Lower Annual Rate of Progression of Short-Segment vs Long-Segment Barrett’s Esophagus to Esophageal Adenocarcinoma

Abstract

BACKGROUND & AIMS:

European guidelines recommend different surveillance intervals of non-dysplastic Barrett’s esophagus (NDBE) based on segment length, as opposed to guidelines in the United States, which do recommend surveillance intervals based on BE length. We studied rates of progression of NDBE to high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC) in patients with short-segment BE using the definition of BE in the latest guidelines (length ≥1 cm).

METHODS:

We collected demographic, clinical, endoscopy, and histopathology data from 1883 patients with endoscopic evidence of NDBE (mean age, 57.3 years; 83.5% male; 88.1% Caucasians) seen at 7 tertiary referral centers. Patients were followed for a median 6.4 years. Cases of dysplasia or EAC detected within 1 year of index endoscopy were considered prevalent and were excluded. Unadjusted rates of progression to HGD or EAC were compared between patients with short (≥1 and <3) and long (≥3) BE lengths using log-rank tests. A subgroup analysis was performed on patients with a documented Prague C&M classification. We used a multivariable proportional hazards model to evaluate the association between BE length and progression. Adjusted hazards ratios were calculated after adjusting for variables associated with progression.

RESULTS:

We found 822 patients to have a short-segment BE (SSBE) and 1061 to have long segment BE (LSBE). We found patients with SSBE to have a significantly lower annual rate of progression to EAC (0.07%) than of patients with LSBE (0.25%) (P = .001). For the combined endpoint of HGD or EAC, annual progression rates were significantly lower among patients with SSBE (0.29%) compared to compared to LSBE (0.91%) (P < .001). This effect persisted in multivariable analysis (hazard ratio, 0.32; 95% CI, 0.18–0.57; P < .001).

CONCLUSION:

We analyzed progression of BE (length ≥1 cm) to HGD or EAC in a large cohort of patients seen at multiple centers and followed for a median 6.4 years. We found a lower annual rate of progression of SSBE to EAC (0.07%/year) than of LSBE (0.25%/year). We propose lengthening current surveillance intervals for patients with SSBE.

Barrett’s esophagus (BE) has long been known to be a precursor lesion for esophageal adenocarcinoma (EAC), a cancer of high mortality with a 5-year survival rate of <15%.¹ Given the dismal prognosis of EAC and its fast rising incidence in the United States, surveillance of BE is recommended for detection and treatment of dysplasia and early stage cancers.^2–4 The evidence supporting surveillance, however, is based solely on observational data as there are no randomized control trials that have looked at its benefit. Current surveillance programs are costly and time consuming making adherence to guidelines problematic.^5,6 This brings forth the need for better risk stratification of patients and tailoring of surveillance intervals accordingly—a long-term but as-yet-unrealized goal of BE surveillance programs.

The annual risk of progression of nondysplastic BE (NDBE) to high-grade dysplasia (HGD) and EAC is approximately 0.22%–0.5%.^7,8 A number of studies suggest that the rate of progression of BE increases with segment length.^8–10 This is reflected in the British Society of Gastroenterology guidelines which recommend surveillance every 2–3 years for patients with long segment BE (LSBE) (≥3 cm) and every 3–5 years for short segment BE (SSBE) (≥1 cm and <3 cm).² U.S. guidelines, however, still recommend surveillance every 3–5 years for all patients with nondysplastic BE (NDBE) regardless of length.^3,4

Given this discrepancy in guideline recommendations, the primary aim of our study was to determine the rate of progression of NDBE patients to HGD or EAC depending on length of BE.

Methods

Participating Centers

This is a multicenter outcome project that includes 7 tertiary referral centers with a large cohort of BE patients. These centers include Veterans Affairs Medical Center, Kansas City, Missouri; Erasmus Medical Centre, Rotterdam, the Netherlands; the Southern Arizona Veterans Affairs Health Care System, Tucson, Arizona; the Cleveland Clinic, Cleveland, Ohio; the Veterans Affairs Medical Center, Portland, Oregon; University of Pennsylvania Medical Center, Philadelphia, Pennsylvania; and the Walter Reed National Military Medical Center, Bethesda, Maryland. Each center’s institutional review board provided approval for the study. Patient information was protected in accordance with the Health Information Portability and Accountability Act. Each patient was de-identified and assigned a unique identification number in association with clinical variables of interest.

