Gastric cancer (GC) is third leading cause of cancer-related death. Only 28.3% of new GC cases survive more than 5 years. Although incidence has declined in the United States, an increase is estimated for 2016. Risk factors include sex (risk is higher in men), Helicobacter pylori infection, heredity, and lifestyle. GC is usually diagnosed between the ages of 60–80 years. Prognosis of GC is largely dependent on the tumor stage at diagnosis and classification as intestinal or diffuse type; diffuse-type GC has worse prognosis. Chemoprevention has been shown to decrease risk, but is currently not used clinically.
Key points
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Although gastric cancer (GC) incidence has declined in the United States during the last decade, an increase in the incidence of GC has been estimated for 2016.
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GC prognosis is very poor. Only 28.3% of newly discovered GCs are expected to survive longer than 5 years after diagnosis.
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Prognosis of GC is largely depends on the tumor stage at diagnosis and classification as intestinal or diffuse.
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Although nonsteroidal anti-inflammatory drugs, aspirins, and statins are reported to decrease GC risk, these have not been implemented for GC chemoprevention in clinical practice.
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Risk assessment and surveillance guidelines have been implemented in Asian countries with high incidence of GC. In the United States, only the American Society for Gastrointestinal Endoscopy has recently published guidelines for the screening and management gastric lesion.
Global impact of gastric cancer
Despite the overall decrease in the incidence of gastric cancer (GC) since the 1930s, it is still a major cause of morbidity and mortality worldwide. As many as 952,000 new GC cases were estimated in 2012 alone; making it the fifth most common incident cancer in the world and the third leading cause of cancer death in both sexes worldwide. Among patients diagnosed with GC, close to 75% die from this disease. GC also is responsible for 1 of the highest cancer burdens as determined by disability-adjusted life years lost.
Globally, GC incidence has been shown to be more common in men and to increase with age, with most cases occurring after the age of 60 years. However, GC incidence rates vary dramatically across countries. The geographic distribution of GC has been mainly attributed to differences in dietary patterns, socioeconomic status, and the prevalence of Helicobacter pylori infections. The highest GC incidence and mortality rates occur in Eastern Asia, Central and Eastern Europe, and South America. Mortality rates associated with GC, even in developed countries, are still very high; only 28.3% of newly diagnosed cases are expected to survive 5 years or longer after diagnosis.
According to the Surveillance, Epidemiology, and End Results Program, approximately 22,220 new GC cases were diagnosed in the United States (US) in 2014. An increase in the incidence of GC in the US has been estimated for 2016; according to the American Cancer Society, approximately 26,370 individuals will be diagnosed with GC and 10,730 are expected to die due to this disease. Within the US, Hispanics, African Americans, and Native Americans are more frequently diagnosed with GC than non-Hispanic whites ( Fig. 1 ).
Global impact of gastric cancer
Despite the overall decrease in the incidence of gastric cancer (GC) since the 1930s, it is still a major cause of morbidity and mortality worldwide. As many as 952,000 new GC cases were estimated in 2012 alone; making it the fifth most common incident cancer in the world and the third leading cause of cancer death in both sexes worldwide. Among patients diagnosed with GC, close to 75% die from this disease. GC also is responsible for 1 of the highest cancer burdens as determined by disability-adjusted life years lost.
Globally, GC incidence has been shown to be more common in men and to increase with age, with most cases occurring after the age of 60 years. However, GC incidence rates vary dramatically across countries. The geographic distribution of GC has been mainly attributed to differences in dietary patterns, socioeconomic status, and the prevalence of Helicobacter pylori infections. The highest GC incidence and mortality rates occur in Eastern Asia, Central and Eastern Europe, and South America. Mortality rates associated with GC, even in developed countries, are still very high; only 28.3% of newly diagnosed cases are expected to survive 5 years or longer after diagnosis.
According to the Surveillance, Epidemiology, and End Results Program, approximately 22,220 new GC cases were diagnosed in the United States (US) in 2014. An increase in the incidence of GC in the US has been estimated for 2016; according to the American Cancer Society, approximately 26,370 individuals will be diagnosed with GC and 10,730 are expected to die due to this disease. Within the US, Hispanics, African Americans, and Native Americans are more frequently diagnosed with GC than non-Hispanic whites ( Fig. 1 ).
