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J Thorac Cardiovasc Surg 1994;107:1059-1066
© 1994 Mosby, Inc.
GENERAL THORACIC SURGERY |
Leuven, Belgium
Los Angeles, Calif.
Address for reprints: T. Lerut, MD, PhD, Department of General Thoracic Surgery, U.Z. Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium.
Abstract
Barrett's carcinoma occurred in 66 of 331 patients with adenocarcinomas of the esophagus or gastroesophageal junction. Only 32 (46%) of these patients had a history of gastroesophageal reflux. A history of alcohol and tobacco abuse was absent in 50% and 47.5%, respectively. The mean length of Barrett's metaplasia was 7.37 cm. Operability was 98.5% and resectability 95.5%. No postoperative or hospital deaths occurred. Pathologic staging was as follows: stage 0 and I, 38.3%; stage II, 20.6%; stage III, 22.2%; and stage IV, 19%. Overall survivals were 80.5% at 1 year, 62.7% at 2 years, and 58.2% at 5 years. Five-year survival for patients with stage I disease was 100%; for stage II, 87.5%; for stage III, 22.2%; and for stage IV, 0%. Thirty-four (51.5%) patients were under surveillance for a related or unrelated condition before diagnosis of their carcinoma; only nine (26.5%) had diseased lymph nodes. In 32 the diagnosis was made at their first medical contact, and 78% of them had diseased lymph nodes. Five-year survival without nodal metastasis was 85.3% and significantly better than for patients with metastasis, 38.3% (p = 0.0033). Of the 66 patients, 19 (28.7%) had a biopsy-proved history of Barrett's metaplasia before malignancy developed. Mean time interval between diagnosis of metaplasia and degeneration was 3.8 years (89.5% > 1 year). Over the surveillance period, the length of metaplastic Barrett's esophagus remained unchanged in all patients. Barrett's ulceration was present from the beginning in 14 patients, and three patients never had an ulcer. Intestinal metaplasia was seen in 18 patients. Resected specimens revealed severe dysplasia in 16 patients. Of the 19 patients, 73.7% had stage I disease. Our data suggest that close endoscopic monitoring and systematic biopsies of the smallest irregularities in the metaplastic mucosa may result in early detection of carcinoma. In this respect, patients with an ulcer within a zone of intestinal metaplasia seem to be at risk. Early detection increases substantially the chances for cure by diminishing the risks of lymph node involvement. Resection remains the treatment of choice in Barrett's adenocarcinoma including high-grade dysplasia, because mortality can be kept low with excellent to very good functional results in the majority of the patients provided the intervention is performed by experienced teams. (J THORAC CARDIOVASC SURG1994;107:1059-66)
Although columnar-lined esophagus is commonly named Barrett's esophagus after the publication by Norman Barrett, 
1 it was Morson and Belcher 2 who first reported the association between columnar-lined esophagus and adenocarcinoma.
Today it is accepted that Barrett's metaplasia is an acquired condition resulting from gastroesophageal reflux, and columnar-lined esophagus is found at endoscopy in 10% to 15% of patients with reflux esophagitis. 3,4 The importance of this finding lies in the fact that columnar-lined esophagus carries a high risk of degeneration into adenocarcinoma with a prevalence ranging from 10% to 45%. 5,6 This risk is estimated to be at least 30 to 40 times higher than in the normal population. 7,8 The prevalence of Barrett's metaplasia and adenocarcinoma in Barrett's esophagus is believed to have increased especially over the past decade. 9 However, because the natural history of the disease is unknown, controversy still exists regarding definition, pathogenesis, and clinical features of the disease. 10-12
The diagnosis of Barrett's adenocarcinoma is frequently made in an advanced stage. This late diagnosis accounts for the often reported poor prognosis of this carcinoma and therefore illustrates the need for early diagnosis and also questions the indications for surgical treatment. 13-15 On the other hand, early adenocarcinoma complicating Barrett's esophagus is not always obvious at endoscopy, and sometimes only cytologic examination or biopsy will disclose malignancy. As a result, the value of endoscopic surveillance is in dispute. 12
The first aim of this study was to analyze the results of the surgical treatment of Barrett's adenocarcinoma and to evaluate the role of surgery in the treatment of this condition. Our second aim, for which we analyzed the morphologic characteristics of a subset of patients with a biopsy-proved history of Barrett's metaplasia, was to provide the clinician, deprived of the more sophisticated methods, 16 with additional data on how to recognize high-risk patients in daily practice.
