Histogenesis of nonurothelial carcinomas of the urinary bladder from pre-existent transitional cell carcinomas. A histopathological and immunohistochemical study

The histogenesis of nonurothelial carcinomas of the urinary bladder is difficult to understand, since the bladder is normally lined exclusively by transitional cell epithelium. To gain more insights into the pathogenesis of nonurothelial carcinomas, the morphology and immunohistochemistry of transitional cell carcinomas (TCC), mixed transitional cell and nonurothelial carcinomas, and pure nonurothelial carcinomas were comparatively studied. Of papillary and of nonpapillary (solid) TCC (overall incidence 6.8%), 4.8% and 15.4%, respectively, disclosed foci of altered celllular and architectural phenotypes, consisting of squamous epithelium, pseudoglandular formations, and true glands with or without mucus production. The diverse phenotypic variants develop obviously by a metaplastic process as a result of the well-known inherent potential of the urothelium to undergo several pathways of cellular differentiation. There is strong evidence that squamous cell carcinomas arise secondarily from a squamous metaplasia and adenocarcinomas from metaplastic glandular epithelium within pre-existing TCC following complete carcinogenic transformation of the initially bland-looking metaplastic tumor cells. The metaplastic origin of nonurothelial bladder carcinomas is supported by immunohistochemical findings. The high molecular weight cytokeratin 34betaE12 identifies tumor cells with squamous characteristics, helping to explain the development of squamous cell carcinomas. Secretion of MUC5AC apomucin is assumed to play a central role in the histogenesis of nonurachal mucus-producing adenocarcinomas, including signet ring cell carcinomas. Metaplastic phenotypic variants of TCC should be recognized as distinct tumor entities with the potential to transform into nonurothelial carcinomas and thus possibly implying a poorer clinical outcome than typical, uniform TCC.