Prevalence of intestinal metaplasia, dysplasia, and esophageal adenocarcinoma in patients with irregular Z-line: a systematic review and meta-analysis

Vishali Moond; Pradeep Yarra; Mannat Bhatia; Sheza Malik; Vineel Malavarappu; Hassam Ali; Saurabh Chandan; Douglas G. Adler; Babu P. Mohan

doi:10.5946/ce.2024.211

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Systematic Review and Meta-Analysis Prevalence of intestinal metaplasia, dysplasia, and esophageal adenocarcinoma in patients with irregular Z-line: a systematic review and meta-analysis: Vishali Moond¹, Pradeep Yarra², Mannat Bhatia¹, Sheza Malik³, Vineel Malavarappu⁴, Hassam Ali⁵, Saurabh Chandan⁶, Douglas G. Adler⁷, Babu P. Mohan⁸; Clinical Endoscopy 2025;58(3):377-385.
DOI: https://doi.org/10.5946/ce.2024.211
Published online: March 31, 2025

¹Department of Internal Medicine, Saint Peter’s University Hospital/Robert Wood Johnson Medical School, New Brunswick, NJ, USA

²Department of Gastroenterology & Hepatology, Saint Louis University, St. Louis, MO, USA

³Department of Internal Medicine, Reading Hospital, West Reading, PA, USA

⁴Carver College of Medicine, University of Iowa, Iowa City, IA, USA

⁵Department of Gastroenterology, Hepatology & Nutrition, ECU Health Medical Center/Brody School of Medicine, Greenville, NC, USA

⁶Division of Gastroenterology & Hepatology, Creighton University School of Medicine, Omaha, NE, USA

⁷Center for Advanced Therapeutic Endoscopy, Centura Health, Porter Adventist Hospital, Denver, CO, USA

⁸Department of Gastroenterology & Hepatology, Orlando Gastroenterology PA, Orlando, FL, USA

Correspondence: Babu P. Mohan Gastroenterology & Hepatology, Orlando Gastroenterology PA, 1507 S Hiawassee Rd., Orlando, FL 32835, USA E-mail: dr.babu.pm@gmail.com

• Received: August 4, 2024 • Revised: November 4, 2024 • Accepted: November 18, 2024

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Abstract
Graphical abstract
INTRODUCTION
METHODS
RESULTS
DISCUSSION
Supplementary Material
NOTES
REFERENCES

Abstract

Background/Aims
The irregular Z-line, defined as a segment of columnar mucosa less than 1 cm in the distal esophagus, is often biopsied despite guidelines advising against it due to a low risk of progression to esophageal adenocarcinoma (EAC). However, the clinical significance of an irregular Z-line remains unclear. This meta-analysis examines the prevalence of Barrett’s esophagus, dysplasia, and EAC in patients with an irregular Z-line.
Methods
We searched Medline, Embase, and Scopus databases up to October 2023 for studies on the prevalence of Barrett’s esophagus, dysplasia, and EAC in these patients. A random-effects model was used for meta-analysis, and heterogeneity was assessed using I² statistics.
Results
Nine studies involving 17,637 patients were analyzed. Among those with an irregular Z-line, the prevalence of intestinal metaplasia was 29.4%. In patients with intestinal metaplasia, dysplasia was found in 6.2%, low-grade dysplasia in 5.9%, high-grade dysplasia in 1.6%, and EAC in 1.5%. These rates were higher compared to those without intestinal metaplasia.
Conclusions
Patients with an irregular Z-line and intestinal metaplasia may be at higher risk and could benefit from endoscopic surveillance. Further studies are needed to determine the necessity of biopsying irregular Z-lines.
Keywords: Barrett esophagus; Esophagus; Guideline adherence; Metaplasia; Neoplasms

