Adenocarcinoma of the Stomach and Other Gastric Tumors

Gastric cancer remains a major cause of cancer-related mortality in the world, despite declining rates of incidence in many industrialized countries. In this chapter, we mainly discuss gastric adenocarcinoma, which makes up the majority of gastric malignancies.

Epidemiology

Gastric cancer remains the second leading cause of cancer mortality in the world,1 although the overall incidence is declining.2 In Western countries, the incidence of gastric cancer has decreased dramatically over the past century; in the United States, gastric cancer mortality has decreased 87% since 1950.3 In the USA, the incidence of gastric cancer has diminished to approximately 7.6 cases per 100,000 people,4 whereas as recently as 1945, gastric cancer was the leading cause of cancer mortality in men.5 Gastric cancer is now the 14th leading cause of cancer mortality in the United States.6 It is estimated that in 2012, approximately 21,320 Americans were diagnosed with gastric cancer and that 10,540 died of it.4

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, with the lowest incidence rates observed in North America, North Africa, South Asia, and Australia.7 Although gastric cancer was common in industrialized countries in the past, the latest epidemiologic data indicate that greater than 60% of new cases of gastric cancer are in developing countries, reflecting a more rapid decline in developed countries.

In the USA, the median age of diagnosis is 70 years.4 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 males is approximately twice that in females (Table 54-1). The incidence of gastric cancer in blacks in the USA is nearly double that in whites. Native Americans and Hispanics also have a higher risk of development of gastric cancer than whites. In contrast to the pattern seen with non-cardia gastric cancers, the incidence rates of gastric cardia cancer are rising2 ; in the USA, cardia cancers now represent 27% of gastric cancers, up from just 10% in 1975.4

There are numerous dietary, environmental, and genetic risk factors for gastric adenocarcinoma (Box 54-1).

 

Etiology and Pathogenesis

Gastric cancer can be subdivided using the Lauren classification into 2 distinct histologic subtypes with different epidemiologic and prognostic features (Fig. 54-2).8 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 is also classified into proximal tumors (esophagogastric junction [EGJ] and gastric cardia) and distal tumors (fundus, body and antrum of the stomach). There is no clear distinction between the genetic and cellular origin of cancers of the EGJ and cardia, which can also be classified as GE junction type II and III adenocarcinomas. Interestingly, with the decreasing incidence of Hp infection, distal tumors have been declining while proximal tumors have been increasing. In a mouse model, it has even been postulated that Barrett’s esophagus–related esophageal cancer and cancer of the EGJ have their origins in the gastric cardia.9 Emerging data from gene expression profiling suggests that differences in pathologic appearance and clinical behavior may be due to the presence of unique molecular phenotypes. Characterization of the gastric cancer genomic landscape reveals the presence of multiple alterations in the expression of tyrosine kinase receptors, which in conjunction with their ligands and downstream effector molecules represent potential pathways for future drug development.

It is now believed that the development of intestinal-type gastric cancer 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,10 but the evidence that gastric cancer follows a comparable sequence of genetic events has been lacking. However, in both the intestinal-type gastric cancer and colorectal cancer, it does appear that DNA mutations are established over time in stem cells in the normal human stomach, and that in intestinal metaplasia these mutations spread through the stomach through a process involving crypt fission and monoclonal conversion of glands.11 The contention that the pathogenesis of intestinal-type gastric cancer is a multistep process is supported mainly by the observation that both chronic 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 52).12

This multistep model of intestinal-type gastric cancer, developed in large part by Correa and colleagues, 13,14 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 intestinaltype gastric cancer is chronic inflammation. Hp infection is the primary cause of gastric inflammation and the leading etiologic agent for gastric cancer (see Chapters 51 and 52). In a subset of patients, 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. 15,16 Unlike the situation observed with colon cancer, the precise genes involved in each step of this progression are still not defined. Nevertheless, next-generation sequencing techniques have shown that there is more heterogeneity in genetic alterations in gastric cancer and cancer of the EGJ than in colon cancer.17 Furthermore, the premalignant stages of gastric cancer are not as readily identifiable during endoscopy 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.18,19 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, as well as the similarities if any to the proposed pathway in Figure 54-3 for the intestinal type of cancer, remain to be clarified.

 

Hp Infection (see also Chapter 51)

Hp is a Gram-negative microaerophilic bacterium that infects nearly half the world’s population and is recognized as the primary etiologic agent for gastric cancer. Indeed, Hp has been classified as a class I (or definite) carcinogen by the International Agency for Research on Cancer (IARC), a branch of the WHO. Infection with Hp has been found in every population studied, although the prevalence is higher in developing countries and much of east Asia.20,21

The natural history of chronic Hp infection includes 3 possible outcomes22 : (1) simple gastritis, where 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 USA. The risk for gastric cancer related to the types of gastritis and, in general, an increased risk is associated with a low acid state. Hp-induced duodenal ulcer disease is associated with a high gastric acid output as well as a reduced risk for developing gastric cancer.23 Studies suggest that Hp-infected patients develop chronic atrophic gastritis at a rate of 1% to 3% per year of infection.14,24,25 Thus, those patients who are genetically predisposed to developing atrophic gastritis in response to Hp infection are predisposed to gastric cancer. Although Helicobacter infection is associated with both diffuse-type and intestinal-type adenocarcinomas, the mechanisms responsible for the formation of intestinal-type adenocarcinoma have been better studied and are focused on here. The association of Hp with mucosa-associated lymphoid tissue (MALT) lymphoma is discussed in Chapter 31.

The increased risk of development of gastric adenocarcinoma due to Hp infection depends on multiple factors including host genetic factors, the strain of bacteria, the duration of infection, and the presence or absence of other environmental risk factors (e.g., poor diet, smoking). In a Japanese cohort, only those infected with Hp developed gastric adenocarcinoma during follow-up (2.9% vs. 0%; P < 0.001).26 Additional cohort studies from China and Taiwan have reported similar findings.27,28 In Western countries, the association between Hp and gastric cancer appears to be confined to non-cardia tumors.29

A combination of a virulent bacterial strain, a genetically permissive host, and a favorable gastric environment may be necessary for cancer to occur. Currently, genetic susceptibility factors of the human host are studied on the basis of individual genes, but new technologies such as next-generation sequencing will enhance the identification of host genetic factors. Nevertheless, the most important factor appears to be the induction of chronic inflammation by Hp 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.30 Indeed, recent studies suggest that animals with deficient DNA repair mechanisms display more severe gastric dysplasia after chronic infection with Hp.31Thus, 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 non-gastric cancers.

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 a mouse model. 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.

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 metaplasiadysplasia-carcinoma sequence.32,33 In contrast, 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.33 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 Th1 (T helper cell type 1, expressing interferon [IFN]-γ and interleukin [IL]-12) type of immune response, whereas resistant strains, such as the BALB/c, have a polarized Th2 response (expressing IL-4 and IL-5).34-36 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 (expressing IL-17), have been shown to be an important component of Hp-induced gastritis.

Although the composite immune milieu most likely dictates disease manifestations, there may be a role for individual cytokines in both the predisposition to and protection from disease. During Helicobacter infection, the Th1 cytokine IFN-γ is able to promote or inhibit inflammation-driven cancer of the stomach, suggesting that a more specific immune response is responsible for cancer promotion or surveillance. While studies in the past have suggested that IFN-γ might promote the development of gastric preneoplasia,37 IFN-γ overexpression in the stomach at low levels was recently shown to be able to suppress gastric cancer in models of IL-1β and Helicobacter felis–dependent carcinogenesis.38 In addition, IFN-γ was shown to counteract the development of Th17 cells.38 Thus, different composition of the same cells and cytokines in the tumor microenvironment can contribute to a constellation that favors or inhibits carcinogenesis. On the other hand, mice lacking IL-10, a cytokine that acts to dampen an immune response, demonstrate severe atrophic gastritis in response to infection.32-36 More recently, genetic murine models have illustrated the importance of the IL-6/IL-11 family of cytokines in the development of gastric cancer.39

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.40 This mouse model mimics both the parasitic infection status and the paradoxical low gastric cancer–high Hp 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/Th1 immune responses to Hp.41,42 In general, the increased Th2 type responses were found in areas where serum IgE levels were high and the prevalence of intestinal parasitism by helminthes is above 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.

