37 Uterine Leiomyomas

Cindy M. P. Duke

Diana Cholakian

Stacey A. Scheib

Uterine leiomyomas, also known as myomas or fibroids, represent the most common pelvic tumors in women. As benign smooth muscle neoplasms, leiomyomas only rarely undergo malignant transformation (80% in blacks.

• The majority of patients with fibroids are asymptomatic, only about 25% of reproductive age women have symptoms. Symptoms may include pelvic pressure, urinary or fecal complaints, reproductive dysfunction, and prolonged or heavy menstruation.

• Leiomyomas represent the single most common indication for hysterectomy and currently, there are several medical and surgical treatment options, including minimally invasive options.

ETIOLOGY AND PATHOPHYSIOLOGY

• Leiomyomas result from monoclonal proliferation of uterine smooth muscle cells or less commonly from smooth muscle cells of uterine blood vessels. They can range in size from millimeters to large tumors reaching the costal margin. These tumors may be solitary or multiple and are classified by location within the uterus. These cells express estrogen synthetase and aromatase and are capable of converting androgens into estrogen.

• Submucosal fibroids develop from myometrium just deep to the endometrial lining. These can often protrude into the endometrial cavity or, if pedunculated, can even grow past the internal cervical os. The main symptoms of this subgroup of fibroids include heavy or abnormal bleeding, reduced fertility, miscarriages, and preterm labor.

• Intramural fibroids, located within the uterine corpus wall, may distort the uterine cavity. Cervical fibroids are intramural but found in the uterine cervix.

• Subserosal fibroids develop below the serosal layer, are often pedunculated, and occasionally extend between folds of the broad ligament. They do not cause abnormal uterine bleeding but more likely contribute to bulk symptoms.

• Extrauterine fibroids are leiomyomas that are found outside of the uterus. They are usually the result of hematogenous spread of neoplastic smooth muscle cells from the uterus. Extrauterine fibroids are histologically and clinically identical to the intrauterine fibroids described earlier. Extrauterine locations most commonly include the genitourinary tract, the gut mesentery, and the cardiopulmonary system. Other rarer locations include the spinal cord and blood vessels.

• A genetic basis for the presence and growth of uterine leiomyomas appears likely. Family history of leiomyomas increases an individual's risk 1.5- to 3.5-fold. It has been suggested that up to 40% of leiomyomas have associated chromosome abnormalities, including deletion of portions of 7q, trisomy 12, or rearrangements

(translocations) of chromosomes 6, 10, and 12. The Val158Met polymorphism on the catechol-O- methyltransferase (COMT) gene has been found to be a protective factor against uterine leiomyoma. The incidence of leiomyomas is estimated to be threefold greater among African American women and often occur at a younger age in this population. In addition, fibroids in African American women respond differently than those in white women. Decreased vitamin D levels may be an etiology for this increased incidence, as darker skin inhibits autologous vitamin D production.

• The growth of uterine leiomyomas is related to circulating estrogen exposure. Progesterone may exert an antiestrogen effect on the growth of leiomyomas. Fibroids are most prominent and demonstrate maximal growth during the reproductive years and tend to regress after menopause. Whenever leiomyomas grow after menopause, malignancy (e.g., leiomyosarcoma) must be considered in the differential diagnosis. Leiomyomas commonly grow during pregnancy, most likely due to the enhanced uterine blood supply that accompanies pregnancy and edematous changes in these tumors.

• As leiomyomas grow, they risk diminution of blood supply, which leads to a continuum of degenerative changes, including calcium deposition.

• Although malignant degeneration of leiomyomas is possible, most leiomyosarcomas are thought to arise de novo. Leiomyosarcomas are diagnosed on the basis of counts of 10 or more mitotic figures per 10 high-power fields (HPFs). Those tumors with 5 to 10 mitotic figures per 10 HPFs are referred to as smooth muscle tumors of uncertain malignant potential. T umors with indirect costs (costs of lost work time because of absenteeism and short-term disability).

