Factors influencing lateral margin diagnosis challenges in Barrett’s esophageal cancer: A bicenter retrospective study

Factors influencing lateral margin diagnosis challenges in Barrett’s esophageal cancer: A bicenter retrospective study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Factors influencing lateral margin diagnosis challenges in Barrett’s esophageal cancer: A bicenter retrospective study Ippei Tanaka, Shuhei Unno, Kazuki Yamamoto, Yoshitaka Nawata, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3992498/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background The endoscopic lateral diagnosis of Barrett's esophageal adenocarcinoma (BEA) has been reported as challenging. Therefore, we aimed to clarify the clinicopathological characteristics and cause of BEA with unclear demarcation. Methods We reviewed BEA cases resected endoscopically or operatively between January 2010 and August 2022 at two institutions. The lesions were classified into two groups: the clear demarcation group (CD group) and the unclear demarcation group (UD group). We then compared clinicopathological findings between the two groups. Furthermore, to elucidate the differences in pathological structures between the cancerous mucosa and the surrounding mucosa, we measured the length and width of foveolar, as well as the width of the marginal crypt epithelium (MCE). Results We analyzed 68 BEA cases, comprising 47 in the CD group and 21 in the UD group. Multivariate analysis revealed long-segment Barrett’s esophagus (LSBE) as the sole significant risk factor (OR; 10.38, 95% CI;2.14–50.19, p = 0.004). Regarding pathological analysis, significant differences were observed in the length and width of foveolar between the cancerous and surrounding mucosa in the CD group (p = 0.03 and 0.00). However, in the UD group, these measurements did not show significant differences (p = 0.53 and 0.72). Nevertheless, the width of MCE in the cancerous area was significantly shorter than that in the surrounding mucosa in both groups (p = < 0.05, and < 0.05). Conclusions The significant risk factor for UD group was LSBE. The width of MCE, showing significant differences between the cancerous and surrounding mucosa, may serve as an important asset in endoscopic diagnosis for BEA. Endoscopic diagnosis Barrett’s esophageal cancer Lateral margin Figures Figure 1 Figure 2 Figure 3 Figure 4 INTRODUCTION []The incidence of Barrett's esophageal adenocarcinoma (BEA) has rapidly increased in Western countries over the past few decades, now constituting more than 50% of all esophageal cancers [ 1 , 2 ]. The main reasons for this increase are the rising prevalence of gastroesophageal reflux disease (GERD) and obesity, coupled with the declining prevalence of Helicobacter pylori ( H. pylori ) infection [ 3 , 4 , 5 ]. On the other hand, in East Asia, including Japan, squamous cell carcinoma of the esophagus remains predominant. However, with the widespread occurrence of GERD and H. pylori eradication, BEA is showing an increasing trend [ 6 , 7 ]. The incidence of BEA per 100,000 person-years in a certain prefecture in Japan was reported to have increased from 0.2 to 0.9 over the 30-year period between 1885 and 2014, and there is a possibility of further increases in the future [ 8 ]. In recent years, advances in endoscopic technology have increased the opportunities for early-stage esophageal cancer detection. Consequently, the number of cases treated with endoscopy, the primary therapeutic approach for early-stage cancer, is also showing an upward trend [ 9 , 10 ]. In endoscopic treatment, achieving en-bloc resection is essential to avoid piecemeal resection, as the latter is considered a risk factor for local recurrence [ 11 ]. The key to en-bloc resection is accurately diagnosing the lateral margin of the cancer. BEA, especially when it occurs in the long-segment Barrett's esophagus (LSBE), often presents challenges in determining the lateral margin of the lesion due to the chronic inflammation [ 12 ]. However, the characteristics of cases that are difficult to diagnose in terms of the lateral margin have not been clearly elucidated to date. Therefore, the objective of this study is to clarify the clinical and pathological features and underlying causes of BEA with unclear demarcation. MATERIALS and METHODS Study design and patients This retrospective study was conducted at two institutions in Japan: Sendai Kousei Hospital and Seirei Hamamatsu General Hospita. Data were collected from patients diagnosed with BEA who underwent endoscopic submucosal dissection (ESD) or surgery from January 2010 to August 2022. The inclusion criteria were patients diagnosed with Barrett's esophageal cancer based on histopathological examination or endoscopically diagnosed as BEA. The exclusion criteria included cases suspected invasion into or beyond muscle layer after diagnostic work-up (≥ T2 carcinoma), cases completely covered with squamous mucosa, and cases with insufficient endoscopic images suitable for review (e.g., those with blood, mucus, or out of focus images). A flow diagram of the enrolled patients in this study is shown in Fig. 1 . The study protocol was approved by the institutional review boards of each institution and adhered to the ethical principles of the Declaration of Helsinki. The approved ethical number in Sendai Kousei Hospital and Seirei Hamamatsu General Hospital was 4–45 and 4119, respectively. Informed consent was obtained comprehensively in an opt-out format. Definition of tumor group classification All endoscopic images of BEA included in this study were retrospectively reviewed. Two expert endoscopists, who experienced more than 100 cases of endoscopic treatment for esophageal cancer, reevaluated all images and classified them based on magnifying narrow-band imaging (M-NBI) findings. Lesions with clearly recognizable circumferential demarcation on M-NBI images were categorized as part of the clear demarcation group (CD group). Conversely, lesions in which the demarcation was unclear, even in a part of the lesion, were classified into the unclear demarcation group (UD group). Figure 2 represents typical images from both the CD group and UD group. Furthermore, the aim of this study was to focus on the demarcation diagnosis between the cancerous and non-cancerous area within the glandular epithelium. Thus, the lateral diagnosis was strictly limited to the glandular epithelium area, excluding the area adjacent to the squamous epithelium. Clinical examination All images were captured using a high-definition magnification endoscopes, such as GIF-H260Z, GIF-H290Z, and GIF-XZ1200 (Olympus Corp., Tokyo, Japan) and EVIS LUCERA ELITE or EVIS-X1 (Olympus Corp.). For patient characteristics, data on age, gender, treatment method, presence or absence of proton pump inhibitor (PPI) and alcohol consumption, and smoking status were collected. Regarding lesion-related information, data on the presence or absence of hiatal hernia and reflux esophagitis, and the condition of the background Barrett's mucosa (SSBE or LSBE), were gathered. Pathological evaluation All specimens were fixed in formalin, embedded in paraffin, and stained with hematoxylin and eosin. The pathological evaluation was performed by two expert pathologists specialized in esophageal cancer diagnosis. Histological diagnosis such as macroscopic type, tumor size, tumor differentiation, depth of invasion, lymphovascular invasion, and positive vertical and horizontal resection margins (VM and HM) were assessed according to the guidelines for the management of esophageal cancer [ 13 ]. Furthermore, in this study, the pathological structures were also meticulously evaluated. First, one slide displaying the demarcation of the lesion is selected as a representative section. Subsequently, the demarcation area is examined (Fig. 3 a), and in both the tumor and non-cancerous areas, the following parameters are measured in five glandular ducts each: the length and width of the foveolar and the width of the marginal crypt epithelium (MCE) (Figure.3b). The average values for these measurements in five glandular ducts are then calculated. The reason why we utilized the average of measurements from five glandular ducts is that a precise vertical section is not always obtained. Statistical analysis Categorical data were expressed as numbers and percentages and compared between two groups using Fisher’s exact test. On the other hand, continuous data were expressed as medians and interquartile ranges (IQR) and compared between two groups using the Mann-Whitney rank-sum test. In order to reveal the risk factor of the UD group, univariate and multivariate logistic regression analysis were performed. The variables that showed statistical significance in univariate analysis were further analyzed as variables in the multivariate analysis. Statistical significance was set at a p value < 0.05. All statistical analyses were performed using STATA version 16 software (StataCorp, College Station, TX, USA). RESULTS Clinicopathological features of BEA lesions and patients’ background The analysis included 67 patients with a total of 68 lesions. Patients’ background are shown in Table.1. Of these, there were 58 male and 9 female patients, with a median age of 72 years (IQR; 66–80 years). ESD treatment was applied to 63 lesions (92.6%), while surgical intervention was conducted in 5 lesions (7.4%). PPI administration was observed in 29 patients (43.4%). Hiatal hernia and reflux esophagitis were observed in 57 (85.0%) and 13 cases (19.4%), respectively. The background mucosa revealed 45 cases of SSBE (67.2%) and 22 cases of LSBE (32.8%). Clinicopathological features of BEA are shown in Table.2. Macroscopic types consisted of 35 protruding (51.4%), 26 depressed (38.2%), and 7 flat lesions (10.2%). Regarding the invasion depth of the lesion, 58 lesions were diagnosed as mucosal lesions (85.3%), while 10 were identified as submucosal invasive lesions (14.7%). The positivity of lymphovascular invasion was observed in 12 cases (17.6%), with 6 cases tesing positive for HM (8.8%) and 2 cases for VM (2.9%). Clinicopathological features of BEA with unclear demarcation Out of the 68 BEA lesions, 47 were classified into the CD group, and 21 into the UD group. Specifically, considering the proportion of unclear demarcation line, 42.8% of lesions exhibited unclear demarcation line for less than half of the circumference, while 57.2% of lesions displayed unclear demarcation line for more than half of the circumference. In the UD group, a significantly higher prevalence of LSBE was observed (p < 0.05), along with macroscopic type 0-Ⅱb (p = 0.046). No significant differences were found in other factors between the CD and UD groups. The risk factors for unclear demarcation line Since the univariate analysis showed that LSBE (OR; 8.44, 95% CI; 2.64-27.00, p = 0.000) and macroscopic type, 0-Ⅱb (OR ; 8.43, 95% CI ; 1.36–52.06, p = 0.046) as the significant risk factors for the UD group, multivariate analysis was performed including these two factors. Subsequently, LSBE was revealed to be the sole significant risk factor for the UD group (OR; 10.38, 95% CI; 2.14–50.19, p = 0.004) (Table.3). Evaluation of the pathological structures between the cancerous mucosa and the surrounding mucosa To elucidate the causes of indistinct demarcation, we conducted a detailed assessment of the pathological foveolar structures in both cancerous and the background mucosa (Table. 4). In the CD group, the length and width of foveolar in the cancerous mucosa was significantly shorter than that in background mucosa (135µm vs. 190µm and 75µm vs. 131µm, p = 0.03 and 0.00). On the other hand, in the UD group, these measurements did not show significant differences (149µm vs. 118µm and 90µm vs. 130µm, p = 0.53, and 0.72). However, in both CD and UD groups, the width of MCE in the cancerous area was significantly shorter than that in the background mucosa (CD group; 24µm vs. 40µm and 26µm vs. 34µm, p < 0.05 and < 0.05). Figure 4 represents the UD group case which showed the difference in the width of MCE between cancerous and noncancerous area endoscopically and pathologically. DISCUSSION In this study, we have revealed three important findings. Firstly, LSBE was identified as the risk factor for unclear demarcation in BEA. Secondly, in the UD group, there were no significant differences in the length and width of foveolar structures between the cancerous and background mucosa, suggesting a similarity in foveolar structures as a contributing factor to unclear demarcation. Thirdly, the width of MCE in the cancerous mucosa was significantly shorter than that in the background mucosa, even in the UD group, indicating its potential as an important diagnostic asset. In 2017, the Japan Esophageal Society introduced the magnified endoscopic classification of Barrett's esophageal neoplasms [ 14 ]. This classification has gained widespread use in Japan due to its simplicity and high diagnostic accuracy. One notable feature of this classification is that, unlike MESDA-G which is a magnified endoscopic classification for gastric cancer, it does not require the presence of the lesion’s demarcation [ 15 ]. This suggests the presence of a certain number of BEA with unclear demarcation. In fact, unclear demarcation in BEA is frequently encountered in real clinical practice. Additionally, in our study, approximately 30% of all BEA cases had unclear demarcation. Therefore, elucidating the characteristics of BEA with unclear demarcation holds significant importance. This study revealed that LSBE is a risk factor for BEA with unclear demarcation. Probst et al. reported that the R0 resection rate for BEA in LSBE was significantly lower than that in SSBE (70.4% vs. 90.0%, P = 0.029) [ 12 ], which supports our results. Barrett's mucosa is an epithelium that develops in the esophagus due to chronic reflux of gastric acid juice. Consequently, it often accompanies chronic inflammatory changes, with its impact being particularly seen in LSBE. Inflamed mucosa sometimes shows mild atypia, which makes it extremely difficult to diagnose the lateral margin of BEA [ 16 ]. However, some previous articles have reported that R0 resection rates in ESD cases were comparable between SSBE and LSBE [ 17 , 18 ]. This could be attributed to the practice of setting wider margins during ESD procedures, even when the actual demarcation is unclear, which might facilitate the achievement of R0 resection. In fact, in the current study, despite the high prevalence of BEA with unclear demarcation, setting the wider margin around the lesion appeared to result in a lower percentage of positive vertical margins. The causes of unclear demarcation were revealed in this study by measuring pathological structures. In BEA with clear demarcation, there were significant differences in foveolar length and width between the cancerous and background mucosa. However, in BEA with unclear demarcation, these structures exhibited nearly identical patterns between the cancerous and background mucosa. This similarity in pathological foveolar structures is considered to be a factor contributing to the difficulty in diagnosing the demarcation. As we previously mentioned, it is possible that the background non-neoplastic mucosa might accompany atypical changes due to the chronic inflammation [ 16 ]. Alternatively, this phenomenon could be a result of the development of low-grade dysplasia. Both low-grade dysplasia and atypical mucosa can arise not only in Barrett's mucosa but also in ulcerative colitis (UC), which is characterized by chronic inflammatory changes. A previous study has even suggested the difficulties in endoscopic recognition of tumors that developed in UC [ 19 ]. Considering these findings, our results in this study could be considered reasonable. Through the investigation of pathological structures, another significant revelation has emerged, which could potentially be deemed one of the most important findings of this study. Regardless of whether the lesions were well-demarcated or indistinct, the MCE width was noticeably narrower in the cancerous mucosa compared to the non-neoplastic surrounding mucosa. This interesting finding was first clarified in our current study. MCE is a term that holds familiarity within the field of pathology and endoscopy, particularly in Japan where endoscopic diagnosis of gastric cancer has become prevalent [ 20 ]. It is sometimes referred to as the "White zone" endoscopically, denoting a white, band-like area surrounding foveolar or duct [ 21 ]. Yagi et al. also reported that the "white zone" observed endoscopically corresponds to the MCE observed pathologically. According to our research results, the width of MCE could imply presence of cancer when narrow or suggest non-neoplastic when wide. Thus, “short MCE” may be the important endoscopic finding to diagnose BEA. To practically utilize this finding in real clinical practice, the following approach could be applied: Initially, when suspicious lesions indicating cancer are identified, follow the algorithm of magnified endoscopic classification for Barrett's esophageal cancer, and assess mucosal and vascular regularity or irregularity to diagnose the lateral margin of the lesion [ 14 ]. However, in cases where it is challenging to diagnose an area as cancerous or non-cancerous based on the criteria, “short MCE” can be a valuable asset. A narrow width of MCE could be indicative of cancer, while a wider width could be non-neoplastic. This could potentially lead to a more accurate diagnosis for Barrett’s esophageal lesions. Therefore, a prospective validation study will be necessary in the future to confirm this implication. This is the first study to elucidate the cause of unclear margin of Barrett cancer based on the evaluation for pathological structures, which is the notable point of this study. However, this study also possesses several limitations. Firstly, it is a retrospective study with relatively small sample size, especially LSBE cases. Secondly, this study does not include the diagnosis of low-grade dysplasia. In Asia, especially in Japan, pathologists are not accustomed to diagnosing low-grade dysplasia, and even in the official guidelines for esophageal cancer management, diagnosis of low-grade dysplasia is not specified [ 13 ]. We hope that future research will address the diagnostic disparities surrounding dysplasia in both Japan and Western countries. Thirdly, the distinction between well-defined and indistinct demarcations was determined by two endoscopy specialists, which may introduce subjectivity into the assessment. Forth, one to one comparison between endoscopic images and pathological findings was not performed in this study. In conclusion, careful attention should be paid to diagnosing the lateral margin of BEA arising in LSBE. Furthermore, the width of MCE, which is endoscopically recognized as White Zone could potentially serve as significant factors in the lateral diagnosis of BEA. It is necessary to conduct a further prospective study to assess whether the width of MCE is useful in the lateral margin diagnosis of BEA in real clinical practice. Declarations Statement of Ethics Opt-out informed consent protocol was used for use of participant data for research purposes. This consent procedure was reviewed and approved by the ethics committee of Sendai Kousei Hospital and Seirei Hamamatsu General Hospital, approval number 4–45 and 4119, date of decision 13/10/2022 and 10/10/2022, respectively.