Adenocarcinoma and Other Tumors of the Stomach

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CHAPTER 54 Adenocarcinoma and Other Tumors of the Stomach

Gastric tumors are defined as benign or malignant based on their potential to metastasize. Gastric adenocarcinoma makes up the majority of malignant gastric tumors, and will be referred to as gastric cancer in this chapter.

EPIDEMIOLOGY

Gastric cancer remains the second leading cause of cancer mortality in the world,1 although the overall incidence is declining.2 The incidence of gastric cancer in Western countries has decreased dramatically over the past century.3 For example, gastric cancer mortality has decreased 86% since 1950 in the United States, and the incidence of gastric cancer has diminished four-fold since 1930 to approximately 8 cases per 100,000 people.4,5 As recently as 1930, gastric cancer was the leading cause of cancer mortality in the United States for men and the third leading cause for women.6 Gastric cancer is now the seventh leading cause of cancer mortality in the United States.5 It was estimated that in 2008, approximately 21,500 Americans would be diagnosed with gastric cancer and 10,880 would die of it.7

There is great geographic variation in gastric cancer incidence, with the highest incidence rates in the Far East (Fig. 54-1). Eastern Europe and Central and South America also have high incidence rates, and the lowest incidence rates are observed in North America, North Africa, South Asia, and Australia.6 Although gastric cancer was common in industrialized countries in the past, the latest epidemiologic data indicate that more than 60% of new cases of gastric cancer are in developing countries, reflecting a more rapid decline in developed countries.

image

Figure 54-1. Worldwide incidence of gastric cancer in men.

(From Parkin DM. International variation. Oncogene 2004; 23:6239-40.)

In the United States, the median age of diagnosis is 71 years, with the highest proportion (28%) diagnosed between the ages of 75 and 84.8 In Japan, a country with a high incidence of gastric cancer, the mean age of diagnosis is roughly a decade earlier, perhaps reflecting lead-time bias due to widespread screening. The incidence of gastric cancer in men is approximately twice that in women (Table 54-1).3 The incidence of gastric cancer in blacks in the United States is nearly double that in whites.5 Native Americans and Hispanics also have a higher risk of development of gastric cancer than whites.9 Lower socioeconomic status is associated with a much higher incidence of gastric cancer.3 In the United States, the distribution of gastric cancer within the stomach is 39% in the proximal third, 17% in the middle third, 32% in the distal third, and 12% involving the entire stomach.10 In contrast to the pattern seen with noncardia tumors, the incidence rates of gastric cardia cancer are rising.2,11

Dietary, environmental, and genetic risk factors for gastric adenocarcinoma are listed in Table 54-2, some of which are or may be protective.

Table 54-2 Risk Factors Including Protective Factors for Gastric Adenocarcinoma

Definite Helicobacter pylori infection
Chronic atrophic gastritis
Intestinal metaplasia
Dysplasia*
Adenomatous gastric polyps*
Cigarette smoking
History of gastric surgery (esp. Billroth II)*
Genetic factors
Family history of gastric cancer (first-degree relative)*
Familial adenomatous polyposis (fundic gland polyps)*
Hereditary nonpolyposis colorectal cancer*
Peutz-Jeghers syndrome*
Juvenile polyposis*
Probable High intake of salt
Obesity (adenocarcinoma of cardia only)
Snuff tobacco use
History of gastric ulcer
Pernicious anemia*
Regular aspirin or NSAID use (protective)
Possible Low socioeconomic status
Ménétrier’s disease
High intake of fresh fruits and vegetables (protective)
High ascorbate intake (protective)
Questionable Hyperplastic and fundic gland polyps
High intake of nitrates
High intake of green tea (protective)

NSAID, nonsteroidal anti-inflammatory drug.

* Surveillance for cancer is suggested in patients with this risk factor.

ETIOLOGY AND PATHOGENESIS

Gastric cancer can be subdivided using the Lauren classification into two distinct histologic subtypes with different epidemiologic and prognostic features (Fig. 54-2).12 The intestinal type of cancer is characterized by the formation of gland-like tubular structures with features reminiscent of intestinal glands. This type of gastric cancer is more closely linked to environmental and dietary risk factors, tends to be the predominant form in regions with a high incidence of gastric cancer, and is the form of cancer that is now declining worldwide. The diffuse type of cancer lacks glandular structure and consists of poorly cohesive cells that infiltrate the wall of the stomach. It is found at the same frequency throughout the world, occurs at a younger age, and is associated with a worse prognosis than the intestinal form. Extensive involvement of the stomach by the diffuse type can result in a rigid and thickened stomach, a condition referred to as linitis plastica. Adenocarcinoma of the stomach can also be classified into proximal tumors (gastric cardia and gastroesophageal junction) and distal tumors (fundus, body and antrum of the stomach). Distal tumors have been declining, whereas proximal tumors have been increasing (see Chapter 46).

It is now believed that the development of intestinal-type cancers occurs through a multistep process in which the normal mucosa is sequentially transformed into a hyperproliferative epithelium, followed by an early adenoma, late adenoma, and then carcinoma. In colon cancer, the evidence is strong that each step in the transition is associated with a specific gene mutation,13 but evidence that gastric cancer follows a comparable sequence of genetic events has been lacking. However, in gastric and colon cancer, it does appear that deoxyribonucleic acid (DNA) mutations are established over time in stem cells; in intestinal metaplasia these mutations spread through the stomach through a process involving crypt fission and monoclonal conversion of glands.14 The contention that the pathogenesis of intestinal-type gastric cancer is a multistep process is supported mainly by the observation that both atrophic gastritis and intestinal metaplasia are found in higher incidences in patients with intestinal-type cancer and in countries with a high incidence of gastric cancer (see Chapter 51).15

This multistep model of intestinal-type gastric cancer, developed in large part by Correa and colleagues,16,17 postulates that there is a temporal sequence of preneoplastic changes that eventually lead to the development of gastric cancer. A common feature of the initiation and progression to intestinal-type gastric cancer is chronic inflammation. Helicobacter pylori infection is the primary cause of gastric inflammation and the leading etiologic agent for gastric cancer (see Chapter 50). In a subset of patients infected with H. pylori, the inflammatory process leads to the development of atrophic gastritis (with loss of glandular tissue) followed by progression to intestinal metaplasia, dysplasia, early gastric cancer, and, eventually, advanced gastric cancer (Fig. 54-3). The current view is that all stages prior to the development of high-grade dysplasia are potentially reversible, although this concept is still somewhat controversial, it has been supported by a number of studies in animal models.18,19 Unlike the situation observed with colon cancer, the precise genes involved in each step of this progression are still not defined. Furthermore, during endoscopy the premalignant stages of gastric cancer are not as readily identifiable as those of colon cancer, and many gastric carcinomas are very heterogeneous, containing a large percentage of stromal cells. These stromal cells, which include cancer-associated fibroblasts known to promote tumor growth, have been reported to show distinct genetic and epigenetic changes that may confound tumor analysis.20 This feature makes characterization of the timing of specific gene mutations in gastric cancer difficult at best. Currently the role of chronic inflammation in the diffuse type of gastric cancer remains to be clarified, and the similarities if any to the proposed pathway in Figure 54-3 for the intestinal type of cancer.

HELICOBACTER PYLORI INFECTION

H. pylori is a gram-negative microaerophilic bacterium that infects nearly half of the world’s population and is recognized as the primary etiologic agent for gastric cancer (see Chapter 50). Indeed, H. pylori has been classified as a class I (or definite) carcinogen by the International Agency for Research on Cancer (IARC), a branch of the World Health Organization (WHO). Infection with H. pylori has been found in every population studied, although the prevalence is higher in developing countries.21,22

The natural history of chronic H. pylori infection includes three possible outcomes23: (1) superficial gastritis, in which most patients remaining asymptomatic; (2) duodenal ulcer phenotype, which occurs in 10% to 15% of infected subjects; and (3) gastric ulcer/gastric cancer phenotype, which is the least common in the United States. In general, the risk for gastric cancer is dependent on the types of gastritis, and an increased risk is associated with a low acid state. H. pylori–induced duodenal ulcer disease is associated with a high gastric acid output as well as a reduced risk for developing gastric cancer.24 Patients with H. pylori–associated gastric ulcer disease exhibit low gastric acid output, and their ulcers are typically associated with preneoplastic changes of atrophic gastritis and metaplasia. Overall, studies suggest that H. pylori–infected patients are at risk for development of chronic atrophic gastritis at a rate of 1% to 3% per year of infection.17,25,26 Thus, those patients who are genetically predisposed to forming atrophic gastritis in response to H. pylori infection are predisposed to gastric cancer. Although Helicobacter infection is associated with both intestinal-type and diffuse-type adenocarcinomas, the mechanisms responsible for the formation of intestinal-type adenocarcinoma have been better studied and are focused on here. The association of H. pylori with mucosa-associated lymphoid tissue (MALT) lymphoma is discussed briefly at the end of this chapter and in more detail in Chapter 29.

The increased risk of development of gastric adenocarcinoma due to H. pylori infection depends on multiple factors including the strain of bacteria, host genetic factors, the duration of infection, and the presence or absence of other environmental risk factors (e.g., poor diet, smoking, etc.). In a Japanese cohort of 1526 patients with peptic ulcer disease, nonulcer dyspepsia, and gastric hyperplasia, only those infected with H. pylori developed gastric adenocarcinoma during follow-up (2.9% vs. 0%, P < 0.001).27 Additional cohort studies from China and Taiwan have reported similar findings.28,29 At least in Western countries, the association between H. pylori and gastric cancer appears to be confined to noncardia gastric tumors.30

Potential mechanisms for H. pylori–induced gastric carcinogenesis include host factors, bacterial factors, environmental factors, and interactions among all three factors. Our latest understanding suggests that a combination of a virulent bacterial strain, a genetically permissive host, and a favorable gastric environment are necessary for disease to occur. The most important factor appears to be the induction of chronic inflammation by H. pylori infection. Several aspects of the inflammatory milieu have been implicated as carcinogens; they include increased oxidative stress and the formation of oxygen free radicals leading to DNA damage, increased CD4+ T cells and myeloid cells, and elevated proinflammatory cytokine production, all leading to accelerated cell turnover, reduced apoptosis, and the potential for faulty or incomplete DNA repair.31 Indeed, recent studies suggest that animals with deficient DNA repair mechanisms display more severe gastric dysplasia after chronic infection with H. pylori.32 Thus, evidence to date clearly indicates that the most important cofactor in the induction of Helicobacter-related disease is the host immune response. Indeed, chronic inflammation has been linked to a large number of cancers.

