A 70-year-old woman was referred to our hospital for management of a large, nearly circumferential, laterally spreading lesion (LSL) of the duodenum involving the ampulla of Vater (Fig. 1A), which was incidentally diagnosed during endoscopic investigation of diarrhea. Her medical history included severe chronic obstructive pulmonary disease; rheumatoid arthritis, for which immunosuppressive medication was prescribed; and heterozygote factor V Leiden requiring anticoagulant therapy. Because of the ampulla involvement, magnetic resonance cholangiopancreatography was performed and showed absence of adenoma intraductal extension and absence of pancreas divisum.