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We read with great interest the well designed study of Couvelard et al (Gut 2001;49:761–6). In agreement with other studies,1–3 the authors reported that cytokeratin (CK) 7 and 20 immunoreactivity in the specialised intestinal metaplasia found in Barrett’s oesophagus differs from the intestinal metaplasia found in the stomach. The specific pattern of CK7/CK20 expression, so-called Barrett’s type, is characterised by strong CK7 staining of both superficial and deep glands together with a strong superficial CK20 stain. The authors report that both clinical and endoscopic findings support this differentiation.
The origin and development of intestinal metaplasia at the gastro-oesophageal junction have been a matter for debate. There are findings suggesting that intestinal metaplasia of the cardia has an immunophenotype similar to Barrett’s oesophagus3 while others suggest that it is similar to the rest of the gastric mucosa.1 We evaluated the CK7/CK20 pattern of gastric cardia with intestinal metaplasia and compared it with Barrett’s oesophagus, corpus, and antrum metaplasia in 68 endoscopic biopsies and selected surgical specimens.4 Immunostaining was performed using the same monoclonal antibodies for CK7 and CK20 as in the study of Couvelard et al for all specimens of Barrett’s (n=17), cardia metaplasia (n=15), corpus metaplasia (n=14), and antrum metaplasia (n=22).
We found three patterns of CK7/CK20 immunostaining and identified them as IM-1, IM-2, and IM-3. IM-1 is characterised by strong diffuse CK7 staining in both superficial and deep glands and strong superficial CK20 immunostaining, corresponding to the so-called Barrett CK7/CK20 pattern. IM-2 is characterised by either negative or weak patchy CK7 staining of the surface and crypt epithelium and a strong diffuse surface epithelium and patchy crypt CK20 staining (corresponding to the so-called gastric CK7/CK20 pattern). IM-3 pattern is characterised by strong and patchy CK7 staining of the surface and crypt epithelium and strong diffuse surface and patchy crypt CK20 immunostaining. Sixteen of the 17 cases with long segment Barrett’s oesophagus (94%) and one of the 15 cases with cardia metaplasia expressed the IM-1 CK7/CK20 pattern. The IM-1 or Barrett’s CK7/CK20 pattern had a high specificity as none of the 36 cases representing intestinal metaplasia of the corpus and antrum had this immunostaining pattern. The IM-2 pattern was present in most of the specimens with intestinal metaplasia in the stomach (34 of 36) (table 1).
We hypothesise that the differences in the immunophenotypes observed in intestinal metaplasia of the cardia are mainly associated with different practices in collecting biopsy samples. As in the study of Couvelard et al, we paid particular attention so as to have the mucosal biopsies directly across from the Z line by adequately positioning the biopsy forceps. None the less, biopsy samples taken less than 1 cm proximal to the gastric folds could actually represent “short segment Barrett’s oesophagus” in some cases.5,6 As stated by the authors, no absolute histological criteria for diagnosing Barrett’s mucosa have yet been established. Therefore, it would be interesting to know the types of epithelium that were revealed on the gastric side of the Z line (cardiac, fundic, or perhaps specialised columnar epithelium).
There is sufficient evidence to suggest that “Barrett’s CK7/CK20 pattern” is a useful tool in distinguishing between Barrett’s oesophagus and intestinal metaplasia of the cardia. However, more research is needed for a better understanding of the development and meaning of intestinal metaplasia of the cardia.
We thank Mouzas et al for their comments on our study. We read with interest their results that are partly in keeping with our data and that confirm that Barrett’s mucosa has a specific pattern of cytokeratin (CK) expression. Two comments can be made with respect to this work. Firstly, we have noticed that the authors identified three CK7/20 patterns of intestinal metaplasia (IM-1, IM-2, and IM-3). Although IM-1 is identical to that designated as Barrett’s pattern by Ormsby et al, it is important to note that IM-2 and IM-3 do not strictly parallel the two other CK7/20 patterns defined by Ormsby et al as corresponding to the gastric type of intestinal metaplasia.1 Thus the significance of IM-2 and IM-3, as proposed by Mouzas et al, have still to be clarified. In the small areas of intestinal metaplasia that are found in biopsy specimen from the gastro-oesophageal junction, we have made the distinction between the typical “Barrett’s phenotype” (as described by Ormsby et al and corresponding to IM-1 type) and other types that we have considered as “gastric phenotypes”. Secondly, Mouzas et al identified only one case of Barrett’s type intestinal metaplasia among 15 cases of cardiac intestinal metaplasia, suggesting that intestinal metaplasia of the gastro-oesophageal junction is only rarely related to short segments of Barrett’s oesophagus. This finding is not consistent with our results in that we found 16 patients presenting with Barrett’s CK7/20 pattern among 34 patients that were evaluated for immunohistochemistry. However, this discrepancy may be related to the limited collection of biopsy samples and may be influenced by Helicobacter pylori status, age, sex, and ethnic origin of the patients, data that were not reported in the present work of Mouzas et al.
At the end of their letter, Mouzas et al question the type of epithelium that we found on the gastric side of the gastro-oesophageal junction. As the site of biopsy sampling may be critically important, we reviewed all gastro-oesophageal junction biopsy specimens for histological evidence of the squamocolumnar junction. Among the 988 biopsy specimens corresponding to the 254 patients with an endoscopically normal gastro-oesophageal junction included in our study, 382 (39%) containing both squamous and columnar epithelium were considered as directly taken across the Z line. Cardiac mucosa was present in 373 of the 382 biopsy specimens (97.6%), in association with fundic mucosa in 74/373 cases (19.8%). In nine of 382 biopsy specimens (2.4%) there was only fundic mucosa. Moreover, we found the same ratio when patients were divided into two groups, one group corresponding to 60 patients with intestinal metaplasia at the gastro-oesophageal junction (116 biopsy specimens across the Z line, containing cardiac mucosa in 113 (97.4%) in association with fundic mucosa in 18/113 (15.9%) and containing only fundic mucosa in 3 (2.6%)) and the other group corresponding to 194 patients without intestinal metaplasia at the gastro-oesophageal junction (266 biopsy specimens across the Z line, containing cardiac mucosa in 260 (97.7%) in association with fundic mucosa in 56/260 (21.5%) and containing only fundic mucosa in 6 (2.26%)). These data, in line with those obtained in an autopsy series, support the concept that the gastric cardia is present as a constant structure.2 However, it must be remembered that some workers recently proposed the hypothesis that cardiac-type mucosa arises as a metaplastic phenomenon.3
Groupe d’etude de l’Oesophage de Barrett (GEOB)
Members of the GEOB: Pathologists: Anne Croué (Angers), Alain Volant (Brest), Marie-Danielle Diebold (Reims), Christiane Vissuzaine (Paris), Christine Sagan (Nantes); Gastroenterologists: Jean Boyer (Angers), Guillaume Cadiot (Reims), Michel Mignon (Paris), Thomas Aparicio (Paris), Jean-Paul Galmiche (Nantes), Marc Le Rhun (Nantes).