Gastrointestinal Oncology
Figure 3: Photomicrographs of Sequential Steps in the Gastric Mucosa for the Development of Adenocarcinoma
A B C Precancerous Cascade Observational studies in Colombia in the 1970s37,38 led to the identification
of a sequence of precancerous lesions in the gastric mucosa.39 After H. pylori was recognized as a causative agent for gastritis in 1983,40
it is D E F
known that the precancerous process starts with the colonization of the gastric mucosa. Although H. pylori remains mainly in the gastric lumen, the contact with the epithelium initiates an inflammatory response with increase in production of cytokines and chemokines that attract inflammatory cells to the mucosa. The immune response is not effective in eliminating the infecting agent, and may last decades, unless the bacterium is eradicated. Persistent, long-term inflammation may cause damage to the epithelial cells and, over time, loss of glands. These gastric glands may then be replaced by glands lined by epithelium with intestinal phenotype. If sustained injury to the gastric mucosa persists, dysplastic changes and malignant transformation may develop. Thus, it is believed that gastric adenocarcinomas of the intestinal type9
are preceded by a
A: Normal gastric antral mucosa; B: Non-atrophic gastritis. Abundant inflammatory cells are seen in the lamina propria and the glands are well conserved; C: Multifocal atrophic gastritis, with prominent loss of deep glands; D: Intestinal metaplasia of the complete type, with well-formed goblet cells and brush border; E: Dysplasia, low-grade. Epithelial cells with enlarged, hyperchromatic, and pseudostratified nuclei that maintain the polarity in terms of the basement membrane; F: Adenocarcinoma of the intestinal type (hematoxylin and eosin stain [H&E] x200).
(see Figure 3). It is generally recognized that the process starts during childhood, triggered by the infection with H. pylori, and advances slowly through the years, eventually leading in a few patients, after several decades, to invasive carcinoma.
The outcome of most human infections is determined by the interaction of the infectious agent with two other major sets of factors: the susceptibility of the host and the external environmental forces. The effects of these factors have been explored in the two populations of contrasting cancer risk in Colombia.
The Geographic Enigmas The overall estimate of H. pylori prevalence in adults is 76% in developing countries and 58% in developed countries.33
In terms of the mechanisms of gastric carcinogenesis, recent studies identifying mitochondrial DNA mutations in human gastric mucosa have demonstrated the presence of multiple stem cells in a gastric unit (defined by the gastric glands associated with a single neck and foveolus) and the process of monoclonal conversion and clonal derivation from a single stem cell.42
However, the
association between gastric cancer and H. pylori infection is challenged by the contrasting geographic distribution of the two nosologic entities in some areas. In Africa, the prevalence of H. pylori infection is very high, but the gastric cancer rates are very low.34
and similar enigmas have given rise to epidemiologic investigations into the causes of the phenomenon.35
Epidemiologic investigations in Colombia describe marked variation in gastric cancer risk among different regions. Very high gastric cancer rates, estimated to be 150 per 100,000 in 197636
precancerous process with the following well-recognized steps: chronic active inflammation → multifocal atrophy (gland loss) → intestinal metaplasia, complete type → intestinal metaplasia, incomplete type → dysplasia39,41
factors, including pathogenicity of the infecting H. pylori strains, genetic background of the populations, nutritional factors, and the type of inflammatory response against H. pylori infection.
In these studies, McDonald et al. demonstrated that human gastric units are able to divide by fission into clonal patches, leading to fields of mutated gastric units.42
It is highly probable that a bud This ‘African enigma’
forms from the stem cell zone in the neck of the gland, giving origin to a new gastric unit. These studies have also shown that crypts with intestinal metaplasia within the human stomach are clonal (incorporating all the major differentiated intestinal lineages), contain multiple multipotential stem cells, and can spread by crypt fission. Such expansion has important implications for gastric carcinogenesis.
and high prevalence of
but also very high prevalence of the infection. Residents of the Pacific coast are predominantly from African ancestry. This phenomenon in Colombia is similar to the fact described by the African enigma. The striking differences in gastric cancer rates in these two Colombian populations may be associated with differences in multiple
62
H. pylori infection is found in inhabitants of the high-altitude Andes Mountains. They are predominantly ‘mestizos’, a mixture of Amerindian and European migrants. By contrast, residents of the Pacific coast, only about 100 miles apart, have very low cancer rates (estimated at six per 100,000),36
Intervention Trials and Use of Non-steroidal Anti-inflammatory Drugs for Prevention of Gastric Cancer and Precancerous Lesions Several reports have confirmed the benefit of H. pylori eradication as a measure to decrease gastric cancer risk.43–45
chemoprevention trial of gastric dysplasia in Colombia46,47
Our experience with a led us to
emphasize the underestimated role of time free of exposure to H. pylori, the putative carcinogenic agent, on the outcome of the intervention. Using a detailed histopathology score that recognizes the type and extension of precancerous lesions of the gastric mucosa, our results at 12 years of follow-up showed that curing the H. pylori infection heals the mucosal damage, expressed as an exponential sigmoid curve, representing the anti-carcinogenic dynamics, the mirror
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