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Transvaginal Ultrasound for the Diagnosis of Adenomyosis: Systematic Review and Meta-Analysis

Published:August 29, 2017DOI:https://doi.org/10.1016/j.jmig.2017.08.653

      Abstract

      Adenomyosis is characterized by the presence of ectopic foci of endometrial glandular tissue and/or stroma within the myometrium. The diagnosis of adenomyosis is traditionally made through histologic evaluation of the postsurgical specimen. More recently, imaging with transvaginal ultrasound (TVUS) has been used for the preoperative diagnosis of adenomyosis. As yet, there is no consensus regarding the best imaging feature or combination thereof for the nonsurgical diagnosis of adenomyosis. This study systematically evaluated the literature in the last 10 years to determine the accuracy of 2-dimensional (2D) TVUS, different imaging features, enhancing methods such as 3-dimensional (3D) TVUS, elastography and color Doppler in the nonsurgical diagnosis of adenomyosis. A total of 8 studies were included. Pooled sensitivity and specificity for 2D TVUS for the diagnosis of adenomyosis for all combined imaging characteristics was 83.8% and 63.9%, respectively. Pooled sensitivity for 355 total patients with use of imaging feature of heterogeneous myometrium with 2D TVUS was highest (86.0%), and pooled specificity for 283 total patients with use of globular uterus was highest (78.1%). After including the “question mark” sign with other TVUS features, higher sensitivity and specificity, of 92% and 88%, respectively, were noted. For 3D TVUS, pooled sensitivity and specificity for all combined imaging characteristics was 88.9% and 56.0%, respectively. Poor definition of junctional zone showed the highest pooled sensitivity (86%) and the highest pooled specificity (56.0%) for the diagnosis of adenomyosis with 3D TVUS. There was no improvement in overall accuracy in 3D TVUS compared with 2D TVUS. Preliminary results of TVUS with color Doppler showed a high sensitivity and specificity for the differentiation between adenomyosis and myomas (95.6% and 93.4%, respectively). Also, TVUS elastography in 1 study showed an improvement in specificity (82.9%) compared with 2D TVUS (63.9%), albeit with comparable sensitivity. Larger studies are needed to advance our understanding of the different types of adenomyosis and their clinical impact.

