Surgical Therapy in
Barrett's Esophagus
TOM R. DEMEESTER, M.D., STEPHEN E. A. ATTWOOD, F.R.C.S.I., THOMAS C. SMYRK, M.D., DAVID H. THERKILDSEN, M.D., and RONALD A. HINDER, M.D.
Seventy-six patients with Barrett's esophagus were cared for during a 10-year period. Fifty-six patients (74%) presented with complications of the disease. There were 20 strictures, 7 giant ulcers, 11 cases of dysplasia, and 29 patients with carcinoma. In patients with benign disease, 93% had mechanically defective sphincters and 83% had peristaltic failure of the lower esophageal body. Esophageal pH monitoring showed excessive esophageal exposure to pH less than 4 in 93% and excessive exposure to pH more than 7 in 34% of the patients tested. Ninety-three per cent of patients with excessive alkaline exposure had complications, compared to only 44% with normal alkaline exposure (p < 0.01). Gastric pH monitoring, serum gastrin levels, and gastric acid analysis supported a duodenal source for the alkaline exposure. Antireflux surgery was performed using Nissen fundoplication in 30, Belsey partial fundoplication in 3, and CollisBelsey gastroplasty in 2. Six required resection with colon interposition. Good symptomatic control was achieved in 77% after antireflux surgery. Four patients had symptoms and signs of duodenogastric reflux; three required a bile diversion procedure. Fifteen patients had an en bloc curative resection with colon interposition. One patient with high-grade dysplasia on biopsy was found to have intramucosal carcinoma after simple esophagectomy. Five tumors were intramucosal, seven were intramural, and four were transmural. Lymph node involvement occurred only in the latter two. Actuarial survival 5 years after curative resection was 53%. Median survival time for patients after palliative resection or no resection was 12 months. Study of en bloc specimens indicated that extent of resection should be adapted to extent of disease: esophagectomy for intramucosal disease, en bloc esophagectomy with splenic preservation for intramural and transmural disease. Serum CEA was useful in detecting recurrent disease after surgery when the primary tumor stained positively for CEA.
C
From Creighton University School of Medicine, the Department of Surgery, Omaha, Nebraska
Barrett's esophagus,' may be complicated by
ration, or malignant degeneration.2'3 Barrett's esophagus is usually associated with gastroesophageal reflux disease, but the reasons why only a portion of patients with reflux develop Barrett's and only some of these are prone to complications are not known. Gastric juice generally is regarded as the damaging agent in gastroesophageal reflux disease. Medical therapy is aimed at suppressing its acid component, allowing other components such as duodenal secretions, pancreatic secretions, and bile to continue further tissue destruction. This may explain why medical therapy, as opposed to surgical therapy, which constructs an antireflux barrier, fails to provide complete symptomatic relief in most patients,4 and allows upward progression of the columnar mucosa.5 While there is strong evidence for sequential progression from low-grade dysplasia to high-grade dysplasia to invasive carcinoma, there is no consensus on the frequency and tempo of progression and whether progression is influenced by medical or surgical therapy.68 Controversy exists over the appropriateness of surveillance because an improved survival by resection of early cancers arising in Barrett's esophagus has not been well documented. The aim of this study was to examine the pathophysiology of Barrett's esophagus and the role of surgery in the treatment of the disease and its benign or malignant
stricture, giant ulceration, hemorrhage, perfo-
complications.
OLUMNAR-LINED LOWER ESOPHAGUS, known as
Presented at the 1 10th Annual Meeting of the American Surgical Association, Washington, D.C., April 5-7, 1990. Accepted for publication April 12, 1990. Address reprint requests to Tom R. DeMeester, M.D., University of Southern California Medical Center, Department of Surgery, 1200 North State St., Los Angeles, CA 90033.
528
Patients and Methods Patients
Seventy-six patients with Barrett's esophagus were diagnosed during a 10-year period by the endoscopic ob-
SURGICAL THERAPY IN BARRETT'S ESOPHAGUS
Vol. 212 * No. 4
servation of a segment of lower esophagus, at least 3 cm in length, lined by columnar epithelium in continuity with the gastric mucosa, and confirmed by histology. The columnarization extended a median of 6.2 cm over the lower esophagus, with a range of 3 to 18 cm. Twenty patients (26%) presented without complications; 27 (36%) with complications of stricture, ulcer, or dysplasia; and 29 (38%) with invasive malignancy. At endoscopy the strictures were fully dilated to relieve any obstruction before performing physiologic tests. Table 1 describes the age and sex distribution of the patients with Barrett's esophagus according to the presence and type of complication. Patients with complications were 10 years older than those without complications. Benign complications were more frequent in female (15 of 21 patients or 71%) compared to male patients ( 12 of 26 patients or 46%). Multiple complications were seen in nine of those with benign disease. The patients with malignant degeneration were almost exclusively male (97%). Cancer of the esophagus developed in 3 of the men in their early 40s and in one in his 30s. During the same time period, we treated 135 patients with esophageal cancer. Sixty-three (47%) had squamous carcinoma, 43 (32%) had adenocarcinoma of the cardia or lower esophagus, and 29 (21 %) had adenocarcinoma in Barrett's esophagus.
Physiologic Testing of Patients with Benign Barrett's Esophagus
Manometry Esophageal manometry was performed using a single catheter assembly consisting of five water-filled polyethylene tubes with five exit ports located at 5 cm intervals along its length and oriented radially around the circumference of the catheter. The catheter was attached to a pump (Arndorfer Medical Specialties Inc., Greendale, WI) capable of a low perfusion rate with distilled water at 0.6 mL per minute with low compliance, (measured at 100 mmHg in 0.08 seconds during occlusion of the distal side TABLE 1. Barrett's Esophagus: Age and Sex Distribution
Study Population
n
Patients with Barrett's No complications
76 20 27 20 7 11 29 28
Benign Complications* Stricture* Ulceration* Dysplasia* Malignant Complications Adenocarcinoma Squamous carcinoma *
Mean Age
59 51 61 55 60 58 63
Age
Range 25-89 27-76 25-89 25-85 37-74 27-74 36-79
Sex M:F 54:22 14:6 12:15 9:11 3:4 6:5 28:1
I
Note that nine patients (mean age, 46 years) had multiple benign
complications.
