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. Author manuscript; available in PMC: 2021 Jul 1.
Published in final edited form as: Aliment Pharmacol Ther. 2020 May 26;52(1):20–36. doi: 10.1111/apt.15760

Systematic review with meta-analysis: Prevalence of prior and concurrent Barrett’s oesophagus in oesophageal adenocarcinoma patients

Mimi C Tan 1, Nabil Mansour 1, Donna L White 1,2, Amy Sisson 3, Hashem B El-Serag 1,2, Aaron P Thrift 4,5
PMCID: PMC7293564  NIHMSID: NIHMS1592957  PMID: 32452599

Abstract

Background:

The proportions of patients with oesophageal adenocarcinoma (OAC) diagnosed by Barrett’s oesophagus surveillance or with preexisting Barrett’s oesophagus are unclear.

Aim:

A systematic review and meta-analysis to estimate the prevalence of prior and concurrent Barrett’s oesophagus diagnosis among patients with OAC or oesophagogastric junction adenocarcinomas (OGJAC).

Methods:

We searched PubMed and Embase to identify studies published 1966–1/8/2020 that examined the prevalence of prior (≥6 months) or concurrent Barrett’s diagnosis (at cancer diagnosis) among OAC and OGJAC patients. Random effects models estimated overall and stratified pooled prevalence rates.

Results:

A total of 69 studies, including 33,002 OAC patients (53 studies) and 2,712 with OGJAC (28 studies) were included. The pooled prevalence of prior Barrett’s oesophagus diagnosis in OAC was 11.8% (95% confidence interval [CI] 8.4–15.6%). The prevalence of prior Barrett’s oesophagus diagnosis was higher in single-center resection studies (16.0%, 95%CI 8.7–24.9%) than population-based cancer registry studies (8.4%, 95%CI 5.5–11.9%). The prevalence of concurrent Barrett’s oesophagus in OAC was 56.6% (95%CI 48.5–64.6%). Studies with 100% early stage OAC had higher prevalence of concurrent Barrett’s oesophagus (91.3%, 95%CI 82.4–97.6%) than studies with <50% early OAC (39.7%, 95%CI 33.7–45.9%). In OGJAC, the prevalence of prior and concurrent Barrett’s oesophagus was 23.2% (95%CI 7.5–44.0%) and 26.3% (95%CI 17.8–35.7%), respectively.

Conclusions:

Most patients with OAC have Barrett’s oesophagus. Our meta-analysis found ~12% of OAC patients had prior Barrett’s diagnosis, but concurrent Barrett’s oesophagus was found in ~57% at the time of OAC diagnosis. This represents a considerable missed opportunity for Barrett’s oesophagus screening.

Keywords: oesophageal adenocarcinoma, Barrett’s oesophagus, oesophagogastric junction adenocarcinoma, prevalence, systematic review, meta-analysis

Introduction

Barrett’s oesophagus is the only known precursor lesion of oesophageal adenocarcinoma (OAC) [1], a rapidly increasing, highly fatal cancer [2, 3]. Much clinical effort has therefore focused on ongoing surveillance after an index Barrett’s oesophagus diagnosis. However, absolute risk of OAC in Barrett’s oesophagus without dysplasia is low (0.1–0.5% per year vs. 6% per year in Barrett’s oesophagus with high-grade dysplasia [1, 4, 5]), with conflicting evidence as to whether Barrett’s oesophagus surveillance reduces OAC-related mortality [6–9].

Furthermore, the vast majority of OAC cases have no prior diagnosis of Barrett’s oesophagus at their cancer diagnosis. The size of this gap is best demonstrated in the last meta-analysis to determine the prevalence of prior Barrett’s oesophagus diagnosis among resected OAC cases that included studies published from 1966–2000 [10]. Among 12 studies involving 1503 patients with resected OAC, only 4.7% had a prior diagnosis of Barrett’s oesophagus. This meta-analysis excluded studies of non-resected OAC cases and therefore did not account for prior diagnosis of Barrett’s oesophagus among patients with all stages of OAC. Additionally, it included studies that combined OAC and oesophagogastric junction adenocarcinomas (OGJAC), therefore independent prevalence estimates for OAC and OGJAC were not reported. Evaluating data from more contemporary studies may be more informative regarding prevalence of Barrett’s oesophagus in OAC as newer cohorts are more likely to have a prior diagnosis of Barrett’s and include early stage OAC patients given increased Barrett’s oesophagus screening and surveillance practices following GI societal recommendations in 1998 [11].

Therefore, we conducted a systematic review and meta-analysis of the published literature to estimate the prevalence of prior as well as concurrent Barrett’s oesophagus diagnosis among OAC and OGJAC patients. In addition, we focused on Barrett’s oesophagus prevalence within studies published in the past 10 years.