PATIENTS AND METHODS
From 1975 until 1991, 685 patients with carcinoma of the hypopharynx, esophagus, and gastroesophageal junction were treated in our department. An adenocarcinoma was diagnosed in 331 patients (48.2%). In the adenocarcinoma group, 66 patients had Barrett's adenocarcinoma, which is a prevalence of 20%. Barrett's adenocarcinoma was defined as tumor located in the tubular part of the esophagus and arising within the zone of Barrett's metaplasia of at least 3 cm as seen with the endoscope and/or confirmed by pathologic examination of the resected specimen. With these criteria, the prevalence for adenocarcinomas of the distal third was 45%.
Resected specimens were staged according to criteria of the revised TNM classification of 1987. 17 Dysplasia was graded according the classically accepted criteria based on those established for inflammatory bowel disease 18: negative dysplasia; indefinite for dysplasia; positive dysplasia, low grade and high grade, the latter being considered as intraepithelial carcinoma or carcinoma in situ (Tis). The patients within this group were classified as having stage 0 carcinomas.
All results and survival curves are based on patients who underwent a resection. Survival curves are calculated according to the Kaplan-Meier method. The curves express the percentage of survivors ± twice the standard error. Statistical significance between slopes of curves was tested by the nonparametric Wilcoxon rank sum test for censored values.
SURGICAL RESULTS
Sixty-six patients with Barrett's carcinoma were treated between 1975 and 1991. The mean age was 62.8 years and the range was from 30 to 85 years. Fifty-one patients (74%) were male and 14 patients (26%) were female. Thirty-two patients (48.5%) had a history of reflux, 33 patients (50%), alcohol abuse, and 34 patients (51.5%), tobacco abuse. Operability was 98.5% (65 patients) and resectability was 95.5% (63 patients).
Of the 63 patients who underwent a resection, 18 patients (28.5%) were treated before 1986. They underwent a simple resection. The remaining 45 patients (71.5%) were operated on after 1986. In those patients special attention was given to more radical resection and to extensive lymphadenectomy of the upper abdominal compartment and the posterior mediastinum.
Radical resection consisted in a subtotal esophagectomy with wide peritumoral resection including the thoracic duct and all peritumoral fatty and lymphatic tissue together with resection of the lesser curvature of the stomach. Extensive lymphadenectomy included the following nodal groups: subcarinal, aortopulmonary window, paraesophageal, mediastinal, parahiatal, left gastric, hepatic, splenic, and celiac nodes. The aim of this more aggressive approach was to obtain a complete resection, the R0 situation according the TNM classification.
No hospital deaths occurred. Morbidity included wound infection in five patients. No anastomotic leaks developed, but one patient with stage IV disease had mediastinitits and empyema as a result of a perforation of the gastric tube and he required reoperation. In this patient the gastroplasty was taken down and esophagostomy and gastrostomy were performed. Generalized metastasis developed before reconstruction was attempted. Postoperative quality of life was judged to be excellent or good in 53 patients (84.2%), that is, no symptoms or only occasional symptoms.
Pathologic staging (pTNM) after resection is shown in Table I. Of the tumors resected, 38.3% were early stage and 41.2% were advanced stage III or stage IV tumors. Two patients had a carcinoma in situ on preoperative biopsy but had microinvasive tumor on the resected specimen.
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Morphologic characteristics
From the 34 patients under medical screening before the onset of the carcinoma, 19 had a biopsy-proved history of Barrett's metaplasia before the carcinoma occurred. In the remaining 15 patients Barrett's metaplasia was recognized endoscopically. However, they were excluded for further study of the morphologic characteristics because, for reasons beyond our control, either a biopsy was not performed initially or the biopsy report or specimen was not available at the time of this study. However, all 15 continued to have regular endoscopic examinations because of Barrett's metaplasia or another upper gastrointestinal tract condition until carcinoma occurred.