529
holes). Each perfused channel was linked to a transducer (Statham transducer model P2306, Gould, Cleveland, OH) and the pressure recorded on a Polygraph pen recorder (ES 1000, Gould) and stored digitally on a computer (IBM AT, White Plains, NY). This dual record allowed a choice of computerized or manual analysis. Computerized analysis was performed using a dedicated program (ESA/Motility, T. DeMeester, G. Schneider, M. Walker, Creighton University). In the fasting patient, the catheter was introduced through the nose into the stomach and pulled back stepwise across the gastroesophageal junction to obtain a pressure profile of the lower esophageal sphincter.9 The upper and lower border of the lower sphincter, the respiratory inversion point, and its height above gastric baseline were defined. From these measurements the sphincter's pressure, overall length, and abdominal length, that is, the length below the respiratory inversion point, were determined. Based on the values obtained in 50 normal subjects,'0 a mechanically defective lower esophageal sphincter was defined as one having one or more of the following characteristics: an average resting pressure of less than 6 mmHg, an average length of less than 2 cm, or an average length exposed to the positive-pressure environment of the abdomen of less than 1 cm. These values are below the 2.5th percentile for the normal range of sphincter pressure and overall length and below the 5th percentile for abdominal length. Esophageal peristalsis was measured by placing the catheter in the body of the esophagus with the proximal port 1 cm below the lower border of the upper sphincter and asking the patient to take 10 dry swallows and 10 swallows of a 5-mL water bolus. The number of interrupted waves, i.e., waves that failed to progress; dropped waves, i.e., waves that failed to occur in a segment; and simultaneous waves over a 5-cm segment, i.e., beginning within 0.25 seconds of each other, were recorded. The median amplitude of contractions was calculated and compared to the 2.5th percentile of the median amplitudes of 50 normal subjects previously studied in our laboratory.' I
pH Monitoring Patients were asked to stop all medication for 48 hours before the study and during the monitoring period. Smoking was not allowed. Twenty-four-hour esophageal and gastric pH monitoring was performed using glass electrodes (Model 440 M4, Ingold, Switzerland) and a portable solid-state monitor (Synectics, Irving, TX) capable of storing pH data from two channels, sampled at four-second intervals. The probes were calibrated before and after monitoring using standard buffers at pH 1 and
530
Ann. Surg. ' October 1990
DEMEESTER AND OTHERS
7. They were introduced so that the tip was 5 cm above the upper border of the manometrically determined lower esophageal sphincter for esophageal placement and 5 cm below the lower border of the lower esophageal sphincter for gastric placement. The patient was sent home and instructed to remain in the upright position until he or she retired for the evening, to avoid strenuous exertion, and to follow a diet sheet restricting him or her to three meals composed offood with a pH between 5 and 6. Only water was permitted between meals. A diary was kept of food and fluid intake, symptoms experienced during the monitoring period, the time when a supine position was assumed in preparation for sleep, and the time of rising in the morning. At the end of the test, the stored data were transferred to an IBM personal computer and analyzed using commercial software (Gastrosoft, Irving, TX). The cumulative exposure of the esophagus to acid was expressed as the percentage of time the pH was less than 4 during the study period and defined as abnormal when it exceeded 4.4% (95th percentile of normal). The cumulative exposure of the esophagus to alkalinity was expressed as the percentage of time the pH was more than 7 and defined as abnormal when it exceeded 10.5% (90th percentile of normal).'2 For gastric pH a discriminant analysis of the pH record was used to diagnose the presence of pathologic duodenogastric reflux. A score of 2.2 previously was shown to distinguish between normals and patients with duodenogastric reflux.'3
when biopsies contained specialized columnar epithelium. The presence ofjunctional or fundic-type epithelium was recorded but not used to make the diagnosis. Dysplasia was diagnosed according to guidelines proposed by the Inflammatory Bowel Disease-Dysplasia Morphology Study Group.'6 Under these guidelines, low-grade dysplasia was characterized by glands lined by cells with enlarged hyperchromatic nuclei and nuclear crowding with stratification. High-grade dysplasia was characterized by nuclear stratification extending to the luminal surface of glands, marked nuclear pleomorphism, or loss of nuclear polarity. Biopsies were graded as indefinite for dysplasia if there were some cytologic changes, as described above in the presence of florid acute inflammation. Malignant Barrett's esophagus. In resected specimens with carcinoma, the depth of invasion was described in relation to the standard anatomic landmarks: intramucosal carcinoma if it penetrated the glandular basement membrane but was limited by the muscularis mucosae, intramural carcinoma if it penetrated the muscularis mucosae but not the muscularis propria, and transmural carcinoma if it penetrated the muscularis propria (Fig. 1). Lymph nodes were dissected carefully from all en bloc specimens and assigned to one of the following groups: subcarinal, inferior paraesophageal, parahiatal, around the resected left gastric artery, around the resected splenic artery, and adjacent to the hepatic and celiac arteries. Lymph nodes were submitted separately by the surgeon from the porta hepatis, subpancreatic, and paratracheal areas. The relationship of the involved lymph nodes to
Gastric Acid Secretion and Serum Gastrin Levels
Gastric acid secretion before and after pentagastrin injection was measured using a standard aspiration technique in fasting patients. 4 Hypersecretion was defined by a basal acid output (BAO) of more than 5.0 mmol/hr or a maximal acid output (MAO) of more than 30 mmol/ hr. Serum gastrin levels were measured in each patient by radioimmunoassay and recorded in pg/L.
Intramucosal
Intramural
Transmural
Gastric Emptying Scans Gastric emptying scans were performed in patients witlh benign disease using a standard meal of radiolabeled Tcoatmeal.'5 The percentage of radioactive emission from the stomach was recorded at 15-minute intervals and the decline in the radioactive emission was compared to the decline in 30 control subjects previously studied in our laboratory. '
Histopathology Benign Barrett's esophagus. Biopsies were obtained at endoscopy, with the number per visit ranging from 4 to 48. The diagnosis of Barrett's esophagus was made only
FIG. 1. Staging of the primary tumor according to depth of invasion using standard anatomic landmarks: intramucosal carcinoma if it penetrated the glandular basement membrane but was limited by the muscularis mucosae, intramural carcinoma if through the muscularis mucosae but not through the muscularis propria, transmural if through the mus-
cularis propria.
SURGICAL THERAPY IN BARRETT'S ESOPHAGUS
Vol. 212 * No. 4
primary tumor was classified as peritumoral when the nodes were within 5 cm of the epicenter of the tumor, regional when they were contained in the en bloc resection but beyond 5 cm, and distant when submitted by the surgeon from areas peripheral to the en bloc dissection. The possibilities for the extent of the primary lesion and lymph node involvement are listed in Table 2. Histologic parameters evaluated were tumor grade, growth pattern, and the presence of squamous and neuroendocrine differentiation. Tumors with well-defined glands were graded as well differentiated; all others were deemed poorly differentiated. Growth pattern was classified as either expanding (well circumscribed, pushing margin) or infiltrative (diffuse permeation oftissue). Neuroendocrine differentiation was suspected if there were sheets or large nests of tumor cells with round nuclei and stippled chromatin; it was confirmed by immunohistochemical stains for chromogranin A and neuron-specific enolase. For immunostaining primary antibodies to neuron-specific enolase and chromogranin A (Biogenex) were applied and an avidin-biotin-peroxidase method was used for immunohistochemical development. Positive controls were represented by unrelated tumors known to contain the appropriate antigens. Substitution of rabbit immunoglobulin for the primary antibodies provided negative controls.
Carcinoembryonic Antigen (CEA) Carcinoembryonic antigen in the serum of patients with malignant disease was measured using the Abbott EIA method. The normal value for healthy adults is less than 5 ngr/mL. Tissue from adenocarcinomas arising in Barrett's esophagus was tested for expression of CEA using methods similar to those described above, except that the primary antibody was a polyclonal antibody directed against CEA (DAKO, Carpinteria, CA). Treatment Benign Disease Medical therapy consisted of conservative measures, antacid medication, and H2 receptor antagonists. Indications for antireflux surgery were persistent symptoms, including evidence of aspiration, or the presence of stricture, ulcer, or hemorrhage. The choice of antireflux opTABLE 2. Adenocarcinoma in Barrett's Esophagus: Classification by Depth of Invasion and Lymph Node Metastases
Primary Tumor 0. 1. 2. 3.
In situ carcinoma Intramucosal carcinoma Intramural carcinoma Transmural carcinoma
Lymph Nodes A. No metastases B. Peritumoral metastases C. Regional metastases D. Distant metastases
53J1
eration was based on the strength of esophageal contractions and the length of the esophagus. A short Nissen fundoplication (1.5 to 2 cm) over a 60-Fr bougie was used in patients with adequate contractility and length of the esophageal body.'7 In patients with inadequate contractility, a Belsey partial fundoplication was done and combined with a Collis gastroplasty when esophageal shortening was present. A resection was considered in patients with high-grade dysplasia or those with poor contractility and a severe stricture.'8
Malignant Disease The decision for a curative resection of a carcinoma in Barrett's esophagus was based on the age (75 years or younger) and physiologic fitness (cardiovascular and pulmonary status) of the patient, the preoperative assessment of tumor spread, and intraoperative staging.'9'20 Preoperative staging was done by computed tomographic (CT) scanning for lymph node involvement and distant organ metastases and by endoscopic assessment and measurement of the primary tumor. Patients with tumor measuring 5 cm or less in length and involving less than one half of the esophageal circumference on endoscopy, and no evidence of lymph node enlargement or distant metastasis on CT scan were considered for curative resection. Intraoperative staging was used to switch from a curative to a palliative procedure.'9 The indications to switch were a tumor that could not be resected, cavitary spread, tumor penetration of the mediastinal pleura, distant metastases, obvious multiple node involvement, or microscopic node involvement at the periphery of the resection: paratracheal, subpancreatic, or porta hepatis nodes. A curative operation consisted of an en bloc resection of the distal esophagus, proximal stomach, spleen, and splenic artery, together with the following nodal groups: subcarinal, inferior paraesophageal, parahiatal, left gastric, celiac, hepatic and splenic artery nodes, and subpancreatic. Gastrointestinal continuity was re-established using a colon interposition, as previously described by our group.'8 Patients who were not candidates for curative surgery and who had dysphagia had a palliative transhiatal resection,' with esophagogastrostomy in the neck.
