BASICSJessica M. Schechtman, DO • Michael P. Hopkins, MD, MEd
BASICS
DESCRIPTION
• Uterine leiomyomas are well-circumscribed, pseudoencapsulated, benign monoclonal tumors composed mainly of smooth muscle with varying amounts of fibrous connective tissue (1,2).
• Three major subtypes
– Subserous: common; external; may become pedunculated
– Intramural: common; within myometrium; may cause marked uterine enlargement
– Submucous: ~5% of all cases; internal, evoking abnormal uterine bleeding and infection; occasionally protruding from cervix
• Rare locations: broad, round, and uterosacral ligaments
• System affected: reproductive
• Synonym(s): fibroids; myoma; fibromyoma; myofibroma; fibroleiomyoma
EPIDEMIOLOGY
Incidence
• Cumulative incidence up to 80%
– 60% in African American women by age 35 years; 80% by age 50 years
– 40% in Caucasian women by age 35 years; 70% by age 50 years (1,3,4)
• Incidence increases with each decade during reproductive years.
• Rarely seen in premenarchal females
• Predominant sex: females only
ETIOLOGY AND PATHOPHYSIOLOGY
• Enlargement of benign smooth muscle tumors that may lead to symptoms affecting the reproductive, GI, or genitourinary system
• Complex multifactorial process involving transition from normal myocyte to abnormal cells and then to visibly evident tumor (monoclonal expansion)
– Hormones (1): Increases in estrogen and progesterone are correlated with myoma formation (i.e., rarely seen before menarche). Estrogen receptors in myomas bind more estradiol than normal myometrium (2).
– Growth factors (1)
Increased smooth muscle proliferation (transforming growth factor β [TGF-β], basic fibroblast growth factor [bFGF])
Increase DNA synthesis (epidermal growth factor [EGF], platelet-derived growth factor [PDGF], activin, myostatin)
Stimulate synthesis of extracellular matrix (TGF-β)
Promote mitogenesis (TGF-β, EGF, insulin-like growth factor [IGF], prolactin)
Promote angiogenesis (bFGF, vascular endothelial growth factor [VEGF])
– Vasoconstrictive hypoxia (1): proposed, but not confirmed, mechanism of myometrial injury during menstruation
Genetics
• A variety of somatic chromosomal rearrangements have been described in 40% of uterine myomas.
– Mutations in the gene encoding mediator complex subunit 12 (MED12) on the X chromosome were found in 70% of myomas in one study (3).
• Higher levels of aromatase and therefore estrogen have been found in myomas in African American women (3).
RISK FACTORS
• African American heritage
– 2.9 times greater risk than Caucasian women; occur at a younger age, are more numerous, larger, and more symptomatic (1,4)
• Early menarche (<10 years)
• Oral contraceptive use before 16 years old (4)
• Nulliparous
• Hypertension
• Familial predisposition
– 2.5 times more likely in women with a first-degree relative with myomas (1)
• Obesity
– Risk increases by 21% with each 10 kg of weight gain (1).
• Alcohol
• Risk decreased by: parity, progesterone only contraceptives, diet (fruits, veggies, low fat dairy) (4)
COMMONLY ASSOCIATED CONDITIONS
Endometrial and breast cancer also associated with high, unopposed estrogen stimulation
DIAGNOSIS
HISTORY
• Usually asymptomatic; 30% present with abnormal symptoms—usually enlarged uterus or heavy bleeding (2,4).
• Symptoms include the following:
– Abnormal uterine bleeding: usually heavy/prolonged menses
– Pain: infrequent; usually associated with torsion of pedunculated myoma, degeneration, or cervical dilation by submucous myoma near cervical os
– Pressure on bladder: suprapubic discomfort, urinary frequency/obstruction
– Pressure on rectosigmoid: may cause low back pain, constipation
– Infertility: rare, estimated 1–2.5% (2); usually from submucous myoma distorting the uterine cavity or interference with implantation
ALERT
Rapid growth, particularly in perimenopausal/postmenopausal patients; may indicate sarcoma. Extremely rare, 0.1–0.3% of cases (2)
PHYSICAL EXAM
• Usually incidental finding on abdominal and pelvic exam
• Firm, smooth nodules/masses arising from uterus
• Masses are mobile without tenderness.
