Helicobacter pylori infection is the single most important factor in the development of gastric cancer. The infection is acquired in childhood (10). Infected children carry the infection and its anatomic consequences into middle and old age (7). Helicobacter pylori gastritis affects 40% to 75% of persons in high-risk populations, yet only 3% to 5% of these infected individuals develop stomach cancer (11,12), indicating that infection alone is not sufficient for carcinogenesis. When compared to other H. pylori strains, the CagA-positive strain is associated with an increased risk of gastric cancer (13). CagA-producing H. Pylori has also been shown to elicit a more robust inflammatory response (14,15). Increased inflammation is an important aspect in the mechanism by which H. pylori infection may increase stomach cancer risk. The inflammatory response leads to exposure of replicating cells to reactive oxygen and nitrogen species, increasing opportunities for DNA damage and somatic mutations. In addition, recent studies have specifically documented CagA-positive H. pylori’s ability to inhibit tumor suppressor genes such as TP53 and RUNX3 (16,17,18). A few countries are noted to have a dramatically low gastric cancer incidence despite a high frequency of H. pylori infection. For example, Bangladesh and Nigeria, two countries noted to be among the lowest in gastric cancer incidence (see Table 5.1), both have a documented H. Pylori prevalence of greater than 90% (1,2,19). Variation of H. pylori strains, combined with other extrinsic and intrinsic risk factors, may account for this paradox.

The initial manifestation of H. pylori infection is severe superficial gastritis, followed by the development of multifocal atrophic gastritis (MAG) and intestinal metaplasia (IM) (see Chapter 4). The process begins at the antral-corpus junction and along the lesser curvature of the antrum. Classically, over time, the atrophic foci expand and fuse so that in old age much of the oxyntic mucosa is replaced by intestinalized tissue. However, the pervasive use of proton pump inhibitors (PPIs) has altered the general pattern of H. pylori-associated gastritis and atrophy. Although still beginning in the antral-corpus junction, the decreased acid production secondary to PPI use provides an earlier opportunity for H. pylori to spread to the gastric body leading to a corpus-predominant pangastritis (20,21). Cancer risk is highest in H. pylori-infected persons with severe gastric atrophy, corpus-predominate pangastritis, and IM (12). Recent reports from both the World Health Organization’s IARC working group and the Kyoto global consensus committee on H. Pylori gastritis emphasize the need for eradication therapy, ideally as a primary prevention of gastric cancer before atrophic changes have occurred (22,23,24).

The pattern of food consumption may increase or reduce the risk of acquiring stomach cancer. The addition of nitroso compounds to the diet of experimental animals produces gastric cancer and its precursor, IM (22). Epidemiologic studies show a direct association between the development of IM and nitrate/nitrite consumption in humans (23). Salt intake also directly relates to stomach cancer risk in humans (24,25). The consumption of dried, salted fish in Japan and the consumption of salted, nitrosated foods through the winter months in northern countries are examples of dietary practices that increase stomach cancer risk. In contrast, fresh fruits and vegetables provide antinitrosating effects that protect the stomach from both exogenous and endogenous mutagenic nitroso compounds. Fresh fruits and vegetables function as antioxidants and contain substantial amounts of folate, ascorbic acid, carotene, and tocopherol. Epidemiologic studies of Japanese and European populations suggest that raw green and yellow vegetables protect against the development of gastric cancer (26), and a Japanese cohort study showed that increased fresh produce consumption and reduced consumption of pickled food reduced the gastric cancer risk, even in the presence of atrophic gastritis (27).
The year-round availability of fresh produce eliminates the need to use salt to preserve vegetables. Smoking and salting of meat is no longer a necessity with the advent of universal household refrigeration. These two factors have contributed to the dramatic decrease in stomach cancer rates in Western countries after World War II.

The International Agency for Research on Cancer (IARC) estimates that smoking is responsible for 10% of all gastric adenocarcinomas (1). Although this association is stronger in adenocarcinomas of the cardia, smoking is also associated with an increased risk of NCGA (28). A meta-analysis looking at 34,557 gastric cancer cases showed a lack of association between moderate alcohol drinking and gastric cancer risk (29). However, there was a positive association with heavy alcohol drinking, defined as greater than or equal to four 12.5 g of ethanol drinks per day. Unfortunately, none of the studies in this meta-analysis reported a relative risk for alcohol consumption and gastric cancer adjusted for H. pylori infection.

A dose-dependent increase in gastric cancer frequency has occurred among Japanese atomic bomb survivors, suggesting that ionizing radiation may play a role in gastric carcinogenesis (30,31). Additionally, radiotherapy in young patients increases their risk of gastric cancer when lymph nodes of the upper abdomen are included in the radiation field, as may occur in the treatment of lymphoma and testicular cancer (32,33).

