Uterine leiomyoma

Uterine leiomyomas (fibroids) are benign, hormone-sensitive uterine neoplasms. These tumors are classified as either submucosal (beneath the endometrium), intramural (within the muscular uterine wall of the uterus), or subserosal (beneath the peritoneum). Symptoms depend on the location, size, and number of myomas, and include menstrual abnormalities (menorrhagia), features of mass effects (e.g., back/abdominal/pelvic pain or bladder and bowel dysfunction), and infertility. Physical examination and sonohysterography are used to establish the diagnosis. Treatment for symptomatic patients includes surgery (myomectomy or hysterectomy) as well as interventional (uterine artery embolization) and/or medical therapy (GnRH agonists).

• 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

• Nulliparity
• Early menarche (< 10 years old)
• 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

References:^[1][2][3]

Leiomyomas are classified according to their location within the uterus:

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

References:^[1]

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

1. Abnormal menstruation
   • Hypermenorrhea, menorrhagia, metrorrhagia (possibly associated anemia)
   • Dysmenorrhea
2. 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, constipation, features of hydronephrosis)
3. Reproductive abnormalities
   • Infertility; (difficulty conceiving and increased risk of miscarriage)
   • Dyspareunia

References:^[1]

• Ultrasound (best initial test)
  • Concentric, hypoechoic, heterogeneous tumors
  • Calcifications or cystic areas suggest necrosis.
  • Saline-infused sonography: can be used to better visualize submucosal and intramural fibroids
• Hysteroscopy: to assess submucosal fibroids
• MRI: to evaluate the uterus and ovaries for potentially complicated surgical cases and visually differentiate between leiomyomas, adenomyomas, and adenomyosis

References:^[1][4]

• 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:^[5]

• 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.

Treatment should only be considered in symptomatic patients because of the side effects of medical therapy and surgery. The goal is to relieve symptoms. Perimenopausal women warrant expectant management in most cases.

Asymptomatic fibroids

• Do not require treatment
• Frequent follow-ups (approx. every 6–12 months) are necessary to monitor any potential growth.

Symptomatic fibroids

Medical therapy

Preoperative medical therapy may help reduce tumor size and decrease tumor vascularization.

• Hormone therapy
  • Gonadotropin-releasing hormone (GnRH) agonists: e.g., leuprolide, goserelin, nafarelin
    • Optimal treatment prior to surgery; but not suited for long-term monotherapy (> 6 months) because they cause osteoporosis, hot flushes, depression
    • Decrease size of leiomyomas
    • Suppress growth of new leiomyomas
    • Decrease tumor vascularization
    • Induce amenorrhea and thereby improve anemia
    • Leiomyomas grow back once therapy is discontinued (rebound growth)
  • Combined oral contraceptive pill and progestin-only contraceptive pill
    • Usually used as add-ons to GnRH agonist therapy
    • Control bleeding and pain but may promote growth of leiomyomas
  • Progestin-releasing intrauterine device (IUD): controls heavy and painful bleeding but does not treat fibroids themselves (only for fibroids that do not distort the inside of the uterus)
• Antifibrinolytics (e.g., tranexamic acid): reduce heavy bleeding
• Androgenic agonists (e.g., danazol): suppress growth of fibroids but have many side effects (e.g., acne, edema, hair loss, etc.)
• NSAIDs: : for dysmenorrhea

Interventional therapy

• Uterine fibroid embolization: uterine artery embolization
  • Procedure: injection of polyvinyl alcohol (PVA) into the arteries that supply blood to the fibroid, causing it to shrink; ¼ of patients may require further invasive treatment
  • Indications:
    • Continued heavy bleeding and/or severe pain with insufficient response to medical treatment
    • Contraindications to surgery or personal preference to avoid surgery
    • No wish to conceive in the future

Surgical therapy

• Indications: rapidly growing fibroid, recurrent refractory bleeding: secondary to medical therapy, severe symptoms
• Procedures
  • Myomectomy: excision of subserosal or intramural fibroids (preferred for women planning future pregnancies)
  • Hysterectomy: definitive treatment

References:^[10]

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

References:^[1]