      Keywords

      Adenomyosis is characterized by the presence of ectopic foci of endometrial glands and/or stroma within the myometrium, which may be diffusely distributed (diffuse adenomyosis) or circumscribed as a nodular lesion (focal adenomyosis or adenomyoma) [
      • Struble J.
      • Reid S.
      • Bedaiwy M.A.
      Adenomyosis: a clinical review of a challenging gynecologic condition.
      ,
      • Garcia L.
      • Isaacson K.
      Adenomyosis: review of the literature.
      ]. The gold standard for the diagnosis of adenomyosis is histopathologic confirmation of the presence of ectopic endometrium within the myometrium [
      • Levgur M.
      • Abadi M.A.
      • Tucker A.
      Adenomyosis: symptoms, histology, and pregnancy terminations.
      ,
      • Bergholt T.
      • Eriksen L.
      • Berendt N.
      • et al.
      Prevalence and risk factors of adenomyosis at hysterectomy.
      ,
      • Bergeron C.
      • Amant F.
      • Ferenczy A.
      Pathology and physiopathology of adenomyosis.
      ,
      • Azziz R.
      Adenomyosis: current perspectives.
      ]. The absence of standardization for the histologic diagnosis of adenomyosis is reflected in the varying prevalence reported, ranging from 5% to 70% worldwide [
      • Abbott J.A.
      Adenomyosis and abnormal uterine bleeding (AUB-A)—pathogenesis, diagnosis, and management.
      ].
      Patients with adenomyosis may be asymptomatic or may present with pain and abnormal bleeding symptoms [
      • Sakhel K.
      • Abuhamad A.
      Sonography of adenomyosis.
      ]. Because adenomyosis lesions can be difficult to identify during surgery and their complete excision is challenging, hysterectomy often remains the definitive treatment. Accurate noninvasive diagnosis of the disease with imaging therefore becomes essential for medical therapy or surgical planning, particularly in patients wishing to retain their fertility [
      • Sharma K.
      • Bora M.K.
      • Venkatesh B.P.
      • et al.
      Role of 3D ultrasound and Doppler in differentiating clinically suspected cases of leiomyoma and adenomyosis of uterus.
      ].
      Magnetic resonance imaging and transvaginal ultrasonography (TVUS) have been used as preoperative imaging tools for adenomyosis and have been shown to have similar diagnostic accuracy [
      • Pistofidis G.
      • Makrakis E.
      • Koukoura O.
      • et al.
      Distinct types of uterine adenomyosis based on laparoscopic and histopathologic criteria.
      ]. Although TVUS has the advantage of incurring less costs, it is operator-dependent [
      • Alabiso G.
      • Alio L.
      • Arena S.
      • et al.
      Adenomyosis: what the patient needs.
      ,
      • Bazot M.
      • Cortez A.
      • Darai E.
      • et al.
      Ultrasonography compared with magnetic resonance imaging for the diagnosis of adenomyosis: correlation with histopathology.
      ]. Various ultrasonographic criteria have been used for the diagnosis of adenomyosis, such as the presence of heterogeneous myometrial areas, findings of anechoic areas of 1 to 3 mm in diameter in the myometrium (known as myometrial cysts), and asymmetry of anterior and posterior uterine wall thickness [
      • Bazot M.
      • Cortez A.
      • Darai E.
      • et al.
      Ultrasonography compared with magnetic resonance imaging for the diagnosis of adenomyosis: correlation with histopathology.
      ]. Other sonographic markers of adenomyosis include the presence of echogenic striations in the subendometrium, subendometrial echogenic nodules, nodular endometrial–myometrial interface, and poor definition of junctional zone [
      • Sharma K.
      • Bora M.K.
      • Venkatesh B.P.
      • et al.
      Role of 3D ultrasound and Doppler in differentiating clinically suspected cases of leiomyoma and adenomyosis of uterus.
      ,
      • Kepkep K.
      • Tuncay Y.A.
      • Göynümer G.
      • et al.
      Transvaginal sonography in the diagnosis of adenomyosis: which findings are most accurate?.
      ,
      • Sun Y.L.
      • Wang C.B.
      • Lee C.Y.
      • et al.
      Transvaginal sonographic criteria for the diagnosis of adenomyosis based on histopathologic correlation.
      ,
      • Exacoustos C.
      • Brienza L.
      • Di Giovanni A.
      • et al.
      Adenomyosis: three-dimensional sonographic findings of the junctional zone and correlation with histology.
      ,
      • Hanafi M.
      Ultrasound diagnosis of adenomyosis, leiomyoma, or combined with histopathological correlation.
      ,
      • Di Donato N.
      • Bertoldo V.
      • Montanari G.
      • et al.
      Question mark form of uterus: a simple sonographic sign associated with the presence of adenomyosis.
      ,
      • Luciano D.E.
      • Exacoustos C.
      • Albrecht L.
      • et al.
      Three-dimensional ultrasound in diagnosis of adenomyosis: histologic correlation with ultrasound targeted biopsies of the uterus.
      ,
      • Acar S.
      • Millar E.
      • Mitkova M.
      • et al.
      Value of ultrasound shear wave elastography in the diagnosis of adenomyosis.
      ,
      • American Institute of Ultrasound in Medicine (AIUM)
      • American College of Radiology (ACR)
      • American College of Obstetricians and Gynecologists (ACOG)
      • et al.
      AIUM practice guideline for the performance of ultrasound of the female pelvis.
      ]. At present, there is no consensus regarding the most accurate imaging feature or combination of features for the ultrasound diagnosis of adenomyosis [
      • Sharma K.
      • Bora M.K.
      • Venkatesh B.P.
      • et al.
      Role of 3D ultrasound and Doppler in differentiating clinically suspected cases of leiomyoma and adenomyosis of uterus.
      ,
      • Kepkep K.
      • Tuncay Y.A.
      • Göynümer G.
      • et al.
      Transvaginal sonography in the diagnosis of adenomyosis: which findings are most accurate?.
      ,
      • Sun Y.L.
      • Wang C.B.
      • Lee C.Y.
      • et al.
      Transvaginal sonographic criteria for the diagnosis of adenomyosis based on histopathologic correlation.
      ,
      • Exacoustos C.
      • Brienza L.
      • Di Giovanni A.
      • et al.
      Adenomyosis: three-dimensional sonographic findings of the junctional zone and correlation with histology.
      ,
      • Hanafi M.
      Ultrasound diagnosis of adenomyosis, leiomyoma, or combined with histopathological correlation.
      ,
      • Di Donato N.
      • Bertoldo V.
      • Montanari G.
      • et al.
      Question mark form of uterus: a simple sonographic sign associated with the presence of adenomyosis.
      ,
      • Luciano D.E.
      • Exacoustos C.
      • Albrecht L.
      • et al.
      Three-dimensional ultrasound in diagnosis of adenomyosis: histologic correlation with ultrasound targeted biopsies of the uterus.
      ,
      • Acar S.
      • Millar E.
      • Mitkova M.
      • et al.
      Value of ultrasound shear wave elastography in the diagnosis of adenomyosis.
      ,
      • American Institute of Ultrasound in Medicine (AIUM)
      • American College of Radiology (ACR)
      • American College of Obstetricians and Gynecologists (ACOG)
      • et al.
      AIUM practice guideline for the performance of ultrasound of the female pelvis.
      ]. Improved imaging recognition of adenomyosis could facilitate better understanding of the natural progression of the disease and advance its clinical treatment options outside of surgery.
      Our main objective is to conduct a systematic review of the literature in the last 10 years regarding the accuracy of TVUS in the preoperative diagnosis of adenomyosis. We also aim to evaluate the accuracy of the specific imaging features used and the role and efficacy of enhancing techniques such as power Doppler, 3-dimensional (3D) imaging, and elastography available with ultrasound.