The creation of a gastroenterostomy after subtotal gastrectomy for peptic ulcer is a well-established risk factor for the development of cancer in the gastric stump (Fig. 5.1) (34). The cancer may not be apparent until 20 years after the creation of the anastomosis. It is preceded by the appearance of gastritis and hyperplastic polyps (HPs) at the anastomotic line (35). The cause of the increased risk is attributed to the reflux of bile and pancreatic juice into the gastric remnant, a hypothesis that is supported by rodent experiments that show the sequential development of gastritis, hyperplasia, metaplasia, and adenocarcinoma after duodenal contents were diverted into the stomach (36). Since subtotal gastrectomy is no longer employed to treat peptic ulcer, it is increasingly rare for patients to carry this risk factor. Another potential source of postenterostomy stomach cancer is the Roux-en-Y gastrojejunostomy used to treat morbid obesity. Up to 30 cases of gastric cancer in patients who previously underwent bariatric surgery have been described between the years of 2007 and 2014 (37,38). The majority of these cancers were noted to occur in the excluded gastric segment, which is subject to the reflux of bile and alkaline secretions and the subsequent development of gastritis (39).

Only a small number, approximately 2% to 8%, of all gastric carcinomas arise from inherited gastric cancer syndromes (44,45). The majority of families with familial gastric carcinoma will have the autosomal dominate hereditary diffuse gastric cancer (HDGC). A germline mutation in the tumor suppressor gene CHD1 (E-cadherin) is identified in approximately 25% to 48% of individuals with HDGC. E-cadherin is a cell adhesion protein (46,47). The loss of its function (and loss of its normal expression on the cell membrane) (Fig. 5.2) due to genetic mutations results in the discohesive cells that characterize sporadic diffuse gastric cancers and lobular breast cancers. It is not surprising, therefore, that familial gastric cancers associated with germline mutations in this gene are diffuse in type and that HDGC kindreds also show an increased frequency of lobular breast cancer (46,48). The CDH1 mutation carries a high penetrance. For those that carry the germline mutation, the estimate lifetime risk of developing gastric cancer is 67% for men and 83% for women (47,48). In general, cancers in HDGC occur at a relatively early age, with the average age of presentation with diffuse gastric carcinoma being 38 years of age (49). Patients who are known to carry the HDGC mutation are generally treated with prophylactic gastrectomy since the early lesions are endoscopically undetectable (50). Multiple superficial mucosal cancers may be found at the time of gastrectomy (Fig. 5.2). The chance discovery of similar lesions in an endoscopic biopsy should alert the pathologist to a possible HDGC mutation (51,52). Lynch et al. (53) suggest that these superficial neoplastic foci represent a widespread field effect due to promoter hypermethylation and that dysregulation of genes required for invasion and metastases are much less common.

The lifetime risk for gastric cancer in patients with Lynch syndrome is 6% to 13% (54). The Netherlands’ Hereditary Cancer Registry documents gastric cancer risk as being 3.4 times higher in Lynch syndrome patients when compared to the general population, specifically those with MSH2 (Fig. 5.3) or MLH1 mutations (55). Lynch syndrome is more extensively discussed in Chapter 12.

Familial adenomatous polyposis (FAP) may involve the stomach as well as the small intestine and colon. Fundic gland polyps (FGPs) are the most common gastric polyps encountered in FAP patients. Unlike those encountered sporadically, FGPs associated with FAP patients tend to be more numerous (Fig. 5.4A) and are known to be neoplastic (Fig. 5.4B) as they frequently carry somatic adenomatous polyposis (APC) gene alterations (56). Although dysplasia, predominately low grade, is present in up to 50% of FAP-associated FGPs, invasive adenocarcinoma is rarely encountered (57,58,59,60). The precursor lesion to FAP-associated gastric cancer may be a flat polypoid adenoma unrelated to FGPs. In a recent review of the clinical characteristics of gastric cancer in Japanese FAP patients, none of the patients with gastric cancer had detectable FGPs (61). In general, Japanese and Korean patients with FAP have more frequent gastric adenomas and neoplastic transformation than Westerners with FAP (62,63,64). This observation may be related to differing environmental risk factors, or it may be genetic given that the location of the mutation in the large APC gene is known to have a striking effect on the FAP phenotype (see Chapter 12).

Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) is a recently described autosomal dominant gastric polyposis syndrome that carries a significant risk of gastric cancer (65). The syndrome is unique in that the polyposis consists of greater than 100 FGPs that are restricted to the gastric body and fundus. Patients with GAPPS have no duodenal or colorectal polyposis. The proximal stomach polyps are predominately FGPs, with and without dysplasia; however, among the FGPs, GAPPS patients were also noted to have HPs, pure adenomatous polyps, and some mixed-morphology polyps. The earliest gastric carcinoma arising in the setting of GAPPS occurred at 33 years of age (65). The causal genetic defect in GAPPS has yet to be identified. Exclusion of other heritable gastric polyposis syndromes is essential before the diagnosis can be made.

Early-onset gastric cancer has been described in association with other inherited cancer syndromes including Li-Fraumeni syndrome in which affected individuals have germline mutation of the TP53 gene (66), Peutz-Jeghers syndrome (67,68), and possibly Cowden syndrome (69). Carriers of BRCA1/2 mutations have a substantial increase in the lifetime risk of breast and ovarian cancer. These mutations have been related to a variety of other sites as well, including the stomach. The Swedish Family Cancer Database assessed the cancer incidence in classified family members (n = 944,723) and compared their cancer experience with that of the general population of Sweden and found a twofold increase in the risk of acquiring stomach cancer before age 70 among male members of families with breast and ovarian cancer (70). Family aggregations of breast cancer and stomach cancer have been well documented, with 20.7% of families harboring both gastric and breast malignancies having mutations in BRCA2 (71,72). It is currently unknown if mutations in specific regions of the BRCA gene predispose patients to an increased gastric cancer risk (72).

Atypical regenerative changes are usually accompanied by active inflammation without significant architectural or differentiation abnormalities. Regenerative cells show increased nuclear-to-cytoplasmic ratio, frequent mitosis, and prominent nucleoli. However, one cytologic clue to regenerative atypia is the ease in identifying nucleoli in the background of characteristically open, finely granular chromatin (Fig. 5.7). In contrast, dysplastic cells show one or more nuclear abnormalities including hyperchromasia with coarsely granular cytoplasm, irregular nuclear borders, and atypical mitoses and form architecturally abnormal glands with branching and occasional back-to-back configuration.

The identification of dysplasia is critical to the management of patients in high-risk populations, but the assignment of grades is subjective, with wide inter- and intravariations in grade selection. A workshop convened to resolve international differences in the definitions of different grades of gastric epithelial dysplasia resulted in the Padova classification (93), as summarized in Table 5.3.

In low-grade dysplasia, the gastric mucosal architecture is generally preserved, although abnormalities sometimes occur, including pseudovilli, irregular branching papillary infoldings, crypt lengthening with serration, and cystic changes. Low-grade nuclei are elongated, have mild-to-moderate cytologic atypia and polarization is preserved (Fig. 5.8A) (94). The nuclei of high-grade gastric dysplasia change from the “pencilate” form, characteristic of low grade, to a more rounded/cuboidal form. These nuclear changes occur with loss of polarity, with nuclei moving from their basal location to the luminal aspect of the cell. Finally, glandular crowding and architectural changes are generally evident in high-grade dysplasia (Fig. 5.8B). Regardless of grade, flat/depressed lesions are general given the term dysplasia (intraepithelial neoplasia), and polypoid lesions are referred to as adenomas.

Intramucosal carcinoma is defined by invasion of the lamina propria. In the stomach, this diagnosis indicates a risk of lymphovascular invasion and lymph node metastasis. The distinction between high-grade dysplasia and intramucosal carcinoma can be challenging on biopsy specimens where fragmentation and lack of desmoplastic response are common. Using the Padova classification (Table 5.3), a diagnosis of high-grade dysplasia suspicious for invasive carcinoma is often appropriate in this setting. Histologic features favoring intramucosal carcinoma include marked glandular crowding, budding (Fig. 5.9A), and intraluminal necrotic debris (Fig. 5.9B) (95). Although there is an increased risk for lymphovascular invasion in gastric intramucosal carcinomas, it is small (<3%) when compared to more advanced stages (96). For this reason, an endoscopic approach (Fig. 5.10), rather than surgical
resection, may be a reasonable treatment option for patients with small intramucosal carcinomas (97).

Like gastric adenocarcinoma, the prevalence of gastric adenomas has marked geographic variation. Gastric and colon polyps share some morphologic features. Grossly, they have a lobulated or mamillated surface and are often covered by a reddened, velvety mucosa (Fig. 5.11). A villous configuration may predominate in larger lesions (Fig. 5.12). The majority of gastric adenomas are intestinal type with some evidence of intestinal differentiation including goblet cells, endocrine cells, or Paneth cells. In addition, this type of adenoma occurs in a background of atrophy and IM (see Fig. 5.5).