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Long-term endoscopic surveillance of patients with Barrett's esophagus. incidence of dysplasia and adenocarcinoma: a prospective study
THE AMERICAN JOURNAL OF GASTROENTEROLOGY © 2003 by Am. Coll. of Gastroenterology Published by Elsevier Inc.
Vol. 98, No. 9, 2003 ISSN 0002-9270/03/$30.00 doi:10.1016/S0002-9270(03)00629-4
ORIGINAL CONTRIBUTION
Long-Term Endoscopic Surveillance of Patients With Barrett’s Esophagus. Incidence of Dysplasia and Adenocarcinoma: A Prospective Study Massimo Conio, M.D., Sabrina Blanchi, Gabriella Lapertosa, M.D., Roberto Ferraris, M.D., Renato Sablich, M.D., Santino Marchi, M.D., Vittorio D’Onofrio, M.D., Teresa Lacchin, M.D., Gaetano Iaquinto, M.D., Guido Missale, M.D., Paolo Ravelli, M.D., Renzo Cestari, M.D., Giorgio Benedetti, M.D., Giuseppe Macrı`, M.D., Roberto Fiocca, M.D., Francesco Munizzi, M.D., and Rosangela Filiberti, Ph.D. Department of Gastroenterology and Department of Environmental Epidemiology, National Institute for Cancer Research, Genova; Department of Pathology, University of Genova; Department of Gastroenterology, Ospedale Mauriziano, Torino; Department of Gastroenterology, Ospedale Civile, Pordenone; Department of Gastroenterology, University of Pisa; Department of Gastroenterology, Ospedale Moscati, Avellino; Division of Endoscopy, University of Brescia; Department of Gastroenterology, Ospedale Civile, Seriate; and Department of Gastroenterology, University of Firenze, Italy
OBJECTIVE: Barrett’s esophagus (BE) is a premalignant condition for which regular endoscopic follow-up is usually advised. We evaluated the incidence of esophageal adenocarcinoma (AC) in patients with BE and the impact of endoscopic surveillance on mortality from AC. METHODS: A cohort of newly diagnosed BE patients was studied prospectively. Endoscopic and histological surveillance was recommended every 2 yr. Follow-up status was determined from hospital and registry office records and telephone calls to the patients. RESULTS: From 1987 to 1997, BE was diagnosed in 177 patients. We excluded three with high-grade dysplasia (HGD) at the time of enrollment. Follow-up was complete in 166 patients (135 male, 31 female). The mean length of endoscopic follow-up was 5.5 yr (range 0.5–13.3). Lowgrade dysplasia (LGD) was present initially in 16 patients (9.6%) and found during follow-up in another 24 patients. However, in 75% of cases, LGD was not confirmed on later biopsies. HGD was found during surveillance in three patients (1.8%), one with simultaneous AC; two with HGD developed AC later. AC was detected in five male patients during surveillance. The incidence of AC was 1/220 (5/ 1100) patient-years of total follow-up, or 1/183.6 (5/918) patient-years in subjects undergoing endoscopy. Four AC patients died, and one was alive with advanced-stage tumor. The mean number of endoscopies performed for surveillance, rather than for symptoms, was 2.4 (range 1–10) per patient. During the follow-up years the cohort had a total of 528 examinations and more than 4000 biopsies.
CONCLUSIONS: The incidence of AC in BE is low, confirming recent data from the literature reporting an overestimation of cancer risk in these patients. In our patient cohort, surveillance involved a large expenditure of effort but did not prevent any cancer deaths. The benefit of surveillance remains uncertain. (Am J Gastroenterol 2003;98: 1931–1939. © 2003 by Am. Coll. of Gastroenterology)
INTRODUCTION In the last three decades, a dramatic increase has been observed in the incidence of esophageal and esophagogastric junction adenocarcinoma (AC) (1, 2). The principal risk factor for AC is Barrett’s esophagus (BE) (3, 4). The esophageal cancer risk for BE patients is 30 –125 times greater than for the general population (5–9). Recently published guidelines define BE as columnar lined epithelium of any length that can be recognized at endoscopy and confirmed histologically to contain specialized intestinal metaplasia, with goblet cells (10). Gastroesophageal reflux is a risk factor for BE occurrence. BE prevalence increases with age, affects 1% of the population older than 60 yr, and is at least twice as great in men than in women (11, 12). Most esophageal AC and many esophagogastric junction AC arise in BE (3, 13, 14). However, in more than 95% of cases of AC, BE is not diagnosed until symptoms of a late-stage cancer cause the patient to seek medical attention (15). This is because most cases of BE in the general population have not been detected (16), although the prevalence of clinically diagnosed BE is now increasing with the greater use of endoscopy (17). The sequence of events from BE to AC goes through several steps, encompassing low-grade (LGD) and high-
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grade dysplasia (HGD). It seems that this evolution spans many years. Surveillance of BE patients with follow-up endoscopic and biopsy examinations is recommended by the American College of Gastroenterology (10). The aim of surveillance is to detect early neoplastic changes, to start therapy before invasive AC develops. As shown in a decision analysis model (18), the optimal timing of surveillance depends on the incidence of cancer in BE. If the yearly cancer incidence is ⬍0.2%, surveillance would not be indicated because the risks outweigh the benefits. In a review of 27 follow-up reports of BE patients, the incidence of AC varied widely (19), which suggested publication bias in small series. Many series included only one to three incident cancers per report. Most of the published follow-up series of BE patients come from Northern Europe or the United States. The aims of our study were to evaluate the incidence of esophageal AC in a large Italian series of patients with BE with a long follow-up and to describe the impact of endoscopic surveillance on mortality from AC.
MATERIALS AND METHODS Patients Between November, 1987 and December, 1997, consecutive patients with histologically proven BE were enrolled in a surveillance program in eight Italian departments of gastroenterology by the GOSPE (Gruppo Operativo per lo Studio delle Precancerosi Esofagee) study group. Endoscopy was performed with standard diagnostic endoscopes with patients under conscious sedation. From 1987 until 1991, a minimum of six biopsies from the BE were required to enroll a patient in the study. Biopsies were also collected from any mucosal abnormality. After the introduction of new guidelines in 1991 (20), four biopsy specimens were collected starting from the esophagogastric junction every 2 cm along the BE, with standard-size forceps. Before the study began, several endoscopic slide sessions were held to minimize interobserver variability and to obtain a consensus on diagnosis. BE was defined as a detectable upward displacement of the squamocolumnar junction at endoscopy, with intestinal metaplasia on biopsy. The esophagogastric junction was defined as the level at which the tubular esophagus joined the saccular stomach. In patients with hiatal hernia, this junction was identified by the proximal margin of gastric folds. The squamocolumnar junction was defined as the location where the normal esophageal squamous epithelium joined the velvety red mucosa of the columnar-lined esophagus. The length of BE was measured from the esophagogastric junction to the most proximal extension of metaplastic epithelium. Patients with metaplastic columnar-lined esophagus of 3 cm or longer were considered to have long-segment Barrett’s esophagus (LSBE), whereas patients with metaplasia less than 3 cm were classified as short segments (SSBE).