</p Conflict of interest disclosure: All authors declare no conflict of interest. Funding Sources: There are no disclosures to be declared. Author Contribution IT, and SU led and designed the study. IT wrote the manuscript. IT and SU contributed to the data collection. IT contributed to the statistical analysis. SU, KY, YN, KI, TM, and DH critically reviewed the manuscript and contributed to discussions. KY assisted in the English editing of the final manuscript. All authors read and approved the final manuscript. Acknowledgment: None. Data Availability Statemen: References Thrift AP, Whiteman DC. The incidence of esophageal adenocarcinoma continues to rise: analysis of period and birth cohort effects on recent trends. Ann Oncol. 2012;23:3155–62. 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Patient characteristics All n= 67 CD group n= 46 UD group n= 21 P value Age, median, years, (IQR) 72 (66-80) 75 (67-80) 70 (65-78) 0.146 Sex, male, n (%) 58 (86.6) 40 (87.0) 18 (85.7) 0.890 The use of PPI, n (%) 28 (41.8) 16 (34.8) 12 (57.1) 0.085 Drinking, n (%) 31 (46.3) 22 (47.8) 9 (42.9) 0.705 Smoking, n (%) 35 (52.2) 22 (47.8) 13 (61.9) 0.285 Hiatal hernia, n (%) 57 (85.0) 37 (80.4) 20 (95.2) 0.115 Reflux esophagitis, n (%) 13 (19.4) 10 (21.7) 3 (14.2) 0.474 Background mucosa 0.000 SSBE, n (%) 45 (67.1) 38 (82.6) 7 (33.3) LSBE, n (%) 22 (32.8) 8 (17.3) 14 (66.6) IQR, interquartile range; CD, clear demarcation; UD, unclear demarcation; PPI, proton pump inhibitor; SSBE, short-segment Barrett’s esophagus; LSBE, long-segment Barrett’s esophagus Table 2. Lesion characteristics All n= 68 CD group n= 47 UD group n= 21 P value Tumor morphology, n (%) 0-IIa or I 35 (51.5) 27 (57.4) 8 (38.1) - 0-IIb 26 (38.2) 18 (38.3) 8 (38.1) 0.022 0-IIc 7 (10.2) 2 (4.2) 5 (23.8) 0.488 Tumor size, median, mm (IQR) 16 (10-25) 16 (11-24) 16 (9-32) 0.114 Tumor differentiation HGD / Well or Moderate 65 (95.6) 45 (95.7) 20 (95.3) - Poor 3 (4.4) 2 (4.2) 1 (4.7) 0.959 Tumor depth T1a 58 (85.2) 39 (83.0) 19 (90.5) - T1b 10 (14.8) 8 (17.0) 2 (9.5) 0.448 Lymphatic invasion, n (%) 8 (11.7) 8 (17.0) 0 - Vascular invasion, n (%) 7 (10.3) 6 (12.8) 1 (4.7) 0.335 Horizontal margin positive, n (%) 6 (8.8) 3 (6.3) 3 (14.2) 0.300 Vertical margin positive, n (%) 2 (2.9) 2 (4.2) 0 - IQR, interquartile range; CD, clear demarcation; UD, unclear demarcation; HGD, high-grade dysplasia Table 3. Multivariate analysis for the risk factor of BEA with unclear demarcation Odds ratio 95% CI P value Background mucosa, n (%) SSBE 1 Reference LSBE 12.17 2.84-47.6 0.001 Tumor morphology, n (%) 0-IIa or I 1 Reference 0-IIb 7.13 0.84-60.13 0.071 0-IIc 3.93 0.85-18.17 0.080 BEA, Barrett’s esophageal adenocarcinoma; CI, confidence interval; SSBE, short-segment Barrett’s esophagus; LSBE, long-segment Barrett’s esophagus Table 4 . The evaluation of pathological structures Cancerous mucosa median, µm (IQR) Background mucosa median, µm (IQR) P value CD group Length of foveolar 135 (95-194) 190 (120-254) <0.05 Width of foveolar 74 (50-100) 131 (100-167) <0.05 Width of MCE 24 (18-30) 40 (33-50) <0.05 UD group Length of foveolar 149 (90-160) 118 (70-160) 0.77 Width of foveolar 90 (73-138) 130 (90-170) 0.06 Width of MCE 26 (18-33) 34 (28-44) <0.05 IQR, interquartile range CD, clear demarcation; UD, unclear demarcation; MCE, marginal crypt epithlium Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3992498","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":275890262,"identity":"85166eb8-6212-40f2-b88d-3ceba54a51e1","order_by":0,"name":"Ippei Tanaka","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABFElEQVRIie2QsUrEQBBAZwlstWg7chJ/YY9ATHX+yoSFqw78AcFU6c5rT+JHWFlvCGgj2kkgFrGxPptDIZw3B4J3kgRLwX3F7iwzj5lZAIfjDyI3R7z6PJ/xjQD2OyWSHoWkJy6T3ypfoieu7U+li73BNK9rJb3gqchLaJ59fWclwtkIvKy9jTx8MJpQybAam0ikr4G+J1ZuDYir9pYSJyGSRhVWHIikiG/s6RJBWhBz6lKO34mdINtUNqw81txl1auEQJa0Hky4UrJS8mAi7VF4F4wTS1iNgyhOi+CkrL0ovjCqa5ejbJq/fbCyn5mXctEU/sGMRLlYjvxhx48Bqq0HbQVqOG83dpXdAbAr43A4HP+MNRguXYTD6XhwAAAAAElFTkSuQmCC","orcid":"","institution":"Sendai Kousei Hospital","correspondingAuthor":true,"prefix":"","firstName":"Ippei","middleName":"","lastName":"Tanaka","suffix":""},{"id":275890263,"identity":"c88d5f9f-8eb0-4304-9d62-a18bd225de2d","order_by":1,"name":"Shuhei Unno","email":"","orcid":"","institution":"Seirei Hamamatsu General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Shuhei","middleName":"","lastName":"Unno","suffix":""},{"id":275890264,"identity":"1ebd5438-e5e2-4666-a3cc-1dbc2c09a55b","order_by":2,"name":"Kazuki Yamamoto","email":"","orcid":"","institution":"Showa University Koto Toyosu Hospital","correspondingAuthor":false,"prefix":"","firstName":"Kazuki","middleName":"","lastName":"Yamamoto","suffix":""},{"id":275890265,"identity":"5f3fbfd2-a034-4497-a568-0c74b139ce95","order_by":3,"name":"Yoshitaka Nawata","email":"","orcid":"","institution":"Sendai Kousei Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yoshitaka","middleName":"","lastName":"Nawata","suffix":""},{"id":275890266,"identity":"74677fad-a263-4fca-9473-270a9c7c62aa","order_by":4,"name":"Kimihiro Igarashi","email":"","orcid":"","institution":"Sendai Kousei Hospital","correspondingAuthor":false,"prefix":"","firstName":"Kimihiro","middleName":"","lastName":"Igarashi","suffix":""},{"id":275890267,"identity":"85c9d2b9-00d0-4dbc-b396-2a2b104577ea","order_by":5,"name":"Tomoki Matsuda","email":"","orcid":"","institution":"Sendai Kousei Hospital","correspondingAuthor":false,"prefix":"","firstName":"Tomoki","middleName":"","lastName":"Matsuda","suffix":""},{"id":275890268,"identity":"035cc1fa-4ac9-4e3f-850b-a253dd3d6937","order_by":6,"name":"Dai Hirasawa","email":"","orcid":"","institution":"Sendai Kousei Hospital","correspondingAuthor":false,"prefix":"","firstName":"Dai","middleName":"","lastName":"Hirasawa","suffix":""}],"badges":[],"createdAt":"2024-02-27 02:29:54","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3992498/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3992498/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":52039392,"identity":"a0b8b261-7a07-47d6-8bc1-f8086a441fcd","added_by":"auto","created_at":"2024-03-05 17:41:08","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":26314,"visible":true,"origin":"","legend":"\u003cp\u003eA flow diagram of the enrolled patients.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-3992498/v1/17d039503c3a538b2b1675f1.png"},{"id":52039390,"identity":"1e411b44-cd8c-470c-9e4b-94bfdf6f3ebc","added_by":"auto","created_at":"2024-03-05 17:41:06","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":2523499,"visible":true,"origin":"","legend":"\u003cp\u003e(A) Endoscopic image of BEA in CD group. (B) Magnifying endoscopy with narrow-band imaging showed clear demarcation of the lesion. (C) Endoscopic image of BEA in UD group. (D) Magnifying endoscopy with narrow-band imaging showed mild irregularity of the lesion and unclear demarcation of the lesion.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-3992498/v1/aee9b01c1b393073d3245a53.png"},{"id":52039393,"identity":"ad4beec6-4435-424a-9f9c-88e8ef6558eb","added_by":"auto","created_at":"2024-03-05 17:41:08","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":566480,"visible":true,"origin":"","legend":"\u003cp\u003eThe evaluation of pathological structures\u003c/p\u003e\n\u003cp\u003e(A) One example slide displaying the demarcation of the lesion. Black arrow indicates the demarcation between cancerous and noncancerous area. (B) This figure specifically illustrates the length and width of foveolar, and the width of marginal crypt epithelium.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-3992498/v1/58ebcd68736f1d9df8d0418a.png"},{"id":52039426,"identity":"1b6a17fa-8a78-4eaf-98ef-0762e53443a7","added_by":"auto","created_at":"2024-03-05 17:41:09","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1860489,"visible":true,"origin":"","legend":"\u003cp\u003eThe representative case of UD group. (A) The reddish depressed lesion were seen at the anterior side of the esophagogastric junction. (B) Magnifying endoscopy with narrow-band imaging showed mild irregular mucosal pattern, and the demarcation of the lesion was unclear. However, there is a distinct difference in the width of MCE between the mucosa on the upper and lower part of this image; the MCE appears narrower on the upper part and wider on the lower, which corresponds to the cancerous mucosa and noncancerous mucosa, respectively. (C) Pathological findings showed significant difference in the width of MCE between cancerous and noncancerous area.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-3992498/v1/8488ed84f6d32db16710fbeb.png"},{"id":52631116,"identity":"9c08d83c-8c9e-465e-a56b-fd6770a1182a","added_by":"auto","created_at":"2024-03-13 19:41:06","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3007856,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3992498/v1/5c608801-5842-403b-b41f-4ab1da43a907.