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Intestinal metaplasia of cardiac mucosa and its immunostaining characteristics
THE AMERICAN JOURNAL OF GASTROENTEROLOGY © 2003 by Am. Coll. of Gastroenterology Published by Elsevier Inc.
Vol. 98, No. 7, 2003 ISSN 0002-9270/03/$30.00
LETTERS TO THE EDITOR Intestinal Metaplasia of Cardiac Mucosa and Its Immunostaining Characteristics TO THE EDITOR: We read with interest two papers on a common subject, namely intestinal metaplasia of cardiac mucosa and its immunostaining characteristics, in two recent issues of the American Journal of Gastroenterology. In the first paper, by DeMeester et al., a panel of monoclonal antibodies including cytokeratins 7 and 20 and DAS-1 was used for immunostaining of endoscopic biopsy samples of 50 patients (among them 12 with Barrett’s esophagus) (1). Biopsy samples were taken from various parts of esophagus and stomach, including the squamocolumnar junction in all patients. The authors found similarities in immunostaining between intestinal metaplasia of the cardia and Barrett’s for CK7/CK20 and DAS-1. Concerning the DAS-1 staining, it was positive in 6% of cardiac mucosa without and in about 90% with intestinal metaplasia (deduction from Fig. 6 of their article). They conclude that immunostaining similarities “point to the possibility of a reflux etiology for intestinal metaplasia of the cardia in some patients.” In the second paper by Rogge-Wolf et al., biopsy samples from a large group of 559 patients were taken (long segment Barrett’s excluded), including squamocolumnar junction and the cardiac region (defined as the area of 2 cm distal to esophagogastric region) in all patients (2). In 464 patients the columnar segment was ⬍1 cm long (deduction from their Table 2). The authors found DAS-1 positivity in the squamocolumnar junction in 41% of patients without and in 88% of patients with intestinal metaplasia of the cardia, and similar histological characteristics in both groups. Supported by this high prevalence of DAS-1 positivity in patients without metaplastic cardiac mucosa, they conclude that DAS-1 positivity “may depict one of the developmental stages in the process of intestinalization,” although they “don’t believe that all DAS-1 reacting cells will progress toward intestinal metaplasia.” There are two groups of questions arising from these two interesting articles: questions on methodology and questions on pathogenesis. As far as methodology is concerned, the importance of the method of obtaining endoscopic biopsy samples can never be overemphasized. When dealing with the cardiac lining, an anatomical region of only few millimeters in length, it is crucial to be as precise as possible. For this reason, biopsy samples always have to be taken directly across the mucosa junction, i.e., the Z line, using a large capacity biopsy forceps, and this has to be reported in histology (3). The discrepancy between the findings of the two studies related to DAS-1 positivity in nonmetaplastic cardia mucosa is a reason for further considerations. In the
first study, DAS-1 positivity in this group was found in one of 17 patients (6%), a sharp contrast to 41% in the second study. The identical monoclonal antibodies that were used in both studies (provided by the University of Medicine and Dentistry, New Jersey, as stated) and the comparable findings of DAS-1 positivity in metaplastic cardia mucosa (90% vs 88%) in both studies make this difference very difficult to clarify. Are there any methodological differences between the two studies that could explain both findings? In the first study, DAS-1 positivity was estimated according to percent staining, whereas in the second study by a “clear crisp brown staining.” We are not convinced that this difference in estimation could account for the diverging results. Second, these papers pose again some interesting questions concerning the pathogenesis of intestinal metaplasia of the cardia. What is the relationship between intestinal metaplasia of the cardia and reflux or Helicobacter pylori infection? This is still a matter for debate (4, 5), and the hard data of the second study, using a novel marker in a large number of cases, do not seem to put an end to it. If there is a risk of adenocarcinoma on intestinal metaplasia of the cardia, is this risk higher in the subgroup with cardia metaplasia due to reflux (an estimation set out in the first paper)? The practical implications of these considerations are obvious. It is expected that future studies will shed more light on these issues. Ioannis A. Mouzas, M.D. Department of Gastroenterology Medical School University of Crete Heraklion, Greece Ivan Jovanovic, M.D. Institute of Digestive Disease University Clinical Center of Serbia Belgrade, Yugoslavia
REFERENCES 1. DeMeester SR, Wickramasinghe KS, Lord RV, et al. Cytokeratin and DAS-1 immunostaining reveal similarities among cardiac mucosa, CIM, and Barrett’s esophagus. Am J Gastroenterol 2002;97:2514 –23. 2. Rogge-Wolf C, Seldenrijk CA, Das KM, et al. Prevalence of mabDAS-1 positivity in biopsy specimens from the esophagogastric junction. Am J Gastroenterol 2002;97:2979 –85. 3. Mouzas IA, Jovanovic I, Milosavljevic T, et al. Cytokeratin immunoreactivity of intestinal metaplasia. Gut 2002;51:894 –5. 4. Oberg S, Johansson J, Wenner J, et al. Metaplastic columnar mucosa in the cervical esophagus after esophagectomy. Ann Surg 2002;235:338 –45. 5. Goldblum JR, Richter JE, Vaezi M, et al. Helicobacter pylori infection, not gastroesophageal reflux, is the major cause of
1654
Letters to the Editor
inflammation and intestinal metaplasia of gastric cardiac mucosa. Am J Gastroenterol 2002;97:302–11. Reprint requests and correspondence: Ioannis A. Mouzas, M.D., Assistant Professor of Gastroenterology, Crete University, Heraklion, Medical School, P.O. Box 1393, 71110 Heraklion, Greece. Received Jan. 15, 2003; accepted Mar. 13, 2003.