Graphical abstract

INTRODUCTION

Barrett’s esophagus (BE) is recognized as the sole precursor to esophageal adenocarcinoma (EAC) and is identified by the presence of intestinal metaplasia (IM) in histological examinations.¹ In cases where visible lesions are absent, several gastrointestinal societies advise against biopsying the irregular Z-line or a Z-line with less than 1 cm deviation from the gastroesophageal junction (GEJ) due to the low occurrence of dysplasia and EAC.²^-⁴ However, these recommendations are based on evidence of low quality, with the recommendation's strength being conditional.⁴

Initially, in the 1980s, the definition of BE required a columnar epithelium length of at least 3 cm, which was later revised to 1 cm after studies showed significant progression to EAC within 1 to 3 cm segments, known as short-segment BE (SSBE).⁵ The American Gastroenterological Association and Australian guidelines recently defined BE as any length of columnar epithelium extending from the GEJ.⁶^,⁷ An irregular Z-line is detected in about 20% of patients undergoing upper endoscopy, often due to dyspepsia or gastroesophageal reflux disease.²

IM is frequently found in biopsies of an irregular Z-line. Once a patient is diagnosed with SSBE, they are enrolled in surveillance endoscopies to monitor progression to dysplasia and EAC. Although current evidence generally supports a low incidence of dysplasia and EAC in patients with an irregular Z-line, existing data are limited and variable.⁸^-¹⁶ Thus, this meta-analysis aims to assess and report the pooled biopsy outcomes from irregular Z-lines.

METHODS

This study was conducted in compliance with the guidelines outlined by the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). These guidelines were instrumental in identifying relevant studies focusing on biopsy outcomes in patients exhibiting an irregular Z-line, specifically those with segments less than 1 cm in length. Detailed checklists for MOOSE and PRISMA can be found in the Supplementary Materials 1 and 2, respectively.¹⁷^,¹⁸

Search strategy

A comprehensive search was performed across various databases and conference proceedings, including PubMed, Cochrane Library, EBM Reviews, and CINAHL, covering all records from their inception until October 2023. The keywords and detailed search strategies are available in Supplementary Materials 3. Two authors (P.Y., M.B.) independently screened the titles and abstracts identified in the initial search, excluding studies that did not meet the predefined inclusion and exclusion criteria. The remaining full-text articles were assessed for relevance. Discrepancies in study selection were resolved by consensus and through discussions with a third author (B.P.M.). Additionally, references from selected articles and related systematic and narrative reviews were manually examined to identify further relevant studies.

Study selection

This meta-analysis incorporated studies analyzing biopsy results from patients with an irregular Z-line undergoing upper endoscopy, regardless of the reason for the procedure. Studies were considered regardless of their setting (inpatient or outpatient), publication status (full manuscripts or conference abstracts), and geographic origin, provided they contained data necessary for the analysis. Exclusion criteria included (1) BE measuring greater than 1 cm, (2) studies involving pediatric populations (age <18 years), and (3) non-English publications. In instances of multiple reports from the same cohort or overlapping cohorts, data from the most recent or most comprehensive study were used.

Data abstraction and risk-of-bias assessment

The extraction of data related to study outcomes was conducted using a standardized form by at least two authors (M.B., V.Mo.), while the quality of the studies was independently evaluated by two authors (P.Y., S.C.). An independent error check on the data was performed by one author (P.Y.). The quality of the studies was assessed using the Newcastle-Ottawa scale¹⁹ for cohort studies, which includes eight questions, detailed in Supplementary Table 1.⁸^-¹⁰^,¹²^-¹⁶^,¹⁸

Outcomes assessed

This study focused on several key outcomes: the prevalence of IM, IM without dysplasia, IM with dysplasia, low-grade dysplasia (LGD), high-grade dysplasia (HGD), and EAC in patients with an irregular Z-line. IM involves the transformation of esophageal squamous epithelium into a columnar type featuring intestinal characteristics, such as goblet cells. IM without dysplasia indicates the presence of IM without neoplastic changes, distinguishing it from dysplastic stages that could progress to EAC. Hence, the difference between IM with and IM without dysplasia lies in the presence or absence of neoplastic changes within the cells.

