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InternalMed_Harrison. Polypoid Adenomas About 25% of benign small-bowel tumors are polypoid adenomas (see Table 110-2). They may present as single polypoid lesions or, less commonly, as papillary villous adenomas. As in the colon, the sessile or papillary form of the tumor is sometimes associated with a coexisting carcinoma. Occasionally, patients with Gardner’s syndrome develop premalignant adenomas in the small bowel; such lesions are generally in the duodenum. Multiple polypoid tumors may occur throughout the small bowel (and occasionally the stomach and colorectum) in the Peutz-Jeghers syndrome. The polyps are usually hamartomas (juvenile polyps) having a low potential for malignant degeneration. Mucocutaneous melanin deposits as well as tumors of the ovary, breast, pancreas, and endometrium are also associated with this autosomal dominant condition.


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InternalMed_Harrison. Leiomyomas These neoplasms arise from smooth-muscle components of the intestine and are usually intramural, affecting the overlying mucosa. Ulceration of the mucosa may cause gastrointestinal hemorrhage of varying severity. Cramping or intermittent abdominal pain is frequently encountered. Lipomas These tumors occur with greatest frequency in the distal ileum and at the ileocecal valve. They have a characteristic radiolucent appearance and are usually intramural and asymptomatic, but on occasion cause bleeding.


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InternalMed_Harrison. Angiomas While not true neoplasms, these lesions are important because they frequently cause intestinal bleeding. They may take the form of telangiectasia or hemangiomas. Multiple intestinal telangiectasias occur in a nonhereditary form confined to the gastrointestinal tract or as part of the hereditary Osler-Rendu-Weber syndrome. Vascular tumors may also take the form of isolated hemangiomas, most commonly in the jejunum. Angiography, especially during bleeding, is the best procedure for evaluating these lesions.


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InternalMed_Harrison. While rare, small-bowel malignancies occur in patients with longstanding regional enteritis and celiac sprue as well as in individuals with AIDS. Malignant tumors of the small bowel are frequently associated with fever, weight loss, anorexia, bleeding, and a palpable abdominal mass. After ampullary carcinomas (many of which arise from biliary or pancreatic ducts), the most frequently occurring small-bowel malignancies are adenocarcinomas, lymphomas, carcinoid tumors, and leiomyosarcomas.


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InternalMed_Harrison. The most common primary cancers of the small bowel are adenocarcinomas, accounting for ∼50% of malignant tumors. These cancers occur most often in the distal duodenum and proximal jejunum, where they tend to ulcerate and cause hemorrhage or obstruction. Radiologically, they may be confused with chronic duodenal ulcer disease or with Crohn’s disease if the patient has long-standing regional enteritis. The diagnosis is best made by endoscopy and biopsy under direct vision. Surgical resection is the treatment of choice with suggested postoperative adjuvant chemotherapy options generally following treatment patterns used in the management of colon cancer.


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InternalMed_Harrison. Lymphoma in the small bowel may be primary or secondary. A diagnosis of a primary intestinal lymphoma requires histologic confirmation in a clinical setting in which palpable adenopathy and hepatosplenomegaly are absent and no evidence of lymphoma is seen on chest radiograph, CT scan, or peripheral blood smear or on bone marrow aspiration and biopsy. Symptoms referable to the small bowel are present, usually accompanied by an anatomically discernible lesion. Secondary lymphoma of the small bowel consists of involvement of the intestine by a lymphoid malignancy extending from involved retroperitoneal or mesenteric lymph nodes (Chap. 134).


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InternalMed_Harrison. Primary intestinal lymphoma accounts for ∼20% of malignancies of the small bowel. These neoplasms are non-Hodgkin’s lymphomas; they usually have a diffuse, large-cell histology and are of T cell origin. Intestinal lymphoma involves the ileum, jejunum, and duodenum, in decreasing frequency—a pattern that mirrors the relative amount of normal lymphoid cells in these anatomic areas. The risk of small-bowel lymphoma is increased in patients with a prior history of malabsorptive conditions (e.g., celiac sprue), regional enteritis, and depressed immune function due to congenital immunodeficiency syndromes, prior organ transplantation, autoimmune disorders, or AIDS.


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InternalMed_Harrison. The development of localized or nodular masses that narrow the lumen results in periumbilical pain (made worse by eating) as well as weight loss, vomiting, and occasional intestinal obstruction. The diagnosis of small-bowel lymphoma may be suspected from the appearance on contrast radiographs of patterns such as infiltration and thickening of mucosal folds, mucosal nodules, areas of irregular ulceration, or stasis of contrast material. The diagnosis can be confirmed by surgical exploration and resection of involved segments. Intestinal lymphoma can occasionally be diagnosed by peroral intestinal mucosal biopsy, but because the disease mainly involves the lamina propria, full-thickness surgical biopsies are usually required.


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InternalMed_Harrison. Resection of the tumor constitutes the initial treatment modality. While postoperative radiation therapy has been given to some patients following a total resection, most authorities favor short-term (three cycles) systemic treatment with combination chemotherapy. The frequent presence of widespread intraabdominal disease at the time of diagnosis and the occasional multicentricity of the tumor often make a total resection impossible. The probability of sustained remission or cure is ∼75% in patients with localized disease but is ∼25% in individuals with unresectable lymphoma. In patients whose tumors are not resected, chemotherapy may lead to bowel perforation.


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InternalMed_Harrison. A unique form of small-bowel lymphoma, diffusely involving the entire intestine, was first described in oriental Jews and Arabs and is referred to as immunoproliferative small intestinal disease (IPSID), Mediterranean lymphoma, or α heavy chain disease. This is a B cell tumor. The typical presentation includes chronic diarrhea and steatorrhea associated with vomiting and abdominal cramps; clubbing of the digits may be observed. A curious feature in many patients with IPSID is the presence in the blood and intestinal secretions of an abnormal IgA that contains a shortened α heavy chain and is devoid of light chains. It is suspected that the abnormal α chains are produced by plasma cells infiltrating the small bowel. The clinical course of 537 patients with IPSID is generally one of exacerbations and remissions, with death frequently resulting from either progressive malnutrition and wasting or the development of an aggressive lymphoma. The use of oral antibiotics such as tetracycline


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InternalMed_Harrison. and remissions, with death frequently resulting from either progressive malnutrition and wasting or the development of an aggressive lymphoma. The use of oral antibiotics such as tetracycline appears to be beneficial in the early phases of the disorder, suggesting a possible infectious etiology. Combination chemotherapy has been administered during later stages of the disease, with variable results. Results are better when antibiotics and chemotherapy are combined.


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InternalMed_Harrison. Carcinoid tumors arise from argentaffin cells of the crypts of Lieberkühn and are found from the distal duodenum to the ascending colon, areas embryologically derived from the midgut. More than 50% of intestinal carcinoids are found in the distal ileum, with most congregating close to the ileocecal valve. Most intestinal carcinoids are asymptomatic and of low malignant potential, but invasion and metastases may occur, leading to the carcinoid syndrome (Chap. 113). Leiomyosarcomas often are >5 cm in diameter and may be palpable on abdominal examination. Bleeding, obstruction, and perforation are common. Such tumors should be analyzed for the expression of mutant c-kit receptor (defining GIST), and in the presence of metastatic disease, justifying treatment with imatinib mesylate (Gleevec) or, in imatinib-refractory patients, sunitinib (Sutent) or regorafenib (Stivarga). Robert J. Mayer Lower gastrointestinal cancers include malignant tumors of the colon, rectum, and anus.


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InternalMed_Harrison. Robert J. Mayer Lower gastrointestinal cancers include malignant tumors of the colon, rectum, and anus. Cancer of the large bowel is second only to lung cancer as a cause of cancer death in the United States: 136,830 new cases occurred in 2014, and 50,310 deaths were due to colorectal cancer. The incidence rate has decreased significantly during the past 25 years, likely due to enhanced and more compliantly followed screening practices. Similarly, mortality rates in the United States have decreased by approximately 25%, resulting largely from earlier detection and improved treatment.


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InternalMed_Harrison. Most colorectal cancers, regardless of etiology, arise from adenomatous polyps. A polyp is a grossly visible protrusion from the mucosal surface and may be classified pathologically as a nonneoplastic hamartoma (e.g., juvenile polyp), a hyperplastic mucosal proliferation (hyperplastic polyp), or an adenomatous polyp. Only adenomas are clearly premalignant, and only a minority of adenomatous polyps evolve into cancer. Adenomatous polyps may be found in the colons of ∼30% of middle-aged and ∼50% of elderly people; however, <1% of polyps ever become malignant. Most polyps produce no symptoms and remain clinically undetected. Occult blood in the stool is found in <5% of patients with polyps.


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InternalMed_Harrison. A number of molecular changes are noted in adenomatous polyps and colorectal cancers that are thought to reflect a multistep process in the evolution of normal colonic mucosa to life-threatening invasive carcinoma. These developmental steps toward carcinogenesis include, but are not restricted to, point mutations in the K-ras protooncogene; hypomethylation of DNA, leading to gene activation; loss of DNA 538 (allelic loss) at the site of a tumor-suppressor gene (the adenomatous polyposis coli [APC] gene) on the long arm of chromosome 5 (5q21); allelic loss at the site of a tumor-suppressor gene located on chromosome 18q (the deleted in colorectal cancer [DCC] gene); and allelic loss at chromosome 17p, associated with mutations in the p53 tumor-suppressor gene (see Fig. 101e-2). Thus, the altered proliferative pattern of the colonic mucosa, which results in progression to a polyp and then to carcinoma, may involve the mutational activation of an oncogene followed by and coupled with the


InternalMed_Harrison

InternalMed_Harrison. proliferative pattern of the colonic mucosa, which results in progression to a polyp and then to carcinoma, may involve the mutational activation of an oncogene followed by and coupled with the loss of genes that normally suppress tumorigenesis. It remains uncertain whether the genetic aberrations always occur in a defined order. Based on this model, however, cancer is believed to develop only in those polyps in which most (if not all) of these mutational events take place. Clinically, the probability of an adenomatous polyp becoming a cancer depends on the gross appearance of the lesion, its histologic features, and its size. Adenomatous polyps may be pedunculated (stalked) or sessile (flat-based). Invasive cancers develop more frequently in sessile polyps. Histologically, adenomatous polyps may be tubular, villous (i.e., papillary), or tubulovillous. Villous adenomas, most of which are sessile, become malignant more than three times as often as tubular adenomas. The likelihood that


InternalMed_Harrison

InternalMed_Harrison. may be tubular, villous (i.e., papillary), or tubulovillous. Villous adenomas, most of which are sessile, become malignant more than three times as often as tubular adenomas. The likelihood that any polypoid lesion in the large bowel contains invasive cancer is related to the size of the polyp, being negligible (<2%) in lesions <1.5 cm, intermediate (2–10%) in lesions 1.5–2.5 cm, and substantial (10%) in lesions >2.5 cm in size. Following the detection of an adenomatous polyp, the entire large bowel should be visualized endoscopically because synchronous lesions are noted in about one-third of cases. Colonoscopy should then be repeated periodically, even in the absence of a previously documented malignancy, because such patients have a 30–50% probability of developing another adenoma and are at a higher-than-average risk for developing a colorectal carcinoma. Adenomatous polyps are thought to require >5 years of growth before becoming clinically significant; colonoscopy need not be


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InternalMed_Harrison. are at a higher-than-average risk for developing a colorectal carcinoma. Adenomatous polyps are thought to require >5 years of growth before becoming clinically significant; colonoscopy need not be carried out more frequently than every 3 years for the vast majority of patients.


