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Etiology and Pathogenesis
Gastric cancer can be subdivided using the Lauren classification into 2 distinct histologic subtypes with different epidemiologic and prognostic features (Fig. 54-2).8 The intestinal type of cancer is characterized by the formation of gland-like tubular structures with features reminiscent of intestinal glands. This type of gastric cancer is more closely linked to environmental and dietary risk factors, tends to be the predominant form in regions with a high incidence of gastric cancer, and is the form of cancer that is now declining worldwide. The diffuse type of cancer lacks glandular structure and consists of poorly cohesive cells that infiltrate the wall of the stomach. It is found at the same frequency throughout the world, occurs at a younger age, and is associated with a worse prognosis than the intestinal form. Extensive involvement of the stomach by the diffuse type can result in a rigid and thickened stomach, a condition referred to as linitis plastica.
Adenocarcinoma of the stomach is also classified into proximal tumors (esophagogastric junction [EGJ] and gastric cardia) and distal tumors (fundus, body and antrum of the stomach). There is no clear distinction between the genetic and cellular origin of cancers of the EGJ and cardia, which can also be classified as GE junction type II and III adenocarcinomas. Interestingly, with the decreasing incidence of Hp infection, distal tumors have been declining while proximal tumors have been increasing. In a mouse model, it has even been postulated that Barrett’s esophagus–related esophageal cancer and cancer of the EGJ have their origins in the gastric cardia.9 Emerging data from gene expression profiling suggests that differences in pathologic appearance and clinical behavior may be due to the presence of unique molecular phenotypes. Characterization of the gastric cancer genomic landscape reveals the presence of multiple alterations in the expression of tyrosine kinase receptors, which in conjunction with their ligands and downstream effector molecules represent potential pathways for future drug development.
It is now believed that the development of intestinal-type gastric cancer occurs through a multistep process in which the normal mucosa is sequentially transformed into a hyperproliferative epithelium, followed by an early adenoma, late adenoma, and then carcinoma. In colon cancer, the evidence is strong that each step in the transition is associated with a specific gene mutation,10 but the evidence that gastric cancer follows a comparable sequence of genetic events has been lacking. However, in both the intestinal-type gastric cancer and colorectal cancer, it does appear that DNA mutations are established over time in stem cells in the normal human stomach, and that in intestinal metaplasia these mutations spread through the stomach through a process involving crypt fission and monoclonal conversion of glands.11 The contention that the pathogenesis of intestinal-type gastric cancer is a multistep process is supported mainly by the observation that both chronic atrophic gastritis and intestinal metaplasia are found in higher incidences in patients with intestinal-type cancer and in countries with a high incidence of gastric cancer (see Chapter 52).12
This multistep model of intestinal-type gastric cancer, developed in large part by Correa and colleagues, 13,14 postulates that there is a temporal sequence of preneoplastic changes that eventually lead to the development of gastric cancer. A common feature of the initiation and progression to intestinaltype gastric cancer is chronic inflammation. Hp infection is the primary cause of gastric inflammation and the leading etiologic agent for gastric cancer (see Chapters 51 and 52). In a subset of patients, the inflammatory process leads to the development of atrophic gastritis (with loss of glandular tissue) followed by progression to intestinal metaplasia, dysplasia, early gastric cancer, and, eventually, advanced gastric cancer (Fig. 54-3). The current view is that all stages prior to the development of high-grade dysplasia are potentially reversible; although this concept is still somewhat controversial, it has been supported by a number of studies in animal models. 15,16 Unlike the situation observed with colon cancer, the precise genes involved in each step of this progression are still not defined. Nevertheless, next-generation sequencing techniques have shown that there is more heterogeneity in genetic alterations in gastric cancer and cancer of the EGJ than in colon cancer.17 Furthermore, the premalignant stages of gastric cancer are not as readily identifiable during endoscopy as those of colon cancer, and many gastric carcinomas are very heterogeneous, containing a large percentage of stromal cells. These stromal cells, which include cancer-associated fibroblasts known to promote tumor growth, have been reported to show distinct genetic and epigenetic changes that may confound tumor analysis.18,19 This feature makes characterization of the timing of specific gene mutations in gastric cancer difficult at best. Currently the role of chronic inflammation in the diffuse type of gastric cancer, as well as the similarities if any to the proposed pathway in Figure 54-3 for the intestinal type of cancer, remain to be clarified.