H. pylori infection leads to innate and adaptive immune responses (see Chapter 2). Initiation of the innate immune response to H. pylori is just beginning to be unraveled. Classically, the innate immune system consists of professional antigen presenting cells (APCs) such as macrophages, dendritic cells, and in some cases epithelial cells. Recent work supports a role for pattern recognition receptors (Toll-like receptors [TLRs]) in the initial response to Helicobacter colonization and the subsequent induction of the adaptive response. The most convincing evidence to date implicates TLR2 as the major TLR in Helicobacter species recognition.33 A role for TLRs 4, 5, and 9 remains more controversial.3437 TLR4, along with CD14 and MD-2, serves as the receptor for Escherichia coli lipopolysaccharide (LPS) and probably H. pylori LPS and thus may be involved as well.

Chronic inflammation appears necessary for the progression through atrophy to gastric cancer. Disease mechanisms are difficult to study in human infection, and therefore much of our understanding of the immune response to Helicobacter organisms comes from work performed in the mouse model of infection. Different inbred strains of mice respond to infection with varying degrees of disease susceptibility, and several knockout models have helped to elucidate the roles of individual components of the immune response in disease.

The C57BL/6 mouse is a susceptible inbred strain, in which initial colonization of the antrum by bacteria later spreads to the body or corpus, leading to severe chronic inflammation and increases in apoptosis (programmed cell death) and proliferation. The alterations in cellular turnover are associated with a loss of parietal and chief cells (atrophy), intestinal metaplasia, and dysplasia, followed by invasive gastric adenocarcinoma in mice 14 to 22 months after infection.38,39 Genetic manipulation of the C57BL/6-susceptible murine strain has facilitated detailed study and has thus led to a deeper understanding of genetic factors that promote murine gastric cancer, and in particular, the role of the adaptive immune response. For example, gastric Helicobacter infection in mice deficient in lymphocytes, including mice with recombinase-activating gene (RAG) deficiency, severe combined immunodeficiency, or T cell deficiency, does not result in tissue damage, cell lineage alterations, or the metaplasia-dysplasia-carcinoma sequence.40,41 Infection in B cell–deficient mice (which retain a normal T cell response) results in severe atrophy and metaplasia identical to that seen in infected wild-type mice.41 Taken together these studies underscore the crucial role of CD4+ T lymphocytes in orchestrating gastric neoplasia.

How do CD4+ T lymphocytes contribute to gastric cancer progression? Susceptible mouse strains, such as C57BL/6, mount a strong helper T cell type 1 (Th1) interferon-γ (IFN-γ), interleukin-12 (IL-12) type of immune response, whereas resistant strains, such as the BALB/c, have an opposite Th2 response (IL-4, IL-5).39,42,43 A Th2 response is associated with protection from mucosal damage despite the inability to eliminate bacterial colonization and in fact is often associated with higher bacterial colonization rates. Mouse strains such as the C3H, which has a mixed Th1/Th2 cytokine profile, show intermediate disease, suggesting that cytokines within an immune response interact to form a continuum of disease rather than discrete disease states. More recently, Th17 cells, which express IL-17, have been shown to be an important component of H. pylori–induced gastritis.

Although the composite immune milieu most likely dictates disease manifestations, studies are beginning to define the role of individual cytokines in the predisposition to disease. This is best illustrated in the IFN-γ knockout mice, in which a lack of IFN-γ protects infected mice from atrophy.39,43 On the other hand, mice lacking IL-10, a cytokine that acts to dampen an immune response, develop severe atrophic gastritis in response to infection.3943 More recently, genetic murine models have illustrated the importance of the IL-6–IL-11 family of cytokines in the development of gastric cancer.44

Manipulation of the immune response within wild-type strains confirms the central role of the Th1/Th2 response in producing disease. For example, infection with the intestinal helminth Heligmosomoides polygyrus skews the immune response toward Th2 polarization and protects the C57BL/6 host from Helicobacter-induced atrophy and metaplasia.45 This mouse model mimics both the parasitic infection status and the paradoxical low gastric cancer–high H. pylori infection rates seen in areas of Africa, potentially explaining this apparent inconsistency. These observations in mice led to human studies in Africa and Latin America that confirmed that geographic regions with low gastric cancer rates had much higher Th2 relative to Th1 immune responses to H. pylori.46,47 In general, the increased Th2-type responses were found in areas where serum immunoglobulin E (IgE) levels were high and the prevalence of intestinal parasitism by helminths is greater than 50%. These findings further stress the importance of the host response to infection and suggest the possibility that manipulation of the genetically predetermined host cytokine profile in response to environmental challenges may lessen or exacerbate the disease process.

There is a great deal of genetic diversity between strains of H. pylori owing to point mutations, insertions, deletions, and base-pair substitutions within its genome. Several strains may infect a single individual, and existing strains can undergo mutations and change over time.48,49 Despite this genetic diversity, several genes are recognized as risk factors for gastric carcinoma, including the cag pathogenicity island, the vacA gene, and the babA2 gene.

The H. pylori genome is 1.65 million base pairs and codes for approximately 1500 genes, two thirds of which have been assigned biological roles.50 The function of the remaining one third of the genome remains obscure. Factors that contribute to carcinogenesis include those that enable the bacteria to effectively colonize the gastric mucosa, those that incite a more aggressive host immune response, and those that affect host cell-growth signaling pathways.

Motility toward epithelial cells of the stomach is a vital feature of H. pylori survival tactics. This function is ensured by several factors, including spiraling movement (FlaA and FlaB proteins), which are designed to navigate the thick gastric mucus and through efficient modifications of the extracellular matrix and mucus layer, thus decreasing viscosity and allowing bacterial penetration.51,52 In addition, H. pylori expresses a variety of genes that contribute to buffering of stomach acid in order to maintain a relatively neutral pH. This includes a urease gene cluster, consisting of seven genes, of which UreA/UreB complex (comprising the urease enzyme) codes for 10% of the protein of H. pylori and is vital for its survival.

A significant proportion (e.g., ≈20%) of H. pylori organisms can be found adherent to the surface of gastric mucous cells. Occasionally H. pylori can also be found intracellularly, particularly in preneoplastic and neoplastic lesions.53 Adhesion of the bacteria to the epithelial layer is facilitated by a large family of 32 related outer-membrane proteins (Hop proteins) that include the adhesins. One of the best-characterized adhesins is BabA, which is encoded by the strain-specific gene babA2, a member of a highly conserved family of outer membrane proteins. BabA binds to the fucosylated Lewis B blood group antigen on gastric epithelial cells and forms a scaffold apparatus that allows bacterial proteins to enter host epithelial cells. Bacterial strains that possess the babA2 gene adhere more tightly to epithelial cells, promote a more aggressive phenotype, and are associated with a higher incidence of gastric adenocarcinoma.54

The cag pathogenicity island is approximately 40 kb and contains 31 genes. The terminal gene of this island, cagA, is often used as a marker for the entire cag locus. Compared with cagA-negative (cag−) strains, cag-positive (cagA+) strains are associated with more severe inflammation, higher degrees of atrophic changes, and a greater chance of progressing to gastric adenocarcinoma.5558 The estimated risk has ranged from an odds ratio of 2 to as high as 28.4.23 However, many of the genes adjacent to cagA code for a type 4 secretion system (TFSS), often viewed as a molecule needle that injects bacterial proteins (such as CagA) into host cells. The remarkable finding that CagA is injected into host cells, where it is phosphorylated by Src and c-Abl kinases, has raised the possibility that CagA could directly promote growth, migration, and transformation. Indeed, transgenic expression of H. pylori CagA induces gastrointestinal (GI) and hematopoietic neoplasms in mice.59 Other genes within the pathogenicity island are also believed to be important for disease (cagE or picB, cagG, cagH, cagI, cagL, cagM) because they appear to be required for in vitro epithelial cell cytokine release, although they do not seem to have as great an effect on immune cell cytokine activation as cagA.6062 These findings may explain the attenuated inflammatory response and lower cancer risk with cagA− strains in vivo.6366

All strains of H. pylori carry the vacA gene, which codes for a pore-forming vacuolating toxin, but expression of vacA differs according to allelic variation. Approximately 50% of H. pylori strains express the vacA protein, which has been shown to be a very powerful inhibitor of T cell activation in vitro.67 Although vacA and cagA map to different loci within the H. pylori genome, the vacA protein is commonly expressed in cagA+ strains. There are various forms of vacA, and the s1m1 strains are highly toxigenic. Other bacterial virulence factors, such as cagE, may play a role in the modulation of apoptosis and the host inflammatory response, thereby contributing to disease manifestations. Indeed, “virulent strains” (cagA+, cagE+, and VacA+ s1m1) appear to be more potent inducers of proinflammatory mediators than “nonvirulent strains” (cagA−, cagE−, and VacA−), possibly explaining the higher association of cagA+ strains with gastric cancer.68

DIETARY FACTORS

Numerous dietary factors have been implicated as risk factors for gastric cancer. The decline in gastric cancer rates has coincided with the widespread use of refrigeration and the concomitant higher intake of fresh fruits and vegetables and lower intake of pickled and salted foods. Use of refrigeration for more than 10 to 20 years has been associated with a decreased risk of gastric cancer.17,69 Lower temperatures reduce the rate of bacterial, fungal, and other contaminants of fresh food, as well as the bacterial formation of nitrites. Additionally, high intake of highly preserved foods may be associated with increased gastric cancer risk,70 likely because of higher contents of salt, nitrates, and polycyclic aromatic amines.71

Much attention has been given to the effects of high nitrate intake. When nitrates are reduced to nitrite by bacteria or macrophages, they can react with other nitrogenated substances to form N-nitroso compounds that are known mitogens and carcinogens.72,73 In rats, N-nitroso compounds have been shown to cause gastric cancer.74 However studies trying to link N-nitroso exposure to gastric cancer risk have been inconclusive, perhaps reflecting the fact that nitrate intake does not necessarily correlate with nitrosation levels.75,76 A Swedish cohort study found a nearly two-fold increased risk of gastric cancer associated with high dietary nitrate intake.70 However, separate large cohort studies from Europe did not demonstrate an association between nitrate intake and risk of gastric cancer.77,78

Another factor implicated in the development of gastric cancer is a diet high in salt (pickled foods, soy sauce, dried and salted fish and meat). High salt intake has been associated with higher rates of atrophic gastritis in humans and animals in the setting of Helicobacter infection79 and increases the mutagenicity of nitrosated food in animal models.17 High salt diets are associated with a roughly two-fold increased risk of gastric cancer.80,81 Cohort and case-control studies have also found an increased risk of gastric cancer associated with processed meat intake.70,82 Possible mechanisms include higher bacterial loads, up-regulation of H. pylori cagA expression, and increased cell proliferation and p21 expression.79,83,84

Epidemiologic studies have had inconsistent findings with regard to fruit and vegetable consumption and risk of gastric cancer. A cohort study from Japan found significantly decreased risks of gastric cancer associated with increased vegetable and fruit intake.85 A Swedish cohort study demonstrated a reduced risk of gastric cancer associated with high vegetable intake, but no association was seen with amount of fruit consumption.86 A large cohort study of nearly 500,000 adults in the United States and a separate nested case-control study from Europe failed to find an association between fruit and vegetable intake and gastric cancer risk.87,88

Other foods or dietary factors that have been implicated as potential risk factors for gastric cancer are high intake of fried food, foods high in fat, high intake of red meat, and aflatoxins.82,8991 Diets with a high intake of fresh fish and antioxidants may be protective.90,9294 However, there are insufficient data to make definitive conclusions regarding these factors.

