, but other studies have reported more disappointing sensitivities in the range of 55 to 66%, perhaps owing to different CT techniques (single versus multidetector CT scanners) and interobserver variability in reading the images. Although fiberoptic colonoscopy remains the “gold standard” for polyp detection, CT colonography may emerge as a viable screening tool for certain sub-sets of patients in the detection of adenomatous polyps and colorectal cancer.

Treatment

The major goal of treatment for adenomatous polyps is removal or destruction of the lesion during endoscopy by electrocautery. This recommendation is based on the overwhelming evidence that endoscopic polypectomy reduces the subsequent incidence and mortality of colorectal cancer. Pedunculated adenomas are generally removed by snare polypectomy with subsequent submission of the tissue for pathologic analysis. Piecemeal snare resection may be required to remove sessile polyps. Surgical resection of a polyp is indicated when endoscopic resection of an advanced adenoma is not possible. The biopsied polyp must be evaluated histologically so the presence or absence of carcinoma can be determined; if a malignant lesion is found, its histologic grade, vascular and lymphatic involvement, and proximity to the margin of resection should be determined. Polypectomy is the definitive therapy for localized cancers that have not spread beyond the muscularis mucosae layer, are not poorly differentiated, do not involve vascular or lymphatic structures, have margins free of carcinoma cells, and have been completely excised by endoscopic inspection. If invasive carcinoma is present in the stalk of a resected polyp and if it is unclear whether any of the stalk remains after polypectomy, then colonic resection may be indicated. The mortality rate associated with colonic resection is less than 2% in patients between the ages of 50 and 69 years, but it rises to 4% in persons older than 70 years of age; it also increases considerably when comorbidities such as chronic liver, renal, or heart disease are present.

Prognosis

Patients who have undergone resection of an adenomatous polyp are at increased risk for subsequent development of adenomas and colorectal adenocarcinoma. In general, a follow-up colonoscopy is recommended in 3 years. Earlier colonoscopies may be warranted in patients who have multiple or large sessile adenomas removed. In contrast, the risk of malignancy is not significantly increased in patients who have had less than three small (<1 cm) tubular adenomas removed; for these individuals, the first follow-up colonoscopy can be delayed to 5 years. If the first follow-up colonoscopy is negative, the second scheduled follow-up can usually be delayed until 5 years.

   Inherited Syndromes Definition

The inherited colorectal cancer syndromes constitute approximately 6% of all cases of colorectal adenocarcinoma. Genetic analyses of these syndromes have led to major advances in understanding how sporadic colorectal cancer develops. Inherited syndromes can be further divided into the following categories: inherited polyposis syndromes, which include familial adenomatous polyposis and its variants Gardner's syndrome and Turcot's syndrome; hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch's syndrome; and hamartomatous polyposis syndromes, which include Peutz-Jeghers syndrome, juvenile polyposis, and the related syndrome of Cowden's disease. Each of these syndromes is characterized by unique genetic lesions, age of onset, and clinical manifestations ( Table 203-1 ). Clinical genetic testing ( Chapter 38 ), which is now part of accepted clinical care of these patients, is indicated (1) in patients in whom the syndrome is clinically apparent or is suspected but not definitively established based on the clinical presentation and (2) in relatives of an individual with an established gene diagnosis. Referral of suspected patients to a genetic counseling service is essential.

TABLE 203-1   -- GENERAL FEATURES OF THE INHERITED COLORECTAL CANCER SYNDROMES

Syndrome Polyp Histology Polyp Distribution Age of Onset Risk of Colon Cancer Genetic Lesion Clinical Manifestations Associated Lesions
Familial adenomatous polyposis Adenoma Large intestine 16-yr (range 8–34 yr) 100% 5q (APC gene) Rectal bleeding, abdominal pain, bowel obstruction Desmoids, CHRPE
Gardner's syndrome Adenoma Large and small intestine 16-yr (range 8–34 yr) 100% 5q (APC gene) Rectal bleeding, abdominal pain, bowel obstruction Desmoids, CHRPE
Peutz-Jeghers syndrome Hamartoma Large and small intestine First decade Slightly above average 19p (STK11) Possible rectal bleeding, abdominal pain, intussusception Orocutaneous melanin pigment spots
Juvenile polyposis Hamartoma (rarely adenoma) Large and small intestine First decade Approximately 9% PTEN, SMAD4, BMPR1 Possible rectal bleeding, abdominal pain, intussusception Congenital abnormalities in 20% of the nonfamilial type
Hereditary nonpolyposis colon cancer Adenoma Large intestine 40-yr (range 18–65 yr) 30% Mismatch repair genes[*] Rectal bleeding, abdominal pain, bowel obstruction Other tumors (e.g., ovary, ureter, pancreas, stomach)

* Including hMSH2, hMSH3, hMSH6, hMLH1, hPMS1, and hPMS2. CHRPE = congenital hypertrophy of the retinal pigment epithelium.