Whereas Hp infection has been unequivocally linked to gastric cancer, the development of dysplasia and invasive cancer tends to occur at a time when Hp colonization has either dramatically declined or, in some cases, has disappeared from the stomach altogether. Gastric cancer almost always occurs in the setting of prolonged gastric atrophy and hypochlorhydria, a condition that predisposes to enteric bacterial overgrowth. While antibiotic eradication therapy targeting Hp delays and inhibits development of gastric cancer in mice,16,43 antibiotics eradicate not only Hp but also other microorganisms that colonize the atrophic, hypochlorhydric stomach. Indeed, infection of otherwise germ-free INS-GAS mice with Hp resulted in delayed progression to gastric cancer compared to Hp-infected INS-GAS mice colonized with conventional flora.44 Thus, Hp may represent simply the initial, or the most prevalent, microbial factor responsible for gastric cancer progression.

There is a great deal of genetic diversity between strains of Hp owing to point mutations, insertions, deletions, and base-pair substitutions within the genome. Several strains may infect a single individual, and existing strains can undergo mutations and change over time.45,46 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 Hp genome is 1.65 million base pairs and codes for approximately 1500 genes, two thirds of which have been assigned biological roles.47 The function of the remaining one third of the genome remains obscure, but genome-wide analyses using DNA microarray or whole-genome sequencing technology will give a broad view of the genome of Hp in the near future. 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 Hp survival tactics. This is ensured by several factors. Spiraling movement is mediated by the FlaA and FlaB proteins, which are designed to navigate the thick gastric mucus. Additionally, Hp produces HP1069. A putative collagenase, which modifies the extracellular matrix and mucus layer, thus decreasing viscosity and allowing bacterial penetration.48,49 In addition, Hp expresses a variety of genes that contribute to buffering of stomach acid in order to main a relatively neutral pH. This includes a urease gene cluster consisting of 7 genes, of which UreA/UreB complex (comprising the urease enzyme) codes for 10% of the protein of Hp and is vital for its survival.

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 (cagA−) strains, cag-positive (cagA+) strains are associated with more severe inflammation, higher degrees of atrophy, and a greater chance of progressing to gastric adenocarcinoma.50-53 The estimated relative risk has ranged from 2 to as high as 28.4.22 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 (e.g., cagA) into host cells. The remarkable finding that CagA is injected into host cells where it is phosphorylated by Srcand c-Abl kinases, has raised the possibility that CagA could directly promote growth, migration, and transformation. Indeed, transgenic expression of Hp CagA induces both GI and hematopoietic neoplasms in mice.54 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.55-57 These findings may explain the attenuated inflammatory response and lower cancer risk with cagA− strains in vivo.58-61

All strains of Hp carry the vacA gene, which codes for a pore-forming, vacuolating toxin, but expression differs according to allelic variation. Approximately 50% of Hp strains express the vacA protein, which has been shown to be a very powerful inhibitor of T cell activation in vitro.62 Although vacA and cagA map to different loci within the Hp 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.63

 

 

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.14 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,64 potentially due to higher contents of salt, nitrates, and polycyclic aromatic amines.

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. In rats, N-nitroso compounds have been shown to cause gastric cancer. 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.65 A Swedish cohort study found a nearly 2-fold increased risk of gastric cancer associated with high dietary nitrate intake.64 However, separate large cohort studies from Europe did not demonstrate an association between nitrate intake and risk of gastric cancer.66,67

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 infection and increases the mutagenicity of nitrosated food in animal models.14,68 High-salt diets are associated with a roughly a 1.5- to 2-fold increased risk of gastric cancer.69 Cohort and case-control studies have also found an increased risk of gastric cancer associated with processed meat intake.64,70 Possible mechanisms include higher bacterial loads, up-regulation of Hp cagA expression, and increased cell proliferation and p21 expression.68,71,72

Epidemiologic studies have had inconsistent findings with regard to fruit and vegetable consumption and risk of gastric cancer.73-76 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.70,77-79 Diets with a high intake of fresh fish and antioxidants may be protective.78,80-82 However, there are insufficient data to make definitive conclusions regarding these factors.

Cigarette smoking, Alcohol and Obesity

Cigarette Smoking

Tobacco has long been established as a carcinogen, and numerous epidemiologic studies have demonstrated an association between cigarette smoking and gastric cancer.83 Several large cohort studies from Europe and Asia have reported a significantly increased risk of gastric cancer among smokers.84-86 A recent meta-analysis found that, compared to never smokers, current smokers had a 1.5- to 2-fold increased risk of gastric cancer, both for the cardia and non-cardia region.87 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 that has reportedly reduced levels of carcinogenic nitrosamines. Nevertheless, results of a Swedish cohort study demonstrated a 1.4-fold increased risk of noncardia gastric cancer among regular snuff users.88 Snuff exposure also increases the rate of gastric carcinogenesis in Hp-infected mice.89

Alcohol

Most epidemiologic studies have failed to demonstrate an association between alcohol consumption and cardia or noncardia gastric cancer.86,90,91 A separate population-based casecontrol study in the USA also found no association between any alcohol use and risk of cardia or noncardia gastric cancer, although there was a reduced risk seen with wine consumption.92 However, a meta-analysis suggested a small but significant association between heavy alcohol use and gastric cancer risk (RR, 1.20), an association largely isolated to non-cardia tumors.93 Interestingly, alcohol intake may increase the risk of gastric cancer in patients with certain polymorphisms of the alcohol dehydrogenase gene.94

Obesity

Obesity is a recognized risk factor for numerous GI malignancies.95 Increased BMI is associated with a mild to moderate increased risk of gastric cardia cancer, but not non-cardia cancer.96-99 Results of the National Institutes of Health– American Association of Retired Persons (NIH-AARP) Diet and Health Cohort Study demonstrated that morbid obesity (defined as a BMI ≥ 35) as well as large waist circumference were associated with a 2- to 3-fold increased risk of gastric cardia cancer, but not non-cardia cancer.100 A separate cohort study from the Netherlands also found an increased risk of cardia cancer with increasing BMI.96 The association between obesity and cardia cancer risk is likely mediated by proinflammatory cytokines and adipokines produced by intra-abdominal visceral fat.101

Genetic Factors

As is true for most malignancies, both 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., Hp 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, Hp, also tends to exhibit familial clustering. Nevertheless, in the future, gastric cancer types might rather be classified by genetic alterations and grouped to molecular subgroups with distinct carcinogenic mechanisms as well as clinical behavior, than to a histologic phenotype.

Overall, 10% of cases of gastric cancer appear to exhibit familial clustering,102 and family history is likely an independent risk factor even after controlling for Hp status.103,104 In a cohort study of relatives of patients with gastric cancer, siblings had a 2-fold increased risk of gastric cancer, adjusted for Hp infection.105 In a case-control study from Japan, a positive family history was associated with a significantly increased odds of gastric cancer in women (OR, 5.10), but not in men.106 A study from Scandinavia showed that having a twin with gastric cancer conferred a markedly higher relative risk for the disease (RR, 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.107

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 Hp infection. Data from South Korea indicate that individuals with a family history of gastric cancer more frequently have both Hp infection and associated atrophic gastritis or intestinal metaplasia.108 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 Hp infection, compared with controls.109 The greater prevalence of atrophy was confined to those patients with Hp infection, suggesting the possibility these individuals were perhaps exhibiting a more vigorous immune response to Hp. In a number of model systems, the development of gastric atrophy has been linked to a strong Th1 immune response.36,40,110 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 Hp infection. Inflammation is modulated by an array of pro- and anti-inflammatory cytokines, and several genetic polymorphisms have been described that influence cytokine response. With the recently started next-generation sequencing approaches, we may be able to determine whether families with increased gastric cancer incidence have a genetic predisposition for a more carcinogenic immune response.