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InternalMed_Harrison. Risk factors for the development of colorectal cancer are listed in Table 110-1. Diet The etiology for most cases of large-bowel cancer appears to be related to environmental factors. The disease occurs more often in upper socioeconomic populations who live in urban areas. Mortality from colorectal cancer is directly correlated with per capita consumption of calories, meat protein, and dietary fat and oil as well as elevations in the serum cholesterol concentration and mortality from coronary artery disease. Geographic variations in incidence largely are unrelated to genetic differences, since migrant groups tend to assume the large-bowel cancer incidence rates of their adopted countries. Furthermore, population groups such as Mormons and Seventh Day Adventists, whose lifestyle and dietary habits differ somewhat risK faCtors for the DeveLopment of CoLoreCtaL CanCer


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InternalMed_Harrison. Diet: Animal fat ? Tobacco use from those of their neighbors, have significantly lower-than-expected incidence and mortality rates for colorectal cancer. The incidence of colorectal cancer has increased in Japan since that nation has adopted a more “Western” diet. At least three hypotheses have been proposed to explain the relationship to diet, none of which is fully satisfactory. animal fats One hypothesis is that the ingestion of animal fats found in red meats and processed meat leads to an increased proportion of anaerobes in the gut microflora, resulting in the conversion of normal bile acids into carcinogens. This provocative hypothesis is supported by several reports of increased amounts of fecal anaerobes in the stools of patients with colorectal cancer. Diets high in animal (but not vegetable) fats are also associated with high serum cholesterol, which is also associated with enhanced risk for the development of colorectal adenomas and carcinomas.


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InternalMed_Harrison. insulin resistance The large number of calories in Western diets coupled with physical inactivity has been associated with a higher prevalence of obesity. Obese persons develop insulin resistance with increased circulating levels of insulin, leading to higher circulating concentrations of insulin-like growth factor type I (IGF-I). This growth factor appears to stimulate proliferation of the intestinal mucosa. fiBer Contrary to prior beliefs, the results of randomized trials and case-controlled studies have failed to show any value for dietary fiber or diets high in fruits and vegetables in preventing the recurrence of colorectal adenomas or the development of colorectal cancer. The weight of epidemiologic evidence, however, implicates diet as being the major etiologic factor for colorectal cancer, particularly diets high in animal fat and in calories.


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InternalMed_Harrison. The weight of epidemiologic evidence, however, implicates diet as being the major etiologic factor for colorectal cancer, particularly diets high in animal fat and in calories. Up to 25% of patients with colorectal cancer have a family history of the disease, suggesting a hereditary predisposition. Inherited large-bowel cancers can be divided into two main groups: the well-studied but uncommon polyposis syndromes and the more common nonpolyposis syndromes (Table 110-2).


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InternalMed_Harrison. Polyposis Coli Polyposis coli (familial polyposis of the colon) is a rare condition characterized by the appearance of thousands of adenomatous polyps throughout the large bowel. It is transmitted as an autosomal dominant trait; the occasional patient with no family history probably developed the condition due to a spontaneous mutation. Polyposis coli is associated with a deletion in the long arm of chromosome 5 (including the APC gene) in both neoplastic (somatic mutation) and normal (germline mutation) cells. The loss of this genetic material (i.e., allelic loss) results in the absence of tumor-suppressor genes whose protein products would normally inhibit neoplastic growth. The presence of soft tissue and bony tumors, congenital hypertrophy of the retinal pigment epithelium, mesenteric desmoid tumors, and ampullary cancers in addition to the colonic polyps characterizes a subset of polyposis coli known as Gardner’s syndrome. The appearance of malignant tumors of the central nervous


InternalMed_Harrison

InternalMed_Harrison. desmoid tumors, and ampullary cancers in addition to the colonic polyps characterizes a subset of polyposis coli known as Gardner’s syndrome. The appearance of malignant tumors of the central nervous system accompanying polyposis coli defines Turcot’s syndrome. The colonic polyps in all these conditions are rarely present before puberty but are generally evident in affected individuals by age 25. If the polyposis is not treated surgically, colorectal cancer will develop in almost all patients before age 40. Polyposis coli results from a defect in the colonic mucosa, leading to an abnormal proliferative pattern and impaired DNA repair mechanisms. Once the multiple polyps are detected, patients should undergo a total colectomy. Medical therapy with nonsteroidal anti-inflammatory drugs (NSAIDs) such as sulindac and selective cyclooxygenase-2 inhibitors such as celecoxib can decrease the number and size of polyps in patients with polyposis coli; however, this effect on polyps is only


InternalMed_Harrison

InternalMed_Harrison. such as sulindac and selective cyclooxygenase-2 inhibitors such as celecoxib can decrease the number and size of polyps in patients with polyposis coli; however, this effect on polyps is only temporary, and the use of NSAIDs has not been shown to reduce the risk of cancer. Colectomy remains the primary therapy/prevention. The offspring of patients with polyposis coli, who often are prepubertal when the diagnosis is made in the parent, have a 50% risk for developing this premalignant disorder and should be carefully screened by annual flexible sigmoidoscopy until age 35. Proctosigmoidoscopy is a sufficient screening procedure because polyps tend to be evenly distributed from cecum to anus, making more invasive and expensive techniques such as colonoscopy or barium enema unnecessary. Testing for occult blood in the stool is an inadequate screening maneuver. If a causative germ-line AP C mutation has been identified in an affected family member, an alternative method for identifying


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InternalMed_Harrison. for occult blood in the stool is an inadequate screening maneuver. If a causative germ-line AP C mutation has been identified in an affected family member, an alternative method for identifying carriers is testing DNA from peripheral blood mononuclear cells for the presence of the specific APC mutation. The detection of such a germline mutation can lead to a definitive diagnosis before the development of polyps.


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InternalMed_Harrison. MYH-Associated Polyposis MYH-associated polyposis (MAP) is a rare autosomal recessive syndrome caused by a biallelic mutation in the MUT4H gene. This hereditary condition may have a variable clinical presentation, resembling polyposis coli or colorectal cancer occurring in younger individuals without polyposis. Screening and colectomy guidelines for this syndrome are less clear than for polyposis coli, but annual to biennial colonoscopic surveillance is generally recommended starting at age 25–30.


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InternalMed_Harrison. Hereditary Nonpolyposis Colon Cancer Hereditary nonpolyposis colon cancer (HNPCC), also known as Lynch’s syndrome, is another autosomal dominant trait. It is characterized by the presence of three or more relatives with histologically documented colorectal cancer, one of whom is a first-degree relative of the other two; one or more cases of colorectal cancer diagnosed before age 50 in the family; and colorectal cancer involving at least two generations. In contrast to polyposis coli, HNPCC is associated with an unusually high frequency of cancer arising in the proximal large bowel. The median age for the appearance of an adenocarcinoma is <50 years, 10–15 years younger than the median age for the general population. Despite having a poorly differentiated, mucinous histologic appearance, the proximal colon tumors that characterize HNPCC have a better prognosis than sporadic tumors from patients of similar age. Families with HNPCC often include individuals with multiple primary cancers;


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InternalMed_Harrison. proximal colon tumors that characterize HNPCC have a better prognosis than sporadic tumors from patients of similar age. Families with HNPCC often include individuals with multiple primary cancers; the association of colorectal cancer with either ovarian or endometrial carcinomas is especially strong in women, and an increased appearance of gastric, small-bowel, genitourinary, pancreaticobiliary, and sebaceous skin tumors has been reported as well. It has been recommended that members of such families undergo annual or biennial colonoscopy beginning at age 25 years, with intermittent pelvic ultrasonography and endometrial biopsy for afflicted women; such a screening strategy has not yet been validated. HNPCC is associated with germline muta-539 tions of several genes, particularly hMSH2 on chromosome 2 and hMLH1 on chromosome 3. These mutations lead to errors in DNA replication and are thought to result in DNA instability because of defective repair of DNA mismatches resulting in


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InternalMed_Harrison. on chromosome 2 and hMLH1 on chromosome 3. These mutations lead to errors in DNA replication and are thought to result in DNA instability because of defective repair of DNA mismatches resulting in abnormal cell growth and tumor development. Testing tumor cells through molecular analysis of DNA or immunohistochemical staining of paraffin-fixed tissue for “microsatellite instability” (sequence changes reflecting defective mismatch repair) in patients with colorectal cancer and a positive family history for colorectal or endometrial cancer may identify probands with HNPCC.


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InternalMed_Harrison. (Chap. 351) Large-bowel cancer is increased in incidence in patients with long-standing inflammatory bowel disease (IBD). Cancers develop more commonly in patients with ulcerative colitis than in those with granulomatous (i.e., Crohn’s) colitis, but this impression may result in part from the occasional difficulty of differentiating these two conditions. The risk of colorectal cancer in a patient with IBD is relatively small during the initial 10 years of the disease, but then appears to increase at a rate of ∼0.5–1% per year. Cancer may develop in 8–30% of patients after 25 years. The risk is higher in younger patients with pancolitis. Cancer surveillance strategies in patients with IBD are unsatisfactory. Symptoms such as bloody diarrhea, abdominal cramping, and obstruction, which may signal the appearance of a tumor, are similar to the complaints caused by a flare-up of the underlying disease.


