Endorectal ultrasound and rectal magnetic resonance are sometimes unable to differentiate between stages T2 and T3 in rectal adenomas that are possible adenocarcinomas, or between stages T1 and T2 in rectal adenocarcinomas. These cases of diagnostic uncertainty raise a therapeutic dilemma: transanal endoscopic surgery (TES) or total mesorectal excision (TME)? Methods: An observational study of a cohort of 803 patients who underwent TES from 2004 to 2021. Patients operated on for adenoma (group

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... ) and low-grade T1 adenocarcinoma (group II) were included. The variables related to uncertain diagnosis, and to the definitive pathological diagnosis of adenocarcinoma stage higher than T1, were analyzed. Results: A total of 638 patients were included. Group I comprised 529 patients, 113 (21.4%) with uncertain diagnosis. Seventeen (15%) eventually had a pathological diagnosis of adenocarcinoma higher than T1. However, the variable diagnostic uncertainty was a risk factor for adenocarcinoma above T1 (OR 2.3, 95% CI 1.1–4.7). Group II included 109 patients, eight with uncertain diagnosis (7.3%). Two patients presented a definitive pathological diagnosis of adenocarcinoma above T1. Conclusions: On the strength of these data, we recommend TES as the initial indication in cases of diagnostic uncertainty. Multicenter studies with larger samples for both groups should now be performed to further assess this strategy of initiating treatment with TES.