BASICSBradley M. Turner, MD, MPH, MHA • Amanda Martin Kelley, MD, MPH&TM
BASICS
DESCRIPTION
• Benign invasion of the endometrium into the myometrium, producing a diffusely enlarged uterus
• 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
• Most frequently presents in the 4th and 5th decades.
• Wide variation among racial and ethnic groups and among different geographic regions
Incidence
• Variability in the criteria used for diagnosis make an accurate determination of true incidence difficult.
• Depending on the criteria used for diagnosis, the incidence has been estimated as between 5% and 50%.
• The incidence has been reported to be higher (35–50%) in women presenting with pelvic pain and infertility.
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.
• 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.
• Other theories for pathogenesis include the following:
– Metaplasia theory: metaplasia of myometrial smooth muscle cells
– Müllerian remnants theory: de novo development from müllerian rests in the myometrium
– Tissue remodeling theory: ectopic endometrial tissue arising secondary to tissue remodeling associated with uterine trauma either physiologic (e.g., during menstruation, childbirth, or spontaneous abortion) or iatrogenic (e.g., during uterine surgery)
– Multipotential perivascular theory: Multipotential perivascular stem cells may be associated with increased angiogenesis and pathophysiologic vascular remodeling, leading to vascular smooth muscle hypertrophy, proliferation, or migration.
– Epithelial–mesenchymal transition theory: Increased estrogen concentrations may enhance endometrial tissue growth, angiogenesis, and invagination into the JZ.
– Hyperproliferation of uterine smooth muscle cell theory: Activation of the MAPK/ERK pathway has been associated with hyperproliferative uterine smooth cells in women with adenomyosis.
– Mast cell activation theory: Nerve growth factor, a mast cell–derived mediator, can be used as an indicator for the severity of adenomyosis. This and other mast cell–derived mediators may contribute to the differentiation and development of the myometrium and maintenance of adenomyosis.
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 >35 years, however, the disease may cause dysmenorrhea and chronic pelvic pain 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:
– 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
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 the patient is often asymptomatic.
• Symptoms often include (1–4) 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 recently been associated with an increased incidence of adenomyosis; however, data are limited (5,6).
PHYSICAL EXAM
Uterus may be enlarged and tender (7).
DIFFERENTIAL DIAGNOSIS
• Pregnancy
• Benign uterine tumors
• Malignant uterine tumors
• Metastatic disease
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
• Transvaginal ultrasound (TVUS) is the imaging method of choice for initial evaluation of suspected adenomyosis (2,4,7)[A].
• TVUS can be either two or three-dimensional (2)[A].
• Three-dimensional TVUS can provide JZ thickness.
• TVUS has a sensitivity of 72–82.5% and a specificity of 81–84.6% (4,7)[A].
• TVUS is less sensitive than MRI in differentiating adenomyosis from leiomyoma (2,7)[A].
• TVUS with power color flow Doppler can be used to differentiate adenomyosis from leiomyoma (2,4)[B], depending on the operator (2,7)[C].
• Although MRI is more sensitive (4,7)[A] than TVUS, the higher cost of the procedure limits its use as a first-line diagnostic tool.
• MRI has a sensitivity of 77–93% and a specificity of 67–99% (4,7)[A].
• Leiomyomas are associated with adenomyosis in 36–50% of cases, making MRI an ideal imaging method (4)[A].
• MRI should be considered when TVUS cannot provide a definitive diagnosis.
Diagnostic Procedures/Other
• Uterine biopsy with histologic interpretation
• Uterine-sparing operative treatment with histologic interpretation
• Hysterectomy with histologic interpretation
Test Interpretation
– Uterine enlargement (with no visualized leiomyoma)
– Cystic anechoic spaces or lakes in the myometrium
– Uterine wall thickening
– Subendometrial echogenic linear striations
– Heterogeneous echo texture
– Obscure endometrial/myometrial border
– Thickening of the transition zone
• With three-dimensional TVUS, a JZ maximum (JZmax) ≥8 mm and a JZ maximum – JZ minimum (JZmin) ≥4 mm have been reported as significantly more associated with adenomyosis than two-dimensional features (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 (2,4,7)[A].
• 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],(7)[A]
– JZmax/total myometrium >40% (2,7)[B]
– JZmax–JZmin >5 mm (2)[B]
• Histologic interpretation has traditionally been considered the most practicable way to establish a definitive diagnosis of adenomyosis (4,7)[C].
• Pathologic interpretation of uterine biopsy:
– Presence of endometrial glands and stromal elements within the myometrium
– Often difficult to definitively diagnose adenomyosis due to sampling bias and/or biopsy artifact (1)[A]
• Pathologic interpretation of uterine-sparing operative treatment 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)[A].
– Even in cases where the surface is accurately referenced, criteria vary among pathologists regarding the depth of invasion, which “definitively” defines adenomyosis (1,4,7,8)[A].
TREATMENT
• The mainstay of treatment has been surgical therapy.
• Medical therapy shows promise in certain patients.
MEDICATION
• The levonorgestrel-releasing intrauterine system (Mirena) has been shown to result in a reduction of symptoms (6,9)[B].
• Gonadotropin-releasing hormone analogs have shown promise in several studies (9)[B].
ADDITIONAL THERAPIES
• Danazol has shown promise in several case series (8)[B].
• Immunomodulators of angiogenesis, and oral progestins (dienogest), may offer future options for medical treatment of adenomyosis (9,10)[B].
SURGERY/OTHER PROCEDURES
• Hysterectomy is curative.
• Uterine-sparing operative treatment (USOT) might be considered for women who wish to preserve fertility or do not wish to have a hysterectomy.