Methods

Search Strategy and Selection Criteria:

We conducted and reported this systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [12]. Two authors (MCT, NM) independently searched Pubmed and Embase databases for full, original research studies published in print or online in English from 1966 to January 8, 2020 with the following inclusion criteria: 1) reported number of patients with OAC and/or OGJAC; 2) reported number of patients within the cohort with prior and/or concurrent Barrett’s oesophagus diagnosis; and 3) only human studies. We excluded: 1) studies that did not report both numbers of patients with OAC/OGJAC and Barrett’s oesophagus; 2) abstracts only; 3) reviews, editorials, letters to the editor; 4) studies with <10 OAC/OGJAC patients due to imprecise prevalence estimates; or 5) studies with OAC/OGJAC cell lines, tissues, or xenografts. The search strategy was conducted by a medical librarian (A.S.), and the details of Medical Subject Headings (MeSH) search are included in Appendix 1. Our search strategy also included ancestry search of bibliographies of all included studies and any relevant systematic reviews to identify additional studies that may have been missed. All studies included by either reviewer underwent a second review to exclude studies with indistinguishably combined OAC/OGJAC cohorts and studies with potentially overlapping populations. For manuscripts with potentially overlapping study populations, only the one with the largest sample size was included. Consensus was reached by both authors (MCT, NM) for final study inclusion.

OAC/OGJAC and Barrett’s oesophagus identification:

In studies that specified cancer locations based on Siewert classification [13], Siewert I tumors (midpoint 1cm to 5cm proximal to anatomic OGJ) were included with OAC, while Siewert II (midpoint 1cm proximal to 2cm distal to anatomic OGJ) were included with OGJAC. Siewert III and cardia cancers were excluded. Early stage OAC/OGJAC, or those amenable to resection, were defined as T1, T2 or stage 1 or 2 cancers. Prior Barrett’s oesophagus was defined as diagnosed ≥6 months prior to OAC/OGJAC diagnosis, when specified. We defined concurrent Barrett’s oesophagus as Barrett’s found on histopathology at the time of cancer diagnosis. Studies that reported numbers with Barrett’s oesophagus at the time of cancer diagnosis but did not specify how many of these were diagnosed prior to cancer diagnosis were classified as concurrent Barrett’s oesophagus to reduce misclassification of prior Barrett’s oesophagus diagnosis. We included studies that defined Barrett’s oesophagus as “specialized intestinal epithelium”, “intestinal metaplasia”, “columnar epithelium”, or endoscopic appearance of Barrett’s oesophagus.

Data Abstraction and Quality Assessment:

Two authors (MCT, NM) independently abstracted data from included studies including: study characteristics (i.e., study design, location, study period, study site, and study population), patient clinical and sociodemographic characteristics (i.e., method of OAC/OGJAC determination, Barrett’s oesophagus determination, Siewert classification, mean age, percent male, percent White, and percent diagnosed with early stage OAC/OGJAC), number of patients with OAC/OGJAC, number of patients with Barrett’s oesophagus, and assessment of study quality. If a subgroup of the study was included in our review but demographics were only reported for the whole population, we included the reported mean age and percent males.

Assessment of study quality was modified from the “The Joanna Briggs Institute Prevalence Critical Appraisal Tool”, which is a validated critical appraisal tool for systematic reviews addressing questions of prevalence [14]. Two authors independently assessed sample representation, participant recruitment, sample size, cohort descriptions, standardized measurement of Barrett’s oesophagus and OAC/OGJAC, reliable measurement, confounding factors, and subpopulation identification. Studies were determined to have adequately identified sub-populations if they included data on number of early stage cancers and type of study as these were the stratified analysis conducted. Discordance in data abstraction or quality assessment were resolved by consensus agreement by both abstractors.

Statistical Analysis:

We used random effects analysis to estimate pooled prevalence rates of prior and concurrent Barrett’s oesophagus diagnosis among OAC and of OGJAC patients along with their 95% confidence intervals (CI). For studies that did not report prevalence of Barrett’s oesophagus, we calculated the prevalence based on reported numbers of OAC/OGJAC and Barrett’s oesophagus. We used recommended Tukey Freeman arcsine transformed proportion and variance estimates for meta-analytic calculations of prevalence data [15], with results presented as forest plots. Between-study heterogeneity was assessed using the Higgins inconsistency index (I2), and I2>50% was considered substantial heterogeneity [16]. To assess for potential small study or publication bias, we used Egger’s and graphically by evaluating asymmetry in funnel plots of the Tukey Freeman arcsine transformed proportion versus its standard error. We also assessed secular trends in pooled estimate over time meta-analyses.

We also performed a priori specified stratified subgroup and sensitivity analyses to better qualify our findings on overall association between prior and concurrent Barrett’s oesophagus and OAC/OGJAC and to identify factors related to design that contributed to any observed between-study (non-random) variation. These included meta-analyses to obtain pooled prevalence for specified sub-groups based on study site (single-center, multi-center, population-based), location (U.S./Canada, Europe/Australia, Asia, other), method of OAC determination (resection only, biopsy/surgical pathology, database/diagnosis code), sample size (<100, 100–1000, >1000), male proportion (in tertiles), and proportion of early cancers (<50%, 50–99%, 100%). We also assessed if any of these factors was a significant contributor to between-study heterogeneity using univariable meta-regression when there were a minimum 10 studies.

