The pathogenesis of deferred cancer; a study of the after-effects of methylcholanthrene upon rabbit skin.

The ears of young adult rabbits were painted with methylcholanthrene (MC) long enough to call forth a few benign tumors (papillomas, frill horns), and the animals were followed throughout their later lives. Soon after the paintings were stopped the tumors began to dwindle and vanished, yet even while they were disappearing other growths of the same kinds arose, only to vanish later in their turn. For a long while more arose than disappeared, and in consequence the number of tumors increased throughout years. They accumulated at a constant rate despite concurrent changes in the supporting skin, which might have been supposed, on previous experience, to have prevented this from happening. Only in the old age of the animals did the number of tumors eventually fall off, and by this time the skin on which they had arisen, long since normal in the gross to all appearance, had become nearly so microscopically. Even then latent neoplastic potentialities still existed in the cutaneous tissue; where punch holes were healing new tumors arose. A great multitude of hidden neoplastic cells were present in the MCed skin, and from them many of the growths called forth by the stimulus of healing undoubtedly derived. Yet the facts make it difficult to suppose that the long accumulation, at a constant rate, of tumors visible in the gross was due wholly to the proliferation of cells rendered neoplastic during the period of exposure to MC, and lying hidden afterwards for periods determined by their differing, evenly graded capabilities. Nor can the accumulation be attributed to a sustained carcinogenesis resulting from the pathological state of the skin. As a whole the findings indicate that the linear increase in growths was due for the most part to a continual arrival at the neoplastic state and subsequent proliferation of cells, or the descendants of cells, that had been no more than started on the way toward becoming neoplastic by the carcinogen. There is clinical evidence for such a course of events. Now and again a carcinoma arose from the skin previously treated with MC, but they were few in all, as would follow from the presence of local conditions unfavorable to malignant change. Some appeared only after years,-in one instance more than 5 years after. The occurrence of deferred cancer in man can be understood in terms of the findings in rabbits.