Gastrointestinal and Liver Tumors

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[edit] Gastrointestinal and Liver Tumors

Paul C. SchroyIII

[edit] TUMORS OF THE STOMACH

A variety of benign and malignant tumors can arise in the stomach (Table 105-1). Adenocarcinomas are the most common malignant neoplasms, followed by lymphomas and leiomyosarcomas. Leiomyomas are the most common benign neoplasms but are rarely clinically significant. Benign gastric polyps tend to be more relevant clinically but are relatively uncommon. Carcinoid tumors may also arise in the stomach. In general these tumors are detected during radiographic or endoscopic evaluation of patients with nonspecific gastrointestinal (GI) complaints such as epigastric pain, nausea, vomiting, and bleeding. Progressive weight loss and the presence of a palpable mass are more ominous signs suggestive of advanced malignancy. Because these tumors share similar radiographic appearances with each other as well as with benign diseases, particularly gastric ulcer, endoscopy with biopsy and brush cytology is the diagnostic modality of choice. Management varies considerably depending on tumor type and, in the case of malignancy, tumor stage.

Table 105-1 Most Common Gastrointestinal and Liver Tumors

[edit] Gastric Cancer

Gastric cancer is one of the most common cancers worldwide, even though both incidence and mortality have declined dramatically worldwide over the past 50 years. Recent advances in understanding the epidemiology and pathogenesis have helped identify etiologic factors. Recent interest has focused on substantiating the causal role of these factors to develop rational preventive strategies. Meanwhile, early diagnosis remains the key to prolonged survival and reduced mortality.

[edit] Epidemiology.

The incidence of gastric cancer varies worldwide. In general the disease is more common in developing countries than industrialized nations and has a predilection for urban and lower socioeconomic groups. Japan, China, South America, and Eastern Europe have the highest rates, whereas the United States, Canada, parts of Africa (e.g., Uganda), and Southeast Asia have the lowest rates. Migrants typically acquire the risk of their host countries, suggesting an important role for environmental factors. Gastric cancer rarely occurs before age 40, after which the incidence rises steadily, peaking in the seventh decade. Men are affected almost twice as often as females.

Curiously, incidence rates have declined steadily in both high-risk and low-risk countries, except in Poland and Portugal. In the United States the annual incidence of gastric cancer declined from more than 30 cases per 100,000 population in the 1930s to less than 10 cases per 100,000 in the 1990s. Nevertheless, gastric cancer remains an important public health concern, with estimates of more than 22,000 new cases and 14,000 deaths for 1999. African, Hispanic, and Native Americans are 1.5 to 2.5 times more likely to develop gastric cancer than whites.

The global decline of gastric cancer incidence rates reflects a decrease in the incidence of cancers arising in the distal stomach (body and antrum); in contrast, the incidence of cancers in the proximal stomach (cardia) and gastroesophageal (GE) junction has steadily increased at a rate exceeding that of any other cancer, except melanoma or lung cancer. Unlike cancers of the distal stomach, cancers of the proximal stomach and GE junction are more common among higher socioeconomic groups.

[edit] Etiology.

The etiology of gastric cancer is obscure. Epidemiologic data provide strong evidence that environmental factors, particularly diet, play a dominant role. Diets rich in complex carbohydrates (e.g., fava beans), salt, pickled or smoked foods, dried fish, and poorly preserved foods have all been linked with an increased risk of gastric cancer. Conversely, diets rich in fresh fruits and vegetables have a negative association. Dietary nitrates have also been implicated on the basis of both epidemiologic evidence and rodent models of gastric carcinogenesis. Dietary nitrates may be reduced by bacteria into nitrites, which then combine with secondary amines in food, drugs, or pesticides to form carcinogenic nitrosamines.

Chronic Helicobacter pylori infection, a causative agent of chronic antral gastritis and peptic ulcer disease (PUD), has also been implicated in the etiology of gastric cancer (see Chapter 102 ). Both descriptive and observational epidemiologic studies have consistently demonstrated a strong association between H. pylori infection and gastric cancer. By 1994 the World Health Organization (WHO) concluded that sufficient evidence had accumulated to classify H. pylori as a group 1 human carcinogen.^[1] More recently, a meta-analysis of existing cohort and case-control studies found that H. pylori–infected individuals were nearly twice as likely to develop gastric cancer as uninfected controls (summary odds ratio, 1.9; confidence interval, 1.3 to 2.8).^[2] The relative risk was found to be greatest for younger individuals (9.3 for under age 29), in whom the absolute risk is quite low. The relative risk was also greater for cancers in the distal stomach than for those located in the cardia but was comparable for intestinal and diffuse cancers.

Genetic factors also play a role in etiology. Gastric cancer is one of the extracolonic malignancies associated with hereditary nonpolyposis colorectal cancer (HNPCC), or Lynch syndrome, a genetic disease caused by germ-line mutations of repair genes with mismatched deoxyribonucleic acid (DNA). Gastric cancer has also been reported in patients with familial polyposis (polyposis coli), a distinct genetic syndrome caused by mutations of the APC gene. As with colorectal cancer, familial clustering has also been observed in the absence of these well-defined genetic syndromes. First-degree relatives (e.g., parent, sibling) of patients with gastric cancer have a twofold to threefold increased risk of developing the disease. Familial risk is more strongly associated with the diffuse histopathologic type of gastric cancer than the intestinal type. Risk of gastric cancer is also increased among persons with blood group A.

[edit] Predisposing Conditions.

A variety of conditions have been associated with an increased risk of gastric cancer. Chronic atrophic gastritis with intestinal metaplasia and achlorhydria is found in the majority of patients with gastric cancer, but its etiologic role is unclear, since fewer than 10% of patients with this condition ultimately develop gastric cancer. Chronic H. pylori infection and pernicious anemia, both also associated with chronic atrophic gastritis, reduced gastric acidity, and intestinal metaplasia, are well-recognized predisposing conditions. Prior gastric surgery for PUD, particularly partial gastrectomy with Billroth II anastomosis, is associated with an increased risk of cancer in the gastric remnant 15 to 20 years after the initial surgery. Other premalignant conditions include gastric adenomatous polyps and Ménétrier's disease (giant hypertrophic gastritis). Although each of these conditions is associated with cancers of the distal stomach, Barrett's esophagus is the only recognized premalignant condition linked with cancers of the cardia and GE junction. Periodic endoscopic surveillance is currently recommended only for patients with adenomatous polyps and Barrett's esophagus. A baseline screening endoscopy has also been recommended for patients with newly diagnosed pernicious anemia, but data are insufficient to warrant long-term surveillance for this condition.

The relationship between chronic gastric ulcer and gastric cancer is controversial. Most authorities currently agree that gastric ulcer does not predispose to gastric cancer, but recent evidence suggests an association with benign duodenal ulcer disease. Because gastric cancers may present as an ulcer, however, histologic and cytologic assessment is recommended for all gastric ulcers, regardless of their radiographic or endoscopic appearance. Follow-up endoscopy after 8 to 12 weeks of appropriate medical therapy is also indicated, since a small but significant number of malignant ulcers can demonstrate healing by radiographic criteria alone.

[edit] Histopathology.

Gastric cancers can arise in any region of the stomach and can assume a myriad of gross morphologic configurations. Early gastric cancers (i.e., tumors confined to the mucosa or submucosa regardless of lymph node status) may appear as a subtle polypoid protrusion, superficial plaque, mucosal discoloration, depression, or ulceration. More advanced cancers typically present as polypoid or fungating masses with ulceration (Fig. 105-1A); superficial spreading or infiltrating (linitis plastica) forms are encountered less often. Histologically the vast majority of malignant neoplasms of the stomach are adenocarcinomas. These can be subdivided into diffuse and intestinal types (Lauren's classification) or infiltrative and expanding types (Ming's classification). The intestinal or expanding type tends to predominate in high-risk populations, is more common in men and older patients, is associated with a relatively better prognosis, and is preceded by a prolonged precancerous state. In contrast, the diffuse or infiltrative type predominates in women and younger patients, carries a poorer prognosis, and is not preceded by a known precancerous lesion.

Figure 105-1 A, Endoscopic appearance of malignant gastric ulcer arising in the fundus of stomach. B, Radiologic appearance of malignant gastric ulcer on upper gastrointestinal series. Note that ulcer (arrow) is within a mass.

[edit] Clinical Presentation.

Although routine endoscopy and biopsy may diagnose early gastric cancers, 90% of patients with gastric cancer seek medical help only when the cancer has progressed to a more advanced stage. Persistent abdominal pain and weight loss are the most common presenting symptoms. Weight loss may be caused by anorexia, nausea and vomiting, or early satiety. Although occult GI blood loss with or without iron deficiency anemia is common, gross hematemesis is rare. Dysphagia and weight loss are typical presenting symptoms in patients with tumors of the gastric cardia or GE junction. A palpable mass may be detected in up to 50% of patients and indicates longstanding advanced disease. Jaundice, ascites, a periumbilical metastatic nodule (Sister Mary Joseph node), left supraclavicular adenopathy (Virchow's or signal node), a palpable enlarged ovary (Krukenberg's tumor), or a firm mass palpable on rectal examination in the anterior cul-de-sac (Blumer's shelf) all suggest widespread metastases and a poor prognosis. Gastric cancer is also associated with a variety of paraneoplastic phenomena, including the sudden appearance of diffuse seborrheic keratoses (Leser-Trélat sign), pigmented dermal lesions (acanthosis nigricans), microangiopathic hemolytic anemia, membranous nephropathy, hypercoagulability with thrombosis (Trousseau's syndrome), and dermatomyositis.

