Analysis of proliferative compartments in human tumors. I. Renal adenocarcinoma.

Vascular perfusion of 16 renal adenocarcinomas with radioactive DNA precursors provides a possibility of characterize proliferative compartments of this tumor type. Immediately after resection of the tumor-bearing kidney, the organ is perfused via renal artery with dextran-diluted, heparinized oxygenated blood at physiological temperature, pH, flow, and pressure in a recirculation system. DNA synthetizing cells are labeled by addition of 3H- or 14C-thymidine or both isotopes at different intervals. Beta camera scans and whole-tumor autoradiograms disclose a striking proliferative heterogeneity of the tumor. Cell proliferation depends on intratumoral localization, cellular differentiation, histological structure and vascular supply. Subpopulations of high proliferative activity are found at the invasive borderline near normal kidney, focally in subcapsular areas and in intrarenal metastases, but also immediately adjacent to necrotic areas in the tumor center. Quantitative evaluation of autoradiograms yields, at the cellular level, a significantly higher labeling index in granular cells (3.21%) than in clear cells (0.65%), with a large variability dependent on the histological structure. The highest number of DNA synthetizing cells is seen in papillary and mixed solid-tubular zones and at peripheral parts of solid areas, whereas in central parts of solid tumor cords and in highly differentiated tubular areas lower labeling indices are observed. The labeling index decreases exponentially as a function of the distance from the supporting blood vessel. In solid cords, no labeled cells are seen at a distance of more than 200 micron from the capillary. The ts determined by 3H/14C-thymidine double labeling is between 9.9 and 16.8 hr for granular cells and about 9.2 hr for clear cells. Potential population doubling time calculated for various subpopulations yields values between 4 and 50 days. It is concluded that cell loss is high, for granular cells in particular. Besides cell loss, a large nonproliferating compartment contributes to a delay of the tumor volume doubling time. Proliferative heterogeneity of advanced human tumors, as exemplified by the renal adenocarcinoma, bears important implications for therapy and prognosis.