Adenomyosis

Basics

Description

  • Benign invasion of the endometrium into the myometrium, producing a diffusely enlarged uterus
  • Considered a specific entity in the PALM-COEIN FIGO (polyp; adenomyosis; leiomyoma; malignancy and hyperplasia; coagulopathy; ovulatory dysfunction; endometrial; iatrogenic; and not yet classified—International Federation of Gynecology and Obstetrics) classification of causes of abnormal uterine bleeding
  • Microscopically, there are ectopic, nonneoplastic endometrial glands and stroma surrounded by hypertrophic and hyperplastic myometrium.
  • Can be either diffuse or focal, depending on the extent of myometrial invasion
  • In some cases, it may manifest as a circumscribed myometrial mass referred to as an adenomyoma.
  • Most commonly affects the posterior wall of the uterus
  • Typically associated with the uterus; however, the term “adenomyosis” can also be applied to benign hyperplastic changes in the bile ducts, gallbladder, and ampulla of Vater.

Epidemiology

  • Historically, adenomyosis had been found to present more frequently in the 4th and 5th decades; however, it is increasingly being identified in younger women with pain, abnormal uterine bleeding, infertility, or no symptoms at all, by using imaging techniques such as transvaginal ultrasound (TVUS) and magnetic resonance imaging (MRI) (1),(2).
  • Wide variation among racial and ethnic groups and among different geographic regions (3)

Incidence

  • Typically considered a uterine condition of women who are multiparous, have had prior cesarean section, or have had prior uterine surgery; however, an increasing amount of evidence suggests that there is also an association with infertility and reproductive failure.
  • Variability in the criteria used for diagnosis makes an accurate determination of true incidence difficult.
  • Depending on the criteria used for diagnosis, the incidence has been estimated as between 10% and 80%.
  • The incidence has been reported to be higher in women presenting with endometriosis.

Prevalence

  • As with incidence, an accurate determination of prevalence is difficult due to the variability in the criteria used for diagnosis.
  • Depending on the criteria used for diagnosis, the prevalence has been reported to vary from 5% to 70%, with the mean frequency of adenomyosis at hysterectomy given as approximately 20–30%.

Etiology and Pathophysiology

  • Adenomyosis has been described as an abnormal ingrowth and invagination of the basal endometrium into the inner layer of the myometrium (junctional zone [JZ]).
  • The exact mechanism regarding how this occurs and is maintained is not clear and likely to be multifactorial.
  • Two main theories predominate to explain the origin and pathogenesis of adenomyosis:
    • Dysregulated tissue injury and repair promoting cell migration and invagination of the endometrial basalis into the myometrium (1)
    • De novo epithelial-mesenchymal transition among displaced embryonic müllerian remnants or adult stem cells (1)
  • Molecular alterations in eutopic endometrium seem to contribute to migration and survival of ectopic endometrial implants beyond the myometrial interface.
  • Sex steroid hormone aberrations, inflammation, altered cell proliferation, and neuroangiogenesis are likely key pathogenic mechanisms of pain, bleeding, and infertility in adenomyosis.
  • In women with adenomyosis, the JZ may represent a region of morphologic dysfunction and structural weakness, with varying susceptibility to invagination of endometrial stromal cells.
  • Increased uterine pressure associated with pregnancy, leiomyomas, or other pathology may modulate the JZ environment, making it more susceptible to invagination of endometrial stromal cells.

Genetics

  • DNA microarray and proteomics analysis have identified specific genes that are differentially expressed in adenomyosis and matched eutopic endometrium.
  • Data suggest that genetic and epigenetic abnormalities contribute to the pathogenesis of adenomyosis.

Risk Factors

  • Age >40 years; however, the disease has been increasing, identified in women of younger age, including adolescents. Reports suggest that early-stage adenomyosis might present a different clinical phenotype compared to late-stage disease.
  • Multiparity
  • Tamoxifen treatment
  • Other possible risk factors:
    • Infertility and reproductive failure (growing body of literature)
    • Previous uterine surgery (studies have been inconsistent)
    • Smoking (studies have been inconsistent)

Commonly Associated Conditions

  • Leiomyomas (uterine fibroids)
  • Endometriosis
  • Endometrial polyps
  • Urinary tract dysfunction

Diagnosis

  • The diagnosis is made through physical examination, radiographic imaging, biopsy, and subsequent histopathologic evaluation.
  • Pelvic pain, dysmenorrhea, and an enlarged uterus are the usual cues that prompt imaging by ultrasound or MRI; endometrial or uterine biopsies may be indicated in some cases.

