Has a metaplasia-dysplasia-carcinoma sequence been identified for carcinoma of the cardia?
S.R. Hamilton (Baltimore)
The gastric cardia is the flared region of the upper stomach where the tubular esophagus enters. Histopathologically, the columnar-lined gastric mucosa which adjoins the squamous epithelium of the esophagus is usually characterized by transition from oxyntic (fundal) mucosa with parietal and chief cells predominating in the glands into the junctional or cardiac mucosa with mucus cells predominating in the glands. Scattered parietal and chief cells are often seen in the cardiac glands. The foveolar epithelium is predominantly composed of columnar mucus cells. The extent of the cardiac mucosa is variable and therefore the definition of normal extent remains elusive .
Adenocarcinoma of the gastric cardia is increasing in incidence, similar to adenocarcinoma of the lower esophagus [2, 3]. The development of neoplasia in Barrett's esophagus with its distinctive incompletely intestinalized mucosa which has replaced the native squamous epithelium is mainly responsible for the increasing incidence of esophageal adenocarcinoma. Because an intestinal metaplasia-dysplasia-adenocarcinoma sequence is well-established in Barrett's esophagus (BE), it is logical that a similar sequence occurs in the native gastric cardiac mucosa as well. Obtaining definitive evidence of this sequence is complicated by the difficulties inherent in distinguishing neoplasia of the distal esophagus arising in short segments of Barrett's mucosa from gastric cardiac neoplasia [4-7].
Metaplasia of two types has been demonstrated in gastric cardiac mucosa. Intestinal metaplasia characterized by goblet cells which contain acid mucopolysaccharides and therefore stain with Alcian blue at pH 2.5, mucicarmine, and related stains has been reported in a substantial minority (18%) of patients in a prospective endoscopic study with biopsies . More subtle intestinalization is also evident in the frequent finding of intestinal-type mucus by histochemistry in columnar mucus cells of cardiac mucosa but without goblet cells. Secondly, pancreatic acinar cell metaplasia has been reported in gastric cardiac mucosa of 24% of patients in one study . This type of metaplasia is characterized by glands lined by cells with the characteristics of pancreatic acinar cells in that they have eosinophilic granules in the apical cytoplasm and basophilic granules in the basal cytoplasm and express pancreatic enzymes such as lipase and alpha-amylase by immunohistochemistry. These two types of metaplasias are analogous to those in Barrett's mucosa and gastric mucosa of other regions of the stomach [1, 10, 11].
Although metaplasia is relatively common in gastric cardiac mucosa, its pathogenesis is unclear at present. Metaplasia in the oxyntic and antral mucosa is usually associated with chronic gastritis. "Gastric carditis" with chronic gastritis predominantly involving the cardiac mucosa but sparing the oxyntic and antral mucosa and unrelated to Helicobacter pylori gastritis is frequently associated with intestinalization and pancreatic acinar cell metaplasia in specimens from our endoscopic patient population. Many of these patients have gastroesophageal reflux disease (unpublished observations). Investigators, however, have found no association of intestinal metaplasia of the cardiac mucosa with gastroesophageal reflux symptoms and have suggested that pancreatic acinar cell "metaplasia" is congenital and unrelated to intestinal metaplasia [1, 8, 9].
Dysplasia in metaplastic mucosa of the gastric cardia is observed only occasionally [12, 13] and dysplasia sometimes occurs in non-metaplastic mucosa. Opportunities to study early cardiac cancers are limited  and attention to the precursor dysplasia and background mucosa in specimens is needed. Data on the frequency and types of metaplasia in cardiac mucosa, the possible associated conditions such as gastroesophageal reflux and short-segment BE  and the possible predisposition to dysplasia and adenocarcinoma are also needed. Such data from careful clinico-pathologic studies can permit rational approaches to the key issues of prevention of surveillance for carcinoma of the gastric cardia and its precursors [1-15].
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