Gastric cancer has significant geographic, ethnic, and socioeconomic differences in distribution. There are two main histologic variants of gastric adenocarcinoma.
The most frequent is the “intestinal type,” so called because of its morphologic similarity to adenocarcinomas arising in the intestinal tract. The less common “diffuse type” gastric cancers are characterized by a lack of intercellular adhesions, which leaves them unable to form glandular structures. In patients with the inherited form of diffuse type gastric cancer, the absence of intercellular adhesions is caused by a germline mutation in the cell adhesion protein E-cadherin (CDH1).
Although several risk factors are described, Helicobacter pylori infection and family history of gastric cancer are the two main risk factors for gastric cancer.
The sequence of molecular events that underlies intestinal type gastric cancer and its well-defined precursor lesions is incompletely understood. In comparison, much more is known about the molecular pathogenesis of diffuse type gastric cancers, which display a prominent molecular abnormality in the cell adhesion protein E-cadherin (CDH1).
One model for intestinal type gastric cancer describes a progression from chronic gastritis to chronic atrophic gastritis, to intestinal metaplasia, to dysplasia, and eventually, to adenocarcinoma.
Longstanding chronic superficial gastritis caused by chronic H. pylori infection, pernicious anemia, or possibly, a high-salt diet leads eventually to chronic atrophic gastritis and intestinal metaplasia.
Gastric atrophy is accompanied by a loss of parietal cell mass and therefore a reduction in acid production (hypochlorhydria or achlorhydria), a decrease in luminal ascorbic acid (vitamin C) levels, and a compensatory increase in serum gastrin, a potent inducer of gastric epithelial cell proliferation.
Similarly, gastric resection results in hypochlorhydria or achlorhydria, secondary hypergastrinemia, and bile reflux, especially after a Billroth II anastomosis. The increase in gastric pH would permit colonization of bacteria capable of converting dietary nitrates into potent mutagenic N-nitroso compounds.
Chronic inflammation results in epithelial cell damage with increased free radical generation, a further reduction in luminal ascorbic acid levels, and increased cell turnover.
Atrophic gastritis is an autoimmune disorder that is characterized by progressive atrophy of the glandular epithelium with loss of parietal and chief cells. The loss of the normal exocrine glands of the gastric mucosa causes hypochlorhydria (a decrease in hydrochloric acid) and a resultant increase in gastric pH. An abnormally high pH in the stomach permits microbial colonization, some of which possess nitrate reductase, allowing nitrosation that is genotoxic. In addition, there is a loss of endocrine cells, which normally secrete epidermal and transforming growth factors, thereby aiding the stomach in regenerating damaged tissue. Populations with a high prevalence of atrophic gastritis also have a high prevalence of gastric cancer and vice versa.
Atrophic gastritis and other conditions that cause gastric atrophy are associated with an increased risk of both cardia and noncardia gastric adenocarcinomas. The magnitude of the risk is variable in the literature, with estimates ranging from 3 to 18 times greater than an age-matched population.
Metaplasia is a potentially reversible change from one fully differentiated cell type to another, a process of adaptation to environmental stimuli. The most common form of metaplasia in the stomach is the intestinal type. It occurs as a result of H. pylori infection or bile reflux, or it can be induced experimentally with irradiation. Intestinal metaplasia is more frequent in countries with a higher incidence of gastric carcinoma, and at least in experimental animal models, it precedes the development of gastric carcinoma.
Most patients diagnosed with high-grade dysplasia of the gastric mucosa either already have or will soon develop gastric cancer. In gastrectomy specimens for gastric cancer, 20 to 40 percent of patients have associated dysplasia. Rates of progression from dysplasia to gastric cancer have been estimated at 21, 33, and 57 percent of cases of mild, moderate, and severe dysplasia, respectively.
In contrast to intestinal type gastric cancers, diffuse type gastric cancers have no clearly defined precancerous lesion.
There are geographic and ethnic differences in the incidence of gastric cancer around the world, as well as trends in each population over time. Emigrants from high-incidence to low-incidence countries often experience a decreased risk of developing gastric carcinoma. Such findings strongly suggest that environmental factors have an important role in the etiology of gastric cancer and that exposure to risk factors occurs early in life.
The World Health Organization’s International Agency for Research on Cancer (IARC) classified H. pylori as a group 1 or definite carcinogen. As noted above, intestinal-type gastric carcinoma is believed to evolve as a progression from atrophy to metaplasia, to dysplasia, and then to carcinoma. The most common cause of gastritis is H. pylori.