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InternalMed_Harrison. In patients with a history of IBD lasting ≥15 years who continue to experience exacerbations, the surgical removal of the colon can significantly reduce the risk for cancer and also eliminate the target organ for the underlying chronic gastrointestinal disorder. The value of such surveillance techniques as colonoscopy with mucosal biopsies and brushings for less symptomatic individuals with chronic IBD is uncertain. The lack of uniformity regarding the pathologic criteria that characterize dysplasia and the absence of data that such surveillance reduces the development of lethal cancers have made this costly practice an area of controversy. OTHER HIGH-RISK CONDITIONS Streptococcus bovis Bacteremia For unknown reasons, individuals who develop endocarditis or septicemia from this fecal bacterium have a high incidence of occult colorectal tumors and, possibly, upper gastrointestinal cancers as well. Endoscopic or radiographic screening appears advisable.


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InternalMed_Harrison. Tobacco Use Cigarette smoking is linked to the development of colorectal adenomas, particularly after >35 years of tobacco use. No biologic explanation for this association has yet been proposed.


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InternalMed_Harrison. Several orally administered compounds have been assessed as possible inhibitors of colon cancer. The most effective class of chemopreventive agents is aspirin and other NSAIDs, which are thought to suppress cell proliferation by inhibiting prostaglandin synthesis. Regular aspirin use reduces the risk of colon adenomas and carcinomas as well as death from large-bowel cancer; such use also appears to diminish the likelihood for developing additional premalignant adenomas following successful treatment for a prior colon carcinoma. This effect of aspirin on colon carcinogenesis increases with the duration and dosage of drug use. Oral folic acid supplements and oral calcium supplements appear to reduce the risk of adenomatous polyps and colorectal cancers in case-controlled studies. The value of vitamin D as a form of chemoprevention is under study. Antioxidant vitamins such as ascorbic acid, tocopherols, and β-carotene are ineffective at reducing the incidence of subsequent adenomas in


InternalMed_Harrison

InternalMed_Harrison. of vitamin D as a form of chemoprevention is under study. Antioxidant vitamins such as ascorbic acid, tocopherols, and β-carotene are ineffective at reducing the incidence of subsequent adenomas in patients who have undergone the removal of a colon adenoma. Estrogen replacement therapy has been associated with a reduction in the risk of colorectal cancer in women, conceivably by an effect on bile acid synthesis and composition or by decreasing synthesis of IGF-I.


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InternalMed_Harrison. 540 SCREENING The rationale for colorectal cancer screening programs is that the removal of adenomatous polyps will prevent colorectal cancer, and that earlier detection of localized, superficial cancers in asymptomatic individuals will increase the surgical cure rate. Such screening programs are particularly important for individuals with a family history of the disease in first-degree relatives. The relative risk for developing colorectal cancer increases to 1.75 in such individuals and may be even higher if the relative was afflicted before age 60. The prior use of proctosigmoidoscopy as a screening tool was based on the observation that 60% of early lesions are located in the rectosigmoid. For unexplained reasons, however, the proportion of large-bowel cancers arising in the rectum has been decreasing during the past several decades, with a corresponding increase in the proportion of cancers in the more proximal descending colon. As such, the potential for proctosigmoidoscopy to


InternalMed_Harrison

InternalMed_Harrison. been decreasing during the past several decades, with a corresponding increase in the proportion of cancers in the more proximal descending colon. As such, the potential for proctosigmoidoscopy to detect a sufficient number of occult neoplasms to make the procedure cost-effective has been questioned. Screening strategies for colorectal cancer that have been examined during the past several decades are listed in Table 110-3. Many programs directed at the early detection of colorectal cancers have focused on digital rectal examinations and fecal occult blood (i.e., stool guaiac) testing. The digital examination should be part of any routine physical evaluation in adults older than age 40 years, serving as a screening test for prostate cancer in men, a component of the pelvic examination in women, and an inexpensive maneuver for the detection of masses in the rectum. However, because of the proximal migration of colorectal tumors, its value as an overall screening modality for colorectal


InternalMed_Harrison

InternalMed_Harrison. and an inexpensive maneuver for the detection of masses in the rectum. However, because of the proximal migration of colorectal tumors, its value as an overall screening modality for colorectal cancer has become limited. The development of the fecal occult blood test has greatly facilitated the detection of occult fecal blood. Unfortunately, even when performed optimally, the fecal occult blood test has major limitations as a screening technique. About 50% of patients with documented colorectal cancers have a negative fecal occult blood test, consistent with the intermittent bleeding pattern of these tumors. When random cohorts of asymptomatic persons have been tested, 2–4% have fecal occult blood-positive stools. Colorectal cancers have been found in <10% of these “test-positive” cases, with benign polyps being detected in an additional 20–30%. Thus, a colorectal neoplasm will not be found in most asymptomatic individuals with occult blood in their stool. Nonetheless, persons found


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InternalMed_Harrison. with benign polyps being detected in an additional 20–30%. Thus, a colorectal neoplasm will not be found in most asymptomatic individuals with occult blood in their stool. Nonetheless, persons found to have fecal occult blood-positive stool routinely undergo further medical evaluation, including sigmoidoscopy and/or colonoscopy—procedures that are not only uncomfortable and expensive but also associated with a small risk for significant complications. The added cost of these studies would appear justifiable if the small number of patients found to have occult neoplasms because of fecal occult blood screening could be shown to have an improved prognosis and prolonged survival. Prospectively controlled trials have shown a statistically significant reduction in mortality rate from colorectal cancer for individuals undergoing annual stool guaiac screening. However, this benefit only emerged after >13 years of follow-up and was extremely expensive to achieve, because all positive tests


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InternalMed_Harrison. cancer for individuals undergoing annual stool guaiac screening. However, this benefit only emerged after >13 years of follow-up and was extremely expensive to achieve, because all positive tests (most of which were falsely positive) were followed by colonoscopy. Moreover, these colonoscopic examinations quite likely provided the opportunity for cancer prevention through the removal of potentially premalignant adenomatous polyps (i.e., computed tomography colonography) because the eventual development of cancer was reduced by 20% in the cohort undergoing annual screening.


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InternalMed_Harrison. With the appreciation that the carcinogenic process leading to the progression of the normal bowel mucosa to an adenomatous polyp and then to a cancer is the result of a series of molecular changes, investigators have examined fecal DNA for evidence of mutations associated with such molecular changes as evidence of the occult presence of precancerous lesions or actual malignancies. Such a strategy has been tested in more than 4000 asymptomatic individuals whose stool was assessed for occult blood and for 21 possible mutations in fecal DNA; these study subjects also underwent colonoscopy. Although the fecal DNA strategy suggested the presence of more advanced adenomas and cancers than did the fecal occult blood testing approach, the overall sensitivity, using colonoscopic findings as the standard, was less than 50%, diminishing enthusiasm for further pursuit of the fecal DNA screening strategy.


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InternalMed_Harrison. The use of imaging studies to screen for colorectal cancers has also been explored. Air contrast barium enemas had been used to identify sources of occult blood in the stool prior to the advent of fiberoptic endoscopy; the cumbersome nature of the procedure and inconvenience to patients limited its widespread adoption. The introduction of computed tomography (CT) scanning led to the development of virtual (i.e., CT) colonography as an alternative to the growing use of endoscopic screening techniques. Virtual colonography was proposed as being equivalent in sensitivity to colonoscopy and being available in a more widespread manner because it did not require the same degree of operator expertise as fiberoptic endoscopy. However, virtual colonography requires the same cathartic preparation that has limited widespread acceptance of endoscopic colonoscopy, is diagnostic but not therapeutic (i.e., patients with suspicious findings must undergo a subsequent endoscopic procedure for


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InternalMed_Harrison. that has limited widespread acceptance of endoscopic colonoscopy, is diagnostic but not therapeutic (i.e., patients with suspicious findings must undergo a subsequent endoscopic procedure for polypectomy or biopsy), and, in the setting of general radiology practices, appears to be less sensitive as a screening technique when compared with endoscopic procedures.


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InternalMed_Harrison. With the appreciation of the inadequacy of fecal occult blood testing alone, concerns about the practicality of imaging approaches, and the wider adoption of endoscopic examinations by the primary care community, screening strategies in asymptomatic persons have changed. At present, both the American Cancer Society and the National Comprehensive Cancer Network suggest either fecal occult blood testing annually coupled with flexible sigmoidoscopy every 5 years or colonoscopy every 10 years beginning at age 50 in asymptomatic individuals with no personal or family history of polyps or colorectal cancer. The recommendation for the inclusion of flexible sigmoidoscopy is strongly supported by the recently published results of three randomized trials performed in the United States, the United Kingdom, and Italy, involving more than 350,000 individuals, which consistently showed that periodic (even single) sigmoidoscopic examinations, after more than a decade of median follow-up, lead to an


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InternalMed_Harrison. and Italy, involving more than 350,000 individuals, which consistently showed that periodic (even single) sigmoidoscopic examinations, after more than a decade of median follow-up, lead to an approximate 21% reduction in the development of colorectal cancer and a more than 25% reduction in mortality from the malignant disease. Less than 20% of participants in these studies underwent a subsequent colonoscopy. In contrast to the cathartic preparation required before colonoscopic procedures, which is only performed by highly trained specialists, flexible sigmoidoscopy requires only an enema as preparation and can be accurately performed by nonspecialty physicians or physician-extenders. The randomized screening studies using flexible sigmoidoscopy led to the estimate that approximately 650 individuals needed to be screened to prevent one colorectal cancer death; this contrasts with the data for mammography where the number of women needing to be screened to prevent one breast cancer


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InternalMed_Harrison. individuals needed to be screened to prevent one colorectal cancer death; this contrasts with the data for mammography where the number of women needing to be screened to prevent one breast cancer death is 2500, reinforcing the efficacy of endoscopic surveillance for colorectal cancer screening. Presumably the benefit from the sigmoidoscopic screening is the result of the identification and removal of adenomatous polyps; it is intriguing that this benefit has been achieved using a technique that leaves the proximal half of the large bowel unvisualized.


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InternalMed_Harrison. It remains to be seen whether surveillance colonoscopy, which has gained increasing popularity in the United States for colorectal cancer screening, will prove to be more effective than flexible sigmoidoscopy. Ongoing randomized trials being conducted in Europe are addressing this issue. Although flexible sigmoidoscopy only visualizes the distal half of the large bowel, leading to the assumption that colonoscopy represents a more informative approach, colonoscopy has been reported as being less accurate for screening the proximal rather than the distal colon, perhaps due to technical considerations but also possibly because of a greater frequency of serrated (i.e., “flat”) polyps in the right colon, which are more difficult to identify. At present, colonoscopy performed every 10 years has been offered as an alternative to annual fecal occult blood testing with periodic (every 5 years) flexible sigmoidoscopy. Colonoscopy has been shown to be superior to double-contract barium enema and


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InternalMed_Harrison. been offered as an alternative to annual fecal occult blood testing with periodic (every 5 years) flexible sigmoidoscopy. Colonoscopy has been shown to be superior to double-contract barium enema and also to have a higher sensitivity for detecting villous or dysplastic adenomas or cancers than the strategy using occult fecal blood testing and flexible sigmoidoscopy. Whether colonoscopy performed every 10 years beginning at age 50 is medically superior and economically equivalent to flexible sigmoidoscopy remains to be determined.


