Heterotopic pancreas (HP) can be detected by accompanying symptoms or incidentally during gastrointestinal (GI) tract tumor resection. We compared clinicopathologic features among 165 resected HPs (57 gastric [35%], 56 duodenal [34%], 30 omental [18%], and 22 jejunal [13%]). Symptomatic HPs (79/135 GI tract wall HPs, 59%) were larger (P=0.05), more common in younger patients and in a gastric location (both P<0.001), and more frequently associated with lymphoid cuffs (P=0.03) than incidentally found HPs. Gastric/jejunal HPs were more frequently symptomatic (P<0.001), deeply located (P=0.03), and associated with lymphoid cuffs (P=0.008) and pancreatic intraepithelial neoplasia/intraductal papillary mucinous neoplasms (PanIN/IPMN; P=0.001) than duodenal HPs. HP was frequently associated with acinar-ductal metaplasias (117/135 GI tract wall HPs, 87%) and PanINs/IPMNs (68/135, 50%); those with PanINs/IPMNs were larger (P<0.001), more frequently located in stomach (P=0.001), had deeper wall involvement (P=0.03), and more often showed infiltrative growth (P<0.001) and lymphoid cuffs (P=0.02). Four HPs containing PanINs abutted adenocarcinomas, all expressing wild-type KRAS and intact SMAD4/DPC4 expression. Thus, symptomatic HP is associated with younger age, larger size, gastric location, and lymphoid cuffs. HPs containing PanINs/IPMNs (usually low grade) are larger and more common in stomach, have deeper wall location, and show infiltrative growth and lymphoid cuffs. Adenocarcinomas are rarely observed adjacent to HPs with PanINs/IPMNs. KRAS mutational and SMAD4/DPC4 immunohistochemical studies can discriminate between adenocarcinoma derived from HP and concurrent adenocarcinoma with HP.