[edit] Diagnosis.

In high-risk countries such as Japan, mass screening of asymptomatic individuals with endoscopy, double-contrast radiography, and cytology has been successful in detecting a high percentage of early gastric cancers. Unfortunately, mass screening cannot be justified in the United States because of the relatively low incidence. Physicians must therefore rely on a high degree of suspicion when evaluating patients with vague nonspecific GI complaints, particularly older patients with new dyspeptic symptoms or high-risk patients. Upper gastrointestinal (UGI) endoscopy, or esophagogastroduodenoscopy (EGD), is widely accepted as the diagnostic procedure of choice because of its superior accuracy. Referral for early endoscopy is indicated for patients over age 45 with new-onset dyspepsia, patients of any age with alarm symptoms (e.g., weight loss, recurrent vomiting, dysphagia, evidence of bleeding, or anemia), or younger patients who fail empiric antisecretory or prokinetic therapy.^[3] At endoscopy a minimum of six biopsies and brush cytology should be obtained of any mass lesion, ulceration, area of discoloration, unexplained mucosal depression, or prominent fold(s). Repeat endoscopy with tissue sampling may be necessary if histologic or cytologic assessment is nondiagnostic.

UGI radiography is an alternative diagnostic strategy if upper endoscopy is not readily available. Double-contrast studies afford greater accuracy, particularly for early mucosal abnormalities. Abnormal findings such as a mass with or without ulceration (Fig. 105-1, B), enlarged gastric folds, and lack of distensibility (leather bottle appearance) require endoscopic follow-up and tissue confirmation. Endoscopy is also warranted for patients with equivocal radiographic findings and those with suspicious clinical presentations but negative x-ray results.

Once the diagnosis is established, evaluation for the extent of disease is warranted to optimize treatment planning and determine prognosis. Endoscopic ultrasound provides an accurate assessment of depth of tumor invasion into the bowel wall and may give useful information regarding perigastric lymph nodes. Computed tomography (CT) provides an accurate assessment of regional and retroperitoneal lymph node involvement, direct extension into contiguous organs, liver metastases, and ascites. Paracentesis with cytologic examination should be performed if ascites is present. Laparoscopy may also be useful in the evaluation of patients with unexplained ascites and negative or equivocal CT scans. Enlarged peripheral lymph nodes (e.g., Virchow's node) require biopsy. Additional studies, such as abdominal ultrasound, radionuclide scanning, magnetic resonance imaging (MRI), and angiography, may be useful in select cases.

[edit] Treatment.

Surgical or endoscopic resection is the only potentially curative treatment for gastric cancer. Tumors amenable to endoscopic removal should be confined to the mucosal layer of the stomach, as determined by endoscopic ultrasound and confirmed histologically. All other patients should be considered for surgery unless (1) there is evidence of widespread metastatic disease, (2) the patient is a poor surgical candidate, (3) the primary tumor is clearly unresectable, or (4) total gastrectomy is required with only palliative intent. Curative resection requires wide excision of the primary tumor and en bloc removal of regional lymph nodes and contiguous structures. The actual extent of resection is determined at surgery and depends on several factors, most notably tumor size, location, and lymph node status. A palliative resection should be considered in patients with incurable disease to diminish the risk of complications, such as bleeding, perforation, or gastric outlet obstruction. Chemotherapy should be considered for patients with surgically incurable disease. Combination regimens comprising the most active single agents, such as FAMTX (5-fluorouracil, doxorubicin, methotrexate) or ELF (etoposide, leucovorin, 5-fluorouracil) have yielded the best response rates but have had little impact on long-term survival. Radiotherapy has been used primarily as a palliative approach to specific tumor-related problems, such as bleeding, obstruction with pain from local extension, liver infiltration, and bone metastases.

Palliation is an important aspect of gastric cancer treatment. With any palliative therapy the physician must consider the patient's overall prognosis to avoid excessive morbidity and mortality or lengthy hospital stays for patients with a limited life span. Although surgical resection and intestinal bypass may be therapeutic options for some patients with obstruction, nonsurgical candidates may benefit from endoscopic approaches (e.g., laser ablation, stent placement) and radiation therapy, which are also preferred for the management of acute or chronic tumor-related bleeding in nonsurgical patients. Decisions regarding nutritional support need to be individualized, but in general, enteral feeding via endoscopically placed gastrostomy (PEG) or jejunostomy (PEJ) tubes is preferred over parenteral feeding.

[edit] Follow-up.

Postoperative management of patients with gastric cancer depends on disease status after resection. Patients with residual or inoperable disease should be considered for radiation or chemotherapy. Those without evidence of disease should be closely monitored for signs or symptoms of recurrence. Since 85% occur within the first 2 years, patients should be evaluated frequently during this period. Follow-up should include a careful history, physical examination, and routine laboratory tests (complete blood count, liver profile) every 3 to 6 months for the first 2 years and every 6 to 12 months thereafter. In addition, a CT scan of the abdomen, chest radiograph, and UGI endoscopy with biopsy of the anastomosis should be obtained 6 to 12 months after surgery, then yearly. Suspicious findings warrant aggressive diagnostic evaluation and tissue confirmation.

[edit] Prognosis.

Prognosis depends on tumor stage at diagnosis. The tumor, node, and metastasis (TNM) classification system is currently the most widely used staging system (Table 105-2). Based on this system, 5-year survival rates range from 85% to 90% for stage I disease to 3% for stage IV. Unfortunately, overall survival is only 18% to 20%, indicating that most patients present with advanced, incurable disease.

Table 105-2 Gastric Cancer: 5-year Survival by Disease Stage at Diagnosis

[edit] Gastric Polyps

Gastric polyps are uncommon, occurring in less than 2% of autopsy surveys, so epidemiologic and etiologic data are scant. Hyperplastic polyps are most common (75% to 90%) and occur frequently in association with H. pylori–associated chronic gastritis; malignant transformation is rare. Adenomatous polyps are much less common (10% to 20%), but unlike hyperplastic polyps, adenomatous polyps are true neoplastic lesions that carry a significant risk of malignant transformation, particularly if greater than 2 cm in size. Although most occur sporadically, adenomatous polyps have been described in patients with pernicious anemia and familial adenomatous polyposis or Gardner's syndrome. Hamartomatous polyps, also referred to fundic gland polyps because of their predilection for the proximal stomach, are the rarest type of gastric polyp and have no malignant potential. These lesions may occur sporadically or in association with a variety of inherited polyposis syndromes, including familial adenomatous polyposis and Gardner's syndrome, Peutz-Jeghers syndrome, Cronkhite-Canada syndrome, and Cowden disease.

Gastric polyps are almost always asymptomatic and usually discovered incidentally at endoscopic or radiologic examination. Patients may complain of vague epigastric pain unrelated to eating, bloating, belching, or nausea. Occult GI bleeding and iron deficiency anemia may also occur, but hematemesis is rare. Patients with pedunculated polyps nearthe pylorus may present with symptoms of intermittent gastric outlet obstruction caused by prolapse.

Management of gastric polyps depends on clinicopathologic considerations. All polypoid gastric lesions require biopsy to establish a histologic diagnosis. All symptomatic polyps should be removed either endoscopically or surgically. Asymptomatic hyperplastic or hamartomatous polyps, if small and adequately biopsied, do not need to be removed. Eradication of H. pylori has been reported to induce regression of hyperplastic polyps and should be considered if coinfection is present. Adenomatous polyps should be completely excised because of their premalignant nature. Surgical resection is indicated for any polyp containing malignant tissue, adenomatous polyps not amenable to complete endoscopic removal, and polyps with nondiagnostic histology. Patients with adenomatous gastric polyps require annual endoscopic surveillance because of the risk of developing new polyps or cancer. Surveillance is not recommended for patients with only hyperplastic or hamartomatous polyps.

[edit] Gastric Lymphoma

Primary gastric lymphoma accounts for 1% to 5% of all gastric malignancies and is anatomically the most common extranodal type of non-Hodgkin's lymphoma. The stomach is also often involved in patients with disseminated disease arising elsewhere. Most primary gastric lymphomas arise from preexisting mucosa-associated lymphoid tissue (MALT) lymphomas. Recent epidemiologic studies support a strong association between MALT lymphomas and chronic H. pylori infection.^[1] MALT lymphomas can also occur in association with various autoimmune and immunodeficiency syndromes. Most develop in individuals over age 50, and there is a slight male predominance. Symptoms are nonspecific and include abdominal pain, nausea, vomiting, anorexia, weight loss, and bleeding.