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Factors influencing lateral margin diagnosis challenges in Barrett’s esophageal cancer: A bicenter retrospective study","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003e[]The incidence of Barrett's esophageal adenocarcinoma (BEA) has rapidly increased in Western countries over the past few decades, now constituting more than 50% of all esophageal cancers [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The main reasons for this increase are the rising prevalence of gastroesophageal reflux disease (GERD) and obesity, coupled with the declining prevalence of Helicobacter pylori (\u003cem\u003eH. pylori\u003c/em\u003e) infection [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. On the other hand, in East Asia, including Japan, squamous cell carcinoma of the esophagus remains predominant. However, with the widespread occurrence of GERD and \u003cem\u003eH. pylori\u003c/em\u003e eradication, BEA is showing an increasing trend [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. The incidence of BEA per 100,000 person-years in a certain prefecture in Japan was reported to have increased from 0.2 to 0.9 over the 30-year period between 1885 and 2014, and there is a possibility of further increases in the future [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn recent years, advances in endoscopic technology have increased the opportunities for early-stage esophageal cancer detection. Consequently, the number of cases treated with endoscopy, the primary therapeutic approach for early-stage cancer, is also showing an upward trend [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. In endoscopic treatment, achieving en-bloc resection is essential to avoid piecemeal resection, as the latter is considered a risk factor for local recurrence [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. The key to en-bloc resection is accurately diagnosing the lateral margin of the cancer.\u003c/p\u003e \u003cp\u003eBEA, especially when it occurs in the long-segment Barrett's esophagus (LSBE), often presents challenges in determining the lateral margin of the lesion due to the chronic inflammation [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. However, the characteristics of cases that are difficult to diagnose in terms of the lateral margin have not been clearly elucidated to date. Therefore, the objective of this study is to clarify the clinical and pathological features and underlying causes of BEA with unclear demarcation.\u003c/p\u003e"},{"header":"MATERIALS and METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and patients\u003c/h2\u003e \u003cp\u003eThis retrospective study was conducted at two institutions in Japan: Sendai Kousei Hospital and Seirei Hamamatsu General Hospita. Data were collected from patients diagnosed with BEA who underwent endoscopic submucosal dissection (ESD) or surgery from January 2010 to August 2022. The inclusion criteria were patients diagnosed with Barrett's esophageal cancer based on histopathological examination or endoscopically diagnosed as BEA. The exclusion criteria included cases suspected invasion into or beyond muscle layer after diagnostic work-up (\u0026ge;\u0026thinsp;T2 carcinoma), cases completely covered with squamous mucosa, and cases with insufficient endoscopic images suitable for review (e.g., those with blood, mucus, or out of focus images). A flow diagram of the enrolled patients in this study is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The study protocol was approved by the institutional review boards of each institution and adhered to the ethical principles of the Declaration of Helsinki. The approved ethical number in Sendai Kousei Hospital and Seirei Hamamatsu General Hospital was 4\u0026ndash;45 and 4119, respectively. Informed consent was obtained comprehensively in an opt-out format.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eDefinition of tumor group classification\u003c/h2\u003e \u003cp\u003eAll endoscopic images of BEA included in this study were retrospectively reviewed. Two expert endoscopists, who experienced more than 100 cases of endoscopic treatment for esophageal cancer, reevaluated all images and classified them based on magnifying narrow-band imaging (M-NBI) findings. Lesions with clearly recognizable circumferential demarcation on M-NBI images were categorized as part of the clear demarcation group (CD group). Conversely, lesions in which the demarcation was unclear, even in a part of the lesion, were classified into the unclear demarcation group (UD group). Figure\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e represents typical images from both the CD group and UD group. Furthermore, the aim of this study was to focus on the demarcation diagnosis between the cancerous and non-cancerous area within the glandular epithelium. Thus, the lateral diagnosis was strictly limited to the glandular epithelium area, excluding the area adjacent to the squamous epithelium.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eClinical examination\u003c/h2\u003e \u003cp\u003eAll images were captured using a high-definition magnification endoscopes, such as GIF-H260Z, GIF-H290Z, and GIF-XZ1200 (Olympus Corp., Tokyo, Japan) and EVIS LUCERA ELITE or EVIS-X1 (Olympus Corp.). For patient characteristics, data on age, gender, treatment method, presence or absence of proton pump inhibitor (PPI) and alcohol consumption, and smoking status were collected. Regarding lesion-related information, data on the presence or absence of hiatal hernia and reflux esophagitis, and the condition of the background Barrett's mucosa (SSBE or LSBE), were gathered.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003ePathological evaluation\u003c/h2\u003e \u003cp\u003eAll specimens were fixed in formalin, embedded in paraffin, and stained with hematoxylin and eosin. The pathological evaluation was performed by two expert pathologists specialized in esophageal cancer diagnosis. Histological diagnosis such as macroscopic type, tumor size, tumor differentiation, depth of invasion, lymphovascular invasion, and positive vertical and horizontal resection margins (VM and HM) were assessed according to the guidelines for the management of esophageal cancer [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFurthermore, in this study, the pathological structures were also meticulously evaluated. First, one slide displaying the demarcation of the lesion is selected as a representative section. Subsequently, the demarcation area is examined (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ea), and in both the tumor and non-cancerous areas, the following parameters are measured in five glandular ducts each: the length and width of the foveolar and the width of the marginal crypt epithelium (MCE) (Figure.3b). The average values for these measurements in five glandular ducts are then calculated. The reason why we utilized the average of measurements from five glandular ducts is that a precise vertical section is not always obtained.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eCategorical data were expressed as numbers and percentages and compared between two groups using Fisher\u0026rsquo;s exact test. On the other hand, continuous data were expressed as medians and interquartile ranges (IQR) and compared between two groups using the Mann-Whitney rank-sum test. In order to reveal the risk factor of the UD group, univariate and multivariate logistic regression analysis were performed. The variables that showed statistical significance in univariate analysis were further analyzed as variables in the multivariate analysis. Statistical significance was set at a p value\u0026thinsp;\u0026lt;\u0026thinsp;0.05. All statistical analyses were performed using STATA version 16 software (StataCorp, College Station, TX, USA).\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eClinicopathological features of BEA lesions and patients\u0026rsquo; background\u003c/h2\u003e \u003cp\u003eThe analysis included 67 patients with a total of 68 lesions. Patients\u0026rsquo; background are shown in Table.1. Of these, there were 58 male and 9 female patients, with a median age of 72 years (IQR; 66\u0026ndash;80 years). ESD treatment was applied to 63 lesions (92.6%), while surgical intervention was conducted in 5 lesions (7.4%). PPI administration was observed in 29 patients (43.4%). Hiatal hernia and reflux esophagitis were observed in 57 (85.0%) and 13 cases (19.4%), respectively. The background mucosa revealed 45 cases of SSBE (67.2%) and 22 cases of LSBE (32.8%).\u003c/p\u003e \u003cp\u003eClinicopathological features of BEA are shown in Table.2. Macroscopic types consisted of 35 protruding (51.4%), 26 depressed (38.2%), and 7 flat lesions (10.2%). Regarding the invasion depth of the lesion, 58 lesions were diagnosed as mucosal lesions (85.3%), while 10 were identified as submucosal invasive lesions (14.7%). The positivity of lymphovascular invasion was observed in 12 cases (17.6%), with 6 cases tesing positive for HM (8.8%) and 2 cases for VM (2.9%).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eClinicopathological features of BEA with unclear demarcation\u003c/h2\u003e \u003cp\u003eOut of the 68 BEA lesions, 47 were classified into the CD group, and 21 into the UD group. Specifically, considering the proportion of unclear demarcation line, 42.8% of lesions exhibited unclear demarcation line for less than half of the circumference, while 57.2% of lesions displayed unclear demarcation line for more than half of the circumference. In the UD group, a significantly higher prevalence of LSBE was observed (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), along with macroscopic type 0-Ⅱb (p\u0026thinsp;=\u0026thinsp;0.046). No significant differences were found in other factors between the CD and UD groups.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eThe risk factors for unclear demarcation line\u003c/h2\u003e \u003cp\u003eSince the univariate analysis showed that LSBE (OR; 8.44, 95% CI; 2.64-27.00, p\u0026thinsp;=\u0026thinsp;0.000) and macroscopic type, 0-Ⅱb (OR ; 8.43, 95% CI ; 1.36\u0026ndash;52.06, p\u0026thinsp;=\u0026thinsp;0.046) as the significant risk factors for the UD group, multivariate analysis was performed including these two factors. Subsequently, LSBE was revealed to be the sole significant risk factor for the UD group (OR; 10.38, 95% CI; 2.14\u0026ndash;50.19, p\u0026thinsp;=\u0026thinsp;0.004) (Table.3).