The pathophysiology of fibroids remains poorly understood. Clonality studies using the homozygosity of glucose-6-phosphate dehydrogenase forms show that multiple tumors in the same uterus are derived from individual myometrial cells rather than occurring through a metastatic process. This, together with their high prevalence,
suggests that initial development arises from a frequently occurring event, the nature of which is currently unknown. Growth of fibroids is partly dependent on the ovarian steroids that act through receptors present on both fibroid and myometrial cells. It is likely that the control of growth is due, in part, to alterations in apoptosis. Bcl-2, an inhibitor of apoptosis, is significantly increased in cultured leiomyoma cells. It is also influenced by the steroid hormone milieu.
Cytogenetic abnormalities occur in 40% of uterine fibroids. Most commonly, these involve translocation within or deletion of chromosome 7, translocations of chromosome 12 and 14, and occasionally structural aberrations of chromosome 6 15. These cytogenetic abnormalities are not observed in normal myometrial tissue and may not be present in all the fibroids in a single uterus 16. In addition, mutations in the gene encoding fumarate hydratase (an enzyme of the tricarboxylic acid cycle) were shown to predispose women to hereditary syndromes involving the presence of multiple uterine fibroids in association with cutaneous leiomyomata and renal cell carcinoma 17. This is an interesting example of a mutation in a gene with a general function causing disease in a highly restricted range of tissue. However, the incidence of this mutation does not appear to be increased in uterine fibroids.
Malignancy in uterine fibroids is extremely uncommon. Leiomyosarcoma is a disease largely occurring in the seventh decade of life whereas fibroids tend to occur
in women 20 to 30 years younger. The cytogenetic profile is completely different between benign and malignant disease and there is the possibility that their origins are separate. Nonetheless, gynecologists with an interest in this area will all have anecdotal examples of malignancy occurring in younger women; thus, the possibility of a sarcoma must be considered in women with fibroids who differ from the norm in clinical presentation or response to treatment.
Myometrium and fibroids consist of spindled cells arranged in fascicles with abundant eosinophilic cytoplasm and uniform nuclei. In contrast, a malignant leiomyosarcoma is hyper cellular and consists of atypical smooth muscle cells with hyperchromatic, enlarged nuclei. Increased mitotic figures and necrosis also commonly occur. However, benign fibroids may also have one or more of these characteristics, making
prediction of malignant potential sometimes extremely difficult 17.
Abnormalities in uterine blood vessels and angiogenic growth factors are also involved in the pathophysiology of uterine fibroids. The myomatous uterus has increased numbers of arterioles and venules and is also associated with venule ectasia or dilatation. It was thought that the latter was due to pressure from these large tumors, but it may also simply be due to the presence of increased numbers of vessels. It has been noted that there are no mature vessels running through uterine fibroids despite the fact that they have a well-developed blood supply. This feature might be useful in trying to distinguish clinically between benign and malignant lesions. Typically, a sarcoma may have large vessels running through it, which could be identified using color Doppler ultrasound.