History

  • Presenting symptoms are nonspecific and one-third of patients with adenomyosis are asymptomatic (2).
  • Symptoms often include the following:
    • Menorrhagia
    • Dysmenorrhea
    • Chronic pelvic pain
    • Abnormal uterine bleeding
  • Urinary tract symptoms (e.g., stress urinary incontinence, urgency, daytime frequency, and urge urinary incontinence) have been associated with an increased incidence of adenomyosis; however, data are limited.

Physical Exam

Uterus may be enlarged and tender.

Differential Diagnosis

  • Pregnancy
  • Benign uterine tumors
  • Malignant uterine tumors
  • Metastatic disease

Diagnostic Tests & Interpretation

Initial Tests (lab, imaging)

  • A shared histologic and radiologic classification system defining the type and severity of adenomyosis has not been developed.
  • A standard radiologic classification system defining the type and severity of adenomyosis has also not been developed.
  • Recently, a uniform standardized reporting system of ultrasound findings of adenomyosis was developed by using the Morphological Uterus Sonographic Assessment (MUSA) criteria.
  • TVUS is the imaging method of choice for initial evaluation of suspected adenomyosis (2)[C].
  • TVUS can be either two- or three-dimensional (2)[C].
  • Three-dimensional TVUS can provide JZ thickness.
  • TVUS has a sensitivity of 65–81% and a specificity of 65–100%, with two-dimensional TVUS being slightly less sensitive and slightly more specific (1),(2)[B].
  • TVUS is less sensitive with more interobserver variability than MRI in differentiating adenomyosis from leiomyoma.
  • MRI has a pooled sensitivity of 77%, specificity of 89%, positive likelihood ratio of 6.5, and negative likelihood ratio of 0.2 for all subtypes, showing better results compared with those of TVUS.
  • Leiomyomas are associated with adenomyosis in 36–50% of cases, making MRI an ideal imaging method (1)[C].
  • MRI may be the preferred imaging method when available if cost is not a concern (4)[C].
  • MRI should definitely be considered when TVUS cannot provide a definitive diagnosis.

Diagnostic Procedures/Other

  • Uterine biopsy with histologic interpretation
  • Uterine-sparing operative treatment (USOT) with histologic interpretation
  • Hysterectomy with histologic interpretation

Test Interpretation

  • The two-dimensional sonographic markers of adenomyosis include the following (1)[C]:
    • Uterine enlargement (with no visualized leiomyoma)
    • Cysts
    • Hyperechoic islands
    • Asymmetrical uterine wall thickening
    • Subendometrial echogenic linear striations
    • Translesional vascularity
    • Fan-shaped shadowing
    • Irregular and/or thickened JZ
    • Interrupted JZ
  • Although several criteria have been proposed, a JZ thickness exceeding 12 mm seems to be highly predictive of adenomyosis (2)[B].
  • Features of adenomyosis on MRI include low-intensity widening of the JZ on T2-weighted images, which corresponds to smooth muscle hyperplasia and thickening of the JZ (2)[C].
  • Three objective parameters have been identified for an MRI diagnosis of adenomyosis:
    • Thickening of the JZ to at least 8 to 12 mm (2)[B]
    • JZ max/total myometrium >40% (2)[B]
    • JZ max–JZ min >5 mm (2)[B]
  • Histologic interpretation has traditionally been considered the most practicable way to establish a definitive diagnosis of adenomyosis (1),(2)[C].
  • Pathologic interpretation of uterine biopsy:
    • Presence of endometrial glands and stromal elements within the myometrium
    • Often difficult to definitively on smaller samples to diagnose adenomyosis due to sampling bias and/or biopsy artifact
  • Pathologic interpretation of USOT and hysterectomy:
    • In morcellated specimens, diagnostic difficulty arises due to modification of the spatial arrangement of the tissue, leading to difficulty in referencing the surface. Sampling bias can also be an issue (1)[C].
    • Even in cases where the surface is accurately referenced, criteria vary among pathologists regarding the depth of invasion, which “definitively” defines adenomyosis (2)[C].

Treatment

  • There are no international guidelines to follow for medical or surgical treatment of adenomyosis.
  • The mainstay of treatment has been surgical therapy.
  • Medical therapy shows promise in certain patients.

Medication

  • Continuous use of oral contraceptive pills, high-dose progestins, and selective progesterone receptor modulators can temporarily improve the symptoms.
  • Use of a levonorgestrel-releasing intrauterine device is also an effective, reversible, and long-term treatment used successfully to treat adenomyosis (1),(2)[C] and is the most effective first-line treatment (5)[C].
  • Gonadotropin-releasing hormone (GnRH) agonists—used for management of menstrual bleeding and pain—and GnRH antagonists—used for treatment of leiomyomas and endometriosis—are both second-line options (5)[C].

