Barrett's Esophagus: Development of Dysplasia and Adenocarcinoma

Transcription

1 GASTROENTEROLOGY 1989;96: Barrett's Esophagus: Development of Dysplasia and Adenocarcinoma W. HAMEETEMAN, G. N. J. TYTGAT, H. J. HOUTHOFF, and J. G. VAN DEN TWEEL Department of Gastroenterology and Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands Barrett's esophagus is considered to be a premalignant condition, and long-term surveillance seems mandatory with a careful search for dysplasia and carcinoma by means of multiple and repeated sets of biopsies. Reliable nonhistologic markers indicative of dysplasia or developing carcinoma are not yet available. To investigate development of dysplasia and carcinoma a prospective follow-up study was performed on 50 patients with Barrett's esophagus, without carcinoma at entrance to the study, for a period of yr (mean, 5.2 yr). Barrett's epithelium was classified as fundic type, junctional or cardia type, or specialized columnar type. When classification in one of these three types was not possible because of lack of the characteristic features of the epithelia, the epithelium was classified as intermediate type. At entrance to the study, low-grade dysplasia was found in 6 patients, highgrade in 1 patient. During follow-up, dysplasia increased in frequency as well as in severity and was found almost exclusively in the specialized columnar- and intermediate-type epithelium. At the end of the observation period dysplasia had been found in 13 patients, in 10 scored as low-grade and in 3 as high-grade, and adenocarcinoma had developed in another 5 patients. This prospective study shows an incidence of carcinoma in Barrett's esophagus of 1 in 52 patient-years, a 125-fold incre~se compared with the general Dutch population. A sequence of worsening of dysplasia with development of carcinoma was observed in specialized columnar and intermediate-type epithelium. The results of this study support the need for a long-term clinical, endoscopic, and histologic follow-up program in patients with Barrett's esophagus. Acolumnar-lined or Barrett's esophagus (BE) is considered to be a premalignant condition. Many authors have reported on the association between BE and adenocarcinoma (1-11). Estimation of the true risk of development of adenocarcinoma is not possible from available studies, as the high prevalence rates, up to 46.5%, probably result from referral bias, patients having been referred to specialized centers for endoscopy and treatment. Accurate estimation of the cancer risk can be obtained only through prospective evaluation of a large, well-defined cohort of unselected BE patients. Careful histologic examination of multiple biopsy specimens is necessary to identify the various epithelial types and to detect dysplasia or carcinoma, which may be present either extensively or only focally and without any visible endoscopic abnormality (12-14). We performed a prospective endoscopic and histologic follow-up study in patients with BE to investigate the histologic pattern of BE, the presence and severity of dysplasia, and the association, if any, of dysplasia with adenocarcinoma. If progression of dysplasia, from low-grade to high-grade and finally to carcinoma, exists, such a sequence might be revealed by a follow-up study. If patients prone to develop carcinoma could be identified during screening, Barrett's carcinoma could be diagnosed at an early stage, offering these patients the possibility of curative therapy. Materials and Methods In 50 patients referred for endoscopy because of upper abdominal complaints, the diagnosis of Barrett's esophagus was made. Barrett's esophagus was defined endoscopically as the presence of a characteristic velvety red mucosa extending in the distal esophagus in such a way that the squamocolumnar mucosal junction was displaced at least 3 cm orad to the esophagogastric junction. Hiatal hernia was distinguished from the columnar-lined Abbreviation used in this paper: BE, Barrett's esophagus by the American Gastroenterological Association /89/$3.50.