Statistical analysis

Meta-analysis techniques were employed to calculate pooled estimates using the random-effects model as proposed by DerSimonian and Laird.²⁰ In cases where an outcome was not observed in a study, a continuity correction of 0.1 was applied prior to analysis.²¹ Heterogeneity among study estimates was assessed using the Cochran Q test and I² statistics, with values indicating low (<30%), moderate (30%–60%), substantial (61%–75%), and considerable (>75%) heterogeneity.²² Publication bias was evaluated qualitatively through funnel plots and quantitatively using the Egger test when more than ten studies were included.²³ All statistical analyses were performed using Comprehensive Meta-Analysis software ver. 3 (BioStat).

RESULTS

Search results and population characteristics

From an initial total of 4,505 search results, 3,470 titles were screened, and 64 articles underwent full-length review. This process identified four study cohorts that focused on patients with an irregular Z-line and biopsy-confirmed IM (578 patients).¹⁰^-¹²^,¹⁵ Six cohorts evaluated patients with an irregular Z-line without specifying IM status (16,995 patients).⁸^,⁹^,¹¹^,¹³^,¹⁴^,¹⁶ The schematic diagram of the study selection process is provided in Supplementary Figure 1. The study by Itskoviz et al.¹¹ included two cohorts: one with known IM status and another with unknown IM status. However, upon further review, it was confirmed that all patients underwent biopsies during their initial endoscopy, and patients were divided into two groups based on biopsy results: those with positive IM and those without IM. Therefore, the two cohorts should be referred to as IM-positive and IM-negative groups rather than cohorts with known and unknown IM status.

The final analysis encompassed nine studies, totaling 17,637 patients.⁸^-¹⁶ The four cohorts with irregular Z-line and IM (n=578) were analyzed separately,¹⁰^-¹²^,¹⁵ as were the six cohorts with irregular Z-line and unknown IM status (n=16,995).⁸^,⁹^,¹¹^,¹³^,¹⁴^,¹⁶ The mean age of patients was 58.2 years, with 63.1% being male, and the majority being Caucasian. In four studies, biopsy specimens for IM and/or dysplasia were confirmed by two pathologists.⁹^,¹¹^,¹²^,¹⁵ Additional population characteristics are detailed in Table 1.⁸^-¹⁶

Characteristics and quality of included studies

All included studies were retrospective analyses. Two studies involved analyses of population-level databases. Among the studies, three were deemed high quality, while the remaining were of medium quality; there were no low-quality studies. The detailed quality assessment is presented in Supplementary Table 1.⁸^-¹⁰^,¹²^-¹⁶^,¹⁸

Meta-analysis outcomes

The final analysis incorporated data from nine studies involving 17,637 patients with an irregular Z-line.⁸^-¹⁶

1) Patients with irregular Z-line and unknown IM status (16,995 patients)

Among these patients, the pooled prevalence of IM at initial endoscopy was 29.4% (95% confidence interval [CI], 24.8%–34.4%; I²=95%) (forest plot; Fig. 1). The prevalence of IM without dysplasia was 27.5% (95% CI, 23.1%–32.5%; I²=96%), IM with dysplasia was 0.8% (95% CI, 0.4%–1.6%; I²= 80%), LGD was 1.3% (95% CI, 1.1%–1.5%; I²=0%), HGD was 0.2% (95% CI, 0.2%–0.4%; I²=0%), and EAC was 0.2% (95% CI, 0%–1.1%; I²=0%).).

2) Patients with irregular Z-Line and IM (578 patients)

For these patients, the pooled prevalence of IM with dysplasia was 6.2% (95% CI, 1.1%–27.8%; I²=93%), IM with LGD was 5.9% (95% CI, 2.5%–13.3%; I²=68%), IM with HGD was 1.6% (95% CI, 0.1%–15.4%; I²=81%), and EAC was 1.5% (95% CI, 0.2%–11.2%; I²=76%).

