Environmental Risk Factors
The continued identification of risk factors for gastric cancer may one day lead to the global development of early detection programs that will change the clinical history of this disease. Environmental factors appear to be related to the intestinal type of gastric cancer. Socioeconomic status is inversely correlated with the incidence of this disease. Factors associated with low socioeconomic status, such as poor sanitation, poor nutrition, and inadequate handling and preservation of food and water, are involved. Diets high in fresh fruit, leafy vegetables, ascorbic acid, and beta-carotene are associated with reduced risk. The literature also reports that decreased use of nitrites in prepared foods has also resulted in a decreased incidence. Though cigarette smoking may increase pre-malignant lesions and gastric dysplasia, a clear relationship has not been demonstrated. Similarly, the relationship between alcohol consumption and gastric cancer is inconclusive (Figure 8).
Adenocarcinoma of the stomach arises in the setting of atrophic gastritis, a condition in which there is loss of stomach glands and infiltration of mononuclear cells into the lamina propria. As the disease process advances and inflammatory processes destroy stomach glands, the ability of the stomach to secrete acid diminishes. In the most severe cases, histology of the gastric mucosa reveals the patchy presence of goblet cells and villous formation, features that characterize a pre-cancerous lesion known as intestinal metaplasia. It is important that a highly trained pathologist review the gastric histology, because not all forms of intestinal metaplasia are believed to be pre-cancerous. Intestinal metaplasia that demonstrates marked cell differentiation and production of a sulfated acid mucin is associated with gastric cancer. The identification of this lesion suggests that an endoscopic surveillance program be considered, though exact guidelines do not currently exist in the United States. Atrophic gastritis may arise in response to: 1) chronic infection with Helicobacter pylori, 2) antibodies to the acid-secreting parietal cells, as seen in pernicious anemia, and 3) surgical resection of the antrum, the portion of the stomach that releases the parietal cell-stimulating hormone gastrin. Gastric carcinoma may develop in as many as 9% of patients with atrophic gastritis.
Helicobacter pylori
The most important risk factor identified in the development of gastric cancer is infection of the stomach with the bacterial organism Helicobacter pylori. Studies with the Mongolian gerbil show that when infected with H. pylori, the gerbil develops gastritis that progresses to gastric cancer. Epidemiological studies further support the link between H. pylori and cancer of the distal stomach (i.e., antrum). The risk of developing gastric cancer is about 1 in 97 in infected individuals, compared to 1 in 750 in uninfected individuals, over a 30-year period. Thus, the risk of developing gastric cancer in H. pylori-infected individuals is about 8 times higher than in uninfected individuals. Despite this, the 1996 NIH consensus panel on H. pylori recommended that treatment not be initiated in asymptomatic infected individuals (Figure 9). Treatment of asymptomatic individuals remains a controversial issue, particularly because it takes more than 30 years before one-third of these individuals develop atrophic gastritis. The matter of treatment is even more confusing, because recent data suggest the eradication of H. pylori predisposes individuals to cancer of the proximal stomach (cardia) and esophagus. The overall incidence of gastric cancer is diminishing in western countries, but the incidence of proximal gastric cancers compared to distal is rising, and coincides with the widespread treatment of H. pylori. Some have proposed that H. pylori exerts a protective effect in the proximal stomach and esophagus by inducing achlorhydria and atrophic gastritis. Eradication of H. pylori restores gastric acid production and, in individuals predisposed to gastroesophageal reflux, could possibly contribute to cancers of the distal esophagus and cardia. Additional data is needed before treatment recommendations can be made in asymptomatic individuals. H. pylori leads to atrophic gastritis through direct and indirect mechanisms (Figure 10). The organism itself induces a host-inflammatory response within the gastric mucosa. This in turn leads to the production of reactive oxygen species, which can induce DNA damage and alterations to the genetic controls of normal cell proliferation. The host-immune response leads to the T-cell release of cytokines, such as interferon-gamma and interleukin-8, which recruit more inflammatory cells. H. pylori also appears to play a role in the pathogenesis of gastric MALT lymphomas, which arise as a reaction to infection of the stomach. Eradication of this organism has demonstrated complete or partial regression of low-grade lymphoma lesions.
Gastric Polyps
Gastric polyps may evolve into gastric cancer. Conversely, gastric cancer may present as a polypoid lesion. Commonly found polyps include hyperplastic, adenomas and early adenocarcinoma. Hyperplastic polyps are the most common and comprise about 80% of all gastric polyps. Their malignant potential significantly increases when their size is greater than 0.5 cm in diameter. Adenomatous polyps have a significant risk of cancer as well, and require endoscopic follow-up after removal.
Hereditary (Familial) Gastric Cancer
The study of familial gastric kindreds has led to the identification of a germline mutation of the CDH1 gene in one third. CDH1 encodes E-cadherin, a cell adhesion molecule that participates in normal cell differentiation and tissue architecture. Mutation of CDH1 diminish the availability of normal E-cadherin protein, thus perturbing normal cell differentiation and cell adhesiveness. Mutations of CDH1 in gastric cancer families may occur anywhere throughout the gene, in contrast to CDH1 mutations occuring almost exclusively in exons 7-9 in individuals with sporadic gastric cancer. A germline mutation of CDH1 has a 70% penetrance, increasing the susceptibility to gastric cancer. CDH1 is a tumor suppressor gene, since mutation of the second CDH1 allele, perhaps as the result of environmental influences such as H. pylori infection or diet, is required for full penetrance. Affected female family members are at higher risk for breast cancer as well and should be screened accordingly. How affected family members should be screened for gastric cancer remains a dilemma. Since familial gastric cancer is the diffuse type, superficial endoscopic mucosal biopsies lack sufficient sensitivity to identify dysplasia or early gastric cancer. Further studies are needed to determine the role of endoscopic ultrasound and PET scanning surveillance of family members. Occult gastric cancer has been found in the surgical specimens of asymptomatic family members with negative endoscopic screening who elected to undergo prophylactic total gastrectomy. Whether all affected family members should consider prophylactic gastrectomy remains unclear, but with a 70% chance of developing gastric cancer and limited surveillance methods, many individuals may opt for this radical procedure.
Molecular Biology
The development of gastric cancer is thought to occur through a multi-step process, in which the earliest lesion is atrophic gastritis, followed by the development of dysplasia, adenoma, and then adenocarcinoma. Progression from the preceding lesion to the next developmental stage is accompanied by molecular genetic events. Abnormalities in protein-encoding genes that regulate normal cell growth have been detected in gastric cancers. Alterations to growth factor receptors like c-met and K-sam are often over-expressed in gastric cancers of the scirrhous type. Proteins such as cyclin E that regulate the cell cycle, critical for the control of normal cell proliferation, are also over-expressed. Mutation to p53, a tumor suppressor gene, is found in 64% of gastric cancers. The detection of replication errors in microstellate loci is an indication that genetic instability is involved. As stated elsewhere, only one third of families with hereditary gastric cancer possess germline mutations in the CDH1, indicating that other gene abnormalities contribute to the development of gastric cancer. CDH1 mutations are also found in indiviuals with sporadic gastric cancer, in addition to other genetic aberrations. Some of these genetic perturbances are found exclusively in one gastric variant or the other (Table 1)
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