CIGARETTE SMOKING

Tobacco has long been established as a carcinogen, and numerous epidemiologic studies have demonstrated an association between cigarette smoking and risk of gastric cancer.95 Several large cohort studies from Europe and Asia have reported a significantly increased risk of gastric cancer among smokers.9698 A meta-analysis found that compared with never smokers, current smokers had a 1.5-fold increased risk of gastric cancer for the cardia as well as noncardia region.99 The authors also reported an increased association with greater amounts of smoking.

Moist snuff is a smokeless tobacco product promoted as an alternative to cigarettes and has reportedly reduced levels of carcinogenic nitrosamines. However, results of a Swedish cohort study demonstrated a 1.4-fold increased risk of noncardia gastric cancer among regular snuff users.100 Snuff exposure also increases the rate of gastric carcinogenesis in H. pylori–infected mice.101

ALCOHOL

Multiple cohort and case-control studies from the United States and Europe have found no significant association between alcohol consumption and cardia or noncardia gastric cancer.98,102,103 A separate population-based case-control study in the United States also found no association between any alcohol use and risk of either cardia or noncardia gastric cancer, although a reduced risk was reported with wine consumption (cardia, odds ratio [OR] 0.6; 95% confidence interval [CI]: 0.5 to 0.9; noncardia, OR 0.7; 95% CI: 0.5 to 0.9).104

OBESITY

Obesity is a recognized risk factor for numerous gastrointestinal malignancies.105 Increased body mass index (BMI) appears to be associated with a mild to moderate increased risk of gastric cardia cancer but not for noncardia gastric cancer.106110 Results of the National Institutes of Health–American Association of Retired Persons (NIH-AARP) Diet and Health Cohort Study demonstrated that marked obesity (BMI = 35 kg/m2) was associated with a significantly increased risk of gastric cardia cancer (hazard ratio, 2.46) but not with noncardia gastric cancer.106 A separate cohort study from the Netherlands also found an increased risk of cardia cancer with increasing BMI.107

INHERITED PREDISPOSITION

As is true for most malignancies, genetic and environmental factors play important roles in the pathogenesis of gastric cancer. Generally, intestinal-type gastric cancer is considered to be largely due to environmental causes (i.e., H. pylori infection), whereas diffuse gastric cancer is considered a primarily genetic malignancy. In the case of intestinal-type gastric cancer, however, assigning relative values to environmental and genetic contributions is complex, given that the major environmental factor, H. pylori, also tends to exhibit familial clustering.

Overall, 10% of cases of gastric cancer appear to exhibit familial clustering,111 and family history is likely an independent risk factor for the disease even after controlling for H. pylori status.112,113 In a cohort study of relatives of patients with gastric cancer, siblings had a two-fold increased risk of gastric cancer, adjusted for H. pylori infection.114 In a case-control study from Japan, a positive family history was associated with a significantly increased odds of gastric cancer in women (OR, 5.1), but not in men.115 A study from Scandinavia showed that having a twin with gastric cancer conferred a markedly higher risk for the disease (hazard ratios, 9.9 for monozygotic twins and 6.6 for dizygotic twins), leading the researchers to calculate that heritable factors accounted for 28% of gastric cancers, compared with 10% for shared environmental factors and 62% for nonshared environmental factors.116

Some of the familial clustering seen with intestinal-type gastric cancer may be related to genetic factors that play a role in the host immune response to H. pylori infection. Data from South Korea indicate that individuals with a family history of gastric cancer more frequently have H. pylori infection as well as associated atrophic gastritis or intestinal metaplasia.117 In a case-control study from Scotland, relatives of patients with gastric cancer had a higher prevalence of atrophy and hypochlorhydria, but a similar prevalence of H. pylori infection, compared with controls.118 The greater prevalence of atrophy was confined to those patients with H. pylori infection, suggesting the possibility these individuals were perhaps exhibiting a more vigorous immune response to H. pylori. In a number of model systems, the development of gastric atrophy has been linked to a strong Th1 immune response.43,45,119 Thus, it was postulated that candidate disease-susceptibility genes for gastric atrophy and cancer might be genes that participate in the innate and adaptive immune responses to H. pylori infection. Inflammation is modulated by an array of pro- and anti-inflammatory cytokines, and several genetic polymorphisms have been described that influence cytokine response.

IL-1β is an important proinflammatory cytokine and a powerful inhibitor of acid secretion. Thus, the initial report in this area described in the setting of H. pylori infection an association between proinflammatory IL-1 gene cluster polymorphisms (IL-1B encoding IL-1β, and IL-1RN encoding its naturally occurring receptor antagonist, IL-1RA) and neoplastic progression. Individuals with the IL-1β-31*C or -511*T and IL-1RN*2/*2 genotypes were shown in the study to be at higher risk for development of H. pylori–dependent hypochlorhydria and gastric cancer.120 The increased risk of progression to cancer with these genotypes was in the two- to three-fold range compared with noninflammatory genotypes. The initial report was confirmed in other studies.121125 Subsequently, Hwang and colleagues126 demonstrated that carriers of the IL-1β-511T/T genotype or the IL-1RN*2 allele had higher mucosal IL-1β levels than noncarriers, and they also confirmed the association between the -511T/T genotype and severe gastric inflammation and atrophy. The importance of IL-1β in carcinogenesis has now been demonstrated in a transgenic study, in which stomach-specific expression of human IL-1β in transgenic mice led to spontaneous gastric inflammation and cancer that correlated with early recruitment of myeloid-derived suppressor cells (MDSCs) to the stomach.127

Additional associations with gastric cancer risk have been reported for genetic polymorphisms in tumor necrosis factor-α (TNF-α) and IL-10. Proinflammatory genotypes of TNF-α and IL-10 each were associated with a two-fold higher risk of noncardia gastric cancer. When combined with proinflammatory genotypes of IL-1β and IL-1RN, patients with three or four high-risk genotypes showed a 27-fold greater risk of gastric cancer.128 Additional studies have shown that polymorphisms of the TLR4 gene also increase the risk of gastric cancer. Carriers of the TLR4+896G polymorphism had an 11-fold increased risk of hypochlorhydria, and significantly more severe gastric atrophy and inflammation.129 Accumulated evidence suggests that the genetic predisposition to gastric cancer may be largely determined by the TLR and cytokine responses to chronic Helicobacter infection.

The best described form of hereditary gastric cancer is the diffuse gastric cancer that is seen in the presence of a germline mutation in the gene CDH1, which encodes the cell adhesion molecule E-cadherin. A large New Zealand kindred was found to have a germline mutation in the E-cadherin gene, and similar mutations have been reported in several additional kindreds, all with diffuse-type gastric cancer.130133 The age of onset of gastric cancer in individuals with CDH1 mutations is less than 40 years but can be highly variable, and the estimated lifetime risk of gastric cancer is close to 70%.134,135 Germline CDH1 mutations are also associated with familial lobular breast cancer.136,137

A small part of the familial clustering of gastric cancer can be attributed to other cancer syndromes (see Chapter 122). Patients with familial adenomatous polyposis (FAP) have a prevalence of gastric adenomas ranging from 35% to 100%, and their risk of gastric cancer is close to 10-fold higher than that of the general population.138 These cancers frequently arise from fundic gland polyps and develop at an early age.139,140 Patients with hereditary nonpolyposis colorectal cancer (HNPCC) syndrome have an approximately 11% risk of developing gastric cancer, predominantly of the intestinal type, with a mean age at diagnosis of 56 years.141 Patients with juvenile polyposis also have a 12% to 20% incidence of gastric cancer.142,143

GENETICS

Although atrophy and intestinal metaplasia correlate with gastric cancer risk, direct cell progression through these stages has not been conclusively shown. Indeed, gastric cancer most likely arises from stem or progenitor cells present within the gastric mucosa rather than directly from terminally differentiated metaplastic cells. Investigators have for several decades sought to unravel the mutations responsible for gastric cancer initiation and progression in an attempt to uncover a logical progression of acquired mutations akin to what is seen in colorectal cancer. However, gastric cancer does not follow a pattern like colorectal carcinoma progression, and there is no clear-cut linear sequence of mutations in gastric cancers. There is likely a need for a genome-wide analysis of somatic mutations in gastric cancer. Nevertheless, even if a genome-wide sequencing study is performed, the precise role, if any, that identified mutations play in initiating malignant transformation, rather than cancer progression, may not be clear.

