Adenocarcinoma of the Esophagogastric Junction and Barrett's Esophagus

Transcription

1 GASTROENTEROLOGY 1995;109: Adenocarcinoma of the Esophagogastric Junction and Barrett's Esophagus ALAN J. CAMERON,* CLIFFORD T. LOMBOY,* MANUEL PERA,* and HERSCHEL A. CARPENTER g *Division of Gastroenterology and Internal Medicine, ~Department of Surgery, and Department of Laboratory Medicine and Pathology, Mayo CLinic and Mayo Foundation, Rochester, Minnesota Background & Aims: Barrett's esophagus is associated with adenocarcinoma of the esophagus. The aim of this study was to find the prevalence of Barrett's esophagus in patients with adenocarcinoma of the esophagogastric junction. Methods: Consecutive, freshly resected surgical esophagogastrectomy specimens were examined, and multiple histological sections were made around the tumor periphery. Barrett's esophagus was defined as specialized columnar epithelium above the esophagogastric junction. Tumors centered -<2 cm from the junction were defined as junction cancers. Results: Barrett's esophagus was found in 9 of 9 (100%) esophageal adenocarcinomas compared with 0 of 8 (0%) squamous carcinoma controls (P < 0.001). Ten of 24 (42%) junction adenocarcinomas had a Barrett's esophagus. A Barrett's esophagus was found in 8 of 12 (67%) junction cancers -<6 cm in length but only 2 of 12 (17%) larger tumors (P < 0.05). Barrett's esophagus was significantly associated with junction tumors <6 cm compared with squamous carcinoma controls (P < 0.02). In 5 specimens with junction cancer, the length of Barrett's esophagus was <3 cm, and in 5 specimens it was ->3 cm. Specialized epithelium was often found below the esophagogastric junction in controls. Conclusions: Adenocarcinomas of the esophagogastric junction are associated with short and long segments of Barrett's esophagus. Larger cancers probably overgrow and conceal the underlying specialized columnar epithelium from which they arise. 'n Barrett's esophagus, the normal squamous epithelial,lining of the lower esophagus, damaged by gastroesophageal reflux, is replaced by columnar epithelium. 1 Most esophageal adenocarcinomas arise in a Barrett's esophagus. 2-4 Patients with Barrett's esophagus have a times increased risk of developing esophageal cancer. 5-7 Adenocarcinoma of the esophagogastric junction is about twice as common as esophageal adenocarcinoma, s'9 Previously considered a type of gastric cancer, adenocarcinoma of the esophagogasrric junction has much in common with esophageal adenocarcinoma. Cancers in both locations are associated with reflux symptoms, 3 predomi- nance in white males, 4's increasing incidence, 8-I4 and similar tumor histology) 5 However, the association of Barrett's esophagus with junction adenocarcinoma is less well defined than for adenocarcinoma of the esophagus. Barrett's esophagus can usually be identified at endoscopy. The junction between pink squamous epithelium and red columnar epithelium is normally found at or within 1-2 cm above the esophagogastric junction. ~ One definition of Barrett's esophagus is the finding of at least 3 cm of columnar epithelium in the esophagus. 16-1s The most common type of epithelium found in Barrett's esophagus is specialized columnar epithelium, an incomplete intestinal metaplasia with goblet cells Adenocarcinoma of the esophagus is associated with this type of epithelium rather than junctional or gastric fundic epithelium. 5'16'23'24 An alternative definition of Barrett's esophagus is the finding of specialized columnar epithelium in the esophagus, regardless of length. 25 Short segments (<3 cm) or tongues of specialized epithelium in the lower esophagus may be associated with adenocarcinoma of the esophagogastric iunction. 4'26 The aim of the present study was to determine the prevalence of short or long segments of specialized (Barrett's) epithelium, a presumed precursor lesion, in patients with adenocarcinoma of the cardia and to compare this with the prevalence of adenocarcinoma of the esophagus and squamous carcinoma controls. Materials and Methods During a period of 10 months, consecutive surgical specimens resected for malignancy of the esophagus or esophagogastric junction were examined prospectively. The surgical procedures were performed at our affiliate hospitals by our thoracic surgical staff. Soon after removal, each specimen was examined in the surgical pathology suite by one of the investigators. Photographs were taken. A map was constructed by placing a transparent sheet over the specimen and tracing its outline and that o the tumor and squamocolurnnar junction when seen. This map served as a reference guide for the location of the histologi by the American Gastroenterological Association /95/$3.00