      Methods

       Search Strategy

      A thorough search of PubMed/MEDLINE for all available current literature in English published in the last 10 years was performed and a review based on Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines conducted [
      • Moher D.
      • Shamseer L.
      • Clarke M.
      • et al.
      Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement.
      ]. The quality of the individual studies was judged using the QUADAS (Quality Assessment of Diagnostic Accuracy Studies) criteria, a tool for the quality assessment of studies of diagnostic accuracy included in systematic reviews [
      • Whiting P.
      • Rutjes A.W.
      • Reitsma J.B.
      • et al.
      The development of QUADAS: a tool for the quality assessment of studies of diagnostic accuracy included in systematic reviews.
      ].
      We used the search terms “adenomyosis” and “ultrasound” and “adenomyosis” as well as “adenomyosis” and “imaging” as key words to recover all possible publications using the PubMed database. MeSH terms used included ((“diagnostic imaging”[Subheading] OR (“diagnostic”[All Fields] AND “imaging”[All Fields]) OR “diagnostic imaging”[All Fields] OR “ultrasound”[All Fields] OR “ultrasonography”[MeSH Terms] OR “ultrasonography”[All Fields] OR “ultrasound”[All Fields] OR “ultrasonics”[MeSH Terms] OR “ultrasonics”[All Fields]) OR (“diagnostic imaging”[Subheading] OR (“diagnostic”[All Fields] AND “imaging”[All Fields]) OR “diagnostic imaging”[All Fields] OR “ultrasonography”[All Fields] OR “ultrasonography”[MeSH Terms]) OR (“ultrasonics”[MeSH Terms] OR “ultrasonics”[All Fields]) OR (“diagnostic imaging”[Subheading] OR (“diagnostic”[All Fields] AND “imaging”[All Fields]) OR “diagnostic imaging”[All Fields] OR “diagnostic imaging”[MeSH Terms] OR (“diagnostic”[All Fields] AND “imaging”[All Fields])) AND (“adenomyosis”[MeSH Terms] OR “adenomyosis”[All Fields]).

       Selection Criteria and Eligibility

      Both retrospective and prospective studies were included that assessed the accuracy of TVUS (considered here as the index test) with or without enhancing techniques (3D, color Doppler, elastography) as a diagnostic tool. All included studies used histopathologic examination (considered as the gold standard) for confirmation of adenomyosis. We excluded single case reports and review articles.

       Data Extraction

      Two authors (MPA and JR) abstracted the data into tables, and another author (GMB) separately confirmed accuracy. In cases of conflict resolution was achieved by discussion with the senior authors (ECB, RMK, and MSA). References of articles were also manually reviewed for other relevant studies. Data obtained from the studies were first author, publication year, sample size, study design, imaging tool, imaging characteristics or features, types of tumors and stage.
      There were 7 main imaging characteristics, criteria, and features assessed in this study: myometrial cysts, heterogeneous myometrial areas, myometrial hypoechoic linear striations, globular-appearing uterus, asymmetry of the myometrial wall, poor definition of the endometrial–myometrial junction, and the “question mark” sign (Fig. 1, Fig. 2). The question mark sign is defined with ultrasound when the uterine corpus is flexed backward, the fundus of the uterus faces the posterior pelvic compartment, and the cervix is directed anteriorly toward the urinary bladder.
      Fig. 1
      Fig. 1Two-dimensional ultrasound imaging of a uterus in a longitudinal section with the sonographic signs associated with presence of adenomyosis. (A) Diffuse adenomyosis with heterogeneous myometrium, asymmetry of posterior myometrial wall, hypoechoic linear striations, poor definition junctional zone, and the “question mark” sign. (B) Globular uterus and heterogeneous myometrium. (C) Myometrial cysts (arrows).
      Fig. 2
      Fig. 2Two-dimensional ultrasound imaging of a uterus in a longitudinal section with the sonographic signs associated with presence of adenomyosis. (A) Diffuse adenomyosis with heterogeneous myometrium, myometrial cysts (arrows), and poor definition junctional zone. (B) Globular uterus, heterogeneous myometrium, and asymmetry of posterior myometrial wall.