– Complete excision (adenomyomectomy)
– Cytoreduction (partial adenomyomectomy)
– Laparoscopic techniques including electrocoagulation, 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
– Other reported techniques include the following: alcohol instillation (cystic adenomyosis), radiofrequency ablation (focal adenomyosis), microwave ablation, and thermoablation (diffuse adenomyosis)
• Of the nonexcisional techniques, HIFU and uterine artery embolization (UAE) seem to offer the most encouraging results (1)[C],(12,13)[B].
• Increasing percentages of necrosis after UAE may be an important factor associated with decreased recurrence of symptoms (14)[B].
• The impact of USOT on fertility outcomes are encouraging; however, data are lacking (11)[A].
ONGOING CARE
PATIENT EDUCATION
Adenomyosis, PubMed health, at http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0024411/
PROGNOSIS
• Adenomyosis is a benign proliferation of endometrial tissue.
• Symptoms usually resolve after menopause.
• Hysterectomy is curative.
• Additional studies are needed to determine the impact of untreated adenomyosis and USOT on fertility and reproductive outcomes.
• Additional studies are 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.
REFERENCES
1. Taran FA, Stewart, EA, Brucker S. Adenomyosis: epidemiology, risk factors, clinical phenotype and surgical and interventional alternatives to hysterectomy. Geburtshilfe Frauenheilkd. 2013;73(9):924–931.
2. Exacoutos C, Manganaro L, Zupi E. Imaging for the evaluation of endometriosis and adenomyosis. Best Pract Res Clin Obstet Gynaecol. 2014;28(5):655–681.
3. Koike N, Tsunemi T, Uekuri C, et al. Pathogenesis and malignant transformation of adenomyosis (review). Oncol Rep. 2013;29(3):861–867.
4. Shwayder J, Sakhel K. Imaging for uterine myomas and adenomyosis. J Minim Invasive Gynecol. 2014;21(3):362–376.
5. Ekin M, Cengiz H, Öztürk E, et al. Genitourinary symptoms in patients with adenomyosis. Int Urogynecol J. 2013;24(3):509–512.
6. Ekin M, Cengiz H, Ayağ ME, et al. Effects of the levonorgestrel-releasing intrauterine system on urinary symptoms in patients with adenomyosis. Eur J Obstet Gynecol Reprod Biol. 2013;170(2):517–520.
7. Champaneria R, Abedin P, Daniels J, et al. Ultrasound scan and magnetic resonance imaging for the diagnosis of adenomyosis: systematic review comparing test accuracy. Acta Obstet Gynecol Scand. 2010;89(11):1374–1384.
8. Maheshwari A, Gurunath S, Fatima F, et al. Adenomyosis and subfertility: a systematic review of prevalence, diagnosis, treatment and fertility outcomes. Hum Reprod Update. 2012;18(4):374–392.
9. Benagiano G, Brosens I, Carrara S. Adenomyosis: new knowledge is generating new treatment strategies. Womens Health (Lond Engl). 2009;5(3):297–311.
10. Hirata T, Izumi G, Takamura M, et al. Efficacy of dienogest in the treatment of symptomatic adenomyosis: a pilot study. Gynecol Endocrinol. 2014;30(10):726–729.
11. Grimbizis GF, Mikos T, Tarlatzis B. Uterus-sparing operative treatment for adenomyosis. Fertil Steril. 2014;101(2):472–487.
12. Dong X, Yang Z. High-intensity focused ultrasound ablation of uterine localized adenomyosis. Curr Opin Obstet Gynecol. 2010;22(4):326–330.
13. Popovic M, Puchner S, Berzaczy D, et al. Uterine artery embolization for the treatment of adenomyosis: a review. J Vasc Interv Radiol. 2011;22(7):901–909.
14. Bae SH, Kim MD, Kim GM, et al. Uterine artery embolization for adenomyosis: percentage of necrosis predicts midterm clinical recurrence. J Vasc Interv Radiol. 2015;26(9):1290.e2–1296.e2.
ADDITIONAL READING
• Benagiano G, Habiba M, Brosens I. The pathophysiology of uterine adenomyosis: an update. Fertil Steril. 2012;98(3):572–579.
• Fedele L, Bianchi S, Frontino G. Hormonal treatments for adenomyosis. Best Pract Res Clin Obstet Gynaecol. 2008;22(2):333–339.
• Streuli I, Santulli P, Chouzenoux S, et al. Activation of the MAPK/ERK cell-signaling pathway in uterine smooth muscle cells of women with adenomyosis. Reprod Sci. 2015;22(12):1549–1560.
• Verit FF, Yucel O. Endometriosis, leiomyoma and adenomyosis: the risk of gynecologic malignancy. Asian Pac J Cancer Prev. 2013;14(10):5589–5597.
• Weiss G, Maseelall P, Schott LL, et al. Adenomyosis a variant, not a disease? Evidence from hysterectomized menopausal women in the Study of Women’s Health Across the Nation (SWAN). Fertil Steril. 2009;91(1):201–206.
CODES
ICD10
N80.0 Endometriosis of uterus
CLINICAL PEARLS
• Adenomyosis is often asymptomatic.
• Both TVUS and MRI are very accurate for the diagnosis of adenomyosis.
• MRI is more sensitive than TVUS, particularly in differentiating adenomyosis from leiomyoma. Differentiation of adenomyosis from leiomyoma is critical because the former is often treated with hysterectomy, whereas the latter is often treated with uterine conservation.
• Various medical and surgical therapeutic options, including uterine-sparing operative techniques, are available for adenomyosis.
• Hysterectomy is curative.