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Other risk factors associated with increased incidence of gastric cancers include cigarette smoking, alcohol abuse, and nitrosoamine intake. Benign adenomas, which are the gastric counterpart of colorectal adenomas, are also associated with a risk of progression to cancers. The vast majority (90-95%) of gastric cancers are gland-forming adenocarcinomas. Other less common tumors of the stomach include lymphomas, carcinoids and gastric stromal tumors. Epidemiologic studies have shown that the two major histologic subtypes of gastric adenocarcinomas - the intestinal (well differentiated) type and diffuse (poorly differentiated) type - arise by distinct pathways. The intestinal type is strongly associated with Helicobacter pylori, and usually arises on a backdrop of chronic gastritis, gastric atrophy, and intestinal metaplasia. In contrast, poorly differentiated adenocarcinomas are usually not associated with these changes. Clinically, the latter often present with diffuse thickening of the stomach wall, rather than a discernible mass (linitis plastica). The intestinal adenocarcinomas have a better prognosis than the diffuse variant, most of which have spread beyond the confines of the stomach at the time of diagnosis. As with other cancers, stage is the most important determinant of outcome. In Japan, intensive screening modalities have led to the emergence of a new variant called early gastric cancers, in which the primary tumor is restricted to the mucosa or submucosa, irrespective of metastasis, at the time of detection.
Several molecular abnormalities have been identified in gastric adenocarcinomas that have a bearing on pathogenesis as well as prognosis of these tumors. Amongst the group of tumor suppressor genes, mutations of p53 are detected in up to 60% of gastric carcinomas, irrespective of histologic type. Notably, a third of gastric adenomas also bear p53 mutations, and this has been shown to have a strong predictive value for malignant transformation in long term follow up. p53 mutations and/or immunohistochemical p53 overexpression are also found in foci of intestinal metaplasia, reiterating their role as precursor lesions. In addition to p53, inactivation of the adenomatous polyposis coli (APC) and deleted in colon carcinoma (DCC) genes are found in approximately 50% of well-differentiated adenocarcinomas, but infrequently in the diffuse variant. As with p53, both APC and DCC mutations have also been detected in gastric adenomas and foci of intestinal metaplasia. Abnormalities of several cell cycle proteins are common in gastric adenocarcinomas, and have been found to correlate with prognosis. For example, loss of expression of the G1-S cyclin dependent kinase inhibitor p21WAF1 protein is found in over half of gastric adenocarcinomas, irrespective of histologic type. This abnormal pattern is seen even at the stage of early gastric cancers and adenomas, suggesting abrogation of p21WAF1 function is an early event. Loss of expression of another cyclin dependent kinase inhibitor p27KIP1 is seen in the majority of advanced gastric cancers, especially those associated with deep invasion and lymph node metastasis, but its expression is preserved in most adenomas and early gastric cancers. Thus, unlike p21WAF1 , p27KIP1 appears to be abrogated late in the carcinogenesis pathway, possibly contributing to tumor progression instead. The importance of immunohistochemistry in detecting cell cycle protein abnormalities is underscored in these studies because mutations of the respective genes have not been detected in gastric cancers. On the same lines, p16INK4a abnormalities are detected in approximately 20% of gastric cancers, and these cases are usually associated with deep muscle invasion and lymph node metastases. As with other cell cycle regulators, p16INK4a is mostly inactivated by epigenetic mechanisms (such as promoter hypermethylation) rather than gene mutations, which makes immunohistochemistry a desirable technique for detecting these abnormalities. Finally, overexpression of either the epidermal growth factor (EGF) or epidermal growth factor receptor (EGFR) is frequently seen in gastric adenocarcinomas, and correlates well with stage of invasion and prognosis in these patients. |