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eEvaluation of the pathological structures between the cancerous mucosa and the surrounding mucosa\u003c/h2\u003e \u003cp\u003eTo elucidate the causes of indistinct demarcation, we conducted a detailed assessment of the pathological foveolar structures in both cancerous and the background mucosa (Table. 4). In the CD group, the length and width of foveolar in the cancerous mucosa was significantly shorter than that in background mucosa (135\u0026micro;m vs. 190\u0026micro;m and 75\u0026micro;m vs. 131\u0026micro;m, p\u0026thinsp;=\u0026thinsp;0.03 and 0.00). On the other hand, in the UD group, these measurements did not show significant differences (149\u0026micro;m vs. 118\u0026micro;m and 90\u0026micro;m vs. 130\u0026micro;m, p\u0026thinsp;=\u0026thinsp;0.53, and 0.72). However, in both CD and UD groups, the width of MCE in the cancerous area was significantly shorter than that in the background mucosa (CD group; 24\u0026micro;m vs. 40\u0026micro;m and 26\u0026micro;m vs. 34\u0026micro;m, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 and \u0026lt;\u0026thinsp;0.05). Figure\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e represents the UD group case which showed the difference in the width of MCE between cancerous and noncancerous area endoscopically and pathologically.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eIn this study, we have revealed three important findings. Firstly, LSBE was identified as the risk factor for unclear demarcation in BEA. Secondly, in the UD group, there were no significant differences in the length and width of foveolar structures between the cancerous and background mucosa, suggesting a similarity in foveolar structures as a contributing factor to unclear demarcation. Thirdly, the width of MCE in the cancerous mucosa was significantly shorter than that in the background mucosa, even in the UD group, indicating its potential as an important diagnostic asset.\u003c/p\u003e \u003cp\u003eIn 2017, the Japan Esophageal Society introduced the magnified endoscopic classification of Barrett's esophageal neoplasms [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. This classification has gained widespread use in Japan due to its simplicity and high diagnostic accuracy. One notable feature of this classification is that, unlike MESDA-G which is a magnified endoscopic classification for gastric cancer, it does not require the presence of the lesion\u0026rsquo;s demarcation [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. This suggests the presence of a certain number of BEA with unclear demarcation. In fact, unclear demarcation in BEA is frequently encountered in real clinical practice. Additionally, in our study, approximately 30% of all BEA cases had unclear demarcation. Therefore, elucidating the characteristics of BEA with unclear demarcation holds significant importance.\u003c/p\u003e \u003cp\u003eThis study revealed that LSBE is a risk factor for BEA with unclear demarcation. Probst et al. reported that the R0 resection rate for BEA in LSBE was significantly lower than that in SSBE (70.4% vs. 90.0%, P\u0026thinsp;=\u0026thinsp;0.029) [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], which supports our results. Barrett's mucosa is an epithelium that develops in the esophagus due to chronic reflux of gastric acid juice. Consequently, it often accompanies chronic inflammatory changes, with its impact being particularly seen in LSBE. Inflamed mucosa sometimes shows mild atypia, which makes it extremely difficult to diagnose the lateral margin of BEA [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. However, some previous articles have reported that R0 resection rates in ESD cases were comparable between SSBE and LSBE [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. This could be attributed to the practice of setting wider margins during ESD procedures, even when the actual demarcation is unclear, which might facilitate the achievement of R0 resection. In fact, in the current study, despite the high prevalence of BEA with unclear demarcation, setting the wider margin around the lesion appeared to result in a lower percentage of positive vertical margins.\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eThe causes of unclear demarcation were revealed in this study by measuring pathological structures. In BEA with clear demarcation, there were significant differences in foveolar length and width between the cancerous and background mucosa. However, in BEA with unclear demarcation, these structures exhibited nearly identical patterns between the cancerous and background mucosa. This similarity in pathological foveolar structures is considered to be a factor contributing to the difficulty in diagnosing the demarcation. As we previously mentioned, it is possible that the background non-neoplastic mucosa might accompany atypical changes due to the chronic inflammation [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Alternatively, this phenomenon could be a result of the development of low-grade dysplasia. Both low-grade dysplasia and atypical mucosa can arise not only in Barrett's mucosa but also in ulcerative colitis (UC), which is characterized by chronic inflammatory changes. A previous study has even suggested the difficulties in endoscopic recognition of tumors that developed in UC [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Considering these findings, our results in this study could be considered reasonable.\u003c/p\u003e\u003cp\u003eThrough the investigation of pathological structures, another significant revelation has emerged, which could potentially be deemed one of the most important findings of this study. Regardless of whether the lesions were well-demarcated or indistinct, the MCE width was noticeably narrower in the cancerous mucosa compared to the non-neoplastic surrounding mucosa. This interesting finding was first clarified in our current study. MCE is a term that holds familiarity within the field of pathology and endoscopy, particularly in Japan where endoscopic diagnosis of gastric cancer has become prevalent [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. It is sometimes referred to as the \"White zone\" endoscopically, denoting a white, band-like area surrounding foveolar or duct [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Yagi et al. also reported that the \"white zone\" observed endoscopically corresponds to the MCE observed pathologically. According to our research results, the width of MCE could imply presence of cancer when narrow or suggest non-neoplastic when wide. Thus, \u0026ldquo;short MCE\u0026rdquo; may be the important endoscopic finding to diagnose BEA. To practically utilize this finding in real clinical practice, the following approach could be applied: Initially, when suspicious lesions indicating cancer are identified, follow the algorithm of magnified endoscopic classification for Barrett's esophageal cancer, and assess mucosal and vascular regularity or irregularity to diagnose the lateral margin of the lesion [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. However, in cases where it is challenging to diagnose an area as cancerous or non-cancerous based on the criteria, \u0026ldquo;short MCE\u0026rdquo; can be a valuable asset. A narrow width of MCE could be indicative of cancer, while a wider width could be non-neoplastic. This could potentially lead to a more accurate diagnosis for Barrett\u0026rsquo;s esophageal lesions. Therefore, a prospective validation study will be necessary in the future to confirm this implication.\u003c/p\u003e\u003cp\u003eThis is the first study to elucidate the cause of unclear margin of Barrett cancer based on the evaluation for pathological structures, which is the notable point of this study.\u003c/p\u003e\u003cp\u003eHowever, this study also possesses several limitations. Firstly, it is a retrospective study with relatively small sample size, especially LSBE cases. Secondly, this study does not include the diagnosis of low-grade dysplasia. In Asia, especially in Japan, pathologists are not accustomed to diagnosing low-grade dysplasia, and even in the official guidelines for esophageal cancer management, diagnosis of low-grade dysplasia is not specified [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. We hope that future research will address the diagnostic disparities surrounding dysplasia in both Japan and Western countries. Thirdly, the distinction between well-defined and indistinct demarcations was determined by two endoscopy specialists, which may introduce subjectivity into the assessment. Forth, one to one comparison between endoscopic images and pathological findings was not performed in this study.\u003c/p\u003e\u003cp\u003eIn conclusion, careful attention should be paid to diagnosing the lateral margin of BEA arising in LSBE. Furthermore, the width of MCE, which is endoscopically recognized as White Zone could potentially serve as significant factors in the lateral diagnosis of BEA. It is necessary to conduct a further prospective study to assess whether the width of MCE is useful in the lateral margin diagnosis of BEA in real clinical practice.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eStatement of Ethics\u003c/h2\u003e \u003cp\u003e Opt-out informed consent protocol was used for use of participant data for research purposes. This consent procedure was reviewed and approved by the ethics committee of Sendai Kousei Hospital and Seirei Hamamatsu General Hospital, approval number 4\u0026ndash;45 and 4119, date of decision 13/10/2022 and 10/10/2022, respectively.\u003c/p \u003ch2\u003eConflict of interest disclosure:\u003c/h2\u003e \u003cp\u003eAll authors declare no conflict of interest.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding Sources:\u003c/h2\u003e \u003cp\u003eThere are no disclosures to be declared.