Patient Data

All patient data were collected in a standardized fashion. Demographic information (age, sex, ethnicity), clinical history (alcohol use; tobacco use; body mass index [BMI]; comorbidities; medication use such as aspirin, nonsteroidal anti-inflammatory drugs, statins, proton pump inhibitors, and histamine receptor antagonists), endoscopy results (procedure date, BE segment length, presence and size of hiatal hernia), and histopathologic diagnosis were collected. BE was defined as columnarlined mucosa ≥1 cm in the distal esophagus with the presence of intestinal metaplasia.¹¹ Patients diagnosed with NDBE on index endoscopy and with a follow-up endoscopy at least 1 year after the initial diagnosis were included in the analysis. Those with HGD or EAC detected within 1 year of NDBE diagnosis were considered as prevalent cases and were excluded. Other exclusion criteria included diagnosis of HGD or EAC at baseline histology and presence of visible lesions at initial endoscopy. Datasets from each center were then merged into the main study database using Microsoft Access for Windows 2007 (Microsoft, Redmond, WA).

Endoscopy Protocol and Histopathology

BE length was measured using the distance from the anatomic gastroesophageal junction to the most proximally displaced squamous-columnar junction. The length of the segment was documented in centimeters. The Prague C&M classification was not uniformly used as the study inception preceded the adoption of the Prague criteria. Any visible lesions within the BE segment were noted. Size and presence of hiatal hernia were also recorded. A minimum of 4 quadrant biopsy specimens were obtained every 2 cm for surveillance of NDBE and every 1 cm for known or suspected dysplasia. Although the biopsy protocol and surveillance intervals were not standardized in the study protocol, each center adhered to the published society guidelines.¹² The duration of follow-up was from the time of the initial endoscopy to the most recent endoscopy with biopsies. Histological assessment and diagnosis were performed by an experienced local pathologist and confirmed by a second pathologist in the presence of dysplasia.^13,14 The most advanced histologic grade was considered the overall histology for each procedure. Presence of intestinal metaplasia on biopsy was a prerequisite criterion for inclusion.

Statistical Analysis

For statistical analyses, the BE segment length recorded on the first endoscopy was used. Patients were divided according to segment length into 3 groups: those with specialized intestinal metaplasia (SIM) <1 cm, SSBE (≥1 and <3 cm), and LSBE (≥3 cm). To note, segments <1 cm did not carry the diagnosis of BE in accordance with current guidelines and were not included in the analysis.^3,4 Unadjusted progression rates to HGD or EAC between patients with short (≥1 cm and <3 cm) and long (≥3 cm) lengths were compared using log-rank tests. Both groups were compared using Student’s t test and chi-square as appropriate. A multivariable proportional hazards model was used to derive an adjusted association between BE length and progression. Adjusted hazard ratio (HR) was calculated after adjusting for variables known to be associated with progression: gender, smoking, age, BMI, and hiatal hernia. A subgroup analysis of patients with documented Prague C&M was also performed. All analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC), and a P value of <.05 was considered statistically significant.

Results

Demographics, Comorbidities, and Medication Use

A total of 1883 patients with NDBE were identified (mean age 57.3 years, 83.5% men, 88.1% Caucasian) (Table 1). The mean length of BE in the entire cohort was 3.9 ± 3.0 cm and 75.3% patients had a hiatal hernia. Both patient groups had a similar burden of comorbidities (diabetes, hypertension) and comparable rates of smoking (Table 1). There was no difference in proton pump inhibitor use (96% in both); however, patients with SSBE had higher rates of aspirin and statin use (P < .001) (Table 1).

Table 1.

Baseline Patient Characteristics, Comorbidities, Medications, and BE length

	All patients (n = 1883)	≥1 cm and <3 cm (n = 822)	≥3 cm (n = 1061)	P value
Age, y	57.3 ± 17.4	58.3 ± 14.3	56.6 ± 19.4	.035
Male	1572 (83.5)	690 (83.9)	882 (83.1)	.637
BMI, kg/m2	27.7 ± 5.4	28.4 ± 5.7	27.2 ± 5.1	<.001
Smoking	1057 (56.1)	490 (59.6)	567 (53.4)	.007
PPI	1821 (96)	794 (96)	1027 (96)	.84
ASA	600 (39.4)	334 (48.8)	498 (31.8)	<.001
Statin	581 (60.3%)	357 (65.4)	224 (53.6)	<.001
Hypertension	673 (64.3)	394 (67.5)	279 (60.3)	.015
Diabetes	361 (33.4)	214 (36.0)	147 (30.2)	.042
H2RA use	1323 (70.3)	525 (63.9)	798 (75.2)	<.001
BE length, cm	3.9 ± 3.0	1.5 ± 0.5	5.7 ± 2.8	<.001
Follow-up time, y	6.4 (3.8–8.4)	5.8 (3.1–8.2)	6.9 (4.1–8.6)	.069

NOTE. Values are mean ± SD, n (%), or median (interquartile range).