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InternalMed_Harrison. CLINICAL FEATURES Presenting Symptoms Symptoms vary with the anatomic location of the tumor. Because stool is relatively liquid as it passes through the ileocecal valve into the right colon, cancers arising in the cecum and ascending colon may become quite large without resulting in any obstructive symptoms or noticeable alterations in bowel habits. Lesions of the right colon commonly ulcerate, leading to chronic, insidious blood loss without a change in the appearance of the stool. Consequently, patients with tumors of the ascending colon often present with symptoms such as fatigue, palpitations, and even angina pectoris and are found to have a hypochromic, microcytic anemia indicative of iron deficiency. Because the cancers may bleed intermittently, a random fecal occult blood test may be negative. As a result, the unexplained presence of iron-deficiency anemia in any adult (with the possible exception of a premenopausal, multiparous woman) mandates a thorough endoscopic and/or


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InternalMed_Harrison. may be negative. As a result, the unexplained presence of iron-deficiency anemia in any adult (with the possible exception of a premenopausal, multiparous woman) mandates a thorough endoscopic and/or radiographic visualization of the entire large bowel (Fig. 110-1).


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InternalMed_Harrison. Because stool becomes more formed as it passes into the transverse and descending colon, tumors arising there tend to impede the passage of stool, resulting in the development of abdominal cramping, occasional obstruction, and even perforation. Radiographs of the abdomen often reveal characteristic annular, constricting lesions (“apple-core” or “napkin-ring”) (Fig. 110-2). Cancers arising in the rectosigmoid are often associated with hematochezia, tenesmus, and narrowing of the caliber of stool; anemia is an infrequent finding. While these symptoms may lead patients and their physicians to suspect the presence of hemorrhoids, the development of rectal bleeding and/or altered bowel habits demands a prompt digital rectal examination and proctosigmoidoscopy.


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InternalMed_Harrison. Staging, Prognostic Factors, and Patterns of Spread The prognosis for individuals having colorectal cancer is related to the depth of tumor penetration into the bowel wall and the presence of both regional lymph node involvement and distant metastases. These variables are incorporated into the staging system introduced by Dukes and subsequently applied to a TNM classification method, in which T represents the depth of tumor penetration, N the presence of lymph node involvement, and M the presence or absence of distant metastases (Fig. 110-3). Superficial lesions that do not involve regional lymph nodes and do not penetrate through the submucosa (T1) or the muscularis (T2) are designated as stage I (T1–2N0M0) disease; tumors that penetrate through the muscularis but have not spread to lymph nodes are stage II disease (T3-4N0M0); regional lymph node involvement defines stage III (TXN1-2M0) disease; and metastatic spread to sites such as liver, lung, or bone indicates stage IV (TXNXM1)


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InternalMed_Harrison. nodes are stage II disease (T3-4N0M0); regional lymph node involvement defines stage III (TXN1-2M0) disease; and metastatic spread to sites such as liver, lung, or bone indicates stage IV (TXNXM1) disease. Unless gross evidence of metastatic disease is present, disease stage cannot be determined accurately before surgical resection and pathologic analysis of the operative specimens. It is not clear whether the detection of nodal metastases by special immunohistochemical molecular techniques has the same prognostic implications as disease detected by routine light microscopy.


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InternalMed_Harrison. Most recurrences after a surgical resection of a large-bowel cancer occur within the first 4 years, making 5-year survival a fairly reliable indicator of cure. The likelihood for 5-year survival in patients with colorectal cancer is stage-related (Fig. 110-3). That likelihood has improved during the past several decades when similar surgical stages have been compared. The most plausible explanation for this improvement is more thorough intraoperative and pathologic staging. In particular, more exacting attention to pathologic detail has revealed that the prognosis following the resection of a colorectal cancer is not related merely to the presence or absence of regional lymph node involvement; rather, prognosis may be more precisely gauged by the number of involved lymph nodes (one to three lymph nodes [“N1”] vs four or more lymph nodes [“N2”]) and the number of nodes examined. A minimum of 12 sampled lymph nodes is thought necessary to


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InternalMed_Harrison. FIGURE 110-1 Double-contrast air-barium enema revealing a ses-sile tumor of the cecum in a patient with iron-deficiency anemia and guaiac-positive stool. The lesion at surgery was a stage II adenocarci-noma. FIGURE 110-2 Annular, constricting adenocarcinoma of the descending colon. This radiographic appearance is referred to as an “apple-core” lesion and is always highly suggestive of malignancy. Staging of colorectal cancer FIGURE 110-3 Staging and prognosis for patients with colorectal cancer.


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InternalMed_Harrison. accurately define tumor stage, and the more nodes examined, the better. Other predictors of a poor prognosis after a total surgical resection include tumor penetration through the bowel wall into pericolic fat, poorly differentiated histology, perforation and/or tumor adherence to adjacent organs (increasing the risk for an anatomically adjacent recurrence), and venous invasion by tumor (Table 110-4). Regardless of the clinicopathologic stage, a preoperative elevation of the plasma carcinoembryonic antigen (CEA) level predicts eventual tumor recurrence. The presence of aneuploidy and specific chromosomal deletions, such as a mutation in the b-raf gene in tumor cells, appears to predict for a higher risk for metastatic spread. Conversely, the detection of microsatellite instability in tumor tissue indicates a more favorable outcome. In contrast to most other cancers, the prognosis in colorectal cancer is not influenced by the size of the primary lesion when adjusted for nodal


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InternalMed_Harrison. in tumor tissue indicates a more favorable outcome. In contrast to most other cancers, the prognosis in colorectal cancer is not influenced by the size of the primary lesion when adjusted for nodal involvement and histologic differentiation.


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InternalMed_Harrison. Cancers of the large bowel generally spread to regional lymph nodes or to the liver via the portal venous circulation. The liver represents the most frequent visceral site of metastasis; it is the initial site of distant spread in one-third of recurring colorectal cancers and is involved in more than two-thirds of such patients at the time of death. In general, colorectal cancer rarely spreads to the lungs, supraclavicular lymph nodes, bone, or brain without prior spread to the liver. A major exception to this rule occurs in patients having primary tumors in the distal rectum, from which tumor cells may spread through the paravertebral preDiCtors of poor outCome foLLoWing totaL surgiCaL reseCtion of CoLoreCtaL CanCer


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InternalMed_Harrison. Tumor spread to regional lymph nodes Number of regional lymph nodes involved Tumor penetration through the bowel wall Poorly differentiated histology Perforation Tumor adherence to adjacent organs Venous invasion Preoperative elevation of CEA titer (>5 ng/mL) Aneuploidy Specific chromosomal deletion (e.g., mutation in the b-raf gene) Abbreviation: CEA, carcinoembryonic antigen. venous plexus, escaping the portal venous system and thereby reaching the lungs or supraclavicular lymph nodes without hepatic involvement. The median survival after the detection of distant metastases has ranged in the past from 6–9 months (hepatomegaly, abnormal liver chemistries) to 24–30 months (small liver nodule initially identified by elevated CEA level and subsequent CT scan), but effective systemic therapy is significantly improving this prognosis.


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InternalMed_Harrison. Efforts to use gene expression profiles to identify patients at risk of recurrence or those particularly likely to benefit from adjuvant therapy have not yet yielded practice-changing results. Despite a burgeoning literature examining a host of prognostic factors, pathologic stage at diagnosis remains the best predictor of long-term prognosis. Patients with lymphovascular invasion and high preoperative CEA levels are likely to have a more aggressive clinical course.


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InternalMed_Harrison. Total resection of tumor is the optimal treatment when a malignant lesion is detected in the large bowel. An evaluation for the presence of metastatic disease, including a thorough physical examination, biochemical assessment of liver function, measurement of the plasma CEA level, and a CT scan of the chest, abdomen, and pelvis, should be performed before surgery. When possible, a colonoscopy of the entire large bowel should be performed to identify synchronous neoplasms and/or polyps. The detection of metastases should not preclude surgery in patients with tumor-related symptoms such as gastrointestinal bleeding or obstruction, but it often prompts the use of a less radical operative procedure. The necessity for a primary tumor resection in asymptomatic individuals with metastatic disease is an area of controversy. At the time of laparotomy, the entire peritoneal cavity should be examined, with thorough inspection of the liver, pelvis, and hemidiaphragm and careful palpation of the


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InternalMed_Harrison. is an area of controversy. At the time of laparotomy, the entire peritoneal cavity should be examined, with thorough inspection of the liver, pelvis, and hemidiaphragm and careful palpation of the full length of the large bowel. Following recovery from a complete resection, patients should be observed carefully for 5 years by semiannual physical examinations and blood chemistry measurements. If a complete colonoscopy was not performed preoperatively, it should be carried out within the first several postoperative months. Some authorities favor measuring plasma CEA levels at 3-month intervals because of the sensitivity of this test as a marker for otherwise undetectable tumor recurrence. Subsequent endoscopic surveillance of the large bowel, probably at triennial intervals, is indicated, because patients who have been cured of one colorectal cancer have a 3–5% probability of developing an additional bowel cancer during their lifetime and a >15% risk for the development of adenomatous


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InternalMed_Harrison. because patients who have been cured of one colorectal cancer have a 3–5% probability of developing an additional bowel cancer during their lifetime and a >15% risk for the development of adenomatous polyps. Anastomotic (“suture-line”) recurrences are infrequent in colorectal cancer patients, provided the surgical resection margins are adequate and free of tumor. The value of periodic CT scans of the abdomen, assessing for an early, asymptomatic indication of tumor recurrence, is an area of uncertainty, with some experts recommending the test be performed annually for the first 3 postoperative years.