The pathologic report after esophagectomy confirmed in all these patients that the malignancy developed in Barrett's metaplasia. The material obtained from the 19 patients who had biopsy-proved Barrett's metaplasia from the beginning, thus before carcinoma developed, therefore offers a unique opportunity to evaluate retrospectively which morphologic characteristics are important in determining the risk of degeneration. Determining these characteristics perhaps may result in earlier diagnosis and therefore better chances for cure. The mean interval between the diagnosis of metaplasia and degeneration is 3.8 years. In 89% of the patients this interval was longer than 1 year.
The macroscopic data show that the mean length of Barrett's metaplasia was 7.37 cm. The length of metaplasia remained unchanged in all patients during the period between diagnosis of Barrett's metaplasia and diagnosis of adenocarcinoma. Barrett's ulcer was present at the time of diagnosis of metaplasia in 14 patients, and at the time of resection 12 patients had an ulcer. Only three patients never had an ulcer. The tumor was located in the ulcer zone in nine patients. All ulcers were in a zone of intestinal metaplasia (Table II).
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Table III). In the mosaic pattern the different types of metaplasia are intermingled as a patchy network. In the zonation pattern these different types of metaplasia can be recognized as distinct separate bands of one single type of metaplasia. In each, the specialized intestinal type is usually found adjacent to squamous epithelium in the proximal segment of Barrett's mucosa. The junctional or cardiac type is next and the fundic type is in the most distal zone.
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Table IV). In only one patient was an evolution from low-grade dysplasia to high-grade dysplasia (carcinoma in situ) noticed.
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COMMENT
It is commonly believed that columnar-lined esophagus or Barrett's esophagus carries an increased risk of malignant change. This belief is mainly based on the prevalence of Barrett's metaplasia in adenocarcinoma of the esophagus. 4,7 Like many other reports, our study confirms this prevalence, which was 20% for all adenocarcinomas and 45% for all adenocarcinomas of the distal esophagus. This prevalence may be even higher, because advanced carcinomas of the distal esophagus or the gastroesophageal junction or carcinomas arising in zones of metaplasia less than 3 cm in length may well be registered as non-Barrett's adenocarcinomas of the distal esophagus in which the columnar-lined segment has been completely destroyed and overgrown by the tumor or as carcinomas of the gastric cardia.
From our data it seems that the prevalence has been increasing, especially during recent years, for indeed 71.5% of all our patients were operated on during the last 6 years of this study. However, the discussion about the true prevalence of adenocarcinoma in Barrett's esophagus remains open as indeed many patients with Barrett's metaplasia, 50% in our series, were asymptomatic for reflux and neither smoked nor abused alcohol. As a result, Barrett's metaplasia probably will never be diagnosed in many who have the disease because they will never consult a doctor and therefore never will be candidates for surveillance programs.
The fact that as many as half of the patients in our series were nonsmokers and nondrinkers perhaps partially explains the high operability rate (98.5%) and the lack of hospital mortality in this series. Contributing to these results is the fact that over the past decade enormous progress has been made in the control of perioperative and postoperative mortality and morbidity. The low mortality and morbidity figures and the excellent or good functional results in the majority of patients favor surgical treatment for Barrett's adenocarcinoma, which is believed to be the only effective treatment. However, many studies report poor long-term survival figures, the overall 5-year survival figures ranging between 15% and 25%. 13,14 Even for early stage carcinomas some data from the literature show low 5-year survivals, ranging between 30% and 50%. 13 In our experience the overall 5-year survival was 58.2%. This high survival can be partially explained by the high number of stage 0 and I carcinomas in this series, in which the 5-year survival was 100%. However, even in the advanced stage III carcinomas 5-year survival of 22.9% was obtained, and for patients with lymph node involvement the 5-year survival was 38.3%.