2 1250 HAMEETEMAN ET AL. GASTROENTEROLOGY Vol. 96, No.5, Part 1 PATIENTS o L--L~~~~nL--L-~--~~~~~~-L->~10 YEARS Figure 1. Patients with BE and years of follow-up. Hatched bars indicate patients who developed an adenocarcinoma. esophagus by either the presence of gastric longitudinal folds or the nontubular appearance of the hiatal hernia. The length of the Barrett's segment was measured endoscopically. The presence of esophagitis, hiatal hernia, stenosis, ulcer, or any other mucosal abnormality was carefully recorded. At least two pinch biopsy specimens were taken from opposite sides of the esophageal circumference for every 2 cm of the Barrett's segment. Additional specimens were taken from mucosal abnormalities as seen at endoscopy. Specimens were fixed in neutral formalin and embedded in paraffin, and sections were stained with hematoxylineosin (H&E). All specimens were blindly reviewed by two pathologists. Barrett's epithelium was classified histologically as was done by Paull and Trier in fundic type, cardia or junctional type, and specialized columnar or intestinal type (15). However, in a substantial number of specimens no parietal or chief cells were present. nor were cardiatype glands, goblet cells, or intestinal-type absorptive cells seen in the H&E-stained sections. This kind of Barrett's epithelium was then described as intermediate type. Dysplasia was scored independently by two pathologists (H.J.H. and J.G.vdT.) and classified according to the criteria of Riddell and colleagues (13,16). which were revised recently (12) and in which dysplasia was divided into three categories: negative, indefinite or low-grade, and high-grade. As a recent consensus study on dysplasia (17) had shown that indefinite for dysplasia and low-grade dysplasia were difficult to differentiate, both were placed in one category. Dysplasia was graded from nuclear abnor- Table 1. Endoscopic Findings in Patients With Barrett's Esophagus (n = 50) Endoscopy Length of BarreU's segment 3-5 cm 5-10 cm > 10 cm Esophagitis Barrett's ulcer Stenosis No. of patients Table 2. Histology at Entrance and Final Histology in 50 Patients With Barrett's Esophagus Entrance histology Final histology Epithelium type No. of patients No. of patients c 5 3 sc 4 3 sc + c c + f 3 4 sc + f 1 im + f 1 1 im + sc 2 3 im + c 5 3 sc + C + f 2 4 sc+im+c 8 7 c+im+f 2 2 sc + im + f 1 sc + im + c + f 2 5 c, cardia type; f, fundic type; im, intermediate type; sc, specialized columnar type. mali ties such as enlargement, stratification, pleomorphism, hyperchromatism, polarity, presence of abnormal mitoses, and from nucleolar changes such as enlargement, multiplicity, or a halo around the nucleolus. Abnormal architectural features included abnormal localization, papillary epithelial extensions into the lumen, cribriform, or dos-a.-dos localization of glands. Inflammatory activity was graded as absent. mild, moderate, or severe and further classified as chronic or chronic-active depending on the presence of neutrophils. Patients who presented with biopsy-proven adenocarcinoma at the first examination were excluded from the study. In general, endoscopy was performed at yearly intervals, occasionally less frequently in elderly patients but more frequently when clinically necessary (for instance, to monitor anti-reflux medical treatment) or when dysplasia was detected in the biopsy specimens. In addition, echoendoscopy was performed in cases of malignancy or high-grade dysplasia to look for abnormal echo patterns in the esophageal wall suggestive of infiltrative or submucosal tumor DYSPLASIA c H r 5,4 l ; I / 1 " /.~.~ IJ,.i 1 1/, ;' /,,,.' i i I./ ---,- --' $- " j,.",,,..:.~' 1I-J I" I /.i /... / \.,,/ /~/.....,...,,/ N~'~~_~:_~- ~=='_=~~_"_'=_~~~ '~ Figure tl I / ' YEARS 2. Development and progression of dysplasia in 5 patients with BE who developed carcinoma. N, negative for dysplasia; L, low-grade dysplasia (including indefinite for dysplasia); H, high-grade dysplasia; C, carcinoma.