Gastric cancer causes and risk factors
Infectious Agents Associated with Gastric Cancer
Helicobacter pylori
In 1994, the International Agency for Research on Cancer classified H pylori , the first formally recognized bacterial carcinogen, as a class I human carcinogen for GC. H pylori are involved in 90% of all gastric malignancies. H pylori incidence varies according to age, ethnicity, and geographic location. In locations such as Mexico, Argentina, and Asian countries the prevalence of H pylori ranges from 30% to 70% by the age of 20 years and 70% to 90% by the age of 60 years. In the US and France, the prevalence is approximately 20% and 40% for younger and older ages, respectively.
H pylori contributes to the development of gastric neoplasia by promoting inflammation in the gastric mucosa (gastritis), which leads to sequential histopathologic changes that may result in the development of GC ( Fig. 2 ). However, not every individual infected with H pylori will develop GC. The exact pathophysiological mechanisms, as well as the contribution of environmental risk factors and host genetic susceptibility in the progression of gastric carcinogenesis, have yet to be fully elucidated. H pylori virulence factors have been associated with a higher risk of GC. Infection with H pylori strains with vacAs1 -, vacAm1 -, and cagA -positive genotypes are associated with an approximate 6-fold increase in GC risk. Increasing evidence supports that the extent of the inflammatory response to H pylori is in large part determined by polymorphisms in host genes encoding cytokines and cytokine receptors. Individuals with proinflammatory interleukin (IL)-1 genotypes infected with H pylori strains with vacAs1 -, vacAm1 -, and cagA -positive genotypes were reported to have up to an 87-fold higher risk of GC compared with H pylori -infected individuals without proinflammatory IL-1 polymorphisms. Recently, GC stem cells were also proposed as a gastric carcinogenesis mechanism. Chronic infection with H pylori induces recruitment of bone marrow-derived cells that, once recruited, differentiate with local gastric epithelial cells, ultimately inducing stem cell properties and leading to cell metaplasia, dysplasia, and adenocarcinoma. Unfortunately, there are currently no robust biomarkers clinically available to reliably predict who will develop GC cancer after H pylori infection.
Epstein-Barr virus
Multiple studies in different parts of the world have found the prevalence of Epstein-Barr virus (EBV) in 5% to 16% of gastric carcinomas, which supports its possible role as an etiologic agent of GC. In Asia, Europe, and the Americas, prevalence of EBV is close to 9% of all GC cases reported. Male patients have been found to be twice as likely to have EBV-positive tumors compared with females. Tumors in the gastric cardia or corpus were found to be twice as likely to be EBV-positive compared with those in the antrum. Although the role of EBV in gastric carcinogenesis is not yet clearly defined, EBV-positivity has been reported to be associated with favorable prognosis.
Genetic Predisposition: Familial Gastric Cancer
An estimated 20% of GC patients have a family history of GC. According to the racial or ethnic group, family history was shown to confer 2-fold to 10-fold increased risk of GC. Although most GCs are sporadic, 10% of the cases have familial clustering and 1% to 3% are hereditary. Hereditary GC includes syndromes such as hereditary diffuse GC (HDGC), gastric adenocarcinoma and proximal polyposis of the stomach, and familial intestinal GC. HDGC is a rare, autosomal dominant disorder that is responsible for 1% to 3% of all familial GC cases. About 40% of individuals with HDGC have germline mutations in the CDH1 gene, which encodes E-cadherin. In the presence of CDH1 mutations, the lifetime risk of developing GC is 70% to 80%. GC can also develop as part of familial cancer syndromes, including Lynch syndrome, familial adenomatous polyposis, Peutz-Jeghers syndrome, and Li-Fraumeni syndrome. GC is part of the Lynch syndrome tumor spectrum; GC risk is 2.9 times higher for subjects with germline MLH1 mutations.