• A review of national health care databases in the United States estimated that the total direct annual cost for treatment (surgery and medications) of fibroids range between 4.1 and 9.4 billion dollars.

• A number of investigators have also looked more specifically at direct and indirect costs for treatment of symptomatic fibroids in individual patients using retrospective reviews of national health care databases and health maintenance organization reimbursement records. Costs can range anywhere from $5,900 to $20,000 per patient annually, when compared to matched controls without fibroids. A review of annual costs associated with the diagnosis of leiomyomas in women with imagingconfirmed fibroids showed a 3.1-fold increase in cost for diagnostic procedures; 10-fold increase in ultrasonic, hysteroscopic, and laparoscopic procedures; and a 35-fold greater rate of surgical procedures. Additionally, it showed that women with fibroids were 50 times more likely to get a hysterectomy than women without fibroids and were 3.1 times more likely to file disability claims.

P.498

• Symptomatic fibroids also lead to significant burden to employers, especially in the time following surgical procedures. The estimated overall lost work hour costs range from $1.55 to $17.2 billion annually.

• Overall, it is estimated that uterine fibroids cost the United States between $5.9 and $34.4 billion annually.

Additionally, the annual cost of obstetric outcomes in the United States attributable to fibroid tumors is estimated at $238 million to $7.76 billion.

CLINICAL MANIFESTATIONS AND DIAGNOSIS

Signs and Symptoms

• Most patients with leiomyomas are asymptomatic. The most commonly experienced symptoms (pain, pressure, fertility dysfunction, and menorrhagia) are related to the size and location of the fibroids or to compromise of blood supply with degeneration.

• Uterine fibroids may be found on routine pelvic exam when an enlarged or irregularly shaped uterus is palpated.

• Various radiologic modalities may be useful for the diagnosis and/or characterization of uterine fibroids (Table 37-1).

TABLE 37-1 Diagnostic Imaging for Uterine Leiomyomas

P.499

• Excessive or prolonged menstrual bleeding is the most frequently encountered symptom and may be due to vascular alterations in the endometrium.

uterine cavity also gives rise to the increased volume of menstrual flow.

• Patients may also present with pressure to adjacent organs and increased abdominal girth. Pressure on the bladder customarily provokes urinary frequency. When the leiomyoma is adjacent to the bladder neck and urethra, incontinence or acute urinary retention with overflow incontinence may occur. Ureteral obstruction is a rare complication of larger leiomyomas extending to the pelvic sidewall causing hydronephrosis. Posteriorly located fibroids may produce constipation, rectal pressure, or tenesmus. With especially enlarged uteri, patients can also present with back pain, lower extremity swelling, or radiating pain down one or both legs.

• Chronic pain symptoms may include dysmenorrhea, dyspareunia, and noncyclic pelvic pain. Acute pain may be a consequence of torsion of the stalk of a pedunculated leiomyoma, cervical dilation by a submucosal leiomyoma protruding through the lower uterine segment, or degeneration of a leiomyoma.

• Submucosal and intramural fibroids are associated with a higher rate of spontaneous miscarriage and infertility/subfertility due to impaired implantation, tubal function, or sperm transport. Although it has been shown that removal of submucosal fibroids significantly improves fertility outcomes, there is conflicting evidence regarding the effect of intramural myomectomy on future fertility. Subserosal fibroids are not associated with subfertility.

• Obstetric complications that are associated with a fibroid uterus include miscarriage, preterm labor and delivery, malpresentation, cesarean delivery, postpartum hemorrhage, and peripartum hysterectomy.