One such factor is IL-1β, an important proinflammatory cytokine and a powerful inhibitor of acid secretion. Indeed, there is 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 in the setting of Hp infection. 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 Hp-dependent hypochlorhydria and gastric cancer.111 The increased risk of progression to cancer with these genotypes was in the 2- to 3-fold range compared with noninflammatory genotypes. The initial report was confirmed in other studies.112-116 Subsequently, Hwang and colleagues117 demonstrated that carriers of the IL-1B-511T/T genotype or the IL-1RN*2 allele had higher mucosal IL-1β levels than noncarriers and also confirmed the association between the -511T/T genotype and severe gastric inflammation and atrophy. The importance of IL-1β carcinogenesis has now been demonstrated in a transgenic study, where 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.118 Of note, in a mouse model of Barrett’s esophagus and esophageal and EGJ tumors, IL-1β expression in the esophageal squamous epithelium also led to esophagitis and expansion of cardia stem cells forming gastroesophageal tumors, suggesting that Barrett’s-associated adenocarcinoma comes from the gastric cardia.9

Additional associations with gastric cancer risk have been reported for genetic polymorphisms in TNF-α and IL-10. Pro- inflammatory genotypes of TNF-α and IL-10 were each associ- ated with a 2-fold higher risk of noncardia gastric cancer. When combined with proinflammatory genotypes of IL-1B and IL-1RN, patients with 3- or 4 high-risk genotypes showed a 27-fold greater risk of gastric cancer.119 Additional studies have shown that polymorphisms of the Toll-like receptor-4 (TLR-4) gene also increases the risk of gastric cancer. Carriers of the TLR4+896G polymorphism had an 11-fold increased odds ratio for hypochlorhydria, and significantly more severe gastric atrophy and inflammation.120 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.121-124 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%.125,126 Germline CDH1 mutations are also associated with familial lobular breast cancer.127,128

A small part of the familial clustering of gastric cancer can be attributed to other cancer syndromes. 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.129 These cancers frequently arise from fundic gland polyps and develop at an early age.130,131 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.132 Patients with juvenile polyposis also have a 12% to 20% incidence of gastric cancer.133,134

Next-generation sequencing techniques such as exome sequencing have led to the detection of new molecules and mechanisms that are involved in gastric carcinogenesis. In 8% to 10% of the gastric cancer patients, a somatic mutation was recently identified in ARID1A gene (also called BAF250a, SMARCF1, or OSA1), an accessory subunit of the SWI-SNF chromatin remodeling complex that is involved in processes of DNA repair, differentiation, and development.135-138 Notably, cancers with Epstein-Barr virus infection showed mutations of ARID1A in 73% of the cases. Additionally, ARID1A mutations were negatively associated with mutations in TP53 and occurred together with PIK3CA mutations. Patients with ARID1A alterations had longer recurrence-free survival, suggesting that these cancers belong to a molecular subgroup with distinct carcinogenic mechanisms as well as clinical behavior.135-138 Analysis of somatic copy number aberrations (SCNAs) have additionally shown significantly amplified genes, including therapeutically targetable kinases such as ERBB2, FGFR1, FGFR2, EGFR, and MET in gastric and gastroesophageal cancers.17

Tumor 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, there is no clearcut linear sequence of mutations in gastric cancers, and there is as an even greater heterogeneity in genetic alterations.17 While initial work has been performed, there remains a need for genome-wide analyses of somatic mutations in gastric cancer, because the precise role, if any, that identified mutations play in initiating malignant transformation, rather than cancer progression, is still not clear.

Aneuploidy is common in gastric cancer (60% to 75%), 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, while chromosomes 8q, 17q, and 20q often have increased DNA copy number.139

There is a general 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.140,141 Loss of heterozygosity (LOH) at the APC locus occurs more commonly. Another genetic abnormality found at high frequency (≈60%) is the deletion or suppression of the fragile histidine triad gene (FHIT), a tumor suppressor locus on chromosome 3p. Genes that inhibit entry into the cell cycle, such as p16 and p27, show diminished expression in nearly one half of gastric cancers.142-147 Absence of p27 expression is associated with a poorer prognosis.142,144 Absence of p16 expression is seen most commonly in poorly differentiated carcinomas but has no measurable impact on prognosis.148 Diminished expression of p16 and p27 occurs in the absence of detectable mutations and is believed to be secondary to hypermethylation.146 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-H) phenotype (see Chapter 1). Multiple tumor suppressor genes have been shown to be methylated in gastric cancers. Emerging evidence suggests that these 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.149

Overexpressions or amplifications of a number of growth factor pathways has been described, including 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 54-2).150 Approximately 15% of gastric cancers have been reported to overexpress both EGF and EGF receptor (EGFR), consistent with an autocrine mechanism. Mutations in PIC3A, a gene that codes for a catalytic subunit of phosphatidylinositol 3-kinase (PI3K), has been found in up to 25% of gastric cancers analyzed.151 In addition, mutations in genes encoding 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.152

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.153,154 Loss of TFF1 has been described in around 50% of gastric carcinomas, and TFF1 knockout mice develop spontaneous gastric antral tumors. Mutations of TFF1 have also been described, and these enhance gastric cancer cell invasion through signaling pathways that include PI3-kinase and phospholipase-C.155 TFF1 expression is repressed by STAT-3, and activation of STAT-3 is also emerging as a key pathway that leads to gastric cancer.39 RUNX3 most likely suppresses gastric epithelial growth by inducing p21 and Bim, attenuates Wnt signaling, and is altered in 82% of gastric cancers.156 Investigations into these genes and their contributions to the gastric cancer phenotype will prove valuable to our understanding of disease progression.

Microsatellite instability (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.132 MSI is found in 15% to 50% of sporadic gastric cancers, with a higher prevalence in intestinal type of cancers.157-162 Low-level microsatellite activity (e.g., MSI-low) can be found in 40% of areas of intestinal metaplasia in patients with gastric cancer162 and in 14% to 20% of adenomatous polyps.160,162,163 MSI-H occurs in only 10% to 16% of gastric cancers. MSI is associated with the less frequent occurrence of TP53 mutations, well- to moder- ately well-differentiated histology, and distal location in the stomach. Studies that have examined the effect of MSI on patient survival have shown inconsistent results.163,164 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-type gastric cancer are less complete. Mutations in the E-cadherin (CDH1) gene have been linked to the development of this cancer. Several families with hereditary diffuse gastric cancer (HDGC) have been found to carry a germline mutation in CDH1, all with diffuse-type cancer.121-123,165,166 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 gastric cancers, with a higher percentage found in diffuse-type cancers.167 Furthermore, E-cadherin underexpression is associated with higher rates of lymph node metastases and reduced survival.168,169 The overall rates of CDH1 mutations in gastric cancer are low. Thus, the decreased expression of E-cadherin seen in gastric cancer is likely secondary to hypermethylation of the CDH1 promoter, which occurs in 50% of gastric cancers and 83% of diffuse-type gastric cancers.170 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.171,172 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.173 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 the question, “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. Recently, several elegant genetic lineagetracing studies in mice established markers that allow the distinction of 2 different types of GI stem cells. Crypt base columnar cells (CBC) are fast-cycling stem cells expressing Lgr5 and CD133 (Prom-1).174,175 A villin transgene has allowed the identification of a multipotent progenitor located in the lower third of a subset of antral gastric glands,176 whereas multiple intestinal stem cell markers could also be identified in the antrum. Interestingly, Lgr5 shows lineage labeling in some antral gastric glands and in the gastric cardia.175 Slower cycling cells, which are usually found at the +4 position of the crypts of the antrum (i.e., the fourth epithelial cell in the crypt, counting from the bottom of the crypt upward); these lowercycling cells are characterized by a pronounced expression of Bmi1 and Tert.177,178 Although these 2 types of cells are functionally interconnected,179 their exact hierarchical relationship remains to be identified.