Demographic, Environmental, and Lifestyle Risk Factors
In addition to infectious agents and family history, additional GC risk factors include age, gender, certain occupations, tobacco use, diet, and being overweight, among others. The risk of developing GC is twice as high in men as in women and it is usually diagnosed between the ages of 60 to 80 years. Individuals with certain occupations, such as those who work in the coal, metal, and rubber industries, have been reported to have an increased risk of GC. Tobacco smoking has been reported to cause a 60% and 20% increase in GC risk in men and women, respectively. It is estimated that 18% of GC cases are attributable to tobacco smoking. No association has been found between smokeless tobacco and GC. In contrast, alcohol consumption has not been consistently shown to be associated with GC; however, it has been identified as a risk factor for disease progression. A 5-fold increased risk of GC has been observed as a result of the combined effect of alcohol and smoking. A high intake of salted, pickled or smoked foods, and preserved foods rich in salt and nitrites have been reported to be associated with an increased risk of GC, whereas foods rich in fiber, vegetables, and fruit were found to be protective. Individuals with moderate and high salt intake had a 1.41 and 1.68 relative risk (RR) for GC, respectively, compared with those who consumed low levels of salt. Additionally, in the presence of H pylori infection, high salt intake further increases the risk of GC. Significant associations were found between the consumption of processed meat (RR 1.45 95%, CI 1.26–1.65) and GC risk. This association between processed meats and GC been described to be stronger in subjects infected with H pylori . Although obesity has not been found to be associated to all GCs, several meta-analyses have reported a positive association between increased body mass index (BMI) and risk of GC in the cardia.
Gastric cancer classification
GC is classified into 2 main groups: early and advanced stages. Prognosis is largely depends on the tumor stage. The 5-year survival rate in patients with early GC (EGC) is between 85% and 100%, whereas it is only 5% to 20% for advanced GC. The degree of invasion defines GC as early or advanced. Early gastric carcinoma is defined as malignancies limited to the mucosa or submucosa, regardless of lymph node invasion. Advanced GC is classified according to the extent of invasion and endoscopic appearance (polypoid lesions, ulcerated with well-defined border, ulcerated with ill-defined borders, or infiltrating diffuse without evidence of mass or ulcers).
Tumor location dictates the anatomic classification as cardia or noncardia (distal from the cardia) ( Fig. 3 ). Cardia and noncardia adenocarcinomas present with different clinical and epidemiologic characteristics. In contrast to cardia tumors, noncardia tumors have decreased in the last decades. Cardia GC affects predominantly white populations and is more often associated with gastroesophageal reflux disease. Cardia adenocarcinomas are aggressive and have a poor prognosis. Cardia tumors invade the gastric and esophageal walls and metastasize to local lymph nodes ( Table 1 ). Due their aggressiveness, the American Joint Classification of Cancer decided to use the esophageal cancer staging system for all GC arising in the esophagogastric junction and any cancer arising in the proximal 5 cm of the stomach with involvement of the esophagogastric junction. Noncardia GC is more likely associated with H pylori and comprises more than 60% all GC cases worldwide.
| Cardia Gastric Cancer | Noncardia Gastric Cancer | |
|---|---|---|
| Intestinal-Type | Diffuse-Type | |
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Histologic Classification
The Lauren classification system, which classifies GC as intestinal (with intercellular junctions) and diffuse (without intercellular junctions), is the most frequently used system to classify GC (see Table 1 ). Intestinal-type adenocarcinomas form glands or tubules lined by epithelium, resembling the intestinal mucosa. Although the incidence of intestinal-type GC has decreased recently, it is still the most frequent type of GC found in high incidence populations. This type of GC usually occurs in a 2:1 male-to-female ratio and in individuals between 55 and 80 years of age. The development of intestinal-type GC is preceded by a sequence of histologic lesions that my take years to develop (see Fig. 2 ).
Diffuse-type gastric adenocarcinomas are more aggressive and have a worse prognosis than intestinal-type. They do not have a gender bias and are generally diagnosed in younger patients (40–60 years of age). Diffuse GC cells lack cohesion, and invade tissues independently or in small clusters. A variant of the diffuse histologic type is the signet ring cell gastric adenocarcinoma. Signet tumor cells contain abundant cytoplasmic mucin that displaces the nucleus toward the periphery. Although diffuse-type GC can be associated with H pylori infections, it is more frequently associated with loss of expression of E-cadherin (HDGC); no precancerous lesions have been defined to date.
Gastric cancer prevention
Lifestyle Modification
Primary prevention aims to prevent the disease before it ever occurs by preventing exposures to hazards, changing unhealthy or unsafe behaviors, and increasing resistance to the disease. Recommended lifestyle changes to prevent GC include limiting exposure to tobacco and maintaining a healthy BMI. In terms of diet, consumption of fresh fruit and vegetables 1 or more days per week significantly reduces GC risk, as demonstrated in numerous prospective studies. Consumption of antioxidants has also been recommended for the prevention of GC; however, some clinical trials have conflicting results.
