Background: Endoscopic submucosal dissection (ESD) for superficial esophageal cancer is technically challenging, and research on predictive factors related to the difficulty in the procedure is limited. This study aimed to investigate the factors predicting the difficulty in esophageal ESD. Methods: This retrospective study analyzed 303 lesions treated at our institution between April 2005 and June 2021. The following 13 factors were evaluated: sex, age, tumor location, tumor localization, macroscopic type, tumor size, tumor circumference, preoperative diagnosis of histological type, preoperative diagnosis of invasion depth, previous radiotherapy for esophageal cancer, metachronous lesion located close to post-ESD scar, operator’s skill, and use of a clip-and-thread traction method. Difficult esophageal ESD cases were defined as those requiring long procedure time (>120 min). Results: Fifty-one lesions (16.8%) met the defined criterion for difficult cases of esophageal ESD. Logistic regression analysis identified tumor size larger than 30 mm (odds ratio: 9.17, 95% confidence interval: 4.27–19.69, p < 0.001) and tumor circumference more than half that of the esophagus (odds ratio 2.53, 95% confidence interval: 1.15–5.54, p = 0.021) as independent predictive factors related to difficulty in esophageal ESD. Conclusion: Tumor size larger than 30 mm and tumor circumference more than half that of the esophagus can predict difficulty in performing esophageal ESD. This knowledge can provide useful information for developing ESD strategies and selecting a suitable operator on a case-by-case basis to achieve favorable clinical outcomes.

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