In the gastric oxyntic glands, the proliferative zone with the gastric stem cell has been localized to the isthmus, the middle portion of the tubule, and cells are thought to migrate bidirectionally to supply gastric surface mucus cells that coat the gastric pits, and gastric parietal and zymogenic cells that comprise the base of the gland.180 The gastric corpus stem cell has not yet been identified; none of the markers discussed earlier labels any specific cells within the gastric isthmus. Recently, progenitor cells (e.g., Krt19+ and TFF2+ cells) have been shown through lineage tracing studies to label different gastric progenitor cells.181,182 Typically, columnar metaplasia is positive for TFF2 and Krt19. Given that intestinal metaplasia arises in the gastric mucosa and in the esophagus, it is plausible that a similar stem cell gives rise to both. Regardless of their localization (CBC or +4 position) or their function, GI stem cells depend on signals from the stem cell niche, such as pericryptal myofibroblasts and neighboring differentiated epithelia.183 Important signaling pathways required for stem cell maintenance and proliferation comprise the Wnt, Notch, bone morphogenetic proteins (BMP), and Hedgehog pathways.184

 

 

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.13,185 The presence of atrophic gastritis has an annual incidence of progression to gastric cancer of approximately 0.5% to 1.0%.186-189 The extent of atrophic gastritis within the stomach correlates with risk of progression to cancer.190-192

There are 2 forms of atrophic gastritis (see Chapter 52). The more common is environmental multifocal atrophic gastritis (EMAG), which is associated with Hp infection and more likely to be associated with metaplasia. The presence of Hp infection is associated with an approximately 10-fold increased risk of atrophic gastritis.193 There is considerable regional variation in the prevalence of atrophic gastritis in Hp-infected individuals, with a roughly 3-fold increase in Asia compared to Western countries.193,194 The second form of atrophic gastritis, autoimmune metaplastic atrophic gastritis (AMAG), is associated with anti–parietal cell and intrinsic factor antibodies. This form of atrophy is confined to the body and fundus. AMAG is associated with pernicious anemia and an increased gastric cancer risk, albeit not as high as that seen with Hp-induced MAG, owing most likely to a lesser degree of inflammation.187,195

Mechanisms underlying the increased risk of gastric cancer in the setting of gastric atrophy may be related to low acid output (hypo- or achlorhydria), which predisposes to increased bacterial overgrowth with non-Helicobacter organisms, greater formation of N-nitroso compounds, and diminished ascorbate secretion into the gastric lumen. 196 Additionally, circulating gastrin levels increase in response to the reduced acid output. Gastrin is a known growth factor for gastric mucosal cells, and sustained elevations of gastrin may contribute to abnormal growth and increased risk of neoplastic progression.197,198

Intestinal Metaplasia and Dysplasia

Intestinal metaplasia (IM) can be subdivided into 3 categories, as classified by Filipe’s group.199Type I (complete) IM contains goblet cells that secrete sialomucins and mature, nonsecretory absorptive cells. Type 1 IM is not a risk factor for gastric cancer. Type II (incomplete) IM contains few if any absorptive cells, columnar “intermediate” cells in various stages of differentiation secreting neutral or acidic sialomucins, and goblet cells secreting sialomucins and/or occasionally sulfomucins. Type III (incomplete) is less differentiated than type II, with the intermediate cells secreting mainly sulfomucins and the goblet cells secreting sialo- and/or sulfomu- cins. Type II or III IM is associated with an approximately 20-fold increased risk of gastric cancer.200,201 Early gastric cancer develops in 42% of patients with type III IM within 5 years of follow-up, suggesting that IM represents a precursor lesion for the intestinal form of gastric cancer.201 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 Hp-infected individuals is higher in Asia (≈40%) as compared to the West.193,194

As mentioned earlier, a number of recent studies have revealed that intestinal metaplasia is not the only possible metaplastic precursor of gastric cancer. While controversy exists as to the sequence and connection of mucosal lineage changes associated with increased risk for gastric cancer, there is a general agreement that the loss of acid secreting parietal cells, also known as oxyntic atrophy, is a prerequisite for induction of metaplasia. Antralization of the fundus, or the presence of metaplastic glands in the fundus with a general phenotype similar to that of the antral or pyloric glands (also known as pseudopyloric metaplasia), is frequently associated with intestinal type adenocarcinoma. This phenotype has also been called spasmolytic polypeptide-expressing metaplasia (SPEM)202 and is characterized by the presence of trefoil factor 2 (TFF2, or spasmolytic polypeptide) immunoreactive cells in the gastric fundus, with morphologic characteristics similar to those of deep antral gland cells. SPEM was observed in association with over 90% of resected gastric cancers in 3 studies in the United States, Japan, and Iceland.202-204 SPEM and intestinal metaplasia might share equal importance as putative preneoplastic lesions in the stomach. Nevertheless, it remains to be determined whether either or both of these metaplasias can progress to dysplasia or neoplasia. Alternatively, intestinal metaplasia may potentially reflect a further benign attempt by the mucosa to increase repair in the face of chronic infection and inflammation.

Histologic assessment of gastric dysplasia and adenocarcinoma is based on the Vienna classification, the result of an international consensus conference of GI pathologists in 2000 (Table 54-3).205 The prevalence of gastric dysplasia ranges from as low as 0.5% in low-risk areas206 to 20% in high-risk areas.207 Prospective studies have shown that low-grade dysplasia may regress in up to 60% of cases, whereas 10% to 20% progress to high-grade dysplasia (Fig. 54-4).208-210 High-grade dysplasia rarely regresses, and is associated with a 2% to 6% annual incidence of progression to gastric cancer.210-212 In Histologic assessment of gastric dysplasia and adenocarcinoma is based on the Vienna classification, the result of an international consensus conference of GI pathologists in 2000 (Table 54-3).205 The prevalence of gastric dysplasia ranges from as low as 0.5% in low-risk areas206 to 20% in high-risk areas.207 Prospective studies have shown that low-grade dysplasia may regress in up to 60% of cases, whereas 10% to 20% progress to high-grade dysplasia (Fig. 54-4).208-210 High-grade dysplasia rarely regresses, and is associated with a 2% to 6% annual incidence of progression to gastric cancer.210-212 In a prospective cohort study from the Netherlands, the presence of high-grade dysplasia was associated with a 40-fold increased risk of progression to gastric cancer.211 High-grade dysplasia is often associated with synchronous cancer and can be uni- or multifocal.213

 

Gastric Polyps

The prevalence of gastric polyps in the general population is approximately 0.8% to 2.4%.214,215 Gastric polyps consist predominantly of fundic gland polyps (≈50%), hyperplastic polyps (≈40%), and adenomatous polyps (≈10%).215,216

The clinical course of fundic gland polyps is generally benign, and they are detected with increasing frequency in the era of PPI use. In a series of 599 consecutive patients who underwent upper endoscopy, use of PPIs for more than 5 years was associated with a nearly 4-fold increased risk of fundic gland polyps.217 The rate of malignant transformation of these polyps is generally quite low (≈1%) and confined to polyps larger than 1 cm.218 One notable exception to the benign nature of fundic gland polyps is in FAP. In this group, the prevalence of fundic gland polyps ranges from 51% to 88%, with dysplasia present in over 40% of cases.130,131

Hyperplastic polyps are generally benign, often multiple, and are typically observed in the setting of chronic inflammatory conditions (e.g., chronic atrophic gastritis), pernicious anemia, chronic antral gastritis, adjacent to ulcers and erosions, and especially at sites of gastroenterostomies. Over time, the polyps may regress, remain stable, or increase in size, and they often regress following Hp eradication. Men and women are equally affected, and the polyps typically appear in mid- to late-adult life.219 The rare hyperplastic polyps that undergo malignant transformation often have areas of dysplasia or intestinal metaplasia and typically form a well-differentiated intestinal-type cancer.218

