Uterine leiomyoma

Uterine leiomyomas (also known as fibroids) are benign, hormone-sensitive uterine neoplasms. They are classified as either submucosal (beneath the endometrium), intramural (within the muscular uterine wall of the uterus), or subserosal (beneath the peritoneum) and can occur within the uterine corpus or the cervix. Symptoms depend on the location, size, and number of leiomyomas, and include menstrual abnormalities (e.g., menorrhagia), mass effect (e.g., back, abdominal, and/or pelvic pain; bladder and/or bowel dysfunction), and infertility. Ultrasound is typically used to establish the diagnosis. Treatment is selected using shared decision-making, taking into consideration the patient's desire for fertility and/or uterine preservation, menopausal status, and symptom severity. Asymptomatic patients can often be managed expectantly. Treatment for symptomatic patients may include surgery (myomectomy or hysterectomy), nonsurgical interventional treatments (e.g., uterine artery embolization), and/or pharmacotherapy, including gonadotropin-releasing hormone (GnRH) agonists, GnRH antagonists, intrauterine devices (IUDs), and/or oral contraceptives.

• A benign, hormone-sensitive smooth muscle tumor of the uterus
• Can be submucosal, intramural, or subserosal
• Arises from a single myometrial cell (monoclonal growth) and causes:
  • Upregulation of hormone receptors, particularly estrogen and progesterone
  • Excessive production of extracellular matrix (hence "fibroids")
• Results in an overgrowth of smooth muscle cells and connective tissue (often multiple tumors)
• The myometrium also develops vascular changes (e.g., increased arterioles and venules, dilated veins).
• The most common tumor of the female genital tract.

Predisposing factors ^[1][2]

• Nulliparity
• Early menarche (< 10 years of age)
• Age: 25–45 years
  • Fibroids are largely found in women of reproductive age.
  • Influenced by hormones (i.e., estrogen, growth hormone, and progesterone)
  • During menopause, hormone levels begin to decrease and leiomyomas begin to shrink.
• Increased incidence in African American individuals
• Obesity
• Family history

Leiomyomas are classified according to their location. ^[3]

• Subserosal leiomyoma: located in the outer uterine wall beneath the peritoneal surface
• Intramural leiomyoma (most common): growing from within the myometrium wall
• Submucosal leiomyoma: located directly below the endometrial layer (uterine mucosa)
• Cervical leiomyoma: located in the cervix
• Diffuse uterine leiomyomatosis: The uterus is grossly enlarged due to the presence of numerous fibroids.

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Symptoms depend on the number, size, and location of leiomyomas. Most women have small, asymptomatic fibroids.

• Abnormal menstruation: (possibly associated with anemia): hypermenorrhea, heavy menstrual bleeding; , metrorrhagia, dysmenorrhea
• Features of mass effect
  • Enlarged, firm and irregular uterus during bimanual pelvic examination
  • Back or pelvic pain/discomfort
  • Urinary tract or bowel symptoms (e.g., urinary frequency/retention/incontinence, constipation, features of hydronephrosis)
• Reproductive abnormalities
  • Infertility; (difficulty conceiving and increased risk of pregnancy loss)
  • Dyspareunia

General principles ^[4][5]

• Obtain a detailed history and perform a thorough abdominal and pelvic examination.
• Perform a pelvic ultrasound to confirm the diagnosis.
• Order laboratory studies to screen for complications (e.g., anemia) and rule out other causes of abnormal uterine bleeding.
• Additional studies may be required:
  • To further characterize leiomyomas prior to interventional procedures or surgery
  • If there is diagnostic uncertainty

Uterine leiomyomas are extremely common (affecting 70% of women) and are often found incidentally on ultrasound; do not attribute abnormal uterine bleeding to leiomyomas until other etiologies have been ruled out! ^[4][6]

Imaging ^[5][7]

Ultrasound pelvis (transvaginal, transabdominal)

• Most appropriate initial test for all patients with a suspected uterine leiomyoma ^[7]
• Supportive findings ^[8]
  • Well-circumscribed hypoechoic solid mass
  • Calcifications and/or cystic areas due to degeneration
  • Mass effect (e.g., hydronephrosis) may be seen in patients with large leiomyomas.

