Comparable Risk of Barrett's Adenocarcinoma Between Japanese Patients With Long‐Segment Barrett's Esophagus and Western Populations

Esophageal cancer is broadly classified into squamous cell carcinoma, which arises from squamous epithelium, and adenocarcinoma, which develops from Barrett's epithelium (BE) located at the esophagogastric junction (EGJ). In Japan, the majority of esophageal cancers detected and treated are squamous cell carcinomas, whereas adenocarcinoma accounts for only approximately 6.5%–7.1% of all esophageal cancers—remarkably lower than the rates reported in Western countries. This discrepancy is primarily attributable to differences in the prevalence of BE, the precursor lesion for adenocarcinoma. While the prevalence of long-segment BE (LSBE) in the general population has been reported to be 1%–7% in Western countries, recent cohort data indicate that its prevalence among Japanese and other Asian individuals is extremely low (0.2%) 1. An important point is that the definition of the EGJ landmark differs between Japan and Western countries 2. In most countries outside Japan, the EGJ is defined as the proximal end of the gastric folds (PEGF), whereas in Japan, it is defined as the distal end of the palisade vessels (DEPV). dev. is difficult to identify under sedation, and even when it is visible, it is often observed to shift orally relative to the PEGF when the two do not coincide. Harmonization of these definitions may further widen the apparent gap in LSBE prevalence between Japan and Western countries. BE develops when the esophageal mucosa of the EGJ is chronically exposed to inflammatory stimuli due to gastroesophageal reflux disease. Persistent inflammation leads to the progression of BE, the development of intestinal metaplasia (IM) within BE, subsequent dysplasia, and ultimately Barrett's adenocarcinoma (BAC) through a multistep carcinogenic pathway. When considering the development of BAC, the length of BE and the presence of IM are critically important predictors of cancer risk. Numerous previous studies have identified LSBE as an independent risk factor for BAC. In Western countries, short surveillance intervals of 2–5 years for patients with LSBE have been recommended 3. However, because the prevalence of LSBE and BAC is low among Japanese individuals, no reliable long-term follow-up data have been available to support the adoption of Western surveillance strategies in Japan. Ishimura et al. conducted a 10-year prospective nationwide study involving 267 patients with LSBE across 32 medical centers in Japan beginning in 2011, tracking the incidence of BAC 4. Over an average follow-up period of 58.0 months, 13 new BAC cases were identified, corresponding to an estimated incidence of 1.01% (0.57%–1.73%) per year—similar to figures reported in Western studies. The major significance of this study is that it is the most extensive and reliable data to demonstrate that the carcinogenic risk associated with LSBE in Japan is comparable to that in Western countries. This finding implies that surveillance strategies for Japanese patients with LSBE should likely follow Western guidelines. In this study, the mean number of surveillance endoscopies among cases in which BAC was detected was 4.7, compared with 4.1 in cases without BAC—an insignificant difference. Considering the length of follow-up, patients typically underwent endoscopy every 1–2 years. These findings suggest that even if LSBE prevalence differs between Japan and Western countries, once LSBE has developed in a Japanese individual, surveillance strategies similar to those used in the West may be required. Compared with the recommended surveillance intervals for LSBE in Western countries (2–5 years), the intervals in the Ishimura study were shorter. This may be because the Japanese guidelines do not specify a precise surveillance interval for patients with LSBE. Although more intensive surveillance is warranted when dysplasia or BAC is detected and treated, further evaluation is needed to determine whether extending surveillance intervals could be appropriate in Japan, considering cost-effectiveness and patient burden. Based on the data from Ishimura et al., all patients with LSBE in whom BAC was detected underwent surveillance at intervals of less than 2 years on average. Therefore, we consider a 2-year surveillance interval safe and consistent with the ESGE guidelines. Of the 13 BAC cases detected in this study, six lesions invaded only the superficial muscularis mucosae (SMM), and all cancers were at an early stage. These findings suggest that performing surveillance endoscopy every 1–2 years, provided that procedural methods