Chemoprevention
Cyclooxygenase (COX)-2 overexpression is characteristic of noncardia stomach cancers and in well-differentiated stomach cancers, suggesting that suppression of COX-2 could be used as a chemopreventive strategy to prevent GC. Several cohort and observational studies have suggested that systematic use of nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin are protective factors, especially for noncardia GC with H pylori infection. However, randomized controlled trials evaluating the role of nonaspirin NSAIDs for regression of intestinal metaplasia (IM) after eradication of H pylori failed to demonstrate a benefit compared with individuals without nonaspirin NSAID use. The use of celecoxib, a nonaspirin NSAID, has been shown to regress precancerous stomach mucosal conditions and/or lesions after H pylori eradication. Statins are associated with a significant decrease in GC risk and have also been studied as potential GC chemopreventive agents.
Helicobacter pylori Eradication
Because only a very small proportion of H pylori -infected subjects develop GC, the benefit of mass H pylori eradication campaigns to prevent GC remains unsubstantiated. However, treatment and eradication of H pylori infection is recommended in patients with gastritis. H pylori eradication has been reported to restore gastric histology to normal in individuals with chronic gastritis and atrophic gastritis without IM. Atrophic gastritis has been reported to undergo regression within 1 or 2 years after successful eradication of H pylori . The presence of IM in H pylori -associated chronic gastritis suggests a less reversible stage compared with atrophic gastritis alone. Evidence suggests that eradication at the IM stage is less effective and that lesions are more likely to progress. In a randomized 6-year follow-up clinical trial examining the role of anti- H pylori treatment and dietary antioxidant micronutrient supplementation in reducing the progression of precancerous lesions, use of anti- H pylori treatment or antioxidants was associated with significant inhibition of precancerous lesions including IM. This reversion of gastric atrophy and IM was confirmed after 12 years. The eradication of H pylori in GC patients with prior endoscopic resection reduces the incidence of new tumors and the extent of IM. There are controversial data regarding the effect of H pylori eradication on the development of gastric epithelial dysplasia. At present, prophylactic H pylori eradication is strongly recommended after endoscopic tumor resection in EGC to prevent recurrence of malignancy.
Screening and surveillance
Because GC can take decades to develop, the identification of precancerous lesions and endoscopic surveillance of patients at high risk may help to detect early-stage malignancies when they are still operable and have better prognosis. In a large-scale 10-year follow-up study, progression rates to GC for subjects with atrophic gastritis, IM, low-grade dysplasia, or high-grade dysplasia were estimated 0.8%, 1.8%, 4.0% and 33.0%, respectively. Therefore, there is insufficient evidence to conclude that it would be beneficial and cost-effective to implement population GC screening in regions not at high risk of GC. It has been suggested that the GC screening strategy should be based on GC incidence in the population and on the individual’s risk.
Asian countries (Japan, South Korea, Singapore, and Taiwan), which have a high incidence of GC, have started national screening programs. The Korean National Cancer Screening Program (NCSP) provides regular 2-year interval GC screening by upper gastrointestinal radiograph or upper endoscopy for citizens aged 40 years or older. The current trend in GC mortality reduction, despite the stable age-standardized GC incidence during last decade, supports that the current screening program has a mortality-reducing effect in Korea. However, the current Korean NCSP does not recommend different screening intervals depending on pre-existing gastric lesions for risk stratification. In Japan, guidelines for GC screening recommend photofluorography (indirect radiograph using small films) for population-based and opportunistic screening. They do not recommend endoscopy as a screening tool in the general population due to the lack of sufficient evidence supporting a reduction of GC as a result of population endoscopy screening.
The European Society of Gastrointestinal Endoscopy, a group of European gastrological societies, recently published management of precancerous conditions and lesions in the stomach (MAPS) guidelines for high-risk groups ( Table 2 ). These guidelines emphasize the importance of GC risk stratification. The application of the operative link on gastritis assessment (OLGA) and operative link for gastric IM (OLGIM) to address the grade and extension of atrophy may be useful for identifying subgroups of patients with risk of progression to GC. Both OLGA and OLGIM have been validated in prospective studies. In the US, only the American Society for Gastrointestinal Endoscopy (ASGE) has recently published guidelines for the screening and management gastric lesions based on MAPS (see Table 2 ).
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