Aneuploidy is common in gastric cancer (seen in 60% to 75% of cases), but cytogenetic studies have failed to identify any consistent chromosomal abnormality. Comparative genomic hybridization studies have shown that chromosome arms 4q, 5q, 9p, 17p, and 18q exhibit frequent decreases in DNA copy number, whereas chromosomes 8q, 17q and 20q often have increased DNA copy number.144

There is a consensus that TP53 is the most commonly mutated gene in gastric cancer (60% to 70% of gastric cancers) and that mutations in Ras, APC, and Myc are rare.145,146 Loss of heterozygosity (LOH) at the APC locus occurs more commonly. Another genetic abnormally found at high frequency includes deletion or suppression of the fragile histidine triad gene (FHIT) (60%), a tumor suppressor locus on chromosome 3p. Genes that normally inhibit entry into the cell cycle, such as p16 and p27, show diminished expression in nearly one half of gastric cancers.147152 Absence of p27 expression is associated with a poorer prognosis.147,149 Absence of p16 expression is seen most commonly in poorly differentiated carcinomas but has no measurable impact on patient prognosis.153 Diminished expression of p16 and p27 occurs in the absence of detectable mutations and is believed to be secondary to hypermethylation of the respective genes.151 Many of these cancers show hypermethylation of a number of promoter regions, including the MLH1 promoter region, and show the high-level microsatellite instability (MSI) phenotype (see Chapter 3). Multiple tumor suppressor genes have been shown to be methylated in gastric cancers. Emerging evidence suggests that epigenetic changes, including global hypomethylation and promoter hypermethylation, occurs quite early in gastric carcinogenesis. In addition, it appears that DNA methylation changes also occur in the tumor-associated stromal fibroblasts, suggesting an important role for the tumor microenvironment.20

Overexpressions or amplifications of a number of growth factor pathways have been described, including cyclooxygenase-2 (COX-2) (70%), hepatocyte growth factor/scatter factor (HGF/SF) (60%), vascular endothelial growth factor (VEGF) (50%), c-met (50%), amplified in breast cancer-1 (AIB-1) (40%), and β-catenin (25%) (Table 54-3).154 Approximately 15% of gastric cancers have been reported to overexpress both epidermal growth factor (EGF) and EGF receptor (EGFR), consistent with an autocrine mechanism. Mutations in PIC3A, a gene that codes for a catalytic subunit of phosphotidylinositol 3-kinase (PI3K), has been found in up to 25% of gastric cancers analyzed.155 In addition, mutations in human protein tyrosine phosphatases (PTPs) were found by the same laboratory in 17% of gastric cancers, with the protein tyrosinase phosphatase–receptor type (PTPRT) the most frequently altered.156

Table 54-3 Genetic Abnormalities in Gastric Adenocarcinoma

ABNORMALITIES APPROXIMATE GENE FREQUENCY (%)
DNA aneuploidy 60-75
Microsatellite instability 15-50
Deletion/Suppression  
TP53 gene 60-70
Fragile histidine triad gene (FHIT) 60
Adenomatous polyposis coli (APC) gene LOH 50
Deleted in colorectal cancer (DCC) gene LOH 50
Decreased Expression Due to Hypermethylation
p16 ≈50
TFF1 ≈50
p27 <50
MLH1 15-20
E-cadherin 50
Amplification/Overexpression  
Cyclooxygenase-2 (COX-2) 70
Hepatocyte growth factor (HGF) 60
Vascular endothelial growth factor (VEGF) 50
c-Met 50
Amplified in breast cancer-1 (AIB-1) 40
Beta-catenin 25
EGF/EGFR 15
Mutations  
PI3K 25
PTPRT 17

DNA, deoxyribonucleic acid; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; LOH, loss of heterozygosity; MLH1, human mutL homolog 1; PI3K, phosphatidylinositol 3-kinase; PTPRT, protein-tyrosine phosphatase receptor-type; TFF1, human trefoil factor 1.

Gastric-specific tumor suppressor genes TFF1 (Trefoil factor 1) and RUNX3 (Runt-related transcription factor 3), which have now been identified and may represent “gatekeepers” of the gastric cancer pathway, are logical targets for further study.157,158 Loss of TFF1 has been described in around 50% of gastric carcinomas, and TFF1 knockout mice develop spontaneous gastric antral tumors. Mutations of TFF1 also have been described, and these enhance gastric cancer cell invasion through signaling pathways that include PI3-K and phospholipase-C.159 TFF1 expression is repressed by STAT-3, and activation of STAT-3 is also emerging as a key pathway that leads to gastric cancer.44 RUNX3 most likely suppresses gastric epithelial growth by inducing p21 and Bim, attenuating Wnt signaling, and is altered in 82% of gastric cancers.160 Investigations into these genes and their contributions to the gastric cancer phenotype will prove valuable to our understanding of disease progression.

MSI in dinucleotide repeats secondary to defects in DNA mismatch repair genes, such as MLH1 and MLH2 (mutL homologs 1 and 2), have been implicated in the development of colorectal cancer, and in particular the HNPCC syndrome. Patients with HNPCC have an 11% incidence of gastric cancer, suggesting that MSI may also play a role in the development of gastric cancer.141 MSI is found in 15% to 50% of sporadic gastric cancers, with a higher prevalence in the intestinal type of cancer.161166 Low-level microsatellite activity (e.g., MSI-low) can be found in 40% of areas of intestinal metaplasia in patients with gastric cancer166 and in 14% to 20% of adenomatous polyps.164,166,167 MSI-high (MSI-H) occurs in only 10% to 16% of gastric cancers. MSI is associated with the less frequent occurrence of TP53 mutations, well- to moderately well differentiated histology, and distal tumor location. Studies that have examined the effect of MSI on patient survival have shown inconsistent results.167,168 When the findings are taken together, it would appear that MSI does play a role in the pathogenesis of gastric cancer, likely before the development of intestinal metaplasia (see Fig. 54-3), and is most commonly due to methylation of the MLH1 promoter.

The data regarding the genetics of diffuse gastric cancer are less complete. Mutations in the E-cadherin (CDH1) gene have been linked to the development of the diffuse type of gastric cancer. Several kindreds, families with hereditary diffuse gastric cancer (HDGC) have been found to carry a germline mutation in the CDH1 gene, all with diffuse-type cancer.130132,169,170 Further evidence supporting a role for E-cadherin in the pathogenesis of gastric cancer comes from studies showing that suppression of E-cadherin expression occurs in 51% of cancers, with a higher percentage found in diffuse-type cancers.171 Furthermore, E-cadherin underexpression is associated with higher rates of lymph node metastases and reduced survival.172,173 The overall rates of CDH1 mutations in gastric cancer are low, however, with the decreased expression of E-cadherin seen in gastric cancer likely secondary to hypermethylation of the CDH1 promoter, which occurs in 50% of gastric cancers and 83% of diffuse-type gastric cancers.174 E-cadherin is a transmembrane protein that connects to the actin cytoskeleton through α- and β-catenins to establish cell polarity and mediates homophilic cellular interactions.175,176 Decreased expression of E-cadherin is believed to promote dissociation of cancer cells from their cell matrix, enhancing the migration and invasion of gastric cancer cells. Expression of α-catenin is also decreased or absent in 68% of gastric cancers.177 Therefore, E-cadherin appears to act as a tumor suppressor gene that may be important in the pathogenesis of diffuse gastric cancer.

Perhaps as important as the genetic alterations acquired during the progression to gastric adenocarcinoma, is in what target cells do these changes occur? In order for a cell to accumulate the quantity of genetic changes necessary for autonomous growth, it must be long lived. For these reasons, the current thinking is that a resident tissue stem cell is the target of genetic mutations and becomes the “cancer stem cell” capable of autonomous growth and with metastatic potential. Work from our laboratory offers a new model for the cancer stem cell. Bone marrow–derived stem cells are capable of homing to injured and inflamed peripheral organs and differentiating into organ-appropriate cell lineages.178181 In an environment of inflammation and altered growth signaling, these cells can differentiate aberrantly and become dysplastic and neoplastic, and we have shown they constitute the majority of cells within in situ as well as invasive gastric adenocarcinoma lesions.182 Although much work needs to be done to understand these findings completely, they offer an exciting possibility for new approaches to understanding and treating gastric and other inflammatory mediated cancers.

PREMALIGNANT CONDITIONS

CHRONIC ATROPHIC GASTRITIS

Chronic atrophic gastritis, which is defined as the loss of specialized glandular tissue in its appropriate region of the stomach, is an established early morphologic change that occurs along the sequence toward the development of gastric cancer.16,183 The presence of atrophic gastritis has an annual incidence of progression to gastric cancer of approximately 0.5% to 1%.184187 The extent of atrophic gastritis within the stomach correlates with risk of progression to cancer.188190

There are two forms of atrophic gastritis. The more common is multifocal atrophic gastritis (MAG), which is associated with H. pylori infection and more likely to be associated with metaplasia. The presence of H. pylori infection is associated with an approximately 10-fold increased risk of atrophic gastritis.191 There is considerable regional variation in the prevalence of atrophic gastritis in H. pylori–infected individuals, with a roughly 3-fold increase in Asian compared with Western countries.191,192 The second form of atrophic gastritis, corporal atrophic gastritis, is associated with antiparietal cell and intrinsic factor antibodies. This form of atrophy is confined to the body and fundus. Corporal atrophic gastritis is associated with pernicious anemia and an increased gastric cancer risk, albeit not as high as that seen with H. pylori–induced multifocal atrophic gastritis, owing most likely to a lesser degree of inflammation.185,193

Mechanisms underlying the increased risk of gastric cancer in the setting of gastric atrophy may be related to low acid output (achlorhydria), which predisposes to gastric bacterial overgrowth (with non-Helicobacter organisms), greater formation of N-nitroso compounds, and diminished ascorbate secretion into the gastric lumen.194 Additionally, serum gastrin levels are increased in response to the reduced acid output. Gastrin is a known growth factor for gastric mucosal cells, and sustained elevations of serum gastrin may contribute to abnormal growth and increased risk of neoplastic progression.195,196

INTESTINAL METAPLASIA

Intestinal metaplasia (IM) can be subdivided into three categories, as classified by Jass and Filipe and as discussed in Chapter 51.197 Type I is the complete form of IM, containing Paneth cells, goblet cells that secrete sialomucins, and absorptive epithelium with well-defined brush borders. Type I metaplasia does not raise the risk of gastric cancer. Type II or incomplete metaplasia contains few absorptive cells, few columnar intermediate cells, and goblet cells that express sialomucins. Type III is intermediate between type I and type II and contains properties of both.198 It is estimated that the presence of type II or III IM is associated with a 20-fold increased risk of gastric cancer. Early gastric cancer develops in 42% of patients with type III IM within five years of follow-up, suggesting that IM represents a precursor lesion for the intestinal form of gastric cancer.199 However, whether cancer arises from areas of IM or whether IM simply represents a marker for higher gastric cancer risk remains unclear. As is the case with atrophic gastritis, the prevalence of IM in H. pylori–infected individuals is higher in Asia (≈40%) as compared with the West.191,192