ASA, acetylsalicylic acid; BE, Barrett’s esophagus; BMI, body mass index; H2RA, histamine 2 receptor antagonist; PPI, proton pump inhibitor.

Endoscopic Surveillance and Risk of Progression

A total of 822 patients with NDBE had a BE length of ≥1 and <3 cm (SSBE) while 1061 patients had a maximum extension of BE ≥3 cm (Table 1). The annual progression rates of SSBE and LSBE patients to EAC were 0.07% vs 0.25% (P = .001) respectively (Table 2). For a combined endpoint of HGD or EAC, the annual progression rates were also significantly lower in the SSBE cohort compared with LSBE patients (0.29% vs 0.91%; P < .001) (Table 2). To note, none of the 182 patients in the SIM <1 cm group progressed to HGD or EAC. The median number of endoscopic exams was 4.0 (range, 2.0–5.0) for SSBE vs 4.0 (range, 3.0–6.0) for LSBE.

Table 2.

Yearly Progression in Short- and Long Segment BE

	All patients	≥1 cm and <3 cm	≥3 cm	P value
1. HGD	60 (0.47)	11 (0.22)	49 (0.67)	<.001
2. EAC	21 (0.16)	3 (0.07)	18 (0.25)	.006
3. HGD or EAC	81 (0.67)	14 (0.29)	67 (0.91)	<.001

NOTE. Values are n (%). BE, Barrett’s esophagus; EAC, esophageal adenocarcinoma; HGD, high-grade dysplasia.

Subgroup Analysis of Patients With Documented Prague C&M Criteria

In a subgroup analysis of patients with documented Prague C&M criteria, there were 489 SSBE patients and 576 LSBE patients. Patients with SSBE progressed to EAC at an annual rate of 0.08% as compared with 0.19% in LSBE (P = .19). The annual rate of progression to HGD or EAC in the SSBE group was 0.35% vs 0.78% in the LSBE group (P = .007) (Table 3).

Table 3.

Progression Among Patients With Prague Classification

		Prague C&M
	Total (N = 1065)	≥3 cm (n = 576)	≥1 cm and <3 cm (n = 489)	P Value
Progression to HGD or EAC	37 (0.6)	28 (0.78)	9 (0.35)	.007
Progression to HGD	28 (0.45)	21 (0.57)	7 (0.27)	.024
Progression to EAC	9 (0.14)	7 (0.19)	2 (0.08)	.190

NOTE. Values are n (%).

EAC, esophageal adenocarcinoma; HGD, high grade dysplasia.

Multivariable Analysis

Multivariate analysis was used to estimate the impact of segment length (≥1 and <3 cm vs ≥3 cm) on progression to HGD or EAC by adjusting for potential confounders. Segment length remained an independent predictor for progression to HGD or EAC when adjusted for BMI, aspirin, statin, and histamine receptor antagonist use. Overall, the risk of progression to HGD or EAC was significantly lower among SSBE vs LSBE patients after adjusting for multiple variables (HR, 0.32; 95% CI, 0.18–0.57; P < .001). This also held true in patients with documented Prague classification (HR, 0.36; 95% confidence interval, 0.2–0.67; P = .001) (Table 4).

Table 4.

Adjusted Hazard Ratio for Short- vs Long-Segment BE

Cohort	>3 cm vs 1–3 cm	P value
Total cohort	0.32 (0.18–0.57)	<.001
With Prague data	0.36 (0.20–0.67)	.001

NOTE. Values are hazard ratio (95% confidence interval). Adjusted for age, sex, race, and smoking.

Discussion

Using the updated definition of BE from recent guidelines, analysis of this multicenter cohort of 1883 patients with nondysplastic BE, over a mean follow-up of 6.4 years, demonstrates a significantly low rate of progression to HGD or EAC in SSBE in comparison to LSBE patients. The annual progression rate from NDBE to EAC for SSBE was significantly lower at 0.07% as compared with 0.25% for LSBE. Similarly, for the combined endpoint of HGD or EAC, rates of progression remained significantly lower in SSBE at 0.29% vs 0.91% for LSBE. After adjusting for multiple risk factors, the rate of progression to HGD or EAC was still significantly lower in SSBE in comparison to LSBE with HR of 0.32, suggesting a 68% lower risk of progression to HGD or EAC in those with segment lengths of ≥1 cm and <3 cm. It is important to also note that none of the patients in the SIM <1 cm group progressed to HGD or EAC.

