The multistep sequence
Only about the intestinal form of adenocarcinoma of the stomach is proposed to follow a multistep progression that is initiated from chronic inflammation of the gastric mucosa. Chronic gastritis of the gastric mucosa, which is mostly caused by H. pylori infection, leads to atrophy of the gastric mucosa; atrophy is followed by metaplasia to intestinal cells, then dysplasia, and finally cancer cell formation. Because each step raises the chance of the next, the sequence explains why long-standing inflammation, rather than a single event, is the starting point.
Gastric adenocarcinoma is strongly influenced by CD4+ T cells, which make the environment suitable for atrophy and carcinogenesis. Helper T cells polarise this response, setting the balance between protection of the mucosa (Th2) and damage to the mucosa with elimination of the infection (Th1). Which way the balance tips matters.
Risk factors
Other than H. pylori infection, several further factors modify the risk.
Dietary changes. Foods that contain a high level of salt, nitrate or polycyclic aromatic compounds are associated with a higher risk of gastric adenocarcinoma; a high-salt diet increases the risk about 1.5- to 2-fold. Recent changes in dietary habits have reduced the incidence: the use of refrigeration, which decreases the chance of growth of microbes in the food; more use of fresh fruit and vegetables; and a lower intake of pickled and salted foods.
Obesity. Obesity is associated with a higher risk of different gastrointestinal tract cancers. Studies show that obesity increases the risk of junctional adenocarcinoma, not the non-junctional one; the risk of cardia adenocarcinoma is increased 2- to 3-fold in a population with a BMI above 35. The relation is probably due to the formation of proinflammatory and adipokine mediators by the visceral fat.
Cigarette smoking. Studies show that cigarette smoking increases the risk of gastric cancer about 1.5- to 2-fold.
Alcohol consumption. A meta-analysis shows that the use of alcohol could be associated with a significant but small increase in the risk of gastric adenocarcinoma formation.
Genetic factors
In general, intestinal-type gastric adenocarcinoma is believed to be caused by environmental factors such as H. pylori infection, while diffuse-type gastric adenocarcinoma is mainly driven by genetic predispositions related to a germline mutation of the CDH1 gene, which encodes the E-cadherin protein. Beyond CDH1, genetic studies also show somatic mutations that are common in gastric cancer, such as ARID1A, which is found in about 10% of gastric cancers and in more than 70% of EBV-positive gastric cancers, and FGFR1, FGFR2, EGFR and MET.
Family history also carries weight. Some studies show that, even after adjustment for H. pylori infection, a family history increases the risk of gastric cancer in a sibling about 2-fold, and another case-control study shows that a family history of gastric cancer raises the odds ratio by 5-fold in women only. Taken together, the different studies about the relevance of genetics and family history conclude that genetic factors account for 28% of gastric cancers, shared environmental factors for 10%, and non-shared environmental factors for 62%.
Some studies point to the importance of polymorphisms of immune-system-related genes, most importantly the IL-1β gene. IL-1 is a proinflammatory cytokine and a potent inhibitor of gastric acid secretion, and some polymorphisms of IL-1 are associated with a 2- to 3-fold higher risk of H. pylori-related gastric adenocarcinoma. Other immune-related genes studied include TNF, IL-10 and TLR-4; carriers of a specific polymorphism of TLR-4 have an 11-fold higher risk of gastric adenocarcinoma progression.
Diffuse-type gastric cancer is highly dependent on a germline mutation of the CDH1 gene: the lifetime risk of diffuse gastric adenocarcinoma is more than 70%, and patients with a CDH1 mutation are also at higher risk of lobular breast cancer. Beyond the intestinal and diffuse types, other gastric cancers can be related to familial genetic syndromes, such as gastric adenoma of the fundus in familial adenomatous polyposis (35 to 100% of these patients will have a gastric adenoma), hereditary non-polyposis colorectal cancer (HNPCC) with an 11% risk of gastric cancer, predominantly intestinal type, and juvenile polyposis with a 12 to 20% incidence of gastric cancer.
The Lauren classification
Based on Lauren’s classification, pathologists classify adenocarcinoma of the stomach into two main groups.
Intestinal adenocarcinoma is the more common form and is mostly associated with H. pylori infection and atrophic gastritis; histologically, glandular tubular cells are seen.
Diffuse adenocarcinoma accounts for about 20% and is mostly related to CDH1 mutation. Histologically there are no glandular cells, and the tumour infiltrates the stomach diffusely and makes it thickened, which is referred to as linitis plastica. Another histologically specific finding of diffuse adenocarcinoma is the presence of signet-ring cells, which are cells full of mucin that push the nucleus to the periphery and leave a rim of cytoplasm.
Location of the tumour
Adenocarcinoma of the stomach can also be classified by location. Junctional adenocarcinoma arises at the esophagogastric junction (EGJ) and can be sub-classified, based on the extension of the tumour, into three forms (the Siewert classification): type I tumours, 1 to 5 cm above the EGJ; type II tumours, 1 cm above to 2 cm below the EGJ; and type III tumours, 2 to 5 cm below the EGJ. Non-junctional adenocarcinoma arises in the fundus, body or antrum.