Leiomyomata are benign, sex steroid–responsive, smooth muscle tumors of the uterus originating as clonal expansions of individual myometrial cells. The histology is virtually indistinguishable from normal myometrium except for a discrete circular whorling pattern with the cellularity and mitotic activity being highly variable. The number of mitoses per high powered field is usually low (<5 to 8 per high-power field), with mitotic activity utilized to predict the risk of malignancy. Leiomyosarcomas do not arise from preexisting leiomyomata and present much later in life, well after menopause. There are often areas of fibrosis interspersed with the smooth muscle and occasional calcification,
especially after pregnancy-induced degeneration and in postmenopausal women. Leiomyomata typically grow in a spherical or nodular fashion with a relatively distinct demarcation from the surrounding normal myometrium, reflecting their clonal origin.

Leiomyomata can arise from cells located anywhere in the myometrium (Fig. 55.1), with women often having very large numbers of fibroids. When the cell of origin is near the serosal surface, the path of least resistance to expansion is to grow outward into the peritoneal cavity, termed a serosal or subserosal fibroid. Serosal tumors can grow very large with few or minimal symptoms, as they do not cause bleeding. Occasionally, a pedunculated fibroid will result with a pedicle narrower than the tumor diameter that contains the vascular supply. These may become detached from the uterus completely and reestablish blood supply from an adjacent organ. This is likely the result of pressure necrosis of the interface between the tumor and the adjacent viscera or torsion of the pedicle and attachment at the new site during healing. When the myometrial cell of origin is within the myometrium, this forms an intramural fibroid. These are associated with menorrhagia and dysmenorrhea, with failure to constrict the vessels supplying the endometrium during menses. If the myometrial cell of origin is near the endometrium, the tumor will find the path of least resistance to growth toward the endometrium, and a submucosal fibroid will result. These are most frequently associated with menorrhagia and dysmenorrhea, even when of relatively small size. If the fibroid originates from a cell immediately adjacent to the endometrial layer, the tumor may completely protrude into the endometrial cavity, and an intracavitary fibroid on a pedicle may develop. These intracavitary tumors can cause the most severe symptoms despite their small size. With uterine contractions increasing the intracavitary pressure, the stalk may elongate, extruding the fibroid through the cervix, typically associated with a sanguineous vaginal discharge and erosion of the surface of the fibroid. Aseptic necrosis may be present, and the degenerating tumor becomes secondarily infected, often making it difficult to distinguish from a necrotic cervical cancer. While cervical fibroids can occur, they are very infrequent, paralleling the small number of myometrial cells within the cervix. There is virtually no neovascularity within fibroids, and they derive their vascular supply from the vessels on the periphery of the tumor at the interface with the normally vascularized myometrium. While fibroids are stimulated to grow by sex steroids but the vascular supply is not, this is the limiting factor for the growth of individual tumors. Once the uterine vasculature
is maximally enlarged, the fibroids will cease growing and the center may even undergo necrosis, limiting their ultimate size. This is initially described as “red degeneration” and later, as the devitalized central tissue is replaced by fibrosis, described as “hyalinized degeneration” and may ultimately become calcified. It is not unusual to find marked calcium deposits in leiomyomata that have long ago undergone degeneration and were never symptomatic. Collateral vascular channels are comparably maximally engorged and may represent a surgical challenge. Not surprisingly, the blood loss with any extirpative surgery may be large, even if performed by experienced surgeons.

There is little doubt that the growth of leiomyomata is dependent on sex steroids as they: (a) are not noted prior to puberty, (b) typically regress after menopause, (c) possess sex steroid receptors (estrogen and progesterone), (d) often dramatically enlarge during pregnancy when estrogen and progesterone levels are very high, and (e) can be made to shrink with medically induced hypogonadism. Clearly, the uterus, like other secondary sex organs, initially develops to its adult size with exposure to the levels of ovarian steroids produced at puberty. However, this growth is programmed and should cease once reaching the appropriate development, despite continued exposure to sex steroids throughout the reproductive life span.

There is no evidence that higher or aberrant patterns of ovarian steroid secretion of estrogens, progestins, or androgens contribute to the development of leiomyomata. However, myomatous tissue has the same number of estrogen receptors but a higher number of progesterone receptors than the adjacent normal myometrium. This coupled with the observations that mitoses within myomas are more frequent in the luteal phase of the cycle and that progesterone up-regulates several growth factors suggests that progesterone is somehow causally involved in either myomatous development or continued growth. Since estrogen stimulates the synthesis of progesterone receptors in other reproductive tissues, a more complex relationship between the two dominant female sex steroids and leiomyomata is likely. Despite these observations, there is no consensus as to the specific roles of the various sex steroids aside from being necessary but not sufficient to develop leiomyomata. Situations that increase lifetime exposure to estrogen such as obesity and early menarche are associated with increased risk with the interval from the last delivery inversely related to risk.