   Familial Adenomatous Polyposis

Definition and Epidemiology

The hallmark of familial adenomatous polyposis is the development of hundreds to thousands of adenomatous polyps in the large bowel at a relatively young age ( Fig. 203-2 ). Estimates of disease incidence vary from 1 in 6850 to 1 in 31,250.

A colon lined with hundreds of adenomatous polyps resected from a patient with familial adenomatous polyposis

FIGURE 203-2  A colon lined with hundreds of adenomatous polyps resected from a patient with familial adenomatous polyposis.

Pathobiology

The disease, which is autosomal dominant with incomplete penetrance, has been mapped to the adenomatous polyposis coli (APC) gene located on the long arm of chromosome 5 (5q21). APC is a tumor suppressor gene that is a critical regulator of intestinal epithelial cell growth. Patients with the familial syndrome inherit one mutant copy of APC; when a loss-of-function mutation develops in the other APC allele, mucosal epithelial cell growth is no longer controlled normally, and polyps develop. Variable phenotypes can be partly attributed to differences in the location of the APC mutation.

Clinical Manifestations and Diagnosis

Adenomas begin to appear early in the second decade of life, and gastrointestinal symptoms begin to appear in the third or fourth decade. Polyps are distributed relatively evenly throughout the colon, although a slight predominance has been noted in the distal colon. Almost all patients with familial adenomatous polyposis develop frank colorectal carcinoma by the age of 40 years if the condition is left untreated. Gastric polyps occur in 30 to 100% of patients, and duodenal adenomas are found in 45 to 90% of patients. Periampullary duodenal cancer develops in approximately 10% of cases. Small bowel lesions that are distal to the duodenum rarely progress into malignancy.

Treatment

The primary treatment option is total proctocolectomy with conventional ileostomy or ileoanal (pouch) anastomosis. First-degree relatives of afflicted individuals should be screened. A blood test to detect mutations in the APC gene has a sensitivity of 85%, but flexible proctosigmoidoscopy should be performed annually from the ages of 12 to 40 years (and every 3 years after the age of 40 years), even in those who test negative for the APC mutation.

   Gardner's Syndrome

Gardner's syndrome, which is also caused by mutations in the APC gene, differs from familial adenomatous polyposis mainly by the presence of extraintestinal manifestations, including osteomas (particularly mandibular), soft tissue tumors (including lipomas, sebaceous cysts, and fibrosarcomas), supernumerary teeth, desmoid tumors, mesenteric fibromatosis, and congenital hypertrophy of the retinal pigment epithelium. The phenotypic differences between Gardner's syndrome and familial adenomatous polyposis appear to result from variations in the location of the APC mutation, the presence of modifying genes, and environmental factors. Adenomatous polyps in Gardner's syndrome have the same malignant potential as those found in familial adenomatous polyposis; hence, colorectal cancer treatment and screening recommendations are similar.

   Turcot's Syndrome

A hallmark of Turcot's syndrome is the combination of colorectal polyposis and malignant diseases of the central nervous system. Mutations in the APC gene account for two thirds of cases, and the remaining one third of cases result from mutations in the DNA mismatch repair genes that are also mutated in HNPCC. The central nervous system manifestations include medulloblastomas, glioblastomas, and ependymomas.

   Hereditary Nonpolyposis Colorectal Cancer

Definition and Epidemiology

HNPCC, also known as Lynch's syndrome, is the most common hereditary colorectal cancer syndrome and accounts for approximately 5% of all cases of colorectal cancer. It is inherited as an autosomal dominant trait and is highly penetrant. Clinically, HNPCC has been defined by the presence of all three of the following: (1) three or more relatives with histologically verified HNPCC-associated cancer (colorectal cancer, or cancer of the endometrium, small bowel, ureter, or renal pelvis), one of whom is a first-degree relative of the other two in the absence of familial adenomatous polyposis; (2) colorectal cancer involving at least two generations; (3) one or more family members with cancer diagnosed before the age of 50 years.