2 1542 CAMERON ET AL. GASTROENTEROLOGY Vol. 109, No. 5 cal specimens. Measurements of tumor size and, when visible, the length of columnar epithelium above the esophagogastric junction were obtained before pinning out the specimen and 24-hour formalin fixation. Multiple full-thickness tissue samples 0.5 X 2.0 cm were then obtained from the tumor and around its perimeter. The tumor perimeter samples were taken so that each contained tumor and grossly normal tissue. A mean of 7.7 tissue samples per patient were examined. Samples were embedded in paraffin, and 5-[.tin-thick sections were cut and stained with H&E and alcian blue (ph 2.5). The esophagogastric junction was identified primarily by the level at which the tubular esophagus widened into the stomach or, if this was indefinite, by the level at which peritoneal reflections of the stomach originated. The midpoint of a carcinoma was taken as the point midway between the most proximal and distal extent of gross tumor. An esophageal adenocarcinoma was defined as one whose vertical midpoint was >2 cm above the esophagogastric junction. Adenocarcinomas with a midpoint ~2 cm above or below the esophagogastric junction were defined as esophagogastric junction tumors. Adenocarcinomas with a midpoint >2 cm below the esophagogastric junction were defined as gastric tumors and excluded from the study. Patients undergoing resection over the same time period for squamous cell carcinoma of the esophagus acted as controls, having a mean of 7.4 histological sections obtained at the squamocolumnar junction. Visible evidence of Barrett's esophagus was considered to be present when the squamocolumnar junction was seen at any distance proximal to the esophagogastric junction with histological confirmation of specialized columnar epithelium. Microscopic evidence of Barrett's esophagus was defined as specialized columnar epithelium with incomplete intestinal metaplasia and goblet ceils seen with either H&E or alcian blue stain, provided that this was found in the esophagus. Intestinal metaplasia found in tissue taken from the stomach was not considered to represent Barrett's esophagus. One pathologist with no prior knowledge of the clinical history or tumor location reviewed the slides for the presence of Barrett's esophagus. After completion of our main study, another group of stored, formalin-preserved esophagogastrectomy specimens from patients with malignancy of the upper esophagus, pharynx, or larynx was examined in a limited manner. None of them were known to have a Barrett's esophagus. Only histological sections of the squamocolumnar mucosal junction were examined in this group. A mean of 14.4 microscopic samples per case were examined. These archival cases were not included in our control group statistics. Statistical analysis was performed using the Z 2 test. Results are reported as the mean + SEM when appropriate. Results A total of 50 resection case patients were studied prospectively. Two had gastric cancer as defined above. In 1 patient with squamous carcinoma, the squamoco- lumnar junction was not present in the specimen. These 3 patients were excluded. In 6 patients, an adenocarcinoma had been found preoperatively as a result of surveillance of known Barrett's esophagus before tumor-related symptoms manifested. Four of them had adenocarcinoma of the esophagus. Two had adenocarcinoma of the esophagogastric junction. These 2 patients had small cancers 0.5 and 0.6 cm in length; the tumor midpoints were located at the esophagogastric junction in 1 and 1.05 cm above the junction in the other. The lengths of Barrett's esophagus in these 2 patients were 5 and 5.5 cm. Because the 6 patients found by surveillance had Barrett's esophagus by definition, they were not included in our general analysis. Twenty-four patients with adenocarcinoma of the esophagogastric junction had tumor-related symptoms. Their initial complaints were dysphagia in 17, gastrointestinal bleeding in 4, and chest pain or discomfort in 3 patients. Seven of 24 (29%) had a preceding history of chronic heartburn. Nine patients with adenocarcinoma of the esophagus had similar symptoms: dysphagia in 7, bleeding in 1, and chest pain in 1. Only 2 of 9 (22%) reported chronic heartburn. There was a predominance of men with cancer in both locations. Twenty-two of 24 (92%) patients with junction adenocarcinomas and 8 of 9 (89%) with esophageal adenocarcinomas were male. Mean age of patients with junction adenocarcinomas was 63 years and with esophageal adenocarcinomas was 53 years. Eight patients underwent resection for squamous carcinoma of the esophagus. Five (62:5%) were men, and [] B n rl g cm +14 cm +12 cm +locm +8 cm +6cm +4 cm Esophagus ~D J- +2cm / ooealloo / Esophago-gastric junction r "- "--2 cm Figure 1, Distribution of resected carcinomas of the esophagus (0) and esophagogastric junction (O). The midpoint of each tumor is shown, i~, squamous caminoma.