Grossly, MALT lymphomas are often indistinguishable from gastric adenocarcinomas and may present as unifocal ulcerated, polypoid, or infiltrating mass lesions involving the antrum and prepyloric region or body of the stomach (Fig. 105-2, A). Multifocal or diffuse involvement is uncommon. Histologically, MALT lymphomas are of B-cell origin and classified as low grade or high grade. Low-grade MALT lymphomas are characterized by the presence of nonneoplastic reactive lymphoid follicles surrounded by small to medium-sized centrocyte-like (CCL) tumor cells that extend into the surrounding tissue and invade individual gastric glands to form lymphoepithelial complexes (Fig. 105-2, B). High-grade MALT lymphomas are characterized by confluent sheets or clusters of centroblastic (large, noncleaved) or plasmablastic tumor cells outside of colonized follicles. Reactive lymphoid follicles and lymphoepithelial lesions may or may not be present; if absent, high-grade MALT lymphomas may be histologically and cytologically indistinguishable from other high-grade B-cell lymphomas.

Figure 105-2 A, Endoscopic appearance of large, ulcerated gastric MALT lymphoma. B, Histologic appearance of low-grade gastric MALT lymphoma with characteristic lymphoepithelial complex (small arrow) on left, and coincident high-grade MALT lymphoma on right (wide arrow).

The diagnosis of gastric lymphoma should be considered in any person found to have diffuse mucosal hypertrophy with irregular thickening of the rugal folds or an ulcerated or polypoid mass at endoscopy or on UGI series. Endoscopic biopsies and brush cytology or fine-needle aspiration should be obtained to establish the diagnosis. Endoscopic ultrasound, CT of the abdomen and chest, and bone marrow aspiration with biopsy provide additional staging information.

Histologic grade and stage of disease dictate the treatment of gastric lymphomas (Table 105-3). Eradication of H. pylori is the treatment of choice for stage IE low-grade lymphomas, with complete regression rates in the range of 70%. Coincident high-grade disease missed on biopsy is the most common reason for resistance. Because of the potential for sampling error and relapse, close follow-up with periodic UGI endoscopy and biopsy is indicated every 4 weeks until resolution, then every 3 to 6 months. Patients who do not respond or relapse still have a high rate of cure. Five-year survival for such patients is as high as 80% to 90% after single-agent chemotherapy (e.g., cyclophosphamide or chlorambucil) or radiation therapy. Multiagent chemotherapy, such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), is reserved for the small percentage of patients who fail to respond or who relapse after other, less aggressivetherapies. CHOP chemotherapy is also the treatment of choice for patients with extensive mucosal involvement or advanced (stage IIIE or IV) disease.

Table 105-3 Ann Arbor Classification of Gastric Lymphomas

Optimal treatment for early-stage high-grade lymphomas remains controversial. Historically, surgery, alone or in combination with radiation therapy or chemotherapy, was the mainstay of therapy for stages IE and IIE disease. Although surgery remains an option, particularly for patients with bulky disease, recent studies suggest that systemic chemotherapy with multiagent regimens (e.g., CHOP) alone may be superior. CHOP chemotherapy remains the treatment of choice for stages IIIE and IV disease. Overall survival for high-grade gastric lymphomas is about 45%.

[edit] Stromal Tumors

Leiomyomas are the most common benign stromal tumor of the stomach, occurring in up to 50% of persons over age 50. The vast majority are small (less than 2 cm) and clinically silent. Larger lesions may ulcerate and produce bleeding or abdominal pain. These tumors arise from the smooth muscle layer of the stomach and therefore appear as intramural filling defects with or without superficial ulceration on UGI series or as submucosal masses endoscopically. Endoscopic biopsies are frequently nondiagnostic, unless the lesion is ulcerated. Local surgical excision is the treatment of choice for symptomatic lesions.

Leiomyosarcomas account for approximately 1% of gastric malignancies. These tumors are sometimes difficult to distinguish from benign leiomyomas unless evidence suggests local extension or distant metastasis. As with leiomyomas, GI bleeding and abdominal pain are the most common presenting symptoms. A palpable abdominal mass and weight loss are highly suggestive of malignancy. Surgical resection is the treatment of choice, but unfortunately, two thirds of patients have extragastric spread at initial laparotomy. Neither radiotherapy nor chemotherapy has demonstrated significant efficacy. Five-year survival rates are 25% to 50%.

[edit] Gastric Carcinoids

Carcinoid tumors of the stomach are rare. They can be separated into three distinct groups: those associated with chronic atrophic gastritis type A, those associated with Zollinger-Ellison syndrome, and so-called sporadic carcinoids. Carcinoids associated with chronic atrophic gastritis (75%) may be unifocal or multifocal and typically present in the sixth or seventh decade of life; most are small (less than 1 cm) and rarely metastasize. Carcinoids associated with Zollinger-Ellison syndrome (5% to 10%) occur almost exclusively in patients with multiple endocrine neoplasia (MEN) type 1 and behave similar to those associated with chronic atrophic gastritis. Sporadic gastric carcinoids (15% to 25%) are much more aggressive and often fatal. Most present with metastatic disease, which may be accompanied by an atypical carcinoid syndrome manifested primarily by flushing.

Most gastric carcinoids, except for the sporadic type, are small and asymptomatic. Grossly they may resemble an ordinary ulcer, polyp, or tumor mass; occasionally, multiple lesions are present. Histologically it is often difficult to distinguish between benign and malignant tumors unless metastases are present. Gastric carcinoids arise in the foregut and may secrete a variety of hormones, including 5-hydroxytryptophan, adrenocorticotropic hormone (ACTH), or 5-hydroxytryptamine (serotonin). Thus patients may present with clinical manifestations of the carcinoid syndrome or Cushing's syndrome, but both are rare in the absence of liver metastases. An elevation in 24-hour urinary levels of 5-hydroxyindoleacetic acid (5-HIAA) confirms the diagnosis in such patients. Decisions regarding management depend on tumor size and histology. Complete endoscopic or surgical excision is the treatment of choice for small (less than 1 cm), incidentally discovered lesions. Larger lesions tend to exhibit more aggressive biologic behavior and warrant wide surgical resection with lymph node dissection. Management of metastatic disease and the carcinoid syndrome is discussed in the next section.

[edit] TUMORS OF THE SMALL BOWEL

Primary tumors of the small bowel are uncommon compared with other sites in the GI tract. The relative paucity of small bowel tumors is intriguing particularly because the small bowel accounts for 75% of the length of the GI tract and more than 90% of its mucosal surface area. Neutral or alkaline luminal pH, rapid transit, the liquid nature of the luminal contents, few anaerobic bacteria, and the presence of detoxifying enzymes (e.g., benzopyrene hydroxylase) capable of nullifying the effects of carcinogens have all been implicated as causing this phenomenon. Despite their rarity, small bowel tumors should be considered in the differential diagnosis of patients with symptoms suggestive of intermittent partial small bowel obstruction or unexplained occult GI blood loss (see Table 105-1).

[edit] Epidemiology

The epidemiology of benign small bowel tumors is not well defined because most are asymptomatic and not evident clinically. Conversely, accurate epidemiologic data for malignant small bowel tumors are available because of their progressive and ultimately symptomatic nature. Overall, tumors of the small bowel account for approximately 1% of all GI malignancies. In 1998, approximately 4500 new cases and 1200 deaths from malignant small bowel tumors occurred in the United States. Adenocarcinomas, carcinoid tumors, and primary lymphomas are the most common small bowel malignancies. Incidence figures suggest a slight male predominance for all three types of malignancies, with an overall incidence of less than one case per 100,000 population. Malignant small bowel tumors tend to be more common in developed countries, with the exception of immunoproliferative small intestinal disease (IPSID), also known as α-chain disease, Mediterranean lymphoma, or diffuse primary small intestinal lymphoma, which predominates in impoverished geographic regions.

[edit] Etiology

The etiology of most small bowel tumors is poorly understood. Although causative factors undoubtedly vary with histologic type, common factors must exist because patients with celiac sprue are predisposed to both adenocarcinoma and lymphoma of the small bowel. As in the colon, small bowel adenocarcinomas probably arise from preexisting benign adenomas, but the molecular mechanisms responsible for malignant transformation are unknown. Microbial colonization appears to be an important etiologic factor in the IPSID form of primary small bowel lymphoma based on its epidemiology and the observation that the disease is reversible if treated with tetracycline at the early prelymphomatous stage. Infectious etiologies have also been linked to other forms of small bowel lymphoma, most notably Epstein-Barr virus and both Burkitt's and Burkitt's-like (sporadic Burkitt's) small bowel lymphomas. Impairment of the normal mechanical or immunologic barriers, resulting in increased mucosal penetration of deleterious pathogens and antigens, has also been implicated in the etiology of small bowel tumors in patients with Crohn's disease and celiac sprue.