Pathobiology

HNPCC is caused by loss-of-function germline mutations in a set of genes involved in the repair of DNA base pair mismatches that occur during DNA replication (also known as the mutation mismatch repair system). Mutation mismatch repair genes include hMSH2, hMSH3, hMSH6, hMLH1, hPMS1, and hPMS2. Mutations in these genes lead to the development of DNA microsatellite instability (MSI) that can be detected using genomic techniques. Tumor cells displaying MSI have increased mutation rates in genes that contain small nucleotide repeats; one common gene mutated in HNPCC resulting from the MSI phenotype is the transforming growth factor-β type II receptor, which is an important component of a signaling pathway that regulates normal intestinal epithelial cell growth and differentiation.

Clinical Manifestations and Diagnosis

The median age for diagnosis of HNPCC is in the mid-40s. Although several adenomas may be present, the diffuse polyposis characteristic of familial adenomatous polyposis is not found, hence the name nonpolyposis. Adenomatous polyps in HNPCC are located predominantly in the right colon proximal to the splenic flexure. These tumors generally have a better prognosis than similar lesions found in sporadic colorectal cancer. Patients with HNPCC also are at high risk for other malignant diseases, including cancers of the ovary, ureter, pancreas, and stomach, probably partly because of the loss of proper DNA repair. Screening strategies for families with a history suggestive of HNPCC may include the use of genetic testing to identify the MSI phenotype, but approximately 15% of all sporadic colorectal cancers also exhibit increased MSI.

Treatment

Persons in families with HNPCC should undergo a colonoscopy every 2 years from the ages of 21 to 40 years and every year after the age of 40 years because their risk is quite high and genetic testing is not perfect. Women in HNPCC-affected families should have pelvic examinations every 1 to 3 years beginning at the age of 18 years; annual pelvic examinations, transvaginal ultrasonography, and endometrial biopsy have been recommended beginning at age 25 years.

   Peutz-Jeghers Syndrome

Definition and Epidemiology

The defining clinical presentation of Peutz-Jeghers syndrome is intestinal hamartomatous polyposis in association with characteristic mucocutaneous pigmentation. The average age of diagnosis is in the mid-20s.

Pathobiology

The syndrome is inherited in an autosomal dominant fashion with high penetrance. It is rare, with an incidence rate one tenth that of familial adenomatous polyposis. The gene responsible for the syndrome is the serine-threonine kinase STK11 gene located on chromosome 19p; a mutation in the STK11 is found in approximately 60% of patients with this syndrome. The hamartomatous polyps in Peutz-Jeghers syndrome are located predominantly in the small intestine (64 to 96%), stomach (24 to 49%), and colon (60%). Histologically, these polyps are benign, and they are unique in that a layer of muscle that extends into the submucosa or muscularis propria may surround the glandular tissue.

Clinical Manifestations and Diagnosis

In rare instances, these polyps may become malignant, particularly in the small bowel. Otherwise, the major gastrointestinal symptoms include recurrent bouts of small bowel intussusception, obstruction, and bleeding that may require surgery. Gastrointestinal bleeding may also occur and lead to iron deficiency anemia. Extraintestinal manifestations include ovarian sex cord stromal tumors and polyps of the gallbladder, ureter, and nasal passages. More than 95% of patients have a characteristic pattern of melanin spots on the lips, buccal mucosa, and skin ( Fig. 203-3 ); in one large series, 23% of patients were diagnosed on the basis of this typical cutaneous pigmentation

 Mucosal pigmentation characteristic of a patient with Peutz-Jeghers syndrome

FIGURE 203-3  Mucosal pigmentation characteristic of a patient with Peutz-Jeghers syndrome.

Treatment

Standard medical care for patients with Peutz-Jeghers syndrome involves an annual physical examination that includes evaluation of the breasts, abdomen, pelvis, and testes, as well as a complete blood count. Currently, it is suggested that large (>5 cm) or hemorrhagic polyps be removed endoscopically. Surveillance for cancer includes small bowel radiography every 2 years, esophagogastroduodenoscopy and colonoscopy every 2 years, and yearly pancreatic ultrasound scanning. For women, ultrasound scanning of the pelvis is recommended yearly, and mammography should be performed at ages 25, 30, 35, 38 years, then every 2 years until the age of 50 years, after which this should be done annually. Surgical care includes push enteroscopy and intraoperative enteroscopy with polypectomy if needed to defer repeated small bowel resections. Laparotomy and resection, as indicated, are recommended for repeated or persistent small intestinal itussusception, obstruction, or persistent intestinal bleeding.