Response to Drs. Mouzas and Jovanovic TO THE EDITOR: Dr. Mouzas correctly points out that precision regarding the method and location of biopsy samples taken at the gastroesophageal junction is crucial both for comparing studies and for gaining insight into the pathophysiology of this region. Furthermore, a complete and careful description of the histology at each biopsy site is critical. Normally cardiac mucosa, if present at all, will exist as only a few millimeters immediately distal to squamous mucosa at the aligned gastroesophageal and squamocolumnar junction. Biopsy samples obtained from ⱖ1 cm distal to the gastroesophageal junction in this circumstance will be samples of gastric fundic mucosa. The term “anatomic cardia” really has no specific meaning or defined boundaries, and attention must be focused instead on the histology of the tissue. Studies that compare fundic or oxynto-cardiac mucosa (cardiac mucosa containing some parietal and chief cells) with others limited to pure cardiac mucosa are likely to reach different conclusions. Interestingly, Dr. RoggeWolf et al. noted that biopsy samples taken 2 cm distal to the gastroesophageal junction showed goblet cells in eight patients, and in three of the eight (37.5%) DAS-1 antibody staining was positive (1). Although the precise histology is not described, at this location almost certainly the biopsy samples were from gastric fundic mucosa, and the presence of intestinal metaplasia would indicate gastric intestinal metaplasia. If so, their prevalence of positive DAS-1 antibody staining of goblet cells in gastric intestinal metaplasia (37.5%) is nearly identical to what we found (36%) (2). Dr. Mouzas also questions why DAS-1 antibody staining of pure cardiac mucosa was positive in only one patient (6%) in our study, but was positive in 41% of patients without intestinal metaplasia at the gastroesophageal junction in the study by Rogge-Wolf et al. (1). One potential explanation is either that some patients with positive DAS-1 staining in cardiac mucosa had a minute focus of intestinal metaplasia that was missed, or that deeper sections from the block would have shown intestinal metaplasia. Alternatively, and more likely, the prevalence of positive DAS-1 staining in cardiac mucosa is related to the length of the cardiac mucosa. It has been clearly demonstrated that the longer the length of cardiac mucosa the greater the likelihood that intestinal metaplasia is present (3). Perhaps there is a gradient within columnar mucosa such that longer
AJG – Vol. 98, No. 7, 2003
lengths begin to share more features with Barrett’s, including a transition to positive staining with DAS-1 antibody. The concept of a gradient is supported by Table 2 in the study by Rogge-Wolf et al., although they noted that DAS-1 staining was more likely to be positive in shorter lengths of nonintestinalized columnar mucosa, exactly the opposite of what one would predict (1). Furthermore, correlating the endoscopic findings in Table 2 of their report with the histological findings in Table 3 of that report is difficult, since the data in Table 3 suggest that cardiac mucosa was found in 93.1% of the intestinal metaplasia negative, DAS-1 positive patients (1). Consequently, I suspect that differences in the lengths of cardiac mucosa and the classification of biopsy specimens accounts for the discrepancy between studies, but this certainly represents a fruitful area for further investigation.
Figure 1. A small nodule of adenocarcinoma is present immediately at the gastroesophageal junction in this patient with CIM. Biopsies taken adjacent to the tumor showed cardiac mucosa with intestinal metaplasia and normal oxyntic gastic mucosa immediately distally. Antral and body biopsy samples showed no intestinal metaplasia and no H. pylori, suggesting a reflux etiology for the CIM and adenocarcinoma in this patient. The tumor was found during an endoscopy to evaluate epigastric discomfort. (A) Antegrade view. (B) Retroflex view.