[edit] Predisposing Conditions

A number of mostly rare conditions appear to be associated with an increased risk of malignant small bowel tumors. Celiac sprue, Crohn's disease, familial adenomatous polyposis or Gardner's syndrome, neurofibromatosis, and various reconstructive procedures involving the ileum (e.g., ileal conduit, ileocystoplasty, ileostomy) have all been associated with an increased risk of small bowel adenocarcinomas. Celiac sprue, Crohn's disease, nodular lymphoid hyperplasia, autoimmune diseases, and immunodeficiency syndromes, including acquired immunodeficiency syndrome (AIDS), predispose to small bowel lymphomas. With the exception of familial adenomatous polyposis, periodic surveillance is generally not recommended for these conditions.

[edit] Histopathology and Differential Diagnosis

[edit] Benign Tumors.

Adenomas, leiomyomas, and lipomas are the most common benign tumors of the small bowel. Adenomas arise from the epithelial elements and can display tubular, tubulovillous, or villous growth patterns. Although the natural history of small bowel adenomas is not well defined, they probably have a similar malignant potential to colorectal adenomas. Most are small and may be sessile or pedunculated. Both sporadic adenomas and those associated with familial polyposis syndromes have a predilection for the proximal small intestine, particularly in the periampullary region of the duodenum. Periampullary adenomas, particularly of the villous type, are associated with a high risk of invasive adenocarcinoma.

Leiomyomas and lipomas arise from smooth muscle and fatty tissue, respectively. It is unknown if they can degenerate into malignant forms, but if this occurs, it must be very rare. Other benign tumors are curiosities.

[edit] Malignant Tumors.

Adenocarcinomas are the most common malignant tumors of the small bowel. Most originate in the proximal small bowel, from the second part of the duodenum to about 20 to 30 cm distant to the ligament of Treitz. Structurally they may be flat, stenosing, infiltrating, ulcerating, or polypoid lesions. Histologic appearance is similar to that of colorectal adenocarcinomas.

Primary small bowel lymphomas are a heterogenous group of unique B-cell and T-cell lymphoid malignancies with distinctive epidemiologic and clinicopathologic features (Table 105-4). The most common are B-cell lymphomas of the MALT type. IPSID is a specialized type of MALT lymphoma that occurs almost exclusively in the Middle East and is characterized by the synthesis of α-heavy chain paraprotein.

Table 105-4 Clinicopathologic Features of Primary Gastrointestinal Non-Hodgkin's Lymphomas

As with benign leiomyomas, Leiomyosarcomas arise from smooth muscle cells. Early-stage tumors may be difficult to distinguish from leiomyomas. More advanced tumors tend to be less differentiated and easier to diagnose histologically.

Small bowel carcinoid tumors (carcinoids) are thought to arise from serotonin-producing intraepithelial neuroendocrine cells. The ileum is the most common site of malignant tumors. Besides serotonin, these tumors may secrete a variety of biologically active substances, including gastrin, histamine, somatostatin, pituitary hormones, catecholamines, kinins, and prostaglandins. In general, localized tumors are rarely associated with the carcinoid syndrome because they secrete only small amounts of hormone(s), which are rapidly inactivated by the liver. The carcinoid syndrome is much more frequently associated with bulky metastatic disease involving the liver.

Histologically, it is often difficult to distinguish benign from malignant tumors. Localized tumors less than 1 cm are generally regarded as benign and those greater than 2 cm as malignant.

[edit] Clinical Presentation

Benign tumors are often asymptomatic and clinically insignificant. Fluctuating abdominal pain from intermittent partial small bowel obstruction is the most frequent presenting manifestation of symptomatic lesions. Obstruction is often caused by intussusception; benign small bowel tumors, particularly lipomas, are the most common cause of intussusception in adults. Occult GI bleeding may also be seen, but frank hematemesis or rectal bleeding is rare.

Because of their progressive nature, malignant tumors eventually become symptomatic and ultimately fatal unless detected early. Abdominal pain is the most common presenting symptom and may be colicky or more constant. Occult GI blood loss and iron deficiency anemia are also common, but frank bleeding is rare except with leiomyosarcomas. Weight loss occurs in up to 50% of patients and may be secondary to malabsorption, particularly with IPSID. Perforation is rare but may be seen with lymphomas or leiomyosarcomas. Jaundice is a common presenting feature of malignant periampullary tumors. Flushing, diarrhea, abdominal pain, and valvular heart disease typify the carcinoid syndrome, but other manifestations may also be present (Table 105-5). Foregut carcinoids may also cause symptoms of hypoglycemia, gastric hypersecretion, or Cushing's syndrome.

Table 105-5 Clinical Manifestations of Carcinoid Syndrome

[edit] Diagnosis

Barium contrast radiography has been the principal modality for the preoperative detection of small bowel tumors. The routine small bowel follow-through after oral ingestion of barium is useful in assessing the terminal ileum but less sensitive than enteroclysis (small bowel enema) in assessing other parts of the small bowel. Since enteroclysis requires duodenal intubation, it is reasonable to obtain a routine small bowel study, with compression views of the terminal ileum as the initial diagnostic study, in patients with suspected small bowel tumors. If this examination is negative or inconclusive, enteroclysis should be performed.

Endoscopic approaches are also useful in the diagnosis of small bowel tumors. In addition to direct visualization, endoscopy provides a means of obtaining tissue for histologic evaluation. Endoscopy is the procedure of choice for patients with occult GI blood loss. Otherwise asymptomatic patients, however, should first undergo colonoscopy to exclude the presence of a colonic neoplasm. Evaluation of the UGI tract is indicated if the colonoscopy is negative or if the condition suggests UGI disease. UGI endoscopy is done to further evaluate abnormal radiographic findings. Other diagnostic modalities, particularly for preoperative staging of malignant tumors, include CT scan, MRI, and in select cases arteriography.

Urinary 5-HIAA, a metabolite of serotonin, should be measured in patients with clinical features suggestive of carcinoid syndrome. Serotonin-containing foods and drugs (e.g., phenothiazines) that elevate serotonin levels can give false-positive results and should be withheld during testing. Malabsorption and chronic intestinal obstruction can also cause modest elevations in urinary 5-HIAA levels. Plasma or platelet serotonin levels can also be measured, but these tests are not widely available. Scintigraphy with radiolabeled octreotide, a long-acting somatostatin analog, is useful in localizing both primary and metastatic carcinoid tumors, with a sensitivity of about 90%.

[edit] Treatment and Prognosis

[edit] Benign Tumors.

Adenomas of the small bowel should be treated because of their premalignant status. Appropriate therapy depends on several factors, including location, size, shape (sessile or pedunculated), and histologic type (tubular or villous). Duodenal adenomas, with the exception of periampullary lesions, are usually amenable to endoscopic removal or ablation. Although some periampullary adenomas can also be treated endoscopically, surgical resection is preferred for most because of their sessile shape, villous histology, and propensity for malignant transformation. Local resection is considered adequate for completely benign tumors; more radical resection (i.e., pancreaticoduodenectomy [Whipple procedure]) is indicated for adenomas containing carcinoma. Unlike with colonic adenomas, long-term surveillance is not indicated for sporadic small bowel adenomas unless incomplete removal is a concern. Surveillance is recommended for patients with familial polyposis or Gardner's syndrome. Although strict guidelines have not been adopted, before prophylactic colectomy it is reasonable to perform a UGI endoscopy in these patients at age 30, then every 3 years.

Limited resection is adequate treatment for other benign tumors of the small bowel. Observation alone may be sufficient for asymptomatic tumors discovered incidentally at endoscopy, assuming biopsies confirm benign histology.

[edit] Malignant Tumors.

Surgical resection is the only potentially curative treatment for adenocarcinomas of the small bowel. Palliative resection or bypass should be considered if curative resection is not feasible. Palliative procedures should also be considered to control bleeding or relieve obstruction. Unfortunately, neither chemotherapy nor radiation therapy is effective in the treatment of advanced disease. Overall 5-year survival is only 10% to 20% even after “curative„ resection.

Optimal treatment of primary small bowel lymphomas depends on extent of involvement, stage, and to a lesser degree, type. Broad-spectrum antibiotics (e.g., tetracycline) alone or in combination with corticosteroids are recommended for the treatment of early-stage (prelymphomatous) IPSID, with response rates of 33% to 71%. Regardless of type, surgical resection is indicated for localized lymphomas confined to the bowel wall (stage IE) or involving contiguous nodes only (stage IIE). The role of adjuvant radiation therapy or chemotherapy after curative resection is controversial. Resection should also be considered for more advanced segmental disease to reduce tumor burden, relieve symptoms (e.g., obstruction), and obviate the risk of bleeding or perforation induced by radiation therapy or chemotherapy. Radiation therapy, alone or in combination with chemotherapy is the treatment of choice for patients with diffuse, unresectable small bowel disease. Disseminated disease is usually treated with radiation therapy plus combination chemotherapy. Overall 5-year survival rates vary but are about 50% for Western-type MALT lymphomas, 67% for IPSID, 60% for mantle cell lymphomas, and less than 10% for enteropathy-associated T-cell lymphoma. Prognosis for Burkitt's-like lymphomas is very good for children, with 5-year survival rates of 75%, but poor for adults, particularly in association with human immunodeficiency virus (HIV) infection.