These results corroborate the findings of other studies that have also noted a low progression rate to HGD or EAC in SSBE patients. A recent study by Pohl et al¹⁵ with 240 patients with SSBE and 573 with LSBE, showed the annual cancer risk to be 0.03% and 0.22%, respectively. The British Society of Gastroenterology guidelines have also relied on meta-analyses and cohort studies to support their recommendation of 5-year surveillance intervals for SSBE with the annual incidence rates of SSBE progression to EAC ranging from 0.19% to 0.61% vs 0.33% to 0.67% for LSBE.^8–10 These meta-analyses, however, despite combining several studies, had fewer patients than those included in our analysis. Desai et al⁸ relied on 16 studies with a total of 967 patients, whereas Thomas et al¹⁰ included 6 studies with a combined number of 258 patients with SSBE. Finally, Yousef et al⁹ also relied on a small number of studies with only 1400 person-years and were unable to conclude with certainty whether there was a difference in cancer incidence between SSBE and LSBE.

Not all published studies have shown a correlation between progression and BE segment length. One such study by Bhat et al,⁷ which followed 8522 patients for a mean of 7 years, found no significant difference in progression risk based on length of BE. It is to be noted, however, that only 20% of patients in that study had BE length documented. In another study by Rudolph et al,¹⁶ which followed 309 patients for an average of 3.8 years, there was no difference in risk for EAC based on length. However, this study was limited by the small number of patients and the short duration of follow-up.¹⁶

Our group had previously reported on the progression in NDBE stratified by different BE lengths. The study included 1175 patients (772 with BE <3 cm) with average follow-up of 6.3 years. Rather than report on 2 dichotomous variables, we had reported that the risk of progression to HGD or EAC increased by 28% for every increase in 1 cm length. The study, however, failed to exclude those patients with segment length <1 cm and did not report on the Prague C&M classification.¹⁷

Our current study’s addition to the previous data was to provide results from a large number of patients from a multicenter cohort involving centers from the United States and Europe with special interest in management of BE. We excluded patients with segment length <1 cm in accordance with recent American College of Gastroenterology guidelines published in 2016 and have performed subgroup analysis in those patients with documented Prague C&M classification.³ Overall, given our study results, the evidence supporting the low risk category of SSBE patients as compared with LSBE seems to be more robust than the contrary. The US guidelines, as mentioned before, have set an interval of 3–5 years’ follow-up for NDBE without regard to segment length.^3,4 Our results indicate that given the low rate of yearly progression of SSBE to cancer, consideration can be given to lengthening current recommended surveillance intervals to more than 3 years. In addition, the finding of no progression among the SIM <1 cm group supports current guidelines that recommend not performing biopsies or diagnosing BE in this group of patients.^3,4

Limitations

Despite this being a large, multicenter cohort study, it has several limitations that should be taken into consideration. Recorded BE length is subject to measurement error by the endoscopist as several factors can influence the location of the gastroesophageal junction such as peristalsis, respiration, and momentary herniation of gastric folds into the esophagus.¹⁸ However, length of BE segment remains fairly consistent on subsequent endoscopies.¹⁹ The histological diagnosis was not done by a central pathologist but instead was performed by local pathologists albeit with expertise in gastrointestinal pathology. Certain confounding factors may not have been accounted for and may have influenced the results. Finally, this is an observational study and not a randomized control trial with the limitations inherent in such a study design.

Conclusions

The results of this large, multicenter study show that patients with SSBE had a significantly lower risk of progression to esophageal cancer and HGD or cancer as compared with those with LSBE. This highlights the importance of BE length in determining risk of progression to cancer and in turn indicates the need for tailoring surveillance according to segment length. Consideration could be given to lengthening the interval time to surveillance for SSBE patients. Further studies are needed to better risk-stratify NDBE and offer more nuanced guidelines for surveillance.

What You Need to Know.

Background

Current US guidelines recommend surveillance of all Barrett’s esophagus (BE) patients every 3–5 years irrespective of segment length.

Findings

Patients with short-segment BE (≥1 cm, <3 cm) have significantly lower annual rates of progression to cancer (0.07%) as compared with long-segment BE (0.25%).

Implications for patient care

Consideration should be given to extending surveillance intervals for patients with short-segment BE.

Abbreviations used in this paper:

BE

Barrett’s esophagus

BMI

body mass index

EAC

esophageal adenocarcinoma

HGD

high-grade dysplasia

HR

hazard ratio

LSBE

long-segment Barrett’s esophagus

NDBE

nondysplastic Barrett’s esophagus

SIM

specialized intestinal metaplasia

SSBE

short-segment Barrett’s esophagus