Patients with an irregular Z-line and confirmed IM exhibited significantly higher rates of dysplasia and LGD compared to those with an irregular Z-line and unknown IM status, as revealed by pairwise comparison. The summarized pooled rates are presented in Table 2, with forest plots available in Supplementary Figures 2–6.

Validation of meta-analysis results

1) Sensitivity analysis

To determine if any single study disproportionately influenced the meta-analysis results, we conducted a sensitivity analysis by sequentially excluding each study and reassessing the main summary estimates. Notable variations in pooled rates were observed when the study by Thota et al.¹⁵ and Freedman et al.¹⁰ were excluded, specifically in patients with an irregular Z-line and confirmed IM. The results of this one-study-remove analysis are detailed in Table 3,¹⁰^-¹²^,¹⁵ with the corresponding forest plot in Figure 2. No significant changes were observed in the analysis of patients with an irregular Z-line and unknown IM status.

2) Heterogeneity

We evaluated the variability in calculated rates using I² statistics. The corresponding I² values are presented in the summary of pooled results table, providing insight into the degree of heterogeneity across studies.

3) Publication bias

An assessment of publication bias was not conducted, as the total number of studies included in the final analysis was less than ten, limiting the robustness of such an evaluation.

DISCUSSION

This meta-analysis, which includes data from nine studies involving 17,637 patients, examines biopsy outcomes in individuals with an irregular Z-line. Among these, 16,995 patients (six study cohorts) had an irregular Z-line with unknown IM status, while 578 patients (four study cohorts) had an irregular Z-line with confirmed IM. The pooled prevalence of IM in patients with an unknown status was found to be 29.4%. Within this group, the prevalence of LGD was 1.3%, HGD was 0.2%, and EAC was 0.2%. In contrast, patients with both an irregular Z-line and confirmed IM showed pooled prevalence rates of 5.9% for LGD, 1.6% for HGD, and 1.5% for EAC.

This study represents the first meta-analysis to document biopsy outcomes for irregular Z-lines. The length of BE is a recognized risk factor for disease progression, with data showing that each additional centimeter of BE length increases the risk of EAC by an odds ratio of 1.25.²⁴ Our analysis highlights the segregation of results based on the presence or absence of IM. A large population-based study of 8,522 patients with BE reported an EAC risk of 0.38% per year in those with IM, compared to 0.07% per year in those without IM.²⁵ In our study, the prevalence of EAC in patients with an irregular Z-line was 1.5%, with significant rates of LGD and HGD, though it is uncertain whether this indicates an increased progression rate.

The “one-study-remove” sensitivity analysis showed considerable variability in pooled rates. Excluding Thota et al.¹⁵ resulted in pooled rates of 11.4% for IM with dysplasia, 8.7% for LGD, 2.8% for HGD, and 2.6% for EAC. Removing Freedman et al.¹⁰ showed pooled rates of 3.4% for both IM with dysplasia and LGD, and 0.6% for both HGD and EAC. This variability reflects the lower disease rates reported by Thota et al.¹⁵ and higher rates by Freedman et al.,¹⁰ suggesting the need for caution in generalizing individual study results to a global population with IM in irregular Z-lines. Our pooled results offer valuable insights in this context.