TREATMENT FOR LEIOMYOMAS

Observation

• No standard size of an asymptomatic myomatous uterus has been determined as an absolute indication for treatment. In a patient with a large asymptomatic myomatous uterus in whom dimensions have not increased and malignancy is unlikely, the patient's age, fertility status, and desire to retain the uterus or avoid surgery must be factored into the treatment plan. Physical and radiologic imaging examinations should be performed initially and may be repeated in 6 months to document the size and growth pattern of the fibroids. If growth is stable, the patient may be followed clinically with annual pelvic examination and imaging as indicated.

• Rapidly growing fibroids can raise concern for malignancy, especially in the menopausal patient. The definition of rapid growth, however, is highly variable. One commonly accepted definition is an increase of 6 weeks size over 1 year. Postmenopausal uterine growth or bleeding increases the suspicion for malignancy; however, premenopausal women with rapid growth do not necessarily require surgical excision.

P.500

Medical Therapy

• Nonhormonal medical therapy is aimed at controlling the symptoms of leiomyomas, specifically excessive menstrual flow or pain. Such therapies include tranexamic acid and nonsteroidal anti-inflammatory drugs.

• Hormonal therapy for fibroids includes contraceptive steroids, progestins, and gonadotropin-releasing agonists or antagonists. Investigations are underway regarding treatments such as aromatase inhibitors, selective estrogen receptor modulators (SERMs), gonadotropin-releasing hormone antagonists, and selective progesterone receptor modulators. A recent study showed a reduction in the size of fibroids after treatment

with SERMs.

• Similar to the nonhormonal medical options, combinations of estrogen and progesterone may control bleeding symptoms while preventing leiomyoma growth. There is conflicting evidence regarding the effect of progestational therapy on changes in fibroid or uterine volume, with some small studies showing a decrease in leiomyoma size during treatment. Conversely, use of mifepristone, an antiprogestin, has been associated with decrease in the size of leiomyomas with slow rate of regrowth following treatment cessation.

• The levonorgestrel-releasing intrauterine system (LNG-IUS), or Mirena, slowly delivers progesterone directly to the uterus and significantly reduces menstrual bleeding. The effect of the LNG-IUS on myoma- mediated menorrhagia depends on the size of uterine cavity and patient characteristics of blood loss. A review of various studies has shown that when compared to combined oral contraceptives, the LNG-IUS significantly decreases fibroid-related menstrual bleeding. No significant decrease of fibroid or uterine volume has been demonstrated.

• Gonadotropin-releasing hormone analogs (GnRHa) have been used successfully to achieve hypoestrogenism in various estrogen-dependent conditions. Maximal reduction in tumor volume of approximately 50% has been observed with the use of GnRHa over a 3-month course of treatment. The effects of hormonal treatment are transient, and within 6 months after withdrawal of hormonal therapy, leiomyomas return to their pretreatment state.

ξ These agents are useful as a conservative therapy in perimenopausal women or as an adjunct to surgical treatment. Longer than 6 months of GnRHa therapy in young patients is neither practical nor desirable because of the possibility of bone loss. Common side effects of GnRHa include hot flashes, nausea, vomiting, diarrhea, constipation, rash, dizziness, acne, breast tenderness, and headaches.

ξ Concomitant treatment with a low dose of steroid hormone, referred to as addback therapy, can be used to minimize the adverse affects of GnRHa in patients who benefit from continued therapy after the initial 3-month course.

ξ Adjunctive presurgical therapy with a 3- to 6-month course of GnRHa can reduce tumor size. Thus, use prior to scheduled hysterectomy may increase the likelihood of success of a minimally invasive approach. Additionally, by inducing amenorrhea, GnRHa therapy enables a patient to preoperatively restore her own hemoglobin levels from baseline menorrhagia-related iron deficiency anemia. There is no decrease in estimated blood loss. However, its preoperative use is associated with obscuring of surgical planes between fibroids and normal myometrium, which may make myomectomy more difficult.

• Aromatase inhibitors have been shown to reduce the volume of fibroids without leading to the side effects caused by systemic hormonal therapy.

