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Etiology and Biological Characteristics

Etiology
 

Factors that have been associated with a higher incidence of gastric cancer include smoked or salted foods, foods contaminated with aflatoxin, low intake of fruits and vegetables, low socioeconomic status, and possibly a decreased use of refrigeration.3,4 Possible occupational relationships include coal mining and rubber or asbestos workers. Precursor pathological conditions include pernicious anemia, achlorhydria atrophic gastritis, gastric ulcers, and adenomatous polyps. Between 5% and 10% of individuals with pernicious anemia subsequently develop malignancy. Prior partial gastrectomy for benign gastric or duodenal ulcer disease produces an increased risk of subsequent malignancy in the gastric remnant with latency periods of 20 years or more.5,6

Several studies have shown a threefold to sixfold increased risk of gastric cancer in individuals with Helicobacter pylori infection versus those with no infection, but the precise role of this bacterium in the etiology of gastric cancer remains unknown.7-9 A variety of bacterial, patient, and environment factors most likely act in combination to affect the development of gastric carcinoma. The increased association of H. pylori with gastric cancer seems to be mainly with distal gastric cancers and intestinal-type malignancy. Only a minority of H. pylori–infected individuals develop gastric cancer, and data do not yet exist on the effect of treatment of the H. pylori infection on subsequent malignancy.

There has been a dramatic increase in the incidence of gastroesophageal and gastric cardia carcinoma during the past few decades, similar to the increase in distal esophagus adenocarcinomas, suggesting that they may have similar etiologies. Although the reasons for these changes are unknown, they may be related to the increased incidence of esophageal reflux and Barrett esophagus.

Biological Characteristics

Prognostic Factors
 

The most meaningful prognostic indicators relate to extent of tumor. With either hematogenous metastasis or peritoneal seeding, prognosis is almost always fatal. Recent immunohistochemical analysis of bone marrow aspirates has shown the presence of tumor cells to be an independent predictor of adverse outcome; however, confirmatory studies have yet to be published.10,11 Survival decreases with progressive direct tumor extension both within and beyond the gastric wall.12,13 Lymph node involvement, per se, is not as important as the number and location of nodes.14-16 Minimal lymph node involvement adjacent to the primary lesion results in the most favorable prognosis in node-positive patients, but even micrometastases in regional nodes may adversely impact survival.17 The solitary finding of either involved nodes or complete penetration of the gastric wall is usually not as ominous as the presence of both12,15 (E-Table 75-1).

The tumor grade and the gross and histologic pathological appearance of the primary malignancy seem to provide some prognostic information, but none of these factors is a prognostic variable independent of the tumor stage. Prognosis is generally worse with higher grade and diffuse-type carcinomas, which usually present with higher pathological stages of disease (see Fig. 75-1). Borrmann types I and II carcinomas have a relatively favorable 5-year survival rate, but patients with type IV tumors (linitis plastica) fare very poorly.18,19

Some investigators have suggested that tumors of the gastric cardia may have epidemiological factors different from cancers of the distal stomach20,21 and may exhibit different tumor biology.22 The prognosis is worse for cardia lesions,23,24 and flow cytometry reveals a greater incidence of aneuploidy when compared with tumors of the antrum and body.25 

Flow cytometry provides valuable prognostic information for gastric cancer and may be an independent prognostic factor.25,26 As noted previously, aneuploidy is associated with unfavorable tumor location such as the cardia25,27 but is also associated with lymph node metastasis26,27 and direct tumor extension.26 Unfavorable DNA flow cytometry characteristics seem to relate closely to an unfavorable prognosis.25,26 In one series in which multivariate analysis of DNA ploidy was analyzed with other known prognostic factors such as stage, age, and sex, DNA ploidy carried statistically significant independent prognostic information.26 The presence of several peptides including estrogen receptor,28 epidermal growth factor receptor,29 the c-erbb2 protein,30 and plasminogen activator inhibitor type 119 seems to affect prognosis adversely. The expression of epidermal growth factor receptor and high levels of epidermal growth factor correlate with a higher incidence of primary tumor infiltration, poor histologic differentiation, and linitis plastica. The pathophysiological relationship between these peptide receptors and poor patient prognosis is not clear. Gastric cancers with class II major histocompatibility complex antigen expression (human leukocyte antigen [HLA]-DR) have a better prognosis, but the loss of expression is not an independent prognostic factor.31 

Molecular Biology


The molecular biology of gastric cancer reflects the heterogeneity of its causes and its histologic subtypes. Identification of the genetic and phenotypic variables may lead to more directed treatment approaches and more accurate prediction of clinical outcomes. Changes that may affect the behavior of gastric tumor cells involve four major types of alterations.

Loss of tumor suppressor gene function, especially inactivation of the p53 gene, plays a key role in tumor suppression and cell-cycle regulation.32 The p53 gene puts a brake on DNA replication and triggers programmed cell death in response to DNA damage.33 Loss of p53 function is associated with the development of gastric cancer, impacts the effectiveness of chemotherapy and irradiation,34,35 and predisposes cells to genetic instability.

A second aberration affecting gastric epithelial cells is alterations in mismatch repair genes, including HMSH3 and HMLH1, which account for replication errors throughout the genome. Mutations in these genes generate genetic instability and are associated with an increased tendency for the development of colorectal and gastric tumors.36,37

Two protooncogenes, c-met and K-sam, are associated with scirrhous carcinoma of the stomach. Overexpression of c-met correlates with tumor progression and metastasis, and K-sam encodes a tyrosine kinase receptor family.38K-sam has a tendency to be activated in women with gastric cancer younger than 40 years of age and c-met to be amplified in men older than 50 years of age.39,40

Modern molecular biology observations confirm the heterogeneity of human gastric cancer.41 Gastric cancers with class II major histocompatibility complex antigen expression (HLA-DR) have a better prognosis, but the loss of expression is not an independent prognostic factor.42