Finally, we performed sensitivity analyses including: 1) restriction to studies published in the last 10 years, and 2) replacing two large, population-based U.S. studies reporting patients from the Surveillance, Epidemiology, and End Results (SEER) [17] and American College of Surgeons (ACS) databases [18] with 11 additional US studies that were initially excluded due to potentially overlapping study populations as the SEER and ACS database studies.

We performed main meta-analyses including pooled estimates, forest plots, I2 and related sub-group analyses using the metafor package implemented in Stata version 14 (StataCorp, College Station, TX) and used OpenMEE (http://www.cebm.brown.edu/openmee/) [19], which stores Tukey Freeman arcsine transformed proportion and variance estimates, for performance of remaining analyses, including meta-regression. All reported p-values are two-sided with p<0.05 indicating statistical significance.

Results

We identified and reviewed 5,057 potentially relevant studies. Of these, 180 studies were included by at least 1 reviewer for a second review. We excluded 117 studies on second review, including 26 that did not meet inclusion criteria, 26 that reported combined OAC/OGJAC numbers, and 63 with potentially overlapping study populations (of which 11 US studies were used in a sensitivity analysis) (Figure 1).

Figure 1.

Figure 1.

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Study flow diagram.

A total of 69 studies met the eligibility criteria and included 33,002 patients with OAC from 53 studies and 2,712 with OGJAC from 28 studies. These studies were published from 1978 to 2019 and were conducted in U.S./Canada (n=25, 36.2%) [17, 18, 20–42], Europe (n=30, 43.5%) [43–72], Asia (n=11, 15.9%) [73–83], Africa (n=1, 1.4%) [84], South America (n=1, 1.4%) [85], or Australia (n=1, 1.4%) [86] and included 55 single-center (79.7%), 7 multi-center (10.1%), and 7 population-based studies (10.1%) (Tables 1, 2). OAC and OGJAC determination was made using surgical or endoscopic specimens (n=59 studies), diagnosis codes (n=3 studies), or cancer registry (n=7 studies). In 15 studies of prior Barrett’s oesophagus diagnosis prevalence, previous Barrett’s oesophagus diagnosis determination was made using histopathology (n=5 studies), Barrett’s oesophagus registry/database/history (n=5 studies), diagnosis codes (n=2 study), a combination of methods (n=1), or using methods that were not reported (n=2 studies). In 59 studies that reported concurrent Barrett’s oesophagus diagnosis prevalence, concurrent Barrett’s oesophagus determination was made using histopathology (n=53 studies), Barrett’s registry/database (n=1 study), survey (n=1 study), a combination of methods (n=1), or was not reported (n=3 studies). Demographic and clinical characteristics of the included studies are shown in Supplementary Table 1.

Table 1.

Study characteristics of 53 studies of 33,002 oesophageal adenocarcinoma (OAC) patients.

