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OVERVIEW, EPIDEMIOLOGY, AND SUBTYPES

Gastric cancer is currently the fifth most common cause of cancer and the third-leading cause of cancer death worldwide, accounting for 1.3 million incident cases and 819,000 deaths annually.1 The incidence of gastric cancer varies geographically, with incidence highest in East Asia and South America and lowest in Western countries. While the incidence of gastric cancer is declining overall (possibly due to treatment of H. pylori infection), incidence of cancers arising from the gastric cardia continues to increase in developed countries (including the United States) for unknown reasons.2 There are gender differences in gastric cancer, with incidence 2- to 3-fold higher in men compared to women.2

Gastric cancers can be divided according to histopathologic subtype. The majority (90%) are adenocarcinomas, with the remaining 10% comprised of lymphomas, leiomyosarcomas, gastrointestinal stromal tumors (GISTs), and other tumor subtypes. Gastric lymphomas are most often B-cell lymphomas, with T-cell lymphoma being rare in the stomach.2,3 MALT-lymphoma is a type of gastric lymphoma most often associated with H. pylori infection. This review will focus on gastric adenocarcinomas.

Gastric adenocarcinomas have historically been subdivided based on location (cardia versus non-cardia) and histology (Lauren’s classification, intestinal 60% versus diffuse 30%). Intestinal adenocarcinomas of the stomach are the most common, often presenting as gastric masses or ulcers, with histopathology demonstrating cohesive cells forming gland-like tubular structures. The main pathway for development of intestinal gastric cancer, referred to as Correa’s cascade, begins with H. pylori infection leading to chronic gastritis, followed by atrophic gastritis, intestinal metaplasia, dysplasia, and finally carcinoma.4 Diffuse gastric cancers (DGC) differ from intestinal gastric cancers in that DGCs often present with linitis plastica and/or peritoneal carcinomatosis as neoplastic epithelial cells with signet ring morphology infiltrating the stomach wall, often without an obvious ulcer or mass lesion. Downregulation or mutation of E-cadherin (CDH1), a tumor suppressor trans-membrane glycoprotein involved in cell to cell adhesion, is instrumental to the development of diffuse gastric cancer.2,3,5

Interestingly, new data suggest a possible correlation between the molecular characteristics of gastric adenocarcinomas with both epidemiology and disease prognosis. A collaborative effort led by the U.S. National Institutes of Health (NIH) and Cancer Genome Atlas (TCGA) employed genomic profiling (genome/exome/methylome DNA sequencing) to identify four molecular subtypes of gastric adenocarcinoma:6 the Epstein-Barr virus subtype (EBV), microsatellite instability subtype (MIS), genomically stable subtype (GS), and chromosomal instability subtype (CIN). Investigations into the clinical features suggest that both the EBV associated subtype and GS subtypes tend to occur more often in younger patients. The CIN subtype has a predilection for the proximal stomach, while the MIS subtype is more commonly in the distal stomach. The EBV associated subtype appears to have the best prognosis, while the GS subtype appears to have the worst. Furthermore, the GS subtype appears to have limited response to adjuvant chemotherapy while the CIN subtype has the best response.7 As ...

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