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InternalMed_Harrison. Radiation therapy to the pelvis is recommended for patients with rectal cancer because it reduces the 20–25% probability of regional recurrences following complete surgical resection of stage II or III tumors, especially if they have penetrated through the serosa. This alarmingly high rate of local disease recurrence is believed to be due to the fact that the contained anatomic space within the pelvis limits the extent of the resection and because the rich lymphatic network of the pelvic side wall immediately adjacent to the rectum facilitates the early spread of malignant cells into surgically inaccessible tissue. The use of sharp rather than blunt dissection of rectal cancers (total mesorectal excision) appears to reduce the likelihood of local disease recurrence to ∼10%. Radiation therapy, either preor postoperatively, further reduces the likelihood of pelvic recurrences but does not appear to prolong survival. Combining radiation therapy with 5-fluorouracil (5-FU)-based


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InternalMed_Harrison. therapy, either preor postoperatively, further reduces the likelihood of pelvic recurrences but does not appear to prolong survival. Combining radiation therapy with 5-fluorouracil (5-FU)-based chemotherapy, preferably prior to surgical resection, lowers local recurrence rates and improves overall survival. Preoperative radiotherapy is indicated for patients with large, potentially unresectable rectal cancers; such lesions may shrink enough to permit subsequent surgical removal. Radiation therapy is not effective as the primary treatment of colon cancer.


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InternalMed_Harrison. Systemic therapy for patients with colorectal cancer has become more effective. 5-FU remains the backbone of treatment for this disease. Partial responses are obtained in 15–20% of patients. The probability of tumor response appears to be somewhat greater for patients with liver metastases when chemotherapy is infused directly into the hepatic artery, but intraarterial treatment is costly and toxic and does not appear to appreciably prolong survival. The concomitant administration of folinic acid (leucovorin) improves the efficacy of 5-FU in patients with advanced colorectal cancer, presumably by enhancing the binding of 5-FU to its target enzyme, thymidylate synthase. A threefold improvement in the partial response rate is noted when folinic acid is combined with 5-FU; however, the effect on survival is marginal, and the optimal dose schedule remains to be defined. 5-FU is generally administered intravenously but may also be given orally in the form of capecitabine (Xeloda) with


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InternalMed_Harrison. on survival is marginal, and the optimal dose schedule remains to be defined. 5-FU is generally administered intravenously but may also be given orally in the form of capecitabine (Xeloda) with seemingly similar efficacy.


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InternalMed_Harrison. Irinotecan (CPT-11), a topoisomerase 1 inhibitor, prolongs survival when compared to supportive care in patients whose disease has progressed on 5-FU. Furthermore, the addition of irinotecan to 5-FU and leucovorin (LV) (e.g., FOLFIRI) improves response rates and survival of patients with metastatic disease. The FOLFIRI regimen is as follows: irinotecan, 180 mg/m2 as a 90-min infusion on day 1; LV, 400 mg/m2 as a 2-h infusion during irinotecan administration; immediately followed by 5-FU bolus, 400 mg/m2, and 46-h continuous infusion of 2.4–3 g/m2 every 2 weeks. Diarrhea is the major side effect from irinotecan. Oxaliplatin, a platinum analogue, also improves the response rate when added to 5-FU and LV (FOLFOX) as initial treatment of patients with metastatic disease. The FOLFOX regimen is as follows: 2-h infusion of LV (400 mg/m2 per day) followed by a 5-FU bolus (400 mg/m2 per day) and 22-h infusion (1200 mg/m2) every 2 weeks, together with oxaliplatin, 85 mg/m2 as a 2-h infusion on


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InternalMed_Harrison. as follows: 2-h infusion of LV (400 mg/m2 per day) followed by a 5-FU bolus (400 mg/m2 per day) and 22-h infusion (1200 mg/m2) every 2 weeks, together with oxaliplatin, 85 mg/m2 as a 2-h infusion on day 1. Oxaliplatin frequently causes a dose-dependent sensory neuropathy that often but not always resolves following the cessation of therapy. FOLFIRI and FOLFOX are equal in efficacy. In metastatic disease, these regimens may produce median survivals of 2 years.


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InternalMed_Harrison. Monoclonal antibodies are also effective in patients with advanced colorectal cancer. Cetuximab (Erbitux) and panitumumab (Vectibix) are directed against the epidermal growth factor recep-543 tor (EGFR), a transmembrane glycoprotein involved in signaling pathways affecting growth and proliferation of tumor cells. Both cetuximab and panitumumab, when given alone, have been shown to benefit a small proportion of previously treated patients, and cetuximab appears to have therapeutic synergy with such chemotherapeutic agents as irinotecan, even in patients previously resistant to this drug; this suggests that cetuximab can reverse cellular resistance to cytotoxic chemotherapy. The antibodies are not effective in the approximate 40% subset of colon tumors that contain mutated K-ras. The use of both cetuximab and panitumumab can lead to an acne-like rash, with the development and severity of the rash being correlated with the likelihood of antitumor efficacy. Inhibitors of the EGFR tyrosine


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InternalMed_Harrison. both cetuximab and panitumumab can lead to an acne-like rash, with the development and severity of the rash being correlated with the likelihood of antitumor efficacy. Inhibitors of the EGFR tyrosine kinase such as erlotinib (Tarceva) or sunitinib (Sutent) do not appear to be effective in colorectal cancer.


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InternalMed_Harrison. Bevacizumab (Avastin) is a monoclonal antibody directed against the vascular endothelial growth factor (VEGF) and is thought to act as an antiangiogenesis agent. The addition of bevacizumab to irinotecan-containing combinations and to FOLFOX initially appeared to significantly improve the outcome observed with chemotherapy alone, but subsequent studies have suggested a lesser degree of benefit. The use of bevacizumab can lead to hypertension, proteinuria, and an increased likelihood of thromboembolic events. Patients with solitary hepatic metastases without clinical or radiographic evidence of additional tumor involvement should be considered for partial liver resection, because such procedures are associated with 5-year survival rates of 25–30% when performed on selected individuals by experienced surgeons.


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InternalMed_Harrison. The administration of 5-FU and LV for 6 months after resection of tumor in patients with stage III disease leads to a 40% decrease in recurrence rates and 30% improvement in survival. The likelihood of recurrence has been further reduced when oxaliplatin has been combined with 5-FU and LV (e.g., FOLFOX); unexpectedly, the addition of irinotecan to 5-FU and LV as well as the addition of either bevacizumab or cetuximab to FOLFOX did not significantly enhance outcome. Patients with stage II tumors do not appear to benefit appreciably from adjuvant therapy, with the use of such treatment generally restricted to those patients having biologic characteristics (e.g., perforated tumors, T4 lesions, lymphovascular invasion) that place them at higher likelihood for recurrence. The addition of oxaliplatin to adjuvant treatment for patients older than age 70 and those with stage II disease does not appear to provide any therapeutic benefit.


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InternalMed_Harrison. In rectal cancer, the delivery of preoperative or postoperative combined-modality therapy (5-FU plus radiation therapy) reduces the risk of recurrence and increases the chance of cure for patients with stage II and III tumors, with the preoperative approach being better tolerated. The 5-FU acts as a radiosensitizer when delivered together with radiation therapy. Life-extending adjuvant therapy is used in only about half of patients older than age 65 years. This age bias is unfortunate because the benefits and likely the tolerance of adjuvant therapy in patients age ≥65 years appear similar to those seen in younger individuals.


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InternalMed_Harrison. Cancers of the anus account for 1–2% of the malignant tumors of the large bowel. Most such lesions arise in the anal canal, the anatomic area extending from the anorectal ring to a zone approximately halfway between the pectinate (or dentate) line and the anal verge. Carcinomas arising proximal to the pectinate line (i.e., in the transitional zone between the glandular mucosa of the rectum and the squamous epithelium of the distal anus) are known as basaloid, cuboidal, or cloacogenic tumors; about one-third of anal cancers have this histologic pattern. Malignancies arising distal to the pectinate line have squamous histology, ulcerate more frequently, and constitute ∼55% of anal cancers. The prognosis for patients with basaloid and squamous cell cancers of 544 the anus is identical when corrected for tumor size and the presence or absence of nodal spread. The development of anal cancer is associated with infection by human papillomavirus, the same organism etiologically linked to


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InternalMed_Harrison. corrected for tumor size and the presence or absence of nodal spread. The development of anal cancer is associated with infection by human papillomavirus, the same organism etiologically linked to cervical cancer. The virus is sexually transmitted. The infection may lead to anal warts (condyloma acuminata), which may progress to anal intraepithelial neoplasia and on to squamous cell carcinoma. The risk for anal cancer is increased among homosexual males, presumably related to anal intercourse. Anal cancer risk is increased in both men and women with AIDS, possibly because their immunosuppressed state permits more severe papillomavirus infection. Vaccination against human papilloma viruses may reduce the eventual risk for anal cancer. Anal cancers occur most commonly in middle-aged persons and are more frequent in women than men. At diagnosis, patients may experience bleeding, pain, sensation of a perianal mass, and pruritus. Radical surgery (abdominal-perineal resection with lymph


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InternalMed_Harrison. and are more frequent in women than men. At diagnosis, patients may experience bleeding, pain, sensation of a perianal mass, and pruritus. Radical surgery (abdominal-perineal resection with lymph node sampling and a permanent colostomy) was once the treatment of choice for this tumor type. The 5-year survival rate after such a procedure was 55–70% in the absence of spread to regional lymph nodes and <20% if nodal involvement was present. An alternative therapeutic approach combining external beam radiation therapy with concomitant chemotherapy (5-FU and mitomycin C) has resulted in biopsy-proven disappearance of all tumor in >80% of patients whose initial lesion was <3 cm in size. Tumor recurrences develop in <10% of these patients, meaning that ∼70% of patients with anal cancers can be cured with nonoperative treatment and without the need for a colostomy. Surgery should be reserved for the minority of individuals who are found to have residual tumor after being managed initially


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InternalMed_Harrison. cured with nonoperative treatment and without the need for a colostomy. Surgery should be reserved for the minority of individuals who are found to have residual tumor after being managed initially with radia tion therapy combined with chemotherapy. tumors of the Liver and Biliary tree Brian I. Carr HEPATOCELLULAR CARCINOMA INCIDENCE 111


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InternalMed_Harrison. Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. The annual global incidence is approx imately 1 million cases, with a male-to-female ratio of approximately 4:1 (1:1 without cirrhosis to 9:1 in many high-incidence countries). The incidence rate equals the death rate. In the United States, approximately 22,000 new cases are diagnosed annually, with 18,000 deaths. The death rates in males in low-incidence countries such as the United States are 1.9 per 100,000 per year; in intermediate areas such as Austria and South Africa, they range from 5.1–20; and in high-incidence areas such as in the Orient (China and Korea), they are as high as 23.1– 150 per 100,000 per year (Table 111-1). The incidence of HCC in the United States is approximately 3 per 100,000 persons, with significant gender, ethnic, and geographic variations. These numbers are rapidly increasing and may be an underestimate. Approximately 4 million chronic hepatitis C virus (HCV) carriers are in


InternalMed_Harrison

InternalMed_Harrison. with significant gender, ethnic, and geographic variations. These numbers are rapidly increasing and may be an underestimate. Approximately 4 million chronic hepatitis C virus (HCV) carriers are in the United States alone. Approximately 10% of them, or 400,000, are likely to develop cirrhosis. Approximately 5%, or 20,000, of these patients may develop HCC annually. Add to this the two other common predisposing factors—hepatitis B virus (HBV) and chronic alcohol consumption—and 60,000 new HCC cases annually seem possible. Future advances in HCC survival will likely depend in part on immunization strategies for HBV (and HCV) and earlier diagnosis by screening of patients at risk of HCC development.