Follow-up Patients with benign disease were seen at yearly intervals, or more often if necessary, for endoscopic surveillance and to assess their response to therapy. Functional results were classified as good: asymptomatic, or with inconsequential symptoms requiring no therapy; fair: improved, but with symptoms and/or endoscopic findings requiring intermittent therapy (antireflux medication or dilatation); poor: unimproved or worse. The median duration of follow-up in benign disease was 3.0 years, with
532
Ann. Surg. ' October 1990
DEMEESTER AND OTHERS
to 12 years. In malignant disease patients 3-month intervals for 3 years and annually thereafter, and no patients were lost to follow-up.
a range of 1 were seen at
Proxka
I
11 5cm Esophageal Segmwz s
Statistical Methods
Nonparametric tests of comparison (Wilcoxon ranktest) and the Fisher's exact test of proportion were used to compare groups with benign disease. For patients who had a curative resection for malignancy, survival was calculated using the Kaplan-Meier actuarial method.22 After palliative resection the median survival in months was calculated. sum
x
xx xx
I
*0 X
xo@**O-o*x
Xi
XX
x
x
III x
* -UncomplIcated -Comli[cated n-41
IV
X
xx x*
*
*
0
V
Distal 20
40
60
80
i6o120
mn
Results Physiologic Tests in Benign Barrett's Esophagus
Esophageal manometry. Esophageal manometry and pH monitoring were performed in 41 of the patients Nwith benign disease. The lower esophageal sphincter was mechanically defective in 37 patients (90%) due to a low pressure alone or in combination with a short overal11 or abdominal length in 29, and a short abdominal leingth alone in 8. There was no difference in the prevalencve of a mechanically defective sphincter between those wit;h or without complications. The median value for each clomponent of the sphincter was less than the 2.5th percerntile of normal (Fig. 2). The amplitude of esophageal contractions in pati ents with Barrett's esophagus was normal in the proximal two
*-
24
mm
Uncomplicated
x -Complicated
22
n-41
20
II
FIG. 3. Distribution of amplitude ofesophageal contractions in 41 patients with Barrett's esophagus. * = uncomplicated Barrett's. X = complicated Barrett's. The boxes represent the normal range (2.5th to 97.5th percentile) of amplitude for each 5-cm segment of the esophageal body. In patients with short esophagi, only three or four segments were able to be measured.
fifths of the esophagus, but markedly reduced in the distal three fifths compared to normal volunteers (Fig. 3). There was also a high prevalence of simultaneous, dropped, and/ or interrupted waves in the distal three fifths of the esophagus (Fig. 4). Thirty-four of forty-one patients (83%) with Barrett's esophagus had peristaltic failure in the distal esophagus due to inadequate contractility and/or abnormalities of wave progression. The frequency ofthe motility abnormalities in the body of the esophagus was similar in those with or without complications. Twenty-four-hour esophageal pH monitoring. Compared to normal values, esophageal acid exposure was increased in 38 (93%) and alkaline exposure in 14 (34%) of
-5
the 41 patients tested. In two of the three patients with normal acid exposure, an increased alkaline exposure was documented. The prevalence of increased acid exposure in patients with complications was the same as in those without complications, whereas the prevalence of in-
18 0
.4
16'
140 160 180 200
Hg
.6 cm
Hg
11
x
0
14
x
12' 0
x
0
x
0x~
.3 10
10xx
__
80*0
x
6-
of Waves in 10 Swallows
#
[2
0
*1
*-
.exx 0
Pressue
ox
x
xx 2-
6
.
_
4-
xx
0@
xxxx ..
8
x.Complcated
4
n-41
x xx
Abdonwl Length
*=Uncompicated
o
Overal Length
FIG. 2. Distribution of lower esophageal sphincter pressure, abdominal length, and overall length in 41 patients with Barrett's esophagus. 0 = uncomplicated Barrett's. X = complicated Barrett's. The boxes represent the normal range (2.5th to 97.5th percentile for pressure and overall length, 5th to 95th percentile for abdominal length).
*xxx
..xx
ex
*ex
2
I exxx
of
I " x xXI
ox
*xx
*xxx
*--.xxx
*.xx
x
Suao Waves
D Waves
hntemfpted Waves
FIG. 4. The frequency of simultaneous, dropped, or interrupted esophageal contractions in 41 patients with Barrett's esophagus. 0 = uncomplicated Barrett's. x = complicated Barrett's. Boxes represent the range of normal.
VOl. 212 NO. 4
_ Acid pHc4 100
533
SURGICAL THERAPY IN BARRETT'S ESOPHAGUS
-
Alkali pH 7
6040
% Patients
% Time >pH 7
80
50-
*
60-
40-
40xx
20-
30.AxlM,M111%,WIW,M,WINMI
0
Uncompliccated (n-18) .
* p
x
Complicated (nw23) 0.01 Fisher's Exact Test
FIG. 5. The prevalence of abnormal esophageal acid and alkaline exposure in patients with or without complications of Barrett's esophagus.
0
20-
xxx
NormTalI--1 u +t*mmm .
.
.
.
.I:. Mean *0000
creased alkaline exposure was significantly higher in those with complications (Fig. 5). This observation of a similar prevalence of acid exposure and different alkaline exposure was also true for the mean percentage time the pH was less than 4 or more than 7 (Figs. 6 and 7). Of the 14 patients who had increased esophageal alkaline exposure, 13 (93%) had complications. Of the 27 patients with normal alkaline exposure, 12 (44%) had complications. The likelihood of a specific complication occurring in a patient with increased alkaline exposure is shown in Table 3. Twenty-four-hour gastric pH monitoring. Discriminant analysis of the 24-hour gastric pH data showed an ab-
60r
xxx
%pHne 7) in patients with or without complications of Barrett's esophagus (p < 0.01).
normal score for duodenogastric reflux in 10 of 24 patients tested. Of the 10 patients with documented duodenogastric reflux, five had increased esophageal alkaline exposure. Of the 14 patients shown not to have duodenogastric reflux, none had increased esophageal alkaline exposure. The prevalence of duodenogastric reflux was higher in patients with complications of Barrett's esophagus (p < 0.05; Fig. 8). Serum gastrin levels. Fasting serum gastrin levels were measured in 22 patients; 11 had normal and 11 increased esophageal alkaline exposure. The mean gastrin level (± SEM) in patients with increased esophageal alkaline exposure was 59 (± 11) pg/mL compared to 35 (± 7.5) pg/mL in those with normal alkaline exposure (p < 0.05). Gastric secretion studies. Gastric hypersecretion was documented in 10 of 23 patients (44%) tested. Table 4 shows that the mean value of acid secretion was similar TABLE 3. The Relationship Between Complications in Barrett's
Mean
Esophagus and Esophageal Alkaline Exposure x x xx xxxxx x x
000 0
10
00
Mean
0
20-
Mean
xxx
0@0 000 0
I ------.-------Uncomlicated n=18
Increased Alkaline Exposure
Complication -
-
(n
=
14)
Normal Alkaline Exposure (n
=
27)
Fisher Test
-
-
xx
Complcated n=23
FIG. 6. Distribution and mean value of esophageal acid exposure (percentage of time pH < 4) in patients with or without complications of Barrett's esophagus (p < 0.05).
