H. pylori infection is implicated in the genesis of both gastric adenocarcinomas and gastric lymphomas. First incriminated as a cause of peptic ulcers, H. pylori now has acquired the dubious distinction of being the first bacterium classified as a carcinogen.
The scenario for the development of gastric adenocarcinoma is similar to that for HBVand HCV-induced liver cancer. It involves increased epithelial cell proliferation on a background of chronic inflammation. As in viral hepatitis, the inflammatory milieu contains numerous genotoxic agents, such as reactive oxygen species. The sequence of histopathologic changes consists of initial development of chronic inflammation/gastritis, followed by gastric atrophy, intestinal metaplasia of the lining cells, dysplasia, and cancer. This sequence takes decades to complete and occurs in only 3% of infected patients. Like those of HBV and HCV, the H. pylori genome also contains genes directly implicated in oncogenesis. Strains associated with gastric adenocarcinoma have been shown to contain a “pathogenicity island” that contains cytotoxin-associated A gene (CagA). Although H. pylori is noninvasive, CagA is injected into gastric epithelial cells, where it has a variety of effects, including the initiation of a signaling cascade that mimics unregulated growth factor stimulation.
As mentioned earlier, H. pylori is associated with an increased risk for the development of gastric lymphomas as well. The gastric lymphomas are of B-cell origin, and because the transformed B cells grow in a pattern resembling that of normal mucosa-associated lymphoid tissue (MALT), they have been referred to as MALT lymphomas (Chapter 12). Their molecular pathogenesis is incompletely understood but seems to involve strain-specific H. pylori factors, as well as host genetic factors, such as polymorphisms in the promoters of inflammatory cytokines such as IL-1β and tumor necrosis factor (TNF). It is thought that
H. pylori infection leads to the activation of H. pylori–reactive T cells, which in turn cause polyclonal B cell proliferation. In time, a monoclonal B cell tumor emerges from the proliferating B cells, perhaps as a result of accumulation of mutations in growth regulatory genes. In keeping with this model, early in the course of disease, eradication of H. pylori with antibiotics causes regression of the lymphoma by removing the antigenic stimulus for T cells. MALT lymphoma is thus a remarkable example of a tumor that depends on signals elicited by interactions with host immune cells for its continued growth and survival.
H. pylori infectionhasbeenimplicatedinbothgastricadenocarcinomaandMALTlymphoma.
ThemechanismofH. pylori–inducedgastriccancersismulti-factorial,includingimmunologicallymediatedchronicinflammation,stimulationofgastriccellproliferation,andproductionofreactiveoxygenspeciesthatdamageDNA.H. pylori pathogenicitygenes,suchasCagA, alsomaycontributebystimulatinggrowthfactorpathways.
ItisthoughtthatH. pylori infectionleadstopolyclonalB-cellproliferationsandthateventuallyamonoclonalB-celltumor(MALTlymphoma)emergesasaresultofaccumulationofmutations.