P.501

Surgical Therapy

Myomectomy

• Myomectomy, or surgical excision of the fibroid tissue, is the only surgical option that is available when future childbearing is desired. The location and size of the myoma(s), along with surgical expertise of the operator, dictate the approach to myomectomy. Subserosal or intramural fibroids may be resected abdominally, laparoscopically, or with robotic assistance. Submucosal myomectomy should be performed hysteroscopically (preferred) or vaginally.

• Complications following myomectomy include substantial blood loss, paralytic ileus, and pain. The risk of

postoperative adhesive disease following abdominal myomectomy is about 25% but may be as high as 90%. A laparoscopic approach with the use of an adhesion barrier at the time of surgery may reduce this risk by half. The recurrence risk of leiomyomas is roughly 30% following myomectomy.

• For patients who wish to conceive, a delay of 4 to 6 months after surgery before attempting pregnancy is advisable, especially if there was significant myometrial disturbance. The most common obstetric complications following myomectomy include uterine rupture, abnormal placentation, and preterm delivery. The preferred delivery method after myomectomy with extensive uterine reconstruction is cesarean section due to an increased risk of uterine rupture with labor.

Hysterectomy

• Removal of the uterus is the definitive procedure for treatment of symptomatic leiomyomas. Hysterectomy should also be considered in the event of a rapidly enlarging tumor or postmenopausal patients, in which a reasonable likelihood of malignancy exists. If malignancy is suspected, referral to a gynecologic oncologist preoperatively or at the time of surgery is advised.

• Surgical approaches to hysterectomy include abdominal, vaginal, laparoscopic, and robotic-assisted. The option of single-incision surgery may be available with laparoscopic and robotic-assisted modalities. Similar to myomectomy, the method of approach is dictated by size, location, number, patient comorbidities, and surgical expertise.

• Patient satisfaction with symptom relief from hysterectomy is very high but accompanied by the surgical morbidity of a major operation. Additionally, some patients have expressed posthysterectomy regret regarding loss of fertility; therefore, adequate preoperative counseling including discussion of desire for, timing of, and planning for future childbearing is essential.

Uterine Artery Embolization

• Uterine artery embolization (UAE) decreases the blood supply to the uterus and ultimately causes ischemic necrosis of leiomyomas. The procedure is performed by interventional radiologists and usually involves catheterization of the femoral artery to gain access to the hypogastric arteries. Under fluoroscopic guidance, the uterine arteries are occluded with substances such as Gelfoam, absolute alcohol, Ivalon particles (polyvinyl alcohol), or metal coils. This procedure is generally reserved for intramural myomas.

• The benefits of UAE include short operating and recovery time, use of local anesthesia, and minimal blood loss. Risks of the procedure include infection (4%), complications of angiography (3%), and uterine ischemia or nontarget embolization. Premature ovarian failure secondary to compromise of the ovarian circulation has

P.502 been reported. Patients typically experience cramping for the first 12 to 18 hours after the procedure. Postembolization syndrome (fever, nausea, vomiting, and severe abdominal pain) has been observed in approximately 30% of patients.

• Outcomes of UAE include a 40% to 60% reduction in uterine size and decreased menstrual bleeding with high rates of patient satisfaction. Patients have significantly less postoperative pain and return to work sooner compared to those undergoing hysterectomy but have increased rates of minor complications. Longterm outcomes may be inferior to myomectomy and hysterectomy, with the rate of reoperation in patients undergoing UAE as high as 30%. The reoperation rate is age dependent, with higher likelihood of success in women older than age 40 years.

• The impact on postprocedure fertility has not been well-studied. However, UAE is not generally recommended in patients who desire future fertility. Initial case reports and case series of pregnancy after UAE indicate an increased risk of obstetric complications such as preterm labor, miscarriage, malpresentation, and abnormal placentation (e.g., placenta accreta). Myomectomy is still the procedure of choice in patients with symptomatic fibroids who desire future fertility.