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Patients with a previous diagnosis of BE and those with HGD at the time of the baseline endoscopy were excluded from the study. Histology Formalin-fixed blocks were sectioned. Sections were stained with hematoxylin and eosin and Alcian blue (pH 2.5)/periodic acid-Schiff to reveal neutral and acid mucins, and high iron diamine/Alcian blue (pH 2.5) to discriminate between sulfo- and sialomucins (21). All biopsy specimens were evaluated at a single pathology unit directed by G.L. and R.F. The type of mucosa in BE was classified according to the criteria of Sampliner (10). The diagnosis of BE required the presence of specialized columnar epithelium (intestinal type) with goblet cells interspersed among columnar mucous cells. Intestinal-type BE was further subclassified into three histochemical varieties according to the Jass criteria (22). In particular, intestinal-type BE might be similar to incomplete colonic mucosa (type III of Jass and Filipe) with sialomucins in the goblet cells and sulfomucins in the columnar cells (22–24). To evaluate the hematoxylin and eosin slides for dysplasia, we used the criteria of Schmidt et al. (25), who proposed a classification system for dysplasia in BE similar to that used for dysplasia in inflammatory bowel disease (26). This classification consists of three groups: negative, indefinite, and positive for dysplasia. The latter comprises LGD and HGD. LGD was defined by the presence of nuclear atypia involving the mucosal surface, nuclear stratification in the base of crypts, and preserved crypt architecture. HGD was defined by the presence of marked nuclear atypia, distorted crypt architecture, and nuclear stratification extending to the luminal surface. Surveillance Surveillance was offered to patients judged potentially fit for major surgery. Patients with significant comorbid diseases were excluded from surveillance, at the discretion of individual clinicians. Patients were advised to have follow-up endoscopy with multiple biopsies every 2 yr. In addition, endoscopy was carried out at any time, independent of the surveillance program, for symptoms such as dysphagia, bleeding, or recurrence of heartburn on medical antireflux therapy. When LGD was detected, endoscopic surveillance was recommended at 6 and 12 months, and then yearly. Patients with HGD were advised to undergo esophagogastrectomy. Patients were considered compliant with surveillance if they underwent endoscopy every 2 yr. Those who omitted some surveillance endoscopies were classified as partially compliant. Patients who refused further endoscopy after a regular endoscopic follow-up were contacted by phone. The patients were also monitored by review of hospital records and through the municipality registry office (mortality records).
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Surveillance of Barrett’s Esophagus: A Prospective Study
Table 1. Barrett’s Patients Characteristics at Baseline Endoscopy
Gender Male Female Age (yr) Indication for endoscopy GERD symptoms Dyspeptic symptoms Work-up for anemia Endoscopy BE length SSBE (⬍3 cm) LSBE (ⱖ3 cm) Histology No dysplasia Low-grade dysplasia
n or Median
% or Range
135 31 59.9
81.3 18.7 20–88
127 30 9
76.5 18.1 5.4
3 59 107
0.5–15 35.5 64.5
150 16
90.4 9.6
Statistical Analysis The 2 test was used to evaluate the relationship between categoric variables. Length of total follow-up was defined as the time from enrollment to the last patient contact. Length of endoscopic follow-up was defined as the time from enrollment to the last surveillance endoscopy. Survival of esophageal AC patients was determined with the Kaplan-Meier method, with the period calculated from the date of cancer diagnosis (27).
RESULTS Patients A new diagnosis of BE was made in 177 patients. Three of these were excluded owing to the presence of HGD. Eight patients, none with dysplasia, were lost to follow-up. We present the results in the 166 patients who met the entry criteria and in whom follow-up was available (Table 1). The median age of these patients was 59.9 yr (range 20 – 88). There were 135 men and 31 women. One hundred twentyseven BE subjects (76.5%) underwent endoscopy for GERD symptoms. The mean length of BE at the baseline endoscopy was 3.9 cm (range 0.5–15). SSBE was detected in 59 patients (35.5%) and LSBE in 107 (64.5%). Esophageal stenosis was found in 10 patients (6.0%) (eight nondysplastic, one with LGD, and one who later developed HGD and AC). At the baseline endoscopy in the 166 patients in the study, 16 (9.6%) had LGD: 11 (10.3%) of those with LSBE, and five (8.5%) of those with SSBE; the difference was not statistically significant (p ⫽ 0.9). Ninety-two patients (55.4%) were compliant in the longterm with the surveillance program. Sixty-two patients (37.3%, two with LGD) were partially compliant, and 12 patients (7.2%) refused further endoscopic follow-up and were interviewed by telephone.
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Follow-Up The mean length of total follow-up was 6.6 yr (range 2–13.9) per patient, for a total 1100 patient-years in the study. The mean length of surveillance up to the last endoscopy performed was 5.5 yr (range 0.5–13.3), a total of 918 patient-years. Altogether, 528 endoscopies were performed for the whole cohort during the follow-up years. The mean number of endoscopies per patient was 3.2 (range 1–22). The total number of biopsies taken was more than 4000. The mean number of endoscopies performed for surveillance, rather than for symptoms, was 2.4 (range 1–10) per patient. Figure 1 shows the characteristics of BE patients at last follow-up. Among the 16 patients with LGD at the first examination, dysplasia was not confirmed in 12 patients (75%) on subsequent endoscopies. However, one patient with LGD progressed to AC. Twenty-four patients were found to have LGD subsequent to the index endoscopy, but dysplasia was only confirmed in six of these subjects during further surveillance. Overall, 21 of 30 patients (70%) in whom LGD was not confirmed had LSBE. The median time to develop LGD was 2.5 yr (range 0.5– 8.8 yr). The patients who developed LGD at any time were 81% male, with a median age of 63 yr (range 28 –77 yr). Incidence of HGD and Adenocarcinoma During surveillance, AC was detected in five male patients (Fig. 2). All of them had a history of GERD lasting more than 15 yr. Descriptions of these five cases follow. Case 1 was a 74-yr-old man (A in Fig. 2) with a 9-cm BE, who had LGD at the baseline endoscopy. A peptic stenosis was present at the level of the squamocolumnar junction, and one session of endoscopic dilation was performed. However, the patient periodically complained of episodes of dysphagia for solid food. HGD was found 2 yr later, but the patient refused surgery and further endoscopic controls. He underwent endoscopy 2 yr later, and an intramucosal AC was diagnosed. Photodynamic therapy was administered, but neoplastic progression occurred, and the patient died 4 yr later. Two months before his death an esophageal stent was placed. Case 2 was a 58-yr-old man (B in Fig. 2) who developed invasive AC 12 yr after diagnosis of a 3-cm BE. Between the last negative surveillance endoscopy (no dysplasia) and the occurrence of dysphagia 35 months had elapsed. A 5-cm hemicircumferential AC was detected in the lower esophagus. One month later, the patient underwent coronary angioplasty. Chemoradiotherapy treatment was started, and an expandable metal stent was placed 2 months before his death. The patient died 15 months after cancer diagnosis. Case 3 was a 65-yr-old man (C in Fig. 2) who developed HGD 1 yr after his enrollment. The length of BE was 15 cm. The patient refused surgery. Further endoscopies were performed 2, 11, and 17 months after the diagnosis of HGD,
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Figure 1. Status at time of last follow-up in 166 patients with BE. The smaller pie (right) highlights the characteristic of the patients still alive. † Deceased patients. ‡ Patient with esophageal adenocarcinoma, deceased of pancreatic cancer.
and histology showed LGD each time. Intramucosal AC developed 3 yr from the baseline endoscopy. The AC was successfully treated with photodynamic therapy, but the patient died from pancreatic AC 1 yr later. Case 4 was a 62-yr-old man (D in Fig. 2) who had a simultaneous diagnosis of HGD and intramucosal AC, 2 yr after the baseline endoscopy showed SSBE. The length of BE was 2 cm, and no mucosal abnormalities were visible at endoscopy. The patient underwent radical esophagectomy. The pathological examination showed AC arising in a 15 ⫻ 12-mm area of metaplastic epithelium. Submucosal infiltration and involvement of lymphatic vessels were present. The patient died 5 yr after surgery for lung metastasis from esophageal AC.