   Juvenile Polyposis

Juvenile (non-neoplastic, hamartomatous) polyposis is a rare syndrome characterized by 10 or more non-neoplastic, hamartomatous polyps throughout the gastrointestinal tract or any number of polyps in a patient with a family history of juvenile polyposis. The syndrome is inherited in an autosomal dominant manner and is caused by mutations in the SMAD4, PTEN, or BMPR1A gene. The hamartomas are histologically distinct from the polyps seen in Peutz-Jeghers syndrome. Patients generally present with rectal bleeding, anemia, abdominal pain, or intussusception in childhood or early adolescence. Extraintestinal symptoms include pulmonary arteriovenous malformations. The risk of malignancy in juvenile polyposis is reported to be 10%; subtotal colectomy may be necessary in patients with severe dysplasia.

   Cowden's Syndrome

Cowden's syndrome ( Chapters 186 and 466 ) is a rare, autosomal dominant syndrome of multiple hamartomatous polyps of the skin and mucous membranes, including gastrointestinal polyps, facial tricholemmomas, oral papillomas, and keratoses of the hands and feet. The rate of associated malignancy is high, particularly in the thyroid and breast. The polyps in Cowden's syndrome are benign. The causative genetic lesion has been mapped to the PTEN tumor suppressor gene.

   Adenocarcinoma of the Colon and Rectum

Definition and Epidemiology

Adenocarcinomas constitute 98% of the malignant diseases found in the large bowel. Most adenocarcinomas are believed to arise from adenomatous polyps that progress from severe dysplasia to invasive carcinoma. The peak incidence is from 60 to 79 years of age, and fewer than 10% of all cases arise before the age of 50 years. The geographic pattern of colorectal cancer worldwide is highly variable. The highest rates are found in industrialized countries, including the United States, Canada, New Zealand, and the countries of northwestern Europe. Most countries in Asia, Africa, and South America (with the exception of Argentina) have a relatively low rate. This geographic distribution is thought to be primarily the result of environmental factors, because ethnic groups from low-incidence countries in Asia develop rates of disease equivalent to those of white persons in the United States after they migrate to the West. African Americans in the United States also have a much higher risk for disease than do black Africans. Population studies have found positive correlations between the risk for colorectal cancer and the dietary intake of red meat. The rate of colorectal cancer has increased significantly in Japan over the last few decades as the Western diet has become more prominent.

In the United States, about 145,000 new cases of colorectal cancer annually lead to about 55,000 expected deaths, thus making colorectal cancer the second leading cause of cancer-related deaths after lung cancer. The 5-year survival rate for colorectal cancer is approximately 55%, but this varies greatly depending on the stage of disease at the time of diagnosis. Men and women have a similar incidence of adenocarcinoma of the colon, but rectal cancer is more common in men in most parts of the world. The overall rate of deaths related to colorectal cancer has declined since the mid-1980s, perhaps owing to more widespread screening and improved treatment.

Environmental Factors

Recommendations for the primary prevention of colorectal cancer are based on risk factors associated with colorectal cancer ( Table 203-2 ); investigators have estimated that adoption of these dietary and lifestyle changes could reduce the incidence of colorectal cancer by 50%. Total energy intake, irrespective of dietary content, is positively associated with the development of colorectal cancer. Colorectal adenomas are associated with tobacco use, and the increased consumption of ethanol, particularly beer, has been associated with a higher risk for colorectal cancer. The higher rates of colorectal cancer in countries that consume “Western-style” diets high in red meat suggests that high dietary fat and low fiber could promote colorectal cancer. However, more recent data show no benefit of low-fat diets on the risk of colorectal cancer despite their other health advantages. The role of dietary fiber is controversial, and major prospective studies have found no correlation between the intake of dietary fiber and the development of colorectal adenomas. Whether diets high in fruits and vegetables can prevent colorectal cancer is under investigation.

TABLE 203-2   -- LIFESTYLE AND DIETARY RECOMMENDATIONS FOR THE PRIMARY PREVENTION OF COLORECTAL CANCER

Dietary Recommendations Lifestyle Recommendations
Increase quantity and variety of fruits and vegetables (at least five servings per day) Maintain normal body weight
Exercise daily
Avoid smoking
Ingest 20–30 g/day of fiber Avoid excessive alcohol
Consider supplementation with 3 g/day of calcium carbonate  

Inherited Predisposition

Individuals who have a first-degree relative with colorectal cancer face a two- to three-fold increase in risk for malignancy, and this risk rises to five- or six-fold if two first-degree relatives are affected. Various genetic studies suggest that a large percentage of the population (≥50%) is susceptible to colorectal neoplasia on a familial basis.