18* Stricture Dysplasia 11 7 Ulcer Any above 25
11/14 (79%) 6/14 (43%) 3/14 (21%)
7/27 (26%) 5/27 (19%) 4/27 (15%)
13/14 (93%)
12/27 (44%)
p < 0.01 p = 0.09 p = 0.33 p < 0.001
Two patients with stricture did not have 24-hour esophageal pH monitoring. *
701-
Ann. SUrg. OctOber 1990
DEMEESTER AND OTHERS
534 Prevalence
% 1201i Mea
(%)
*
-
Retahwd 801
100
601 5040=-
T
1/2
(mnuges) NS
70
806040......-
-
--------
201
301
-----
0
2010
0
o
1S
30
60
45
l UncobMIcatd
Uncomplicated *
p
(n=10)
Complicated (nw14)
.05 Fisher's Exact Test
FIG. 8. The frequency of duodenogastric reflux in patients with or without complications of Barrett's esophagus (p < 0.05).
in patients with and without complications of Barrett's esophagus. Gastric emptying. Gastric emptying scans were reported abnormal in 17 of 32 (53%) patients tested, with delayed emptying in 13 and rapid in 4. Gastric emptying was similar in those with normal or increased alkaline esophageal exposure. Figure 9 illustrates that the mean gastric emptying rate in the 26 patients whose curves were available was initially slower in those with complications of Barrett's esophagus. There was no statistically significant difference in the retention half life (T'/2) between the two groups, and both curves were within the normal range.
Pathology in Benign Barrett's Esophagus By definition the 47 patients with benign Barrett's esophagus had specialized columnar epithelium in the lower esophagus. In seven patients there was also junctional-type epithelium and in six fundic-type epithelium was evident. Paneth cells were identified in the specialized epithelium of six patients and neuroendocrine cells were present in four. Eleven of the patients with benign Barrett's esophagus showed evidence of dysplasia, low grade in nine and high grade in two. Two patients had biopsies indefinite for dysplasia. The dysplastic changes always were localized TABLE 4. Gastric Secretion Studies in Patients with Benign Barrett's Esophagus
Study Prevalence of hypersecretion Basal acid output (mmol/hour) Maximum acid output
(mmol/hour) NS, not significant.
Uncomplicated Complicated Barrett's p Barrett's Value (n = 15) (n = 8) 5/8 7.1 ± 5.8
28 ± 14
5/15 3.2 ± 2.5
NS NS
18 ± 9.4
NS
76
90
105 120
Compicated
FIG. 9. The gastric emptying rate in 26 patients with or without complications of Barrett's esophagus. The fine dotted lines represent the 10th to 90th percentiles of normal. The mean TI is illustrated in the bar graph. There was no difference between the groups (p > 0.05).
to specialized columnar epithelium. In five patients dysplasia was seen concomitantly with stricture and in two, with an ulcer.
Results of Therapy in Benign Barrett's Esophagus Antireflux surgery was performed in 35 patients: a Nissen fundoplication in 31 (combined with a proximal gastric vagotomy in 6), a Belsey partial fundoplication in 3, and a Collis gastroplasty combined with a Belsey partial fundoplication in 2. Six patients had an esophageal resection. In four patients the indication for resection was an esophageal stricture with inadequate esophageal contractility and persistent dysphagia after dilatation, and in two patients the indication was the presence of high-grade dysplasia. One of the patients with a stricture had an associated ulcer that penetrated into the mediastinum and two had low-grade dysplasia. Neither of the latter had intramucosal carcinoma in the resected specimen, whereas it was discovered in one of the specimens resected for high-grade dysplasia. The symptomatic results of surgical therapy are shown in Table 5. Four patients who had relief of heartburn and dysphagia continue to have abdominal pain, nausea, and bilious vomiting after antireflux surgery, suggesting persistence of duodenogastric reflux. Three of the four were tested for duodenogastric reflux. All three were positive and subsequently had bile diversion procedures. Three patients required continuation of acid suppression therTABLE 5. Symptomatic Results of Surgical Therapy Procedure
n
Good
Nissen Belsey Collis-Belsey Total Resection
30 3 2 35 6
23 3 1 27 (77%) 3
Fair 6 0 1 7
3
(20%)
Poor 1 0 0 1 (3%) 0
Vol. 212 * No. 4
SURGICAL THERAPY IN BARRETT'S ESOPHAGUS
apy, one for recurrent heartburn and two for symptomatic gastritis associated with gastric hypersecretion. Only 1 of the 20 stricture patients required postoperative dilatations and no strictures developed after surgery. All six of the Barrett's ulcers treated by antireflux operation healed on endoscopic follow-up and have not recurred. Overall 77% of the patients had a good result after antireflux surgery. Carcinoma has not develped in any of the 35 patients who underwent antireflux surgery. Of the nine patients with dysplasia, none has progressed and one has persisted as high grade. Neither the total length of the Barrett's esophagus nor the size of the dysplastic area appears to have changed during a mean follow-up of 3 years, totalling 123 patient years. In six patients surgery was not performed. In three the operative risk was high because of age or poor cardiovascular condition, and in three the patients chose not to have an operation. In these patients symptoms persisted despite the continuation of therapy with H2 receptor antagonists.
535
Actuarial Survival Following Curative Resection
100-10-
n=16
11
75-i % Surviviing 50-
4
2
2
3 Years
4
5
251
2
FIG. 10. The actuarial survival times of patients with adenocarcinoma in Barrett's esophagus after curative resection, calculated by the KaplanMeier method, illustrating a 77% 2-year survival rate and 53% 5-year survival rate. The numbers on the curve refer to the number of patients alive at the start of each year.
Surgical Resection for Carcinoma in Barrett's Esophagus A curative resection was performed in 15 patients with adenocarcinoma. One of the two patients who had an esophagectomy for high-grade dysplasia had intramucosal carcinoma in the specimen, increasing the number of patients with early adenocarcinoma to 16. These patients were all less than 75 years of age, with good cardiorespiratory function. One patient with an intramural tumor died while hospitalized, resulting in a hospital mortality rate of 6%. Palliative surgery was performed in 10 patients because of extensive local disease. In four patients no resection was performed because of extensive local disease in each along with the intraoperative discovery of undiagnosed liver metastases in two. In none of these patients did CT scanning detect the mediastinal or liver involvement. Survival After Resection for Carcinoma An actuarial survival curve was calculated for the 15 patients who underwent a curative resection and one patient who had intramucosal carcinoma discovered in the specimen resected for high-grade dysplasia. Two years after resection, the survival rate was 77% and after 5 years it was 53% (Fig. 10). Table 6 shows the relationship of the depth of the primary tumor and lymph node involvement to survival. Four of the five patients with intramucosal carcinoma are alive 20, 24, 39, and 105 months after resection. One died at home from an acute pulmonary embolus 2 months after surgery. In contrast the median survival time for patients after palliative resection or no resection was 12 months.
Histopathology of Carcinoma in Barrett's Esophagus Of the 29 carcinomas arising in Barrett's esophagus, 25 were resected and available for pathologic assessment. All 25 specimens contained specialized columnar epithelium adjacent to the adenocarcinoma. Six of the twenty-five also contained junctional-type epithelium and four contained fundic-type epithelium. In every specimen there was low-grade dysplasia adjacent to the tumor, and in 13 specimens high-grade dysplasia also could be identified (Fig. 11). The dysplastic changes were confined to the specialized columnar epithelium, except for one specimen in which dysplastic cells occurred in fundic-type Barrett's
epithelium. The pathologic features for each cancer in which an en bloc resection was done for cure are summarized in Table 7. There are several salient observations to be made. (1) Among 16 specimens the tumor was intramucosal in 5, intramural in 7, and transmural in 4. (2) The extent of lymph node involvement was related to the extent of the primary tumor. Lymph node involvement was not seen with intramucosal carcinoma. In the seven patients with intramural tumor, five had positive nodes. They were few and peritumoral in four patients, and many and regional in one patient. All four patients with transmural tumor had peritumoral lymph node metastases and two had extension to regional and distant nodes. The latter were discovered at operation after the opportunity to convert to a palliative resection had passed. None of the 15 patients who had an en bloc resection for cure had positive nodes along the splenic artery. (3) Differentiation and growth
DEMEESTER AND OTHERS
536
Ann. Surg. * October 1990
TABLE 6. Outcome After Resection for Cure Years Follow-up
Stage
n
Intramucosal* nodes negative Intramural nodes negative Intramural nodes positive Transmural nodes positive
5 2 5 4
Barrett's Esophagus
TOM R. DEMEESTER, M.D., STEPHEN E. A. ATTWOOD, F.R.C.S.I., THOMAS C. SMYRK, M.D., DAVID H. THERKILDSEN, M.D., and RONALD A. HINDER, M.D.