Case 5 was a 67-yr-old man (E in Fig. 2) who developed invasive AC 4 yr after the last negative endoscopic evaluation and 13 yr after diagnosis of BE and LGD. LGD was not detected after 2 yr from the baseline endoscopy. The length of BE was 12 cm. The patient underwent endoscopy after the onset of dysphagia 1 month before the AC diagnosis. The neoplasm involved the distal 8 cm of the lower esophagus. CT scan showed pathological mediastinal lymph nodes and a lung metastasis. The patient was treated with an esophageal metal stent and was alive at last follow-up. Overall, three patients (1.8%) developed HGD during surveillance, with an incidence rate of 1/302.7 patient-years (3/908). Patients who developed HGD were male, with a median age of 66 yr (range 64 –76 yr). The median time to develop HGD was 2 yr (range 1–2 yr). The incidence of AC was 1/220 (5/1100) patient-years of total follow-up, or 1/183.6 (5/918) patient-years in subjects undergoing endoscopy. Overall, 18 of 166 patients (10.8%), median age 74.4 yr, died during the follow-up. Among cancer deaths there were three esophageal AC, one pancreatic AC, five lung carcinomas, one colon carcinoma, and one with undefined primary site. Six BE patients died from cardiovascular disease, and one from respiratory disease. Median survival of patients with esophageal AC was 48.9 months (range 2.2– 63.1).
Figure 2. Clinical outcome of five patients (A–E) who developed esophageal adenocarcinoma. ND ⫽ no dysplasia; LGD ⫽ lowgrade dysplasia; HGD ⫽ high-grade dysplasia; AC ⫽ adenocarcinoma.
DISCUSSION In our prospective study, five patients with BE developed AC during a total follow-up of 1100 patient-years. This
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Surveillance of Barrett’s Esophagus: A Prospective Study
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Table 2. Studies Showing the Proportion of Deaths in BE Patients That Were Due to Esophageal Adenocarcinoma
Reference
BE Patients Entered (n)
Deaths From All Causes (n)
Deaths From AC (n)
% Deaths From AC
Active Endoscopic Surveillance
Spechler et al., 1984 (5) Cameron et al., 1985 (6) Van der Veen et al., 1989 (33) Van der Burgh et al., 1996 (31) Drewitz et al., 1997 (7) Katz et al., 1998 (61) Macdonald et al., 2000 (57) Eckardt et al., 2001 (34) Conio et al., 2001 (17) Present study
105 104 155 166 170 102 143 60 117 166
16 25 35 79 38 19 27 11 35 18
1 1 2 2 2 2 2 0 1 3
6.3 4 6 2.5 5.3 10.5 7.4 0 2.9 16.7
Yes No No No Yes Yes Some Yes Some Yes
Most BE patients died from other causes. Patients in studies in which routine surveillance was advised did not seem to fare better than those without surveillance.
represents an incidence of one cancer per 220 patient-years. The incidence of AC in reported follow-up series of BE patients varies considerably, between one cancer in 46 patient-years and one in 441 patient-years (28). Part of the wide range of reported data on AC risk might be due to different study populations, for example the inclusion of cases with no intestinal-type BE on histology, cases with HGD at baseline endoscopy, or cases already under surveillance. One strength of our study was that only incidence cases of BE were included; the cancer risk of prevalence cases already under surveillance for some time might be different from incidence cases. Another cause of apparent incidence variation is lack of statistical power due to small numbers; many series had only one to three incidence cancers. In an important contribution, Shaheen et al. (19) analyzed 27 BE follow-up series, finding that small studies reported higher cancer risks than large studies. This suggested publication bias, with small studies more likely to be published if they showed a high cancer incidence. Thus, the cancer incidence in BE has probably been overestimated in the literature. In the review by Shaheen et al. (19), only three of 27 reports included more than 1000 patient-years of follow-up (equivalent to 200 BE patients followed for a mean of 5 yr). Even the three largest series only found four to eight incident cancers per report. Our study and another recently published (29), also with more than 1000 patient-years of follow-up, provide additional data on the cancer risk in BE. In these five studies, the BE cancer risk was 1/306 (30), 1/180 (31), 1/287 (32), 1/95 (29), and 1/220 patient-years in our report. The mean of these results is approximately 1/220 patient-years, or 0.45%/year, slightly less than the 0.5%/ year estimate of Shaheen et al. (19). If the incidence of AC is one case per 200 –220 patientyears, it follows that most BE patients will not develop AC in their lifetime. This is confirmed by noting the proportion of deaths of BE patients that are caused by esophageal AC versus other causes, as shown in Table 2. In follow-up series extending over years, patients, who often are old at the time of BE diagnosis, will die of various causes. Combining the 10 series in Table 2, only 16 of 303 (5.3%) of deaths in BE
patients were caused by AC. There was no apparent difference between the proportion of BE deaths due to AC in earlier series, generally without endoscopic surveillance, and more recent series in the era of surveillance, such as our present report. Most patients with BE do not die of AC, and a diagnosis of BE does not imply reduced life expectancy. In three reports, the survival of BE patients was not significantly different from the age- and sex-matched general population (6, 33–35). The review by Shaheen et al. (19) included reports from both the United States and Europe, but recent reports indicate that the AC risk might vary in different countries. The AC incidence in the general population is higher in the United Kingdom than in other parts of Europe or the United States, whereas the incidence in Italy is lower than in the United Kingdom or the United States (2). These data do not take BE into account. However, an analysis of eight follow-up series of patients with BE from the United Kingdom, avoiding publication bias, found a mean AC risk of about 1% per year (36), twice the risk estimated by Shaheen et al. (19) for the United States and Western Europe generally. Defining the size of the cancer risk in BE has clinical relevance (37). In a decision analysis study, Provenzale et al. (18) found that the optimal frequency of BE surveillance depended on the cancer incidence. Their Markov model took into account many other factors, including the cost and complications of endoscopy, and the cost, mortality, and morbidity of esophageal resection. The model assumed that esophagectomy was performed if HGD was found, and that this would usually prevent subsequent death from cancer. For a cancer risk of 0.5%/year, surveillance every 4 year was indicated; if the risk was 0.4%/year, surveillance every 5 yr was the only strategy that increased quality-adjusted life expectancy. A recent review of BE surveillance programs concluded that too-frequent endoscopic follow-up might actually decrease quality-adjusted life expectancy, corroborating the need for longer intervals than those previously applied (37). Thus, the American College of Gastroenterology updated practice guidelines for Barrett’s esophagus in 2002 (10). Surveillance at 3-yr intervals was considered
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Table 3. Dysplasia Grade at Study Entry Correlates With the Proportion of BE Patients Developing AC by the End of the Study Reference
Total BE Patients (n)
Follow-Up yr (Mean)
Nondysplastic, Developed AC (%)
LGD, Developed AC (%)
HGD, Developed AC (%)
Miros et al., 1991 (45) Hameeteman et al., 1989 (44) O’Connor et al., 1999 (9) Weston et al., 1999 (47) Reid et al., 2000 (62)
124 50 136 108 327
3.6 5.2 4.2 3.3 5
0/111 (0) 2/43 (5) 1/125 (1) 2/80 (2.5) 5/129 (4)
2/3 (67) 0/1 (0) 0/1 (0) 2/8 (25) 45/76 (59)
Montgomery et al., 2001 (60)
125
Varied
0/44 (0)
1057
7.3
0/230 (0)
1/10 (10) 3/6 (50) 1/10 (10) 1/20 (5) 1/79 (1) (Indef) 3/43 (7) (LGD) 4/22 (18) (Indef) 4/26 (15) (LGD) 10/748 (1.3)
Schnell et al., 2001 (54)
20/33 (61) 12/75 (16)
Note that dysplasia sometimes developed after study entry (not shown). Indef ⫽ indefinite for dysplasia.
