Leiomyoma

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Roukoz A. Karam, M.D.[2]; Cafer Zorkun, M.D., Ph.D. [3]; Shanshan Cen, M.D. [4]; Ammu Susheela, M.D. [5]

Synonyms and keywords: Uterine myoma; Fibroid; Fibroids; Uterine; Fibroid Tumor; Fibroid Uterus; Uterine fibromyoma; Leiomyomata

Overview

Uterine leiomyoma was first discovered by Hippocrates in 460-375 B.C and called it “uterine stone”. Uterine leiomyoma may be classified according to their location into 3 subtypes: submucosal, subserous, and intramural. The pathogenesis of leiomyoma is characterized by benign smooth muscle neoplasm. They can occur in any organ, but the most common forms occur in the uterus, small bowel and the esophagus. Chromosome aberrations such as t(12; 14)(q14-q15;q23–24), del(7)(q22q32), rearrangements involving 6p21, 10q, trisomy 12, and deletions of 1p3q has been associated with the development of leiomyoma. Uterine leiomyoma must be differentiated from other diseases that cause uterine mass, such as: uterine adenomyoma, pregnancy, hematometra, uterine sarcoma, uterine carcinosarcoma, and metastasis. Leiomyoma is more commonly observed among patients aged 40 years and older. Common risk factors in the development of uterine leiomyoma include African-American race, early menarche, prenatal exposure to diethylstilbestrol, having one or more pregnancies extending beyond 20 weeks, obesity, significant consumption of beef and other red meats, hypertension, family history, and alcohol consumption. Physical examination may be remarkable for enlarged, mobile uterus with an irregular contour on bimanual pelvic examination. The mainstay of therapy for uterine leiomyoma is oral contraceptive pills, either combination pills or progestin-only, Gonadotropin-releasing hormone analogs. Surgery is also part of mainstay therapy for uterine leiomyoma.

Historical Perspective

• Uterine leiomyoma was first discovered by Hippocrates, an ancient Greek physician, in 460-375 B.C and called it “uterine stone”.
• In the second century AD, Galen described the lesion as "scleromas".
• In 1860 and 1863, Rokitansky and Klob coined the term fibroid.
• In 1854, Virchow, a German pathologist, demonstrated that those tumors originated from the uterine smooth muscle.
• In 1809, the first laparotomy was conducted by Ephraim McDowell to treat leiomyoma in Danville, USA.

Classification

• Uterine leiomyoma may be classified according to the International Federation of Gynecology and Obstetrics (FIGO) classification system, based on their location in the uterus, into 8 subtypes:
  • Intramural myomas
    • FIGO types 3, 4, and 5
    • Located within the uterine wall
  • Submucosal myomas
    • Derived from myometrial cells below the endometrium and may protrude into the uterine cavity
    • May be subclassified according to this protrusion:
      • Type 0: pedunculated intracavitary
      • Type 1: < 50% intramural
      • Type 2: ≥ 50% intramural
  • Subserosal myomas
    • FIGO types 6 and 7
    • Derived from myometrium at the at the serous surface of the uterus
  • Cervical myomas
    • FIGO type 8
    • Usually located in the cervix

Pathophysiology

• The pathogenesis of leiomyoma is characterized by benign smooth muscle neoplasm. They can occur in any organ, but the most common forms occur in the uterus, small bowel and the esophagus.
• It is thought that leiomyoma is the result of either transformation of normal uterine muscle cells into abnormal cells through somatic mutations, or through the growth of abnormal uterine muscle cells into tumors.
• Genetic mutations involved in the pathogenesis of leiomyoma include:
  • t(12;14)(q14-q15;q23–24)
  • del(7)(q22q32)
  • Rearrangements involving 6p21, 10q, trisomy 12
  • Deletions of 1p3q
• On gross pathology, round, well circumscribed, non-encapsulated, solid white or tan nodules, and whorled are characteristic findings of leiomyoma.
• On microscopic histopathological analysis, elongated and spindle-shaped cells with a cigar-shaped nucleus are characteristic findings of leiomyoma.

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  Leiomyoma enucleated from a uterus. External surface on left; cut surface on right

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  A large, solitary leiomyoma in the uterus, distoring the endometrial cavity into a Y shape by splaying and pressing it downwards.
  (Image courtesy of Ed Uthman, MD)

Causes

• Chromosome aberrations such as t(12;14)(q14-q15;q23–24), del(7)(q22q32), rearrangements involving 6p21, 10q, trisomy 12, and deletions of 1p3q have been associated with the development of leiomyoma.

Differentiating Leiomyoma from other Diseases

Leiomyoma is a cause of abnormal uterine bleeding and can result in infertility. There are several diseases which can result in excessive uterine bleeding and the following table is a description of various causes of excessive uterine bleeding.