The use of oral contraceptives has not been demonstrated to impact the likelihood of developing or enhancing the growth of fibroids. Treatment of postmenopausal women with hormonal replacement therapy may allow continued growth of previously existent but quiescent leiomyomata. There is no evidence to suggest that if leiomyomata are not present they will develop in response to hormone replacement therapy after menopause. In clinical decision making, there is no rationale for withholding hormone replacement therapy for fear of stimulating leiomyomata in otherwise appropriate candidates for postmenopausal hormonal replacement. Special note should be made of postmenopausal women with breast cancer treated with tamoxifen, as this compound has mixed estrogen agonist and antagonist properties and has the potential to influence the pattern of fibroid growth. Undoubtedly, gonadal steroids are important in the growth of leiomyomata.

Leiomyomas represent monoclonal neoplasms, a situation in which etiologic genetic mutations in individual tumors are likely. Cytogenetic studies of individual leiomyomas reveal that approximately one third have some type of chromosomal aberration, but these are not consistent between individual tumors in the same woman, further supporting their clonal nature. The most common aberrant patterns are translocations between chromosomes 12 and 14, deletions of the short arm of chromosome 7, and rearrangements of the long arm of chromosome 6. It is not clear whether there is clinical relevance to these differences in terms of the rate of tumor growth, recurrence rates, and responses to the various therapies. Interestingly, when tumors have translocations between chromosomes 12 and 14, they are more likely to be larger myomas, whereas deletions of the long arm of chromosome 7 are found more often in smaller tumors. While there are no consistent alterations in gene expression noted in leiomyomata, the transcription factor high-motility group A2 is up-regulated
in leiomyomata with expressing the 12;14 chromosome translocation. These observations imply that despite similar histologic appearance and benign growth characteristics, there may be several molecular mechanisms by which these tumors develop.

Undoubtedly, individual myometrial cells become neoplastic as a result of a complex interaction between ethnicity, genetic mutations, endogenous sex steroids, and reproductive patterns. Molecular geneticists have noted abnormal expression of a variety of genes leading to altered growth factors and steroid receptors in individual leiomyomata, but there remains no single predominant molecular mechanism or group of mechanisms underlying their development and growth. In the coming years, this molecular puzzle will undoubtedly be better understood but will just as likely prove to be very complex without a single abnormality identified.

The impact of leiomyomata on pregnancy remains difficult to define for individual patients (Table 55.2). Clearly, the most logical approach to achieving pregnancy is for a woman with leiomyomata to attempt to conceive and elect treatment only if difficulty is encountered. There is general agreement that intracavitary and submucosal leiomyomata can be causally related to infertility on the basis of implantation failure. The presence of fibroids within the endometrial cavity or impinging on the cavity contour can be detected by a hysterosalpingogram, sonohysterography, or hysteroscopy, and their removal should improve fertility. With intramural leiomyomata, a relationship to infertility is less certain, and all other potential etiologies should be considered before considering leiomyomata etiology. Intramural leiomyomata have been associated with a reduced pregnancy rate following assisted reproductive technology (ART), suggesting that they may have an impact on implantation. Given the time and expense of ART, it is prudent to remove intramural fibroids in selected infertile women prior to undergoing ART. Postoperative adhesions that may form after myomectomy are of lesser importance when undergoing ART, as they will not affect oocyte retrieval. While fibroids can be found anywhere in the myometrium, when they arise adjacent to the tubal ostia, they may occlude a tube or impede its function. For this to be seriously considered a problem related to infertility, however, both fallopian tubes would need to be affected, which is an infrequent circumstance.

Whether leiomyomata are associated with a higher risk of first-trimester pregnancy loss, preterm labor, or intrauterine growth restriction is much more controversial. The impact of fibroids in individual patients is critically dependent on location, not simply size or number. Clearly, many women with large myomatous uteri deliver infants without difficulty, whereas in others, fibroids may compromise the ability of the endometrial cavity to accommodate a growing fetus or the maternal vascular adaptation necessary for normal placental function. Complicating this picture is our inability to predict which women with leiomyomata will experience rapid enlargement of their fibroids during pregnancy. An abruption can occasionally occur when the placental bed overlies an enlarging fibroid. Lower-segment fibroids have the potential to obstruct labor, and a classic cesarean delivery is occasionally required when the presenting part is unable to be directly applied to the cervix. If the leiomyomata are extremely large and intramural in location, preconception removal may be considered, but the potential benefit must be carefully weighed against the complications of the procedure. Clinical judgment will be sorely taxed to make correct decisions in the absence of a previous adverse clinical outcome. Overall, term delivery rates following myomectomy for symptomatic leiomyomata in an unselected patient population vary from 40% to 50%. The need to also perform a cesarean following myomectomy needs to be considered in any risk–benefit analysis.