Neither plain radiography nor CT is recommended in the workup of leiomyomas because of poor visualization (unless calcified). ^[7][9]

Further imaging ^[7][10]

• Sonohysterography: to further evaluate endometrial abnormalities detected on ultrasound
  • Can distinguish between endometrial polyps and submucosal leiomyomas
  • Used to characterize submucosal leiomyomas (e.g., before interventional procedures or surgery)
• MRI pelvis without and with IV contrast
  • Helps further characterize leiomyomas (e.g., before interventional procedures or surgery)
  • Can rule out comorbid conditions or differential diagnoses of uterine leiomyomas

Although imaging cannot definitively distinguish between a leiomyoma and a leiomyosarcoma, hypervascularity within a solitary heterogeneous uterine mass should raise suspicion for a leiomyosarcoma. ^[8]

Laboratory studies ^[4][5][11]

• Routine initial studies
  • CBC: to assess for anemia
  • BMP: to assess renal function
  • Urine pregnancy test: if patient is of childbearing age
• Studies to evaluate abnormal uterine bleeding ^[11]
  • PT, PTT, fibrinogen
  • Diagnostic studies for von Willebrand disease
  • Consider TSH and liver enzymes if clinically indicated. ^[11]

Advanced studies

Not routinely performed; consider in case of diagnostic uncertainty

• Hysteroscopy: to evaluate endometrial abnormalities ^[4][5]
• Endometrial biopsy: to assess for alternative etiologies of abnormal uterine bleeding (e.g., polyps, hyperplasia, endometrial carcinoma) ^[12]

Consult a gynecologic oncologist early to help guide further diagnostic studies if leiomyosarcoma is suspected (e.g., in patients with continued leiomyoma growth after menopause).

• Macroscopic
  • Grayish-white surface
  • Homogeneous; tissue bundles on cross-section partly in a whorled pattern
  • Some leiomyomas may involve regressive changes: scar formation, calcification, and cysts
• Microscopic: Smooth muscle tissue in a whorled pattern with well-demarcated borders, consisting of monoclonal cells interspersed with connective tissue

References:^[13]

Overview ^[4][14]

Management should be based on shared decision-making and tailored to the patient's symptoms and desire for fertility and/or uterine preservation.

• Asymptomatic or mild symptoms: expectant management
• Symptomatic leiomyoma
  • Fertility desired: pharmacotherapy or myomectomy
  • Fertility not desired
    • Uterine preservation desired: nonsurgical interventional therapy
    • Uterine preservation not desired (definitive treatment): hysterectomy

Leiomyomas tend to regress after menopause; expectant management or pharmacotherapy as a bridge to menopause is recommended for most perimenopausal patients. ^[4]

Racial disparity exists in the treatment of leiomyomas: Typically, Black patients are less likely to be offered nonsurgical or minimally invasive therapies than White patients, even after adjusting for clinical features such as leiomyoma size. ^[4]

Expectant management ^[4]

Indications

• Asymptomatic or minimally symptomatic patients
• Perimenopausal patients

Management

• Monitor reported symptoms for any worsening at annual well-woman exams.
• Typically, no active treatment is required.
• Surveillance imaging is not routinely required. ^[14]
• Recommend follow-up if symptoms change or pregnancy is planned.

Pharmacotherapy ^[4]

• Medications can either be used long-term for symptom control or temporarily as a bridge until a more definitive modality can be performed.
• Pharmacotherapy should be selected based on the patient's symptoms.
• There is currently insufficient evidence to recommend one agent over other for first-line therapy.

Selective progesterone receptor modulators (e.g., ulipristal acetate) and androgenic agonists (e.g., danazol) are used in some countries for the management of leiomyomas; these medication classes are not FDA-approved for managing leiomyomas in the US, as the potential adverse effects are thought to outweigh the benefits.