3 November 1995 ADENOCARCINOMA AND BARRETT'S ESOPHAGUS 1543 Figure 2, Two resection specimens with adenocarcinoma of the esophagogastric junction. (A) A small tumor (large arrows) with three short tongues of Barrett's esophagus above (small arrows), (B) A larger tumor with no visible Barrett's esophagus. Specialized columnar epithelium was found microscopically at one side of this tumor. the mean age was 61 years. In 1 of the patients who had preoperative radiation therapy, there was no remaining tumor in the surgical specimen. Figure 1 shows the location of the midpoint of each tumor (excluding surveillance patients). One patient had two separate junction adenocarcinomas, and the larger adenocarcinoma was used for reference. Squamous carcinomas were distributed along the esophagus, and adenocarcinomas were concentrated at its distal end and near the esophagogastric junction. Barrett's esophagus was found in 10 of 24 (42%) resection specimens with junction adenocarcinoma. In 5 specimens, the Barrett's esophagus was seen to be a long segment of dark red columnar epithelium 3-8 cm in length. In 5 other specimens, histological analysis showed specialized columnar epithelium in the esophagus extending only cm above the esophagogastric junction. Two of these 5 specimens had visible short tongues of columnar epithelium (Figure 2A). The other 3 specimens had only microscopic evidence of Barrett's esophagus, fragments of specialized epithelium being found in the esophagus at the tumor margins. Mean tumor length of the 24 junction adenocarcinomas was 6.4 cm. Eight of 12 (67%) junction adenocarcinomas with a tumor length of --<6 cm had an associated Barrett's esophagus. By contrast, a Barrett's esophagus was only found with 2 of 12 (17%) junction tumors longer than 6 cm (P < 0.05). This is shown in Figure 2. We reviewed the specimen maps of the 14 patients with junction carcinoma and no Barrett's esophagus. In 3, the tumor involved the entire circumference of more than 3 cm of the lower esophagus. Only in these 3 patients could the enlarging cancer have obliterated the evidence of a long segment of Barrett's esophagus. Barrett's esophagus was found in all 9 (100%) nonsurveillance patients with adenocarcinoma of the esophagus. A long segment ( cm) was seen in 7 patients in

4 1544 CAMERON ET AL. GASTROENTEROLOGY Vol. 109, No. 5 the specimen and in 1 patient at preoperative endoscopy; in this patient, the operative specimen did not include the squamocolumnar junction. In 1 patient, the evidence for Barrett's was microscopic only and its length was indeterminate. Mean tumor length of these esophageal adenocarcinomas was 5.6 cm. Eight control patients had esophagogastric resection while the study was in progress for squamous carcinoma; none of them (0%) had visible or microscopic evidence of columnar epithelium in the esophagus. Compared with these controls, Barrett's esophagus was more often found with esophageal adenocarcinomas (P < 0.001); however, with junction adenocarcinomas, the difference did not reach significance (0.1 > P > 0.05). However, Barrett's esophagus was found significantly more often when smaller ( cm) junction adenocarcinomas were compared with squamous carcinoma controls (P < 0.02). High-grade dysplasia in the Barrett's esophagus not involved by tumor was found in 7 of 9 patients with esophageal adenocarcinomas and 7 of 10 with junction adenocarcinomas. Surgical specimens may shrink when preserved in formalin. Our measurements were therefore made on fresh tissue soon after excision. Lengths corresponded closely to endoscopic measurements. In 12 patients (including surveillance cases), the length of Barrett's epithelium was recorded both at endoscopy and in the resection specimen. Mean length of Barrett's was cm on endoscopy and cm in the specimen. An unexpected finding