Seventy-six patients with Barrett's esophagus were cared for during a 10-year period. Fifty-six patients (74%) presented with complications of the disease. There were 20 strictures, 7 giant ulcers, 11 cases of dysplasia, and 29 patients with carcinoma. In patients with benign disease, 93% had mechanically defective sphincters and 83% had peristaltic failure of the lower esophageal body. Esophageal pH monitoring showed excessive esophageal exposure to pH less than 4 in 93% and excessive exposure to pH more than 7 in 34% of the patients tested. Ninety-three per cent of patients with excessive alkaline exposure had complications, compared to only 44% with normal alkaline exposure (p < 0.01). Gastric pH monitoring, serum gastrin levels, and gastric acid analysis supported a duodenal source for the alkaline exposure. Antireflux surgery was performed using Nissen fundoplication in 30, Belsey partial fundoplication in 3, and CollisBelsey gastroplasty in 2. Six required resection with colon interposition. Good symptomatic control was achieved in 77% after antireflux surgery. Four patients had symptoms and signs of duodenogastric reflux; three required a bile diversion procedure. Fifteen patients had an en bloc curative resection with colon interposition. One patient with high-grade dysplasia on biopsy was found to have intramucosal carcinoma after simple esophagectomy. Five tumors were intramucosal, seven were intramural, and four were transmural. Lymph node involvement occurred only in the latter two. Actuarial survival 5 years after curative resection was 53%. Median survival time for patients after palliative resection or no resection was 12 months. Study of en bloc specimens indicated that extent of resection should be adapted to extent of disease: esophagectomy for intramucosal disease, en bloc esophagectomy with splenic preservation for intramural and transmural disease. Serum CEA was useful in detecting recurrent disease after surgery when the primary tumor stained positively for CEA.
C
From Creighton University School of Medicine, the Department of Surgery, Omaha, Nebraska
Barrett's esophagus,' may be complicated by
ration, or malignant degeneration.2'3 Barrett's esophagus is usually associated with gastroesophageal reflux disease, but the reasons why only a portion of patients with reflux develop Barrett's and only some of these are prone to complications are not known. Gastric juice generally is regarded as the damaging agent in gastroesophageal reflux disease. Medical therapy is aimed at suppressing its acid component, allowing other components such as duodenal secretions, pancreatic secretions, and bile to continue further tissue destruction. This may explain why medical therapy, as opposed to surgical therapy, which constructs an antireflux barrier, fails to provide complete symptomatic relief in most patients,4 and allows upward progression of the columnar mucosa.5 While there is strong evidence for sequential progression from low-grade dysplasia to high-grade dysplasia to invasive carcinoma, there is no consensus on the frequency and tempo of progression and whether progression is influenced by medical or surgical therapy.68 Controversy exists over the appropriateness of surveillance because an improved survival by resection of early cancers arising in Barrett's esophagus has not been well documented. The aim of this study was to examine the pathophysiology of Barrett's esophagus and the role of surgery in the treatment of the disease and its benign or malignant
stricture, giant ulceration, hemorrhage, perfo-
complications.
OLUMNAR-LINED LOWER ESOPHAGUS, known as
Presented at the 1 10th Annual Meeting of the American Surgical Association, Washington, D.C., April 5-7, 1990. Accepted for publication April 12, 1990. Address reprint requests to Tom R. DeMeester, M.D., University of Southern California Medical Center, Department of Surgery, 1200 North State St., Los Angeles, CA 90033.
528
Patients and Methods Patients
Seventy-six patients with Barrett's esophagus were diagnosed during a 10-year period by the endoscopic ob-
SURGICAL THERAPY IN BARRETT'S ESOPHAGUS
Vol. 212 * No. 4
servation of a segment of lower esophagus, at least 3 cm in length, lined by columnar epithelium in continuity with the gastric mucosa, and confirmed by histology. The columnarization extended a median of 6.2 cm over the lower esophagus, with a range of 3 to 18 cm. Twenty patients (26%) presented without complications; 27 (36%) with complications of stricture, ulcer, or dysplasia; and 29 (38%) with invasive malignancy. At endoscopy the strictures were fully dilated to relieve any obstruction before performing physiologic tests. Table 1 describes the age and sex distribution of the patients with Barrett's esophagus according to the presence and type of complication. Patients with complications were 10 years older than those without complications. Benign complications were more frequent in female (15 of 21 patients or 71%) compared to male patients ( 12 of 26 patients or 46%). Multiple complications were seen in nine of those with benign disease. The patients with malignant degeneration were almost exclusively male (97%). Cancer of the esophagus developed in 3 of the men in their early 40s and in one in his 30s. During the same time period, we treated 135 patients with esophageal cancer. Sixty-three (47%) had squamous carcinoma, 43 (32%) had adenocarcinoma of the cardia or lower esophagus, and 29 (21 %) had adenocarcinoma in Barrett's esophagus.
Physiologic Testing of Patients with Benign Barrett's Esophagus
Manometry Esophageal manometry was performed using a single catheter assembly consisting of five water-filled polyethylene tubes with five exit ports located at 5 cm intervals along its length and oriented radially around the circumference of the catheter. The catheter was attached to a pump (Arndorfer Medical Specialties Inc., Greendale, WI) capable of a low perfusion rate with distilled water at 0.6 mL per minute with low compliance, (measured at 100 mmHg in 0.08 seconds during occlusion of the distal side TABLE 1. Barrett's Esophagus: Age and Sex Distribution
Study Population
n
Patients with Barrett's No complications
76 20 27 20 7 11 29 28
Benign Complications* Stricture* Ulceration* Dysplasia* Malignant Complications Adenocarcinoma Squamous carcinoma *
Mean Age
59 51 61 55 60 58 63
Age
Range 25-89 27-76 25-89 25-85 37-74 27-74 36-79
Sex M:F 54:22 14:6 12:15 9:11 3:4 6:5 28:1
I
Note that nine patients (mean age, 46 years) had multiple benign
complications.