are standardized, allows for timely detection of early-stage BAC. Importantly, this study did not adopt the Seattle protocol for biopsy sampling at baseline or during surveillance; instead, BAC was diagnosed solely based on targeted biopsies from areas with optical suspicion of cancer or dysplasia. At least among the 32 high-volume centers participating in the study, LSBE surveillance may not require routine use of the Seattle protocol. In daily practice, the Seattle protocol is often avoided in many Japanese institutions because it is time-consuming and requires a large number of biopsies. The study's findings may therefore support omitting routine Seattle protocol biopsies in LSBE surveillance. Although the omission of the Seattle protocol makes the study highly relevant to real-world clinical practice in Japan, one major limitation is the lack of quantitative assessment of IM formation within LSBE and the presence of low-grade dysplasia (LGD), which is often difficult to identify endoscopically. Because baseline IM and LGD status were not assessed before initiating follow-up, determining the optimal surveillance intensity for newly diagnosed patients with LSBE remains challenging. Notably, when neoplastic lesions are present within LSBE, metachronous neoplasms have been reported to develop in 21.5% of cases 5. Premalignant lesions such as LGD cannot be reliably detected solely by optical diagnosis, and high adherence to the Seattle protocol has been emphasized as essential to ensure adequate examination quality and improve LGD detection 6. Additionally, in Western countries, radiofrequency ablation (RFA) is often performed when dysplasia is detected during surveillance—although it is not yet reimbursed in Japan 7. RFA is widely used in Western practice as an effective therapeutic option for eliminating the precancerous field and reducing future cancer risk. If Japanese surveillance were to adopt the Seattle protocol, more LGD cases might be identified. A future challenge in Japan will be the introduction of RFA for detected LGD cases among patients with LSBE to prevent progression to BAC. Furthermore, predictive models incorporating noninvasive parameters—such as baseline endoscopic findings, neutrophil-to-lymphocyte ratios, and smoking status—have been proposed to estimate the likelihood of LGD development 8, suggesting that surveillance strategies could be optimized by integrating these models. Confirmation of the presence of LSBE requires EGD. Conversely, there is no practical method other than endoscopy to assess the presence of LSBE or the risk of BAC. In Japan, endoscopic screening is widely implemented for gastric cancer screening; however, as Helicobacter pylori infection rates have dramatically decreased among younger individuals, the gastric cancer screening program itself is expected to become less efficient and less cost-effective in the near future 9. Under such circumstances, the overall scale of gastric cancer screening in Japan is anticipated to decline. Because patients with LSBE are often asymptomatic, opportunities to detect LSBE—the precursor to BAC—may consequently diminish. In fact, over half of the patients with LSBE in that study did not report heartburn or regurgitation at their index EGD. In contrast to the ESGE guidelines, Japan currently lacks explicit recommendations for detecting BE in asymptomatic individuals. As Ishimura et al. demonstrated that LSBE patients in Japan carry a cancer risk comparable to their Western counterparts, the development of risk stratification tools capable of identifying asymptomatic individuals at high risk for LSBE is urgently needed. As recommended by the ESGE guidelines, individuals at high risk for LSBE, such as those with obesity, should undergo proactive screening with EGD. Nonendoscopic approaches, such as cytosponge-based sampling combined with biomarker analysis for risk assessment, have been reported 10, but even more noninvasive, cost-effective methods will be required in the future. Integration of such novel approaches with existing clinical strategies could enable more efficient identification of patients with LSBE and facilitate the early detection of BAC. F.I. and S.S. designed this study. F.I. and S.S. collected data. F.I. wrote the manuscript. S.S. critically revised the manuscript. All the authors have approved the final manuscript. The authors have nothing to report. Sho Suzuki is Associate Editor of Digestive Endoscopy. The other author declares no conflicts of interest. Cancer Incidence in Japanese Patients With Long-Segment Barrett's Esophagus-Japan Nationwide 10-Year Prospective Cohort Study. https://doi.org/10.1111/den.70070.