was the frequency of microscopic loci of intestinal metaplasia below the esophagogastric junction, i.e., in the upper stomach. This was found in 6 of 24 junction adenocarcinomas and in 4 of 8 squamous carcinoma controls. By definition, this was not considered to represent Barrett's esophagus. We then examined an additional 10 archival, formalin-preserved esophagogastric resection specimens from patients undergoing resection for squamous carcinoma of the pharynx or upper esophagus (8 patients), carcinoma of the larynx (1 patient), or esophageal leiomyosarcoma (1 patient). Seven of 10 were men with a mean age of 65 years. Preoperative endoscopy in 8 patients showed an obstructing mass in 5 and a normal appearing esophagogastric junction in 3 patients. None had a clinical diagnosis of Barrett's esophagus. Eight of 10 patients showed evidence of focal (6 patients) or larger areas (2 patients) of intestinal metaplasia below the squamocolumnar junction. Discussion This study showed Barrert's esophagus in association with 100% of esophageal adenocarcinomas and 0% of squamous carcinoma controls. Barrett's esophagus was defined as the presence of specialized columnar epithelium (intestinal metaplasia) in the esophagus. Using this definition, we found Barrert's esophagus in 42% of patients with adenocarcinomas located within 2 cm of the esophagogastric junction. All except 1 of our patients with esophageal adenocarcinoma had a long segment (---> 3 cm) of specialized epithelium in the esophagus. In contrast, when Barrett's esophagus was found associated with junction adenocarcinoma, this was a short segment (<3 cm) in half of the patients. It is probable that more cases of junction adenocarcinoma are associated with Barrett's esophagus than the overall numbers indicate. Barrett's esophagus was found with 67% of junction cancers when the tumor length was --<6 cm but only with 17% of larger tumors. This suggests that enlarging tumors may overgrow and obliterate the columnar epithelium from which they arise. Reported cases of early junction adenocarcinoma show the probable development of this lesion. Hamilton et al. 4 noted adenocarcinomas associated with 1 or 2 cm of columnar epithelium in the esophagus. Schnell et al. 26 described 4 patients with short tongues of columnar epithelium extending cm upwards from the esophagogastric junction. At endoscopy, none had a visible tumor, but an adenocarcinoma in specialized epithelium was found histologically in each patient. We found small adenocarcinomas at the esophagogastric junction in 2 surveillance patients with long segments of Barrett's esophagus. Junction adenocarcinomas can clearly arise in short or long segments of specialized epithelium. The mean tumor length of junction adenocarcinoma was 6.4 cm in our patients, and although not all tumors were circumferential, it is easy to envisage that short segments of Barrett's esophagus, especially, may have been destroyed by an expanding malignancy. Comparison of Figure 2A and B shows the proposed sequence of events. Five of 24 junction adenocarcinomas were associated with a Barrett's esophagus --->3 cm in length. Review of our specimen maps showed that the tumor could have overgrown cm of Barrett's esophagus in 3 other cases. Therefore, 5-8 of 24 (21%- 33 %) of our junction adenocarcinomas could have arisen in a long segment of Barrett's esophagus. Five junction adenocarcinomas were associated with a Barrett's esophagus <3 cm in length. In all the remaining patients, except those with a long segment, the tumor could have overgrown a short Barrert's esophagus. Therefore, 5-19 (21%-799g) of 24. junction adenocarcinomas could have arisen in a short Barrett's esophagus <3 cm in length. Our findings are consistent with previous reports. Hamilton et al. 4 found Barrett's esophagus in 39 of 61