We believe that these favorable survival curves may result from our efforts in performing more radical resections and more extensive lymphadenectomies, which were done in over two thirds of the patients. This impression is also based on the analysis of our overall experience with the surgical treatment of patients with carcinoma of the thoracic esophagus from 1975 until 1988, including 198 resections. Part of the present series of Barrett's adenocarcinoma (until 1988) is incorporated in this study. We found a statistically significantly better 5-year survival in patients who underwent radical resections with extensive lymphadenectomies than in those treated by simple resection. 19 However, we were not able to substantiate the same conclusion for the present series of patients with Barrett's carcinoma because the majority of patients (71.5%) were treated after 1986, thus undergoing a more extensive resection and lymphadenectomy, whereas only 28.5% were treated before 1986, receiving a standard resection. Nevertheless, we like others 3,10 believe that at present surgery offers the best chance for cure and good quality palliation in patients with Barrett's adenocarcinoma. In this series 51.5% of the patients were being screened medically before the diagnosis of carcinoma was made. The reason for this high percentage may be related to rules imposed by the Belgian government to reimburse for the cost of H2 blockers and omeprazole. An endoscopic report at regular intervals is mandatory to obtain reimbursement for these medications, perhaps explaining the high detection rate of early carcinomas.
In the group of patients receiving medical screening, 73% of the patients had no lymph node invasion. As expected, a most important survival-related prognostic factor was lymph node involvement, with a 5-year survival of 85.3% for patients without lymph node disease versus a 38.8% 5-year survival for those with lymph node disease, which is a highly statistically significant difference (p = 0.0033). Early detection is of paramount importance because it results in clearly better chances for cure and thus is in our opinion is an argument in favor of surveillance programs in Barrett's metaplasia.
In this respect, a unique opportunity is offered by the group of 19 patients in whom there was a biopsy-proved history of Barrett's metaplasia. The retrospective evaluation of which morphologic characteristics are of importance in determining the risk of degeneration may provide additional data to the clinician as to how and when to recognize high-risk and early carcinoma populations.
Microscopic examination indicates that a more extensive length of metaplasia is to be considered as a predisposing factor for malignant degeneration. In our group the mean length was 7.37 cm and some patients had extensive metaplasia up to 18 cm. Iftikhar and associates 20 showed that the length of columnar-lined esophagus in subjects with dysplasia was significantly longer than in patients without dysplasia and concluded therefore that the length of columnar-lined esophagus is a significant risk factor in the development of dysplasia and subsequent carcinoma.
Although Iftikhar and colleagues 20 were able to show progression of columnar-lined esophagus in 12.7% of their patients, we could not confirm this finding. In this respect, however, we have to stress the fact that ours was a retrospective study with all the inherent drawbacks. Fourteen patients had an ulcer within the zone of metaplasia either preoperatively or at the time of resection, and the tumor was found in the ulcer in the majority of the patients. All but one ulcer was located in the zone of intestinal metaplasia. Besides the presence of ulceration, however, attention should be focused on small irregularities or minute elevated lesions of the mucosa as possible indicators of early carcinoma.
From the microscopic point of view, intestinal metaplasia invariably was present in all patients. A specialized type of metaplasia can be a mosaic pattern or can be part of a more distinct zonation pattern. These patterns are noticed in both surface epithelium and glandular epithelium. Thus a marked heterogeneity of mucosa exists in columnar-lined esophagus. The most frequent combination is a mixture of junctional and specialized mucosa, which was present in 61% of the resected material. Tumor and dysplasia were always found in zones of intestinal metaplasia. Whether the presence of an intestinal type of metaplasia should be considered to be a useful marker is not clear, because biopsy specimens of a majority of patients with columnar-lined esophagus probably have intestinal metaplasia. However, the overall impression of our pathologists is that the fraction of specialized epithelium in patients with carcinoma is much more important than in those with benign metaplasia. 21
Dysplasia was noticed on the resected specimen in 16 patients, and the dysplasia was mostly located in the zone of intestinal metaplasia (14 patients). Of those 16 patients, 14 had a high-grade dysplasia (i.e., carcinoma in situ) showing unequivocal neoplastic characteristics. In only one patient was an evolution from low-grade dysplasia to carcinoma in situ noticed.
