The cellular features of developing carcinoma in murine urinary bladder

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Abstract
Bladder cancer often results from a widespread reaction of urothelial cells to carcinogenic stimuli. Although developing carcinoma is widely considered to progress through various grades of epithelial atypia, well-controlled prospective studies detailing the morphologic features of these lesions at the cellular level have not appeared in the literature. This study was designed to document the cellular features of developing urothelial carcinoma in experimental animals using the BHBN model system. Developing lesions were monitored by periodic collection of urine and tissue. The specimens were coded and examined by cytology and histology using multiple discriminators. The morphologic changes in the treated bladders were statistically different from those in control tissue. They could be divided into three stages: 1) The earliest abnormalities were an increase in the number of cell layers, loss of polarity, and slight crowding of nuclei in the tissue sections. Among the cellular features, there were increased nuclear size and sharply angulated indentations (notches) in the nuclear borders. A few nuclei exhibited a finely granular pattern, but dusty chromatin predominated. 2) In the intermediate stage, nuclear crowding became more prominent, and there were numerous areas with finely granular, regularly distributed chromatin. A few nucleoli were identified. Mitoses were prominent in the tissue sections. 3) In the late stage, as papillary tumors developed elsewhere, the urothelium of the flat areas changed significantly. Nuclear crowding and notching remained constant but were overshadowed by the appearance of nucleoli and irregularly distributed chromatin. The pattern was finely granular in some cases but coarsely granular in most. Nuclear size decreased markedly as the cells became smaller and more numerous. Cytologically, it was not possible to distinguish these cells from neoplastic cells emanating from the papillary areas. This experimental study tends to confirm deductions made from clinical material that urothelial carcinoma develops through an orderly sequence of morphologic severity. It further indicates that invasive carcinoma can arise from neoplastic cells that neither occupy the full thickness of the epithelium nor represent lateral migration from an adjacent full thickness lesion. The detailed cellular features documented can be used to identify atypical cells in correlative cytologic preparations. Studies such as this could provide an experimental basis for future evaluations of the cytologic characteristics of human urothelial atypia.