Inflammatory Bowel Disease

Adenocarcinoma of the colon is 10 to 20 times more common in persons with ulcerative colitis ( Chapter 144 ) than in the general population. Between 2 and 4% of all patients with long-term ulcerative colitis develop this malignancy, and the cumulative incidence over a 25-year period is approximately 12%. The two most important predictors for eventual development of carcinoma are the duration of the inflammatory disease and the extent of colonic involvement. Identification of dysplasia in the setting of ulcerative colitis is the best indicator of early cancer, but it is difficult to distinguish true dysplastic lesions from areas of intense mucosal regeneration. Dysplasia in a plaque or elevated mass and high-grade dysplasia warrant consideration of colectomy. Most experts agree that colonoscopy every 2 years with multiple biopsies is warranted after 8 years of symptomatic ulcerative colitis with extensive colonic involvement. The recent evolution of surgical procedures, such as ileoanal pull-through, favors the use of prophylactic colectomy in high-risk patients. Individuals with Crohn's colitis have a four to seven times higher risk of colorectal cancer as compared with the general population. Although this risk is less than that seen with ulcerative colitis, routine surveillance is recommended in patients with extensive colonic disease.

Other High-Risk Factors

Persons diagnosed with endocarditis or septicemia caused by Streptococcus bovis have a high rate of occult colorectal neoplasias and other upper gastrointestinal malignant diseases; endoscopic or radiographic screening may be warranted in this setting. A 5 to 10% increase in colorectal cancer rates 15 to 30 years after ureterosigmoidostomy to correct congenital exstrophy of the bladder has been reported; the lesions are typically distal to the ureteral implant, where the mucosa is chronically exposed to urine and feces.

Pathobiology

Pathology

The anatomic distribution of carcinoma of the colon ( Fig. 203-4 ) is associated with distinct morphologic patterns. Right-sided tumors commonly grow as polypoid, exophytic masses that bleed, often on an occult basis, and rarely cause obstruction, whereas carcinomas of the distal colon are generally annular, encircling lesions that both bleed and lead to constriction of the bowel (“napkin ring” or “apple core” constriction). Almost all colorectal cancers are adenocarcinomas that exhibit differing degrees of glandular differentiation; most tend to produce mucin that aids in extension of the lesion and worsens prognosis. Lesions spread by direct extension through the wall of the bowel into the pericolonic fat and mesentery, and they can also invade surrounding organs. Alternatively, tumors can enter the lymphatic system and spread to regional lymph nodes, or they may enter the venous system and drain to the liver through the portal vein. Colorectal cancers can spread throughout the peritoneal cavity and can also metastasize to the lung and bone marrow through the blood stream. Rectal cancers can invade the perirectal fat and surrounding structures, including the vagina, prostate, bladder, ureters, and bony pelvis; they may also spread to the lungs and liver. 

Distribution of colorectal cancers in various regions of the large intestine

FIGURE 203-4  Distribution of colorectal cancers in various regions of the large intestine.

Molecular Genetics and the Adenoma-to-Carcinoma Sequence

Colorectal cancer is caused by the accumulation of multiple genetic lesions in a specific sequence over time. Both the tissue architecture and the cellular genotype change as the disease progresses ( Fig. 203-5 ). Approximately 80 to 85% of sporadic colorectal cancers are aneuploid tumors that exhibit chromosomal instability. Somatic mutations in the APC gene, which is responsible for familial adenomatous polyposis, are common. APC is a multifunctional protein with an essential role in the regulation of the growth of intestinal epithelial cells. One of the important consequences of loss of normal APC is the accumulation of the β-catenin oncogene within the nucleus of cells, where it can participate in the regulation of gene expression that promotes malignancy. Other genomic abnormalities, including gain-of-function mutations in the k-Ras proto-oncogene and allelic loss at 18q21 (where several putative tumor suppressor genes reside), herald the progression of the lesion from dysplastic epithelium to early and late adenomas. Loss-of-function mutations in the p53 tumor suppressor gene are commonly associated with progression to full-blown carcinoma and can occur even after transformation to cancer. Other genetic and epigenetic alterations, including the expression of genes capable of cleaving extracellular matrix and a protein tyrosine phosphatase, lead to metastasis.

The molecular basis of colorectal cancer

FIGURE 203-5  The molecular basis of colorectal cancer. Sequence-specific genetic lesions result in the transition from normal large bowel mucosa to invasive carcinoma. BAX = apoptosis-related protein; CRC = colorectal cancer; FAP = familial adenomatous polyposis; HNPCC = hereditary nonpolyposis colorectal cancer; IIR = type II receptor; MMR = mutation mismatch repair; MSI = microsatellite instability; TGFβ = transforming growth factor-β.

