Glands near the surface of the papilla of Vater may become distended with mucus and become hyperplastic; that is, become distended. In this study, we tried to clarify carcinogenesis in these distended glands. Twenty-nine pancreatoduodenectomized nontumorous duodenal papilla specimens from carcinoma of the pancreas and bile duct and 34 resected ampullary carcinoma specimens were studied histopathologically and immunohistochemically, using cytokeratins and mucin immunohistochemical features/phenotypes. Distended glands were found in 11 of the 29 pancreatoduodenectomized specimens. These glands were immunopositive for cytokeratin (CK) 7 and MUC-5AC Glycoprotein (MUC5AC), but not for CK20, while the intrapapillary portion was CK7-positive and CK20-negative, but mostly negative for MUC5AC. Immunopositivity for CK7, CK20, and MUC5AC was found in 25, 21, and 18 of the 34 specimens of ampullary carcinoma, respectively. In 23 of the 34 specimens, immunoreactivity for MUC5AC and that for CK7 was coincident, that is, when the former was immunopositive, so was the latter, and vice versa, while in 25 of the 34 specimens, immunoreactivity for MUC5AC was opposite to that for CK20. Among the 23 cases in which immunoreactivity for MUC5AC and CK7 was coincident, 10 were MUC5AC+, CK7+, CK20- and 7 were MUC5AC-, CK7-, CK20+, suggestive of disease arising from the pancreaticobiliary mucosa or the distended glands in the former and disease arising from the duodenal mucosa in the latter. In MUC5AC+ cases, other than the 10 cases of MUC5AC+, CK7+, CK20-, 6 were double-positive and 1 was double-negative for CK7 and CK20, and 1 was CK20-positive, and at least 1 case showing double-negativity for CK7 and CK20 was suggestive of disease arising from the distended glands. Although most ampullary carcinomas arise from the duodenal mucosa or intra-ampullary mucosa, both CK7-positive and MUC5AC-positive or only MUC5ACpositive ampullary carcinomas may arise from the distended glands.