DIFFERENTIAL DIAGNOSIS
• Intrauterine pregnancy
• Cancer, including ovarian, uterine, or leiomyosarcoma
• Cecal/sigmoid tumor
• Appendiceal abscess
• Diverticulitis
• Pelvic kidney
• Urachal cyst
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
• Pregnancy test
• Hemoglobin
• Pelvic ultrasound: standard confirmatory test; shows characteristic hypoechoic appearance (4,5)
• Saline infusion hysterosonography: helps to distinguish submucosal myomas
• Hysterosalpingogram: evaluates the contour of the endometrial cavity (5)
• CT scan or MRI: provides info on degeneration and special relationships (4); may help to differentiate complex cases or used when uterine artery embolization is planned (5)[B]
Follow-Up Tests & Special Considerations
Consider cancer antigen 125 (CA-125): may be slightly elevated in some cases of uterine myoma but generally more useful in differentiating myomas from various gynecologic adenocarcinomas
• IV pyelogram: if suspect ureteral distortion (5)
• Barium enema
Diagnostic Procedures/Other
• Fractional dilation and curettage: aids in ruling out cervical/uterine carcinomas when clinically suspicious
• Hysteroscopy: helps to diagnose submucosal/intracavitary myomas
• Laparoscopy: useful in complex cases and to rule out other pelvic diseases/disorders
Test Interpretation
• Myomas are usually multiple and vary in size and location; have been reported up to 100 lb
• Gross pathology: firm tumors with characteristic whorl-like trabeculated appearance; a thin pseudocapsular layer is present.
• Microscopic: bundles of smooth muscle mixed with varying amounts of connective tissue elements running in different directions
• Cellular variant has a preponderance of muscle cells. Mitoses are rare.
• May undergo various types of degeneration
– Hyaline degeneration: very common
– Calcification: late result of circulatory impairment to myomas
– Infection and suppuration: most common with submucosal myomas
– Necrosis: most common with pedunculated myomas secondary to torsion
TREATMENT
• Treatment must be individualized and based on symptoms, fertility desires, and time until menopause.
• Medical therapy may be of benefit.
• Patients with minimal symptoms may be treated with iron preparations and analgesics.
• Conservative management of asymptomatic myomas
– Pelvic exams and ultrasounds at ≥3-month intervals if size remains stable
– Substantial regression usually occurs after menopause.
• Surgical options should be considered if symptomatic or worrisome myomas are unresponsive to conservative/medical management.
GENERAL MEASURES
Patients not desiring pharmacologic therapy or surgery may consider the following:
• Uterine artery embolization: averages 50% shrinkage of myomas (6)[A]; painful and may cause ovarian failure (1–2%), amenorrhea, postembolization syndrome, or other complications; shorter hospital stay and quicker recovery but no difference in satisfaction compared with hysterectomy (2,4)[B]; high reintervention rate (15–32% by 2 years) compared to hysterectomy/myomectomy (7% by 2 years) (6)
• MR-guided focused ultrasound (MRgFUS): noninvasive, ultrasound transducer passes through abdominal wall and causes coagulative necrosis of fibroid; up to 98% reduction in myoma volume and symptoms. Not appropriate for some types of myomas (2)[B]. Efficacy may be comparable with other hysterectomy-sparing procedures (7)[B]. Fertility has been shown to be preserved (4)[A] although risks and outcomes data is limited (4).
MEDICATION
• Progestins may reduce overall uterine size (5)[B].
– Norethindrone 10 mg/day
– Medroxyprogesterone 200 mg IM monthly
– Levonorgestrel intrauterine device (2)[B]
• Combination oral contraceptives: may help prevent development of new fibroids and control bleeding
– Contraindications: history of thromboembolic events
• Gonadotropin-releasing hormone agonists
– Nafarelin (nasal spray), goserelin acetate, and leuprolide
– Induces abrupt artificial menopause; may reduce myoma symptoms dramatically; induces atrophy of myomas by up to 40% in 2 to 3 months (5)[B]
– May be valuable as preoperative adjunct to myomectomy/hysterectomy by allowing recovery of anemia, donation of autologous blood, and possibly converting abdominal to vaginal hysterectomy (4,5,8)[B]
– Not recommended for use >6 months because of osteoporosis risk
– Following discontinuation, myomas return within 60 days to pretherapy size.
• Antiprogesterones
– Mifepristone
Shown to have similar reduction in myoma size as gonadotropin-releasing hormone agonists (7)[B]
Decreases heavy bleeding and increases quality of life (9)[A]
– Selective progesterone receptor modulator (SPRM)
Ulipristal acetate: may be as effective as gonadotropin-releasing hormones with fewer side effects (4)[B]
ISSUES FOR REFERRAL
• Medical therapy may be initiated by a primary care physician/gynecologist after adequate pelvic examination.
• Surgical considerations may be pursued with gynecologic consultation.
• Uterine embolization may be discussed with an interventional radiologist.
SURGERY/OTHER PROCEDURES
• Surgical management is indicated in the following situations (5)[B]:
– Excessive uterine size or excessive rate of growth (except during pregnancy)
– Submucosal myomas when associated with hypermenorrhea
– Pedunculated myomas that are painful or undergo torsion, necrosis, and hemorrhage.
– If a myoma causes symptoms from pressure on bladder/rectum
– If differentiation from ovarian mass is not possible
– If associated pelvic disease is present (endometriosis, pelvic inflammatory disease)
– If infertility/habitual abortion is likely due to the anatomic location of the myoma
• Surgical procedures
– Preliminary pelvic examination, Pap smear, and endometrial biopsy should be performed to rule out malignant/premalignant conditions.