appropriate for patients in whom two consecutive biopsies showed no dysplasia. Some BE patients have a higher AC risk than others. All five patients with AC in our study were male. Most BE series include both men and women, in a ratio of about 2:1 (11, 12, 19). However, the male:female AC incidence is greater, 8:1 in the general U.S. white population (38). Men with BE might have a greater AC risk than do women. In two follow-up reports (29, 39), the AC incidence was 1/59 and 1/69 patient-years for men and 1/167 and 1/537 patientyears for women. Obesity (40) and smoking (41) also increase the risk of AC in the general population, but gender, obesity and smoking have not been routinely considered in planning BE surveillance programs. In a referral-center study of 308 patients followed for a mean 3.8 yr, the risk for progression to AC for patients with SSBE was not substantially lower than for those with LSBE. The authors suggested that surveillance frequency should be the same, regardless of BE length (42). Dysplasia is the most widely used marker of cancer risk in BE. During surveillance, BE cases often show a multistep progression through LGD then HGD, eventually developing invasive AC (43– 46). In two of our five patients who developed AC, surveillance showed both LGD and HGD before the AC was found. LGD is more common than HGD. At entry to our study, 10% of BE patients had LGD, and 2% were excluded because they had HGD. Other reports (9, 44, 45, 47) are similar, LGD being found at baseline in 7%, 8%, 12%, and 19% of patients and HGD in 1%, 2%, 2%, and 7%, respectively. As shown in Table 3, the AC risk is somewhat increased in LGD and much increased in HGD. The value of LGD as a risk marker in our study was limited by frequent inability to confirm the finding on subsequent examinations. In 30 of 40 patients (75%) with an endoscopic biopsy showing LGD, a later examination failed to show LGD. Similar figures of 73% (9) and 75% (47) have been reported by others. Although we cannot exclude true regression of dysplasia, sampling error and observer variation might be more significant. Sampling error might occur owing to the irregular, patchy distribution of LGD; in one study, the mean area of LGD was less than half the total BE
surface area (48). An aggressive sampling protocol might minimize sampling error, but it is time-consuming (49). Another important problem is observer variation in biopsy interpretation, agreement on the diagnosis of LGD between two pathologists being statistically fair to poor (50). Interobserver ability to distinguish any grade of dysplasia from no dysplasia was only 72% in another study (51). Interpretation of the presence and degree of dysplasia by general pathologists in community practice varied considerably (52). In two large series of BE patients, LGD was reported in only 1.1% of patients (53) in one study, compared with 67.2% of patients in the other study (54). HGD is an uncommon but serious problem. Only 2% of our BE patients had HGD (and were therefore excluded) when the study began, and a further 2% were found to have HGD during follow-up. Three of our five patients with AC also had HGD, found before the AC in two of three cases, and at the same time as the AC in one case. The AC risk in patients with HGD is high, and AC might already be present. After esophagectomy for an endoscopic and histological diagnosis of HGD, a “missed” invasive AC (usually early) was found in the resected esophagus in 10 –50% of cases (48). In the two largest series in Table 3, 59 – 61% of HGD patients developed AC within 4 –5 yr, although one provocative study found a lower incidence, with only 12/75 (16%) developing AC during a mean 7.3-yr follow-up (54). We do not usually advise surveillance in HGD. Instead, if the patient is otherwise healthy, esophagectomy is often recommended. Newer methods of removing dysplastic epithelium are now available, such as photodynamic therapy (55) and endoscopic mucosal resection (56), which can also be used to treat early cancer; the long-term results are awaited. AC found by surveillance is more likely to be early-stage disease than AC diagnosed in nonsurveillance patients with tumor-related symptoms, such as dysphagia, bleeding, or weight loss (37). In two surgical series, lymph node involvement was found in 6 –17% of surveillance cases and in 52– 63% of nonsurveillance cases (39, 46). Early diagnosis of AC might result in more effective treatment. In one report (46), 2-yr survival was 86% in cases of AC found by surveillance, and 43% in cases not found by surveillance. In
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a recent population-based study, Corley et al. (15) showed that 73% of 15 surveillance-detected versus 0% of eight nonsurveillance patients with AC were still alive (p ⬍ 0.001) 5 yr after diagnosis, even though postoperative mortality was 3/15 in the surveillance group and 1/8 in the nonsurveillance. By contrast, our BE surveillance program did not prevent deaths from AC. We followed 166 patients for a total of 1100 patient-years, and five patients developed AC. Despite treatment including surgery, chemoradiation and photodynamic therapy, three of our five AC patients died from esophageal cancer, one died from coexistent pancreatic cancer, and one had metastatic esophageal cancer at the time of writing. It should be pointed out that three of the five patients who developed esophageal AC, did not follow our recommendations. Endoscopy successfully detected HGD in case 1, but the patient refused surgery. Cases 2 and 5 were only partially compliant with the recommended endoscopic follow-up. They underwent endoscopy for recent onset of dysphagia 35 and 48 months from their last surveillance examinations. Earlier surgical treatment might have changed the clinical outcome of these patients. Certainly, our experience shows what can occur in daily clinical practice. The performance of 528 endoscopic examinations and more than 4000 biopsies in our 166 BE patients did not prevent any cancer deaths in this group. Some other authors reached similar conclusions. Van der Burgh (31) followed 155 BE patients without surveillance for a mean of 9.3 yr and stated that their patients would not have benefited from an endoscopic surveillance program. Macdonald et al. (57) followed 143 patients for a mean of 4.4 yr and concluded that the value of their surveillance program was extremely limited, because no individual patient benefited from it. As noted earlier, the number of incident AC in any one follow-up series is small. It is not surprising that some series include individual patients who were probably helped by early detection and surgical treatment, whereas other series do not include any such patients. But, it is clear that overall, a BE surveillance program involves a large number of invasive tests with attendant risk of complications and expenditure of time and money, from which only a very small minority of the patients might benefit. A control study to show that surveillance improves survival would require a large number of patients and years of follow-up; no such study has been reported. At present, surveillance of all BE patients is of very limited value (58). Apart from dysplasia, we are unable to identify patients at increased risk of neoplastic progression (59, 60). New molecular or other markers could lead to a better selection of high-risk patients and a tailoring of a more effective follow-up program.
ACKNOWLEDGMENT The authors thank Dr. Alan J. Cameron, Mayo Clinic, Rochester, MN, for his assistance in revising the manuscript.
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Reprint requests and correspondence: Massimo Conio, M.D., National Institute for Cancer Research – Genova, Via Trento 42/14, 16145 Genova, Italy. Received Sep. 23, 2002; accepted Apr. 14, 2003.
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39. Wright TA, Gray MR, Morris AI, et al. Cost effectiveness of detecting Barrett’s cancer. Gut 1996;39:574 –9. 40. Lagergren J, Bergstrom R, Nyren O. Association between body mass and adenocarcinoma of the esophagus and gastric cardia. Ann Int Med 1999;130:883–90. 41. Gammon MD, Schoenberg JB, Ahsan H, et al. Tobacco, alcohol and socioeconomic status and adenocarcinoma of the esophagus and gastric cardia. J Natl Cancer Inst 1997;89: 1277–84. 42. Rudolph RE, Vaughan TL, Storer BE, et al. Effect of segment length for neoplastic progression in patients with Barrett’s esophagus. Ann Int Med 2000;132:612–20. 43. Robertson CS, Mayberry JF, Nicholson DA, et al. Value of endoscopic surveillance in the detection of neoplastic changes in Barrett’s esophagus. Br J Surg 1988;75:760 –3. 44. Hameeteman W, Tytgat GNJ, Houthoff HJ, et al. Barrett’s esophagus: Development of dysplasia and adenocarcinoma. Gastroenterology 1989;96:1248 –56. 45. Miros M, Kerlin P, Walker N. Only patients with dysplasia progress to adenocarcinoma in Barrett’s oesophagus. Gut 1991;32:1441–6. 46. Van Sandick JW, Van Lanschot JJB, Kuiken BW, et al. Impact of endoscopic biopsy surveillance on pathological stage and clinical outcome of Barrett’s carcinoma. Gut 1998;43:216 –22. 47. Weston AP, Badr AS, Hassanein RS. Prospective multivariate analysis of clinical, endoscopic, and histological factors predictive of the development of Barrett’s multifocal high-grade dysplasia or adenocarcinoma. Am J Gastroenterol 1999;94: 3413–9. 48. Cameron AJ, Carpenter HA. Barrett’s esophagus, high-grade dysplasia and early adenocarcinoma: A pathologic study. Am J Gastroenterol 1997;92:586 –91. 49. Levine DS, Haggitt RC, Blount PL, et al. An endoscopic biopsy protocol can differentiate high-grade dysplasia from early adenocarcinoma in Barrett’s esophagus. Gastroenterology 1993;105:40 –50. 50. Skacel M, Petras RE, Gramlich TL, et al. The diagnosis of low-grade dysplasia in Barrett’s esophagus and its implications for disease progression. Am J Gastroenterol 2000;95: 3383–7. 51. Reid BJ, Haggitt RC, Rubin CE, et al. Observer variation in the diagnosis of dysplasia in Barrett’s esophagus. Hum Pathol 1988;19:166 –78. 52. Alikhan M, Rex D, Khan A, et al. Variable pathologic interpretation by general pathologists in community practice. Gastrointest Endosc 1999;50:23–6. 53. Vieth M, Stolte M. Barrett’s esophagus and neoplasia: Data from the Bayreuth Barrett’s archive. Gastroenterology 2002; 122:590. 54. Schnell TG, Sontag SJ, Chejfec G, et al. Long-term nonsurgical management of Barrett’s esophagus with high-grade dysplasia. Gastroenterology 2001;120:1607–19. 55. Overholt BF, Panjehpour M, Haydek JM. Photodynamic therapy for Barrett’s esophagus: Follow-up in 100 patients. Gastrointest Endosc 1999;49:1–7. 56. Ell C, May A, Gossner L, et al. Endoscopic mucosal resection of early cancer and high-grade dysplasia in Barrett’s esophagus. Gastroenterology 2000;118:670 –7. 57. Macdonald CE, Wicks AC, Playford RJ. Final results from 10 year cohort of patients undergoing surveillance for Barrett’s esophagus: Observational study. BMJ 2000;321:1252–5. 58. Shaheen N. Is there a “Barrett’s iceberg”? Gastroenterology 2002;123:636 –9. 59. Dulai GS, Guha S, Kahn KL, et al. Preoperative prevalence of Barrett’s esophageal adenocarcinoma: A systematic review. Gastroenterology 2002;122:26 –33.