DYSPLASIA

Histologic assessment of gastric dysplasia and adenocarcinoma is based on the 2000 Vienna classification (Table 54-4).200 The prevalence of gastric dysplasia ranges from as low as 0.5% in low-risk areas201 to 20% in high-risk areas.202 Prospective studies have shown that low-grade dysplasia may regress in up to 60% of cases, whereas it progresses to high-grade dysplasia in 10% to 20% of cases (Fig. 54-4).203205 High-grade dysplasia rarely regresses, and is associated with an annual incidence of progression to gastric cancer of 2% to 6%.205207 In a prospective cohort study from the Netherlands, the presence of high-grade dysplasia was associated with a markedly increased risk of progression to cancer (adjusted hazard ratio, 40.1).206 High-grade dysplasia is often associated with synchronous cancer and can be uni- or multifocal.208

Table 54-4 Padova International Classification System for Gastric Dysplasia

CATEGORY DEFINITION HISTOLOGIC DESCRIPTION
I 1.0 Normal Normal gastric architecture with absent or minimal inflammatory infiltrates.
  1.1 Reactive foveolar hyperplasia The general architecture is well preserved, with evidence of hyperproliferative epithelium, enlarged nuclei, and mitotic figures.
  1.2 Intestinal metaplasia Type I. Closely resembles the morphology of the small intestine, with absorptive enterocytes, well-defined brush borders, and well-formed goblet cells.
    Type II. Incomplete metaplasia with irregular mucous vacuoles, absence of brush borders, and difficult-to-identify absorptive enterocytes. Cells secrete mainly sialomucins.
    Type III. Same as type II except cells secrete mainly sulfomucins.
II Indefinite for dysplasia Inability to discern whether cells are neoplastic or non-neoplastic. Usually found in setting of inadequate biopsy specimens and presence of architectural distortion and nuclear atypia.
III Noninvasive neoplasia Phenotypically neoplastic epithelium confined to glandular structures inside the basement membrane. Includes adenomas.
    Should be divided into “low grade” and “high grade.”
IV Suspicious for invasive cancer Presence of neoplastic epithelium, but where invasion cannot be clearly identified.
V Invasive cancer Invasive carcinoma.

Adapted from Rugge M, Correa P, Dixon M, et al. Gastric dysplasia: The Padova International Classification. Am J Surg Pathol 2000; 24:167.

GASTRIC POLYPS

The prevalence of gastric polyps in the general population is approximately 0.8% to 2.4%.209,210 Gastric polyps consist predominantly of fundic gland polyps (≈50%), hyperplastic polyps (≈40%), and adenomatous polyps (≈10%).210,211 The clinical course of fundic gland polyps is generally benign, and they are detected with increasing frequency in the era of proton pump inhibitor (PPI) use. In a series of 599 consecutive patients who underwent upper endoscopy, use of PPIs for 5 years or longer was associated with a significantly increased risk of fundic gland polyps (hazard ratio, 3.8).212 The rate of malignant transformation of fundic gland polyps is generally quite low (≈1%) and confined to polyps larger than 1 cm.213 One notable exception to the benign nature of fundic gland polyps is in patients with FAP. In this group the prevalence of fundic gland polyps ranges from 51% to 88%, with dysplasia present in more than 40% of cases.139,140

Hyperplastic polyps are almost always benign lesions. The rare hyperplastic polyps that undergo malignant transformation often contain areas of intestinal metaplasia or dysplasia and typically form a well-differentiated intestinal-type cancer.213

In contrast to fundic gland and hyperplastic polyps, gastric adenomas undergo malignant transformation at a high rate. Gastric adenomas that were followed by serial endoscopy with biopsy were documented to progress to dysplasia and then to carcinoma in situ, which developed within 4 years of follow-up in approximately 11% of cases.214 Endoscopic biopsy of gastric polyps to find dysplasia or carcinoma is associated with significant sampling error.215 Therefore, it is suggested that all adenomas (and other polyps larger than 1 cm or those causing symptoms such as occult bleeding) be removed by endoscopic polypectomy. Decisions regarding surveillance intervals should be made on an individual basis.

PREVIOUS GASTRECTOMY

It has been reported by several groups that gastric surgery for benign conditions can predispose patients to a higher risk of gastric cancer, beginning 20 years after the surgery.216219 The risk is greatest for those who underwent surgery before the age of 50 years, perhaps reflecting the long lag period necessary between the operation and the development of cancer.217 The cancers tend to occur at or near the surgical anastomosis on the gastric side; only rarely do they reside on the intestinal side of the anastomosis.220

Numerous theories have been proposed to explain the increased propensity for cancer to form at the surgical anastomosis site. They include hypochlorhydria resulting in gastric bacterial overgrowth, with increased production of nitrites, chronic enterogastric reflux of bile salts and pancreatic enzymes, which are potent gastric irritants, and atrophy of the remaining fundic mucosa secondary to low levels of antral hormones such as gastrin.17,221,222 The Billroth II operation predisposes to the development of cancer at a four-fold higher rate than a Billroth I procedure, suggesting that bile reflux may be a significant predisposing factor.217 H. pylori and associated intestinal metaplasia are found less frequently in postgastrectomy gastric cancers as compared to distal gastric cancers in the nonoperative stomach.223 It is unclear whether screening for gastric cancer in this population of patients in areas of low cancer incidence would be cost effective. With the advent of H. pylori eradication therapy as well as PPIs, the number of gastric resections for peptic ulcer disease has decreased dramatically, significantly reducing the effect of the postgastrectomy state as a risk factor for gastric cancer.

PEPTIC ULCER DISEASE

Large epidemiologic studies have demonstrated a consistently increased risk of gastric cancer in patients with a history of a gastric ulcer. In a cohort study of nearly 58,000 adults from Sweden who were followed for an average of nine years, a history of gastric ulcer was associated with a significant 1.8-fold increased risk of gastric cancer.224 Interestingly, a history of duodenal ulcer was associated with a significant 40% decreased risk of gastric cancer. A separate case control study of more than 90,000 U.S. veterans found a similarly increased risk of noncardia gastric cancer (but not cardia cancer) in patients with a history of gastric ulcer, and a corresponding decreased risk in those with a history of duodenal ulcer.225 The reasons for these disparate cancer risks are not entirely clear.

MÉNÉTRIER’S DISEASE (see Chapter 51)

In a review of case reports, 15% of patients with Ménétrier’s disease had associated gastric cancer,226 including several cases that documented a progression from dysplasia to cancer.227,228 Because of the rarity of Ménétrier’s disease, it has been difficult to study its relationship with gastric cancer in any controlled fashion, and no recommendations regarding endoscopic surveillance can be made.

SCREENING AND PREVENTION

SCREENING AND SURVEILLANCE

The majority of the literature regarding screening for gastric cancer comes from east Asia, where the prevalence of this disease is among the highest in the world.229 Since 1960, the Japanese have been performing mass screening, using upper GI barium studies followed by endoscopy if any suspicious lesions are found. Japanese researchers have reported a sensitivity of 66% to 90% and a specificity of 77% to 90% for this screening approach.230 Not surprisingly, studies from Japan have also shown that use of screening leads to a diagnosis of gastric cancer at earlier stages, with one study reporting that more than 50% of cases detected by screening were diagnosed as stage I.231 (Staging of gastric cancer is discussed later.) Long-term follow-up data from the Japanese Public Health Center cohort of more than 42,000 adults showed that subjects who underwent screening had a nearly 50% reduced risk of death from gastric cancer.232 A separate cohort study of 87,000 adults from Japan found a 25% to 35% risk reduction in death from gastric cancer among those who participated in gastric cancer screening.233 However, similar risk reductions were seen for death from all causes, casting a level of uncertainty on the true magnitude of benefit associated with screening with respect to preventing death from gastric cancer.

The serum pepsinogen (PG) test is increasingly used to screen for patients at highest risk for having preneoplastic gastric lesions.234 As discussed in Chapter 49, the stomach produces two types of pepsinogen: PGI and PGII. In the presence of atrophic gastritis, production of PGI from oxyntic glands is reduced, whereas PGII production remains relatively constant. Therefore, low serum pepsinogen I levels (<70 mg/L) and a serum pepsinogen I/II ratio less than 3 are useful for the identification of patients with atrophic gastritis.229 A prospective cohort study found that patients with low serum PGI concentrations had a significantly elevated risk of gastric cancer.235

Screening for gastric cancer with upper endoscopy is likely cost-effective in moderate- to high-risk populations, such as older Asian men.236 However, in populations with a lower incidence of gastric cancer, screening is less likely to have the same degree of benefit.

PREVENTION

Given the lethal nature of gastric cancer and its link to chronic infection and inflammation, much attention has been paid to the possibility of “chemoprevention” of gastric neoplastic lesions. The approach most studied has been H. pylori eradication, but consideration also has been given to supplementation with antioxidants, nonsteroidal anti-inflammatory drugs (NSAIDs), and COX-2 antagonists. In this section, we first summarize the literature regarding possible beneficial effects of H. pylori eradication and then consider other strategies.

Eradication of Helicobacter pylori

The effect of eradicating H. pylori on the subsequent risk of gastric cancer is not entirely clear. There is little question that chronic inflammation in a variety of organ systems can lead to malignancy237 and that H. pylori eradication can reduce or alleviate gastric inflammation. Studies in patients have demonstrated that H. pylori eradication can lead to decreased oxidative stress and cell proliferation.238 In addition, limited studies involving eradication of gastric Helicobacter organisms in Mongolian gerbils suggest that eradication can partially reverse atrophy and metaplasia and inhibit progression to gastric cancer.239242 Studies in mice confirm the reversibility of metaplasia and prevention of gastric cancer with early eradication. With later eradication, cancer progression was slowed and cancer mortality dramatically decreased.18

Nevertheless, with regard to published trials in humans, conclusive evidence that treatment of H. pylori infection prevents gastric cancer is lacking, in part because of the rare endpoint—gastric cancer—needed for these studies. One approach has been to examine intermediate biomarkers such as gastric atrophy and intestinal metaplasia, which are generally considered premalignant lesions. Thus, a number of studies have looked at the effect of H. pylori eradication on these intermediate biomarkers, and a majority have shown a beneficial effect in preventing progression of gastric disease.243247 In a randomized placebo-controlled trial of 587 Chinese patients with H. pylori infection, assignment to eradication therapy was associated with a significantly reduced risk of progression of intestinal metaplasia (odds ratio, 0.63).248 However, a randomized placebo-controlled trial of Mexican adults did not demonstrate any benefit of H. pylori eradication in the prevention of histologic progression.247

In an open-label randomized controlled trial of patients with resected early gastric cancer, patients were assigned to receive either H. pylori eradication therapy or placebo. After three years of follow-up, H. pylori eradication was associated with a reduced odds of development of metachronous gastric cancer (OR 0.35; 95% CI: 0.16 to 0.78).249 In a retrospective analysis of a cohort of Japanese patients who were treated for H. pylori, successful eradication (as compared to persistent infection) was associated with a significant 80% reduced risk of gastric cancer.250

A prospective, randomized placebo-controlled trial sought to determine whether H. pylori eradication in a high-risk population in China would reduce the incidence of gastric cancer.246 Although no overall benefit was seen in the group receiving H. pylori eradication, there was a clear reduction in gastric cancer incidence in a post hoc subgroup analysis of H. pylori carriers who did not have precancerous lesions (gastric atrophy, intestinal metaplasia, or dysplasia) at study initiation. It is possible that some of the patients in the eradication arm may have passed a “point of no return,” when cellular alterations had sufficiently accumulated to promote cancer.251 Further randomized trials are needed, but the evidence to date supports the notion that early eradication of H. pylori may prevent or delay progression to gastric cancer in high-risk patients.