Carcinoid tumors of the small bowel should be resected because of their potential to invade and metastasize. Tumors less than 1 cm are usually benign and can be cured with a limited surgical resection. Larger tumors, particularly those greater than 2 cm, require more radical surgical resection. Surgical resection of liver metastases should be considered for patients with limited hepatic disease, since it offers the most effective long-term palliation of symptoms and may prolong survival. Hepatic artery occlusion or embolization are alternatives for patients who are not candidates for resection, but responses tend to be of short duration. Cytotoxic chemotherapy is rarely of benefit and should be reserved for patients with significant symptoms or those who exhibit poor prognostic signs, such as impaired liver function, clinically evident carcinoid heart disease, or very high levels of urinary 5-HIAA. Synthetic analogs of somatostatin (e.g., octreotide) are highly effective in relieving the symptoms of carcinoid syndrome and have emerged as the treatment of choice for symptomatic disease. Although overall 5-year survival is only about 54%, prolonged survival does occur, even in the patient with metastatic disease.

Surgical resection is the treatment of choice for leiomyosarcomas. Chemotherapy with doxorubicin-containing regimens and radiation therapy both have a role in the management of unresectable disease. Surgery has also been advocated in the treatment of solitary liver or lung metastases. Overall 5-year survival rates of 20% to 50% have been reported.

[edit] TUMORS OF THE LARGE BOWEL

Colorectal tumors are often encountered in the evaluation of both symptomatic and asymptomatic patients. Polyps are the most common benign tumors and may be classified as neoplastic (adenomatous polyps), nonneoplastic (e.g., hyperplastic polyps), or submucosal (e.g., lipomas). Adenomatous polyps (adenomas) are premalignant precursors of most colorectal cancers; in contrast, nonneoplastic polyps have little or no malignant potential. Adenocarcinomas are by far the most common malignant tumors. Lymphomas, carcinoids, sarcomas, and a variety of extremely rare malignant tumors may also occur in the large bowel. This discussion focuses primarily on adenocarcinoma of the large bowel, commonly referred to as colorectal cancer, and its precursor, the adenomatous polyp.

[edit] Epidemiology

Worldwide incidence and mortality of colorectal cancer vary considerably. With the notable exception of Japan, industrialized countries are at greatest risk. High rates are found in North America, Western Europe, and New Zealand, whereas lower rates are found in Eastern Europe, most South American countries, Asia, and Africa. In the United States, both incidence and mortality rates have declined in recent years. Nevertheless, colorectal cancer remains the third most common form of cancer, with a standardized age-adjusted incidence of approximately 31 cases per 100,000 population, and the second leading cause of cancer-related death. In 1999 approximately 129,000 new cases were diagnosed and 56,600 persons died from their disease. Americans of average risk have approximately a 6% chance of developing colorectal cancer during their lifetime. Age is an important determinant of risk. Although extremely uncommon in persons under age 35 (except with rare predisposing genetic syndromes), the incidence of colorectal cancer increases steadily with age, particularly after age 50. Cancers of the colon affect men and women at similar rates, whereas cancers of the rectum are more common in men. Overall 5-year survival rates have improved significantly in recent years, presumably because of improved therapy and early detection, and are currently about 60%. Low-income minority groups, particularly black males, tend to have lower survival rates even after adjustment for tumor stage.

The epidemiology of colorectal adenomas is similar to that of colorectal cancer. In general the prevalence of colorectal adenomas in a given country parallels the prevalence of colorectal cancer. Age is an important determinant of prevalence in high-risk countries. U.S. autopsy studies suggest an overall prevalence of 50%, from about 30% at age 50 to 55% at age 80. Unlike colorectal cancer, adenomas are more common in men.

[edit] Etiology

The etiology of colorectal adenomas and subsequent colorectal cancer is unknown but seems related to both environmental and genetic factors. The importance of environmental factors is supported by the wide geographic variation in incidence rates and studies of migrant populations. Diet is probably the major environmental factor that explains these epidemiologic associations. In general, populations with a relatively high prevalence of colorectal adenomas and cancer consume high-calorie, high-fat diets. Conversely, populations at low risk consume diets rich in fruits, vegetables, and crude fiber. Observational studies have suggested that red meat rather than total fat may be responsible for the increased risk. Such studies have also challenged the protective effect of fiber.

Environmental factors other than diet have been linked with colorectal cancer risk. Lack of physical activity, obesity, daily alcohol consumption, and long-term exposure to cigarette smoke all appear to increase risk, whereas high levels of physical activity, multivitamins containing folic acid, regular use of aspirin, and for women, use of postmenopausal hormones and possibly oral contraceptives may reduce risk. More than 50% of colorectal cancers could be prevented if these lifestyle modifications were adopted at an early enough age to reverse risk.

Genetic factors are also important in the etiology of colorectal adenomas and cancers. It is now well established that germ-line mutations of the APC (adenomatous polyposis coli) tumor suppressor gene are responsible for familial adenomatous polyposis (FAP) and its variants. Germ-line mutations of at least five DNA-mismatch repair genes (hMLH1, hMSH2, hMSH3, hPMS1, and hPMS2) have also been identified as the causal events in HNPCC. Somatic mutations of APC and the DNA-mismatch repair genes, particularly hMLH1, and alterations in a number of other genes, including the K-ras protooncogene, p53 tumor suppressor gene, and DCC (deleted in colon cancer) gene, have also been identified in a variable percentage of familial and sporadic colorectal cancers and adenomas.

[edit] Predisposing Conditions

A number of conditions have been associated with an increased risk of colorectal cancer (Box 105-1). Recognition of these high-risk groups has important implications for screening.

[edit] Personal History.

With rare exception, virtually all colorectal cancers arise from adenomas. Metachronous adenomas can be identified in 12% to 60% of patients at follow-up colonoscopy, depending on the surveillance interval employed, with a 5% to 8% risk of developing a cancer within 15 years of follow-up. Patients with a history of colorectal cancer have a 5% to 10% risk of developing a metachronous cancer with 15 years and a 30% risk of developing metachronous adenomas.

[edit] Familial Adenomatous Polyposis.

The inherited polyposis syndromes, including FAP, Gardner's syndrome, and Turcot's syndrome, account for about 1% of colorectal cancer cases. FAP is a rare autosomal dominant condition characterized by the presence of 100 or more colorectal adenomas. The disease is caused by mutations of the APC gene on chromosome 5. The polyps are not present at birth but appear during the second or third decade of life. If left untreated, the risk of colorectal cancer is 100% by age 40. The incidence of gastric and small bowel polyps is also increased. The duodenal papilla and periampullary region have a particular propensity for adenomatous and occasionally carcinomatous change. Gardner's syndrome is a variant of FAP and can be distinguished from FAP by extraintestinal manifestations, including desmoids, osteomas, benign soft tissue tumors (e.g., lipomas), and dental abnormalities. Congenital hypertrophy of the retinal pigment epithelium is an early manifestation of both FAP and Gardner's syndrome. Turcot's syndrome is another rare genetic condition sometimes associated with APC mutations and characterized by colorectal adenomatous polyposis and brain tumors. %Two other conditions have been linked to mutations of the APC gene and are believed to be FAP variants: an attenuated form typically presenting later in life, with far fewer, predominantly right-sided adenomas, and the so-called flat adenoma syndrome, which is phenotypically similar to the attenuated form except that the adenomas are flat rather than polypoid.

[edit] Hereditary Nonpolyposis Colorectal Cancer.

HNPCC is an autosomal dominant condition caused by mutations of at least five different DNA-mismatch repair genes with high penetrance. The syndrome accounts for 5% to 10% of colorectal cancer cases and is characterized by early-onset colorectal cancer (average age, 44 years) in the absence of polyposis, a predominance of tumors proximal to the splenic flexure (approximately 70%), and an excess of both synchronous and metachronous colorectal cancers. Patients are also at increased risk of cancers at other sites, including the endometrium, ovaries, stomach, small intestine, upper urinary tract, biliary tract, and brain (Turcot's syndrome). Torre's syndrome (Muir-Torre syndrome), a rare familial condition characterized by multiple sebaceous gland tumors and colorectal cancer, is a subtype of HNPCC. The estimated lifetime risk of developing colorectal cancer in any of the HNPCC syndromes is 80% to 90%, with approximately 50% of cases occurring before age 50. Patients tend to develop multiple, predominantly right-sided, flat adenomas at a higher frequency and younger age than sporadic cases. These adenomas typically exhibit an aggressive histology and diminished dwell time, even though HNPCC-associated cancers have a better prognosis stage for stage than those arising in the general population. Revised criteria have been adopted by which to identify HNPCC families (Box 105-2).

[edit] Family History.

It has long been recognized that a family history of colorectal cancer increases an individual's risk of colorectal cancer. Results of several epidemiologic surveys indicate that individuals with a single first-degree affected relative have a twofold to threefold increased lifetime risk of developing colorectal cancer compared with the average person in the general population. Individuals with two first-degree affected relatives are at even greater risk. The same is true for persons with a first-degree affected relative diagnosed with a colorectal adenoma before age 60.

[edit] Inflammatory Bowel Disease.