It is thought that H. pylori infection triggers inflammation at the corpus mucosa, which results in atrophy and intestinal metaplasia. H. pylori infection has been associated with an approximately sixfold increase in the risk of adenocarcinomas distal to the cardia, including both the intestinal and diffuse types.
Substantial evidence strongly suggests that the risk of gastric cancer increases with a high intake of salt and various traditional salt-preserved foods, such as salted fish, cured meat, and salted vegetables. In 2007, salt and salted/salty foods were classified as probable risk factors for gastric cancer.
A potential synergistic effect of salt and H. pylori has also been described, although not in all studies. High salt intake damages stomach mucosa and increases the susceptibility to carcinogenesis in rodents. The induced proliferative change may act to promote the effect of food-derived carcinogens.
The declining incidence of gastric cancer worldwide over the last 50 years has been attributed, at least in part, to the spread of refrigeration, the use of which would inversely correlate with salting and other salt-based methods of preservation, such as curing and smoking, and with the overall volume of salt in the diet.
Humans are exposed to N-nitroso compounds from diet, tobacco smoke, and other environmental sources, as well as from endogenous synthesis, which contributes to 40 to 75 percent of total exposure. N-nitroso compounds are generated after consumption of nitrates, which are natural components of foods like vegetables and potatoes and are used as a food additive in some cheeses and cured meats. Dietary nitrates are absorbed in the stomach and secreted in saliva in a concentrated form, where they are reduced to nitrites by oral bacteria.
In 2015, the World Health Organization’s IARC reviewed the evidence linking intake of processed meat with a variety of cancer sites and concluded that there was a positive association between consumption of processed meat and stomach cancer.
A meta-analysis of epidemiology studies found an inconsistent association between low levels of folate and the risk of gastric cancer.
Excess body weight is associated with an increased risk of gastric cancer. In a meta-analysis of cohort studies identifying 9492 gastric cancer cases, excess body weight ([BMI] ≥25 kg/m2) was associated with an increased risk of gastric. The strength of the association increased with increasing BMI.
Several studies have examined the relationship between tobacco smoking and gastric cancer. A meta-analysis of 42 studies estimated that the risk was increased approximately 1.53-fold and was higher in men . A prospective study from Europe (EPIC) found a similar magnitude of risk, which diminished after 10 years of smoking cessation. Approximately 18 percent of gastric cancer cases were attributed to smoking.
There is some evidence that occupations in coal and tin mining, metal processing (particularly steel and iron), and rubber manufacturing industries lead to an increased risk of gastric cancer; however, the data are disparate.
Influence of salt and intake of salted foods:
There is a link between intake of salt and highly salted foods and gastric cancer risk; high salt intake damages stomach mucosa and increases the susceptibility to carcinogenesis.
The consumption of salted food appears to increase the possibility of persistent infection with H. pylori.
Infection with Epstein-Barr virus (EBV) is associated with a number of malignancies, especially nasopharyngeal carcinoma.
A possible role in gastric cancer was initially suggested in a study from Korea in which evidence of EBV was found in the tumor cells of 12 of 89 (13 percent) gastric carcinoma patients compared with none of 27 controls with a benign ulcer or any of the benign tissues from the cases. Some of the tumor cells had a histologic appearance similar to that of nasopharyngeal carcinoma.
Since then, it has been estimated that between 5 and 10 percent of gastric cancers worldwide are associated with EBV.
A consistent association between alcohol consumption and the risk of gastric cancer has not been demonstrated. At least one European study suggests that daily intake of wine may be protective.
The risk of distal gastric cancer is increased by approximately twofold in populations with low socioeconomic status. By contrast, proximal gastric cancers have been associated with higher socioeconomic class.
There is an increased risk of gastric cancer after gastric surgery, with both the risk and the interval between initial gastric surgery and the development of remnant gastric cancer depending on the reason for the initial surgery and the type of reconstruction.
Cancer survivors who received abdominal irradiation:
An elevated risk of gastric cancer has been reported in adult survivors of testicular cancer and Hodgkin lymphoma and in childhood cancer survivors who received abdominal radiation therapy. An especially high risk has been noted in Hodgkin lymphoma survivors who received both subdiaphragmatic radiation therapy and high-dose procarbazine.