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60. Montgomery E, Goldblum JR, Greenson JK, et al. Dysplasia as a predictive marker for invasive carcinoma in Barrett esophagus: A follow-up study based on 138 cases from a diagnostic variability study. Hum Pathol 2001;32:379 –88. 61. Katz D, Rothstein R, Schned A, et al. The development of dysplasia and adenocarcinoma during endoscopic surveil-
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lance of Barrett’s esophagus. Am J Gastroenterol 1998;93: 536 –41. 62. Reid BJ, Levine DS, Longton G, et al. Predictors of progression to cancer in Barrett’s esophagus: Baseline histology and flow cytometry identify low- and high-risk patient subset. Am J Gastroenterol 2000;95:1669 –76.
Vol. 98, No. 9, 2003 ISSN 0002-9270/03/$30.00 doi:10.1016/S0002-9270(03)00629-4
ORIGINAL CONTRIBUTION
Long-Term Endoscopic Surveillance of Patients With Barrett’s Esophagus. Incidence of Dysplasia and Adenocarcinoma: A Prospective Study Massimo Conio, M.D., Sabrina Blanchi, Gabriella Lapertosa, M.D., Roberto Ferraris, M.D., Renato Sablich, M.D., Santino Marchi, M.D., Vittorio D’Onofrio, M.D., Teresa Lacchin, M.D., Gaetano Iaquinto, M.D., Guido Missale, M.D., Paolo Ravelli, M.D., Renzo Cestari, M.D., Giorgio Benedetti, M.D., Giuseppe Macrı`, M.D., Roberto Fiocca, M.D., Francesco Munizzi, M.D., and Rosangela Filiberti, Ph.D. Department of Gastroenterology and Department of Environmental Epidemiology, National Institute for Cancer Research, Genova; Department of Pathology, University of Genova; Department of Gastroenterology, Ospedale Mauriziano, Torino; Department of Gastroenterology, Ospedale Civile, Pordenone; Department of Gastroenterology, University of Pisa; Department of Gastroenterology, Ospedale Moscati, Avellino; Division of Endoscopy, University of Brescia; Department of Gastroenterology, Ospedale Civile, Seriate; and Department of Gastroenterology, University of Firenze, Italy
OBJECTIVE: Barrett’s esophagus (BE) is a premalignant condition for which regular endoscopic follow-up is usually advised. We evaluated the incidence of esophageal adenocarcinoma (AC) in patients with BE and the impact of endoscopic surveillance on mortality from AC. METHODS: A cohort of newly diagnosed BE patients was studied prospectively. Endoscopic and histological surveillance was recommended every 2 yr. Follow-up status was determined from hospital and registry office records and telephone calls to the patients. RESULTS: From 1987 to 1997, BE was diagnosed in 177 patients. We excluded three with high-grade dysplasia (HGD) at the time of enrollment. Follow-up was complete in 166 patients (135 male, 31 female). The mean length of endoscopic follow-up was 5.5 yr (range 0.5–13.3). Lowgrade dysplasia (LGD) was present initially in 16 patients (9.6%) and found during follow-up in another 24 patients. However, in 75% of cases, LGD was not confirmed on later biopsies. HGD was found during surveillance in three patients (1.8%), one with simultaneous AC; two with HGD developed AC later. AC was detected in five male patients during surveillance. The incidence of AC was 1/220 (5/ 1100) patient-years of total follow-up, or 1/183.6 (5/918) patient-years in subjects undergoing endoscopy. Four AC patients died, and one was alive with advanced-stage tumor. The mean number of endoscopies performed for surveillance, rather than for symptoms, was 2.4 (range 1–10) per patient. During the follow-up years the cohort had a total of 528 examinations and more than 4000 biopsies.
CONCLUSIONS: The incidence of AC in BE is low, confirming recent data from the literature reporting an overestimation of cancer risk in these patients. In our patient cohort, surveillance involved a large expenditure of effort but did not prevent any cancer deaths. The benefit of surveillance remains uncertain. (Am J Gastroenterol 2003;98: 1931–1939. © 2003 by Am. Coll. of Gastroenterology)
INTRODUCTION In the last three decades, a dramatic increase has been observed in the incidence of esophageal and esophagogastric junction adenocarcinoma (AC) (1, 2). The principal risk factor for AC is Barrett’s esophagus (BE) (3, 4). The esophageal cancer risk for BE patients is 30 –125 times greater than for the general population (5–9). Recently published guidelines define BE as columnar lined epithelium of any length that can be recognized at endoscopy and confirmed histologically to contain specialized intestinal metaplasia, with goblet cells (10). Gastroesophageal reflux is a risk factor for BE occurrence. BE prevalence increases with age, affects 1% of the population older than 60 yr, and is at least twice as great in men than in women (11, 12). Most esophageal AC and many esophagogastric junction AC arise in BE (3, 13, 14). However, in more than 95% of cases of AC, BE is not diagnosed until symptoms of a late-stage cancer cause the patient to seek medical attention (15). This is because most cases of BE in the general population have not been detected (16), although the prevalence of clinically diagnosed BE is now increasing with the greater use of endoscopy (17). The sequence of events from BE to AC goes through several steps, encompassing low-grade (LGD) and high-
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grade dysplasia (HGD). It seems that this evolution spans many years. Surveillance of BE patients with follow-up endoscopic and biopsy examinations is recommended by the American College of Gastroenterology (10). The aim of surveillance is to detect early neoplastic changes, to start therapy before invasive AC develops. As shown in a decision analysis model (18), the optimal timing of surveillance depends on the incidence of cancer in BE. If the yearly cancer incidence is ⬍0.2%, surveillance would not be indicated because the risks outweigh the benefits. In a review of 27 follow-up reports of BE patients, the incidence of AC varied widely (19), which suggested publication bias in small series. Many series included only one to three incident cancers per report. Most of the published follow-up series of BE patients come from Northern Europe or the United States. The aims of our study were to evaluate the incidence of esophageal AC in a large Italian series of patients with BE with a long follow-up and to describe the impact of endoscopic surveillance on mortality from AC.