Ref Author Year Study Design Study Location Study Period OAC determination Barrett’s Oesophagus determination # Total OAC # Prior BE Diagnosis # Concurrent BE
Single-center Studies
[40] Amlashi 2018 cross-sectional Houston, Texas 2002–2015 hospital cancer registry of patients after chemoradiation therapy pathology 129 71
[73] Bai 2006 cross-sectional Xian, China 1/1995–12/1999 pathology reports (biopsy, surgical resection) pathology (biopsy or surgery) 29 11
[43] Bellone 2007 case series Turin, Italy 1/2002–12/2005 surgical resection pathology pathology 21 5
[20] Bergeron 2014 case series Ann Arbor, Michigan 7/2005–7/2011 surgical resection pathology (only Tis or T1 cancers) pathology 89 67
[45] Cavallin 2018 cohort Padova, Italy 1/1980–12/2011 hospital database hospital database 1243 208
[41] Chandrasoma 2007 case series Los Angeles, California 1997–2000 surgical resection pathology pathology 38 25
[22] Chen 1995 case series Winston-Salem, North Carolina 1975–1992 hospital cancer registry pathology (biopsy or surgery) 64 25
[46] Cijs 2010 cohort Rotterdam, Netherlands 1/1985–1/2005 surgical resection pathology pathology 596 179
[47] Collard 2001 cohort Brussels, Belgium 11/1984–1/2000 surgical resection pathology pathology 183 77
[48] Curran 1992 case series Galway, Ireland NR surgical resection pathology pathology 23 4
[49] Driessen 2003 cross-sectional Leuven, Belgium 1993–2000 surgical resection pathology pathology (biopsy or surgery) 135 127
[24] Duhaylongsod 1991 cross-sectional Durham, North Carolina 1985–1990 surgical resection pathology pathology 57 16
[86] Epari 2009 case series Melbourne, Australia 5/1993–5/2006 surgical resection pathology pathology (biopsy or surgery) 93 53
[67] Grimm 2010 case series Wuerzburg, Germany 1/2001–6/2004 surgical resection pathology pathology 60 41
[51] Holscher 1997 cohort Cologne, Germany 1982–1995 surgical resection pathology BE surveillance, pathology (EGD or surgery) 41 8 36
[26] Haggitt 1978 case series Boston, Massachusetts 1927–1976 surgical resection pathology pathology 14 12
[85] Henry 2014 cross-sectional Botucatu, Brazil 2007–2012 pathology NR 50 9
[52] Khan 2004 cohort Nottingham, UK 1987–2001 surgical resection pathology pathology 130 45
[54] Le Page 2015 cross-sectional Edinburgh, UK 2005–2013 endoscopic or surgical resection pathology pathology 83 68
[38] Levine 1984 case series Philadelphia, Pennsylvania 1979–1982 hospital pathology records pathology 17 17
[29] Li 2017 case series Halifax, Canada 2005–2013 endoscopic or surgical resection pathology (only T1 cancers) pathology 23 23
[76] Liu 2014 case series Henan, China 2002–2011 pathology; surgical resection pathology pathology 217 10
[37] Melis 2013 case series Tampa, Florida 6/1994–1/2011 oesophageal cancer database of surgical resections history of BE 540 155
[55] Moghissi 2009 case series East Yorkshire, UK 1997–2009 pathology (only intramucosal cancers) pathology 35 20
[30] Moon 1992 cross-sectional Milwaukee, Wisconsin 1974–1990 surgical resection pathology pathology 88 40
[31] Naunheim 1995 case series St. Louis, Missouri 1986–1993 pathology (cancers treated with neoadjuvant chemotherapy) pathology 28 16
[68] Nowicki 2018 case series Bydgoszcz, Poland 2004–2014 hospital endoscopy database BE surveillance 46 3
[32] Nurkin 2014 case series Buffalo, New York 2001–2012 endoscopic resection pathology pathology 44 44
[65] Peracchia 1999 case series Milan, Italy 11/1992–5/1998 surgical resection pathology BE surveillance 59 6
[34] Qumseya 2013 case series Jacksonville, Florida 2003–2010 endoscopic resection pathology pathology 64 61
[35] Reyes 1981 case series Hines, Illinois 1953–1979 surgical resection pathology pathology 12 6
[57] Reynolds 2011 case series Dublin, Ireland 2004–2008 pathology from database BE surveillance 100 23
[66] Ribet 1992 cross-sectional Lille Cedex, France 1970–1988 surgical resection pathology pathology 28 2 13
[69] Ruffato 2016 case series Bologna, Italy 2001–2013 surgical resection pathology pathology 202 58
[39] Sawas 2019 cohort Rochester, Minnesota 1996–1997, 2009–2012 hospital database endoscopy and/or pathology 462 241
[59] Schurr 2006 case series Hamburg, Germany NR surgical resection pathology pathology 45 22
[60] Shearer 2007 cross-sectional Glasgow, UK 1995–2000 surgical resection pathology pathology 15 12
[70] Siewert 2006 cohort Munich, Germany 7/1982–12/2005 surgical resection pathology pathology 621 494
[36] Steiger 1987 case series Allen Park, Michigan 1975–1982 surgical resection pathology pathology 11 2
[62] Van Sandick 2000 case series Amsterdam, Netherlands 1/1993–1/1998 surgical resection pathology (only pT1 cancers) pathology 20 20
[64] Wijnhoven 1999 cross-sectional Rotterdam, Netherlands 1987–1997 surgical resection pathology pathology 111 60
Multi-center Studies
[72] Borg 2016 case series Lund & Malmo, Sweden 1/2006–12/2010 surgical resection pathology pathology 60 23
[81] Imamura 2019 case series Tokyo, Kumamoto, Fukuoka, Japan 2006–2013 surgical resection pathology pathology 47 35
[71] Kunzli 2018 case series Amsterdam & Nieuwegein, Netherlands 1/2012–8/2016 endoscopic resection pathology pathology 35 30
[84] Mchembe 2013 case series Bugando, Tanzania 2008–2013 pathology pathology 13 3
[61] Sillah 2009 cross-sectional Manchester, UK 2004–2007 surgical resection pathology NR 248 107
Population-based Studies
[44] Bhat 2015 cross-sectional Northern Ireland 2003–2008 Northern Ireland Cancer Registry Northern Ireland Barrett’s Oesophagus Register >6 months prior to OAC 716 52
[102] Cook 2016 case-control USA (SEER-Medicare) 1994–2009 SEER-Medicare Cancer Registry (based on ICD9/10 codes) ICD 9/10 code >6 months prior to OAC diagnosis 5271 662
[18] Daly 2000 case series USA (National Cancer Database) 1/1994–12/1994 National Cancer Database- American College of Surgeons (based on ICD codes) survey 2110 777
[53] Lagergren 1999 case-control Sweden 1994–1997 pathology pathology 189 118
[56] Rantanen 2016 case series Finland 1980–2007 EGD/surgical resection pathology pathology (biopsy or surgery) 103 12 31
[63] Verbeek 2014 cross-sectional Netherlands 1999–2009 Netherlands Cancer Registry Dutch Pathology Registry 9780 791
[42] Wenker 2018 cross-sectional USA (National VA Database) 2002–2016 VA Cancer Registry (based on ICD codes) ICD 9 code >6 months prior to OAC diagnosis 8564 419
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BE: Barrett’s oesophagus; NR: not reported; EGD: esophagogastroduodenoscopy

Table 2.