In Western countries, gastric cancer prevention has not been extensively pursued due to the low prevalence of H. pylori and decreasing incidence of gastric cancer. However, a study by Parsonnet and colleagues252 suggested that screening and treatment of H. pylori infection would be cost-effective in the prevention of gastric cancer, particularly in high-risk populations, if it was assumed that treatment of H. pylori infection prevented 30% of attributable gastric cancers. Using a more conservative 10% reduction in gastric cancer risk, an analysis from the United Kingdom also concluded that H. pylori eradication was cost-effective.253

Antioxidants

Chronic inflammatory states such as H. pylori gastritis can result in the generation of free radicals derived from oxygen and nitrogen.254 These free radicals can promote carcinogenesis via numerous mechanisms, including direct DNA damage and inhibition of DNA repair mechanisms, inhibition of apoptosis, and activation of cellular proliferation pathways. Antioxidants, such as carotenoids and vitamins C and E, bind with reactive oxygen and nitrogen species to neutralize their damaging effects.

Epidemiologic data support a relationship between increased antioxidant intake and reduced risk of gastric cancer.255259 In a nested case-control study from Japan, low plasma β-carotene levels were associated with an increased risk of gastric cancer.257 A case-control study from Korea found that elevated nitrate-to-antioxidant intake ratios were associated with an increased risk of gastric cancer.258 In a Swedish cohort study, high levels of vitamin A, retinol, and α- and β-carotene intake were associated with a 50% risk reduction in gastric cancer.259

However, in a randomized placebo-controlled trial of antioxidants (either vitamin A, C, or E) in patients with precancerous gastric lesions (nonatrophic or atrophic gastritis, intestinal metaplasia, or dysplasia), antioxidant supplementation did not result in either reduced histologic progression or increased histologic regression.260 A randomized controlled trial in China also found no effect of combined vitamin C, E, and selenium supplementation on the prevalence of a combined endpoint of atrophic gastritis, intestinal metaplasia, dysplasia, or cancer.261 Based on these results as well as those of the Beta Carotene and Retinol Efficacy Trial, in which subjects who received β-carotene and vitamin A had an increased risk of lung cancer,262 antioxidant supplementation for the prevention of gastric cancer cannot yet be recommended.

Aspirin and Nonsteroidal Anti-inflammatory Drugs

Among other effects, aspirin and other NSAIDs inhibit cyclooxygenases. COX-1 is constitutively expressed in the GI tract. COX-2 expression is generally not observed in normal GI mucosa, but has been described in multiple epithelial malignancies, including gastric cancer.263,264 COX-2 expression is associated with aggressive cell growth in human as well as mouse models of cancer265268 and has been found to be overexpressed in 70% of gastric cancers.269 In this setting, COX-2 could promote the growth of tumors, inhibit apoptosis, and increase angiogenesis. COX-2 expression has been reported to be elevated in preneoplastic lesions, including intestinal metaplasia and dysplasia, and COX-2 levels appear to diminish after H. pylori eradication.270

Multiple epidemiologic studies have demonstrated a consistent association between NSAID use and a reduced risk of gastric cancer.271274 In a case-control study from Los Angeles County, NSAID use for more than 5 years was associated with a significantly decreased risk of noncardia gastric cancer (OR, 0.61), and there was a significant dose-related effect.272 A nested case-control study using the General Practitioners Research Database found that long-term users of non-aspirin NSAIDs had a significantly reduced risk of gastric cancer (OR, 0.65), although there was no observed association between aspirin use and gastric cancer.274 A meta-analysis reported a significant association between any NSAID use and reduced risk of gastric cancer (OR, 0.78), with similar findings for both acetylsalicylic acid (ASA) and non-ASA NSAIDs.273

In a randomized controlled trial of H. pylori–negative patients with intestinal metaplasia, patients receiving the COX-2 selective inhibitor rofecoxib or placebo had no difference in the rate of regression of intestinal metaplasia after two years.275 This trial was limited by the relatively short follow-up period and use of premalignant endpoints. Further trials in high-risk patients are warranted to determine if NSAIDs are effective for gastric cancer prevention; at the present time they cannot be recommended due to their unproven efficacy and known side effects.

Green Tea

Green tea is widely consumed in Asian countries and is hypothesized to have protective effects against cancer of the upper digestive tract. Polyphenols and other metabolites present in green teas, such as epigallocatechin-3-gallate (EGCG) and other catechins, have a variety of antitumor effects, including induction of apoptosis, inhibition of tumor cell growth and proliferation, and reduction in COX-2 expression.276278 EGCG also has antioxidant properties and may have anti-inflammatory properties as well.279,280

The majority of case-control studies have shown an inverse association between the risk of gastric cancer and the consumption of green tea.281283 However, a population-based prospective cohort study in northern Japan found no association between green tea consumption and the risk of gastric cancer.284 A separate cohort study from Japan reported a reduced risk of gastric cancer in women with high green tea consumption, but no change in risk among men.285 Thus, prospective controlled trials are needed, and at present, green tea cannot be recommended as chemoprevention for gastric cancer.

CLINICAL FEATURES

Early gastric cancers are asymptomatic in up to 80% of cases. When symptoms occur they tend to mimic those of peptic ulcer disease. With advanced gastric cancer, the common symptoms are weight loss (≈60% of patients) and abdominal pain (≈50%).10 Other presenting symptoms include nausea, vomiting, anorexia, dysphagia, melena, and early satiety. Pyloric outlet obstruction can occur with tumors of the antrum and pylorus, and tumors of the cardia can cause dysphagia due to involvement of the lower esophageal sphincter and development of pseudoachalasia.286 Rarely, paraneoplastic syndromes occur, such as thrombophlebitis (Trousseau’s sign), neuropathies, nephrotic syndrome, and disseminated intravascular coagulation.287289 Dermatologic paraneoplastic syndromes may occur uncommonly (see Chapter 22) and include hyperpigmented patches in the axilla (acanthosis nigricans) and the sudden onset of seborrheic dermatosis (senile warts) and pruritus (sign of Leser-Trélat).290

The physical examination is usually unremarkable. Cachexia and signs of bowel obstruction are the most common abnormal findings. Occasionally it is possible to detect an epigastric mass, hepatomegaly, ascites, and lower extremity edema.291 Laboratory studies are generally unrevealing until the cancer reaches advanced stages. Anemia and a positive test result for fecal occult blood may occur from chronic bleeding of an ulcerated mass. Hypoproteinemia can occur in patients with weight loss. Liver enzyme values, particularly alkaline phosphatase, can be elevated secondary to hepatic metastases.

Gastric cancer is metastatic at the time of diagnosis in 33% of cases.292 The most common sites of metastasis are the liver (40%) and peritoneum.293 Other sites of spread include the periumbilical area (Sister Mary Joseph’s nodule), left supraclavicular sentinel nodes (Virchow’s node), the pouch of Douglas (rectal shelf of Blumer), and the ovaries (Krukenberg’s tumor). Gastric cancer has also been reported to metastasize to the kidney, bladder, brain, bone, heart, thyroid, adrenal glands, and skin.291 There are reports of unusual presentations of metastatic disease, such as shoulder-hand syndrome from bone metastasis, diplopia and blindness from orbit and retinal metastases, and virilization due to Krukenberg’s tumors.294297

DIAGNOSIS

ENDOSCOPY

Esophagogastroduodenoscopy (EGD) is currently the procedure of choice for the diagnosis of gastric cancer (Fig. 54-5A). When a nonhealing gastric ulcer is found, at least six to eight biopsy specimens from the edge and base of the ulcer are recommended.298 As discussed in Chapter 13, the American Gastroenterological Association has recommended that an upper endoscopy be performed in patients who are older than 55 years with new-onset dyspepsia and in patients younger than 55 years who have “alarm” symptoms (weight loss, recurrent vomiting, dysphagia, evidence of bleeding, anemia).299 Dyspeptic patients in whom an empirical trial of proton pump inhibitors and eradication of H. pylori do not relieve symptoms should undergo prompt endoscopic evaluation as well. The basis for these recommendations is the low incidence of gastric cancer in individuals younger than 55 years. The yield of upper endoscopy for the detection of gastric cancer in patients with occult bleeding and a normal colonoscopy will vary based on the patient’s baseline risk of gastric cancer. Extensive involvement by the diffuse type of gastric cancer can manifest as a rigid and thickened stomach, also known as linitis plastica.

image

Figure 54-5. Endoscopic examples of gastric cancer. A, Ulcerated gastric adenocarcinoma mass lesion. B, Chromoendoscopic view of a superficial depressed gastric cancer, highlighted with indigo carmine (arrow).

(From Toyoda H, Tanaka K, Hamada Y, et al. Endoscopic diagnosis of hypopharyngeal, esophageal and gastric neoplasm. Dig Endosc 2006; 18:S41-3.)

