Incidence

Uterine leiomyomas are the most common neoplasms of the female pelvis. They occur in ∼20–25% of women of reproductive age, but careful pathologic inspection of the uterus reveals that they are present in more than 80% of women. The neoplasm is more frequently found in the fourth and fifth decades of life and most commonly in patients of African descent. Age-standardized rates by race were 8.9 new cases per 1,000 women per year for Caucasian women and 30.6 new cases per 1,000 women per year for black women. Hispanic and Asian women had rates similar to those seen in Caucasian women: 11.0 and 8.0 new cases per 1,000 women per year, respectively. There is an increased risk of leiomyomas in women with greater  body mass index (BMI), but risk is decreased in women who smoke, who have given birth, or who use oral contraceptive pills. Leiomyomas rarely occur before menarche and typically regress after menopause, indicating  estrogen as a promoter of growth. Rarely, malignant changes may occur, usually in postmenopausal women. The most common warning sign is rapid enlargement of a  fibroid with definitive diagnosis usually made at the time of surgery.

Gross Features

Microscopic Features

Symptoms

It is estimated that only 10–40% of leiomyomas are symptomatic. Patients may complain of a self-detected mass, abnormal uterine bleeding, pelvic pain, or pressure-related symptoms.

Bleeding is the most common presenting symptom in uterine leiomyomas. The most frequent presentation includes the development of progressively heavier menstrual flow that lasts longer than the normal duration (menorrhagia). Although menorrhagia can occur in any women with leiomyomas, women with submucous leiomyomas appear to be particularly prone to this complication. Blood loss from this type of menstrual bleeding may be heavy enough to contribute to iron-deficiency anemia.

Another common presenting symptom is pelvic pressure. This is caused by slowly enlarging leiomyomas, which may attain a massive size. Pressure on the bladder produces urinary frequency, urgency and rarely the inability to void. Constipation may result from pressure on the rectum. Pressure of the uterine leiomyomas on the ureters may cause hydroureter and, on occasion, hydronephrosis.

Acute onset of pain in previously asymptomatic leiomyomas raises the possibility of necrosis, inflammation, or torsion of a pedunculated subserous leiomyoma. Prolapse of submucous leiomyoma may present as intense cramping pain, often accompanied by discharge or bleeding. Pain in the low back or legs may reflect alterations in body posture or pressure on lumbosacral nerve trunks.

Uterine leiomyomas can also be associated with other kinds of reproductive dysfunction, including recurrent miscarriage, infertility, premature labor, fetal malpresentation, and other complications of labor.

Diagnosis

The diagnosis of such tumors is usually made by the pelvic examination. A leiomyoma may be suspected based on a bimanual examination that reveals an enlarged, firm, non-tender, and irregularly shaped uterus. Ultrasonography is the most common method of confirming the diagnosis. A combination of transabdominal and transvaginal ultrasonography should provide information regarding uterine volume, the number of leiomyoma, their location relative to the endometrial stripe, and evaluation of the adnexa. Of other available imaging techniques, magnetic resonance imaging (MRI) may prove to be the most useful but does not improve the findings seen on ultrasonography and is of much higher costs.

Treatment

The majority of patients with uterine leiomyomas do not require treatment. If the tumors are stable and slow growing, an annual follow-up including an optimized symptom control is a viable option. Symptomatic patients should usually be offered a trial of conservative management before considering surgery.