The remaining 15 to 20% of colorectal cancers without chromosomal instability exhibit the phenotype of genomic MSI characteristic of the hereditary syndrome HNPCC: mutations in mismatch repair genes and mutations in important growth regulatory genes such as transforming growth factor-β type II receptor. Loss-of-function mutations in p53 commonly occur in carcinomas that arise in the setting of inflammatory bowel disease.

Clinical Manifestations

Colorectal adenocarcinomas can remain clinically silent for years. When present, symptoms often develop insidiously over a period of months and years. The major symptoms suggesting colorectal cancer are rectal bleeding, pain, and a change in bowel habits. Symptoms typically vary depending on where the lesion resides. Neoplasms in the proximal colon, where intestinal contents are relatively liquid, do not generally cause the abdominal pain or change in bowel habits characteristic of obstructive lesions. These lesions often ulcerate and cause chronic blood loss; patients commonly present with complaints of fatigue, palpitations, or even angina pectoris. Physical examination often reveals Hemoccult-positive stools ( Chapter 137 ), and laboratory testing demonstrates hypochromic, microcytic anemia characteristic of iron deficiency ( Chapter 163 ). Thus, the presence of unexplained iron deficiency anemia in any adult male patient or postmenopausal female patient should prompt a rigorous evaluation for colorectal cancer, that is, endoscopic and/or radiographic visualization of the entire colon. In contrast to right-sided lesions, cancers in the distal colon may bleed, but they often cause constriction of the gut wall and can manifest with abdominal cramping, stool obstruction, or even perforation ( Fig. 203-6 ). Tumors of the rectosigmoid region may manifest with hematochezia, tenesmus, and narrowing of the caliber of the stool. The differential diagnosis for rectal bleeding should include hemorrhoids, angiodysplasia, diverticulosis, and other benign and malignant tumors ( Chapter 137 ).

A barium enema radiograph in which a colorectal cancer in the distal segment of the large intestine has formed an annular, encircling lesion that leads to constriction of the bowel wall.

FIGURE 203-6  A barium enema radiograph in which a colorectal cancer in the distal segment of the large intestine has formed an annular, encircling lesion that leads to constriction of the bowel wall.

Clinically apparent metastatic disease may manifest before or after resection of primary colorectal cancer. Symptoms may include pain related to distention of the liver capsule caused by massive hepatomegaly. If disease has spread to the abdomen, both ascites and bowel obstruction may occur. Metastatic spread to the pelvic region may become evident as bladder dysfunction, sacral or sciatic nerve pain, and vaginal discharge or bleeding. Lesions that have spread to the lung or bone marrow can remain silent until very advanced disease is present.

Diagnosis

The history, physical examination, and judicious use of both laboratory and radiologic tests are important in diagnosing colorectal cancer. Pertinent history should include a prior history of colorectal cancer or adenomatous polyps, inflammatory bowel disease, and any inherited colorectal cancer syndromes, as well as assessing whether the patient has any first-degree relatives with colorectal cancer. On physical examination, extraintestinal lesions characteristic of Peutz-Jeghers or Gardner's syndrome may be noticed. Metastatic disease is suggested by enlargement of the supraclavicular lymph nodes or liver or by the presence of an umbilical mass or ascites. The digital rectal examination may reveal a distal rectal cancer or the spread of tumor to the rectal shelf or pelvis. The stool shows evidence of frank or occult blood in 40 to 80% of advanced cases. Iron deficiency anemia or an elevation in liver enzymes may aid in diagnosis.

Methods for diagnosing colorectal cancer are similar to those used to detect adenomatous polyps. Colonoscopy is the procedure of choice for all patients who have occult blood in their stools or who present with signs and symptoms characteristic of colorectal cancer ( Fig. 203-7 ). Colonoscopy is more accurate than radiographic studies for the detection of colorectal neoplasms of all sizes and has the advantage of enabling the clinician to detect synchronous (simultaneously present, additional

Two manifestations of colorectal cancer

FIGURE 203-7  Two manifestations of colorectal cancer. A, Exophytic growth within the lumen. B, “Stricturing” (apple core) lesion.

The staging of rectal cancers is helped by the use of endoscopic ultrasonography, by which the depth of lesion invasion can be accurately assessed. Patients with colorectal cancers who present with generalized abdominal pain or symptoms characteristic of multiple diseases may be diagnosed initially by CT scanning of the abdomen. A CT scan may also play a role in determining the extent of tumor spread. Both a chest radiograph and a CT scan may detect lung or liver metastases.