Vol. 98, No. 7, 2003 ISSN 0002-9270/03/$30.00
LETTERS TO THE EDITOR Intestinal Metaplasia of Cardiac Mucosa and Its Immunostaining Characteristics TO THE EDITOR: We read with interest two papers on a common subject, namely intestinal metaplasia of cardiac mucosa and its immunostaining characteristics, in two recent issues of the American Journal of Gastroenterology. In the first paper, by DeMeester et al., a panel of monoclonal antibodies including cytokeratins 7 and 20 and DAS-1 was used for immunostaining of endoscopic biopsy samples of 50 patients (among them 12 with Barrett’s esophagus) (1). Biopsy samples were taken from various parts of esophagus and stomach, including the squamocolumnar junction in all patients. The authors found similarities in immunostaining between intestinal metaplasia of the cardia and Barrett’s for CK7/CK20 and DAS-1. Concerning the DAS-1 staining, it was positive in 6% of cardiac mucosa without and in about 90% with intestinal metaplasia (deduction from Fig. 6 of their article). They conclude that immunostaining similarities “point to the possibility of a reflux etiology for intestinal metaplasia of the cardia in some patients.” In the second paper by Rogge-Wolf et al., biopsy samples from a large group of 559 patients were taken (long segment Barrett’s excluded), including squamocolumnar junction and the cardiac region (defined as the area of 2 cm distal to esophagogastric region) in all patients (2). In 464 patients the columnar segment was ⬍1 cm long (deduction from their Table 2). The authors found DAS-1 positivity in the squamocolumnar junction in 41% of patients without and in 88% of patients with intestinal metaplasia of the cardia, and similar histological characteristics in both groups. Supported by this high prevalence of DAS-1 positivity in patients without metaplastic cardiac mucosa, they conclude that DAS-1 positivity “may depict one of the developmental stages in the process of intestinalization,” although they “don’t believe that all DAS-1 reacting cells will progress toward intestinal metaplasia.” There are two groups of questions arising from these two interesting articles: questions on methodology and questions on pathogenesis. As far as methodology is concerned, the importance of the method of obtaining endoscopic biopsy samples can never be overemphasized. When dealing with the cardiac lining, an anatomical region of only few millimeters in length, it is crucial to be as precise as possible. For this reason, biopsy samples always have to be taken directly across the mucosa junction, i.e., the Z line, using a large capacity biopsy forceps, and this has to be reported in histology (3). The discrepancy between the findings of the two studies related to DAS-1 positivity in nonmetaplastic cardia mucosa is a reason for further considerations. In the
first study, DAS-1 positivity in this group was found in one of 17 patients (6%), a sharp contrast to 41% in the second study. The identical monoclonal antibodies that were used in both studies (provided by the University of Medicine and Dentistry, New Jersey, as stated) and the comparable findings of DAS-1 positivity in metaplastic cardia mucosa (90% vs 88%) in both studies make this difference very difficult to clarify. Are there any methodological differences between the two studies that could explain both findings? In the first study, DAS-1 positivity was estimated according to percent staining, whereas in the second study by a “clear crisp brown staining.” We are not convinced that this difference in estimation could account for the diverging results. Second, these papers pose again some interesting questions concerning the pathogenesis of intestinal metaplasia of the cardia. What is the relationship between intestinal metaplasia of the cardia and reflux or Helicobacter pylori infection? This is still a matter for debate (4, 5), and the hard data of the second study, using a novel marker in a large number of cases, do not seem to put an end to it. If there is a risk of adenocarcinoma on intestinal metaplasia of the cardia, is this risk higher in the subgroup with cardia metaplasia due to reflux (an estimation set out in the first paper)? The practical implications of these considerations are obvious. It is expected that future studies will shed more light on these issues. Ioannis A. Mouzas, M.D. Department of Gastroenterology Medical School University of Crete Heraklion, Greece Ivan Jovanovic, M.D. Institute of Digestive Disease University Clinical Center of Serbia Belgrade, Yugoslavia
REFERENCES 1. DeMeester SR, Wickramasinghe KS, Lord RV, et al. Cytokeratin and DAS-1 immunostaining reveal similarities among cardiac mucosa, CIM, and Barrett’s esophagus. Am J Gastroenterol 2002;97:2514 –23. 2. Rogge-Wolf C, Seldenrijk CA, Das KM, et al. Prevalence of mabDAS-1 positivity in biopsy specimens from the esophagogastric junction. Am J Gastroenterol 2002;97:2979 –85. 3. Mouzas IA, Jovanovic I, Milosavljevic T, et al. Cytokeratin immunoreactivity of intestinal metaplasia. Gut 2002;51:894 –5. 4. Oberg S, Johansson J, Wenner J, et al. Metaplastic columnar mucosa in the cervical esophagus after esophagectomy. Ann Surg 2002;235:338 –45. 5. Goldblum JR, Richter JE, Vaezi M, et al. Helicobacter pylori infection, not gastroesophageal reflux, is the major cause of
1654
Letters to the Editor
inflammation and intestinal metaplasia of gastric cardiac mucosa. Am J Gastroenterol 2002;97:302–11. Reprint requests and correspondence: Ioannis A. Mouzas, M.D., Assistant Professor of Gastroenterology, Crete University, Heraklion, Medical School, P.O. Box 1393, 71110 Heraklion, Greece. Received Jan. 15, 2003; accepted Mar. 13, 2003.