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eIT, and SU led and designed the study. IT wrote the manuscript. IT and SU contributed to the data collection. IT contributed to the statistical analysis. SU, KY, YN, KI, TM, and DH critically reviewed the manuscript and contributed to discussions. KY assisted in the English editing of the final manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgment:\u003c/h2\u003e \u003cp\u003eNone.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e \u003cp\u003eStatemen:\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eThrift AP, Whiteman DC. The incidence of esophageal adenocarcinoma continues to rise: analysis of period and birth cohort effects on recent trends. Ann Oncol. 2012;23:3155\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDrahos J, Wu M, Anderson WF, et al. Regional variations in esophageal cancer rates by census region in the United States, 1999\u0026ndash;2008. PLoS ONE. 2013; \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003edoi.org/10.1371/journal.pone.0067913\u003c/span\u003e\u003cspan address=\"10.1371/journal.pone.0067913\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLagergren J, Bergstrom R, Lindgren A, et al. Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. N Engl J Med. 1999;340:825\u0026ndash;31.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCorley DA, Kubo A, Levin TR, et al. Abdominal obesity and body mass index as risk factors for Barrett\u0026rsquo;s esophagus. Gastroenterology. 2007;133:34\u0026ndash;41.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang Z, Shaheen NJ, Whiteman DC, et al. \u003cem\u003eHelicobacter pylori\u003c/em\u003e infection is associated with reduced risk of Barrett\u0026rsquo;s esophagus: an analysis of the Barrett\u0026rsquo;s and esophageal adenocarcinoma consortium. Am J Gastroenterol. 2018;113:1148\u0026ndash;55.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKoizumi S, Motoyama S, Iijima K. Is the incidence of esophageal adenocarcinoma increasing in Japan? Trends from the data of a hospital-based registration system in Akita Prefecture, Japan. J Gastroenterol. 2018;53:827\u0026ndash;33.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNishi T, Makuuchi H, Ozawa S, et al. The present status and future of Barrett\u0026rsquo;s esophageal adenocarcinoma in Japan. Digestion. 2019; 99:185\u0026ndash;90.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKenshi Matsuno, Ryu Ishihara, Masayasu Ohmori, et al. Time trends in the incidence of esophageal adenocarcinoma, gastric adenocarcinoma, superficial esophagogastric junction adenocarcinoma. J Gastroenterol. 2019; 54:784\u0026ndash;791.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMasayuki Watanabe, Yasushi Toh, Ryu Ishihara, et al. Comprehensive registry of esophageal cancer in Japan, 2015. Esophagus. 2023; 20:1\u0026ndash;28.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYuji Tachimori, Soji Ozawa, Hodaka Numasaki, et al. Comprehensive registry of esophageal cancer in Japan, 2009.Esophagus, 2016;13:110\u0026ndash;37.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePech O, Behrens A, May A, et al. Long term results and risk factor analysis for recurrence after curative endoscopic therapy in 349 patients with high-grade intraepithelial neoplasia and mucosal adenocarcinoma in Barrett\u0026rsquo;s esophagus. Gut 2008; 57:1200\u0026ndash;06\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eProbst A, Aust D, M\u0026auml;rkl B, et al. Endoscopic submucosal dissection in early esophageal cancer in Europe: endoscopic treatment by endoscopic submucosal dissection. Endoscopy 2015; 47:113\u0026ndash;21\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJapan Esophageal Society. Japanese Classification of Esophageal Cancer, 11th edition. Esophagus, 2017; 14: 1\u0026ndash;36.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGoda K, Fujisaki J, Ishihara R. et al. Newly developed magnifying endoscopic classification of the Japan Esophageal Society to identify superficial Barrett\u0026rsquo;s esophagus-related neoplasms. Esophagus 2018; 15:153\u0026ndash;159\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMuo M, Yao K, Kaise M, et al. Magnifying endoscopy simple diagnostic algorithm for early gastric cancer. Dig Endosc. 2016;28:379\u0026ndash;393.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOdze RD. Diagnosis and grading of dysplasia in Barrett\u0026rsquo;s oesophagus. J Clin Pathol 2006; 59:1029\u0026ndash;38\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShimizu T, Fujisaki J, Omae M et al. Treatment outcomes of endoscopic submucosal dissection for adenocarcinoma originating from long-segment Barrett\u0026rsquo;s esophagus versus short-segment Barrett\u0026rsquo;s esophagus. Digestion 2018; 97:316\u0026ndash;23\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOyama T, Takahashi A, Yorimitsu N et al. Endoscopic Diagnosis of Superficial Barrett\u0026rsquo;s Esophageal Adenocarcinoma. Stomach Intestine 2016; 51:1322\u0026ndash;32\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eR.H. Riddell, H. Goldman, D.F.Ransohoff, et al. Dysplasia in inflammatory bowel disease: standardized classification with provisional clinical applications. Hum Pathol.1983;14:931\u0026ndash;68.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKenshi Yao. Clinical Application of Magnifying Endoscopy with Narrow-Band Imaging in the Stomach. Clin Endosc.2015; 48:481\u0026ndash;90.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKazuyoshi Yagi, Yujiro Nozawa, Shinsaku Endou, et al. Diagnosis of Early Gastric Cancer by Magnifying Endoscopy with NBI from Viewpoint of Histological Imaging: Mucosal Patterning in terms of White Zone Visibility and Its Relationship to Histology. Diagn Ther Endosc. 2012; doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1155/2012/954809\u003c/span\u003e\u003cspan address=\"10.1155/2012/954809\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1.\u003c/strong\u003e Patient characteristics\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.98233215547703%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.724381625441696%\"\u003e\n \u003cp\u003eAll\u003c/p\u003e\n \u003cp\u003en= 67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.84452296819788%\"\u003e\n \u003cp\u003eCD group\u003c/p\u003e\n \u003cp\u003en= 46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.374558303886925%\"\u003e\n \u003cp\u003eUD group\u003c/p\u003e\n \u003cp\u003en= 21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.074204946996467%\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.98233215547703%\"\u003e\n \u003cp\u003eAge, median, years, (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.724381625441696%\"\u003e\n \u003cp\u003e72 (66-80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.84452296819788%\"\u003e\n \u003cp\u003e75 (67-80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.374558303886925%\"\u003e\n \u003cp\u003e70 (65-78)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.074204946996467%\"\u003e\n \u003cp\u003e0.146\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.98233215547703%\"\u003e\n \u003cp\u003eSex, male, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.724381625441696%\"\u003e\n \u003cp\u003e58 (86.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.84452296819788%\"\u003e\n \u003cp\u003e40 (87.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.374558303886925%\"\u003e\n \u003cp\u003e18 (85.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.074204946996467%\"\u003e\n \u003cp\u003e0.890\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.98233215547703%\"\u003e\n \u003cp\u003eThe use of PPI, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.724381625441696%\"\u003e\n \u003cp\u003e28 (41.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.84452296819788%\"\u003e\n \u003cp\u003e16 (34.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.374558303886925%\"\u003e\n \u003cp\u003e12 (57.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.074204946996467%\"\u003e\n \u003cp\u003e0.085\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.98233215547703%\"\u003e\n \u003cp\u003eDrinking, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.724381625441696%\"\u003e\n \u003cp\u003e31 (46.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.84452296819788%\"\u003e\n \u003cp\u003e22 (47.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.374558303886925%\"\u003e\n \u003cp\u003e9 (42.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.074204946996467%\"\u003e\n \u003cp\u003e0.705\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.98233215547703%\"\u003e\n \u003cp\u003eSmoking, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.724381625441696%\"\u003e\n \u003cp\u003e35 (52.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.84452296819788%\"\u003e\n \u003cp\u003e22 (47.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.374558303886925%\"\u003e\n \u003cp\u003e13 (61.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.074204946996467%\"\u003e\n \u003cp\u003e0.285\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.98233215547703%\"\u003e\n \u003cp\u003eHiatal hernia, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.724381625441696%\"\u003e\n \u003cp\u003e57 (85.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.84452296819788%\"\u003e\n \u003cp\u003e37 (80.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.374558303886925%\"\u003e\n \u003cp\u003e20 (95.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.074204946996467%\"\u003e\n \u003cp\u003e0.115\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.98233215547703%\"\u003e\n \u003cp\u003eReflux esophagitis, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.724381625441696%\"\u003e\n \u003cp\u003e13 (19.