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Cancers of the ampulla are unusual and morphologically heterogeneous. The NCI's SEER Program is now large enough so that unusual cancers can be studied. Based on pathologic and epidemiologic characteristics of cancer of the ampulla available in SEER, important clinicopathological correlations can be made.All patients with cancer of the ampulla were identified between 1973 and 2005. Demographic features, distribution of histological types, age-specific incidence rates, and 5-year survival rates according to stage and histologic type were compared.There were 5,625 cases of ampullary cancer. Ampullary cancer has been increasing since 1973. In both African Americans and Caucasians, the disease is more common in men. Adenocarcinomas, NOS comprised 65% of all histological types. Survival depends on stage, grade, and histologic type. Papillary carcinomas had a more favorable survival than other types; carcinomas arising in adenomas had a more favorable survival than adenocarcinomas not associated with adenomas. Logarithmic transformation of age-related incidence data demonstrates that cancers having differing histopathologic phenotypes represent a single population of tumors.Prognostic factors include histologic type, grade, stage, and coexisting adenomas. These data should be included in pathology reports. Although certain histologic types exhibit morphologic differences, their pathogenesis appears to be similar.