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

Uterine leiomyomas during pregnancy

• Elevated concentrations of progestin and estrogen foster the growth of leiomyomas.
• Pain may be caused by:
  • Mass effect
  • Necrosis
  • Peritoneal irritation
• Premature contractions
• Depending on location and size:
  • Fetal malpresentation
  • Fetal growth retardation
  • Prematurity and miscarriages
  • Extrauterine pregnancy
  • Placental abruption
• Cervical leiomyoma: obstruction of the birth canal is an indication for cesarean delivery
• Postpartum: atonic hemorrhages
• Puerperium: fibroid regression accompanied by calcification

References:^[11]

1. Stewart EA, Laughlin-Tommaso SK. Uterine leiomyomas (fibroids): Epidemiology, clinical features, diagnosis, and natural history. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. http://www.uptodate.com/contents/uterine-leiomyomas-fibroids-epidemiology-clinical-features-diagnosis-and-natural-history.Last updated: December 21, 2016. Accessed: February 17, 2017.
2. Malik M, Norian J, McCarthy-Keith D, Britten J, Catherino WH. Why leiomyomas are called fibroids: the central role of extracellular matrix in symptomatic women.. Semin Reprod Med. 2010; 28 (3): p.169-179. doi: 10.1055/s-0030-1251475 . | Open in Read by QxMD
3. Ciavattini A, Di Giuseppe J, Stortoni P, et al. Uterine fibroids: Pathogenesis and interactions with endometrium and endomyometrial junction. Obstet Gynecol Int. 2013; 2013 : p.1-11. doi: 10.1155/2013/173184 . | Open in Read by QxMD
4. Uterine leiomyoma. https://radiopaedia.org/articles/uterine-leiomyoma. Updated: February 17, 2017. Accessed: February 17, 2017.
5. Uterus Stromal tumors Leiomyoma. http://www.pathologyoutlines.com/topic/uterusleiomyoma.html. Updated: February 9, 2017. Accessed: March 14, 2017.
6. Memarzadeh S, Berek JS. Uterine sarcoma: Classification, epidemiology, clinical manifestations, and diagnosis. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/uterine-sarcoma-classification-epidemiology-clinical-manifestations-and-diagnosis.Last updated: November 1, 2019. Accessed: June 22, 2020.
7. Roberts ME, Aynardi JT, Chu CS. Uterine leiomyosarcoma: A review of the literature and update on management options. Gynecol Oncol. 2018; 151 (3): p.562-572. doi: 10.1016/j.ygyno.2018.09.010 . | Open in Read by QxMD
8. Wethington SL, Herzog TJ, Burke WM, et al. Risk and Predictors of Malignancy in Women with Endometrial Polyps. Ann Surg Oncol. 2011; 18 (13): p.3819-3823. doi: 10.1245/s10434-011-1815-z . | Open in Read by QxMD
9. Stewart E. Uterine adenomyosis. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/uterine-adenomyosis?source=search_result&search=adenomyosis&selectedTitle=1~51#H6.Last updated: February 9, 2017. Accessed: February 17, 2017.
10. Stewart EA. Overview of treatment of uterine leiomyomas (fibroids). In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/overview-of-treatment-of-uterine-leiomyomas-fibroids.Last updated: May 27, 2016. Accessed: February 17, 2017.
11. Ouyang DW, Norwitz ER. Pregnancy in Women with Uterine Leiomyomas (Fibroids). In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/pregnancy-in-women-with-uterine-leiomyomas-fibroids.Last updated: December 19, 2017. Accessed: February 21, 2018.
12. Stewart EA. Histology and pathogenesis of uterine leiomyomas (fibroids). In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. http://www.uptodate.com/contents/histology-and-pathogenesis-of-uterine-leiomyomas-fibroids?source=search_result&search=uterine+leiomyoma&selectedTitle=9~150.Last updated: June 5, 2014. Accessed: March 14, 2017.
13. Bharambe BM, Deshpande KA, Surase SG, Ajmera AP. Malignant transformation of leiomyoma of uterus to leiomyosarcoma with metastasis to ovary. J Obstet Gynaecol India. 2012; 64 (1): p.68-69. doi: 10.1007/s13224-012-0202-4 . | Open in Read by QxMD