MATERIALS AND METHODS Patients Between November, 1987 and December, 1997, consecutive patients with histologically proven BE were enrolled in a surveillance program in eight Italian departments of gastroenterology by the GOSPE (Gruppo Operativo per lo Studio delle Precancerosi Esofagee) study group. Endoscopy was performed with standard diagnostic endoscopes with patients under conscious sedation. From 1987 until 1991, a minimum of six biopsies from the BE were required to enroll a patient in the study. Biopsies were also collected from any mucosal abnormality. After the introduction of new guidelines in 1991 (20), four biopsy specimens were collected starting from the esophagogastric junction every 2 cm along the BE, with standard-size forceps. Before the study began, several endoscopic slide sessions were held to minimize interobserver variability and to obtain a consensus on diagnosis. BE was defined as a detectable upward displacement of the squamocolumnar junction at endoscopy, with intestinal metaplasia on biopsy. The esophagogastric junction was defined as the level at which the tubular esophagus joined the saccular stomach. In patients with hiatal hernia, this junction was identified by the proximal margin of gastric folds. The squamocolumnar junction was defined as the location where the normal esophageal squamous epithelium joined the velvety red mucosa of the columnar-lined esophagus. The length of BE was measured from the esophagogastric junction to the most proximal extension of metaplastic epithelium. Patients with metaplastic columnar-lined esophagus of 3 cm or longer were considered to have long-segment Barrett’s esophagus (LSBE), whereas patients with metaplasia less than 3 cm were classified as short segments (SSBE).
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Patients with a previous diagnosis of BE and those with HGD at the time of the baseline endoscopy were excluded from the study. Histology Formalin-fixed blocks were sectioned. Sections were stained with hematoxylin and eosin and Alcian blue (pH 2.5)/periodic acid-Schiff to reveal neutral and acid mucins, and high iron diamine/Alcian blue (pH 2.5) to discriminate between sulfo- and sialomucins (21). All biopsy specimens were evaluated at a single pathology unit directed by G.L. and R.F. The type of mucosa in BE was classified according to the criteria of Sampliner (10). The diagnosis of BE required the presence of specialized columnar epithelium (intestinal type) with goblet cells interspersed among columnar mucous cells. Intestinal-type BE was further subclassified into three histochemical varieties according to the Jass criteria (22). In particular, intestinal-type BE might be similar to incomplete colonic mucosa (type III of Jass and Filipe) with sialomucins in the goblet cells and sulfomucins in the columnar cells (22–24). To evaluate the hematoxylin and eosin slides for dysplasia, we used the criteria of Schmidt et al. (25), who proposed a classification system for dysplasia in BE similar to that used for dysplasia in inflammatory bowel disease (26). This classification consists of three groups: negative, indefinite, and positive for dysplasia. The latter comprises LGD and HGD. LGD was defined by the presence of nuclear atypia involving the mucosal surface, nuclear stratification in the base of crypts, and preserved crypt architecture. HGD was defined by the presence of marked nuclear atypia, distorted crypt architecture, and nuclear stratification extending to the luminal surface. Surveillance Surveillance was offered to patients judged potentially fit for major surgery. Patients with significant comorbid diseases were excluded from surveillance, at the discretion of individual clinicians. Patients were advised to have follow-up endoscopy with multiple biopsies every 2 yr. In addition, endoscopy was carried out at any time, independent of the surveillance program, for symptoms such as dysphagia, bleeding, or recurrence of heartburn on medical antireflux therapy. When LGD was detected, endoscopic surveillance was recommended at 6 and 12 months, and then yearly. Patients with HGD were advised to undergo esophagogastrectomy. Patients were considered compliant with surveillance if they underwent endoscopy every 2 yr. Those who omitted some surveillance endoscopies were classified as partially compliant. Patients who refused further endoscopy after a regular endoscopic follow-up were contacted by phone. The patients were also monitored by review of hospital records and through the municipality registry office (mortality records).
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Table 1. Barrett’s Patients Characteristics at Baseline Endoscopy
Gender Male Female Age (yr) Indication for endoscopy GERD symptoms Dyspeptic symptoms Work-up for anemia Endoscopy BE length SSBE (⬍3 cm) LSBE (ⱖ3 cm) Histology No dysplasia Low-grade dysplasia
n or Median
% or Range
135 31 59.9
81.3 18.7 20–88
127 30 9
76.5 18.1 5.4
3 59 107
0.5–15 35.5 64.5
150 16
90.4 9.6
Statistical Analysis The 2 test was used to evaluate the relationship between categoric variables. Length of total follow-up was defined as the time from enrollment to the last patient contact. Length of endoscopic follow-up was defined as the time from enrollment to the last surveillance endoscopy. Survival of esophageal AC patients was determined with the Kaplan-Meier method, with the period calculated from the date of cancer diagnosis (27).
RESULTS Patients A new diagnosis of BE was made in 177 patients. Three of these were excluded owing to the presence of HGD. Eight patients, none with dysplasia, were lost to follow-up. We present the results in the 166 patients who met the entry criteria and in whom follow-up was available (Table 1). The median age of these patients was 59.9 yr (range 20 – 88). There were 135 men and 31 women. One hundred twentyseven BE subjects (76.5%) underwent endoscopy for GERD symptoms. The mean length of BE at the baseline endoscopy was 3.9 cm (range 0.5–15). SSBE was detected in 59 patients (35.5%) and LSBE in 107 (64.5%). Esophageal stenosis was found in 10 patients (6.0%) (eight nondysplastic, one with LGD, and one who later developed HGD and AC). At the baseline endoscopy in the 166 patients in the study, 16 (9.6%) had LGD: 11 (10.3%) of those with LSBE, and five (8.5%) of those with SSBE; the difference was not statistically significant (p ⫽ 0.9). Ninety-two patients (55.4%) were compliant in the longterm with the surveillance program. Sixty-two patients (37.3%, two with LGD) were partially compliant, and 12 patients (7.2%) refused further endoscopic follow-up and were interviewed by telephone.
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Follow-Up The mean length of total follow-up was 6.6 yr (range 2–13.9) per patient, for a total 1100 patient-years in the study. The mean length of surveillance up to the last endoscopy performed was 5.5 yr (range 0.5–13.3), a total of 918 patient-years. Altogether, 528 endoscopies were performed for the whole cohort during the follow-up years. The mean number of endoscopies per patient was 3.2 (range 1–22). The total number of biopsies taken was more than 4000. The mean number of endoscopies performed for surveillance, rather than for symptoms, was 2.4 (range 1–10) per patient. Figure 1 shows the characteristics of BE patients at last follow-up. Among the 16 patients with LGD at the first examination, dysplasia was not confirmed in 12 patients (75%) on subsequent endoscopies. However, one patient with LGD progressed to AC. Twenty-four patients were found to have LGD subsequent to the index endoscopy, but dysplasia was only confirmed in six of these subjects during further surveillance. Overall, 21 of 30 patients (70%) in whom LGD was not confirmed had LSBE. The median time to develop LGD was 2.5 yr (range 0.5– 8.8 yr). The patients who developed LGD at any time were 81% male, with a median age of 63 yr (range 28 –77 yr). Incidence of HGD and Adenocarcinoma During surveillance, AC was detected in five male patients (Fig. 2). All of them had a history of GERD lasting more than 15 yr. Descriptions of these five cases follow. Case 1 was a 74-yr-old man (A in Fig. 2) with a 9-cm BE, who had LGD at the baseline endoscopy. A peptic stenosis was present at the level of the squamocolumnar junction, and one session of endoscopic dilation was performed. However, the patient periodically complained of episodes of dysphagia for solid food. HGD was found 2 yr later, but the patient refused surgery and further endoscopic controls. He underwent endoscopy 2 yr later, and an intramucosal AC was diagnosed. Photodynamic therapy was administered, but neoplastic progression occurred, and the patient died 4 yr later. Two months before his death an esophageal stent was placed. Case 2 was a 58-yr-old man (B in Fig. 2) who developed invasive AC 12 yr after diagnosis of a 3-cm BE. Between the last negative surveillance endoscopy (no dysplasia) and the occurrence of dysphagia 35 months had elapsed. A 5-cm hemicircumferential AC was detected in the lower esophagus. One month later, the patient underwent coronary angioplasty. Chemoradiotherapy treatment was started, and an expandable metal stent was placed 2 months before his death. The patient died 15 months after cancer diagnosis. Case 3 was a 65-yr-old man (C in Fig. 2) who developed HGD 1 yr after his enrollment. The length of BE was 15 cm. The patient refused surgery. Further endoscopies were performed 2, 11, and 17 months after the diagnosis of HGD,
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Figure 1. Status at time of last follow-up in 166 patients with BE. The smaller pie (right) highlights the characteristic of the patients still alive. † Deceased patients. ‡ Patient with esophageal adenocarcinoma, deceased of pancreatic cancer.