Thota et al.,¹⁵ in a prospective multi-center cohort study of 167 patients with an irregular Z-line and IM, found no cases of HGD or EAC during a median follow-up of 4.8 years. Conversely, Freedman et al.¹⁰ reported dysplasia or EAC in 34.6% of patients with IM segments less than 1 cm, and 57.7% in the 1–2 cm BE group. Notably, visible lesions were more prevalent in the 1 to 2 cm BE group (30.9%) compared to the IM <1 cm group (17.8%). Even without visible lesions, dysplasia or EAC was observed in 44.8% of the 1 to 2 cm BE group, versus 27% in the IM <1 cm group. The inclusion of Freedman et al.’s study¹⁰ raises concerns about the classification of SSBE as an irregular Z-line, potentially introducing bias due to the HGD and adenocarcinoma rates reported. To address this, our sensitivity analysis extended beyond the “one-study-remove” approach, revealing significant variability in pooled rates with the removal of Thota et al.¹⁵ and Freedman et al.,¹⁰ but no changes in the analysis of irregular Z-lines with unknown IM status.

Recent guidelines recommend enhancing current surveillance strategies.⁴^,⁶ The American College of Gastroenterology advises against endoscopic biopsies for Z-lines with 1 cm variability (irregular Z-lines) due to low dysplasia and EAC rates, poor endoscopic standardization, and potential costs, anxiety, risks, and inconvenience associated with the procedure.⁴ Observational evidence supports surveillance endoscopy in non-dysplastic BE (NDBE) patients every 3 to 5 years.⁴

Wani et al.¹⁶, in a nationwide registry analysis, identified significant gaps in adherence to BE surveillance guidelines. They found that surveillance recommendations were frequently given to patients without BE, with 81% having IM and 20% without IM in those with normal Z-lines, and similarly high rates for irregular Z-lines. Conversely, about one-third of patients with confirmed NDBE were undergoing surveillance at intervals shorter than the recommended three years, highlighting the need for stricter guideline adherence.

This review’s strengths include a systematic literature search with well-defined inclusion criteria, careful exclusion of redundant studies, inclusion of all high-quality studies, and detailed extraction of IM, LGD, HGD, and EAC rates. However, the study has limitations, mainly due to its reliance on retrospective data, which limits long-term outcome insights on disease progression, especially from a population-based perspective in patients with irregular Z-lines. We could not assess the impact of established BE risk factors, such as male gender, age, race, smoking, central obesity, and hiatal hernia. Not all studies confirmed dysplasia on biopsy by two pathologists, and three studies were conference abstracts. Despite these limitations, our study provides valuable data on the prevalence of LGD, HGD, and EAC in patients with an irregular Z-line and IM.

In conclusion, the pooled prevalence of dysplasia in patients with an irregular Z-line and IM was 6.2%, including 5.9% for LGD, 1.6% for HGD, and 1.5% for EAC. The presence of IM is a crucial factor in managing this patient population, and our findings support current clinical guidelines.

Supplementary Material

Supplementary Material 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist.

ce-2024-211-Supplementary-Material-1.pdf

Supplementary Material 2. Meta-Analysis of Observational Studies in Epidemiology checklist.

ce-2024-211-Supplementary-Material-2.pdf

Supplementary Material 3. Literature search strategy.

ce-2024-211-Supplementary-Material-3.pdf

Supplementary Table 1. Study quality assessment.

ce-2024-211-Supplementary-Table-1.pdf

Supplementary Fig. 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses study selection flow chart.

ce-2024-211-Supplementary-Fig-1.pdf

Supplementary Fig. 2. Forest plot, intestinal metaplasia (IM) in patients with irregular Z-line.

ce-2024-211-Supplementary-Fig-2.pdf

Supplementary Fig. 3. Forest plot, intestinal metaplasia (IM) without dysplasia in patients with irregular Z-line.

ce-2024-211-Supplementary-Fig-3.pdf

Supplementary Fig. 4. Forest plot, intestinal metaplasia (IM) with low-grade dysplasia.

ce-2024-211-Supplementary-Fig-4.pdf

Supplementary Fig. 5. Forest plot, intestinal metaplasia (IM) with high-grade dysplasia.

ce-2024-211-Supplementary-Fig-5.pdf

Supplementary Fig. 6. Forest plot, esophageal adenocarcinoma (EAC).

ce-2024-211-Supplementary-Fig-6.pdf

Supplementary materials related to this article can be found online at https://doi.org/10.5946/ce.2024.211.