Study characteristics of 28 studies of 2,712 oesophagogastric junction adenocarcinomas (OGJAC) patients.

Ref Author Year Study Design Study Location Study Period OGJAC determination Barrett’s oesophagus determination OGJAC definition # Total OGJAC # Prior BE Diagnosis # Concurrent BE
Single-center Studies
[40] Amlashi 2018 cross-sectional Houston, Texas 2002–2015 hospital cancer registry of patients after chemoradiation therapy pathology Siewert 2 98 26
[73] Bai 2006 cross-sectional Xian, China 1/1995–12/1999 pathology reports (biopsy, surgical resection) pathology (biopsy or surgery) Siewert 2 80 5
[21] Cameron 2002 case-control Rochester, Minnesota 1/1996–12/1999 endoscopic or surgical resection pathology (only cancers <2cm) pathology within 2 cm of OGJ 22 7
[23] Demicco 2011 case series Boston, Massachusetts 1/2000–5/2008 surgical resection pathology pathology (biopsy or surgery) Siewert 2 106 19 64
[50] Fein 1998 case series Wuerzburg, Germany 1992–1997 surgical resection pathology pathology Siewert 2 30 1
[25] Gaca 2006 cross-sectional Durham, North Carolina 7/1992–2/2001 surgical resection pathology NR within 5cm of OGJ 96 42
[83] Gupta 2001 case series Chandigarh, India 1989–1994 surgical resection pathology NR at or extending 2cm distal to OGJ 28 0
[74] Horii 2011 case-control Sendai, Japan 2000–2009 pathology (cancers limited to submucosa) pathology within 2cm of OGJ and midpoint on oesophageal side 46 23
[82] Imai 2013 case series Shizuoka, Japan 9/2002–3/2009 endoscopic resection pathology pathology Siewert 2 49 7
[75] Kamada 2012 cross-sectional Kurashiki, Japan 1/2001–12/2008 endoscopic or surgical resection pathology pathology Siewert 2 80 6
[27] Karl 2000 cross-sectional Tampa, Florida 1989–1999 surgical resection pathology pathology NR 115 56
[28] Lada 2013 cohort Rochester, New York 2000–2011 surgical resection pathology medical record review, EGD, pathology NR 211 73
[77] Nagami 2014 cross-sectional Osaka, Japan 2007–2011 endoscopic dissection pathology pathology Siewert 2 43 14
[33] Pera 1993 cross-sectional Rochester, Minnesota 1974–1989 pathology pathology extending across OGJ 14 5
[57] Reynolds 2011 cohort Dublin, Ireland 2004–2008 pathology from database NR Siewert 2 53 1
[58] Saha 2009 case-control West Yorkshire, UK 1/2000–12/2006 surgical resection pathology (only pT1 cancers) pathology Siewert 2 44 28 31
[39] Sawas 2019 cohort Rochester, Minnesota 1996–1997, 2009–2012 hospital database endoscopy and/or pathology Siewert 2 288 140
[59] Schurr 2006 prospective case series Hamburg, Germany NR surgical resection pathology pathology Siewert 2 40 5
[60] Shearer 2007 prospective case series Glasgow, UK 1995–2000 surgical resection pathology pathology Siewert 2 26 13
[70] Siewert 2006 cohort Munich, Germany 7/1982–12/2005 surgical resection pathology pathology Siewert 2 485 27
[78] Tsuji 2004 cross-sectional Osaka, Japan NR surgical resection pathology pathology Siewert 2 23 2
[62] Van Sandick 2000 cross-sectional Amsterdam, Netherlands 1/1993–1/1998 surgical resection pathology (only pT1 cancers) pathology 12 12
[64] Wijnhoven 1999 cross-sectional Rotterdam, Netherlands 1987–1997 surgical resection pathology pathology Siewert 2 141 18
Multi-center Studies
[72] Borg 2016 case series Lund & Malmo, Sweden 1/2006–12/2010 surgical resection pathology pathology NR 45 11
[80] Huang 2011 cross-sectional Nanjing, China and Boston, Massachusetts 2004–2008, 1991–2008, 1999–2008 surgical resection pathology pathology within 2 cm of OGJ 70 26
[81] Imamura 2019 case series Tokyo, Kumamoto, Fukuoka, Japan 2006–2013 surgical resection pathology pathology Siewert 2 273 69
[79] Yuasa 2006 case series Nagoya, Japan 1987–2003 surgical resection pathology pathology Siewert 2 40 2
Population-based Studies
[56] Rantanen 2016 cross-sectional Finland 1980–2007 biopsy/surgical resection pathology EGD/pathology NR 154 4 24
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BE: Barrett’s oesophagus; OGJ: oesophagogastric junction; NR: not reported; EGD: esophagogastroduodenoscopy

Evaluation of Studies for Risk of Bias

Risk of bias assessments for the 69 included studies are shown in Supplementary Table 2. Overall, only 10 of 69 studies included a representative sample of the target population, enrolled consecutive patients, had adequate sample size, and reliably measured OAC/OGJAC and Barrett’s oesophagus using objective criteria [18, 23, 24, 46–49, 53, 63, 73]. Few studies fully described the characteristics of OAC/OGJAC patients (n=10), but most studies did not clearly state that consecutive patients were included (n=44) or reliably measure both OAC/OGJAC and Barrett’s oesophagus using histopathology and intestinal metaplasia or goblet cells as standard criteria (n=41). All studies had adequate sample size as we excluded studies with <10 OAC/OGJAC patients. Twenty-nine studies had a representative sample of OAC/OGJAC patients (i.e., included all cancer stages). Most studies included cancer stage data allowing stratified subgroup analysis based on percent early cancers (n=48).

