Pathological Considerations

The normal esophagus is lined by squamous epithelium, but it is readily damaged by the chronic injury of duodeno-gastroesophageal reflux disease. Repair is affected in this abnormal environment by columnar intestinal and gastric cells, an example of phenotypic plasticity. The mucosa has adapted to hostile environmental conditions by a metaplastic response. Three distinct

types of columnar metaplasia are recognized. The commonest and clinically most important is intestinal metaplasia, and it is most likely to undergo malignant transformation to adenocarcinoma. The malignant potential of cardiac and fundic metaplasia is uncertain (24). The malignant degeneration within a segment of Barrett's esophagus occurs in a probabilistic rather than in an inevitably deterministic manner. Yet Barrett's does appear to be a necessary intermediary step, allowing interventional opportunities to stabilize the epithelium or destroy it. There is often a relatively long time sequence prior to the development of cancer. This may allow early intervention with endoscopic ablation, chemo, or surgical prophylaxis.

Pathological diagnosis is dependent on the endoscopist clearly identifying the site of biopsy in the gastric cardia, a hiatus hernia, or in the esophagus. The endoscopic problem is that the anatomy and position of the gastroesophageal junction is difficult to define. There is a lack of a universally accepted and reproducible set of criteria to endoscopically identify the cardia of the stomach from the distal esophagus. During endoscopy, it is important to identify certain important landmarks in order to allow some delineation of abnormal columnar-lined esophagus. The squamo-columnar junction is usually visible as the pale squamous epithelium merges into redder columnar mucosa. The gastroesophageal junction is imaginary, but, at present, is defined endoscopically as the level of the most proximal gastric fold. Some patients with an hiatus hernia have defective and weak lower-esophageal sphincters, and, therefore, there is no clear-cut flare as one enters the stomach with the endoscope. The proximal margin of the gastric folds must be determined when the distal esophagus is minimally inflated. Overinflation will flatten and obscure all the gastric folds. If the squamo-columnar and gastro-esophageal junction coincides, the entire esophagus is lined with squamous mucosa. When the squamo-columnar junction is proximal to the gastroesophageal junction, there is a columnar-lined segment or Barrett's esophagus. Pathology can give a clear indication of esophageal origin when an esoph-ageal gland or, more usually (in a biopsy sample), a duct from these glands is seen. The depth of biopsy required makes these findings unusual. The requirement of the presence of intestinal metaplasia in a biopsy to diagnose Barrett's esophagus is difficult, as it can be found in the macroscopically normal squamocolumnar junction in up to 18% of patients undergoing endoscopy. The debate has deepened as the cytokeratin immunoreactivity (CK7/CK20 pattern) may be able to differentiate the intestinal metaplasia associated with Barrett's esophagus from that associated with Helicobacter pylori gastritis (24,25).

Dysplasia, "the unequivocal neoplastic alteration of the gastrointestinal epithelium which has the potential to progress to invasive malignancy that remains confined within the basement membrane of the gland within which it arose" (28) remains the best predictor for the development of invasive malignancy. The classification of neoplastic change in the gastrointestinal mucosa has five categories: negative for dysplasia, indefinite for dysplasia, low-grade dysplasia, high-grade dysplasia, and invasive carcinoma (26-29). Inter- and intraobserver studies have demonstrated that pathologists can demonstrate acceptable levels of agreement for the two major comparative groups of high-grade dysplasia combined with carcinoma, against negative for dysplasia combined with indefinite and low-grade dysplasia (kappa values of 0.8). However, the division into the four groups of negative for dysplasia, combined indefinite for dysplasia and low-grade dys-plasia, high-grade dysplasia, and carcinoma has revealed that there are poorer levels of agreement (intraobserver kappa values of 0.64 and interobserver kappa values of 0.43) (30). The vital separation of high-grade dysplasia from intramucosal cancer depends on the penetration of neo-plastic cells through the basement membrane. This classification is also difficult with interobserver agreement between all pathologists and specific gastrointestinal pathologists for high-grade dysplasia and intramucosal carcinoma having a kappa value of 0.42 and 0.56, respectively, even from resection specimens. These data have serious consequences for patients undergoing endo-scopic surveillance, when the number of biopsies are often collected in a hurried fashion, small, and difficult to orientate correctly (31,32).

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