and histology showed LGD each time. Intramucosal AC developed 3 yr from the baseline endoscopy. The AC was successfully treated with photodynamic therapy, but the patient died from pancreatic AC 1 yr later. Case 4 was a 62-yr-old man (D in Fig. 2) who had a simultaneous diagnosis of HGD and intramucosal AC, 2 yr after the baseline endoscopy showed SSBE. The length of BE was 2 cm, and no mucosal abnormalities were visible at endoscopy. The patient underwent radical esophagectomy. The pathological examination showed AC arising in a 15 ⫻ 12-mm area of metaplastic epithelium. Submucosal infiltration and involvement of lymphatic vessels were present. The patient died 5 yr after surgery for lung metastasis from esophageal AC.
Case 5 was a 67-yr-old man (E in Fig. 2) who developed invasive AC 4 yr after the last negative endoscopic evaluation and 13 yr after diagnosis of BE and LGD. LGD was not detected after 2 yr from the baseline endoscopy. The length of BE was 12 cm. The patient underwent endoscopy after the onset of dysphagia 1 month before the AC diagnosis. The neoplasm involved the distal 8 cm of the lower esophagus. CT scan showed pathological mediastinal lymph nodes and a lung metastasis. The patient was treated with an esophageal metal stent and was alive at last follow-up. Overall, three patients (1.8%) developed HGD during surveillance, with an incidence rate of 1/302.7 patient-years (3/908). Patients who developed HGD were male, with a median age of 66 yr (range 64 –76 yr). The median time to develop HGD was 2 yr (range 1–2 yr). The incidence of AC was 1/220 (5/1100) patient-years of total follow-up, or 1/183.6 (5/918) patient-years in subjects undergoing endoscopy. Overall, 18 of 166 patients (10.8%), median age 74.4 yr, died during the follow-up. Among cancer deaths there were three esophageal AC, one pancreatic AC, five lung carcinomas, one colon carcinoma, and one with undefined primary site. Six BE patients died from cardiovascular disease, and one from respiratory disease. Median survival of patients with esophageal AC was 48.9 months (range 2.2– 63.1).
Figure 2. Clinical outcome of five patients (A–E) who developed esophageal adenocarcinoma. ND ⫽ no dysplasia; LGD ⫽ lowgrade dysplasia; HGD ⫽ high-grade dysplasia; AC ⫽ adenocarcinoma.
DISCUSSION In our prospective study, five patients with BE developed AC during a total follow-up of 1100 patient-years. This
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Table 2. Studies Showing the Proportion of Deaths in BE Patients That Were Due to Esophageal Adenocarcinoma
Reference
BE Patients Entered (n)
Deaths From All Causes (n)
Deaths From AC (n)
% Deaths From AC
Active Endoscopic Surveillance
Spechler et al., 1984 (5) Cameron et al., 1985 (6) Van der Veen et al., 1989 (33) Van der Burgh et al., 1996 (31) Drewitz et al., 1997 (7) Katz et al., 1998 (61) Macdonald et al., 2000 (57) Eckardt et al., 2001 (34) Conio et al., 2001 (17) Present study
105 104 155 166 170 102 143 60 117 166
16 25 35 79 38 19 27 11 35 18
1 1 2 2 2 2 2 0 1 3
6.3 4 6 2.5 5.3 10.5 7.4 0 2.9 16.7
Yes No No No Yes Yes Some Yes Some Yes
Most BE patients died from other causes. Patients in studies in which routine surveillance was advised did not seem to fare better than those without surveillance.
represents an incidence of one cancer per 220 patient-years. The incidence of AC in reported follow-up series of BE patients varies considerably, between one cancer in 46 patient-years and one in 441 patient-years (28). Part of the wide range of reported data on AC risk might be due to different study populations, for example the inclusion of cases with no intestinal-type BE on histology, cases with HGD at baseline endoscopy, or cases already under surveillance. One strength of our study was that only incidence cases of BE were included; the cancer risk of prevalence cases already under surveillance for some time might be different from incidence cases. Another cause of apparent incidence variation is lack of statistical power due to small numbers; many series had only one to three incidence cancers. In an important contribution, Shaheen et al. (19) analyzed 27 BE follow-up series, finding that small studies reported higher cancer risks than large studies. This suggested publication bias, with small studies more likely to be published if they showed a high cancer incidence. Thus, the cancer incidence in BE has probably been overestimated in the literature. In the review by Shaheen et al. (19), only three of 27 reports included more than 1000 patient-years of follow-up (equivalent to 200 BE patients followed for a mean of 5 yr). Even the three largest series only found four to eight incident cancers per report. Our study and another recently published (29), also with more than 1000 patient-years of follow-up, provide additional data on the cancer risk in BE. In these five studies, the BE cancer risk was 1/306 (30), 1/180 (31), 1/287 (32), 1/95 (29), and 1/220 patient-years in our report. The mean of these results is approximately 1/220 patient-years, or 0.45%/year, slightly less than the 0.5%/ year estimate of Shaheen et al. (19). If the incidence of AC is one case per 200 –220 patientyears, it follows that most BE patients will not develop AC in their lifetime. This is confirmed by noting the proportion of deaths of BE patients that are caused by esophageal AC versus other causes, as shown in Table 2. In follow-up series extending over years, patients, who often are old at the time of BE diagnosis, will die of various causes. Combining the 10 series in Table 2, only 16 of 303 (5.3%) of deaths in BE
patients were caused by AC. There was no apparent difference between the proportion of BE deaths due to AC in earlier series, generally without endoscopic surveillance, and more recent series in the era of surveillance, such as our present report. Most patients with BE do not die of AC, and a diagnosis of BE does not imply reduced life expectancy. In three reports, the survival of BE patients was not significantly different from the age- and sex-matched general population (6, 33–35). The review by Shaheen et al. (19) included reports from both the United States and Europe, but recent reports indicate that the AC risk might vary in different countries. The AC incidence in the general population is higher in the United Kingdom than in other parts of Europe or the United States, whereas the incidence in Italy is lower than in the United Kingdom or the United States (2). These data do not take BE into account. However, an analysis of eight follow-up series of patients with BE from the United Kingdom, avoiding publication bias, found a mean AC risk of about 1% per year (36), twice the risk estimated by Shaheen et al. (19) for the United States and Western Europe generally. Defining the size of the cancer risk in BE has clinical relevance (37). In a decision analysis study, Provenzale et al. (18) found that the optimal frequency of BE surveillance depended on the cancer incidence. Their Markov model took into account many other factors, including the cost and complications of endoscopy, and the cost, mortality, and morbidity of esophageal resection. The model assumed that esophagectomy was performed if HGD was found, and that this would usually prevent subsequent death from cancer. For a cancer risk of 0.5%/year, surveillance every 4 year was indicated; if the risk was 0.4%/year, surveillance every 5 yr was the only strategy that increased quality-adjusted life expectancy. A recent review of BE surveillance programs concluded that too-frequent endoscopic follow-up might actually decrease quality-adjusted life expectancy, corroborating the need for longer intervals than those previously applied (37). Thus, the American College of Gastroenterology updated practice guidelines for Barrett’s esophagus in 2002 (10). Surveillance at 3-yr intervals was considered
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Table 3. Dysplasia Grade at Study Entry Correlates With the Proportion of BE Patients Developing AC by the End of the Study Reference
Total BE Patients (n)
Follow-Up yr (Mean)
Nondysplastic, Developed AC (%)
LGD, Developed AC (%)
HGD, Developed AC (%)
Miros et al., 1991 (45) Hameeteman et al., 1989 (44) O’Connor et al., 1999 (9) Weston et al., 1999 (47) Reid et al., 2000 (62)
124 50 136 108 327
3.6 5.2 4.2 3.3 5
0/111 (0) 2/43 (5) 1/125 (1) 2/80 (2.5) 5/129 (4)
2/3 (67) 0/1 (0) 0/1 (0) 2/8 (25) 45/76 (59)
Montgomery et al., 2001 (60)
125
Varied
0/44 (0)
1057
7.3
0/230 (0)
1/10 (10) 3/6 (50) 1/10 (10) 1/20 (5) 1/79 (1) (Indef) 3/43 (7) (LGD) 4/22 (18) (Indef) 4/26 (15) (LGD) 10/748 (1.3)
Schnell et al., 2001 (54)
20/33 (61) 12/75 (16)
Note that dysplasia sometimes developed after study entry (not shown). Indef ⫽ indefinite for dysplasia.