Pooled Prevalence of Barrett’s oesophagus in OAC

Among 11 studies including 25,248 patients with OAC, the pooled prevalence of prior Barrett’s oesophagus diagnosis was 11.8% (95% CI 8.4–15.6%; I2=98%) (Figure 2). Three studies defined prior Barrett’s oesophagus diagnosis as that was diagnosed ≥6 months prior to cancer diagnosis [17, 42, 44] but did not specify the number of Barrett’s oesophagus detected within 12 months; one study defined prior Barrett’s oesophagus as that diagnosed ≥12 months prior to cancer diagnosis [63], and the rest did not specify time interval for defining prior Barrett’s oesophagus. The pooled prevalence of prior Barrett’s oesophagus among 814 OAC patients was higher in the 6 single-center studies, including mostly surgical resections (16.0%, 95% CI 8.7–24.9%; I2=83%) than among the 24,434 OAC patients in the 5 population-based cancer registry studies (8.4%, 95% CI 5.5–11.9%; I2=98%) (heterogeneity between groups p=0.05). Of 5 studies that specify patients who received Barrett’s oesophagus surveillance endoscopy [51, 57, 63, 65, 68], the prevalence of OAC patients that were diagnosed based on Barrett’s oesophagus surveillance endoscopy was 11.6% (95% CI 4.0–22.1%).

Figure 2.

Figure 2.

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Pooled prevalence of prior Barrett’s oesophagus diagnosis among 25,248 oesophageal adenocarcinoma patients from 11 studies.

In 45 studies of 7,926 OAC patients, the prevalence of concurrent Barrett’s oesophagus was 56.6% (95% CI 48.5–64.6%; I2=98%). Stratified meta-analyses showed numerically lower prevalence of concurrent Barrett’s oesophagus among population based studies (3 studies; 2,402 OAC patients; prevalence=43.0%, 95% CI 26.5–60.4%; I2 not calculated) than single-center studies (39 studies; 5,121 OAC patients; prevalence=58.3%, 95% CI 47.5–68.6%; I2=98%) and multi-center studies (5 studies; 403 OAC patients; prevalence=54.7%, 95% CI 34.8–73.8%; I2=91%); however, the test for heterogeneity between these three sub-groups was not statistically significant (p=0.35) (Figure 3). When evaluating the association between cancer stage and prevalence of concurrent Barrett’s oesophagus, we found that in 10 studies (451 OAC patients) with 100% early stage cancers, the pooled prevalence of concurrent Barrett’s oesophagus was higher (91.3%, 95% CI 82.4–97.6%; I2=86%) than in 7 studies (1,011 OAC patients) with 50–99% of the cohort with early stage cancers (43.8%, 95% CI 12.2–78.4%; I2=99%) and 13 studies (3,616 OAC patients) with <50% of the cohort with early stage cancers (39.7%, 95% CI 33.7–45.9%; I2=89%) (p<0.001) (Figure 4).

Figure 3.

Figure 3.

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Pooled prevalence of concurrent Barrett’s oesophagus diagnosis among 7,926 oesophageal adenocarcinoma patients from 45 studies.

Figure 4.

Figure 4.

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Pooled prevalence of concurrent Barrett’s oesophagus diagnosis among oesophageal adenocarcinoma (OAC) patients comparing 10 studies (451 OAC patients) with 100% early stage cancers to 7 studies (1,011 OAC patients) with 50–99% early stage cancers and 13 studies (3,616 OAC patients) with <50% early stage cancers.

Sensitivity analyses

Meta-analysis restricted to studies published in the last 10 years of the review (2010–2020) showed pooled prevalence of prior Barrett’s oesophagus was 11.8% (95% CI 8.2–16.0, I2=98%) (8 studies; 25,120 OAC patients) and the pooled prevalence of concurrent Barrett’s oesophagus was 56.2% (95% CI 42.0–69.9%, I2=98%) (18 studies; 3,520 OAC patients), which was not different from the overall prevalence (Figure not shown).

We conducted a sensitivity analysis excluding the two large US population-based cohorts [17, 18] and replaced them with 11 US studies with potentially overlapping study populations that were excluded in the primary analysis (Supplementary Table 3) [87–97]. The pooled prevalence of prior Barrett’s oesophagus among 14 studies including 20,891 OAC patients was 11.4% (95% CI 8.3–14.8%; I2=96%) (Supplementary Figure 1). The prevalence of concurrent Barrett’s oesophagus among 6,867 OAC patients in 53 studies was 53.4% (95% CI 45.5–61.1%; I2=97%) (Supplementary Figure 2). Both estimates were similar to the pooled prevalence of prior Barrett’s oesophagus diagnosis in the primary analysis.