In contrast to other polyps of the stomach, gastric adenomas undergo malignant transformation at a high rate. When gastric adenomas were followed by serial endoscopy with biopsy, progression through dysplasia to carcinoma in situ developed within 4 years in approximately 11% of cases.220 Endoscopic biopsy of gastric polyps can be associated with significant sampling error.221 The British Society of Gastroenterology published guidelines in 2010 regarding the management of gastric polyps.222 Among the recommendations were: (1) all gastric polyps should be at least biopsied; (2) all gastric adenomas, symptomatic polyps, and polyps with dysplasia should be removed; and (3) Hp, if present, should be eradicated in patients with hyperplastic or adenomatous polyps. 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.223-226 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.224 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.227

remaining fundic mucosa due to low levels of antral hormones, including gastrin.14,228,229 The Billroth II operation with gastrojejunostomy predisposes to the development of cancer at a 4-fold higher rate than a Billroth I procedure with gastroduodenostomy, suggesting that bile reflux may be a significant predisposing factor.224 Hp and associated intestinal metaplasia are found less frequently in postgastrectomy gastric cancers as compared to distal gastric cancers in the nonoperative stomach.230 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 Hp eradication therapy as well as PPIs, the number of gastric resections for peptic ulcer disease has decreased dramatically, significantly reducing the impact of the postgastrectomy state as a risk factor for gastric cancer.

PUD (see also Chapter 53)

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 Swedish adults who were followed for an average of 9 years, a history of gastric ulcer was associated with a 1.8-fold increased risk of gastric cancer.231 Interestingly, a history of duodenal ulcer was associated with a reduced risk of gastric cancer. These findings were replicated in a case control study of U.S. veterans.232The associations were confined to non-cardia gastric cancer; there was no association between history of gastric ulcer and cardia cancer.232 It is unclear whether gastric ulcers per se predispose to the development of cancer. The increase risk may be mediated by infection with Hp, which can lead to atrophic gastritis, intestinal metaplasia, and cancer.

Ménétrier’s Disease (see also Chapter 52)

In a review of case reports, 15% of patients with Ménétrier’s disease had associated gastric cancer,233 including several cases that documented a progression from dysplasia to cancer.234,235 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 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.236 Since 1960, the Japanese have been performing mass screening using upper GI barium studies followed by endoscopy if any suspicious lesions are found, and this continues to represent the recommended approach based on current Japanese cancer screening guidelines.237 Japanese researchers have reported a sensitivity of 66% to 90% and a specificity of 77% to 90% for this screening method.238 However, survey studies have shown that, in clinical practice, upper endoscopy is the most widely employed screening test for gastric cancer in Asia.239

Not surprisingly, studies from Japan have also shown that screening results in diagnosis of gastric cancer at earlier stages, with 1 study reporting more than half of screened cases diagnosed as stage I.240Long-term follow-up data from the Japanese Public Health Center cohort showed that subjects who underwent screening had a nearly 50% reduced risk of death from gastric cancer.241 A separate cohort study from Japan found a 25% to 35% risk reduction in death from gastric cancer among those who participated in gastric cancer screening.242 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.243The stomach produces 2 types of pepsinogens: PGI and PGII. In chronic atrophic gastritis, production of PGI is reduced, whereas PGII levels remain relatively constant (see Chapter 52). Therefore, both low serum PGI levels (<70 mg/L) and a low PGI/II ratio (<3.0) are useful for the identification of patients with atrophic gastritis.236 Large prospective cohort studies have shown that baseline PGI, PGI/II, and Hp antibody levels combined can successfully identify patients at highest risk for developing gastric cancer.244,245

Screening with upper endoscopy is likely cost-effective in moderate- to high-risk populations, such as older Asian men.246 However, in populations with a lower incidence of gastric cancer, screening is less likely to have the same degree of beneficial impact. In the USA, there are currently no practice guidelines with regard to surveillance of patients incidentally found to have intestinal metaplasia of the stomach. However, results of a recent decision analysis suggested that surveillance of patients with intestinal metaplasia without dysplasia is extremely cost-ineffective.247

 

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 Hp eradication, but consideration has also been given to supplementation with antioxidants and the use of NSAIDs and COX-2 inhibitors.

Eradication of Hp

The effect of eradicating Hp on the subsequent risk of gastric cancer is not entirely clear, although the majority of studies suggest a reduction in cancer risk. There is little question that chronic inflammation in a variety of organ systems can lead to malignancy and that Hp eradication can reduce or alleviate gastric inflammation. Hp eradication can lead to decreased oxidative stress and cell proliferation.248 In addition, limited studies involving eradication of gastric Helicobacter organisms in Mongolian gerbils suggest that eradication of infection can partially reverse atrophy and metaplasia and inhibit progression to gastric cancer.249 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.15

Nevertheless, with regard to published trials in humans, the evidence that treatment of Hp infection prevents gastric cancer is less conclusive, 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 Hp eradication on these intermediate biomarkers, and a majority has shown a beneficial effect in preventing progression of gastric disease.250-255 In 1 randomized placebo-controlled trial from China of 587 patients with Hp infection, assignment to eradication was associated with a significantly reduced risk of progression of intestinal metaplasia (odds ratio, 0.63).255 In contrast, a separate randomized placebo-controlled trial of Mexican adults did not demonstrate a benefit of Hp eradication for the prevention of histologic progression.254

A prospective randomized placebo-controlled trial sought to determine whether Hp eradication in a high-risk population in China would reduce the incidence of gastric cancer.253 Although no overall benefit was seen in the group receiving Hp eradication, there was a clear reduction in gastric cancer incidence in the subgroup of Hp carriers who did not already have precancerous lesions (gastric atrophy, intestinal metaplasia, or dysplasia) at study initiation. It is possible that some of the patients in the eradication arm had passed a “point of no return,” when cellular alterations had sufficiently accumulated to promote cancer.256 A more recent meta-analysis of randomized trials found that Hp eradication was associated with a significant 35% reduction in the risk of gastric cancer.257

There may also be benefit to Hp eradication after treatment of early gastric cancer in light of the high rate of multifocal dysplasia and subsequent progression to cancer. In a an open-label randomized controlled trial of patients with resected early gastric cancer, Hp eradication was associated with a reduction in the risk of development of metachronous gastric cancer (odds ratio, 0.35).258

In Western countries, gastric cancer prevention has not been extensively pursued due to the lower prevalence of Hp infection and decreasing incidence of gastric cancer. However, a cost-effectiveness model by Parsonnet and colleagues259 suggested that screening and treatment of Hp infection would be potentially cost-effective in the prevention of gastric cancer, particularly in high-risk populations, if it was assumed that treatment of Hp 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 Hp eradication was cost-effective.260

Aspirin and other NSAIDs, Including COX-2 Inhibitors

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 is induced in multiple epithelial malignancies, including gastric cancer.261,262 COX-2 expression is associated with aggressive cell growth in both human and mouse models of cancer263-266 and has been found to be overexpressed in 70% of gastric cancers.267 In this setting, COX-2 could potentially promote the growth of tumors, inhibit apoptosis, and increase angiogenesis. COX-2 expression has been reported to be elevated in preneoplastic lesions, including both intestinal metaplasia and dysplasia, and COX-2 expression appears to diminish after Hp eradication.268

Multiple epidemiologic studies have demonstrated a consistent association between NSAID use and reduced risk of gastric cancer.269-272 In a case-control study from Los Angeles County, NSAID use for more than 5 years was associated with a reduced risk of noncardia gastric cancer (odds ratio, 0.61), and there was a significant NSAID dose-related effect.270 A nested case-control study using the General Practitioners Research Database in the United Kingdom found that longterm users of non-aspirin NSAIDs decreased the risk of gastric cancer (odds ratio, 0.65), although there was no effect of aspirin use on the risk of gastric cancer.272 A meta-analysis reported a significant association between any NSAID use and reduced risk of gastric cancer (odds ratio, 0.78), with similar findings for both ASA and non-ASA NSAIDs.271

In a randomized controlled trial of Hp-negative patients with intestinal metaplasia, there was no difference in the rate of regression of intestinal metaplasia after 2 years between patients receiving the COX-2 selective inhibitor rofecoxib and placebo.273 This trial was limited by the relatively short follow-up period and use of premalignant endpoints. In a separate randomized controlled trial in patients with Hp and histology showing chronic atrophic gastritis (or worse), both Hp eradication and 24 months of the COX-2 selective inhibitor celecoxib resulted in histologic regression, although no additive effect was observed.274In a summary analysis of randomized trials of aspirin versus no aspirin for various outcomes, those studies with 10 to 20 years’ follow-up reported a reduced risk of gastric cancer in those assigned to aspirin (odds ratio, 0.42).275 Further trials in high-risk patients are warranted to determine if NSAIDs are effective for gastric cancer prevention.

