What Is an Irregular z-Line and How Is It Different from Barrett’s Esophagus?

The z-line refers to the squamocolumnar junction (SCJ) which marks the transition between the stratified squamous epithelium of the distal esophagus and the columnar epithelium of the gastric cardia. A “regular” z-line refers to the SCJ having a concentric and symmetric appearance without any irregularities or zig-zag appearance, whereas an “irregular” z-line refers to an irregular appearing SCJ characterized by the presence of columnar mucosa less than 1 cm in length that extends above the gastroesophageal junction (GEJ, Fig. 1). In contrast to an irregular z-line, Barrett’s esophagus (BE), which arises in the setting of longstanding gastroesophageal reflux disease (GERD), is diagnosed when columnar mucosa of at least 1 cm is seen in the distal esophagus extending above the GEJ and biopsies from this area demonstrate specialized intestinal metaplasia (IM), a histologic finding that is characterized by presence of goblet cells [1, 2]. BE is the only known precursor to esophageal adenocarcinoma (EAC), which remains associated with a dismal 5-year survival rate estimated at 20% [3].

Fig. 1
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A comparison of distal esophageal landmarks seen with a normal z-line, b irregular z-line, and c short-segment Barrett’s esophagus. Adapted with permission from Wolters Kluwer Health, Inc.: Wani et al. [18]. The Creative Commons license does not apply to this content. Use of the material in any format is prohibited without written permission from the publisher, Wolters Kluwer Health, Inc. Please contact permissions@lww.com for further information

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An irregular z-line is not a rare occurrence and is frequently found at the time of esophagogastroduodenoscopy (EGD) in up to a quarter of cases [4]. Biopsies taken from an irregular z-line may or may not demonstrate IM. Rates of IM in biopsies taken from an irregular z-line are variable and range from 9 to 44% [5, 6]. The primary difference between an irregular z-line and BE relates to the length of the salmon-colored mucosa in the distal esophagus proximal to the GEJ, namely whether this is < 1 cm or ≥ 1 cm in length, respectively. As such, an irregular z-line even with biopsies demonstrating IM does not constitute BE given differences between these entities related to the length of salmon-colored mucosa in the distal esophagus and consequently, this finding should not be considered equivalent to BE.

In this review, we highlight the importance of landmark identification of the distal esophagus and GEJ at the time of endoscopy, share recommendations from current guidelines related to the z-line, examine rates of neoplastic progression in those with an irregular z-line, discuss consequences of routinely biopsying an irregular z-line, and highlight strategies on how to approach an irregular z-line if seen on EGD.

Landmark Identification at Time of Endoscopy

Landmark identification should be performed at time of EGD for complete assessment of the distal esophagus and proximal stomach. In patients undergoing EGD, the location of the SCJ, GEJ, and hiatus (site of hiatal opening) should be routinely documented (Fig. 1). As described above, the SCJ (z-line) marks the transition between the stratified squamous epithelium of the distal esophagus, which is classically pink in color, and the columnar epithelium of the gastric cardia, which is salmon colored. The GEJ is the anatomic area that represents the junction between the distal esophagus and proximal stomach and is readily recognized on endoscopy as the most proximal extent of the gastric folds. In addition, the distal end of the palisading small vessels in the lower esophagus can help to identify the GEJ [7, 8]. The site of hiatal opening can be identified by locating the diaphragmatic pinch which can be visualized based on patient respiration.

The z-line is considered irregular when the SCJ extends above the GEJ but with a length of < 1 cm. While sometimes in literature, the finding of a z-line extending < 1 cm above the GEJ was sometimes referred to as ultra-short-segment BE [9,10,11], this terminology has now largely been replaced by the irregular z-line in the Western literature. It is important to note that an irregular z-line demonstrating IM is distinct from IM of the gastric cardia as the latter reflects biopsies taken at or below the GEJ rather than above it as is the case with an irregular z-line. When the endoscopic examination shows the z-line extending ≥ 1 cm above the GEJ suggestive of BE, the Prague Criteria should also be used to report both the circumferential and maximal extent of the columnar mucosa in the distal esophagus and the BE segment should be classified as either short segment (1 to < 3 cm in length) or long segment (≥ 3 cm) [2]. The overall reliability coefficient for BE ≥ 1 cm length is 0.72 (substantial reliability) as compared to 0.22 for an irregular z-line (only slightly reliable) [12]. This suggests significant interobserver variability among endoscopists with respect to an irregular z-line and what may appear to be an irregular z-line for one gastroenterologist may not appear so irregular for another.