Bias and heterogeneity assessments

Graphical funnel plot and Egger’s test demonstrated significant small study bias (p<0.001); although pooled meta-analytic estimates of studies stratified by sample size (<100, 100–1000, >1000 OAC cases) demonstrated only modest differences in pooled prevalence estimates (Figure 5). Among the other variables examined as potential factors explaining observed between-study heterogeneity in univariable meta-regression, method of OAC determination (resection only, biopsy/surgical pathology, database/diagnosis code) and proportion of early cancers (categorically <50%, 50–99%, 100%) were significant predictors (p=0.03 and <0.001, respectively) (Supplementary Table 4).

Figure 5.

Figure 5.

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Funnel plot showing significant small study bias among 45 studies evaluating prevalence of concurrent Barrett’s oesophagus diagnosis among 7,926 oesophageal adenocarcinoma patients.

In the cumulative meta-analysis where we examined how the observed pooled estimate changed with studies subsequently added over time, the cumulative pooled prevalence was initially much higher based on studies published prior to 1990, then attenuated with addition of studies published in the 1990s, and largely stabilized by 2000 onwards (Supplementary Figure 3).

Pooled Prevalence of Barrett’s oesophagus in OGJAC

Our primary analysis included 6 studies with 664 patients with OGJAC and found a pooled prevalence of prior Barrett’s oesophagus diagnosis of 23.2% (95% CI 7.5–44.0%; I2=97%) (Supplementary Figure 4). The pooled prevalence of prior Barrett’s oesophagus was higher in the 5 single-center OGJAC studies (29.3%, 95% CI: 13.1–48.8%) compared with the 1 population-based study (2.6%, 95% CI: 1.0–6.5%) (p<0.001). In 25 studies of 2,352 OGJAC patients, the pooled prevalence of concurrent Barrett’s oesophagus was 26.3% (95% CI 17.8–35.7%; I2=95%) (Supplementary Figure 5). The pooled prevalence of concurrent Barrett’s oesophagus among OGJAC patients was no different in the 20 single-center studies (28.1%, 95% CI: 17.1–40.5%) as the 4 multi-center (22.3%, 95% CI: 12.0–34.7%) and 1 population-based study (15.6%, 95% CI: 10.7–22.1%) (p=0.11). Given limited number of studies, we did not perform the Egger’s test or meta-regression for OGJAC studies.

Discussion

Among patients with OAC, prior Barrett’s oesophagus diagnosis was present in 11.8%, while 56.6% had concurrent Barrett’s oesophagus diagnosed at the time of OAC. Studies that included all early stage OAC patients had a higher prevalence of concurrent Barrett’s oesophagus (91.3%) than studies that included all stages of OAC (39.7%). Among those with OGJAC, the pooled prevalence of prior Barrett’s oesophagus diagnosis was 23.2%, and concurrent Barrett’s oesophagus was 26.3%.

Our study reported a higher prevalence of prior Barrett’s oesophagus diagnosis than the one previous meta-analysis (4.7% ± 2.9%) of studies published through 2000 [10]. The previous meta-analysis included 12 studies comprising 1503 cases of OAC/OGJAC but included studies that combined OAC with high-grade dysplasia, gastric cardia and OGJAC (5 studies), which may account for the smaller Barrett’s oesophagus prevalence compared to our meta-analysis. We excluded 6 of these studies from our analysis (5 indistinguishably combined OAC and OGJAC, 1 with overlapping population as another included study). We found a similar prevalence of prior Barrett’s oesophagus diagnosis (11.8%) when pooling contemporary studies published in the last 10 years, although these studies included cohorts as far back as 1980, so likely did not reflect the most contemporary practice patterns. We were unable to restrict to solely contemporary cohorts as none of the studies reporting prior Barrett’s oesophagus diagnosis were limited to cohorts from the last 10 years.

The low prevalence of previously known Barrett’s oesophagus diagnosis among OAC patients likely reflects missed screening opportunities in patients who did in fact have underlying Barrett’s oesophagus. It is possible but less likely that these patients did not have any of the known demographic or clinical Barrett’s oesophagus risk factors (reflux symptoms, obesity, age >50, male, Caucasians, family history of esophageal cancer). Detailed data on Barrett’s oesophagus risk factors were not reported in the studies, and 15.9% of studies reported racial breakdown. We did not estimate prevalence of prior endoscopy in this meta-analysis but previous studies suggest Barrett’s oesophagus is under-diagnosed prior to OAC due to lack of endoscopic screening. Our previous study of 182 patients with OAC reported only 24.7% underwent any pre-OAC diagnosis endoscopy, and of those who did not undergo previous endoscopy, most had risk factors for Barrett’s oesophagus or OAC (63.5%) [98]. When we pooled studies that confirmed the concurrent presence of Barrett’s oesophagus on histopathology at the time of cancer diagnosis, we found a much higher prevalence of Barrett’s oesophagus, indicating that the majority of OAC patients have underlying Barrett’s oesophagus that was not previously diagnosed. We further examined studies that included only early stage OAC and found the pooled prevalence of concurrent Barrett’s oesophagus was much higher (91.3%) compared to studies with all stages of OAC (39.7%). This finding strongly supports that advanced OAC likely overgrows the underlying Barrett’s oesophagus making Barrett’s detection easier in earlier stages [99]. A second explanation to account for the considerable proportion of OAC patients without Barrett’s oesophagus at the time of OAC diagnosis (60.3% in studies with all OAC stages) may be a mechanism of OAC development that excludes Barrett’s oesophagus. A recent study found improved survival in OAC patients with synchronous Barrett’s oesophagus compared to those without Barrett’s oesophagus after adjusting for cancer stage, proposing the possibility of a different phenotype of OAC development [8].