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.84452296819788%\"\u003e\n \u003cp\u003e10 (21.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.374558303886925%\"\u003e\n \u003cp\u003e3 (14.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.074204946996467%\"\u003e\n \u003cp\u003e0.474\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.98233215547703%\"\u003e\n \u003cp\u003eBackground mucosa\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.724381625441696%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.84452296819788%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.374558303886925%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.074204946996467%\"\u003e\n \u003cp\u003e0.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.98233215547703%\"\u003e\n \u003cp\u003e\u0026nbsp;SSBE, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.724381625441696%\"\u003e\n \u003cp\u003e45 (67.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.84452296819788%\"\u003e\n \u003cp\u003e38 (82.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.374558303886925%\"\u003e\n \u003cp\u003e7 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.074204946996467%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.98233215547703%\"\u003e\n \u003cp\u003e\u0026nbsp;LSBE, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.724381625441696%\"\u003e\n \u003cp\u003e22 (32.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.84452296819788%\"\u003e\n \u003cp\u003e8 (17.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.374558303886925%\"\u003e\n \u003cp\u003e14 (66.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.074204946996467%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eIQR, interquartile range; CD, clear demarcation; UD, unclear demarcation; PPI, proton pump inhibitor; SSBE, short-segment Barrett\u0026rsquo;s esophagus; LSBE, long-segment Barrett\u0026rsquo;s esophagus\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2.\u003c/strong\u003e Lesion characteristics\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.696113074204945%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.547703180212014%\"\u003e\n \u003cp\u003eAll\u003c/p\u003e\n \u003cp\u003en= 68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.547703180212014%\"\u003e\n \u003cp\u003eCD group\u003c/p\u003e\n \u003cp\u003en= 47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.547703180212014%\"\u003e\n \u003cp\u003eUD group\u003c/p\u003e\n \u003cp\u003en= 21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.66077738515901%\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.696113074204945%\"\u003e\n \u003cp\u003eTumor morphology, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.547703180212014%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.547703180212014%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.547703180212014%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.66077738515901%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.696113074204945%\"\u003e\n \u003cp\u003e\u0026nbsp;0-IIa or I\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.547703180212014%\"\u003e\n \u003cp\u003e35 (51.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.547703180212014%\"\u003e\n \u003cp\u003e27 (57.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.547703180212014%\"\u003e\n \u003cp\u003e8 (38.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.66077738515901%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.696113074204945%\"\u003e\n \u003cp\u003e\u0026nbsp;0-IIb\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.547703180212014%\"\u003e\n \u003cp\u003e26 (38.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.547703180212014%\"\u003e\n \u003cp\u003e18 (38.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.547703180212014%\"\u003e\n \u003cp\u003e8 (38.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.66077738515901%\"\u003e\n \u003cp\u003e0.022\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.696113074204945%\"\u003e\n \u003cp\u003e\u0026nbsp;0-IIc\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.547703180212014%\"\u003e\n \u003cp\u003e7 (10.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.547703180212014%\"\u003e\n \u003cp\u003e2 (4.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.547703180212014%\"\u003e\n \u003cp\u003e5 (23.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.66077738515901%\"\u003e\n \u003cp\u003e0.488\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.696113074204945%\"\u003e\n \u003cp\u003eTumor size, median, mm (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.547703180212014%\"\u003e\n \u003cp\u003e16 (10-25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.547703180212014%\"\u003e\n \u003cp\u003e16 (11-24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.547703180212014%\"\u003e\n \u003cp\u003e16 (9-32)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.66077738515901%\"\u003e\n \u003cp\u003e0.114\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.696113074204945%\"\u003e\n \u003cp\u003eTumor differentiation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.547703180212014%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.547703180212014%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.547703180212014%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.66077738515901%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.696113074204945%\"\u003e\n \u003cp\u003e\u0026nbsp;HGD / Well or Moderate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.547703180212014%\"\u003e\n \u003cp\u003e65 (95.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.547703180212014%\"\u003e\n \u003cp\u003e45 (95.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.547703180212014%\"\u003e\n \u003cp\u003e20 (95.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.66077738515901%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.696113074204945%\"\u003e\n \u003cp\u003e\u0026nbsp;Poor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.547703180212014%\"\u003e\n \u003cp\u003e3 (4.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.547703180212014%\"\u003e\n \u003cp\u003e2 (4.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.547703180212014%\"\u003e\n \u003cp\u003e1 (4.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.66077738515901%\"\u003e\n \u003cp\u003e0.959\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.696113074204945%\"\u003e\n \u003cp\u003eTumor depth\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.547703180212014%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.547703180212014%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.547703180212014%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.66077738515901%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.696113074204945%\"\u003e\n \u003cp\u003e\u0026nbsp;T1a\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.547703180212014%\"\u003e\n \u003cp\u003e58 (85.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.547703180212014%\"\u003e\n \u003cp\u003e39 (83.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.547703180212014%\"\u003e\n \u003cp\u003e19 (90.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.66077738515901%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.696113074204945%\"\u003e\n \u003cp\u003e\u0026nbsp;T1b\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.547703180212014%\"\u003e\n \u003cp\u003e10 (14.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.547703180212014%\"\u003e\n \u003cp\u003e8 (17.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.547703180212014%\"\u003e\n \u003cp\u003e2 (9.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.66077738515901%\"\u003e\n \u003cp\u003e0.448\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.696113074204945%\"\u003e\n \u003cp\u003eLymphatic invasion, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.547703180212014%\"\u003e\n \u003cp\u003e8 (11.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.547703180212014%\"\u003e\n \u003cp\u003e8 (17.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.547703180212014%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.66077738515901%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.696113074204945%\"\u003e\n \u003cp\u003eVascular invasion, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.547703180212014%\"\u003e\n \u003cp\u003e7 (10.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.547703180212014%\"\u003e\n \u003cp\u003e6 (12.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.547703180212014%\"\u003e\n \u003cp\u003e1 (4.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.66077738515901%\"\u003e\n \u003cp\u003e0.335\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.696113074204945%\"\u003e\n \u003cp\u003eHorizontal margin positive, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.547703180212014%\"\u003e\n \u003cp\u003e6 (8.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.547703180212014%\"\u003e\n \u003cp\u003e3 (6.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.547703180212014%\"\u003e\n \u003cp\u003e3 (14.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.66077738515901%\"\u003e\n \u003cp\u003e0.300\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.696113074204945%\"\u003e\n \u003cp\u003eVertical margin positive, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.547703180212014%\"\u003e\n \u003cp\u003e2 (2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.547703180212014%\"\u003e\n \u003cp\u003e2 (4.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.547703180212014%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.66077738515901%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eIQR, interquartile range; CD, clear demarcation; UD, unclear demarcation; HGD, high-grade dysplasia\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3.