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Background. Endoscopic submucosal dissections (ESDs) allow removal of large gastrointestinal tumors and help patients avoid major oncologic surgery. In this study, the challenges and development of approaches toward successfully handling ESDs were analyzed in 279 colorectal specimens (114 rectal, 47 left, 118 right colonic; 90% adenoma with/without carcinoma). Methods. Each specimen was processed according to an established protocol including gross photography, mapping, and total submission for histopathologic examination. Results. Mean lesion size was 4.2 cm (range: 0.5-22 cm; 28% ≥5 cm; 6% ≥10 cm). Invasive carcinoma was present in 38 cases (14%), which had a mean overall tumor size of 3.8 cm (range: 1.1-17.5 cm), and mean largest size of the invasive component was 0.93 cm (range: 0.04-3 cm). Fifteen cases were staged as pT1a (submucosal invasion of <1000 µm) and 13 cases as pT1b (submucosal invasion of ≥1000 µm). En-bloc and R0 resection rates were 99.3% and 90.6%, respectively. Conclusion. Various histopathologic challenges were encountered, which were carefully evaluated by dedicated pathologists with familiarity to the subtleties in handling and reporting these specimens. We recommend these specimens to be prepared in the endoscopy suite, submitted to the Pathology Department oriented, pinned, and placed into copious amount of fixative. Total sampling, gross photography, mapping, and proper fixation are crucial components in the histopathologic evaluation. Micromeasurement of invasion depth and substaging per European/Japanese guidelines as well as accurate measurement of the distance from the resection margins are highly recommended. In conclusion, ESD is an adequate method that can be successfully implemented in a tertiary care center to perform en-bloc and margin-free resections of clinically selected large colorectal superficial lesions.