Patients with both chronic idiopathic ulcerative colitis and Crohn's disease have an increased risk of colorectal cancer. The actual degree of risk, however, is debatable. For ulcerative colitis the duration of disease and extent of involvement are important determinants of risk. Patients with pancolitis of greater than 7 years' duration or left-sided colitis of 15 years' duration are at increased risk. Duration of disease also appears to be a factor for patients with Crohn's disease. Unlike most colorectal cancers that arise from adenomas, cancers associated with inflammatory bowel disease tend to arise in flat mucosa and therefore are more difficult to detect at an early stage. Dysplasia, the presence of DNA aneuploidy, and mutations of the p53 tumor suppressor gene are early markers of neoplastic transformation.

[edit] Inherited Nonadenomatous Polyposis Syndromes.

Generalized juvenile polyposis and Peutz-Jeghers syndrome are both associated with an increased risk of colorectal cancer. Generalized juvenile polyposis is an autosomal dominant condition characterized by numerous juvenile polyps of the colon. Juvenile polyps are nonneoplastic hamartomas composed of a fibrovascular stroma, cystic epithelial glandular structures, and a conspicuous inflammatory component. The increased risk of colorectal cancer, although small, is related to the presence of adenomatous epithelium in some juvenile polyps. Single juvenile polyps are not associated with an increased risk of colorectal cancer. Peutz-Jeghers syndrome is another autosomal dominant hereditary disease characterized by hamartomatous polyposis of the small and large bowels and by mucocutaneous pigmentation. A small percentage of patients develop colorectal cancer at a young age, presumably related to the occasional presence of adenomatous epithelium within the hamartomas.

[edit] Miscellaneous Conditions.

Women with a history of breast, ovarian, or endometrial cancer are at increased risk of colorectal cancer, as are patients with a history of abdominal or pelvic irradiation. Additional risk factors include the presence of a ureterosigmoidostomy, Streptococcus bovis bacteremia and endocarditis, Schistosoma japonicum infections of the colon, and Bloom syndrome. The association between cholecystectomy and colorectal neoplasia appears to be relatively weak.

[edit] Histopathology and Differential Diagnosis

[edit] Adenomatous Polyps.

Adenomatous polyps are benign glandular neoplasms. They are classified as tubular, villous, or tubulovillous. Clinicopathologic studies suggest a strong correlation between extent of the villous component and adenoma size. Based on endoscopic surveys, approximately 80% of adenomas are tubular, 5% to 15% tubulovillous, and 3% to 5% villous. The distribution of adenomas is similar to that of colorectal cancers.

All adenomas display some degree of dysplasia, which is defined on the basis of cytologic atypia and architectural abnormality. According to the WHO classification system, low-grade dysplasia incorporates the categories of mild and moderate dysplasia, whereas high-grade dysplasia incorporates the categories of severe dysplasia and carcinoma in situ. Adenomas with mild dysplasia exhibit few of the pathologic criteria of malignancy; those with severe dysplasia have most of the cytologic and structural characteristics of cancer, but the glands themselves are not invasive. Adenomas containing invasive cancer are referred to as malignant polyps. It is estimated that fewer than 5% of adenomas undergo malignant transformation. The likelihood of finding invasive cancer in an adenoma increases with size (larger than 2 cm), villous component, and presence of high-grade dysplasia. Multiplicity and age may also be determinants.

[edit] Nonadenomatous Polyps.

In addition to adenomas, other types of benign polyps arise in the colon and rectum. The most common of these is the hyperplastic polyp. Hyperplastic polyps tend to be small (under 5 mm) and have a predilection for the rectum and sigmoid colon. Depending on the method of study, hyperplastic polyps may be found in up to 80% of individuals. As with adenomas, their frequency increases with age. Hyperplastic polyps are nonneoplastic and have no malignant potential. Although subtle differences have been described in terms of gross appearance, it is nearly impossible to distinguish these lesions from small adenomas endoscopically.

Juvenile polyps are nonneoplastic hamartomas with a characteristic histology. They are the most common polyps of childhood. Bleeding and rectal prolapse are the most common clinical manifestations. Many will infarct and pass spontaneously. Unlike generalized juvenile polyposis, isolated juvenile polyps have no malignant potential. Pseudopolyps are nonneoplastic polypoid remnants seen in longstanding inflammatory bowel disease. Multiple lesions are usually found throughout the involved area of colon and frequently have a friable, inflamed appearance. Although these pseudopolyps are not themselves neoplastic, the entire colon of a patient with inflammatory bowel disease is at risk of developing a malignancy.

Lipomas originate within the wall of the colon, but as they enlarge, they frequently become polypoid. They may be found anywhere in the colon but are usually seen near the ileocecal valve. The surface is smooth and red and may have a yellow tinge reflecting the fat content. Usually these tumors are asymptomatic and do not require removal. Leiomyomas and lymphoid polyps are very unusual. When seen, they are smooth, sessile, and firmly attached to the wall. They rarely cause symptoms. Carcinoid tumors of the colon are almost always benign. They are usually seen as small yellow nodules in the rectum. No treatment is needed unless they enlarge.

[edit] Cancers.

Colorectal cancers may present as exophytic, ulcerative, infiltrating, or annular lesions. With the exception of the cecum, where exophytic, polypoid lesions predominate, no correlation exists between site and configuration. The anatomic distribution of colorectal cancers has shifted proximally in recent decades. Currently, approximately 30% of cancers arise in the rectum, 25% in the sigmoid, 6% in the descending colon, 11% in the transverse colon, 9% in the ascending colon, and 13% in the cecum. Histologic grades for colorectal adenocarcinomas include well differentiated, moderately differentiated, poorly differentiated, and undifferentiated or anaplastic, depending on the degree of cytologic atypia and glandularity. Mucinous or signet cell carcinomas are variants of undifferentiated tumors.

Metastatic pathways usually involve lymphatic invasion with spread to mesenteric lymph nodes or hematogenous spread through the portal system to the liver. Ultimately, spread occurs through the systemic circulation to the lungs and other parts of the body. Rarely, tumors in the rectal region metastasize directly to the lungs, presumably by hemorrhoidal veins that connect directly to the systemic circulation.

Occasionally, other types of colorectal tumors are encountered. Malignant tumors of the anorectal junction are squamous cell or cloacogenic carcinomas. These metastasize through lymphatics to groin nodes before spreading systemically. These tumors are rare, comprising only about 1% of colorectal tumors. Lymphomas, leiomyosarcomas, and liposarcomas may also occur but are even rarer. Direct invasion of the colon from adjacent malignancy (ovary or prostate) or metastasis to the colon from distant sites (breast, lung, stomach, and melanoma) may occur late in the disease course but rarely presents a diagnostic problem.

[edit] Staging and Prognosis

Since Dukes' original staging system for rectal cancers in 1932, several modifications have been made in an attempt to incorporate additional prognostic information. The Astler- Coller system and the TNM system (proposed by the American Joint Committee on Cancer and International Union Against Cancer) are currently the most widely used and are applicable to both colon and rectal cancers (Table 105-6). Both are defined on the basis of depth of mural invasion and lymph node status. Prognosis, as defined by a 5-year survival rates, is closely correlated with tumor stage at diagnosis and ranges from 97% for stage I tumors to only 4% for stage IV tumors.

Table 105-6 Staging Classifications and Prognosis of Colorectal Cancer

Dukes'	Astler-Coller	AJCC/UICC		Description	5-year survival (%)
A				Penetration into bowel wall	Stage I: 90-97
	A			Submucosa
	B1			Muscularis
B	B2			Penetration through bowel wall ±involvement of adjacent organs	Stage II: 63-78
C				Lymph node involvement	Stage III: 37-66
	C1			Without penetration of bowel wall
	C2		Stage III	With penetration of bowel wall
			N1	1-3 nodes
			N2	>4 nodes
			N3	Any node along a major vascular trunk
D	D		Stage IV	Any T, any N, distant metastases present	Stage IV: 4
			M1
AJCC, American Joint Committee on Cancer;UICC, International Union Against Cancer.

Poorly differentiated histology, mucin production, abnormal DNA content (aneuploidy), perforation, tumor invasion of adjacent organs, venous involvement, and a preoperative elevation in the plasma carcinoembryonic antigen (CEA) titer are also correlated with a poor prognosis. Loss of the DCC tumor suppressor gene has been identified as a poor prognostic factor in patients with stage II (Dukes' B) tumors but not stage III (Dukes' C) tumors. Loss of the p53 tumor suppressor gene has also been identified as a poor prognostic factor independent of stage. Unlike most other carcinomas or sarcomas, prognosis is not influenced by tumor size.

[edit] Clinical Presentation

[edit] Adenomas.

Adenomatous polyps usually are asymptomatic. Intermittent bleeding, which is usually occult, is the most common manifestation. Visible but scant bleeding occasionally occurs, either mixed in the stool or on its surface; massive bleeding is rare. Patients may complain of a change in bowel habits, but this is unusual. Rarely, profuse watery diarrhea, resulting in dehydration and electrolyte abnormalities, is associated with large villous adenomas of the distal colon and rectum. Patients may also complain of vague discomfort; more severe pain is very uncommon and may be attributable to intussusception. Rectal prolapse of polyps has also been described.