	Clinical Features	Physical Examination	Diagnostic Findings
Endometriosis	Dysmenorrhea Dyspareunia Infertility Common in women between 25 to 35 years	Nodules in the posterior fornix Adnexal masses Fixed retroverted uterus Lateral displacement of the cervix	Increased serum cancer antigen-125  Nodules of the recto vaginal septum and hypoechoic, vascular mass on MRI Laproscopic visualization confirms the diagnosis
Adenomyosis	Abnormal uterine bleeding Dysmenorrhea Common in women aged 40 and 50 years	Diffuse uterine enlargement always less than size corresponding to less than 12 weeks of gestation	Asymmetric thickening of the myometrium on MRI
Submucous uterine leiomyomas	Menorrhagia Pelvic pressure and pain Infertility Peak age of onset 25 to 44 years of age	Mobile uterus with an irregular contour	Transvaginal ultrasound will demonstrate the presence of myomas
Pelvic Inflammatory disease	Seen in patients with history of sexually transmitted disease History of multiple sexual partners  Common in women younger than 25 years of age	Abdominal tenderness  Acute cervical motion, uterine, and adnexal tenderness Visualization of purulent endocervical discharge	Positive Nucleic acid amplification tests for Chlamydia trachomatis and N. gonorrhoeae Gram negative diplococci on gram stain
Pelvic congestion Syndrome	Shifting lower abdominal pain Deep dyspareunia Post-coital pain Exacerbation of pain after prolonged standing	Bimanual tenderness Cervical motion tenderness	Pelvic varicosities on ultrasound with reduced blood flow

Epidemiology and Demographics

Age

• Leiomyoma commonly affects individuals between menarche and menopause.
• The incidence increases with age during reproductive years.

Race

• Leiomyoma usually affects African-American women.
  • Incidence rates are approximately threefold greater in African-American women than in white women.

Risk Factors

• Common risk factors in the development of uterine leiomyoma include:
  • African-American race
  • Early menarche
  • Prenatal exposure to diethylstilbestrol
  • Parity
    • Having one or more pregnancies extending beyond 20 weeks
  • Obesity
  • Diet
    • Significant consumption of beef and other reds meats
    • Vitamin D deficiency
  • Alcohol consumption
  • Smoking
  • Hormonal contraception

Natural History, Complications and Prognosis

• The majority of patients with uterine leiomyoma remain asymptomatic for a long time; they are usually found incidentally on imaging or examined after patients start having symptoms.
• Studies have shown that 7 to 40% of premenopausal patients with leiomyoma may witness regression of fibroids over 6 months to 3 years.
• At menopause most fibroids will start to shrink as menstrual cycles stop and hormone levels wane.
• Common complications of uterine leiomyoma include:
  • Dysmenorrhea
  • Dyspareunia
  • Leiomyoma degeneration or torsion
  • Transcervical prolapse
  • Miscarriage
• Less common complications of uterine leiomyoma include:
  • Venous compression
  • Polycythemia from autonomous production of erythropoietin
  • Hypercalcemia from autonomous production of parathyroid hormone-related protein
  • Hyperprolactinemia

Diagnosis

Diagnostic Study of Choice

• The diagnosis of uterine leiomyoma is based on a clinical diagnosis, which includes a pelvic exam and pelvic ultrasound finding of leiomyomas.
• A pelvic ultrasound is indicated when patients suffer from symptoms of leiomyoma.
• A biopsy is usually not needed to make the diagnosis, but should be performed if clinician is suspicious that the mass is not a fibroid.

Symptoms

• The majority of patients with leiomyoma are usually asymptomatic.
• Symptoms of uterine leiomyoma may include the following:

• Abnormal uterine bleeding
• Heavy or prolonged menstrual bleeding
• Painful sexual intercourse
• Abdominal discomfort or bloating
• Back pain
• Urinary frequency
• Urinary retention
• Constipation
• Infertility

Physical Examination

• Common physical examination findings of uterine leiomyoma include enlarged, mobile uterus with an irregular contour on bimanual pelvic examination.

Imaging Findings

• Pelvic ultrasound is helpful in the diagnosis of uterine leiomyoma.
• Findings on an ultrasound diagnostic of uterine leiomyoma include fibroids as focal masses with a heterogeneous texture, which usually cause shadowing of the ultrasound beam.

Other Diagnostic Studies

• Uterine leiomyoma may also be diagnosed using diagnostic hysteroscopy, magnetic resonance imaging, and hysterosalpingography.

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Patient #1: MR images demonstrate large degenerating leiomyomas

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Patient #2: MR images demonstrate a leiomyoma prolapsing into the endometrial canal

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Hysterosalpingogram(HSG) reveals a submucosal leiomyoma

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Treatment

Medical Therapy

• Uterine leiomyomas usually shrink and regress during menopause and the postpartum period.
• Literature is lacking concerning the medical therapy for leiomyoma, and due to their self-limited nature, expectant management is considered in some cases.
• Pharmacologic medical therapy in the form of oral contraceptives is recommended among premenopausal patients with mild symptoms and mildly enlarged uteri.
• Pharmacologic medical therapies for leiomyoma include:
  • Estrogen-progestin contraceptives
  • Levonorgestrel-releasing intrauterine system
  • Progestin implants, injections, and pills
  • Progesterone receptor modulators
  • Ulipristal acetate
  • Mifepristone
  • Gonadotropin-releasing hormone agonists
  • Nonsteroidal anti-inflammatory drugs
  • Danazol and gestrinone

Surgery

• Surgery is the mainstay of therapy for uterine leiomyoma.
• Uterine artery embolization in conjunction with laparotomic myomectomy is the most common approach to the treatment of leiomyoma.
• Hysteroscopic myomectomy can also be performed for patients with uterine leiomyoma.
• Surgical indications of leiomyoma include followings:
  • Abnormal uterine bleeding or bulk-related symptoms
  • Infertility or recurrent pregnancy loss
• There is different types of surgery for leiomyoma include followings:
  • Hysterectomy
  • Myomectomy
  • Endometrial ablation
  • Myolysis
  • Uterine artery occlusion