appropriate for patients in whom two consecutive biopsies showed no dysplasia. Some BE patients have a higher AC risk than others. All five patients with AC in our study were male. Most BE series include both men and women, in a ratio of about 2:1 (11, 12, 19). However, the male:female AC incidence is greater, 8:1 in the general U.S. white population (38). Men with BE might have a greater AC risk than do women. In two follow-up reports (29, 39), the AC incidence was 1/59 and 1/69 patient-years for men and 1/167 and 1/537 patientyears for women. Obesity (40) and smoking (41) also increase the risk of AC in the general population, but gender, obesity and smoking have not been routinely considered in planning BE surveillance programs. In a referral-center study of 308 patients followed for a mean 3.8 yr, the risk for progression to AC for patients with SSBE was not substantially lower than for those with LSBE. The authors suggested that surveillance frequency should be the same, regardless of BE length (42). Dysplasia is the most widely used marker of cancer risk in BE. During surveillance, BE cases often show a multistep progression through LGD then HGD, eventually developing invasive AC (43– 46). In two of our five patients who developed AC, surveillance showed both LGD and HGD before the AC was found. LGD is more common than HGD. At entry to our study, 10% of BE patients had LGD, and 2% were excluded because they had HGD. Other reports (9, 44, 45, 47) are similar, LGD being found at baseline in 7%, 8%, 12%, and 19% of patients and HGD in 1%, 2%, 2%, and 7%, respectively. As shown in Table 3, the AC risk is somewhat increased in LGD and much increased in HGD. The value of LGD as a risk marker in our study was limited by frequent inability to confirm the finding on subsequent examinations. In 30 of 40 patients (75%) with an endoscopic biopsy showing LGD, a later examination failed to show LGD. Similar figures of 73% (9) and 75% (47) have been reported by others. Although we cannot exclude true regression of dysplasia, sampling error and observer variation might be more significant. Sampling error might occur owing to the irregular, patchy distribution of LGD; in one study, the mean area of LGD was less than half the total BE
surface area (48). An aggressive sampling protocol might minimize sampling error, but it is time-consuming (49). Another important problem is observer variation in biopsy interpretation, agreement on the diagnosis of LGD between two pathologists being statistically fair to poor (50). Interobserver ability to distinguish any grade of dysplasia from no dysplasia was only 72% in another study (51). Interpretation of the presence and degree of dysplasia by general pathologists in community practice varied considerably (52). In two large series of BE patients, LGD was reported in only 1.1% of patients (53) in one study, compared with 67.2% of patients in the other study (54). HGD is an uncommon but serious problem. Only 2% of our BE patients had HGD (and were therefore excluded) when the study began, and a further 2% were found to have HGD during follow-up. Three of our five patients with AC also had HGD, found before the AC in two of three cases, and at the same time as the AC in one case. The AC risk in patients with HGD is high, and AC might already be present. After esophagectomy for an endoscopic and histological diagnosis of HGD, a “missed” invasive AC (usually early) was found in the resected esophagus in 10 –50% of cases (48). In the two largest series in Table 3, 59 – 61% of HGD patients developed AC within 4 –5 yr, although one provocative study found a lower incidence, with only 12/75 (16%) developing AC during a mean 7.3-yr follow-up (54). We do not usually advise surveillance in HGD. Instead, if the patient is otherwise healthy, esophagectomy is often recommended. Newer methods of removing dysplastic epithelium are now available, such as photodynamic therapy (55) and endoscopic mucosal resection (56), which can also be used to treat early cancer; the long-term results are awaited. AC found by surveillance is more likely to be early-stage disease than AC diagnosed in nonsurveillance patients with tumor-related symptoms, such as dysphagia, bleeding, or weight loss (37). In two surgical series, lymph node involvement was found in 6 –17% of surveillance cases and in 52– 63% of nonsurveillance cases (39, 46). Early diagnosis of AC might result in more effective treatment. In one report (46), 2-yr survival was 86% in cases of AC found by surveillance, and 43% in cases not found by surveillance. In
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a recent population-based study, Corley et al. (15) showed that 73% of 15 surveillance-detected versus 0% of eight nonsurveillance patients with AC were still alive (p ⬍ 0.001) 5 yr after diagnosis, even though postoperative mortality was 3/15 in the surveillance group and 1/8 in the nonsurveillance. By contrast, our BE surveillance program did not prevent deaths from AC. We followed 166 patients for a total of 1100 patient-years, and five patients developed AC. Despite treatment including surgery, chemoradiation and photodynamic therapy, three of our five AC patients died from esophageal cancer, one died from coexistent pancreatic cancer, and one had metastatic esophageal cancer at the time of writing. It should be pointed out that three of the five patients who developed esophageal AC, did not follow our recommendations. Endoscopy successfully detected HGD in case 1, but the patient refused surgery. Cases 2 and 5 were only partially compliant with the recommended endoscopic follow-up. They underwent endoscopy for recent onset of dysphagia 35 and 48 months from their last surveillance examinations. Earlier surgical treatment might have changed the clinical outcome of these patients. Certainly, our experience shows what can occur in daily clinical practice. The performance of 528 endoscopic examinations and more than 4000 biopsies in our 166 BE patients did not prevent any cancer deaths in this group. Some other authors reached similar conclusions. Van der Burgh (31) followed 155 BE patients without surveillance for a mean of 9.3 yr and stated that their patients would not have benefited from an endoscopic surveillance program. Macdonald et al. (57) followed 143 patients for a mean of 4.4 yr and concluded that the value of their surveillance program was extremely limited, because no individual patient benefited from it. As noted earlier, the number of incident AC in any one follow-up series is small. It is not surprising that some series include individual patients who were probably helped by early detection and surgical treatment, whereas other series do not include any such patients. But, it is clear that overall, a BE surveillance program involves a large number of invasive tests with attendant risk of complications and expenditure of time and money, from which only a very small minority of the patients might benefit. A control study to show that surveillance improves survival would require a large number of patients and years of follow-up; no such study has been reported. At present, surveillance of all BE patients is of very limited value (58). Apart from dysplasia, we are unable to identify patients at increased risk of neoplastic progression (59, 60). New molecular or other markers could lead to a better selection of high-risk patients and a tailoring of a more effective follow-up program.
ACKNOWLEDGMENT The authors thank Dr. Alan J. Cameron, Mayo Clinic, Rochester, MN, for his assistance in revising the manuscript.
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Reprint requests and correspondence: Massimo Conio, M.D., National Institute for Cancer Research – Genova, Via Trento 42/14, 16145 Genova, Italy. Received Sep. 23, 2002; accepted Apr. 14, 2003.
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