[edit] Cancers.

The clinical manifestations of colorectal cancers tend to vary with anatomic location. Cancers of the right colon most often present with occult bleeding and iron deficiency anemia. Obstruction is unusual because of the voluminous and distensible nature of the cecum. Occasionally a mass may be palpated in the right lower quadrant. Since stool becomes more concentrated as it passes through the transverse and descending colon, cancers of these sites cause crampy abdominal pain, obstruction, or less often, perforation. Cancers of the transverse colon may also present with occult bleeding but more often with obstruction. Cancers of the left colon and sigmoid typically produce rectal bleeding or symptoms related to partial bowel obstruction, such as crampy abdominal pain, change in bowel habits, and changes in stool size and consistency. Cancers of the rectum characteristically produce increased stool frequency, changes in stool caliber or consistency, small amounts of bright-red bleeding, rectal urgency, tenesmus, and incontinence. Advanced tumors may also produce perianal pain, hematuria, urinary frequency, or vaginal fistula caused by local invasion. Cancers of any site may perforate, resulting in signs and symptoms of a localized abscess or peritonitis.

Anorexia and weight loss are common systemic symptoms, although their presence is not specific for colorectal cancers; patients may have far-advanced colon cancers without these findings. When they are present, however, especially in the older age group, colon cancer must be a prime diagnostic possibility. Signs and symptoms of metastatic disease vary according to the site of involvement.

[edit] Evaluation of Symptomatic Patients: Diagnosis

Colonoscopy is the most widely used diagnostic modality for symptomatic patients, since it permits direct visualization of the entire large bowel in 90% to 95% of patients, as well as a means of obtaining tissue for histologic evaluation of suspicious lesions or removal of polyps. Depending on the nature of the symptoms or other mitigating circumstances, a sigmoidoscopy and barium enema may also be obtained. If a lesion is found by sigmoidoscopy or barium enema, a colonoscopy should be performed to ascertain the nature of the lesion, obtain tissue for histologic evaluation, anddetermine whether synchronous lesions are present elsewhere in the bowel. A colonoscopy should also be performed in patients with persistent symptoms and negative sigmoidoscopy or barium studies. If the entire bowel is not well visualized because of an obstructing lesion, technical difficulties, or poor patient tolerance, a double-contrast barium enema should be obtained. Once the diagnosis is established, preoperative staging is pursued with a CT scan of the abdomen, chest radiograph, and for patients with rectal cancer, endoscopic ultrasound. MRI, scintigraphy with radiolabeled anti-CEA monoclonal antibodies, and intraoperative ultrasound may also be of value in select patients.

[edit] Evaluation of Asymptomatic Patients: Screening and Surveillance

Although the survival rates from colorectal cancer have improved significantly in recent years, more than 40% of patients still die from their disease. As with many other cancers, prognosis is closely correlated with stage of disease at diagnosis. Despite improvements in diagnostic capability, almost 40% of patients have locoregional spread of their tumors, and another 20% have metastatic disease. This is largely because most patients remain entirely asymptomatic until their tumors reach an advanced stage. Sufficient evidence has accumulated to suggest that colorectal cancer screening is effective in reducing not only colorectal cancer mortality but also its incidence through the identification and removal of adenomatous polyps.

Proponents of colorectal cancer screening agree that case finding rather than mass screening is the most appropriate approach for early detection. Case finding refers to the performance of screening individuals at increased risk for the disease of interest. High-risk groups have been identified for colorectal cancer. Patients in whom age (50 or older) is the only risk factor are considered to be of average risk (Table 105-7). Fecal occult blood testing (FOBT), sigmoidoscopy, double-contrast barium enema, and colonoscopy have all been advocated as appropriate screening tests for average-risk individuals, beginning at age 50. The digital rectal examination (DRE) has not been shown to be effective and thus is no longer recommended as a screening test for colorectal cancer, although it should still be performed as part of a routine physical examination in persons over age 40. The common practice of using DRE to obtain a stool sample for fecal occult blood testing should be discouraged, except perhaps in noncompliant patients, since it compromises both the sensitivity and the specificity of FOBT.

Table 105-7 Colorectal Cancer Screening and Surveillance Strategies

✢Two samples should be taken from each of three consecutive bowel movements. Restricted diet is recommended before test. Test is positive if one or more of the six samples are positive.

†Family history of one or more affected first-degree relatives with colorectal cancer or adenoma before age 60.

It has long been recognized that occult bleeding is an early sign of colorectal cancer. The tests used most often to detect occult bleeding are based on hemoglobin's peroxidase activity, which can be easily detected at the bedside by the addition of a hydrogen peroxide reagent to a guaiac-impregnated slide (e.g., Hemoccult II, Hemoccult II Sensa). These guaiac-based tests are not specific for blood; foods containing peroxidase and pseudoperoxidase, such as red meat and certain vegetables, will also produce a positive test. Immunologic assays for hemoglobin (e.g., HemeSelect) or its porphyrin derivatives (e.g., Hemoquant) are more costly and less amenable to widespread clinical use. Three separate randomized controlled trials demonstrated that FOBT followed by diagnostic colonoscopy significantly reduces colorectal cancer mortality by 15% to 18% if performed biannually and 33% if performed annually.^[4][5][6] The major limitations of FOBT relate to test sensitivity and specificity. Although the trials reported sensitivities of 72% to 78% for nonhydrated slides and 88% to 92% after hydration, other studies have observed false-negative rates as high as 75% for cancers and greater than 90% for adenomas. False-negative tests result primarily because not all neoplasms bleed and those that do may bleed only intermittently.

Another typical screening test for average-risk individuals is sigmoidoscopy. The rationale for sigmoidoscopy is that it permits direct visualization of the distal large bowel and biopsy of any abnormal lesions. Several types of sigmoidoscopes are available, including the 25-cm rigid scope, the 60-cm flexible fiberoptic scope, and the 60-cm flexible videoscopes. Flexible instruments afford a significantly higher diagnostic yield than the rigid scopes and have demonstrated much better patient tolerance and acceptance. Case-control studies suggest that periodic sigmoidoscopy, even every 5 to 10 years, can reduce mortality from colorectal cancers arising in the distal large bowel as much by 70% to 80%.^[7][8] Since both studies used rigid instruments, they provide only indirect evidence of the effectiveness of flexible sigmoidoscopy. Additional studies suggest that sigmoidoscopy may also reduce the incidence of colorectal cancer through the identification and removal of adenomas. The major disadvantage of sigmoidoscopy is that only the distal half of the large bowel can be visualized, and thus only about half of all colorectal cancers and adenomas can be detected by this technique alone.

Colonoscopy is the only screening strategy that allows direct visualization of the entire large bowel, biopsy of suspicious lesions not amenable to endoscopic removal, and polypectomy. Overall sensitivity for polyps and cancer is about 90%, ranging from 75% to 85% for polyps less than 1 cm in diameter to 95% for larger polyps and cancers, whereas specificity approaches 100% for all lesions. Failure to reach the cecum and suboptimal bowel preparation account for the majority of missed lesions. No direct evidence proves that colonoscopy is an effective screening test, but extrapolation of data from the FOBT trials, screening sigmoidoscopy studies, and the National Polyp Study indicates that screening colonoscopy can reduce both the incidence of and the mortality from colorectal cancer. The major disadvantages of colonoscopy relate to higher procedural costs and risk of complications.

Double-contrast barium enema (DCBE) offers a less expensive, less invasive, and safer alternative to colonoscopy for evaluating the entire colon. As with colonoscopy, however, no direct evidence shows that DCBE is an effective screening test for colorectal cancer. The sensitivity of DCBE ranges from 50% to 80% for polyps less than 1 cm, 70% to 90% for polyps 1 cm or greater, and 55% to 85% for Dukes' A and B cancers. Specificity also varies according to polyp size, ranging from about 50% for small polyps to 90% to 95% for large polyps and more than 95% for cancers. Sensitivity increases slightly when sigmoidoscopy is combined with DCBE. Besides sensitivity and specificity concerns, the major limitation of DCBE is the need for follow-up colonoscopy to evaluate abnormal findings.

The optimal strategy for colorectal cancer screening remains controversial (see Table 105-7). Although widely endorsed by authoritative groups, guidelines vary and might include any of the following options: annual FOBT, sigmoidoscopy every 5 years, the combination of annual FOBT and flexible sigmoidoscopy every 5 years, DCBE every 5 to 10 years, or colonoscopy every 10 years.^[9][10][11] One analysis suggested that these strategies have comparable and favorable cost-effectiveness ratios (less than $20,000 per year of life saved) and should be offered to all average-risk individuals beginning at age 50.^[11] Selection of a given strategy needs to be individualized on the basis of potential risks and benefits, compliance issues, availability, insurance coverage, and local expertise. Decisions about when to stop screening also needs to be individualized, but in general, screening should be discontinued in patients with significant comorbidity or when the lead time between screening and its benefits (about 10 years) is longer than the patient's life expectancy.