The significance of high-grade dysplasia still remains controversial because its natural history is not well known. As also reported by others, one of our patients did not have any change in his high-grade dysplasia over a period of 5 years. For this reason some authors advocate a conservative attitude with close endoscopic and biopsy surveillance, the risks of such an attitude being less than the risk of postresection surgical mortality. 22 However, in some series, as many as 50% of the patients with a preoperative diagnosis of high-grade dysplasia had microinvasive or invasive carcinoma in the resected specimens. 10,11 As a consequence, those patients were exposed to the risk of metastasis. In our series, two patients with a preoperative diagnosis of high-grade dysplasia had a microinvasive tumor on the resected specimen. Another patient who refused surgery for 4 years after diagnosis of high-grade dysplasia was found to have a transmural invasive carcinoma with distant lymph node metastasis at the time of resection.
Close endoscopic and echoendoscopic surveillance will enable early diagnosis of carcinoma, as was the case in our group of 17 patients who were under very close endoscopic monitoring, which allowed early diagnosis in 82%. However, in the remaining 12% (three patients) the final staging showed stage III carcinoma.
Because the risk of degeneration in patients with high-grade dysplasia is distinctly higher than in the general population, because close endoscopic and echoendoscopic monitoring even in the hands of the most experienced groups is still not a guarantee of successful early diagnosis in all patients, and because esophageal resection could be done safely with no mortality in our series, we believe that patients with high-grade dysplasia in Barrett's metaplasia should undergo esophageal resection and reconstruction whenever possible. Perhaps in the future, with the development of new techniques such as flow cytometry and p53 oncogene identification, it may become possible to differentiate better between patients who are at risk and those who are not. 16
Appendix: DISCUSSION
Dr. F. Henry Ellis, Jr. (Boston, Mass.).
I would like to congratulate Professor Lerut and his colleagues for their extraordinarily good 5-year survival, unequaled I think in any other report on the same topic. Pertinent to this is the fact that over half of their patients were under surveillance at the time that the cancer was diagnosed, which led to the fact that over half of them were in stages 0, I, and II. Relevant to this, I would like to present a brief summary of our date on patients with benign Barrett's patients disease who are under surveillance and ask a few questions.
Several years ago one of my residents, Dr. John Streitz, reviewed the Lahey Clinic experience with 65 cases of adenocarcinoma in Barrett's esophagus. Similar to the Belgian experience, there was a preponderance of white men, of whom less than half had a history of reflux. The operability and resectability rates were high, being 93.8% and 100%, respectively; however, the 5-year survival was considerably lower, 23.7%, similar to the 5-year survival for patients with squamous cell carcinoma and adenocarcinoma of the cardia. Very few of these patients were under surveillance.
We updated our data last summer. Among the 88 patients with cancer in Barrett's esophagus, 67 Barrett's esophagus was diagnosed at the time the carcinoma was diagnosed, and 21 were under surveillance when the cancer was diagnosed.
When one compares the staging of the resected specimens, three quarters of those under surveillance were in stages 0, I, and IIA, whereas 74% of those not under surveillance were in stages IIB, III and IV. This is reflected in the 5-year survival rate, for those under surveillance had a 62.2% 5-year survival as compared with 20% for those not under surveillance.
This leads me to the view, which sounds similar to Dr. Lerut's, that early diagnosis is the key to long-term survival rather than the use of neoadjuvant therapy or extending the scope of the operation by radical en bloc resection. I would appreciate your comments on this point.
Finally, could you elaborate on your recommendations regarding surveillance of patients with benign Barrett's esophagus? Do you recommend yearly endoscopic surveillance for them? If you find low-grade dysplasia, do you increase the frequency of endoscopy? I assume that you now recommend resection for high-grade dysplasia, which most people would consider carcinoma in situ.
Dr. David B. Skinner (New York, N.Y.).
I would like to clarify a couple of points. In the staging system, were you using the current staging system or the one that was in effect before 1987? In other words, did stage II, in which you had a 87% survival, include patients who would have T1-2 N1 disease in some cases or T3 N0 disease? Those are truly outstanding results.
Second, please describe the extent of the operations. Was this esophagectomy without thoracotomy or was it a radical removal of the mediastinal tissues? That would seem to be an important question.
Third, how radical an operation should be done for early stage disease, and what is the correlation between preoperative stage I and pathologic findings at operation? This slide shows a lymph node that I removed during an en bloc resection about 3 weeks ago in a patient who had stage I disease before the operation. A 4 mm node includes a 1 mm circle of adenocarcinoma. The node was sitting out in the mesoesophagus a small distance away from the wall of the esophagus.