3 May 1989 BARRETT'S E80PHAGUS 1251 Table 3. Histology in Patients With Barrett's Esophagus in Whom Development of Dysplasia Was Found Entrance Entrance Final Follow-up Sex histology dysplasia Final histology dysplasia (yr) M c + sc + f c + sc + f LG 4 M c + f + im LG c + f + sc + im LG 3.5 M c + sc c + se + f HG 4 M c + im c + im Indef/LG 5 F c + sc + im Indef/LG c + sc + im + f LG 8 M f + im im + sc + f LG 4 M c + sc + im HG c + sc + im HG 4 F c + sc + im LG c + sc + im HG 4 M sc sc + im LG 5 M sc t c + im c + sc + im IndeflLG 4 M c + f + sc + im c + sc IndeflLG 5 M c + sc c + f + im Indef/LG 4 F c + sc + im c = sc = im Indef/LG 5 c, cardia-type epithelium; f, fundic type; F, female; HG, high-grade dysplasia; im, intermediate type; Indef. indefinite for dysplasia; LG, low-grade dysplasia; M, male; sc, specialized columnar type. growth not obvious at endoscopy and the presence of adjacent, enlarged lymph nodes. When endoscopy showed signs of active reflux esophagitis, medical treatment with H 2 -receptor antagonists and antacids was given. In 3 elderly patients, omeprazole was given because of refractory Barrett-type ulceration. Alltireflux surgery was performed on 6 patients who did not respond satisfactorily to medical treatment. In case of stenosis, Eder-Puestow dilatation was performed using metal olives or Savary dilatators. In cases of malignancy, radical surgery was performed when clinically possible and when cure seemed possible. For palliative purposes, radiotherllpy, laser coagulation, or intubation with an endoprosthesis was given. Results Fifty patients, 30 men and 20 women, aged yr (mean, 59.3 yr) were studied during a follow-up period of yr (mean, 5.? yr) (Figure 1). In all patients endoscopic signs of reflux esophagitis, such as longitudinal erosions, were present (Table 1). Histologic study of the biopsy specimens from the columnar-lined segment revealed more than One epithelium type in all b4t 9 patients (Table 2). The intermediate-type epithelium was found in 20 patients. Dysplasia was found in 7 patients at entrance to the study-low-grade in 6 (one of whom was scored as indefinite), high-grflde in 1. Dysplasia was seen only in relation to the specialized columnar- and intermediate-type epithelium. During follow-up an increase in frequency as well as in severity of dysplasia was seen. At the end of the study indefinite or low-grade dysplasia was present in 10 patients and high-grade in 3 patients, and adenocarcinoma had developed in 5. There was agreement On the dysplasia score in 82% of the patients and in 77.4% of the biopsies. In 9 patients dysplasia was scored differently by the two pathologists: in 4 patients dysplasia being absent or indefinite and in another 4, indefinite or low-grade: in 1 patient there was discussion as to whether the dysplasia was high-grade or lowgrade. There was a consistency in the scoring in that in 8 of these 9 patients it was always the same pathologist who scored dysplasia as less severe. In a simultaneous study of the biopsy sections, agreement on severity was obtained. The results are presented in Tables 3 and 4. Before the discovery of carcinoma in patients, an increase in the severity of dysplasia was seen during the observation period (Figure 2). Table 4. Histology in Patients With Barrett's Esophagus in Whom Development of Carcinoma Was Found Entrance Entrance Final Final Follow-up Survival Sex histology dysplasia histology dysplasia (yr) Endoscopy Treatment (mo) F c (+im)q c + im ca 10 Polypoid lesion Radiotherapy 10, DOD F c + sc (+im)b c + sc + im ca 9 Polypoid lesion Radiotherapy 18, DOD M c + im LG c + im ca 4 Small erosion Surgery 48, ANED M c + im + sc LG im + sc ca 3.5 Small erosion Surgery POD M sc + im LG im + sc ca 1.5 No abnormalities Surgery 12, ANED See Table 3 for key to abbreviations. ANED, alive, no evidence of disease; ca, carcinoma; DOD, death of disease; POD, postoperative death. Q Intermediate-type epithelium found 7 yr before carcinoma. b Intermediate-type epithelium found 4 yr before carcinoma.