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InternalMed_Harrison. Current Directions With the U.S. HCV epidemic, HCC is increasing in most states, and obesity-associated liver disease (nonalcoholic steatohepatitis [NASH]) is increasingly recognized as a cause. Persons per 100,000 per Year Argentina 6.0 2.5 Brazil, Recife 9.2 8.3 Brazil, Sao Paulo 3.8 2.6 Mozambique 112.9 30.8 South Africa, Cape: Black 26.3 8.4 South Africa, Cape: White 1.2 0.6 Senegal 25.6 9.0 Nigeria 15.4 3.2 Gambia 33.1 12.6 Burma 25.5 8.8 Japan 7.2 2.2 Korea 13.8 3.2 China, Shanghai 34.4 11.6 India, Bombay 4.9 2.5 India, Madras 2.1 0.7 Great Britain 1.6 0.8 France 6.9 1.2 Italy, Varese 7.1 2.7 Norway 1.8 1.1 Spain, Navarra 7.9 4.7 There are two general types of epidemiologic studies of


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InternalMed_Harrison. India, Madras 2.1 0.7 Great Britain 1.6 0.8 France 6.9 1.2 Italy, Varese 7.1 2.7 Norway 1.8 1.1 Spain, Navarra 7.9 4.7 There are two general types of epidemiologic studies of HCC—those of country-based incidence rates (Table 111-1) and those of migrants. Endemic hot spots occur in areas of China and sub-Saharan Africa, which are associated both with high endemic hepatitis B carrier rates as well as mycotoxin contamination of foodstuffs (aflatoxin B1), stored grains, drinking water, and soil. Environmental factors are important, for example, Japanese in Japan have a higher incidence than Japanese living in Hawaii, who in turn have a higher incidence than those living in California.


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InternalMed_Harrison. studied along two general lines. First are agents identified as carcinogenic in experimental animals (particularly rodents) that are thought to be present in the human environment (Table 111-2). Second is the association of HCC with various other clinical conditions. Probably the best-studied and most potent ubiquitous natural chemical carcinogen is a product of the Aspergillus fungus, called aflatoxin B1. This mold and aflatoxin product can be found in a variety of stored grains in hot, humid places, where peanuts and rice are stored in unrefrigerated conditions. Aflatoxin contamination of foodstuffs correlates well with incidence rates in Africa and to some extent in China. In endemic areas of China, even farm animals such as ducks have HCC. The most potent carcinogens appear to be natural products of plants, fungi, and bacteria, such as bush trees containing pyrrolizidine alkaloids as well as tannic acid and safrole. Pollutants such as pesticides and insecticides are known rodent


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InternalMed_Harrison. products of plants, fungi, and bacteria, such as bush trees containing pyrrolizidine alkaloids as well as tannic acid and safrole. Pollutants such as pesticides and insecticides are known rodent carcinogens.


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InternalMed_Harrison. Hepatitis Both case-control and cohort studies have shown a strong association between chronic hepatitis B carrier rates and increased incidence of HCC. In Taiwanese male postal carriers who were hepatitis B surface antigen (HBsAg)-positive, a 98-fold greater risk for HCC was found compared to HBsAg-negative individuals. The incidence of HCC in Alaskan natives is markedly increased related to a high prevalence of HBV infection. HBV-based HCC may involve rounds of hepatic destruction with subsequent proliferation and not necessarily frank cirrhosis. The increase in Japanese Abbreviations: NAFL, nonalcoholic fatty liver; NASH, nonalcoholic steatohepatitis.


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InternalMed_Harrison. HCC incidence rates in the last three decades is thought to be from hepatitis C. A large-scale World Health Organization (WHO)sponsored intervention study is currently under way in Asia involving HBV vaccination of the newborn. HCC in African blacks is not associated with severe cirrhosis but is poorly differentiated and very aggressive. Despite uniform HBV carrier rates among the South African Bantu, there is a ninefold difference in HCC incidence between Mozambicans living along the coast and inland. These differences are attributed to the additional exposure to dietary aflatoxin B1 and other carcinogenic mycotoxins. A typical interval between HCV-associated transfusion and subsequent HCC is approximately 30 years. HCV-associated HCC patients tend to have more frequent and advanced cirrhosis, but in HBV-associated HCC, only half the patients have cirrhosis, with the remainder having chronic active hepatitis (Chap. 362).


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InternalMed_Harrison. Other Etiologic Conditions The 75–85% association of HCC with underlying cirrhosis has long been recognized, more typically with macronodular cirrhosis in Southeast Asia, but also with micronodular cirrhosis (alcohol) in Europe and the United States (Chap. 365). It is still not clear whether cirrhosis itself is a predisposing factor to the development of HCC or whether the underlying causes of the cirrhosis are actually the carcinogenic factors. However, ∼20% of U.S. patients with HCC do not have underlying cirrhosis. Several underlying conditions are associated with an increased risk for cirrhosis-associated HCC (Table 111-2), including hepatitis, alcohol, autoimmune chronic active hepatitis, cryptogenic cirrhosis, and NASH. A less common association is with primary biliary cirrhosis and several metabolic diseases including hemochromatosis, Wilson’s disease, α1 antitrypsin deficiency, tyrosinemia, porphyria cutanea tarda, glycogenesis types 1 and 3, citrullinemia, and orotic


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InternalMed_Harrison. and several metabolic diseases including hemochromatosis, Wilson’s disease, α1 antitrypsin deficiency, tyrosinemia, porphyria cutanea tarda, glycogenesis types 1 and 3, citrullinemia, and orotic aciduria. The etiology of HCC in those 20% of patients who have no cirrhosis is currently unclear, and their HCC natural history is not well-defined.


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InternalMed_Harrison. Current Directions Many patients have multiple etiologies, and the interactions of HBV, HCV, alcohol, smoking, and aflatoxins are just beginning to be explored.


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InternalMed_Harrison. Symptoms These include abdominal pain, weight loss, weak ness, abdominal fullness and swelling, jaundice, and nausea (Table 111-3). Presenting signs and symptoms differ somewhat between highand low-incidence areas. In high-risk areas, especially in South African blacks, the most common symptom is abdominal pain; by contrast, only 40–50% of Chinese and Japanese patients present with abdominal pain. Abdominal swelling may occur as a consequence of ascites due to the underlying chronic liver disease or may be due to a rapidly expanding tumor. Occasionally, central necrosis or acute hemorrhage into the peritoneal cavity leads to death. In countries with an active surveillance program, HCC tends to be identified at an earlier stage, when symptoms may be due only to the underlying disease. Jaundice is usually due to obstruction of the intrahepatic ducts from underlying liver disease. Hematemesis may occur due to Symptom No. of Patients (%)


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InternalMed_Harrison. Symptom No. of Patients (%) No symptom 129 (24) Abdominal pain 219 (40) Other (workup of anemia and various 64 (12) diseases) Routine physical exam finding, elevated LFTs 129 (24) Weight loss 112 (20) Appetite loss 59 (11) Weakness/malaise 83 (15) Jaundice 30 (5) Routine CT scan screening of known cirrhosis 92 (17) Cirrhosis symptoms (ankle swelling, 98 (18) abdominal bloating, increased girth, pruritus, GI bleed) Diarrhea 7 (1) Tumor rupture 1 Mean age (yr) 56 ± 13 Male:Female 3:1 Ethnicity Abbreviations: CT, computed tomography; GI, gastrointestinal; LFT, liver function test. esophageal varices from the underlying portal hypertension. Bone pain is seen in 3–12% of patients, but necropsies show pathologic bone metastases in ∼20% of patients. However, 25% of patients may be asymptomatic.


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InternalMed_Harrison. Physical Signs Hepatomegaly is the most common physical sign, occurring in 50–90% of the patients. Abdominal bruits are noted in 6–25%, and ascites occurs in 30–60% of patients. Ascites should be examined by cytology. Splenomegaly is mainly due to portal hypertension. Weight loss and muscle wasting are common, particularly with rapidly growing or large tumors. Fever is found in 10–50% of patients, from unclear cause. The signs of chronic liver disease may often be present, including jaundice, dilated abdominal veins, palmar erythema, gynecomastia, testicular atrophy, and peripheral edema. Budd-Chiari syndrome can occur due to HCC invasion of the hepatic veins, with tense ascites and a large tender liver (Chap. 365).


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InternalMed_Harrison. Paraneoplastic Syndromes Most paraneoplastic syndromes in HCC are biochemical abnormalities without associated clinical consequences. They include hypoglycemia (also caused by end-stage liver failure), erythrocytosis, hypercalcemia, hypercholesterolemia, dysfibrinogenemia, carcinoid syndrome, increased thyroxin-binding globulin, changes in secondary sex characteristics (gynecomastia, testicular atrophy, and precocious puberty), and porphyria cutanea tarda. Mild hypoglycemia occurs in rapidly growing HCC as part of


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InternalMed_Harrison. Tumors of the Liver and Biliary Tree 546 terminal illness, and profound hypoglycemia may occur, although the cause is unclear. Erythrocytosis occurs in 3–12% of patients and hypercholesterolemia in 10–40%. A high percentage of patients have thrombocytopenia associated with their fibrosis or leukopenia, resulting from portal hypertension, and not from cancer infiltration of bone marrow, as in other tumor types. Furthermore, large HCCs have normal or high platelet levels (thrombocytosis), as in ovarian and other gastrointestinal cancers, probably related to elevated interleukin 6 (IL-6) levels.