This slide is a section through a serially sectioned part of the perimediastinal tissues. The high-power field shows that the only focus of disease outside the wall of the esophagus, but again enclosed within the boundaries of an en bloc resection. We do practice and advocate an extensive resection for stage I disease. Do you use the same operation for high-grade dysplasia and stage I disease that you use for more advanced disease?
Dr. Tom R. DeMeester (Los Angeles, Calif.).
This series is one of the largest experiences in the management and outcome of patients with Barrett's esophagus who are undergoing malignant degeneration.
Dr. Lerut, an important observation was the marked effect that the presence of lymph node metastasis had on the outcome of these patients. You indicated that the earlier the disease, the less likely that lymph node metastases seemed to be present. My question is this: When can we essentially fish the esophagus out without the fear of leaving lymph nodes behind, and when do we have to do more? Has your experience given you some criteria as to when you would consider doing a lesser procedure as Dr. Ellis suggests or a more extensive procedure as Dr. Skinner has championed?
Dr. Lerut.
Thank you very much for these interesting questions. Dr. Ellis, I agree that early diagnosis plays a major role in the improvement of the survival curves. However, I believe that, besides early diagnosis, important factors are the more radical resections and extensive lymphadenectomies of the upper abdominal compartment and the posterior mediastinum. All of our patients except two were operated on through a transthoracic approach. Because the majority of these patients have been treated in the second half of the 1980s, they underwent a more radical resection and extensive lymphadenectomies, which in our opinion improved survival. Indeed we recently compared radical versus nonradical resection for esophageal carcinoma in patients treated between 1975 and 1988. This study strongly suggested that extensive resection improves results. Over half of the current series of patients with Barrett's carcinoma were incorporated in this analysis, and almost all of them belonged to the radical resection group.
I think that indeed yearly endoscopy is to be advised for Barrett's metaplasia. When there is a low-grade dysplasia, the frequency should certainly be increased and multiple biopsies, centimeter by centimeter and in the four different quaderants, are essential. It is clear in our mind that high-grade dysplasia equals resection. Indeed, other authors such as Dr. Skinner and Dr. Trastek have shown that invasive carcinoma will be present in resected specimens from a number of patients with high-grade dysplasia. We too had two patients in whom carcinoma in situ was diagnosed on endoscopy but who had invasive carcinoma at resection.
Dr. Skinner, we used the revised 1987 TNM classification. I believe in doing an extensive operation, because some patients might have a microinvasive carcinoma, even if preoperative staging shows an in situ carcinoma, as we experienced in two cases as I already mentioned. Some of those patients with microinvasive carcinoma will indeed have diseased lymph nodes, which I think is an argument for doing extensive lymphadenectomies in the abdomen and in the chest as well. There are very few candidates in whom a stripping operation should be done because we can do transthoracic resections with a very low postoperative mortality rate.
Footnotes
From the Department of General Thoracic Surgery and Histopathology, a University Hospitals, K.U. Leuven, Belgium. 
Read at the Seventy-third Annual Meeting of The American Association for Thoracic Surgery, Chicago, Ill., April 25-28, 1993.
References
This article has been cited by other articles:
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  K. Oyama, T. Fujimura, I. Ninomiya, T. Miyashita, S. Kinami, S. Fushida, T. Ohta, and M. Koichi A COX-2 inhibitor prevents the esophageal inflammation-metaplasia-adenocarcinoma sequence in rats Carcinogenesis, March 1, 2005; 26(3): 565 - 570. [Abstract] [Full Text] [PDF]
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 R. E. Rudolph, T. L. Vaughan, A. R. Kristal, P. L. Blount, D. S. Levine, P. C. Galipeau, L. J. Prevo, C. A. Sanchez, P. S. Rabinovitch, and B. J. Reid Serum Selenium Levels in Relation to Markers of Neoplastic Progression Among Persons With Barrett's Esophagus J Natl Cancer Inst, May 21, 2003; 95(10): 750 - 757. [Abstract] [Full Text] [PDF]
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