GnRH antagonists have a faster clinical effect than GnRH agonists, as there is no initial increase in FSH/LH and estrogen with GnRH antagonists.

Nonsurgical interventional treatments ^[4][17]

Recommended in patients with symptomatic leiomyoma who desire uterine preservation and/or want to avoid surgery.

Uterine artery embolization (UAE)

• A minimally invasive percutaneous radiologic procedure in which an embolic agent (e.g., polyvinyl alcohol) is injected into the uterine arteries that supply the leiomyoma, causing it to shrink
• Significantly reduces leiomyoma size and bleeding
• Complications ^[4][18]
  • Postembolization syndrome
    • Common complication of transarterial embolization
    • Clinical features: fever, pelvic pain, nausea, and vomiting < 72 hours of UAE in the absence of infection
    • Typically self-limited
  • Thromboembolic events (e.g., pulmonary embolism, uterine ischemia and necrosis)
  • Bleeding/blood-tinged vaginal discharge; : typically self-limited
  • Endometritis
  • Treatment failure
• Unknown effects on fertility : Counsel patients who wish to conceive about the possible effects of UAE on fertility.

Radiofrequency ablation (RFA) ^[4][17]

• Ultrasound-guided targeted coagulative necrosis of leiomyoma
• A significant decrease in leiomyoma size and symptoms have been noted in studies.
• Low risk of further surgical intervention
• Unknown effects on fertility

Additional modalities (not currently recommended)

• MRI-guided focused ultrasound: a noninvasive procedure that uses high-intensity ultrasound waves; results in coagulative necrosis of the leiomyoma ^[4]
• Endometrial ablation: may be beneficial in patients with abnormal uterine bleeding due to leiomyomas

Nonsurgical interventional therapies preserve the uterus; however, there is insufficient data regarding their effect on fertility to support their use in women who may wish to conceive in the future.

Surgery ^[4]

Myomectomy

A uterus-preserving surgical option for the removal of leiomyomas

• Indications
  • Patients with symptomatic leiomyomas who wish to preserve fertility
  • Consider in patients with leiomyomas and a history of infertility or pregnancy loss who are hoping to conceive. ^[19]
• Approach
  • Hysteroscopic myomectomy; is preferred for submucosal leiomyomas.
  • Laparoscopic myomectomy may be preferred for subserosal and most intramural leiomyomas.
• Recurrence rate: ∼ 25% within 40 months ^[4]

Hysterectomy

• Indications
  • Patients seeking definitive treatment who do not desire fertility and/or have had an insufficient response to alternative treatments
  • Suspected leiomyosarcoma ^[20]
• Approach : vaginal, abdominal, or laparoscopic

Patients often receive GnRH agonists or antagonists prior to surgery to reduce leiomyoma size, which may allow less invasive procedures to be performed. ^[4]

• Uterine fibroids, adenomyosis, and endometriosis may be present simultaneously in the same patient.
• See also endometrial cancer, benign tumors of the endometrium, and differential diagnosis of dysmenorrhea and menorrhagia

The differential diagnoses listed here are not exhaustive.

• Infertility
• Iron deficiency anemia (due to heavy menstrual bleeding)
• Fibroid torsion
• Thromboembolism
• Very rare: malignant transformation to uterine leiomyosarcoma

We list the most important complications. The selection is not exhaustive.

Uterine leiomyomas during pregnancy ^[26]

• Estimates of leiomyoma occurrence during pregnancy range from 2.7% to > 25%. ^[27]
• The majority of patients with leiomyomas have good outcomes, but increased surveillance by a maternal-fetal medicine specialist is recommended because of the elevated risk of pregnancy complications.
• Select appropriate agents to manage pain caused by uterine leiomyomas; see “Analgesics in pregnancy.”

After pregnancy, leiomyomas typically return to their prepartum size; however, some leiomyomas may spontaneously resolve. ^[28]