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InternalMed_Harrison. Multiple clinical staging systems for HCC have been described. A widely used one has been the American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) classification. However, the Cancer of the Liver Italian Program (CLIP) system is now popular because it takes cirrhosis into account, based on the original Okuda system (Table 111-4). Patients with Okuda stage III disease have a dire prognosis because they usually cannot be curatively resected, and the condition of their liver typically precludes chemotherapy. Other staging systems have been proposed, and a consensus is needed. They are all based on combining the prognostic features of liver damage with those of tumor aggressiveness and include the Barcelona Clinic Liver Cancer (BCLC) system from Spain (Fig. 111-1), which is externally validated and incorporates baseline survival estimates; the Chinese University Prognostic Index (CUPI); the important and simple Japan Integrated Staging Score (JIS); and SLiDe, which stands


InternalMed_Harrison

InternalMed_Harrison. validated and incorporates baseline survival estimates; the Chinese University Prognostic Index (CUPI); the important and simple Japan Integrated Staging Score (JIS); and SLiDe, which stands for s tage, li ver damage, and de s-γ-carboxy prothrombin. CLIP and BCLC appear most popular in the West, whereas JIS is favored in Japan. Each system i. Tumor number Single Multiple – Hepatic replacement by tumor (%) <50 <50 >50 ii. Child-Pugh score A B C iii. α Fetoprotein level (ng/mL) <400 ≥400 – iv. Portal vein thrombosis (CT) No Yes –


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InternalMed_Harrison. CLIP stages (score = sum of points): CLIP 0, 0 points; CLIP 1, 1 point; CLIP 2, 2 points; CLIP 3, 3 points. Okuda stages: stage 1, all (−); stage 2, 1 or 2 (+); stage 3, 3 or 4 (+). aExtent of liver occupied by tumor. Abbreviation: CLIP, Cancer of the Liver Italian Program. has its champions. The best prognosis is for stage I, solitary tumors less than 2 cm in diameter without vascular invasion. Adverse prognostic features include ascites, jaundice, vascular invasion, and elevated α fetoprotein (AFP). Vascular invasion in particular has profound effects


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InternalMed_Harrison. Resection Liver transplantation (CLT/LDLT) Curative treatments (30%) 5-yr survival: 40–70% Randomized controlled trials (50%) Median survival 11–20 months Symptomatic treatment (20%) Survival <3 months PEI/RF TACE Sorafenib Advanced stage (C) Portal invasion, N1, M1, PST 1-2 Intermediate stage (B) Multinodular, PST 0 Very early stage (0) Single <2 cm carcinoma in situ Single Portal pressure/ bilirubin Normal Increased Associated diseases No Yes 3 nodules ˜3 cm Stage 0 PST 0, Child-Pugh A Early stage (A) Single or 3 nodules <3 cm, PST 0 PST End stage (D) Stage D PST >2, Child-Pugh C Stage A-C PST 0–2, Child-Pugh A–B HCC


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InternalMed_Harrison. FIGURE 111-1 Barcelona Clinic Liver Cancer (BCLC) staging classification and treatment schedule. Patients with very early hepatocellular carcinoma (HCC) (stage 0) are optimal candidates for resection. Patients with early HCC (stage A) are candidates for radical therapy (resection, liver transplantation [LT], or local ablation via percutaneous ethanol injection [PEI] or radiofrequency [RF] ablation). Patients with intermediate HCC (stage B) benefit from transcatheter arterial chemoembolization (TACE). Patients with advanced HCC, defined as presence of macroscopic vascular invasion, extrahepatic spread, or cancer-related symptoms (Eastern Cooperative Oncology Group performance status 1 or 2) (stage C), benefit from sorafenib. Patients with end-stage disease (stage D) will receive symptomatic treatment. Treatment strategy will transition from one stage to another on treatment failure or contraindications for the procedures. CLT, cadaveric liver transplantation; LDLT, living donor liver


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InternalMed_Harrison. treatment. Treatment strategy will transition from one stage to another on treatment failure or contraindications for the procedures. CLT, cadaveric liver transplantation; LDLT, living donor liver transplantation; PST, Performance Status Test. (Modified from JM Llovet et al: JNCI 100:698, 2008.) on prognosis and may be microscopic or macroscopic (visible on computed tomography [CT] scans). Most large tumors have microscopic vascular invasion, so full staging can usually be made only after surgical resection. Stage III disease contains a mixture of lymph node– positive and–negative tumors. Stage III patients with positive lymph node disease have a poor prognosis, and few patients survive 1 year. The prognosis of stage IV is poor after either resection or transplantation, and 1-year survival is rare.


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InternalMed_Harrison. New Directions Consensus is needed on staging. These systems will soon be refined or upended by proteomics. APPROACH TO THE PATIENT: The history is important in evaluating putative predisposing factors, including a history of hepatitis or jaundice, blood transfusion, or use of intravenous drugs. A family history of HCC or hepatitis should be sought and a detailed social history taken to include job descriptions for industrial exposure to possible carcinogenic drugs as well as contraceptive hormones. Physical examination should include assessing stigmata of underlying liver disease such as jaundice, ascites, peripheral edema, spider nevi, palmar erythema, and weight loss. Evaluation of the abdomen for hepatic size, masses or ascites, hepatic nodularity and tenderness, and splenomegaly is needed, as is assessment of overall performance status and psychosocial evaluation.


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InternalMed_Harrison. AFP is a serum tumor marker for HCC; however, it is only increased in approximately one-half of U.S. patients. The lens culinaris agglutinin-reactive fraction of AFP (AFP-L3) assay is thought to be more specific. The other widely used assay is that for des-γ-carboxy prothrombin (DCP), a protein induced by vitamin K absence (PIVKA-2). This protein is increased in as many as 80% of HCC patients but may also be elevated in patients with vitamin K deficiency; it is always elevated after warfarin use. It may also predict for portal vein invasion. Both AFP-L3 and DCP are U.S. Food and Drug Administration (FDA) approved. Many other assays have been developed, such as glypican-3, but none have greater aggregate sensitivity and specificity. In a patient presenting with either a new hepatic mass or other indications of recent hepatic decompensation, carcinoembryonic antigen (CEA), vitamin B12, AFP, ferritin, PIVKA2, and antimitochondrial antibody should be measured, and standard liver function


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InternalMed_Harrison. other indications of recent hepatic decompensation, carcinoembryonic antigen (CEA), vitamin B12, AFP, ferritin, PIVKA2, and antimitochondrial antibody should be measured, and standard liver function tests should be performed, including prothrombin time (PT), partial thromboplastin time (PTT), albumin, transaminases, γ-glutamyl transpeptidase, and alkaline phosphatase. γ-Glutamyl transpeptidase and alkaline phosphatase may be particularly important in the 50% of HCC patients who have low AFP levels. Decreases in platelet count and white blood cell count may reflect portal hypertension and associated hypersplenism. Hepatitis A, B, and C serology should be measured. If HBV or HCV serology is positive, quantitative measurements of HBV DNA or HCV RNA are needed.


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InternalMed_Harrison. New Directions Newer biomarkers are being evaluated, especially tissueand serum-based genomics profiling. Newer plasma biomarkers include glypican-3, osteopontin, insulin-like growth factor I, and vascular endothelial growth factor. However, they are still in process of validation. Furthermore, the commercial availability of kits for isolating circulating tumor cells is permitting the molecular profiling of HCCs without the need for further tissue biopsy.


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InternalMed_Harrison. An ultrasound examination of the liver is an excellent screening tool. The two characteristic vascular abnormalities are hypervascularity of the tumor mass (neovascularization or abnormal tumor-feeding arterial vessels) and thrombosis by tumor invasion of otherwise normal portal veins. To determine tumor size and extent and the presence of portal vein invasion accurately, a helical/ triphasic CT scan of the abdomen and pelvis, with fast-contrast bolus technique, should be performed to detect the vascular lesions typical of HCC. Portal vein invasion is normally detected as an obstruction and expansion of the vessel. A chest CT is used to exclude metastases. Magnetic resonance imaging (MRI) can also provide detailed information, especially with the newer contrast agents. Ethiodol (Lipiodol) is an ethiodized oil emulsion retained by liver tumors that can be delivered by hepatic artery injection (5–15 mL) for CT imaging 1 week later. For small tumors, Ethiodol injection is very helpful


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InternalMed_Harrison. is an ethiodized oil emulsion retained by liver tumors that can be delivered by hepatic artery injection (5–15 mL) for CT imaging 1 week later. For small tumors, Ethiodol injection is very helpful before biopsy because the histologic presence of the dye constitutes proof that the needle biopsied the mass under suspicion. A prospective comparison of triphasic CT, gadolinium-enhanced MRI, ultrasound, and fluorodeoxyglucose positron emission tomography (FDG-PET) showed similar results for CT, MRI, and ultrasound; PET imaging appears to be positive in only a subset of HCC patients. Abdominal CT versus MRI/CT uses a faster single breath-hold, is less complex, and is less dependent on patient cooperation. MRI requires a longer examination, and ascites can cause artifacts, but MRI is better able to distinguish dysplastic or regenerative nodules from HCC. Imaging criteria have been developed for HCC that do not require biopsy proof, as they have >90% specificity. The criteria include nodules


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InternalMed_Harrison. to distinguish dysplastic or regenerative nodules from HCC. Imaging criteria have been developed for HCC that do not require biopsy proof, as they have >90% specificity. The criteria include nodules >1 cm with arterial enhancement and portal venous washout and, for small tumors, specified growth rates on two scans performed less than 6 months apart (Organ Procurement and Transplant Network). Nevertheless, explant pathology after liver transplant for HCC has shown that ∼20% of patients diagnosed without biopsy did not actually have a tumor.


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InternalMed_Harrison. New Directions The altered tumor vascularity that is a consequence of molecularly targeted therapies is the basis for newer imaging techniques including contrast-enhanced ultrasound (CEUS) and dynamic MRI.


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InternalMed_Harrison. Histologic proof of the presence of HCC is obtained through a core liver biopsy of the liver mass under ultrasound guidance, as well as random biopsy of the underlying liver. Bleeding risk is increased compared to other cancers because (1) the tumors are hypervascular and (2) patients often have thrombocytopenia and decreased liver-dependent clotting factors. Bleeding risk is further increased in the presence of ascites. Tracking of tumor has an uncommon problem. Fine-needle aspirates can provide sufficient material for diagnosis of cancer, but core biopsies are preferred. Tissue architecture allows the distinction between HCC and adenocarcinoma. Laparoscopic approaches can also be used. For patients suspected of having portal vein involvement, a core biopsy of the portal vein may be performed safely. If positive, this is regarded as an exclusion criterion for transplantation for HCC.


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InternalMed_Harrison. New Directions Immunohistochemistry has become mainstream. Prognostic subgroupings are being defined based on growth signaling pathway proteins and genotyping strategies, including a prognostically significant five-gene profile score. Furthermore, molecular profiling of the underlying liver has provided evidence for a “fieldeffect” of cirrhosis in generating recurrent or new HCCs after primary resection. In addition, characteristics of HCC stem cells have been identified and include EpCAM, CD44, and CD90 expression, which may form the basis of stem cell therapeutic targeting strategies.