529
holes). Each perfused channel was linked to a transducer (Statham transducer model P2306, Gould, Cleveland, OH) and the pressure recorded on a Polygraph pen recorder (ES 1000, Gould) and stored digitally on a computer (IBM AT, White Plains, NY). This dual record allowed a choice of computerized or manual analysis. Computerized analysis was performed using a dedicated program (ESA/Motility, T. DeMeester, G. Schneider, M. Walker, Creighton University). In the fasting patient, the catheter was introduced through the nose into the stomach and pulled back stepwise across the gastroesophageal junction to obtain a pressure profile of the lower esophageal sphincter.9 The upper and lower border of the lower sphincter, the respiratory inversion point, and its height above gastric baseline were defined. From these measurements the sphincter's pressure, overall length, and abdominal length, that is, the length below the respiratory inversion point, were determined. Based on the values obtained in 50 normal subjects,'0 a mechanically defective lower esophageal sphincter was defined as one having one or more of the following characteristics: an average resting pressure of less than 6 mmHg, an average length of less than 2 cm, or an average length exposed to the positive-pressure environment of the abdomen of less than 1 cm. These values are below the 2.5th percentile for the normal range of sphincter pressure and overall length and below the 5th percentile for abdominal length. Esophageal peristalsis was measured by placing the catheter in the body of the esophagus with the proximal port 1 cm below the lower border of the upper sphincter and asking the patient to take 10 dry swallows and 10 swallows of a 5-mL water bolus. The number of interrupted waves, i.e., waves that failed to progress; dropped waves, i.e., waves that failed to occur in a segment; and simultaneous waves over a 5-cm segment, i.e., beginning within 0.25 seconds of each other, were recorded. The median amplitude of contractions was calculated and compared to the 2.5th percentile of the median amplitudes of 50 normal subjects previously studied in our laboratory.' I
pH Monitoring Patients were asked to stop all medication for 48 hours before the study and during the monitoring period. Smoking was not allowed. Twenty-four-hour esophageal and gastric pH monitoring was performed using glass electrodes (Model 440 M4, Ingold, Switzerland) and a portable solid-state monitor (Synectics, Irving, TX) capable of storing pH data from two channels, sampled at four-second intervals. The probes were calibrated before and after monitoring using standard buffers at pH 1 and
530
Ann. Surg. ' October 1990
DEMEESTER AND OTHERS
7. They were introduced so that the tip was 5 cm above the upper border of the manometrically determined lower esophageal sphincter for esophageal placement and 5 cm below the lower border of the lower esophageal sphincter for gastric placement. The patient was sent home and instructed to remain in the upright position until he or she retired for the evening, to avoid strenuous exertion, and to follow a diet sheet restricting him or her to three meals composed offood with a pH between 5 and 6. Only water was permitted between meals. A diary was kept of food and fluid intake, symptoms experienced during the monitoring period, the time when a supine position was assumed in preparation for sleep, and the time of rising in the morning. At the end of the test, the stored data were transferred to an IBM personal computer and analyzed using commercial software (Gastrosoft, Irving, TX). The cumulative exposure of the esophagus to acid was expressed as the percentage of time the pH was less than 4 during the study period and defined as abnormal when it exceeded 4.4% (95th percentile of normal). The cumulative exposure of the esophagus to alkalinity was expressed as the percentage of time the pH was more than 7 and defined as abnormal when it exceeded 10.5% (90th percentile of normal).'2 For gastric pH a discriminant analysis of the pH record was used to diagnose the presence of pathologic duodenogastric reflux. A score of 2.2 previously was shown to distinguish between normals and patients with duodenogastric reflux.'3
when biopsies contained specialized columnar epithelium. The presence ofjunctional or fundic-type epithelium was recorded but not used to make the diagnosis. Dysplasia was diagnosed according to guidelines proposed by the Inflammatory Bowel Disease-Dysplasia Morphology Study Group.'6 Under these guidelines, low-grade dysplasia was characterized by glands lined by cells with enlarged hyperchromatic nuclei and nuclear crowding with stratification. High-grade dysplasia was characterized by nuclear stratification extending to the luminal surface of glands, marked nuclear pleomorphism, or loss of nuclear polarity. Biopsies were graded as indefinite for dysplasia if there were some cytologic changes, as described above in the presence of florid acute inflammation. Malignant Barrett's esophagus. In resected specimens with carcinoma, the depth of invasion was described in relation to the standard anatomic landmarks: intramucosal carcinoma if it penetrated the glandular basement membrane but was limited by the muscularis mucosae, intramural carcinoma if it penetrated the muscularis mucosae but not the muscularis propria, and transmural carcinoma if it penetrated the muscularis propria (Fig. 1). Lymph nodes were dissected carefully from all en bloc specimens and assigned to one of the following groups: subcarinal, inferior paraesophageal, parahiatal, around the resected left gastric artery, around the resected splenic artery, and adjacent to the hepatic and celiac arteries. Lymph nodes were submitted separately by the surgeon from the porta hepatis, subpancreatic, and paratracheal areas. The relationship of the involved lymph nodes to
Gastric Acid Secretion and Serum Gastrin Levels
Gastric acid secretion before and after pentagastrin injection was measured using a standard aspiration technique in fasting patients. 4 Hypersecretion was defined by a basal acid output (BAO) of more than 5.0 mmol/hr or a maximal acid output (MAO) of more than 30 mmol/ hr. Serum gastrin levels were measured in each patient by radioimmunoassay and recorded in pg/L.
Intramucosal
Intramural
Transmural
Gastric Emptying Scans Gastric emptying scans were performed in patients witlh benign disease using a standard meal of radiolabeled Tcoatmeal.'5 The percentage of radioactive emission from the stomach was recorded at 15-minute intervals and the decline in the radioactive emission was compared to the decline in 30 control subjects previously studied in our laboratory. '
Histopathology Benign Barrett's esophagus. Biopsies were obtained at endoscopy, with the number per visit ranging from 4 to 48. The diagnosis of Barrett's esophagus was made only
FIG. 1. Staging of the primary tumor according to depth of invasion using standard anatomic landmarks: intramucosal carcinoma if it penetrated the glandular basement membrane but was limited by the muscularis mucosae, intramural carcinoma if through the muscularis mucosae but not through the muscularis propria, transmural if through the mus-
cularis propria.
SURGICAL THERAPY IN BARRETT'S ESOPHAGUS
Vol. 212 * No. 4
primary tumor was classified as peritumoral when the nodes were within 5 cm of the epicenter of the tumor, regional when they were contained in the en bloc resection but beyond 5 cm, and distant when submitted by the surgeon from areas peripheral to the en bloc dissection. The possibilities for the extent of the primary lesion and lymph node involvement are listed in Table 2. Histologic parameters evaluated were tumor grade, growth pattern, and the presence of squamous and neuroendocrine differentiation. Tumors with well-defined glands were graded as well differentiated; all others were deemed poorly differentiated. Growth pattern was classified as either expanding (well circumscribed, pushing margin) or infiltrative (diffuse permeation oftissue). Neuroendocrine differentiation was suspected if there were sheets or large nests of tumor cells with round nuclei and stippled chromatin; it was confirmed by immunohistochemical stains for chromogranin A and neuron-specific enolase. For immunostaining primary antibodies to neuron-specific enolase and chromogranin A (Biogenex) were applied and an avidin-biotin-peroxidase method was used for immunohistochemical development. Positive controls were represented by unrelated tumors known to contain the appropriate antigens. Substitution of rabbit immunoglobulin for the primary antibodies provided negative controls.
Carcinoembryonic Antigen (CEA) Carcinoembryonic antigen in the serum of patients with malignant disease was measured using the Abbott EIA method. The normal value for healthy adults is less than 5 ngr/mL. Tissue from adenocarcinomas arising in Barrett's esophagus was tested for expression of CEA using methods similar to those described above, except that the primary antibody was a polyclonal antibody directed against CEA (DAKO, Carpinteria, CA). Treatment Benign Disease Medical therapy consisted of conservative measures, antacid medication, and H2 receptor antagonists. Indications for antireflux surgery were persistent symptoms, including evidence of aspiration, or the presence of stricture, ulcer, or hemorrhage. The choice of antireflux opTABLE 2. Adenocarcinoma in Barrett's Esophagus: Classification by Depth of Invasion and Lymph Node Metastases
Primary Tumor 0. 1. 2. 3.
In situ carcinoma Intramucosal carcinoma Intramural carcinoma Transmural carcinoma
Lymph Nodes A. No metastases B. Peritumoral metastases C. Regional metastases D. Distant metastases
53J1
eration was based on the strength of esophageal contractions and the length of the esophagus. A short Nissen fundoplication (1.5 to 2 cm) over a 60-Fr bougie was used in patients with adequate contractility and length of the esophageal body.'7 In patients with inadequate contractility, a Belsey partial fundoplication was done and combined with a Collis gastroplasty when esophageal shortening was present. A resection was considered in patients with high-grade dysplasia or those with poor contractility and a severe stricture.'8
Malignant Disease The decision for a curative resection of a carcinoma in Barrett's esophagus was based on the age (75 years or younger) and physiologic fitness (cardiovascular and pulmonary status) of the patient, the preoperative assessment of tumor spread, and intraoperative staging.'9'20 Preoperative staging was done by computed tomographic (CT) scanning for lymph node involvement and distant organ metastases and by endoscopic assessment and measurement of the primary tumor. Patients with tumor measuring 5 cm or less in length and involving less than one half of the esophageal circumference on endoscopy, and no evidence of lymph node enlargement or distant metastasis on CT scan were considered for curative resection. Intraoperative staging was used to switch from a curative to a palliative procedure.'9 The indications to switch were a tumor that could not be resected, cavitary spread, tumor penetration of the mediastinal pleura, distant metastases, obvious multiple node involvement, or microscopic node involvement at the periphery of the resection: paratracheal, subpancreatic, or porta hepatis nodes. A curative operation consisted of an en bloc resection of the distal esophagus, proximal stomach, spleen, and splenic artery, together with the following nodal groups: subcarinal, inferior paraesophageal, parahiatal, left gastric, celiac, hepatic and splenic artery nodes, and subpancreatic. Gastrointestinal continuity was re-established using a colon interposition, as previously described by our group.'8 Patients who were not candidates for curative surgery and who had dysphagia had a palliative transhiatal resection,' with esophagogastrostomy in the neck.