Statins, Antioxidants and Green Tea

Statins

Statins, the widely prescribed class of HMG CoA–inhibiting cholesterol-lowering drugs, have been found in numerous epidemiologic studies to be associated with decreased risks of various malignancies. In addition to their cholesterol-lowering properties, statins also have antiproliferative and proapoptotic effects.276 A population-based case-control study from Taiwan found a significantly reduced risk of gastric cancer in patients prescribed statins (odds ratio, 0.68), with greater risk reduction observed among those with the highest cumulative statin use.277 In a separate case-control study of diabetics from South Korea, a history of statin use was associated with an 80% reduced likelihood of gastric cancer.278 A pharmacy database study from the Netherlands found a significant association between statin use and a decreased risk of cancer of any type; however, there was no significant association with gastric cancer, although the number of cases was relatively small.279 Future randomized controlled trials of various statins in patients at high risk for gastric cancer will help define the role of this class of drugs as chemopreventive agents.

 

Antioxidants

Chronic inflammatory states such as Hp gastritis can result in the generation of free radicals derived from oxygen and nitrogen.280 These free radicals can promote carcinogenesis via numerous different means, 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.281-285 In a nested case-control study from Japan, low plasma beta carotene levels were associated with an increased risk of gastric cancer.283 A case-control study from Korea found that elevated nitrate/antioxidant intake ratios were associated with increased risk of gastric cancer.284In a Swedish cohort study, high levels of vitamin A, retinol, and alpha and beta carotene intake were associated with a 50% risk reduction in gastric cancer.285

Randomized controlled trials have shown inconsistent effects of antioxidant supplementation on gastric cancer risk. 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.286 A randomized controlled trial in China also found no effect of combined vitamin C, E, and selenium supplementation on the prevalence of a combined end point of atrophic gastritis, intestinal metaplasia, dysplasia, or cancer.287 In a 10-year follow-up of the General Population Nutrition Intervention Trial in China, subjects who received a combination of selenium, vitamin E, and beta carotene were found to have reduced mortality from gastric cancer.288 Given a lack of convincing chemopreventive effect as well as the results of the Beta Carotene and Retinol Efficacy Trial, in which subjects who received beta carotene and vitamin A had an increased risk of lung cancer,289 antioxidant supplementation for the prevention of gastric cancer cannot yet be recommended.

 

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.290-292 EGCG also has antioxidant properties and may have anti-inflammatory properties as well.293,294 While case-control studies have shown an inverse association between the risk of gastric cancer and the consumption of green tea, cohort studies have largely failed to show an association.295,296 One cohort study from Japan did report a reduced risk of gastric cancer in women with high green tea consumption, but no change in risk among men.297 Thus, in the absence of prospective controlled trials, 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 do occur, they tend to mimic peptic ulcer disease. With advanced gastric cancer, the most common symptoms are weight loss (≈60% of patients) and abdominal pain (≈50%).298 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 (see Chapter 43).299 Rarely, paraneoplastic syndromes occur. There have been reports of thrombophlebitis (Trousseau’s sign), neuropathies, nephrotic syndrome, and DIC.300-302 Dermatologic paraneoplastic syndromes are also uncommon and include hyperpigmented patches in the axilla (acanthosis nigricans; see Chapter 24) and the sudden onset of seborrheic dermatosis (senile warts) and pruritus (sign of Leser-Trélat).303

The physical exam 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.304 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. Liver enzyme values, particularly serum alkaline phosphatase levels, can be elevated secondary to hepatic metastases.

Gastric cancer is metastatic at the time of diagnosis in 33% of cases.305 The most common sites of metastasis are the liver (40%) and peritoneum.306 Other sites of spread include periumbilical lymph nodes (Sister Joseph’s nodule), left supraclavicular sentinel nodes (Virchow’s node), the pouch of Douglass (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.304 There are reports of unusual presentations of metastatic disease, such as shoulder-hand syndrome from bone metastasis, diplopia and blindness from orbital and retinal metastases, and virilization due to Krukenberg’s tumors.307-310

 

Diagnosis

Endoscopy

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 6 to 8 biopsy specimens from the edge and base of the ulcer are recommended.311 The American Gastroenterological Association (AGA) 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).312 Dyspeptic patients in whom an empirical trial of PPIs and eradication of Hp 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.

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.313 There are also ongoing investigations into the utility of newer techniques such as autofluorescence and confocal microendoscopy for the diagnosis of early gastric neoplasia.314,315 In the past, barium studies have been reported to have 60% to 70% sensitivity and 90% specificity for the detection of advanced gastric cancer.316 Nevertheless, upper GI series has been largely replaced by upper endoscopy as the initial test of choice for the diagnosis of gastric cancer.

A classification system has been developed for early gastric cancer based on endoscopic appearance,317 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 3 types include superficial polypoid (type 0-I), superficial flat/ depressed (types 0-IIa-c), and superficial excavated (type 0-III) lesions. The most commonly observed subtype is 0-IIc, the non-polypoid depressed lesion.317 This classification system is used most often in Japan, where endoscopic mucosal resection and submucosal dissection are frequently performed for early gastric neoplasia.

CT Gastrography

While CT colonography has gained significant attention for its potential role as a screening modality for colon polyps and colon cancer, CT gastrography has also been studied for the diagnosis of early gastric cancer. In a study from South Korea of 39 patients with early gastric cancer, CT gastrography had a sensitivity of 73% to 76% and good interobserver reliability (κ = 0.84).318 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 high sensitivity and specificity for the diagnosis of gastric cancer. Low serum PGI levels, low ratios of PGI to PGII, and hypergastrinemia have been reported in patients with atrophic gastritis and intestinal metaplasia, but the results for the detection of gastric cancer have been mixed.319,320 In a study of 17,000 Japanese males, a positive PG test (defined as PGI < 50 μg/L, and PGI/II < 3.0) in combination with upper GI series identified gastric cancer in only 0.28% of subjects; however, 88% of these cancers were early cancers.321 Additionally, 89% of the cancers identified by the PG test alone were early gastric cancers. The major limitation of this test is the low specificity for the diagnosis of gastric cancer.322

Serum CEA and carbohydrate antigen (CA) 19-9 have both been extensively studied for the diagnosis of gastric cancer. The sensitivities of these markers is especially low for early gastric cancer,323and elevated levels are levels are 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.324 More recent studies have identified, among others, TGF-β1, CA 72-4, tumor M2-pyruvate kinase, and hepatocyte growth factor as potential markers for the diagnosis of gastric cancer.325-328 However, larger studies are required to determine their clinical utility.