Response to Drs. Mouzas and Jovanovic TO THE EDITOR: Dr. Mouzas correctly points out that precision regarding the method and location of biopsy samples taken at the gastroesophageal junction is crucial both for comparing studies and for gaining insight into the pathophysiology of this region. Furthermore, a complete and careful description of the histology at each biopsy site is critical. Normally cardiac mucosa, if present at all, will exist as only a few millimeters immediately distal to squamous mucosa at the aligned gastroesophageal and squamocolumnar junction. Biopsy samples obtained from ⱖ1 cm distal to the gastroesophageal junction in this circumstance will be samples of gastric fundic mucosa. The term “anatomic cardia” really has no specific meaning or defined boundaries, and attention must be focused instead on the histology of the tissue. Studies that compare fundic or oxynto-cardiac mucosa (cardiac mucosa containing some parietal and chief cells) with others limited to pure cardiac mucosa are likely to reach different conclusions. Interestingly, Dr. RoggeWolf et al. noted that biopsy samples taken 2 cm distal to the gastroesophageal junction showed goblet cells in eight patients, and in three of the eight (37.5%) DAS-1 antibody staining was positive (1). Although the precise histology is not described, at this location almost certainly the biopsy samples were from gastric fundic mucosa, and the presence of intestinal metaplasia would indicate gastric intestinal metaplasia. If so, their prevalence of positive DAS-1 antibody staining of goblet cells in gastric intestinal metaplasia (37.5%) is nearly identical to what we found (36%) (2). Dr. Mouzas also questions why DAS-1 antibody staining of pure cardiac mucosa was positive in only one patient (6%) in our study, but was positive in 41% of patients without intestinal metaplasia at the gastroesophageal junction in the study by Rogge-Wolf et al. (1). One potential explanation is either that some patients with positive DAS-1 staining in cardiac mucosa had a minute focus of intestinal metaplasia that was missed, or that deeper sections from the block would have shown intestinal metaplasia. Alternatively, and more likely, the prevalence of positive DAS-1 staining in cardiac mucosa is related to the length of the cardiac mucosa. It has been clearly demonstrated that the longer the length of cardiac mucosa the greater the likelihood that intestinal metaplasia is present (3). Perhaps there is a gradient within columnar mucosa such that longer
AJG – Vol. 98, No. 7, 2003
lengths begin to share more features with Barrett’s, including a transition to positive staining with DAS-1 antibody. The concept of a gradient is supported by Table 2 in the study by Rogge-Wolf et al., although they noted that DAS-1 staining was more likely to be positive in shorter lengths of nonintestinalized columnar mucosa, exactly the opposite of what one would predict (1). Furthermore, correlating the endoscopic findings in Table 2 of their report with the histological findings in Table 3 of that report is difficult, since the data in Table 3 suggest that cardiac mucosa was found in 93.1% of the intestinal metaplasia negative, DAS-1 positive patients (1). Consequently, I suspect that differences in the lengths of cardiac mucosa and the classification of biopsy specimens accounts for the discrepancy between studies, but this certainly represents a fruitful area for further investigation.
Figure 1. A small nodule of adenocarcinoma is present immediately at the gastroesophageal junction in this patient with CIM. Biopsies taken adjacent to the tumor showed cardiac mucosa with intestinal metaplasia and normal oxyntic gastic mucosa immediately distally. Antral and body biopsy samples showed no intestinal metaplasia and no H. pylori, suggesting a reflux etiology for the CIM and adenocarcinoma in this patient. The tumor was found during an endoscopy to evaluate epigastric discomfort. (A) Antegrade view. (B) Retroflex view.