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InternalMed_Harrison. There are two goals of screening, both in patients at increased risk for developing HCC, such as those with cirrhosis. The first goal is to detect smaller tumors that are potentially curable by ablation. The second goal is to enhance survival, compared with patients who were not diagnosed by surveillance. Evidence from Taiwan has shown a survival advantage to population screening in HBV-positive patients, and other evidence has shown its efficacy in diagnosis for HCV. Prospective studies in


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InternalMed_Harrison. Tumors of the Liver and Biliary Tree 548 high-risk populations showed that ultrasound was more sensitive than AFP elevations alone, although most practitioners request both tests at 6-month intervals for HBV and HCV carriers, especially in the presence of cirrhosis or worsening of liver function tests. However, an Italian study in patients with cirrhosis identified a yearly HCC incidence of 3% but showed no increase in the rate of detection of potentially curable tumors with aggressive screening. Prevention strategies including universal vaccination against hepatitis are more likely to be effective than screening efforts. Despite absence of formal guidelines, most practitioners obtain 6-month AFP and ultrasound (cheap and ubiquitous, even in poor countries) or CT (more sensitive, especially in overweight patients, but more costly) studies when following high-risk patients (HBV carriers, HCV cirrhosis, family history of HCC).


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InternalMed_Harrison. Current Directions Cost-benefit analysis is not yet convincing, even though screening is intuitively sound. However, studies from areas with high HBV carrier rates have shown a survival benefit for screening as a result of earlier stage at diagnosis. A definitive clinical trial on screening is unlikely, due to difficulties in obtaining informed consent for patients who are not to be screened. γ-Glutamyl transpeptidase appears useful for detecting small tumors.


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InternalMed_Harrison. Prevention strategies can only be planned when the causes of a cancer are known or strongly suspected. This is true of few human cancers, with significant exceptions being smoking and lung cancer, papilloma virus and cancer of the cervix uteri, and cirrhosis of any cause or dietary contamination by aflatoxin B1 for HCC. Aflatoxin B1is one of the most potent known chemical carcinogens and is a product of the Aspergillus mold that grows on peanuts and rice when stored in hot and humid climates. The obvious strategy is to refrigerate these foodstuffs when stored and to conduct surveillance programs for elevated aflatoxin B1 levels, as happens in the United States, but not usually in Asia. HBV is commonly transmitted from mother to fetus in Asia (except Japan), and neonatal HBV vaccination programs have resulted in a big decrease in adolescent HBV and, thus, in predicted HCC rates. There are millions of HBV and HCV carriers (4 million with HCV in the United States) who are already


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InternalMed_Harrison. programs have resulted in a big decrease in adolescent HBV and, thus, in predicted HCC rates. There are millions of HBV and HCV carriers (4 million with HCV in the United States) who are already infected. Nucleoside analogue–based chemoprevention (entecavir) of HBV-mediated HCC in Japan resulted in a fivefold decrease in HCC incidence over 5 years in cirrhotic but not in non-cirrhotic HBV patients. More powerful and effective HCV therapies promise the possibility of prevention of HCV-based HCC in the future.


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InternalMed_Harrison. Most HCC patients have two liver diseases, cirrhosis and HCC, each of which is an independent cause of death. The presence of cirrhosis usually places constraints on resection surgery, ablative therapies, and chemotherapy. Thus patient assessment and treatment planning have to take the severity of the nonmalignant liver disease into account. The clinical management choices for HCC can be complex (Fig. 111-2, Tables 111-5 and 111-6). The natural history of HCC is highly variable. Patients presenting with advanced tumors (vascular invasion, symptoms, extrahepatic spread) have a median survival of ∼4 months, with or without treatment. Treatment results from the literature are difficult to interpret. Survival is not always a measure of the efficacy of therapy because of the adverse effects on survival of the underlying liver disease. A multidisciplinary team, including a hepatologist, interventional radiologist, surgical oncologist, resection surgeon, transplant surgeon, and medical


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InternalMed_Harrison. on survival of the underlying liver disease. A multidisciplinary team, including a hepatologist, interventional radiologist, surgical oncologist, resection surgeon, transplant surgeon, and medical oncologist, is important for the comprehensive management of HCC patients.


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InternalMed_Harrison. Early-stage tumors are successfully treated using various techniques, including surgical resection, local ablation (thermal, radiofrequency [RFA], or microwave ablation (MWA]), and local injection therapies (Table 111-6). Because the majority of patients with HCC suffer from a field defect in the cirrhotic liver, they are at risk for subsequent multiple primary liver tumors. Many will also have significant underlying liver disease and may not tolerate major surgical loss of hepatic parenchyma, and they may be eligible for orthotopic liver transplant (OLTX). Living related donor transplants have increased in popularity, resulting in absence of waiting for a transplant. An important principle in treating early-stage HCC in the nontransplant


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InternalMed_Harrison. PEI/RFA/MWA Single lesion <5 cm Child’s A/B Tumor progression Transplant TACE/90Yttrium/ New agent trials Multifocal >5 cm Child’s A/B Sorafenib/Palliative care hormonal therapies Child’s C Bilirubin ˜2 Metastases Neoadjuvant bridge therapy RFA/TACE/90Yttrium Living donor transplant Suitable donor UNOS + criteria Ablation candidate Resection/RFA Non-cirrhotic Child’s A Single lesion No metastases Transplant candidate Transplant evaluation 1 lesion <5 cm 3 lesions all less than 3 cm Child’s A/B/C; AFP <1000 ng/mL No gross vascular invasion Not suitable for surgery Medical evaluation Comorbid factors 4 lesions Gross vascular invasion LN (+) or metastasis HCC diagnosed Cadaver donor wait list Yes Sorafenib/New agent clinical trials FIGURE 111-2 Hepatocellular carcinoma (HCC) treatment algorithm. The initial clinical evaluation is aimed at assessing the extent of the tumor and the underlying functional compromise of the liver by cirrhosis. Patients are classified as having resectable


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InternalMed_Harrison. The initial clinical evaluation is aimed at assessing the extent of the tumor and the underlying functional compromise of the liver by cirrhosis. Patients are classified as having resectable disease or unresectable disease or as being candidates for transplantation. AFP, α fetoprotein; LN, lymph node; MWA, microwave ablation; OLTX, orthotopic liver trans-plantation; PEI, percutaneous ethanol injection; RFA, radiofrequency ablation; TACE, transcatheter arterial chemoembolization; UNOS, United Network for Organ Sharing. Child’s A/B/C refers to the Child-Pugh classification of liver failure.


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InternalMed_Harrison. Regional Therapies: Hepatic Artery Transcatheter Treatments Transarterial chemotherapy Transarterial embolization Transarterial chemoembolization Transarterial drug-eluting beads Transarterial radiotherapies: Molecularly targeted therapies (sorafenib, etc.) setting is to use liver-sparing treatments and to focus on treatment of both the tumor and the cirrhosis.


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InternalMed_Harrison. Surgical Excision The risk of major hepatectomy is high (5–10% mortality rate) due to the underlying liver disease and the potential for liver failure, but acceptable in selected cases and highly dependent on surgical experience. The risk is lower in high-volume centers. Preoperative portal vein occlusion can sometimes be performed to cause atrophy of the HCC-involved lobe and compensatory hypertrophy of the noninvolved liver, permitting safer resection. Intraoperative ultrasound is useful for planning the surgical approach. The ultrasound can image the proximity of major vascular structures that may be encountered during the dissection. In cirrhotic patients, any major liver surgery can result in liver failure. The Child-Pugh classification of liver failure is still a reliable prognosticator for tolerance of hepatic surgery, and only Child A patients should be considered for surgical resection. Child B and C patients with stages I and II HCC should be referred for OLTX if 549


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InternalMed_Harrison. for tolerance of hepatic surgery, and only Child A patients should be considered for surgical resection. Child B and C patients with stages I and II HCC should be referred for OLTX if 549 appropriate, as well as patients with ascites or a recent history of variceal bleeding. Although open surgical excision is the most reliable, the patient may be better served with a laparoscopic approach to resection, using RFA, MWA, or percutaneous ethanol injection (PEI). No adequate comparisons of these different techniques have been undertaken, and the choice of treatment is usually based on physician skill. However, RFA has been shown to be superior to PEI in necrosis induction for tumors <3 cm in diameter and is thought to be equivalent to open resection and, thus, is the treatment of first choice for these small tumors. As tumors get larger than 3 cm, especially ≥5 cm, the effectiveness of RFA-induced necrosis diminishes. The combination of transcatheter arterial chemoembolization (TACE) with


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InternalMed_Harrison. for these small tumors. As tumors get larger than 3 cm, especially ≥5 cm, the effectiveness of RFA-induced necrosis diminishes. The combination of transcatheter arterial chemoembolization (TACE) with RFA has shown superior results to TACE alone in a prospective, randomized trial. Although vascular invasion is a preeminent negative prognostic factor, microvascular invasion in small tumors appears not to be a negative factor.


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InternalMed_Harrison. Local Ablation Strategies RFA uses heat to ablate tumors. The maxi mum size of the probe arrays allows for a 7-cm zone of necrosis, which would be adequate for a 3to 4-cm tumor. The heat reliably kills cells within the zone of necrosis. Treatment of tumors close to the main portal pedicles can lead to bile duct injury and obstruction. This limits the location of tumors that are anatomically suited for this technique. RFA can be performed percutaneously with CT or ultrasound guidance, or at the time of laparoscopy with ultrasound guidance.


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InternalMed_Harrison. Local Injection Therapy Numerous agents have been used for local injection into tumors, most commonly ethanol (PEI). The relatively soft HCC within the hard background cirrhotic liver allows for injection of large volumes of ethanol into the tumor without diffusion into the hepatic parenchyma or leakage out of the liver. PEI causes direct destruction of cancer cells, but it is not selective for cancer and will destroy normal cells in the vicinity. However, it usually requires multiple injections (average three), in contrast to one for RFA. The maximum size of tumor reliably treated is 3 cm, even with multiple injections.


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InternalMed_Harrison. current directions Resection and RFA each obtain similar results. However, a distinction has been made between the causes and prevention strategies needed to prevent early versus late tumor recurrences after resection. Early recurrence has been linked to tumor invasion factors, especially microvascular tumor invasion with elevated transaminases, whereas late recurrence has been associated with cirrhosis and virus hepatitis factors and, thus, the development of new tumors. See the section on virus-directed adjuvant therapy below. Liver Transplantation (OLTX) A viable option for stages I and II tumors in the setting of cirrhosis is OLTX, with survival approaching that for noncancer cases. OLTX for