Follow-up Patients with benign disease were seen at yearly intervals, or more often if necessary, for endoscopic surveillance and to assess their response to therapy. Functional results were classified as good: asymptomatic, or with inconsequential symptoms requiring no therapy; fair: improved, but with symptoms and/or endoscopic findings requiring intermittent therapy (antireflux medication or dilatation); poor: unimproved or worse. The median duration of follow-up in benign disease was 3.0 years, with
532
Ann. Surg. ' October 1990
DEMEESTER AND OTHERS
to 12 years. In malignant disease patients 3-month intervals for 3 years and annually thereafter, and no patients were lost to follow-up.
a range of 1 were seen at
Proxka
I
11 5cm Esophageal Segmwz s
Statistical Methods
Nonparametric tests of comparison (Wilcoxon ranktest) and the Fisher's exact test of proportion were used to compare groups with benign disease. For patients who had a curative resection for malignancy, survival was calculated using the Kaplan-Meier actuarial method.22 After palliative resection the median survival in months was calculated. sum
x
xx xx
I
*0 X
xo@**O-o*x
Xi
XX
x
x
III x
* -UncomplIcated -Comli[cated n-41
IV
X
xx x*
*
*
0
V
Distal 20
40
60
80
i6o120
mn
Results Physiologic Tests in Benign Barrett's Esophagus
Esophageal manometry. Esophageal manometry and pH monitoring were performed in 41 of the patients Nwith benign disease. The lower esophageal sphincter was mechanically defective in 37 patients (90%) due to a low pressure alone or in combination with a short overal11 or abdominal length in 29, and a short abdominal leingth alone in 8. There was no difference in the prevalencve of a mechanically defective sphincter between those wit;h or without complications. The median value for each clomponent of the sphincter was less than the 2.5th percerntile of normal (Fig. 2). The amplitude of esophageal contractions in pati ents with Barrett's esophagus was normal in the proximal two
*-
24
mm
Uncomplicated
x -Complicated
22
n-41
20
II
FIG. 3. Distribution of amplitude ofesophageal contractions in 41 patients with Barrett's esophagus. * = uncomplicated Barrett's. X = complicated Barrett's. The boxes represent the normal range (2.5th to 97.5th percentile) of amplitude for each 5-cm segment of the esophageal body. In patients with short esophagi, only three or four segments were able to be measured.
fifths of the esophagus, but markedly reduced in the distal three fifths compared to normal volunteers (Fig. 3). There was also a high prevalence of simultaneous, dropped, and/ or interrupted waves in the distal three fifths of the esophagus (Fig. 4). Thirty-four of forty-one patients (83%) with Barrett's esophagus had peristaltic failure in the distal esophagus due to inadequate contractility and/or abnormalities of wave progression. The frequency ofthe motility abnormalities in the body of the esophagus was similar in those with or without complications. Twenty-four-hour esophageal pH monitoring. Compared to normal values, esophageal acid exposure was increased in 38 (93%) and alkaline exposure in 14 (34%) of
-5
the 41 patients tested. In two of the three patients with normal acid exposure, an increased alkaline exposure was documented. The prevalence of increased acid exposure in patients with complications was the same as in those without complications, whereas the prevalence of in-
18 0
.4
16'
140 160 180 200
Hg
.6 cm
Hg
11
x
0
14
x
12' 0
x
0
x
0x~
.3 10
10xx
__
80*0
x
6-
of Waves in 10 Swallows
#
[2
0
*1
*-
.exx 0
Pressue
ox
x
xx 2-
6
.
_
4-
xx
0@
xxxx ..
8
x.Complcated
4
n-41
x xx
Abdonwl Length
*=Uncompicated
o
Overal Length
FIG. 2. Distribution of lower esophageal sphincter pressure, abdominal length, and overall length in 41 patients with Barrett's esophagus. 0 = uncomplicated Barrett's. X = complicated Barrett's. The boxes represent the normal range (2.5th to 97.5th percentile for pressure and overall length, 5th to 95th percentile for abdominal length).
*xxx
..xx
ex
*ex
2
I exxx
of
I " x xXI
ox
*xx
*xxx
*--.xxx
*.xx
x
Suao Waves
D Waves
hntemfpted Waves
FIG. 4. The frequency of simultaneous, dropped, or interrupted esophageal contractions in 41 patients with Barrett's esophagus. 0 = uncomplicated Barrett's. x = complicated Barrett's. Boxes represent the range of normal.
VOl. 212 NO. 4
_ Acid pHc4 100
533
SURGICAL THERAPY IN BARRETT'S ESOPHAGUS
-
Alkali pH 7
6040
% Patients
% Time >pH 7
80
50-
*
60-
40-
40xx
20-
30.AxlM,M111%,WIW,M,WINMI
0
Uncompliccated (n-18) .
* p
x
Complicated (nw23) 0.01 Fisher's Exact Test
FIG. 5. The prevalence of abnormal esophageal acid and alkaline exposure in patients with or without complications of Barrett's esophagus.
0
20-
xxx
NormTalI--1 u +t*mmm .
.
.
.
.I:. Mean *0000
creased alkaline exposure was significantly higher in those with complications (Fig. 5). This observation of a similar prevalence of acid exposure and different alkaline exposure was also true for the mean percentage time the pH was less than 4 or more than 7 (Figs. 6 and 7). Of the 14 patients who had increased esophageal alkaline exposure, 13 (93%) had complications. Of the 27 patients with normal alkaline exposure, 12 (44%) had complications. The likelihood of a specific complication occurring in a patient with increased alkaline exposure is shown in Table 3. Twenty-four-hour gastric pH monitoring. Discriminant analysis of the 24-hour gastric pH data showed an ab-
60r
xxx
%pHne 7) in patients with or without complications of Barrett's esophagus (p < 0.01).
normal score for duodenogastric reflux in 10 of 24 patients tested. Of the 10 patients with documented duodenogastric reflux, five had increased esophageal alkaline exposure. Of the 14 patients shown not to have duodenogastric reflux, none had increased esophageal alkaline exposure. The prevalence of duodenogastric reflux was higher in patients with complications of Barrett's esophagus (p < 0.05; Fig. 8). Serum gastrin levels. Fasting serum gastrin levels were measured in 22 patients; 11 had normal and 11 increased esophageal alkaline exposure. The mean gastrin level (± SEM) in patients with increased esophageal alkaline exposure was 59 (± 11) pg/mL compared to 35 (± 7.5) pg/mL in those with normal alkaline exposure (p < 0.05). Gastric secretion studies. Gastric hypersecretion was documented in 10 of 23 patients (44%) tested. Table 4 shows that the mean value of acid secretion was similar TABLE 3. The Relationship Between Complications in Barrett's
Mean
Esophagus and Esophageal Alkaline Exposure x x xx xxxxx x x
000 0
10
00
Mean
0
20-
Mean
xxx
0@0 000 0
I ------.-------Uncomlicated n=18
Increased Alkaline Exposure
Complication -
-
(n
=
14)
Normal Alkaline Exposure (n
=
27)
Fisher Test
-
-
xx
Complcated n=23
FIG. 6. Distribution and mean value of esophageal acid exposure (percentage of time pH < 4) in patients with or without complications of Barrett's esophagus (p < 0.05).
