Morphology and anatomic localization of renal microneoplasms and proximal tubule dysplasias induced by four different estrogens in the hamster.

Estrogens are known to induce tumors in high frequency in orchiectomized Syrian golden hamsters, but the histogenesis of the tumors is controversial. In order to identify the earliest precursors of the tumors, animals were implanted with pellets of four different estrogens, sacrificed at times ranging up to 6.4 months, and the various neoplastic and nonneoplastic lesions were characterized. Infiltrating cancers were identified in 80% of animals exposed to diethylstilbestrol, 17 beta-estradiol, and hexestrol for periods of 5.3-6.4 months; however hamsters exposed to ethinyl estradiol for comparable times did not develop any tumors. Proximal tubule dysplasia, identified as focal collections of abnormal-appearing cells with increased [3H]thymidine-labeling indices (eight times higher than nondysplastic cells), was the only nonmalignant change that, for every agent, either preceded or accompanied the development of cancer. The dysplastic lesions were further subdivided into two types when it became apparent that they and carcinoma in situ, another lesion in the proximal tubules, might be part of a continuum of tumor progression that results in infiltrating cancer. Another dysplastic variant, classified as florid dysplasia because of its extensive involvement of tubules, showed well-differentiated features; it was seen only in the ethinyl estradiol-treated hamsters. In a quantitative study of the anatomic localization of dysplasias and microcancers (less than 0.5 mm in diameter) induced by diethylstilbestrol, both lesions showed highest incidence in the deep renal parenchyma. The dysplasias were at least eight times more prevalent in the proximal tubules of the innermost 10% of the cortex and subjacent medulla than in the rest of the cortex. We conclude that proximal tubule dysplasias developing in the deep renal parenchyma are the most likely precursors of the estrogen-induced cancers.