Tumor Staging

Accurate anatomic staging of colorectal cancer is essential, because the most important predictive factor for post-surgical outcome and for the need for adjuvant chemotherapy is the stage of disease at the time surgery. Colorectal cancers are staged using both the Dukes method and the universal TNM classification system ( Table 203-3 ). Stage A tumors (T1N0M0) are superficial lesions that do not penetrate the muscularis or involve regional lymph nodes. Neoplasms that are more invasive but have not yet spread to the lymph nodes are categorized as stage B. Stage C cancer involves regional lymph nodes, and stage D indicates distant metastases.

TABLE 203-3   -- CLASSIFICATION SYSTEMS USED TO STAGE COLON CANCER AND THEIR CORRELATION TO DISEASE OUTCOME

Dukes TNM[*] Stage Pathology Prognosis (∼5-yr Survival Rate,%)
A T1N0M0 I No invasion beyond submucosa >90
B1 T2N0M0 I Extension into muscularis 85
B2 T3N0M0 II Extension into or through the serosa 70–80
C TxN1M0 III Involvement of regional lymph nodes 35–65
D TxNxM1 IV Distant metastases present 5

* T is the depth of tumor penetration, N is the presence of lymph node involvement, and M indicates the presence of distant metastases.

Treatment
Surgery

Total resection of all malignant tissue is the treatment of choice for most patients with colorectal cancer and is currently the only treatment option that offers a reasonable chance of cure or long-term survival. The primary goal is complete removal of the involved bowel and associated lymphatic drainage. Laparoscopic resection, which is now the most common approach, is equivalent to open colectomy for achieving complete removal of the tumor and leads to a faster recovery. [1] [2] A hemicolectomy is performed when lesions are present in the left or right portions of the colon. Tumors located in the sigmoid region and upper rectum are resected anteriorly, with removal of normal colon both proximal and distal to the lesion; modern stapling techniques allow a sphincter-saving resection to be performed in a high percentage of cases. Lesions within 5 cm of the anal verge are treated by abdominoperineal resection and permanent colostomy; this approach is also used for large tumors that reside deep in the pelvis, for all neoplasms with high-grade histologic type, and when marked local spread of rectal lesions has occurred.

A palliative colostomy is often helpful in the presence of colonic obstruction caused by a tumor that is unresectable because it is widely metastatic or widely advanced into the peritoneum. Perforated lesions are generally managed by primary resection and colostomy followed by subsequent closure of the colostomy within a few months after the original surgery; in some patients, however, a permanent colostomy may be required. Focal surgical resection of a well-defined single liver metastasis or a wedge resection of a few lesions may be indicated depending on the medical condition of the patient; such procedures are associated with 5-year survival rates of 25 to 30% in patients who do not have advanced liver disease or other significant comorbidities.

Radiation Therapy

For rectal cancer, radiation therapy can be combined with 5-fluorouracil and leucovorin preoperatively to minimize local recurrence and metastasis. Radiation therapy is also useful in reducing tumor size and enabling large, otherwise unresectable lesions to be resected. Postoperative radiation therapy and chemotherapy reduce local recurrence and distant metastasis.

Chemotherapy

The mainstay of adjuvant chemotherapy for colorectal cancer for decades has been 5-fluorouracil, a compound that targets the enzyme thymidylate synthase. The drug is well tolerated but produces response rates in only 10 to 20% of patients with advanced disease. Leucovorin acts as a biomodulator by enhancing the binding of 5-fluorouracil to its target. Regimens combining 5-fluorouracil with leucovorin can improve disease-free survival in patients with Dukes type C cancers. Direct infusion of the drug into the hepatic artery can improve response rates in patients with hepatic involvement, but the effect on survival is marginal and may not outweigh the cost and toxicity of this approach.