\u003c/strong\u003e Multivariate analysis for the risk factor of BEA with unclear demarcation\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"43.738977072310405%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.634920634920636%\"\u003e\n \u003cp\u003eOdds ratio\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.634920634920636%\"\u003e\n \u003cp\u003e95% CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.991181657848324%\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"43.738977072310405%\"\u003e\n \u003cp\u003eBackground mucosa, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.634920634920636%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.634920634920636%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.991181657848324%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"43.738977072310405%\"\u003e\n \u003cp\u003e\u0026nbsp;SSBE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.634920634920636%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.634920634920636%\"\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.991181657848324%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"43.738977072310405%\"\u003e\n \u003cp\u003e\u0026nbsp;LSBE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.634920634920636%\"\u003e\n \u003cp\u003e12.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.634920634920636%\"\u003e\n \u003cp\u003e2.84-47.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.991181657848324%\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"43.738977072310405%\"\u003e\n \u003cp\u003eTumor morphology, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.634920634920636%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.634920634920636%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.991181657848324%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"43.738977072310405%\"\u003e\n \u003cp\u003e\u0026nbsp;0-IIa or I\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.634920634920636%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.634920634920636%\"\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.991181657848324%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"43.738977072310405%\"\u003e\n \u003cp\u003e\u0026nbsp;0-IIb\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.634920634920636%\"\u003e\n \u003cp\u003e7.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.634920634920636%\"\u003e\n \u003cp\u003e0.84-60.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.991181657848324%\"\u003e\n \u003cp\u003e0.071\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"43.738977072310405%\"\u003e\n \u003cp\u003e\u0026nbsp;0-IIc\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.634920634920636%\"\u003e\n \u003cp\u003e3.93\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.634920634920636%\"\u003e\n \u003cp\u003e0.85-18.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.991181657848324%\"\u003e\n \u003cp\u003e0.080\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eBEA, Barrett\u0026rsquo;s esophageal adenocarcinoma; CI, confidence interval; SSBE, short-segment Barrett\u0026rsquo;s esophagus; LSBE, long-segment Barrett\u0026rsquo;s esophagus\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e4\u003c/strong\u003e\u003cstrong\u003e.\u003c/strong\u003e The evaluation of pathological structures\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.725352112676056%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.929577464788732%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.598591549295776%\"\u003e\n \u003cp\u003eCancerous mucosa\u003c/p\u003e\n \u003cp\u003emedian, \u0026micro;m (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.598591549295776%\"\u003e\n \u003cp\u003eBackground mucosa\u003c/p\u003e\n \u003cp\u003emedian, \u0026micro;m (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.147887323943662%\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.725352112676056%\" rowspan=\"3\"\u003e\n \u003cp\u003eCD group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.929577464788732%\"\u003e\n \u003cp\u003eLength of foveolar\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.598591549295776%\"\u003e\n \u003cp\u003e135 (95-194)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.598591549295776%\"\u003e\n \u003cp\u003e190 (120-254)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.147887323943662%\"\u003e\n \u003cp\u003e\u0026lt;0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.940803382663844%\"\u003e\n \u003cp\u003eWidth of foveolar\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.735729386892178%\"\u003e\n \u003cp\u003e74 (50-100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.735729386892178%\"\u003e\n \u003cp\u003e131 (100-167)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587737843551798%\"\u003e\n \u003cp\u003e\u0026lt;0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.940803382663844%\"\u003e\n \u003cp\u003eWidth of MCE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.735729386892178%\"\u003e\n \u003cp\u003e24 (18-30)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.735729386892178%\"\u003e\n \u003cp\u003e40 (33-50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587737843551798%\"\u003e\n \u003cp\u003e\u0026lt;0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.725352112676056%\" rowspan=\"3\"\u003e\n \u003cp\u003eUD group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.929577464788732%\"\u003e\n \u003cp\u003eLength of foveolar\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.598591549295776%\"\u003e\n \u003cp\u003e149 (90-160)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.598591549295776%\"\u003e\n \u003cp\u003e118 (70-160)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.147887323943662%\"\u003e\n \u003cp\u003e0.77\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.940803382663844%\"\u003e\n \u003cp\u003eWidth of foveolar\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.735729386892178%\"\u003e\n \u003cp\u003e90 (73-138)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.735729386892178%\"\u003e\n \u003cp\u003e130 (90-170)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587737843551798%\"\u003e\n \u003cp\u003e0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.940803382663844%\"\u003e\n \u003cp\u003eWidth of MCE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.735729386892178%\"\u003e\n \u003cp\u003e26 (18-33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.735729386892178%\"\u003e\n \u003cp\u003e34 (28-44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587737843551798%\"\u003e\n \u003cp\u003e\u0026lt;0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eIQR, interquartile range CD, clear demarcation; UD, unclear demarcation; MCE, marginal crypt epithlium\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Endoscopic diagnosis, Barrett’s esophageal cancer, Lateral margin","lastPublishedDoi":"10.21203/rs.3.rs-3992498/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3992498/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThe endoscopic lateral diagnosis of Barrett's esophageal adenocarcinoma (BEA) has been reported as challenging. Therefore, we aimed to clarify the clinicopathological characteristics and cause of BEA with unclear demarcation.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe reviewed BEA cases resected endoscopically or operatively between January 2010 and August 2022 at two institutions. The lesions were classified into two groups: the clear demarcation group (CD group) and the unclear demarcation group (UD group). We then compared clinicopathological findings between the two groups. Furthermore, to elucidate the differences in pathological structures between the cancerous mucosa and the surrounding mucosa, we measured the length and width of foveolar, as well as the width of the marginal crypt epithelium (MCE).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eWe analyzed 68 BEA cases, comprising 47 in the CD group and 21 in the UD group. Multivariate analysis revealed long-segment Barrett\u0026rsquo;s esophagus (LSBE) as the sole significant risk factor (OR; 10.38, 95% CI;2.14\u0026ndash;50.19, p\u0026thinsp;=\u0026thinsp;0.004). Regarding pathological analysis, significant differences were observed in the length and width of foveolar between the cancerous and surrounding mucosa in the CD group (p\u0026thinsp;=\u0026thinsp;0.03 and 0.00). However, in the UD group, these measurements did not show significant differences (p\u0026thinsp;=\u0026thinsp;0.53 and 0.72). Nevertheless, the width of MCE in the cancerous area was significantly shorter than that in the surrounding mucosa in both groups (p\u0026thinsp;=\u0026thinsp;\u0026lt;\u0026thinsp;0.05, and \u0026lt;\u0026thinsp;0.05).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThe significant risk factor for UD group was LSBE. The width of MCE, showing significant differences between the cancerous and surrounding mucosa, may serve as an important asset in endoscopic diagnosis for BEA.\u003c/p\u003e","manuscriptTitle":"Factors influencing lateral margin diagnosis challenges in Barrett’s esophageal cancer: A bicenter retrospective study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-05 17:40:59","doi":"10.21203/rs.3.rs-3992498/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7b47edcc-6129-4cfa-8784-d75876cfe3a6","owner":[],"postedDate":"March 5th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-03-13T19:32:57+00:00","versionOfRecord":[],"versionCreatedAt":"2024-03-05 17:40:59","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3992498","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3992498","identity":"rs-3992498","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}