4 1252 HAMEETEMAN ET AL. GASTROENTEROLOGY Vol. 96, No.5, Part 1 All patients with endoscopic evidence of active reflux esophagitis were treated with antacids or H 2 -receptor antagonists, or both, sometimes combined with sucralfate. In 3 elderly patients a Barrett's ulcer resistant to this therapy was healed with omeprazole (18). An anti reflux procedure was performed in 6 patients because of failure of conservative therapy or upon request of the patient. Medical treatment for esophagitis was considered satisfactory in the other patients. Of the 5 patients who developed adenocarcinoma, 3 were considered to be candidates for surgery (Table 4). Preoperative echoendoscopy in 2 of these 3 patients suggested limitation of the carcinoma to the mucosa and submucosa. At surgery a radical esophageal resection with tubularization of the stomach was performed. Tumor was found not to have penetrated the muscularis propria in any of the 3 patients. There were no tumor-invaded lymph nodes. One patient died postoperatively due to respiratory insufficiency after cardiac arrest. The other 2 patients are alive and well without evidence of disease for 12 and 48 mo. In the 2 elderly patients the polypoid tumor was treated with endoscopic snare polypectomy and laser coagulation. On relapse, radiotherapy was given, and finally an endoprosthesis was inserted because of progressive stenosis. Discussion There is still much debate and uncertainty about the risk of development of adenocarcinoma in a columnar-lined esophagus. The prevalence reported in the literature varies between 0% and 46.5% (2,5,19-21) with an average rate of -10%. In three retrospective studies with long-term follow-up of patients with BE (22-24), an incidence of carcinoma was found of 1 in 441 to 1 in 81 patient-years, which is a 30- to 40-fold increased risk compared with the general population. In patients with a Barrett's carcinoma, dysplasia has been demonstrated adjacent to the tumor region as well as in other parts of the Barrett's segment (4,9,25-27). Most frequently, dysplasia is seen in the specialized columnar epithelium (7,8,13,25-29). A sequence from mild or low-grade dysplasia to severe or high-grade dysplasia with progression to carcinoma is thought to occur (7,8,13,14,28). To investigate the development of dysplasia and carcinoma we prospectively studied a well-defined group of patients in whom BE was diagnosed at endoscopy. Multiple biopsy specimens were taken at every 2 cm from the columnar-lined segment. All three epithelial types known to be present in BE were found. However, in 40% of the H&E-stained specimens no classification into one of these three types was possible. There were no parietal or chief cells, no cardia-type mucus-secreting cells and glands, no villiform surface with goblet cells or Paneth cells. This intermediate-type epithelium was found in specimens from 20 of the 50 patients (Figures 3A and 3B). These problems in classification of the Barrett's epithelium have been discussed by various authors (9,30,31). Columnar cells have been described as "variant cells" and "intermediate cells" and are thought to be part of the specialized columnar-type epithelium because of their sulfomucin and sialomucin content. In junctional and fundic gastric epithelium, mainly neutral mucins are found. The assessment of the intestinal-type epithelium is important because dysplasia is usually related to this epithelium type (7,8,25,26,28). Estimation of the severity of dysplasia in BE may be difficult. In European studies, criteria of gastric dysplasia by Morson et al. (32) are used, grading dysplasia as mild, moderate, and severe. In American studies, criteria from inflammatory bowel disease have been used (16), but these have recently been revised and modified (12). In a consensus study (17), it appeared that the interobserver variation was considerable in deciding on indefinite dysplasia or low-grade dysplasia. We therefore followed the modifications of Reid et al. (12). In a few patients, however, we had the impression that dysplasia that was present should be categorized between lowgrade and high-grade. This may partly be explained by the experience of our pathologists in