Clinicians have known for some time that certain neoplasms may remain in the organism for many years without expressing their malignancy to any significant degree (cf. Berg et al., 1971).
An anatomical structure once known as the lateral aberrant thyroid has, in retrospect, been shown in many cases to be a very slowly growing metastatic carcinoma of the thyroid (Black,1948). These tumors may remain in the host for decades, exhibiting little if any of their lethal potential (Seigal and Modan, 1981). Similar latent lesions of mammary glands may occur in association with carcinoma of the breast (Jensen et al., 1976). Such latent neoplastic cells are not to be confused with the recently termed “minimal residual disease,” which occurs in both leuke- mias (Coustan-Smith et al., 1998) and carcinomas (Lindemann et al., 1992). Newer methods of molecular biology have allowed the detection of minimal residual disease at the cellular level by a variety of techniques involving the detection of specific nucleic acids and proteins (Hirsch- Ginsberg, 1998).
Fisher and Fisher (1959) demonstrated dormancy in tumor cells in an experiment in which more than 100 rats were inoculated with 50 cells of a highly malignant neoplasm. When the animals were left alone for 20 weeks, they did not show any clinical signs of the presence of malignant cells. However, when a surgical laparotomy was performed, this procedure alone was sufficient to stimulate malignant growth, with subsequent lethal consequences in all the operated animals, even when the inoculated cells had remained dormant in the animal for 3 months. The mechanism(s) for such an effect is still not clear, but recently Holmgren and associates (1995) demonstrated that when angiogenesis is inhibited (Chapter 18), lung micrometastases will re- main dormant in mice until relief of the angiogenesis inhibition. In this case, neoplastic cells of the dormant micrometastases exhibited a greater than threefold higher incidence of apoptosis than those in metastases growing in animals not subjected to angiogenesis suppression. Another potential mechanism for this effect was suggested by Kodama and associates (1992), who found that experimental pulmonary metastases were facilitated in mice by hydrocortisone pretreat- ment, which they suggested as a substitute for the surgical stress that occurred in the Fisher and Fisher experiment. In any event, this experiment clearly demonstrates that neoplastic cells in the stage of progression, having already metastasized, may remain dormant in the host until some alteration within the internal environment of the host occurs, allowing such cells to continue their natural development in the stage of progression and leading ultimately to the destruction of the host. This critical interaction between the host and the neoplasm is discussed further in Chapters 17, 18, and 19.