Ethical Statements

Not applicable.

Conflicts of Interest

Douglas G. Adler is a consultant for Boston Scientific. The other authors have no potential conflicts of interest.

Funding

None.

Acknowledgments

Anne Rosebrock, MLS, a Reference Librarian at the Health Sciences Library, Orlando Health, provided invaluable assistance with the literature search for this study.

Author Contributions

Conceptualization: BPM; Data curation: PY, MB, VMa, SM; Formal analysis: VMo, BPM, SC; Resources: HA, DGA; Supervision: DGA; Writing–original draft: VM, BPM, DGA, HA; Writing–review & editing: all authors.

Fig. 1.

Forest plot of dysplasia in patients with irregular Z-line. IM, intestinal metaplasia; CI, confidence interval.

Fig. 2.

Forest plot, ‘one study exclusion’ irregular Z-line. IM, intestinal metaplasia; CI, confidence interval.

Table 1.

Study and population characteristics

Study	Year published	Study design	Age (yr, n or mean±SD)	Male/female	Total patient (n)	Study group	Total n	Follow-up (yr)	IM	IM without dysplasia	IM with dysplasia	LGD	HGD	EAC
Ferguson et al.⁹	2004	Retrospective, single center, 7/1/2003–10/31/2003, USA	NR	NR	1,521	Irregular Z-line	366	NR	94	92	2	2	0	0
Freedman et al.¹⁰	2020	Retrospective, single center, 09/2009–09/2016, USA	60.2	166/109	372	Irregular Z-line with IM	275	NR	275	95	69	31	38	26
Itskoviz et al.¹¹	2018	Retrospective, single center, 01/01/2006–12/31/2006, Israel	57.5±11.5	58/108	2,000	Irregular Z-line with IM	166	5.83	50	42	2	2	0	0
Jung et al.¹²	2011	Retrospective, population-based cohort, multi-center, 1976–2006, USA	60±14.5	339/148	487	Irregular Z-line with IM	86	8	86	80	6	6	0	0
Dickman et al.⁸	2010	Retrospective, single center, 01/01/2006–12/31/2006, Israel	57.3±13.0	96/70	2,000	Irregular Z-line	166	NR	72	64	NR	NR	NR	NR
Kaminsky et al.¹³	2021	Retrospective, single center, 2011-2016, USA	NR	NR	794	Irregular Z-line	619	NR	104	103	1	NR	NR	NR
Srinivasan et al.¹⁴	2021	Retrospective, multi-center registry, 2020–2021, USA	56	4,199/1,400	5,599	Irregular Z-line	4,143	NR	1,858	1,450	31	NR	NR	NR
Thota et al.¹⁵	2017	Retrospective, multi-center registry, USA, Europe	56±17	1,505/285	1,791	Irregular Z-line with IM	167	5.9	NR	NR	0	0	0	0
Wani et al.¹⁶	2020	Retrospective, population database, 01/2013–01/2019, USA	60.6±13.1	6,048/5,601	135,704	Irregular Z-line	11,649	5	3,942	3,476	178	149	29	NR

SD, standard deviation; IM, intestinal metaplasia; LGD, low-grade dysplasia; HGD, high-grade dysplasia; EAC, esophageal adenocarcinoma; NR, not reported.

Table 2.