In Japan and other areas of high gastric cancer prevalence, chromoendoscopy, magnification endoscopy, and narrow band imaging are used alone or in combination as aids in the detection of early gastric cancer (see Fig. 54-5B). Distinct irregular mucosal surface and vascular patterns have been found to correlate with the presence of dysplasia and carcinoma.300 There are also ongoing investigations into the utility of newer techniques such as autofluorescence and confocal microendoscopy for the diagnosis of early gastric neoplasia.301,302

A classification system has been developed for early gastric cancer based on endoscopic appearance,303 the purpose of which is to assess early lesions for risk of submucosal invasion as well as risk of lymph node spread (Fig. 54-6). The three types include superficial polypoid (type 0-I), superficial flat/depressed (types 0-IIa to 0-IIc), and superficial excavated (type 0-III) lesions. The most commonly observed subtype is 0-IIc, the nonpolypoid depressed lesion.303 This classification system is used most often in Japan, where endoscopic mucosal resection and submucosal dissection are frequently performed for early gastric neoplasia.

image

Figure 54-6. Schematic representation of the major variants of type 0 neoplastic lesions of the stomach: polypoid (Ip and Is), nonpolypoid (IIa, IIb, and IIc), nonpolypoid and excavated (III).

(From The Paris endoscopic classification of superficial neoplastic lesion: Esophagus, stomach, and colon: November 30 to December 1, 2002. Gastrointest Endosc 2003; 58:S3-43.)

COMPUTED TOMOGRAPHY GASTROGRAPHY

Computed tomography (CT) colonography has gained significant attention for its potential role as a screening modality for colon polyps and colon cancer (see Chapter 123). CT gastrography has also been studied for the diagnosis of early gastric cancer. In a study of 39 patients from South Korea with early gastric cancer, CT gastrography had a sensitivity of 73% to 76% and good interobserver reliability (R = 0.84).305 Only small studies have been performed thus far using this imaging modality, and CT gastrography cannot yet be recommended for screening outside of the research setting.

SERUM MARKERS

To date no reliable serum marker has been identified with sufficient sensitivity and specificity for the diagnosis of gastric cancer. Low serum pepsinogen I levels, low ratios of serum pepsinogen I to pepsinogen II, and hypergastrinemia have been reported in patients with atrophic gastritis and intestinal metaplasia, but the utility for the detection of gastric cancer has been mixed.306,307 In a screening study of 17,000 Japanese men, a positive pepsinogen test (defined as a serum pepsinogen I <50 µg/L and a pepsinogen I/II <3), in combination with upper GI series, identified gastric cancer in 0.28% of subjects (≈1 in 350), and 88% of these were early gastric cancers.308 Additionally, 89% of the cancers identified by the pepsinogen test alone were early gastric cancers. The major limitation of this test is the low specificity for the diagnosis of gastric cancer.309

Serum carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 have been extensively studied for the diagnosis of gastric cancer. The sensitivities of these markers is quite low for early gastric cancer,310 and elevated levels are levels also seen in other epithelial malignancies. These tumor markers are frequently elevated in recurrent gastric cancer, especially in patients who had elevated levels prior to surgical resection.311 More recent studies have identified, among others, transforming growth factor-β1, CA 72-4, tumor M2-pyruvate kinase, hepatocyte growth factor, and others as potential markers for the diagnosis of gastric cancer.312315 However, larger studies are required to determine their clinical utility.

CLASSIFICATION AND STAGING

Several classification systems further define gastric cancer and predict prognosis. As mentioned (see Fig. 54-2), gastric cancers can be subdivided into intestinal and diffuse types. Gastric cancer can also be divided into early and advanced lesions. Early gastric cancer is defined as a cancer that does not invade beyond the submucosa regardless of lymph node involvement. Early gastric cancer has a much higher prevalence in the Far East, especially Japan, and carries a very favorable prognosis, with five-year survival rates greater than 90% being reported in Asia and greater than 80% in Western countries.316319

The most commonly used clinical staging classification system for gastric cancer is the TNM system, used by the International Union Against Cancer (UICC) and the American Joint Committee on Cancer (AJCC).320,321 In the TNM staging system, T (tumor) indicates the depth of penetration (Fig. 54-7): T1 denotes a tumor confined to the mucosa or submucosa, T2 denotes involvement of the muscularis propria, T3 denotes invasion through the serosa, and T4 denotes invasion through the serosa and into adjacent organs or structures. N (nodes) indicates the amount of lymph node invasion: N0 denotes no lymph node involvement, N1 denotes involvement of 1 to 6 regional lymph nodes, N2 denotes involvement of 7 to 15 regional lymph nodes, and N3 denotes involvement of more than 15 regional lymph nodes. M (metastasis) indicates the presence of metastases, with M0 denoting no metastases and M1 denoting distant metastases (Table 54-5).

METHODS OF STAGING

Accurate staging in gastric cancer is important for treatment decisions. Endoscopic ultrasound (EUS) is the best-studied modality for the staging of gastric cancer and remains the test of choice. However, improvements in image quality for both CT and magnetic resonance imaging (MRI) make these studies potential alternatives to EUS.

Endoscopic Ultrasonography

EUS allows the visualization of the five layers of the gastric wall. The superficial gastric mucosa is represented by an echogenic first layer, and the deeper mucosa by a hypoechogenic second layer; the submucosa is represented by an echogenic third layer, the muscularis propria as a hypoechogenic fourth layer, and the serosa as an echogenic fifth layer.322 Studies of the ability of EUS to determine T stage have reported an accuracy rate of 67% to 92%, with accuracy of determination of serosal involvement ranging from 78% to 100%.323 EUS is particularly useful for staging early gastric cancer, which can be potentially resected endoscopically (Fig. 54-8). In a study of 295 patients with early gastric cancer, high-frequency EUS was found to have 90% accuracy for differentiating between mucosal and submucosal tumor invasion.324

In terms of N staging, the rate of detection of perigastric lymph nodes with EUS is comparable to staging with CT, with a diagnostic accuracy ranging from 50% to 80%.325329 A particular difficulty with N staging lies in the fact that many small lymph nodes can also harbor metastases, and thus understaging can occur. One study of 1253 lymph nodes in 31 patients with gastric cancer found that 55% of lymph nodes containing tumor were smaller than 5mm.330

EUS also has the ability to identify and biopsy submucosal lesions, such as gastric lymphomas and stromal tumors (discussed later and in Chapters 29 and 31). These lesions typically involve thickening of the submucosa and muscularis propria and may appear as gastric fold thickening on barium studies or endoscopy.

PROGNOSIS AND TREATMENT

Overall, the five-year survival rate in the United States from gastric cancer is 24% compared with 64% for colon cancer.292 The TNM classification is used to stratify disease into four clinical stages (I through IV) to predict prognosis in patients treated with gastrectomy (Table 54-6).336 The survival data from Japanese studies are generally superior to those seen in Western countries, perhaps because of the preference in Japan for extended lymphadenectomy or because of less understaging than is found in Western countries.336

SURGICAL THERAPY

Surgical resection remains the primary curative treatment for gastric cancer. In addition, surgical resection often provides the most effective palliation of symptoms, particularly those of obstruction. In some cases, surgery is required for diagnosis, as in cases of nonhealing gastric ulcers with negative biopsy results or in cases with persistent pyloric outlet obstruction suggesting an antral carcinoma. Surgery should be attempted in most cases of gastric cancer. However, in the presence of extensive involvement of diffuse-type cancer (or linitis plastica), bulky metastatic disease, retroperitoneal invasion, or peritoneal carcinomatosis, or if the patient has severe comorbid illnesses, the prognosis may be sufficiently poor to make the value of resection questionable.

Surgery, and laparoscopy in particular, can be useful in the staging of cancer. Laparoscopy can help identify primary tumor resectability, peritoneal deposits, and appropriate candidates for neoadjuvant therapy. Laparoscopic peritoneal lavage has been used to detect occult intraperitoneal free cancer cells. A positive peritoneal lavage correlates significantly with eventual development of overt peritoneal metastases.337

In general, total gastrectomy is performed for proximal gastric tumors and diffuse gastric cancer, and partial gastrectomy is reserved for tumors in the distal stomach. Large, randomized multicenter trials performed in France and Italy compared subtotal with total gastrectomy for adenocarcinoma of the antrum and found no differences in five-year survival rates or operative mortality.338,339 Some centers have argued for performing a complete splenectomy with gastrectomy. However, several retrospective and prospective studies found that concurrent splenectomy increased morbidity and had either no effect on or worsened survival.340,341

The extent of lymphadenectomy accompanying the gastrectomy has been a subject of debate for many years. The Japanese advocate a more extensive lymph node dissection (D2 resection) than their Western counterparts (D1 resection) and have higher published survival rates. A D2 resection entails resection of the nodes of the celiac axis and the hepatoduodenal ligament in addition to the perigastric lymph nodes taken in a D1 procedure. The differences in reported survival rates may reflect the fact that the Japanese have a much higher incidence of early gastric cancer, and the more extensive lymph node dissection performed in Japan may find more positive lymph nodes, making survival rates of Japanese patients with N0 staging appear to be higher than those of their potentially understaged Western counterparts. A large prospective multicenter Dutch study of more than 1000 patients reported no significant difference in five-year survival, with higher rates of postoperative death and complications for D2 lymphadenectomy than for the more conservative D1 lymphadenectomy.342 A British prospective study of 400 patients likewise showed no benefit from more extensive surgery; five-year survival rates were 35% for D1 resection and 33% for D2 resection.340 At present, data are insufficient to support extended lymph node resection in centers outside Japan. To prevent understaging, the current recommendation is a minimum D1 lymphadenectomy with removal of at least 15 nodes.343

ENDOSCOPIC MUCOSAL RESECTION AND SUBMUCOSAL DISSECTION

Advances in endoscopic techniques have permitted endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) to be used as curative therapies for select early gastric cancers (EGCs). This technique has been used widely for intestinal-type cancers in Japan, where studies have shown that only 3.5% of patients with EGCs smaller than 2 to 3 cm have lymph node involvement, making these lesions amenable to local therapy. Lesions larger than 4.5 cm have a greater than 50% chance of spread into the submucosa, are associated with “positive” nodes, and are therefore less likely to be endoscopically resectable.344

The following criteria have been suggested for choosing to perform EMR in gastric cancer: (1) the cancer is located in the mucosa and the lymph nodes are not involved, as indicated by EUS; (2) the maximum size of the tumor is less than 2 cm when the lesion is slightly elevated (type IIa) and less than 1 cm when the tumor is flat or slightly depressed (type IIb or IIc, respectively) without an ulcer scar (see Fig. 54-6); (3) there is no evidence of multiple gastric cancers or simultaneous abdominal cancers; and (4) the cancer is of the intestinal type.345

It is generally not possible to remove lesions larger than 1.5 to 2 cm en bloc by EMR. Endoscopic submucosal dissection is a technique developed in Japan and permits en bloc resection of larger early gastric cancers. With ESD, submucosal saline injection is performed, followed by the use of endoscopic electrosurgical knives to resect the entire tumor (Fig. 54-9).346 In addition to an R0 resection, ESD allows for more precise histopathologic assessment of depth of invasion and lymphovascular involvement, and permits appropriate assessment for risk of lymph node metastasis. If the preprocedure evaluation does not reveal regional lymph node involvement, much larger superficial lesions can be resected. Because experience with this technique has increased, en bloc resection rates are now reported to be greater than 90%, with local recurrence rates less than 3%.346 Due to the large size of some of the lesions being resected, the risk of perforation is relatively high (2% to 6%).347,348 However, perforations recognized early can generally be treated with closure using endoscopic clipping.346

No randomized clinical trials have yet been performed comparing surgery to endoscopic resection for early gastric cancer.