Current Guidelines Related to Z-Line and Barrett’s Esophagus

The American College of Gastroenterology (ACG) published updated guidelines on diagnosis and management of Barrett’s esophagus in 2022 (Table 1) [2]. These guidelines recommend against routinely taking biopsies from a normal-appearing z-line [2]. Furthermore, in the absence of visible abnormalities, routine biopsies should not be taken from z-line that demonstrates < 1 cm proximal displacement from the top of the gastric folds [2]. As the diagnosis of BE requires presence of columnar mucosa of at least 1 cm in length, biopsies for BE should only be taken when such findings are seen on EGD. The European Society of Gastrointestinal Endoscopy (2023) also recommends against routine biopsies and endoscopic surveillance in patients with an irregular z-line or columnar-lined mucosa < 1 cm in length [13]. Additionally, the British Society of Gastroenterology (2014) also defines Barrett’s esophagus as presence of columnar epithelium ≥ 1 cm in length above the GEJ and generally recommends against surveillance in patients with an irregular z-line regardless of the presence of IM [14]. The Asia–Pacific consensus (2016) on GERD and BE states that the diagnostic criteria for BE is replacement of the normal distal squamous epithelium by columnar epithelium, which must be ≥ 1 cm above the GE junction and confirmed by histology [11]. The latest American Society for Gastrointestinal Endoscopy guidelines (2019) and American Gastroenterological Association Clinical Practice Update (2022) on Barrett’s esophagus do not explicitly comment on an irregular z-line [15, 16]. On the other hand, the Kyoto international consensus (2022) and Japanese Esophageal Society (2015) define BE as any columnar epithelium in the esophagus continuous from the stomach with or without IM regardless of length [7, 8, 17].

Table 1 Guidelines from the national and international gastroenterological societies with regards to the z-line
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Poor Adherence to Guidelines Regarding the Z-Line

Contrary to the aforementioned recommendations from multiple national and international organizations that recommend against routine biopsies from the z-line, there appears to be a sizable number of patients without BE that undergo biopsies from the z-line and are subsequently recommended to undergo surveillance endoscopies. In a study utilizing data from GI Quality Improvement Consortium (GIQUIC) Registry, there were 13,042 and 10,986 EGDs with a normal and irregular appearing z-line, respectively, where biopsies were obtained from GE junction [18]. IM was seen in 38% of normal and 34% of irregular z-line cases. In patients with normal z-line, surveillance EGD was recommended in 81% of patients with IM and 20% without IM. In patients with irregular z-line, surveillance EGD was recommended in 81% with IM and 24% without IM.

Irregular Z-Line Does Not Appear to Be a Significant Risk Factor for Advanced Neoplasia

Multiple gastroenterology society guidelines generally recommend against taking routine biopsies from an irregular z-line in the absence of visible abnormalities, in large part, based on evidence from long-term follow-up studies showing lack of progression to advanced neoplasia such as high-grade dysplasia (HGD) or EAC in patients with irregular z-line [6, 10, 19,20,21].

In a prospective, multicenter study at tertiary care referral centers across the USA and Europe, an irregular z-line with IM was seen in 167 (9.3%) of 1791 patients that underwent endoscopic examination for BE [6]. During a median follow-up period of 4.8 years, no patients with an irregular z-line had progression to low-grade dysplasia (LGD), HGD, or EAC. Furthermore, none of the patients with an irregular z-line were found to have BE ≥ 1 cm on follow-up. After adjusting for baseline differences in groups, there was a significant association between irregular z-line and lack of progression to HGD or EAC.

In a population-based cohort study of patients from Olmsted County, Minnesota, a total of 86 patients with IM of the GEJ were identified between 1976 and 2006 [19]. No patients with IM–GEJ developed BE, EAC, or gastric adenocarcinoma during median follow-up of 8 years. A finding of baseline LGD was found in 6 patients; however, 5 of these patients underwent follow-up EGDs and did not have evidence of LGD on follow-up. The overall survival in patients with IM–GEJ was similar to that expected for Minnesota population with similar age and sex distribution.

A European study estimated that the annual EAC transition rate for those with ultra-short-segment (< 1 cm) BE was 0.01% [20]. Additionally analyses demonstrated that in order to detect one EAC, a total of 12,364 patients with ultra-short-segment BE would need to undergo annual surveillance endoscopy. A prospective cohort study examined long-term outcomes in patients with irregular z-line (defined as z-line variability < 5 mm) with and without IM [21]. None of the 102 patients with an irregular z-line that underwent at least one follow-up EGD developed HGD or EAC during a median follow-up of 70 months regardless of presence or absence of IM at baseline.

In a Japanese study consisting of 3318 patients with an irregular z-line (referred to as ultra-short-segment BE in this study), only 2 EACs developed over an observation period of 54 months with an annual incidence of 0.0068% [10].

In the aforementioned GIQUIC registry study [18], the vast majority of patients with normal (85%) and irregular (88%) z-line with IM did not have dysplasia. However, LGD/indefinite for dysplasia was seen in 7.4% and HGD in 2% of those with IM from a normal z-line. Among cases with IM from an irregular z-line, LGD/indefinite for dysplasia was diagnosed in 3.8% and HGD in 0.7%. The authors emphasized that results on dysplasia from the z-line from this study should be interpreted with caution given limitations in the data source and inability to obtain patient-level information regarding EGD findings and that these results do not imply that HGD occurs commonly in this population [18]. The authors also performed subgroup analyses that demonstrated that higher rates of dysplasia were seen in patients with history of BE dysplasia or EAC and those undergoing EGD for non-BE indication compared to those undergoing screening or surveillance EGD. Additional possibilities for the higher dysplasia rates in this study include unclear use of expert gastrointestinal pathologist to confirm dysplasia and the possibility of erosive esophagitis being present at time of biopsies. In another retrospective, single-center study consisting of 99 cases of LGD and 61 HGD in the background of BE (including ultra-short-segment BE) between 2014 and 2019 found that 20% of LGD cases and 18% HGD cases were found in those with BE ≤ 1 cm [22]. The rates of dysplasia with IM from normal and irregular z-line demonstrated in the last two studies are significantly higher than those from the various other studies highlighted above and suggest the need for additional, higher-quality studies to further understand the long-term outcomes in this patient population.