Cumulative outcomes of irregular Z-line and IM

Outcomes	Pooled rate (95% CI)	No. of studies	I²% heterogeneity	p-value^* (no IM vs. with IM)
Irregular Z-line (IM status unknown)
IM	29.4 (24.8–34.4)	6	95	-
IM without dysplasia	27.5 (23.1–32.5)	6	96	-
IM with dysplasia	0.8 (0.4–1.6)	5	80	-
IM with LGD	1.3 (1.1–1.5)	3	0	-
IM with HGD	0.2 (0.2–0.4)	4	0	-
EAC	0.2 (0.0–1.1)	3	0	-
Irregular Z-line with IM
IM with dysplasia	6.2 (1.1–27.8)	4	93	0.03
IM with LGD	5.9 (2.5–13.3)	4	68	0.001
IM with HGD	1.6 (0.1–15.4)	4	81	0.1
EAC	1.5 (0.2–11.2)	4	76	0.1

IM, Intestinal metaplasia; CI, confidence interval; LGD, low-grade dysplasia; HGD, high-grade dysplasia; EAC, esophageal adenocarcinoma; -, not available.

^*A p-value less than 0.05 was considered statistically significant.

Table 3.

‘One-study-remove’ analysis for pooled rates in irregular Z-line with IM

Variable	Study removed	Pooled rate (95% CI)
IM with dysplasia	Thota et al.¹⁵	11.4 (2.3–41.5)
	Freedman et al.¹⁰	3.4 (0.9–12.0)
	Itskoviz et al.¹¹	7.2 (1.0–37.2)
	Jung et al.¹²	5.1 (0.4–43.9)
IM with low-grade dysplasia	Thota et al.¹⁵	8.7 (5.2–14.1)
	Freedman et al.¹⁰	3.4 (0.9–12.0)
	Itskoviz et al.¹¹	6.2 (2.2–16.3)
	Jung et al.¹²	3.9 (0.8–17.5)
IM with high-grade dysplasia	Thota et al.¹⁵	2.8 (0.2–25.4)
	Freedman et al.¹⁰	0.6 (0.1–2.7)
	Itskoviz et al.¹¹	1.8 (0.1–26.2)
	Jung et al.¹²	2.2 (0.1–26.2)
EAC	Thota et al.¹⁵	2.6 (0.3–17.9)
	Freedman et al.¹⁰	0.6 (0.1–27.0)
	Itskoviz et al.¹¹	1.6 (0.1–18.2)
	Jung et al.¹²	1.9 (0.2–18.4)

IM, intestinal metaplasia; CI, confidence interval; EAC, esophageal adenocarcinoma.

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Prevalence of intestinal metaplasia, dysplasia, and esophageal adenocarcinoma in patients with irregular Z-line: a systematic review and meta-analysis

Clin Endosc. 2025;58(3):377-385. Published online March 31, 2025

DOI: https://doi.org/10.5946/ce.2024.211

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Prevalence of intestinal metaplasia, dysplasia, and esophageal adenocarcinoma in patients with irregular Z-line: a systematic review and meta-analysis

Fig. 1. Forest plot of dysplasia in patients with irregular Z-line. IM, intestinal metaplasia; CI, confidence interval.

Fig. 2. Forest plot, ‘one study exclusion’ irregular Z-line. IM, intestinal metaplasia; CI, confidence interval.

Graphical abstract

Fig. 1.

Fig. 2.

Graphical abstract

Prevalence of intestinal metaplasia, dysplasia, and esophageal adenocarcinoma in patients with irregular Z-line: a systematic review and meta-analysis