The addition of either irinotecan[3] or oxaliplatin[4] to a 5-fluorouracil/leucovorin protocol improves response rates in advanced colorectal cancer. Irinotecan is a topoisomerase inhibitor, whereas oxaliplatin forms bulky DNA adducts that induce cellular apoptosis. Furthermore, oxaliplatin in combination with bolus 5-fluorouracil and leucovorin is superior to 5-fluorouracil/leuovorin alone as adjuvant therapy in patients with both stage II and stage III disease.[5]

The most recent drugs approved by the U.S. Food and Drug Administration for colorectal cancer, cetuximab and bevacizumab, are both monoclonal antibodies against specific cellular targets. Cetuximab is a monoclonal antibody that targets the extracellular binding domain of the epidermal growth factor receptor. Several phase II clinical trials have shown that cetuximab is synergistic with chemotherapy for advanced colorectal cancers. Bevacizumab is a humanized antibody directed against the vascular endothelial growth factor. The addition of bevacizumab (5 mg/kg given once every 14 days as an intravenous infusion until disease progression is detected) to a regimen of irinotecan, 5-fluorouracil, and leucovorin can provide a statistically significant increase in both response rates and median overall survival.[6]

Follow-up

A primary goal following curative resection for colorectal cancer is to detect curable recurrences or second primary tumors. Patients whose colon cancers have been cured face a 3 to 5% probability of developing an additional cancer of the large intestine during their lifetime and a more than 15% risk of developing an adenomatous polyp. It is also important to detect both synchronous (occurring at the same time) and metachronous (occurring at different times) cancers that may develop later. After curative resection, surveillance colonoscopy should be performed at 3 years and, if negative, at 5-year intervals thereafter. For patients who have had a low anterior resection of a stage B or C rectosigmoid cancer, flexible sigmoidoscopy should be performed to examine the lower bowel every 3 to 6 months for 2 years, and a colonoscopy will be required to evaluate bowel beyond 60 cm. Additional follow-up measures include semiannual physical examinations and yearly blood chemistry studies. No clear consensus exists on the value of obtaining periodic chest radiographs or CT scans of the abdomen and pelvis in the absence of meaningful symptoms or signs. If the serum carcinoembryonic antigen (CEA) level was normal after the initial resection, a rising CEA suggests recurrent colorectal cancer; some experts advocate periodic assays for blood CEA levels following curative resection.

Prevention

Colorectal cancer is particularly amenable to widespread screening ( Table 203-4 , Chapter 13 ). First, it is one of the most common and lethal malignant diseases in many countries, thereby justifying the public health cost associated with a population-wide screening. Second, the natural progression of the lesion from dysplastic mucosa to invasive disease takes on average 10 to 20 years, a range that allows suitable time to detect the disease before it progresses to an incurable state. Finally, clear clinical evidence indicates that early detection of colorectal cancer improves survival. The major approaches to screen for colon cancer are the fecal occult blood test, flexible sigmoidoscopy, and colonoscopy.

TABLE 203-4   -- SCREENING RECOMMENDATIONS FOR COLORECTAL CANCER

Risk Test Interval Age to Begin (yr)
Average FOBT or sigmoidoscopy or colonoscopy Annually 50
Every 5 yr
Every 10 yr
Familial adenomatous polyposis Sigmoidoscopy Every 6–12 mo 10–12
Hereditary nonpolyposis colorectal cancer Colonoscopy Every 2 yr until age 40 and annually thereafter 25
Low familial risk for sporadic cancer FOBT Annually 40
or sigmoidoscopy Every 5 yr
or colonoscopy Every 10 yr
High familial risk for cancer Colonoscopy Every 5 yr 40

FOBT = fecal occult blood testing.

Controlled prospective clinical trials performed in Minnesota, New York, Denmark, and the United Kingdom indicate that fecal occult blood test screening is relatively sensitive and reduces the rate of colorectal cancer mortality by 15 to 43%. However, the fecal occult blood test has a low sensitivity for detecting precancerous polyps and cancers of the rectosigmoid or distal rectum. Because many other conditions can cause blood in the stool, the fecal occult blood test is relatively nonspecific. Although no randomized trials have demonstrated the efficacy of flexible sigmoidoscopy for screening of colorectal cancer, case-control and cohort studies have shown a 60 to 85% reduction in the rate of mortality from distal colorectal cancers. Flexible sigmoidoscopy is well tolerated, can be performed relatively quickly, and does not require sedation. It is also highly accurate, with a high positive predictive value. The major drawback of flexible sigmoidoscopy is its inability to detect the 40% or more of large bowel neoplasms that reside beyond its reach; as a result, a full colonoscopy is recommended if flexible sigmoidoscopy reveals a polyp or tumor. Other screening options that may be considered but for which supportive clinical evidence is limited include a barium enema plus flexible sigmoidoscopy every 5 years or a colonoscopy every 10 years. An emerging screening test is to examine recovered DNA from stool for genetic abnormalities. A recent large study found that fecal DNA testing for 21 gene mutations had a sensitivity of 52% and specificity of 94% for the detection of colorectal cancer. The low sensitivity and high cost of this method limit its current use, but ongoing research may