We found 23.2% of those with OGJAC had a prior Barrett’s oesophagus diagnosis and 26.3% had Barrett’s oesophagus confirmed on histopathology at the time of cancer diagnosis; this estimate has not previously been reported. OGJAC shares several risk factors with OAC (e.g., reflux, obesity) [100]. OGJAC are classified by location using the Siewert classification [13]. Siewert type I and II are treated similarly to OAC, while Siewert III and cardia cancers are treated following gastric cancer protocols [50, 101]. We included Siewert I OGJAC with OAC, and Siewert II cancers with OGJAC [13]. Our findings confirm that Siewert II OGJAC occurs sometimes in the setting of Barrett’s oesophagus, and some OGJAC may follow the same carcinoma sequence and share the same risk factors as Barrett’s oesophagus. However, Barrett’s oesophagus was found at the time of cancer diagnosis less commonly in OGJAC than in OAC, which may point to a different mechanism of OGJAC pathogenesis apart from Barrett’s oesophagus in some cases of OGJAC.

Our meta-analysis has multiple strengths including structured comprehensive search strategy resulting in >5000 reviewed studies by 2 reviewers, use of ancestry/bibliography searches to identify any missed studies, contacting study authors for unpublished data, and defining prior and concurrent Barrett’s oesophagus diagnosis, OAC, and OGJAC a priori. We employed a methodologically rigorous approach including sub-group analysis by study site and proportion of early cancers and sensitivity analyses restricted to contemporary studies from the last 10 years and replacing 2 large US population-based studies with 11 excluded US single-center studies. Additionally, we used multiple methods including meta-regression and cumulative meta-analysis to identify potential sources of between-study heterogeneity and bias.

Our meta-analysis has several limitations. There were no studies that were prospectively conducted with the aim of evaluating Barrett’s oesophagus prevalence among OAC/OGJAC patients, thus systematic evaluation for Barrett’s oesophagus was lacking across studies. Especially among studies that define Barrett’s oesophagus using registry or databases, the prevalence of Barrett’s oesophagus may have been under-estimated as it was not systematically captured at the time of cancer diagnosis. The definitions of Barrett’s oesophagus, OAC, OGJAC varied across studies in completeness. Only 3 studies specified prior Barrett’s oesophagus diagnosis as >6 months [17, 42, 44] and 1 additional study as >12 months [63] prior to cancer diagnosis. In order to reduce misclassification of prior Barrett’s oesophagus diagnosis cases, we classified cases as concurrent Barrett’s oesophagus diagnosis when studies did not specifically state that there was a prior diagnosis or that cancer was found on Barrett’s oesophagus surveillance endoscopy; therefore, in the studies without mention of timing of Barrett’s oesophagus diagnosis, cases of prior Barrett’s oesophagus and concurrent Barrett’s oesophagus may have been misclassified. There was also poor reporting on race/ethnicity and consecutiveness of study population. The overall sample size was relatively small, including those with prior Barrett’s oesophagus diagnosis in OAC and OGJAC. Additionally, significant heterogeneity was seen among the reported pooled prevalence. Meta-regression analyses demonstrated that variable proportion of early OAC accounted for some of this heterogeneity, and stratified meta-analysis by proportion of early OAC decreased the heterogeneity seen in the overall pooled prevalence. The significant small study bias is likely substantially explained by the relation of sample size to method of OAC determination, as smaller studies tended to determine OAC on resection specimens and larger studies on registry/diagnosis codes.

Overall, although up to 91% of all newly diagnosed early stage OAC patients had Barrett’s oesophagus seen on histopathology at the time of cancer diagnosis, the prevalence of known Barrett’s oesophagus prior to OAC diagnosis remains low among these patients. These findings call for increased use of Barrett’s oesophagus screening protocols.

Supplementary Material

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Acknowledgements

Financial support: The work was supported in part by the Center for Gastrointestinal Development, Infection and Injury (NIDDK P30 DK 56338) and in part by the resources at the VA HSR&D Center for Innovations in Quality, Effectiveness and Safety (#CIN 13-413), at the Michael E. DeBakey VA Medical Center, Houston, TX. Dr. White receives research support from the U.S. Department of Veterans Affairs (CX001430).

Footnotes

Competing interests: None.

DISCLAIMER

The opinions expressed reflect those of the authors and not necessarily those of the Department of Veterans Affairs, the US government or Baylor College of Medicine.

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