18* Stricture Dysplasia 11 7 Ulcer Any above 25
11/14 (79%) 6/14 (43%) 3/14 (21%)
7/27 (26%) 5/27 (19%) 4/27 (15%)
13/14 (93%)
12/27 (44%)
p < 0.01 p = 0.09 p = 0.33 p < 0.001
Two patients with stricture did not have 24-hour esophageal pH monitoring. *
701-
Ann. SUrg. OctOber 1990
DEMEESTER AND OTHERS
534 Prevalence
% 1201i Mea
(%)
*
-
Retahwd 801
100
601 5040=-
T
1/2
(mnuges) NS
70
806040......-
-
--------
201
301
-----
0
2010
0
o
1S
30
60
45
l UncobMIcatd
Uncomplicated *
p
(n=10)
Complicated (nw14)
.05 Fisher's Exact Test
FIG. 8. The frequency of duodenogastric reflux in patients with or without complications of Barrett's esophagus (p < 0.05).
in patients with and without complications of Barrett's esophagus. Gastric emptying. Gastric emptying scans were reported abnormal in 17 of 32 (53%) patients tested, with delayed emptying in 13 and rapid in 4. Gastric emptying was similar in those with normal or increased alkaline esophageal exposure. Figure 9 illustrates that the mean gastric emptying rate in the 26 patients whose curves were available was initially slower in those with complications of Barrett's esophagus. There was no statistically significant difference in the retention half life (T'/2) between the two groups, and both curves were within the normal range.
Pathology in Benign Barrett's Esophagus By definition the 47 patients with benign Barrett's esophagus had specialized columnar epithelium in the lower esophagus. In seven patients there was also junctional-type epithelium and in six fundic-type epithelium was evident. Paneth cells were identified in the specialized epithelium of six patients and neuroendocrine cells were present in four. Eleven of the patients with benign Barrett's esophagus showed evidence of dysplasia, low grade in nine and high grade in two. Two patients had biopsies indefinite for dysplasia. The dysplastic changes always were localized TABLE 4. Gastric Secretion Studies in Patients with Benign Barrett's Esophagus
Study Prevalence of hypersecretion Basal acid output (mmol/hour) Maximum acid output
(mmol/hour) NS, not significant.
Uncomplicated Complicated Barrett's p Barrett's Value (n = 15) (n = 8) 5/8 7.1 ± 5.8
28 ± 14
5/15 3.2 ± 2.5
NS NS
18 ± 9.4
NS
76
90
105 120
Compicated
FIG. 9. The gastric emptying rate in 26 patients with or without complications of Barrett's esophagus. The fine dotted lines represent the 10th to 90th percentiles of normal. The mean TI is illustrated in the bar graph. There was no difference between the groups (p > 0.05).
to specialized columnar epithelium. In five patients dysplasia was seen concomitantly with stricture and in two, with an ulcer.
Results of Therapy in Benign Barrett's Esophagus Antireflux surgery was performed in 35 patients: a Nissen fundoplication in 31 (combined with a proximal gastric vagotomy in 6), a Belsey partial fundoplication in 3, and a Collis gastroplasty combined with a Belsey partial fundoplication in 2. Six patients had an esophageal resection. In four patients the indication for resection was an esophageal stricture with inadequate esophageal contractility and persistent dysphagia after dilatation, and in two patients the indication was the presence of high-grade dysplasia. One of the patients with a stricture had an associated ulcer that penetrated into the mediastinum and two had low-grade dysplasia. Neither of the latter had intramucosal carcinoma in the resected specimen, whereas it was discovered in one of the specimens resected for high-grade dysplasia. The symptomatic results of surgical therapy are shown in Table 5. Four patients who had relief of heartburn and dysphagia continue to have abdominal pain, nausea, and bilious vomiting after antireflux surgery, suggesting persistence of duodenogastric reflux. Three of the four were tested for duodenogastric reflux. All three were positive and subsequently had bile diversion procedures. Three patients required continuation of acid suppression therTABLE 5. Symptomatic Results of Surgical Therapy Procedure
n
Good
Nissen Belsey Collis-Belsey Total Resection
30 3 2 35 6
23 3 1 27 (77%) 3
Fair 6 0 1 7
3
(20%)
Poor 1 0 0 1 (3%) 0
Vol. 212 * No. 4
SURGICAL THERAPY IN BARRETT'S ESOPHAGUS
apy, one for recurrent heartburn and two for symptomatic gastritis associated with gastric hypersecretion. Only 1 of the 20 stricture patients required postoperative dilatations and no strictures developed after surgery. All six of the Barrett's ulcers treated by antireflux operation healed on endoscopic follow-up and have not recurred. Overall 77% of the patients had a good result after antireflux surgery. Carcinoma has not develped in any of the 35 patients who underwent antireflux surgery. Of the nine patients with dysplasia, none has progressed and one has persisted as high grade. Neither the total length of the Barrett's esophagus nor the size of the dysplastic area appears to have changed during a mean follow-up of 3 years, totalling 123 patient years. In six patients surgery was not performed. In three the operative risk was high because of age or poor cardiovascular condition, and in three the patients chose not to have an operation. In these patients symptoms persisted despite the continuation of therapy with H2 receptor antagonists.
535
Actuarial Survival Following Curative Resection
100-10-
n=16
11
75-i % Surviviing 50-
4
2
2
3 Years
4
5
251
2
FIG. 10. The actuarial survival times of patients with adenocarcinoma in Barrett's esophagus after curative resection, calculated by the KaplanMeier method, illustrating a 77% 2-year survival rate and 53% 5-year survival rate. The numbers on the curve refer to the number of patients alive at the start of each year.
Surgical Resection for Carcinoma in Barrett's Esophagus A curative resection was performed in 15 patients with adenocarcinoma. One of the two patients who had an esophagectomy for high-grade dysplasia had intramucosal carcinoma in the specimen, increasing the number of patients with early adenocarcinoma to 16. These patients were all less than 75 years of age, with good cardiorespiratory function. One patient with an intramural tumor died while hospitalized, resulting in a hospital mortality rate of 6%. Palliative surgery was performed in 10 patients because of extensive local disease. In four patients no resection was performed because of extensive local disease in each along with the intraoperative discovery of undiagnosed liver metastases in two. In none of these patients did CT scanning detect the mediastinal or liver involvement. Survival After Resection for Carcinoma An actuarial survival curve was calculated for the 15 patients who underwent a curative resection and one patient who had intramucosal carcinoma discovered in the specimen resected for high-grade dysplasia. Two years after resection, the survival rate was 77% and after 5 years it was 53% (Fig. 10). Table 6 shows the relationship of the depth of the primary tumor and lymph node involvement to survival. Four of the five patients with intramucosal carcinoma are alive 20, 24, 39, and 105 months after resection. One died at home from an acute pulmonary embolus 2 months after surgery. In contrast the median survival time for patients after palliative resection or no resection was 12 months.
Histopathology of Carcinoma in Barrett's Esophagus Of the 29 carcinomas arising in Barrett's esophagus, 25 were resected and available for pathologic assessment. All 25 specimens contained specialized columnar epithelium adjacent to the adenocarcinoma. Six of the twenty-five also contained junctional-type epithelium and four contained fundic-type epithelium. In every specimen there was low-grade dysplasia adjacent to the tumor, and in 13 specimens high-grade dysplasia also could be identified (Fig. 11). The dysplastic changes were confined to the specialized columnar epithelium, except for one specimen in which dysplastic cells occurred in fundic-type Barrett's
epithelium. The pathologic features for each cancer in which an en bloc resection was done for cure are summarized in Table 7. There are several salient observations to be made. (1) Among 16 specimens the tumor was intramucosal in 5, intramural in 7, and transmural in 4. (2) The extent of lymph node involvement was related to the extent of the primary tumor. Lymph node involvement was not seen with intramucosal carcinoma. In the seven patients with intramural tumor, five had positive nodes. They were few and peritumoral in four patients, and many and regional in one patient. All four patients with transmural tumor had peritumoral lymph node metastases and two had extension to regional and distant nodes. The latter were discovered at operation after the opportunity to convert to a palliative resection had passed. None of the 15 patients who had an en bloc resection for cure had positive nodes along the splenic artery. (3) Differentiation and growth
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TABLE 6. Outcome After Resection for Cure Years Follow-up
Stage
n
Intramucosal* nodes negative Intramural nodes negative Intramural nodes positive Transmural nodes positive
5 2 5 4