grading dysplasia according to Morson's criteria (32). When using the revised criteria of dysplasia (absent, indefinite/low-grade, or high-grade), we found dysplasia in 7 patients (14%) at entrance to the study. At the end of the study, dysplasia or carcinoma was seen in 18 patients (36%) (Tables 3 and 4). Carcinoma as well as dysplasia (Figure 4) were seen in specialized columnar- or intermediate-type epithelium in all patients, confirming the relation of dysplasia, carcinoma, and intestinal-type epithelium mentioned earlier. In looking in more detail at the patients who developed carcinoma, the intermediate-type epithelium was found at the first endoscopy in 3 patients; in the other 2 it was seen after 3 and 5 yr of follow-up (Table 4). Though this epithelium may have been missed in the specimens taken at the first endoscopies, it seems more likely that it developed during the follow-up period, as three endoscopies, with multiple specimens taken at various levels, had been performed before discovery of the intermediate epithelium type. The absence of dysplasia at a followup endoscopy after a preceding endoscopy had shown dysplasia to be present (as seen in patients 2 and 5 in Figure 2) may be explained by sampling error and by dysplasia being present only focally. An

5 May 1989 BARRETT'S ESOPHAGUS 1253 A B Figure 3. A. Biopsy specimen from Barrett's mucosa. Hematoxylin-eosin, X200. This epithelium was classified as cardia type and as intermediate type (*); the latter lacks specialized characteristics. There are areas with stratification of nuclei and nuclear polymorphy (arrow). Dysplasia was scored as low-grade. B. Biopsy specimen from a BE showing a villiform mucosa. Hematoxylin-eosin, X200. This epithelium was classified as intermediate type (*). Goblet cells are not present. Nuclei in this intermediate-type epithelium are not located basally; there is nuclear polymorphy. Dysplasia was considered to be low-grade.

6 1254 HAMEETEMAN ET AL. GASTROENTEROLOGY Vol. 96. No.5. Part 1 Figure 4. In this biopsy specimen from a BE an irregular villiform mucosa is seen. Hematoxylin-eosin. X80. There is an irregular distribution of glands. In the center is an area with dysplastic changes. increase in severity of dysplasia was seen in all 5 patients with subsequent development of carcinoma. The time between findings of low-grade dysplasia and carcinoma in these patients varied from 1.5 to 4 yr. It is known that severe or high-grade dysplasia may be present in BE for several years without obvious progression to carcinoma (12,14). Two patients in this study also have shown severe dysplasia without histologic or (echo) endoscopic signs of tumor growth for a long observation period. One presented with high-grade dysplasia, and in the other, in which dysplasia scored initially as lowgrade, it was found after 1 yr of follow-up. Highgrade dysplasia has been present now in these 2 patients for 36 and 44 mo, respectively. Progression of dysplasia and development of carcinoma thus may show considerable variation, which hampers the decision on how to treat a patient with highgrade dysplasia. The incidence of carcinoma in this group of patients was 1 in 52 patient-years, which corresponds to 1920 Barrett's carcinomas per 100,000 patients, in contrast to an annual incidence of 15 esophageal cancers in the general Dutch population of the same age group (33). Compared with other reported studies on the incidence of carcinoma (22-24), the risk in our patients was increased approximately 125-fold, which is higher than the figures of the Boston and Mayo Clinic studies but comparable to the Lahey Clinic study. The incidence of Barrett's carcinoma may even be higher, as advanced adenocarcinomas in the distal esophagus or esophageal-gastric junction may be registered as gastric cardia carcinoma, the columnar-lined segment having been overgrown by tumor. The aim of a follow-up program in patients with a premalignant condition is to diagnose malignancy in an early phase, offering the patient a chance of curative treatment. The prognosis of esophageal carcinoma is related to the depth of invasion of the esophageal wall and the spread to adjacent lymph nodes (6,10,25,34,35). Though in all 3 patients who were operated on the carcinoma was detected at an early stage, limited to the mucosa or submucosa, only 2 patients had benefit of surgical treatment; 1 patient died postoperatively. The morbidity and mortality of esophageal surgery have improved considerably, with mortality figures now varying between 4% and 10% (10,35). Considering the risk of surgical treatment and the problems the pathologists may have in differentiating between high-grade dysplasia and intramucosal carcinoma in biopsy material obtained from the Barrett's segment, and with the knowledge that high-grade dysplasia may be present for a long period, we believe that resection should be performed only when unquestionable carcinoma has been found. In the detection of submucosal tumor growth, echo endoscopy may prove of great diagnostic value (36). In this prospective study in patients with BE we showed that with regular endoscopy and multiple biopsies, an increase in dysplasia could be found. In 5 of 50 patients a carcinoma developed corresponding to an incidence of carcinoma of 1 in 52 patient-

7 May 1989 BARRETT'S ESOPHAGUS 1255 years. Carcinoma was preceded by progression of dysplasia. Both dysplasia and carcinoma were found in intestinal-type epithelium. Our data support the concept that a sequence of progression of dysplasia to carcinoma exists. The time it takes for such a development shows considerable variation, and high-grade dysplasia has been found to exist for as long as 3.5 yr without evidence of carcinomatous degeneration. Our study shows that BE is a premalignant condition and that high-grade dysplasia should be considered an ominous marker for potential malignancy. Patients with specialized columnaror intermediate-type epithelium seem especially at risk of developing the dysplasia-carcinoma sequence. In view of the high risk we think endoscopic screening and biopsy are justified in patients with BE (37). The use of flow cytometry (38) may be of value as part of such a surveillance program. What to do once high-grade dysplasia has been detected remains controversial. We prefer to follow such patients closely and recommend surgery only when unquestionable proof of malignancy has been obtained, histologically or ultrasonographically, or both, because it is unknown if and when high-grade dysplasia will progress to carcinoma in an individual patient and because the risks of surgical resection are substantial. References 1. Morson BC, Belcher JR. Adenocarcinoma of the esophagus and ectopic gastric mucosa. Br J Cancer 1952;6: Naef AP, Savary M, Ozzello 1. Columnar-lined lower esophagus: an acquired lesion with malignant predisposition. J Thorac Cardiovasc Surg 1975;70: Berenson MM, Riddell RH, Skinner DB, Freston JW. Malignant transformation of esophageal columnar epithelium. Cancer 1978;41: Haggit RC, Tryzelaar J, Ellis FH, Colcher H. Adenocarcinoma complicating columnar epithelium-lined (Barrett's) esophagus. Am J Clin Pathol 1978;70: Hawe A, Payne WS, Weiland LH. 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8 1256 HAMEETEMAN ET AL. GASTROENTEROLOGY Vol. 96, No.5, Part Information CBS (Centraal Bureau voor Statistiek). The Hague, The Netherlands, Skinner DB. Dowlatshahi KD, DeMeester TR. Potentially curable cancer of the esophagus. Cancer 1982;50: Skinner DB. En bloc resection for neoplasma of the esophagus and cardia. J Thorac Cardiovasc Surg 1983;85: Tio TL, Tytgat GN. Endoscopic ultrasonography in the assessment of intra- and transmural infiltration of tumour in the esophagus, stomach and papilla of Vater and in the detection of extra-oesophageal lesions. Endoscopy 1984;16: Spechler SJ. Endoscopic surveillance for patients with Bar- rett's esophagus: does the cancer risk justify the practice? Ann Intern Med 1987;106: Reid BJ, Haggitt RC, Rubin CE, Rabinovitch PS. Barrett's esophagus. Correlation between flow cytometry and histology in the detection of patients at risk for adenocarcinoma. Gastroenterology 1987;93:1-11. Received December 3, Accepted December 4, Address requests for reprints to: W. Hameeteman, M.D., Free University Hospital, Department of Gastroenterology, P.O. Box 7057,1007 MB Amsterdam, the Netherlands.