5 November 1995 ADENOCARCINOMA AND BARRETT'S ESOPHAGUS 1545 patients (64%) undergoing resection for adenocarcinoma of the esophagus or esophagogastric junction. Twentynine patients had tumors centered within 2 cm of the junction and a Barrett's esophagus. Specimens were measured after formalin fixation. In a retrospective review, Clark et al. 27 found Barrett's esophagus in 42% of junction and in 79% of esophageal adenocarcinomas. As in the present report, the mean length of Barrett's esophagus was shorter in patients with junction than with esophageal tumors. The cancer risk for patients with Barrett's esophagus has been evaluated in many reports 7 and lies between 1 in 48 and 1 in 441 patient-years. Most patients in these reports had an easily identified long-segment Barrett's esophagus. 6,v'2s Our data show that adenocarcinoma of the esophagogastric junction is associated with short segments of specialized epithelium at least as frequently as with long segments. We defined a junction adenocarcinoma as one with its midpoint located within 2 cm of the esophagogastric junction. Especially in the presence of a tumor that can distort the anatomy, the exact location of the junction may be difficult to determine. As shown in Figure 1, most adenocarcinomas arise near the esophagogastric junction. This zone is the usual area of occurrence of reflux esophagitis, and Barrett's esophagus is associated with reflux. 1 We and other investigators 2%26'29 have defined a shortsegment Barrett's esophagus as the presence of <3 cm specialized epithelium in the lower esophagus. Patients with intestinal metaplasia only found below the esophagogastric junction were not considered to have a Barrett's esophagus. We found this type of epithelium in most patients undergoing resection for squamous carcinoma, below a normally located squamocolumnar junction. Because the distal stomach was not resected in our cases, we do not know whether the intestinal metaplasia involved the cardia only or was associated with a more widespread gastric metaplastic change. We used patients with squamous carcinoma as controls because they were available; obviously, such patients, most of whom are smokers and alcohol users, are not representative of the general population. The exact location of the esophagogastric junction may be difficult to determine. Thus, the definition of a short-segment Barrett's esophagus on the basis of specialized epithelium above the junction, and its exclusion when this type of epithelium is only found below the junction, may be impractical. It is possible that only a subset of junction adenocarcinomas arise in specialized epithelium confined to the esophagus and related to gastroesophageal reflux, i.e., Barrett's esophagus, and that other adenocarcinomas arise in intestinal metaplastic epithelium involving a wider area of the stomach. However, most adenocarcinomas are found near the esophagogastric junction (Figure 1); adenocarcinomas of the upper stomach >2 cm distal to the junction are uncommon in our experience. In recent reports, specialized epithelium was also found on biopsy of the esophagogastric junction in 18%- 24% of patients undergoing endoscopy with 3 '3. or without 3 reflux symptoms. If specialized epithelium in this location is so common, then the cancer risk to the individual patient with this finding is probably low. We think that the value of endoscopic biopsy surveillance in patients with short segments or tongues of specialized epithelium remains to be proven. In conclusion, this study provides quantitative data for the association between adenocarcinoma of the esophagogastric junction and a premalignant disorder, Batrett's esophagus. Many, perhaps most, junction cancers arise in a short or long segment of specialized columnar epithelium. Larger tumors are thought to grow over and conceal