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Background and Aims: Early esophageal squamous cell neoplasia (ESCN) is preferably treated with en-blocendoscopic resection. Ablation might be an alternative for flat ESCN, but ESCN extension along the epithelial lining of ducts and submucosal glands (SMGs) might jeopardize ablation efficacy. Clinical studies suggest that localrecurrence might arise from such buried ESCN niches after ablation. We studied human endoscopic resectionspecimens of ESCN to quantify ESCN extension into ducts/SMGs and performed a prospective porcine studyto evaluate the depth of radiofrequency ablation (RFA) and CryoBalloon ablation (CBA) into ducts/SMGs.Methods: Endoscopic submucosal dissection specimens of flat-type ESCN from a Japanese (n Z 65) and Dutchcohort (n Z 14) were evaluated for presence and neoplastic involvement of ducts/SMGs. Twenty-seven pigs weretreated with circumferential RFA (c-RFA; n Z 4), focal CBA (n Z 20), and focal RFA (n Z 3) with 4, 60, and 9treatment areas, respectively. After prespecified survival periods (0 hours, 8 hours, 2 days, 5 days, and 28days), treatment areas were evaluated for uniformity and depth of ablation and affected SMGs.Results: Neoplastic extension in ducts/SMGs was observed in most lesions: 58% (38/65) in the Japanese and 64%(9/14) in the Dutch cohort. In the animal study, 33% of SMGs (95% confidence interval, 28-50) were not affectedafter c-RFA, although the overlying epithelium was ablated. Focal RFA and CBA resulted in uniform ablations witheffective treatment of all SMGs.Conclusions: ESCN extends into ducts/SMGs in most patients. In an animal model, focal RFA and CBA effectivelyablated SMGs, whereas c-RFA inadequately ablated SMGs. Given this potential reason for recurrence, endoscopicresection should remain the standard of care. (Gastrointest Endosc 2021;94:832-42.)

Background and Aims: Endoscopic resection is the cornerstone of treatment of Barrett's esophagus (BE)-related neoplasia. However, accurate histopathologic evaluation of endoscopic resection specimens can be challenging, and the preferred specimen handling method remains unknown. Therefore, the aim of our study was to compare 3 different specimen handling methods for assessment of all clinically relevant histopathologic parameters and time required for specimen handling. Methods: In this multicenter, randomized study EMR specimens of BE-related neoplasia with no suspicion of submucosal invasion during endoscopy were randomized to 3 specimen handling methods: pinning on paraffin using needles, direct fixation in formalin without prior tissue handling, and the cassette technique (small box for enclosing specimens). The histopathologic evaluation scores were assessed by 2 dedicated GI pathologists blinded to the handling method. Results: Of the 126 randomized EMR specimens, 45 were assigned to pinning on paraffin, 41 to direct fixation in formalin, and 40 to the cassette technique. The percentages of specimens with overall optimal histopathologic evaluation scores were similar for the pinning method (98%; 95% confidence interval [CI], 88.0-99.9) and for no handling (90%; 95% CI, 76.9-97.3) but were significantly lower (64%; 95% CI, 47.2-78.8) for the cassette technique (P < .001). Time required for specimen handling was shortest when no handling method was used (P < .001 vs pinning and cassette). Conclusions: Both pinning on paraffin and direct fixation in formalin resulted in optimal histopathologic evaluation scores in a high proportion of specimens, whereas the cassette technique performs significantly worse, and its use in clinical daily practice should be discouraged. Given the significantly shorter handling time, direct fixation in formalin appears to be the preferred method over pinning on paraffin. However, the latter needs to be confirmed in larger studies with inclusion of all EMR specimens. (Clinical trial registration number: ISRCTN50525266.)