– Hysterectomy: may be performed vaginally, laparoscopically, robotically, or by laparotomy
Effective in relieving symptoms and improving quality of life (4,7)[B]
Similar fertility and live birth rates between laparoscopic and abdominal myomectomy (2)[B]
FDA discourages the use of laparoscopic power morcellation during hysterectomy or myomectomy for uterine fibroids given the risk of spreading an occult malignancy and all patient should be counseled preoperatively of risk (4).
– Abdominal, laparoscopic, robotic, or hysteroscopic myomectomy may be performed in younger women who want to maintain fertility (5,10)[B].
– Hysteroscopic/laparoscopic cautery/laser myoma resection can be performed in selected patients.
– Endometrial ablation: for small submucosal myomas
ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS
• Usually outpatient
• Inpatient for some surgical procedures
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
• Pelvic examination and ultrasound: every 2 to 3 months for newly diagnosed symptomatic/excessively large myomas
• Hemoglobin and hematocrit: if uterine bleeding is excessive
• Once uterine size and symptoms stabilize, monitor every 6 to 12 months although no high quality evidence exists (4).
DIET
No restrictions
PATIENT EDUCATION
• Society of Interventional Radiology: http://sirweb.org/patients/uterine-fibroids/
• U.S. Department of Health and Human Services: http://www.womenshealth.gov/publications/our-publications/fact-sheet/uterine-fibroids.html?from=AtoZ
• American Congress of Obstetricians and Gynecologists: http://www.acog.org
PROGNOSIS
• Resection of submucosal fibroids has been associated with increased fertility (7)[B].
• At least 10% of myomas recur after myomectomy; however, only 25% require further treatment (4,7)[B].
COMPLICATIONS
• May mask other gynecologic malignancies (e.g., uterine sarcoma, ovarian cancer)
• Degenerating fibroids may cause pain and bleeding.
• May rarely prolapse through the cervix
Pregnancy Considerations
• Rapid growth of fibroids is common.
• Pregnant women may need additional fetal testing if placenta is located over or near fibroid.
• Complications during pregnancy: abortion, premature labor, 2nd-trimester rapid growth leading to degeneration/pain, 3rd-trimester fetal malpresentation, and dystocia during labor and delivery
• Cesarean section is recommended if the endometrial cavity was entered during myomectomy due to increased risk of uterine rupture.
Geriatric Considerations
In postmenopausal patients with newly diagnosed uterine myoma/enlarging uterine myomas have a high suspicion of uterine sarcoma/other gynecologic malignancy.
REFERENCES
1. Parker WH. Etiology, symptomatology, and diagnosis of uterine myomas. Fertil Steril. 2007;87(4):725–736.
2. Duhan N, Sirohiwal D. Uterine myomas revisited. Eur J Obstet Gynecol Reprod Biol. 2010;152(2):119–125.
3. Bulun SE. Uterine fibroids. N Engl J Med. 2013;369(14):1344–1355.
4. Stewart EA. Clinical practice. Uterine fibroids. N Engl J Med. 2015;372(17):1646–1655.
5. Wallach EE, Vlahos NF. Uterine myomas: an overview of development, clinical features, and management. Obstet Gynecol. 2004;104(2):393–406.
6. Gupta JK, Sinha A, Lumsden MA, et al. Uterine artery embolization for symptomatic uterine fibroids. Cochrane Database Syst Rev. 2014;(12):CD005073.
7. Parker WH. Uterine myomas: management. Fertil Steril. 2007;88(2):255–271.
8. Lethaby A, Vollenhoven B, Sowter M. Pre-operative GnRH analogue therapy before hysterectomy or myomectomy for uterine fibroids. Cochrane Database Syst Rev. 2001;(2):CD000547.
9. Tristan M, Orozco LJ, Steed A, et al. Mifepristone for uterine fibroids. Cochrane Database Syst Rev. 2012;(8):CD007687.
10. NICE interventional procedure guidance 522. Hysteroscopic morcellation of uterine leiomyomas (fibroids). June 2015. Available at www.guidance.nice.org.uk/ipg522
ADDITIONAL READING
Laughlin SK, Schroeder JC, Baird DD. New directions in the epidemiology of uterine fibroids. Semin Reprod Med. 2010;28(3):204–217.
CODES
ICD10
• D25.9 Leiomyoma of uterus, unspecified
• D25.2 Subserosal leiomyoma of uterus
• D25.1 Intramural leiomyoma of uterus
CLINICAL PEARLS
• Uterine myomas are benign smooth muscle tumors composed mainly of fibrous connective tissue.
• Usually incidental finding on pelvic exam or ultrasound but may cause pelvic pain and pressure, abnormal uterine bleeding, and/or infertility
• Management ranges from conservative to medical to surgical.