Additional Therapies

Selective progesterone receptor modulators, aromatase inhibitors, valproic acid, and anti-platelet therapy are under development for the treatment of adenomyosis (1),(2)[C].

Surgery/Other Procedures

  • Hysterectomy is curative.
  • USOT might be considered for women who wish to preserve fertility or do not wish to have a hysterectomy.
  • USOT excisional techniques (1)[C]:
    • Complete excision (adenomyomectomy)
    • Cytoreduction (partial adenomyomectomy)
    • Uterine wedge resection
  • USOT nonexcisional techniques (1)[C]:
    • Laparoscopic techniques including electrocoagulation and uterine artery ligation
    • Hysteroscopic techniques including endometrial ablation, endomyometrial resection
    • MRI or ultrasound-guided high-frequency ultrasound ablation (high-intensity focused ultrasound [HIFU])
    • Uterine artery embolization (UAE)
    • Other reported techniques include the following:
      • Alcohol instillation (cystic adenomyosis)
      • Radiofrequency ablation (focal adenomyosis)
      • Microwave ablation
      • Thermoablation (diffuse adenomyosis)
  • Of the nonexcisional techniques, HIFU and UAE seem to offer the most encouraging results (1)[C].
  • A systemic review of USOT for adenomyosis in reproductive-aged women suggests that excisional USOT—including uterine wedge resection, adenomyomectomy, and hysteroscopic excision—may possibly improve fertility, although the best method of surgery is yet to be seen (6)[C]. Nonexcisional USOT that may improve fertility include HIFU and radiofrequency ablation (6)[C].
  • Hysterectomy, UAE, and endometrial ablation are only options if future fertility is not desired.

Ongoing Care

Patient Education

https://www.mayoclinic.org/diseases-conditions/adenomyosis/symptoms-causes...

Prognosis

  • Adenomyosis is a benign proliferation of endometrial tissue.
  • Symptoms usually resolve after menopause.
  • Hysterectomy is curative.
  • Additional studies are still needed to determine the impact of untreated adenomyosis and USOT on fertility and reproductive outcomes.
  • Additional studies are still needed to clarify the role of medical treatment in women with adenomyosis.
  • A consensus on the criterion for diagnosing adenomyosis needs to be reached.

Complications

  • Anemia from blood loss associated with heavy periods
  • Patients with adenomyosis have been reported to be at increased risk for malignant disease; however, to date, there has not been sufficient morphologic, genetic, or epigenetic evidence to substantiate the malignant transformation of adenomyosis.

Codes

ICD-10

  • N80.0 Endometriosis of uterus

ICD-9

  • 617.0 Endometriosis of uterus

SNOMED

  • 237115002 Endometriosis of myometrium (disorder)
  • 76376003 endometriosis of uterus (disorder)

Clinical Pearls

  • Adenomyosis is often asymptomatic.
  • MRI is more sensitive than TVUS, particularly in differentiating adenomyosis from leiomyoma.
  • Histologic diagnosis is the gold standard.
  • Various medical options exist; however, only hysterectomy is curative.

Authors

Bradley M. Turner, MD, MPH, MHA

Bibliography

  1. Tan J, Yong P, Bedaiwy MA. A critical review of recent advances in the diagnosis, classification, and management of uterine adenomyosis. Curr Opin Obstet Gynecol. 2019;31(4):212–221. [PMID:31192829]
  2. Vannuccini S, Petraglia F. Recent advances in understanding and managing adenomyosis. F1000Res. 2019;8:F1000 Faculty Rev–283. [PMID:30918629]
  3. Upson K, Missmer SA. Epidemiology of adenomyosis. Semin Reprod Med. 2020;38(2-03):89–107. [PMID:33105509]
  4. Tellum T, Nygaard S, Lieng M. Noninvasive diagnosis of adenomyosis: a structured review and meta-analysis of diagnostic accuracy in imaging. J Minim Invasive Gynecol. 2020;27(2):408–418.e3. [PMID:31712162]
  5. Cope AG, Ainsworth AJ, Stewart EA. Current and future medical therapies for adenomyosis. Semin Reprod Med. 2020;38(2-03):151–156. [PMID:33124017]
  6. Kho KA, Chen JS, Halvorson LM. Diagnosis, evaluation, and treatment of adenomyosis. JAMA. 2021;326(2):177–178. [PMID:34255015]


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