Classification and Staging

Several classification systems exist to further define gastric cancer and predict prognosis. As mentioned earlier (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. This form of cancer has a much higher prevalence in the Far East, especially Japan, and carries a very favorable prognosis, with 5-year survival rates greater than 90% being reported in Asia and greater than 80% in Western countries.329-332

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).333,334 In the TNM staging system, T (Tumor) indicates the depth of penetration (Fig. 54-7): T1a denotes a tumor that invades the lamina propria or mucosa, T1b denotes invasion of the submucosa, T2 denotes invasion of the muscularis propria, T3 denotes invasion of the subserosal connective tissue, T4a denotes invasion of the serosa (visceral peritoneum), and T4b denotes invasion 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 2 lymph nodes, N2 denotes involvement of 3 to 6 lymph nodes, and N3 denotes involvement of 7 or more lymph nodes. M (Metastasis) indicates the presence of metastases, with M0 denoting no metastases and M1 denoting distant metastases, including positive peritoneal cytology (Table 54-4). In the most recent AJCC staging manual, cardia cancer (tumors within 5 cm of and crossing the GE junction) is now classified together with esophageal and GE junction tumors.334

Recent studies have investigated reclassification of gastric cancer based on biological characteristics. Using gastric cancer cell lines, distinct gene expression patterns were identified for intestinal-type and diffuse-type gastric cancer. Subsequent analyses showed that patients who had tumors with intestinaltype gene expression profiles had improved survival when treated with 5-fluorouracil-based chemotherapy.335 The prospect of incorporating tumor biology into staging classification systems is intriguing, although future validation studies are required for this to occur.

Accurate staging in gastric cancer is important for treatment decisions. EUS is the best-studied modality for the staging of gastric cancer and remains the test of choice for assessing tumor depth and nodal involvement. However, improvements in image quality for both CT and MRI make these studies potential alternatives and adjuncts to EUS.

EUS

EUS allows the visualization of the 5 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. EUS also has the ability to identify and biopsy submucosal lesions, such as gastric lymphomas and stromal tumors. These lesions typically involve thickening of the submucosa and muscularis propria and may appear as gastric fold thickening on barium studies or endoscopy.

Based on results of a meta-analysis of EUS for gastric cancer staging, EUS has sensitivity of 86% and specificity of 91% to distinguish T1-2 versus T3-4 tumors.336 Intramucosal lesions (T1a) are identified with 83% sensitivity and 79% specificity. EUS may be particularly useful for identifying early gastric cancer lesions amenable to endoscopic mucosal resection or submucosal dissection337(Fig. 54-8). In terms of N staging, the rate of detection of perigastric nodes with EUS is comparable to staging with CT.338,339 EUS is slightly less accurate in the assessment of nodal status as compared to depth of tumor invasion, with 69% sensitivity and 84% specificity to distinguish positive from negative lymph node status.336 A particular difficulty with N staging lies in the fact that many small lymph nodes can also harbor metastases, and thus understaging can occur.

CT and PET

Advances in imaging technology have greatly improved the ability of CT to stage gastric tumors. While not as extensively studied as EUS, multidetector row CT (MDCT), by which the wall of the stomach can be seen as 3 layers (an inner layer corresponding to the mucosa, an intermediate layer corresponding to the submucosa, and an outer layer of slightly higher attenuation corresponding to the muscularis propria and serosa), appears to have comparable accuracy to EUS in terms of both T and N staging. The loss of fat planes between the gastric mass and an adjacent organ suggests tumor invasion. The accuracy of MDCT for overall T staging ranges from 77% to 91%, and discriminates serosal involvement with an accuracy of 83% to 100%.340,341 Accuracy with respect to N staging may be as high as 89% with MDCT.342,343 As with all other imaging modalities, CT has difficulty discerning metastases in lymph nodes smaller than 5 mm. At present, the role of CT is mainly for the detection of distant metastases and as a complement to EUS for assessing regional lymph node involvement. It is not yet clear whether EUS or MDCT (or the combination) is superior for T and N staging in gastric cancer, and the underlying technology continues to evolve and improve.

PET scanning alone is not recommended as a sole imaging test for gastric cancer staging, largely because most gastric adenocarcinomas have low FDG uptake and there are false positives as well (see Chapter 52).344 However, in patients initially staged as having localized gastric cancer, combined PET/CT increases the detection of metastatic disease by 10%, thus altering clinical management.345

 

Laparoscopy with Peritoneal Lavage

Approximately half of gastric cancer patients with metastatic disease have cancer involving the peritoneum.306 Current imaging techniques such as EUS and CT have limited ability to detected peritoneal dissemination. In fact, up to one third of patients with seemingly resectable disease will have evidence of peritoneal spread at the time of staging laparoscopy.346 National Comprehensive Cancer Network guidelines recommend consideration of laparoscopy with peritoneal lavage for patients with seemingly resectable disease in whom neoadjuvant chemotherapy is being considered.347 However, the United States has been slow to adopt this practice; a study using SEER-Medicare data found that only 8% of gastric cancer patients who had any surgery underwent laparoscopy.348

 

Other Imaging Modalities

MRI with gadolinium has also been used for gastric cancer staging. It is similar to CT in its advantages (ability to find distant metastases) and weaknesses (need for adequate gastric distention). The accuracy of MRI ranges from 90% to 93% for T staging and from 91% to 100% for N staging.340 However, given the small number of studies, MRI cannot yet be advocated as the test of choice for staging gastric cancer.

Restaging after Neoadjuvant Treatment

The accuracy of restaging gastric cancer after neoadjuvant chemotherapy decreases considerably. EUS has less than 50% accuracy for both T and N restaging, and similarly disappointing results have been reported for post-treatment staging with CT.349 However, the use of preoperative clinical staging to assess response to neoadjuvant chemoradiation may correlate well with both overall and disease-free survival.350 Restaging is therefore primarily used to rule out distant metastasis as part of the assessment for surgical resectability.

Prognonsis and Treatment

Overall, the 5-year survival rate in the USA from gastric cancer is 27% (compared with 64% for colon cancer). 4 The TNM classification is used to stratify disease into 4 clinical stages (I through IV) to predict prognosis in patients treated with gastrectomy (see Table 54-4). 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.351 There are data to suggest that large tumor size (>5 cm) may be independently associated with worse survival, independent of nodal status or overall tumor stage.352

 

Surgery

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 and 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 intraperitoneal free cancer cells. A positive peritoneal lavage correlates significantly with eventual development of overt peritoneal metastases.353

In general, total gastrectomy is performed for proximal gastric tumors and for diffuse gastric cancer, and partial gastrectomy is reserved for tumors in the distal stomach. Large, randomized multicenter trials in France and Italy comparing subtotal with total gastrectomy for adenocarcinoma of the antrum found no differences in 5-year survival rates or operative mortality.354,355 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.356,357

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 multicenter randomized trial from the Netherlands reported no significant improvement in 5-year survival and more postoperative deaths and complications with D2 lymphadenectomy than with the more conservative D1 lymphadenectomy.358 In a subsequent 15-year follow-up of these patients, the investigators reported no significant difference in overall survival, although there was significantly reduced gastric cancer-related mortality in the D2 resection arm (37% vs. 48% in the D1 arm).359 A British randomized trial of 400 patients likewise showed no benefit from more extensive surgery: 5-year survival rates were 35% for D1 resection and 33% for D2 resection.356 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.360

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 and South Korea, 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.361

The following criteria have been suggested for EMR in gastric cancer: (1) the cancer is located in the mucosa and the lymph nodes are not involved, as indicated by EUS examination; (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) without an ulcer scar; (3) there is no evidence of multiple gastric cancers or simultaneous abdominal cancers; and (4) the cancer is of the intestinal type.362 Despite these guidelines, it is generally not possible to remove lesions larger than 1.5 to 2.0 cm en bloc by EMR, and piecemeal removal of EGC is associated with decreased rates of curative resection.363

ESD is a technique developed in Japan and permits en bloc resection of larger EGCs, as well as selected tumors with submucosal invasion. With ESD, submucosal injection is performed, followed by the use of endoscopic electrosurgical knives to resect the entire tumor364 (Fig. 54-9). 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 preprocedure evaluation does not reveal regional lymph node involvement, much larger superficial lesions can be resected. The Japanese have developed expanded criteria for ESD for early gastric cancer: (1) mucosal intestinal-type cancer of any size without ulceration, (2) mucosal intestinal-type cancer less than 3 cm with ulceration, and (3) submucosal intestinal-type cancer less than 3 cm and with submucosal invasion less than 500 μm.365,366 As experience with this ESD has increased, en bloc resection rates are now reported to be over 90%, with local recurrence rates lower than 3%.364 Owing to the large size of some of the lesions being resected, the risk of gastric perforation is relatively high (2% to 6%).367,368 However, perforations recognized early can generally be treated conservatively with closure using endoscopic clipping.364 Limited data from Western centers with fewer patients report good but slightly lower resection rates and higher complication rates.369,370 For patients with EGC but higher risk of lymph node involvement and who are poor candidates for surgical gastrectomy, combination ESD with laparoscopic lymph node dissection may be an alternative approach.371 There are no published randomized clinical trials comparing surgery to endoscopic resection for early gastric cancer.