Study	Year published	Study design	Age (yr, n or mean±SD)	Male/female	Total patient (n)	Study group	Total n	Follow-up (yr)	IM	IM without dysplasia	IM with dysplasia	LGD	HGD	EAC
Ferguson et al.9	2004	Retrospective, single center, 7/1/2003–10/31/2003, USA	NR	NR	1,521	Irregular Z-line	366	NR	94	92	2	2	0	0
Freedman et al.10	2020	Retrospective, single center, 09/2009–09/2016, USA	60.2	166/109	372	Irregular Z-line with IM	275	NR	275	95	69	31	38	26
Itskoviz et al.11	2018	Retrospective, single center, 01/01/2006–12/31/2006, Israel	57.5±11.5	58/108	2,000	Irregular Z-line with IM	166	5.83	50	42	2	2	0	0
Jung et al.12	2011	Retrospective, population-based cohort, multi-center, 1976–2006, USA	60±14.5	339/148	487	Irregular Z-line with IM	86	8	86	80	6	6	0	0
Dickman et al.8	2010	Retrospective, single center, 01/01/2006–12/31/2006, Israel	57.3±13.0	96/70	2,000	Irregular Z-line	166	NR	72	64	NR	NR	NR	NR
Kaminsky et al.13	2021	Retrospective, single center, 2011-2016, USA	NR	NR	794	Irregular Z-line	619	NR	104	103	1	NR	NR	NR
Srinivasan et al.14	2021	Retrospective, multi-center registry, 2020–2021, USA	56	4,199/1,400	5,599	Irregular Z-line	4,143	NR	1,858	1,450	31	NR	NR	NR
Thota et al.15	2017	Retrospective, multi-center registry, USA, Europe	56±17	1,505/285	1,791	Irregular Z-line with IM	167	5.9	NR	NR	0	0	0	0
Wani et al.16	2020	Retrospective, population database, 01/2013–01/2019, USA	60.6±13.1	6,048/5,601	135,704	Irregular Z-line	11,649	5	3,942	3,476	178	149	29	NR

Outcomes	Pooled rate (95% CI)	No. of studies	I²% heterogeneity	p-value^* (no IM vs. with IM)
Irregular Z-line (IM status unknown)
IM	29.4 (24.8–34.4)	6	95	-
IM without dysplasia	27.5 (23.1–32.5)	6	96	-
IM with dysplasia	0.8 (0.4–1.6)	5	80	-
IM with LGD	1.3 (1.1–1.5)	3	0	-
IM with HGD	0.2 (0.2–0.4)	4	0	-
EAC	0.2 (0.0–1.1)	3	0	-
Irregular Z-line with IM
IM with dysplasia	6.2 (1.1–27.8)	4	93	0.03
IM with LGD	5.9 (2.5–13.3)	4	68	0.001
IM with HGD	1.6 (0.1–15.4)	4	81	0.1
EAC	1.5 (0.2–11.2)	4	76	0.1

Variable	Study removed	Pooled rate (95% CI)
IM with dysplasia	Thota et al.15	11.4 (2.3–41.5)
	Freedman et al.10	3.4 (0.9–12.0)
	Itskoviz et al.11	7.2 (1.0–37.2)
	Jung et al.12	5.1 (0.4–43.9)
IM with low-grade dysplasia	Thota et al.15	8.7 (5.2–14.1)
	Freedman et al.10	3.4 (0.9–12.0)
	Itskoviz et al.11	6.2 (2.2–16.3)
	Jung et al.12	3.9 (0.8–17.5)
IM with high-grade dysplasia	Thota et al.15	2.8 (0.2–25.4)
	Freedman et al.10	0.6 (0.1–2.7)
	Itskoviz et al.11	1.8 (0.1–26.2)
	Jung et al.12	2.2 (0.1–26.2)
EAC	Thota et al.15	2.6 (0.3–17.9)
	Freedman et al.10	0.6 (0.1–27.0)
	Itskoviz et al.11	1.6 (0.1–18.2)
	Jung et al.12	1.9 (0.2–18.4)

Table 1. Study and population characteristics

SD, standard deviation; IM, intestinal metaplasia; LGD, low-grade dysplasia; HGD, high-grade dysplasia; EAC, esophageal adenocarcinoma; NR, not reported.

Table 2. Cumulative outcomes of irregular Z-line and IM

IM, Intestinal metaplasia; CI, confidence interval; LGD, low-grade dysplasia; HGD, high-grade dysplasia; EAC, esophageal adenocarcinoma; -, not available.

A p-value less than 0.05 was considered statistically significant.

Table 3. ‘One-study-remove’ analysis for pooled rates in irregular Z-line with IM

IM, intestinal metaplasia; CI, confidence interval; EAC, esophageal adenocarcinoma.