Individuals at risk of FAP or HNPCC should be offered genetic counseling and testing. Because of the potential for false-negative results, affected relatives should be screened first. Those who test positive for APC mutations should undergo flexible sigmoidoscopy every 6 to 12 months beginning at puberty (age 10 to 12 years). Those who test positive for one of the DNA-mismatch gene mutations associated with HNPCC should undergo colonoscopy every 2 years beginning at age 25 and then yearly after age 35. When affected relatives test negative or refuse testing, individuals should be offered similar screening as those who test positive. Individuals with a positive family history of colorectal cancer or adenomas before age 60 should be offered the same options as for average-risk individuals but beginning at age 40. Patients with longstanding ulcerative colitis should undergo colonoscopy with biopsy for dysplasia beginning 8 years after age of onset for pancolitis and at 15 years for distal disease. Recommendations for surveillance of patients with a history of colorectal cancer or adenoma(s) are discussed under Treatment.

[edit] Evaluation of Patients with Positive Screening Tests.

Colonoscopy is the diagnostic procedure of choice for patients with positive FOBT. The likelihood of finding a neoplastic lesion in these patients increases with age. Approximately 50% of positive-FOBT patients have either an adenoma (38%) or cancer (12%). Colonoscopy is also indicated for patients with distal adenomas detected at sigmoidoscopy, particularly those with advanced histology (i.e., 1-cm or larger lesion, villous growth, or high-grade dysplasia). Up to 50% of patients with adenomas detected by sigmoidoscopy have a proximal adenoma, and a small percentage have a proximal cancer. Colonoscopy is not recommended for patients with only a hyperplastic polyp found by sigmoidoscopy.

[edit] Treatment

[edit] Adenomas.

Endoscopic polypectomy is the treatment of choice for all colorectal adenomas, regardless of whether they are symptomatic or discovered incidentally. Since histologic evaluation is the only reliable means of distinguishing adenomas from nonneoplastic polyps, particularly for diminutive lesions (5 mm or smaller), endoscopic removal or ablation is recommended for all colorectal polyps. The major risks of endoscopic polypectomy are bleeding and perforation. If a polyp cannot be removed endoscopically, surgical resection should be considered after careful assessment of the patient's operative risk vs. the risk of malignancy. Periodic endoscopic assessment and piecemeal removal every 6 months to 1 year is a reasonable alternative in poor surgical candidates. Laser ablation is also an option in such patients.

The treatment of malignant polyps (i.e., adenomas containing invasive cancer) depends on polyp morphology and histology. Endoscopic polypectomy is considered curative for pedunculated polyps if (1) there is a ``clean margin (1 mm or more) of resection, (2) there is no lymphatic or vascular invasion, (3) the cancer is well or moderately differentiated, and (4) there is no residual or recurrent tumor at the polypectomy site on follow-up examination. If all these criteria are not met, surgical resection is warranted. Surgical resection is recommended for all patients with malignant sessile polyps if they have acceptable surgical risks.

[edit] Cancer.

Surgical resection is the only potentially curative treatment for colorectal cancer. Curative resection requires wide excision of the primary tumor and en bloc removal of draining lymph nodes, lymphatics, and contiguous structures. The actual extent of resection varies according to anatomic location. The introduction of stapling devices has been an important advance in that it has shortened operative time, reduced the incidence of anastomotic leaks and infection, and reduced the need for colostomy in patients with low-lying rectal cancers. Although an abdominoperineal resection with colostomy is often recommended for rectal tumors not amenable to low anterior resection with primary anastomosis, alternate sphincter-sparing approaches, including coloanal anastomosis and local excision, may be curative in select patients. Tumors amenable to local excision should be less than 4 cm in size, mobile, and confined to the mucosa (T1) or submucosa (T2) and limited to one quadrant of the rectal circumference. Endoscopic ultrasound is particularly valuable in identifying lesions amenable to local excision. A more limited palliative resection is recommended for patients with metastatic disease at diagnosis.

Evidence supports the use of adjuvant therapy after curative resection.^[12] Combined-modality treatment with chemotherapy (5-fluorouracil alone or in combination with levamisole or leucovorin) and postoperative radiation has been shown to reduce local recurrence rates and improve disease-free survival and overall survival in patients with Astler-Coller (modified Dukes classification) B2 and C rectal cancers (see Table 105-6). Combination chemotherapy with 5-fluorouracil and levamisole or leucovorin has also been shown to improve disease-free survival and overall survival in patients with C cancers arising above the pelvic-peritoneal reflection; its efficacy in the treatment of B2 tumors remains unproven.

Chemotherapy is the treatment of choice for patients with metastatic disease. Since this approach is rarely curative, efficacy is generally defined in terms of initial response rates (i.e., tumor shrinkage) and improved 5-year survival. 5-Fluorouracil is the most active single agent, with response rates of about 20%. Combination chemotherapy with 5-fluorouracil plus leucovorin has replaced single-agent therapy as the standard for patients with advanced, unresectable colorectal cancer. Intraarterial hepatic infusion of 5-fluorouracil or floxuridine has demonstrated superior efficacy in the treatment of hepatic disease but has had little impact on survival and is associated with significant toxicity.

Aggressive surgical intervention may be warranted with isolated hepatic or pulmonary metastases in an otherwise healthy patient. Although the cure rate is not high, many case reports document the value of attempting tumor removal in this otherwise 100% fatal situation.

Palliation is the goal of treatment for patients with advanced, incurable disease. Segmental resection of the primary tumor is generally recommended to reduce the morbidity associated with recurrent bleeding and obstruction. Diverting colostomy should be considered for unresectable tumors, particularly low-lying rectal cancers. Radiation therapy is often effective in the management of advanced or recurrent pelvic disease, particularly in patients with pain unresponsive to chemotherapy. Endoscopic approaches, such as laser ablation or stent placement, may also be of value in the management of tumor bleeding or obstruction in select patients.

[edit] Follow-up

[edit] Adenomas.

Periodic surveillance colonoscopy is warranted in patients with a history of colorectal adenomas because of the risk of metachronous adenomas and cancer. An interval of at least 3 years has been recommended for repeat colonoscopy after removal of all adenomas.^[13] If the initial follow-up examination is negative for adenomas, subsequent examination can be deferred for at least 5 years. Patients with malignant polyps or large sessile adenomas, multiple adenomas, and identified polyps that have not been removed may require more frequent examinations.

[edit] Cancer.

Close surveillance is also indicated for patients with colorectal cancer after curative resection. A reasonable follow-up program includes office visits every 3 months for the first 3 years and then every 6 months, with CEA determination every visit and complete blood count (CBC) and liver profile every 6 months. An annual CT scan of the abdomen and pelvis and a chest radiograph should also be obtained for the first 5 years. Colonoscopy should also be performed at 1 year to detect anastomotic recurrences, then every 3 years to detect metachronous adenomas or cancer. Patients in whom a complete preoperative colonoscopy or DCBE could not be performed because of obstructing tumors should undergo a postoperative examination at 3 to 6 months.

The detection of a rising CEA level after stable low levels necessitates thorough evaluation. Scintigraphy with radiolabeled anti-CEA antibodies may be of value in localizing recurrences; if negative, some oncologists and surgeons suggest exploratory second-look laparotomy in hope of finding resectable disease.

[edit] TUMORS OF THE LIVER

Tumors of the liver are frequently encountered in clinical practice. Depending on geographic location, the majority of such tumors may be either primary liver tumors or metastatic tumors. Primary liver tumors may be benign or malignant and may arise from hepatic parenchymal tissue, the biliary tree, or vascular structures (see Table 105-1). Hepatocellular carcinomas (hepatomas) and cholangiocarcinomas are the most common malignant tumors;hemangiomas are the most common benign tumors. All other types of benign or malignant primary tumors are rare.

[edit] Epidemiology

The global distribution of hepatocellular carcinoma correlates with the geographic prevalence of chronic hepatitis B virus (HBV) carriers. Incidence rates range from less than 2% of malignant tumors found at autopsy in North and South America and Europe to 20% to 30% in parts of Africa and Asia. Although still a rare disease (2.4 cases per 100,000 population) in the United States, incidence rates have nearly doubled over the past two decades and will continue to rise because of the large pool of persons infected with hepatitis C virus (HCV).^[14] Hepatocellular carcinoma is up to four times more common in men than women. The peak incidence occurs in the fifth or sixth decades of life in low-risk countries but one to two decades earlier in high-risk areas.

Unlike hepatocellular carcinoma, the incidence of cholangiocarcinoma is dispersed more evenly throughout the world. Peak incidence is in the sixth decade of life, and there is no male predominance.

Hemangiomas occur in approximately 5% of the population, based on all autopsies. The epidemiology of other types of benign tumors is essentially unknown.

[edit] Etiology

Between 30% and 70% of patients with hepatocellular carcinoma have underlying cirrhosis. The risk of hepatocellular carcinoma varies with the type of cirrhosis. Cirrhosis from hemochromatosis has the highest risk; up to 22% of such patients develop hepatocellular carcinoma even if treated with phlebotomy. Hepatocell