the specialized epithelium in which they arise. References 1. Spechler S J, Goyal RK. Barrett's esophagus. N Engl J Med 1986;315: Rogers EL, Goldkind SF, Iseri OA, Bustin M, Goldkind L, Hamilton SR, Smith RRL. Adenocarcinoma of the lower esophagus. A disease primarily of white men with Barrett's esophagus. J Clin Gastroenterol 1986;8: MacDonald WC, MacDonald JB. Adenocarcinoma of the esophagus and/or gastric cardia. Cancer 1987;60: Hamilton SR, Smith RRL, Cameron JL. Prevalence and characteristics of Barrett esophagus in patients with adenocarcinoma of the esophagus or esophagogastric junction. 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6 1546 CAMERON ET AL. GASTROENTEROLOGY Vol. 109, No. 5 pattern of gastric cancer in Oxfordshire. Gut 1992;33: Hansson LE, Sparen P, Nyren O. Increasing incidence of carcinoma of the gastric cardia in Sweden from 1970 to Br J Surg 1993; 80: Kalish R J, Clancy PE, Orringer MB, Appelman HD. Clinical, epidemiologic, and morphologic comparison between adenocarcinomas arising in Barrett's esophageal mucosa and in the gastric cardia. Gastroenterology 1984;86: Skinner DB, Walther BC, Riddell RH, Schmidt H, lascone C, De- Meester TR. Barrett's esophagus. Comparison of benign and malignant cases. Ann Surg 1983; 198: Menke-Pluymers MBE, Hop WCJ, Dees J, van Blankenstein M, Tilanus HW. Risk factors for the development of an adenocarcinoma in columnar-lined (Barrett) esophagus. Cancer 1993; 72: Stein H J, Siewert JR. Barrett's esophagus: pathogenesis, epidemiology, functional abnormalities, malignant degeneration, and surgical management. Dysphagia 1993;8: Paull A, Trier JS, Dalton MD, Camp RC, Loeb P, Goyal RK. The histologic spectrum of Barrett's esophagus. N Engl J Med 1976; 295: Rothery GA, Patterson JE, Stoddard C J, Day DW. Histological and histochemical changes in the columnar lined (Barrett's) oesophagus. Gut 1986; 27: Hamilton SR, Smith RRL. The relationship between columnar epithelial dyspiasia and invasive adenocarcinoma arising in Barrett's esophagus. Am J Clin Pathol 1987;87: Sampliner RE, Garewal HS, Fennerty MB, Aickin M. Lack of impact of therapy on extent of Barrett's esophagus in 67 patients. Dig Dis Sci 1990;35: Kerlin P, D'Mellow G, Van Deth A. Barrett's esophagus: clinical, endoscopic, and histologic spectrum in fifty patients. Aust NZ J Med 1986; 16: Haggitt RC. Adenocarcinoma in Barrett's esophagus: a new epidemic? Hum Pathol 1992;23: Levine DS, Haggitt RC, Blount PL, Rabinovitch PS, Rusch VW, Reid BR. An endoscopic biopsy protocol can differentiate highgrade dysplasia from early adenocarcinoma in Barrett's esophagus. Gastroenterology 1993; 105: Schnell TG, Sontag S J, Chejfec G. Adenocarcinomas arising in tongues or short segments of Barrett's esophagus. Dig Dis Sci 1992; 37: Clark GWB, Smyrk TC, Burdiles P, Hoeft SF, Peters JH, Kiyabu M, Hinder RA, Bremner CG, DeMeester TR. Is Barrett's metaplasia the source of adenocarcinomas of the cardia? Arch Surg 1994; 129: Hameeteman W, Tytgat GNJ, Houthoff H J, Van Den Tweel JG. Barrett's esophagus: development of dysplasia and adenocarcinoma. Gastroenterology 1989; 96: Conio M, Aste H, Bonelli L. "Short" Barrett's esophagus: a condition not to be underestimated. Gastrointest Endosc 1994;40: Spechler S J, Zeroogian JM, Antonioli DA, Wang HH, Goyal RK. Prevalence of metaplasia at the gastro-oesophageal junction. Lancet 1994; 344: Clark GWB, Ireland AP, Chandrasoma P, DeMeester TR, Peters JH, Bremner CG. Inflammation and metaplasia in the transitional epithelium of the gastroesophageal junction: a new marker for gastroesophageal reflux disease (abstr). Gastroenterology 1994; 106:A63. Received February 27, Accepted June 14, Address requests for reprints to: Alan J. Cameron, M.D., Mayo Clinic, 200 First Street Southwest, Rochester, Minnesota Fax: (507) Supported by the Mayo Foundation.