To gain more detailed insight into the histogenesis of primary nonurachal adenocarcinomas and signet ring cell carcinomas of the urinary bladder, we analyzed by immunohistochemistry the expression of a broad panel of proteins, associated with cell differentiation (pS2 peptide, MUC5AC, MUC6, spasmolytic polypeptide, cyclooxygenases-1 and -2, caveolin-1), and of various novel known or candidate tumor suppressors (14-3-3 sigma, SYK, PTEN, maspin). Included were 12 adenocarcinomas admixed to urothelial carcinomas, 10 pure adenocarcinomas and 5 signet ring cell carcinomas. As the most important finding, the majority of signet ring cell carcinomas and three quarters of the adenocarcinomas (72.7%) expressed the pS2 peptide, and nearly half of the adenocarcinomas (45.5%) as well as most of the signet ring cell carcinomas were observed to secrete the MUC5AC apomucin. Since expression of both proteins was absent in the normal nonneoplastic urothelium, their tumor-associated appearance is regarded as a neoexpression or reexpression, respectively, of normally cryptic antigenic determinants, and is assumed to be involved in the phenotypical formation of vesical adenocarcinomas, including signet ring cell carcinomas. The expression of both pS2 and MUC5AC in variants of urothelial carcinomas with a glandular differentiation and an extracellular mucus production support the concept that adenocarcinomas may histogenetically develop from preexistent TCC. Adenocarcinomas which secrete the pS2 peptide and the MUC5AC glycoprotein are proposed to be subclassified as adenocarcinomas of the intestinal type, as distinguished from those of the common type lacking an expression. The tumor suppressor genes showed a loss of protein expression in adenocarcinomas, ranging from 54.5% (14-3-3 sigma), to 31.8 (PTEN), 27.3% (SYK) and 18.2% (maspin). Similar expression profiles in the coexistent urothelial carcinomas argue against a specific involvement of these genes during the morphogenesis of adenocarcinomas.