The Natural History of Uterine Leiomyomas: Morphometric Concordance with Concepts of Interstitial Ischemia and Inanosis

Based upon our morphologic observations, we hypothesize and also provide morphometric evidence for the occurrence of progressive developmental changes in many uterine fibroids, which can be arbitrarily divided into 4 phases. These developmental phases are related to the ongoing production of extracellular collagenous matrix, which eventually exceeds the degree of angiogenesis, resulting in the progressive separation of myocytes from their blood supply and a condition of interstitial ischemia. The consequence of this process of slow ischemia with nutritional and oxygen deprivation is a progressive myocyte atrophy (or inanition), culminating in cell death, a process that we refer to as inanosis. The studies presented here provide quantitative and semiquantitative evidence to support the concept of the declining proliferative activity as the collagenous matrix increases and the microvascular density decreases. 1. Introduction We hypothesize that many uterine leiomyomas (fibroids) undergo progressive obsolescence and eventual involution, largely as a result of the excessive elaboration of collagen into the interstitial matrix, thereby increasing the distance between tumor myocytes and their blood supply. Since the smooth muscle cells of fibroid blood vessels mirror the phenotypic transformational changes of the tumor myocytes, the blood vessels of fibroids also become progressively more fibrotic and hyalinized. Thus, tumor myocytes are subjected to a reduced supply of essential nutrients and oxygen as a consequence of both vascular and interstitial ischemia. If the growth of fibroid tumors was solely dictated by those genetic and epigenetic changes that promote an increased proliferative rate, then the tumor myocytes should continue to proliferate and the tumor would continue to grow. On the other hand, if vascular and interstitial ischemia do develop within these tumors as the deposition of collagen continues, the proliferative capacity of myocytes would probably be diminished as the diffusion of nutrients and oxygen is impeded in both the fibrotic, thickened vessels and the fibrotic interstitium. In addition, if the rate of angiogenesis is not equivalent to or greater than the rate of fibrogenesis, the tumor myocytes would be subjected to the additional stress of an increased distance between myocytes and capillaries (reduced microvascular density). With these concepts of excessive production and accumulation of collagen, reduced microvascular density, and combined vascular and interstitial ischemia in mind, we hypothesized that, in general, tumors