E. Strong (ed.). Gastric cancer. Principles and practice. Springer (2015)
It has been well established that gastroesophageal junctional (GEJ) mucosa is frequently associated with acid reflux from the stomach. Patients with cardia cancer share similar characteristic risk factors with those for GEJ adenocarcinoma, such as age of onset and age distribution, a higher male-to-female ratio, morphologic phenotypes, and ethnic differences in disease distribution [8–12]. The association of cardia cancer with Barrett’s esophagus and gastroesophageal reflux disease is a subject of debate, since the definition of true cardia carcinoma can be challenging when the tumor is large and involves the gastroesophageal junction . As many as 70% of the cardia carcinomas have a component of intestinal metaplasia, an early pathologic process similar to that observed in Barrett’s esophagus associated adenocarcinoma at the GEJ.
Fig. 4.1. H. pylori and Epstein–Barr virus infection associated gastric adenocarcinoma. a An adenocarcinoma arises in association with active chronic gastritis with H. pylori organisms identified on immunohistochemical stain (insert). b) A poorly differentiated carcinoma with intense intraepithelial and stromal lymphocytic infiltration (arrow) and EBV genome is identified by in situ hybridization (insert)
Interestingly, prior gastric surgery in male patients, particularly subtotal gastrectomy with Billroth II reconstruction is associated with an increased risk for the subsequent development of remnant gastric cancer, probably due to enterogastric reflux of bile and pancreatic secretions [13–16].
Helicobacter pylori infection is a major environmental cause of gastric cancer. Long-standing H. pylori infection induces chronic gastritis, which results in mucosal atrophy and intestinal metaplasia [17, 18] (Fig. 4.1a). There is a 4–9 fold increased risk of gastric neoplastic lesions among patients with H. pylori infection, particularly if infection began in early childhood [19–21]. Certain aspects of H. pylori virulence have been associated with risk of gastric cancer. In particular, the strains which are positive for cytotoxin-associated gene A (CagA) produce higher levels of interleukin 8 which elicit more intense inflammation. These strains are associated with an increased risk of gastric carcinoma . However, gastric cancer does not develop in most individuals who have H. pylori infection, and other environmental and host factors are presumed to be important in the pathogenesis of this disease [23,24].
Epstein–Barr virus (EBV) has long been recognized as a distinct pathogenic cause of gastric carcinoma [25, 26]. EBV is detected in about 10% of the gastric carcinoma cases (Fig. 4.1b). All tumor cells in EBV-associated gastric carcinoma harbor the clonal EBV genome. Gastric carcinoma associated with EBV occurs predominately in men and in younger-aged individuals. These carcinomas exhibit a unique histologic phenotype, genetic/epigenetic genotype, and distinct clinicopathological features [25, 27–29].
Autoimmune gastritis arises secondary to an immune-mediated destruction of parietal cells (pernicious anemia), is confined to the body and fundus of the stomach, and is characteristically associated with neuroendocrine cell (enterochromaffin-like cell) hyperplasia and neoplasia (Fig. 4.2). In patients with autoimmune associated atrophic gastritis, most adenocarcinomas are of the intestinal type and the risk of gastric cancer increases at least three fold . In contrast, gastric type-1 neuroendocrine (carcinoid) tumors arising in autoimmune atrophic gastritis are relatively indolent in their behavior .
Fig. 4.2. Type-I gastric neuroendocrine tumor and the coexisting adenocarcinoma. Histopathology of a neuroendocrine tumor (?star) exhibits a nested pattern (a) and the immunoreactivity for chromogranin (b) is present in the background of hyperplastic neuroendocrine cells and neuroendocrine tumor. A well differentiated and glandforming adenocarcinoma (arrow) invades the muscularis mucosa and infiltrates the submucosa
Environmental factors in addition to H. pylori infection, including cigarette smoking and diet, play an important role in gastric carcinogenesis . Foods that are salted, smoked, pickled, and preserved foods rich in salt, nitrites, or preformed N-nitroso compounds are associated with an increased risk of gastric cancer .
Genetic polymorphisms may also contribute to the etiology of gastric cancer by altering the activity of enzymes that are involved in multiple molecular processes, such as DNA synthesis and repair, carcinogen metabolism, the inflammatory response, and tumor suppression . Individuals who carry high-risk genetic variants and highrisk diets have an increased risk of gastric cancer compared with those who do not carry high-risk genetic variants or those with high-risk genetic variants but low-risk diets. Distinctive dietary patterns and regional variations in genetic polymorphisms may explain regional variations in gastric cancer incidence [35–37].
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