Introduction: Colorectal non-polypoid lesions (NPLs) are flat, hard-to-detect, and mainly right-sided lesions. We aimed to assess the prevalence and endoscopic features of NPL lesions in a large cohort of screening patients in Northern Italy. Methods: Fecal immunochemical test (FIT)-positive subjects between 50 and 69 years old who had undergone at least a screening colonoscopy from March 2005 to December 2017 at the Endoscopy Unit of Ferrara were included. We selected only non-diminutive (>5 mm) and neoplastic polyps (i.e., adenomas, serrated adenomas, and carcinomas). Patients’ demographics and polyps’ endoscopic-histopathological data were collected. Categorical variables were compared using the Pearson’s χ2 test and Fisher’s exact test, while odd ratios and confidence intervals were estimated with univariate analysis. Results: A total of 6,676 FIT-positive subjects underwent 7,616 colonoscopies during the study period. Total lesions were 3,231, of which 133 were NPLs and among these 123 were neoplastic. The prevalence of NPLs among total lesions was 4.1%, while prevalence of neoplastic NPLs among total neoplastic lesions was 4.6%. The prevalence of NPLs and neoplastic NPLs among total colonoscopies was 1.7% and 1.6%, respectively. Neoplastic NPLs were more frequent between 60 and 64 years old (p = 0.03) and associated with other colonic polyps in subjects older than 60 years (p = 0.016). Cancerized NPLs were more likely in younger patients (50–59 years old, p = 0.04). Conclusions: Prevalence of NPLs is low among the screening population, but NPLs are frequently associated with other colorectal polyps in patients older than 60 years and carry a higher risk of cancer in patients younger than 60 years old.

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