CHEMOTHERAPY

In Western countries, approximately 75% of patients with gastric cancer have disease that has spread to the perigastric lymph nodes or have distant metastases at the time of diagnosis.322 In such patients who have undergone potentially curative resection, recurrence rates are high. Unfortunately, gastric cancer appears to be fairly resistant to conventional chemotherapy. Numerous clinical trials have been performed evaluating the role of adjuvant chemotherapy following attempted curative resection for gastric cancer.349 The majority of the studies were inconclusive, but a series of meta-analyses of these trials suggested a 15% to 20% reduction in the risk of death in patients who received adjuvant chemotherapy.350,351 More recent randomized trials of cisplatin- or epirubicin-based adjuvant chemotherapy have largely failed to show a benefit.352,353

Neoadjuvant chemotherapy, on the other hand, does appear to benefit patients with resectable disease. In the United Kingdom MAGIC trial, 503 patients with gastric, gastroesophageal junction, or distal esophageal cancer were randomly assigned to undergo surgery alone or surgery with neoadjuvant epirubicin, cisplatin, and 5-fluorouracil (5-FU). Compared with surgery alone, the neoadjuvant group had significantly improved five-year survival (36% vs. 23%), progression-free survival (hazard ratio, 0.66), and overall survival (hazard ratio, 0.75).354 As a result, preoperative chemotherapy is now considered an acceptable treatment option for gastric cancer.

INTRAPERITONEAL CHEMOTHERAPY

Because systemic chemotherapy is ineffective for peritoneal metastasis, intraperitoneal (IP) chemotherapy can be considered in patients whose tumors are resected for cure but have a high likelihood of microscopic residual disease. In a randomized trial of 248 patients with gastric cancer, postoperative hyperthermic IP chemotherapy was associated with improved overall survival compared with surgery alone.357 The treatment benefits were most pronounced in patients with stage III and IV disease, serosal invasion, and lymph node metastases. Although a second clinical trial reported similar results,358 other studies have failed to demonstrate a benefit of hyperthermic IP chemotherapy.359,360 A meta-analysis of studies of IP chemotherapy for patients with resectable gastric cancer reported a significantly reduced risk of death in patients who received hyperthermic IP chemotherapy (hazard ratio, 0.6).361 At present, the use of hyperthermic IP chemotherapy should be confined to patients enrolled in clinical trials, especially in Western countries.

UNRESECTABLE DISEASE

Unfortunately, up to one third of patients with gastric cancer will have unresectable disease at the time of diagnosis.292 Chemotherapy for locally advanced gastric cancer without distant metastases can result in shrinking of the tumor to the point at which successful curative resection is possible.362,363 Even when curative surgery is not possible, chemotherapy has been shown both to improve survival as well as quality of life compared to best supportive care in this group of patients.364 Several randomized clinical trials have demonstrated efficacy of multidrug cisplatin-based regimens.365,366 A newer clinical trial using the EOX regimen (epirubicin, oxaliplatin, and capecitabine) was found to be noninferior to cisplatin-based regimens, and had a median survival of 11.2 months.367 The benefit of the EOX regimen is the substitution of oxaliplatin and capecitabine for cisplatin and 5-FU, respectively, resulting in greater convenience, ease of administration, and potentially fewer side effects.

Patients with advanced gastric cancer of the distal antrum or pylorus are at risk for developing gastric outlet obstruction. Traditionally, surgical gastrojejunostomy was performed for relief of symptoms and to allow continued enteral nutrition. With the advent of endoscopic stents, duodenal stenting across the obstructing tumor has emerged as a nonsurgical alternative for palliation. The results of a literature review of studies evaluating gastrojejunostomy and stenting found no differences between rate of technical success (96% to 100%), early and late complications, and persistent symptoms.368 Recurrent obstructive symptoms were more common with stenting. Both gastrojejunostomy and endoscopic stenting are acceptable options for the relief of malignant gastric outlet obstruction. The decision should be based on the individual clinical scenario as well as the availability of appropriate surgical or endoscopic expertise.

GASTRIC LYMPHOMA

Gastric lymphomas account for approximately 3% of all gastric malignancies, and can be subdivided into those in which the stomach is the primary site of involvement and those with disseminated nodal disease and secondary involvement of the stomach. More than 95% of gastric lymphomas are non-Hodgkin’s lymphomas. Gastric lymphoma is the most common form of extranodal non-Hodgkin’s lymphoma, accounting for more than 30% of all cases.369,370

The clinical manifestations of gastric lymphoma are similar to those of gastric adenocarcinoma. Patients tend to be asymptomatic in the early stages. With more advanced disease, patients may present with nonspecific complaints including abdominal pain, nausea, vomiting, anorexia, weight loss, bleeding, fever, night sweats, swelling, and diarrhea.371 On endoscopy, gastric lymphomas manifest in a variety of ways and can appear as fungating lesions, polypoid masses, thickened gastric folds, or ulcerating lesions. Because of frequent involvement of the submucosa, deep biopsy specimens, obtained by snare technique, mucosal resection, or use of jumbo forceps, are often needed for a pathologic diagnosis. Endoscopic ultrasonography is essential to document extent of disease and may be more useful than CT in the evaluation of perigastric lymph node involvement. Other imaging modalities, such as CT and MRI, may be of value in determining involvement of the liver and spleen as well as of distant lymph nodes. Gastric lymphoma is discussed in detail in Chapter 29.

GASTRIC CARCINOID TUMORS

Gastric carcinoid tumors (Fig. 54-10) account for 7% of all GI carcinoids and 0.2% of all gastric neoplasms.372 In the stomach, the well-differentiated tumors are mainly of enterochromaffin-like (ECL) cell origin, with a small minority being of other endocrine cell types.373 Although gastric carcinoids often contain neuroendocrine peptides, carcinoid syndrome does not occur unless there is hepatic involvement. The large majority of gastric carcinoid tumors express somatostatin receptors, and somatostatin receptor scintigraphy is a useful test to evaluate extent of and spread of disease. Classification, staging, prognosis, and therapy of gastric carcinoids are discussed in detail in Chapter 31.

MISCELLANEOUS TUMORS

Metastatic disease to the stomach can occur with melanoma and with primary tumors of the breast, lung, ovary, liver, colon, and testis, with breast cancer being the most common.375 Other rare malignant tumors that can involve the stomach are Kaposi’s sarcoma (see Chapter 33), myenteric schwannoma, glomus tumor, small cell carcinoma, and parietal cell carcinoma.376379 Miscellaneous benign tumors can involve the stomach and include pancreatic rests, xanthelasma, and fundic gland cysts.

KEY REFERENCES

Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006;355:11-20. (Ref 354.)

de Vries AC, van Grieken NC, Looman CW, et al. Gastric cancer risk in patients with premalignant gastric lesions: A nationwide cohort study in the Netherlands. Gastroenterology. 2008;134:945-52. (Ref 206.)

El-Omar EM, Carrington M, Chow WH, et al. Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature. 2000;404:398-402. (Ref 120.)

Fukase K, Kato M, Kikuchi S, et al. Effect of eradication of Helicobacter pylori on incidence of metachronous gastric carcinoma after endoscopic resection of early gastric cancer: An open-label, randomised controlled trial. Lancet. 2008;372:392-7. (Ref 249.)

Hartgrink HH, van de Velde CJ, Putter H, et al. Extended lymph node dissection for gastric cancer: Who may benefit? Final results of the randomized Dutch gastric cancer group trial. J Clin Oncol. 2004;22:2069-77. (Ref 342.)

Kaurah P, MacMillan A, Boyd N, et al. Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer. JAMA. 2007;297:2360-72. (Ref 133.)

Lichtenstein P, Holm NV, Verkasalo PK, et al. Environmental and heritable factors in the causation of cancer—Analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med. 2000;343:78-85. (Ref 116.)

Macdonald JS, Smalley SR, Benedetti J, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med. 2001;345:725-30. (Ref 355.)

McDonald SA, Greaves LC, Gutierrez-Gonzalez L, et al. Mechanisms of field cancerization in the human stomach: The expansion and spread of mutated gastric stem cells. Gastroenterology. 2008;134:500-10. (Ref 14.)

Ohnishi N, Yuasa H, Tanaka S, et al. Transgenic expression of Helicobacter pylori CagA induces gastrointestinal and hematopoietic neoplasms in mouse. Proc Natl Acad Sci U S A. 2008;105:1003-8. (Ref 59.)

Plummer M, Vivas J, Lopez G, et al. Chemoprevention of precancerous gastric lesions with antioxidant vitamin supplementation: A randomized trial in a high-risk population. J Natl Cancer Inst. 2007;99:137-46. (Ref 260.)

Soetikno R, Kaltenbach T, Yeh R, Gotoda T. Endoscopic mucosal resection for early cancers of the upper gastrointestinal tract. J Clin Oncol. 2005;23:4490-8. (Ref 345.)

Tu S, Bhagat G, Cui G, et al. Overexpression of interleukin-1beta induces gastric inflammation and cancer and mobilizes myeloid-derived suppressor cells in mice. Cancer Cell. 2008;14:408-19. (Ref 127.)

Uemura N, Okamoto S, Yamamoto S, et al. Helicobacter pylori infection and the development of gastric cancer. N Engl J Med. 2001;345:784-9. (Ref 27.)

Wong BC, Lam SK, Wong WM, et al. Helicobacter pylori eradication to prevent gastric cancer in a high-risk region of China: A randomized controlled trial. JAMA. 2004;291:187-94. (Ref 246.)

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