Consequences of Mislabeling Irregular Z-Line as Barrett’s Esophagus

There are significant downstream consequences of labeling an irregular z-line as BE (Fig. 2). The Lyon Consensus 2.0 considers biopsy-proven BE as conclusive for a diagnosis of GERD [23]. In addition, at least once daily proton pump inhibitor (PPI) therapy is recommended in patients with BE per current guidelines [2]. As such, patients with an irregular z-line with IM who are mislabeled as BE may be subject to long term, often lifelong, acid suppression such as with once or twice daily PPIs when they never truly required these medications. A mislabeled diagnosis of BE can also carry significant financial implications and these patients may have significantly higher healthcare and insurance costs despite multiple studies showing these patients have a normal life expectancy. As outlined above, these patients may be subject to repeated EGDs for surveillance which can carry substantial costs and associated risks. In one study, the yearly preferred premium for a 20-year guaranteed term life insurance for a 43-year-old man without BE was $1255 and significantly higher compared to the cost for the same individual with BE as a pre-existing condition which was $2731 [24]. For a 36-year-old woman, the base rate without BE was $517; however with a diagnosis of with BE, the rate increased by 177% to $1434 [24]. These patients may also have increased healthcare utilization and spending compared to the general population and even individuals with GERD [25].

Fig. 2
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Potential consequences of mislabeling an irregular z-line as Barrett’s esophagus

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Perhaps, most importantly, patient quality of life can suffer, and individuals may have anxiety surrounding the diagnosis of BE and worries about progression to neoplasia. In a systematic review, a diagnosis of BE was associated with a significant reduction in health-related quality of life [25]. Moreover, such patients may have psychological consequences such as depression, anxiety, and stress possibly related to disease progression to EAC [25].

How to Approach an Irregular Z-Line at Time of EGD

A high-quality endoscopic examination is essential when evaluating a patient with an irregular z-line. The goal of this would be to identify visible lesions, which if present, should be targeted for biopsies. While guidelines recommend against routine biopsy of an irregular z-line, it is important to note that this only applies to a situation where no visible abnormalities are present. In the vast majority of cases of HGD and early EAC at the GEJ, visible endoscopic abnormalities exist; these are often subtle and therefore, it requires a careful, systematic endoscopic exam to guide targeted biopsies. Table 2 outlines a checklist of best practices when performing endoscopy and encountering an irregular z-line or BE. For one, as the distinction between an irregular z-line and BE is based on the length of BE (< 1 cm vs ≥ 1 cm in length, respectively), the distal esophagus and GE junction should be examined carefully using both insufflation and desufflation. Overinsufflation can flatten gastric folds and make an irregular z-line resemble a longer segment of columnar-lined mucosa erroneously leading to a diagnosis of BE. As outlined above, landmarks including the SCJ, GE junction, and site of hiatal opening should be accurately identified and documented. In cases where the z-line is difficult to examine circumferentially, use of a distal attachment cap can be used to examine and localize distinct areas for careful visualization. Oftentimes, the z-line can have overlying air bubbles or mucus present, interfering with visualization. In these cases, the use of water jet and simethicone followed by careful suctioning while ensuring patient’s head of the bed elevated can help with improved endoscopic visualization. The use of the near focus feature on the endoscope can help magnify areas to better highlight the mucosa and make visible abnormalities more apparent. In addition to white light endoscopy, narrow band imaging or other forms of chromoendoscopy can help identify irregular mucosal or vascular patterns seen with dysplasia and neoplasia and can further provide detailed visualization of the z-line [26]. Lastly, a close-up retroflexed examination of the cardia should strongly be considered as it can help provide further evaluation of the z-line, GE junction, and cardia and may help identify lesions that may not be readily apparent on the standard forward view.

Table 2 Best practices for endoscopic examination of an irregular z-line to identify any visible lesions
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Conclusion

An irregular z-line refers to an irregular appearing SCJ with columnar mucosa less than 1 cm in length that extends above the GEJ and is different from BE which requires presence of columnar mucosa ≥ 1 cm in the distal esophagus extending above the GEJ and biopsies from this area demonstrating specialized intestinal metaplasia (IM). An irregular z-line is a relatively common finding at time of endoscopy and our current understanding suggests that this is overall a low-risk lesion which should not be routinely biopsied. As available studies on the neoplastic potential of an irregular z-line are not definitive and have methodological limitations, additional, higher-quality studies are needed on this topic [27]. When encountering an irregular z-line, a careful endoscopic examination should be performed to rule out any abnormalities, which, if present, may require targeted biopsies to rule out the presence of dysplasia and neoplasia.