Magnetic Resonance Imaging-Guided Focused Ultrasound Surgery

• With magnetic resonance imaging-guided focused ultrasound surgery (MRgFUS), fibroid tissue is heated and destroyed using targeted ultrasonic energy passing through the anterior abdominal wall. This procedure is performed with magnetic resonance imaging (MRI) thermal mapping and conducted over several outpatient visits. MRgFUS is not appropriate for pedunculated myomas or those adjacent to bowel or bladder. Although the procedure is currently U.S. Food and Drug Administration approved for premenopausal women who do not desire future fertility, outcome data beyond 24 months is lacking. Potential side effects include skin or nerve burns.

• Studies are being performed to investigate similar MRI-guided radiofrequency ablation or laser photocoagulation techniques.

Myolysis/Cryomyolysis

• Laparoscopic coagulation of a leiomyoma, or myolysis, is performed with a neodymium: yttrium-aluminum- garnet (YAG) laser by causing degeneration of protein and destruction of vascularity. Dense pelvic adhesions have been found on follow-up. Bipolar coagulation and cryomyolysis affect similar results using radiofrequency energy or supercooling, respectively. There is limited long-term efficacy or safety data for these methods, and they are not recommended for women desiring future fertility.

Laparoscopic Uterine Artery Occlusion

• Laparoscopic uterine artery occlusion accesses the uterine arteries retroperitoneally and surgically occluded. Similar short-term outcomes to UAE have been shown; however, there is limited longitudinal data.

Doppler-Guided Uterine Artery Occlusion

• Doppler-guided uterine artery occlusion, currently in development, uses a transvaginal vascular clamp with Doppler guidance to occlude the uterine arteries for 6 hours after which time the clamp is removed at the bedside. This may be a future alternative to UAE.

P.503

SUGGESTED READINGS

American College of Obstetricians and Gynecologists. ACOG practice bulletin no. 96: alternatives to hysterectomy in the management of leiomyomas. Obstet Gynecol 2008;112:387-400.

Breech LL, Rock JA. Leiomyomata uteri and myomectomy. In Rock JA, Jones HW, eds. Telinde's Operative Gynecology, 10th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2008:687-727.

Cardozo ER, Clark AD, Banks NK, et al. The estimated annual cost of uterine leiomyomata in the United States. Am J Obstet Gynecol 2012;206(3):211.e1-211.e9.

Carls GS, Lee DW, Ozminkowski RJ, et al. What are the total costs of surgical treatment for uterine fibroids? J Wom Health 2008; 17(7): 1119-1132.

Eltoukhi HM, Modi MN, Weston M, et al. The health disparities of uterine fibroid tumors for African American women: a public health issue. Am J Obstet Gynecol 2014;210(3): 194-199.

Gupta JK, Sinha A, Lumsden M, et al. Uterine artery embolization for symptomatic uterine fibroids (review). Cochrane Database Syst Rev2012;(5):CD005073.

Lee DW, Ozminkowski RJ, Carls GS, et al. The direct and indirect cost of burden of clinically significant and symptomatic uterine fibroids. J Occup Environ Med 2007;49:493-506.

Levy G, Hill MJ, Beall S, et al. Leiomyoma: genetics, assisted reproduction, pregnancy and therapeutic advances. J Assist Reprod Genet 2012;(29):703-712.

Pritts EA, Parker WH, Olive DL. Fibroids and infertility: an updated systematic review of the evidence. Fertil Steril 2009;91 (4): 1215-1223.

Sangkomkamhang US, Lumbiganon P, Laopaiboon M, et al. Progestogens or progrestogen-releasing intrauterine systems for uterine fibroids. Cochrane Database Syst Rev2013;(2):CD008994.

Van der Kooij SM, Ankum WM, Hehenkamp WJ. Review of nonsurgical/minimally invasive treatments for uterine fibroids. Curr Opin Obstet Gynecol 2012;24:368-375.