Chemotherapy and Radiation

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.372 Patients presenting at early stages are often treated with surgery plus perioperative or adjuvant chemotherapy with curative intent. Unfortunately, gastric cancer appears to be fairly resistant to conventional chemotherapy. Numerous clinical trials have been performed evaluating the role of adjuvant chemotherapy after curative resection for gastric cancer.373 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.374,375 More recent randomized trials of cisplatin- or epirubicin-based adjuvant chemotherapy have largely failed to show a benefit.376,377 The optimal regimen for first-line chemotherapy has yet to be clearly established. Whether a 3-drug regimen is more effective than a potentially less toxic doublet is a point of controversy. Historically, clinical trials have included as a group esophageal, EGJ, and gastric adenocarcinomas. Pooling these conditions may have hidden relevant location-dependent outcomes, although Chau and coworkers demonstrated that, despite a slightly better outcome in esophageal and EGJ adenocarcinomas, no statistical differences were found in terms of overall survival or response rates in the 3 groups.378 The European Organization for Research and Treatment of Cancer Expert Panel differentiated treatment and staging recommendations for tumors near the GE junction. Preoperative chemoradiation was recommended for adenocarcinoma of the esophagogastric junction (AEG) type I and II tumors. For AEG type III (cardia) tumors, perioperative chemotherapy was suggested as the best choice.

Neoadjuvant chemotherapy appears to benefit patients with resectable disease. In the U.K. MAGIC trial, 503 patients with gastric, gastroesophageal, or distal esophageal cancer were randomly assigned to undergo surgery alone or surgery following neoadjuvant epirubicin, cisplatin, and 5-fluorouracil (5FU). Compared to surgery alone, the neoadjuvant group had significantly improved 5-year (36% vs. 23%), progression-free, and overall survival.379 As a result, preoperative chemotherapy is now considered an acceptable treatment option prior to surgery for gastric cancer.

Chemoradiation

Combined chemoradiation after surgical resection appears to be effective at improving progression-free and overall survival in gastric cancer. The Intergroup Trial 0116 randomized 603 patients with gastric or gastroesophageal cancer to undergo surgery alone or surgery followed by 5FU, leucovorin, and radiation therapy. Subjects in the surgery alone group had a shorter median survival time (27 months vs. 36 months) and a worse overall and relapse-free survival.380 Following publication of the results of this study, adjuvant chemoradiation became the standard of care in the USA, although the optimal chemotherapy regimen is not yet clear. Early studies of the use of neoadjuvant chemoradiation have also shown promising results.381

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 to surgery alone.382 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,383 other studies have failed to demonstrate a benefit of hyperthermic IP chemotherapy.384,385 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 (odds ratio, 0.60).386 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.305 Chemotherapy for locally advanced gastric cancer without distant metastases can result in shrinking of the tumor to the point where successful curative resection is possible.387,388 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.389

A meta-analysis by Wagner and colleagues390 demonstrated a small but significant survival benefit for combination chemotherapies, with a median survival of 8.3 months with combination regimens and 6.7 months for single-agent therapies. As expected, toxicity was increased in the combination schedules, and thus, combination chemotherapy should only be considered in patients with good performance status. Although there is no single standard of care in advanced gastric cancer, there is some evidence coming from metaanalyses. Drugs related to increased survival in phase III trials are cisplatin, docetaxel and trastuzumab, a monoclonal antibody that interferes with the HER2/neu receptor. HER2 is amplified and is a key driver of tumorigenesis in 7% to 34% of gastric cancers. In the ToGA phase III multicenter randomized study, patients with gastric cancer and HER2 overexpression received chemotherapy and trastuzumab, resulting in a median overall survival of 13.8 months, compared with 11.1 months in those treated with chemotherapy alone.391 Further manipulation of this pathway using the novel anti-HER2– directed agents pertuzumab and T-DM1, in addition to dual EGFR/HER2 blockade with lapatinib, may yield positive results. As a consequence, tumor assessment for HER2 overexpression should be performed, and the addition of trastuzumab to palliative chemotherapy should be considered for every patient with HER2+ gastric adenocarcinoma. In contrast, targeting of the EGFR pathway in combination with chemotherapy in unselected patients has not been fruitful to date. Other new targeted agents, such as panitumumab, a human immunoglobulin (Ig)G-2 monoclonal antibody that blocks the EGFR receptor, are currently under investigation. Similarly, use of the anti-angiogenic monoclonal antibody bevacizumab was not successful in a large global randomized trial.392-396 Careful selection of patient subsets will become a key factor in future clinical trials as novel targeted agents such as those targeting the MET/HGF and FGFR axes move forward into clinical development.

Several randomized clinical trials have demonstrated efficacy of multidrug cisplatin-based regimens.397,398 A newer clinical trial using the EOX regimen (epirubicin, oxaliplatin, and capecitabine [Xeloda]) was found to be non-inferior to cisplatin-based regimens, and had a median survival of 11.2 months.399 The benefit of the EOX regimen is the substitution of oxaliplatin and capecitabine for cisplatin and 5FU, respectively, resulting in greater convenience, ease of administration, and potentially fewer side effects.

Second-line chemotherapy may also be superior to best supportive care, but again no standard regimens have been defined. Monotherapy with docetaxel or irinotecan has been shown to be superior to best supportive care,400-402 and a recent study showed no superiority of irinotecan over weekly paclitaxel. Thus, monotherapy with irinotecan or taxanes such as paclitaxel can be considered an option in advanced gastric cancer patients as a second-line treatment.403

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 versus stenting found no differences in rate of technical success (96% to 100%), early and late complications, and persistent symptoms.404 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.

Miscellaneous Gastric Tumors

Gastric lymphomas, GISTs, and neuroendocrine (carcinoid) tumors are covered in Chapters 31, 32, and 33. Metastatic disease to the stomach can occur with primary tumors of the breast, melanoma, lung, ovary, liver, colon, and testicular cancers, with breast cancer being the most common.405 Other rare malignant tumors that can involve the stomach are Kaposi’s sarcoma (see Chapter 34), myenteric schwannoma, glomus tumor, small cell carcinoma, and parietal cell carcinoma.406-409 Miscellaneous benign tumors of the stomach include lipomas, pancreatic rests (see Chapter 55), xanthelasma, and fundic gland cysts.

Key References

Full references for this chapter can be found on www.expertconsult.com.

11. 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.

17. Dulak AM, Schumacher SE, van Lieshout J, et al. Gastrointestinal adenocarcinomas of the esophagus, stomach, and colon exhibit distinct patterns of genome instability and oncogenesis. Cancer Res 2012; 72:4383-93.

26. 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.

38. Tu S, Quante M, Bhagat G, et al. Interferon-{gamma} inhibits gastric carcinogenesis by inducing epithelial cell autophagy and T cell apoptosis. Cancer Res 2011; 71:4247-59.

54. 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.

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

124. 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.

211. 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.

253. 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.

257. Fuccio L, Zagari RM, Eusebi LH, et al. Meta-analysis: Can Helicobacter pylori eradication treatment reduce the risk for gastric cancer? Ann Intern Med 2009; 151:121-8.

358. 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.

362. 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.

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391. Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): A phase 3, open-label, randomised controlled trial. Lancet 2010; 376:687-97.

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