 Gonadotropin-releasing hormone (GnRH) agonists are analogs of gonadotropin-releasing hormone. With continuous administration, they induce a hypoestrogenic pseudomenopausal state. Because uterine leiomyomas are estrogen-dependent benign tumors, this causes shrinkage of these tumors and of the myometrial mass. In addition, treatment with a GnRH agonist induces amenorrhea, allowing women with menorrhagia-induced anemia to increase iron stores and hemoglobin concentrations leading to a technically easier surgery with markedly diminished blood loss. But once the treatment is stopped, the leiomyoma tends to regrow to pretreatment size. The major use of GnRH agonists is as a preoperative treatment to facilitate surgical procedures, either myomectomy or hysterectomy. This class of drug cannot be used long term (>6 months) because of the attendant risks of prolonged hypoestrogenism, such as osteoporosis and cardiovascular disease. Combinations of GnRH agonists and low doses of estrogen and progesterone (that is, “add-back” regimens) can minimize the adverse hypoestrogenic effects caused by GnRH agonist treatment.

Androgenic agents (danazol, gestrinone) and progestins (medroxyprogesterone acetate, depomedroxyprogesterone acetate, norethindrone) have also been used to minimize uterine bleeding in women with uterine leiomyomas. However, these kinds of medication do not consistently decrease uterine or leiomyoma volume, and their mechanism of action is thought to be the induction of endometrial atrophy. If there is significant endometrial cavity distortion by interstitial or submucous leiomyomas, these agents are often not successful in controlling menorrhagia, because the excessive bleeding is usually related to profound anatomic and vascular distortion.

The use of endoscopic resection will be more widely used for the surgical management of uterine leiomyomas. This technique causes less patient discomfort, less bleeding, and has a shorter recovery time. Hysteroscopic resection of submucous leiomyomas can be done using a resectoscope with unipolar cautery loops or with a neodymium:yttrium-aluminum garnet laser (Nd:YAG). The use of the Nd:YAG laser has its problems and the operating surgeon must have expertise not only with the hysteroscope but also with the intrauterine laser. Laparoscopic myomectomy and laparoscopically assisted vaginal  hysterectomy (LAVH) are safe and reliable treatment options, but can be difficult to perform technically and are not available universally.

Uterine artery  embolization is a new, investigational treatment of leiomyomas. The method involves the catheterization of both uterine arteries using a femoral arterial approach. Preliminary studies in women who had large, symptomatic leiomyomas have shown significant improvement in their symptoms. More trials need to be carried out to confirm the efficacy and safety of this surgical treatment.

Cytogenetic Changes

Evidence from glucose-6-phosphate dehydrogenase isoenzyme analysis and from polymorphism analysis in the androgen receptor demonstrates that uterine leiomyomas are monoclonal and that each tumor within the same uterus arises independently. Although the classic paradigm suggests that the sex steroid hormones ( estrogen and  progesterone) are the only important modulators of leiomyoma growth and transformation, it is now clear that chromosomal abnormalities play a role in the pathogenesis of these neoplasms. In uterine leiomyomas, non-random chromosomal changes such as translocations, duplications, and deletions have been identified in ∼50% of tumors studied by cytogenetic analysis. The most frequent abnormalities are translocations between chromosomes 12 and 14, t(12;14)(q14–15;q23–24) and deletions on chromosome 7, del(7)(q22–32). The frequencies of these abnormalities are ∼20% and 15%, respectively.

Recently, the  high-mobility group protein gene HMGIC was identified as the target gene affected by the 12q14–15 aberrations. HMGIC is an architectural transcription factor in the nuclear scaffold, a function critical for the correct assembly of stereo-specific transcriptional complexes. The frequent rearrangement of the HMGIC gene in uterine leiomyomas suggests that this gene is directly involved in the aberrant growth control observed in these tumors. Gene-targeting experiments indicate that HMGIC plays an important role in mammalian growth and development, since inactivation of the murine HMGIC gene results in the pygmy phenotype. In uterine leiomyomas, the mitochondrial aldehyde dehydrogenase (ALDH2) gene in 12q24.1, the recombinational repair gene RAD51B in 14q23–24, and the cytochrome c oxidase subunit VIc (COX6C) gene in 8q22–23 were identified as translocation partners to HMGIC. Deletions of chromosome 7 imply that tumor enlargement in some leiomyomas is probably due to loss of tumor suppressor genes.