Quantifying the frequency of radiogenic thyroid cancer per clonogenic cell in vivo

We used quantitative cell transplantation to evaluate the frequencies of the formation of radiogenic thyroid cancer per clonogenic rat thyroid epithelial cell in vivo. Irradiation of thyroid cells with 5 Gy 137Cs gamma rays before transplantation significantly increased the incidence of thyroid carcinoma formation in such grafts compared to similar grafts of unirradiated thyroid cells. We calculated the frequencies of radiogenic cancer by subtracting cancer incidences in unirradiated groups from incidences in irradiated groups and dividing by the number of clonogens grafted. The highest observed frequencies of radiogenic thyroid cancer so calculated were 0.141 and 0.046 cancers per surviving irradiated clonogenic cell. These cancer frequencies occurred in grafts containing averages of three and ten clonogens per site, respectively, and represent one cancer per approximately 7 and approximately 22 irradiated clonogens. We conclude that the highest observed frequencies of radiogenic cancer are likely to be the best estimates of the "real" frequency per irradiated clonogen in that virtually all the methodological sources of inaccuracy tend to decrease the observed frequency compared to the "real" frequency. Radiogenic initiation of cancer is thus a highly common cellular event among surviving irradiated clonogenic thyroid cells. To examine the role of endocrine-mediated tumor promotion on the expression of radiogenic cancer, we attenuated the intensity of thyrotropin (TSH)-mediated tumor promotion in some groups of recipient animals. We found that the incidence rates for radiation-associated cancer were significantly higher in rats with higher serum TSH levels compared to rats with lower TSH levels. We conclude from these data that (1) radiogenic thyroid cancer occurs with a high frequency and (2) chronic TSH stimulation accelerates progression of radiogenic neoplasms to overt carcinomas and promotes development of later-arising carcinomas in grafts of unirradiated thyroid clonogens.