       Statistical Analysis

      Data were extracted to construct 2 × 2 contingency tables of diagnostic performance (numbers of true-positive, false-negative, false-positive, and true-negative test results). Meta-analysis was performed using the Meta-Disc (Clinical Biostatistics Unit, Ramon y Cajal Hospital, Madrid, Spain), a Windows-based software for meta-analysis of test accuracy data [
      • Zamora J.
      • Abraira V.
      • Muriel A.
      • et al.
      Meta-DiSc: a software for meta-analysis of test accuracy data.
      ]. Summary estimates of sensitivity and specificity with 95% confidence intervals were calculated using the Der Simonian and Laird random-effects model.

      Results

      From 648 initial ARTICLES obtained from the primary computerized search, 595 studies were excluded (Fig. 3). All reviews, studies not written in English, and studies not published in the last 10 years were excluded. The abstracts of the 53 remaining studies were read, and using the inclusion/exclusion criteria, 21 were selected to be read in full text. A total of 8 papers were included in the final systematic review for qualitative synthesis [
      • Sharma K.
      • Bora M.K.
      • Venkatesh B.P.
      • et al.
      Role of 3D ultrasound and Doppler in differentiating clinically suspected cases of leiomyoma and adenomyosis of uterus.
      ,
      • Kepkep K.
      • Tuncay Y.A.
      • Göynümer G.
      • et al.
      Transvaginal sonography in the diagnosis of adenomyosis: which findings are most accurate?.
      ,
      • Sun Y.L.
      • Wang C.B.
      • Lee C.Y.
      • et al.
      Transvaginal sonographic criteria for the diagnosis of adenomyosis based on histopathologic correlation.
      ,
      • Exacoustos C.
      • Brienza L.
      • Di Giovanni A.
      • et al.
      Adenomyosis: three-dimensional sonographic findings of the junctional zone and correlation with histology.
      ,
      • Hanafi M.
      Ultrasound diagnosis of adenomyosis, leiomyoma, or combined with histopathological correlation.
      ,
      • Di Donato N.
      • Bertoldo V.
      • Montanari G.
      • et al.
      Question mark form of uterus: a simple sonographic sign associated with the presence of adenomyosis.
      ,
      • Luciano D.E.
      • Exacoustos C.
      • Albrecht L.
      • et al.
      Three-dimensional ultrasound in diagnosis of adenomyosis: histologic correlation with ultrasound targeted biopsies of the uterus.
      ,
      • Acar S.
      • Millar E.
      • Mitkova M.
      • et al.
      Value of ultrasound shear wave elastography in the diagnosis of adenomyosis.
      ], of which 7 [
      • Sharma K.
      • Bora M.K.
      • Venkatesh B.P.
      • et al.
      Role of 3D ultrasound and Doppler in differentiating clinically suspected cases of leiomyoma and adenomyosis of uterus.
      ,
      • Kepkep K.
      • Tuncay Y.A.
      • Göynümer G.
      • et al.
      Transvaginal sonography in the diagnosis of adenomyosis: which findings are most accurate?.
      ,
      • Sun Y.L.
      • Wang C.B.
      • Lee C.Y.
      • et al.
      Transvaginal sonographic criteria for the diagnosis of adenomyosis based on histopathologic correlation.
      ,
      • Exacoustos C.
      • Brienza L.
      • Di Giovanni A.
      • et al.
      Adenomyosis: three-dimensional sonographic findings of the junctional zone and correlation with histology.
      ,
      • Hanafi M.
      Ultrasound diagnosis of adenomyosis, leiomyoma, or combined with histopathological correlation.
      ,
      • Di Donato N.
      • Bertoldo V.
      • Montanari G.
      • et al.
      Question mark form of uterus: a simple sonographic sign associated with the presence of adenomyosis.
      ,
      • Luciano D.E.
      • Exacoustos C.
      • Albrecht L.
      • et al.
      Three-dimensional ultrasound in diagnosis of adenomyosis: histologic correlation with ultrasound targeted biopsies of the uterus.
      ] were included for quantitative analysis (meta-analysis).
      Fig. 3
      Fig. 3Flow diagram showing selection of articles for systematic review.
      With regards to the imaging tools and number of patients included in this review, 5 articles assessed 2-dimensional (2D) TVUS, 3 assessed 3D TVUS, and 1 evaluated TVUS with elastography (TVUS elastography) (Table 1). All studies were case series evaluating the accuracy of TVUS imaging tool confirmed by histopathologic evaluation. All studies included patients submitted to hysterectomy due to dysmenorrhea, menometrorrhagia, or suspected adenomyosis [
      • Sharma K.
      • Bora M.K.
      • Venkatesh B.P.
      • et al.
      Role of 3D ultrasound and Doppler in differentiating clinically suspected cases of leiomyoma and adenomyosis of uterus.
      ,
      • Kepkep K.
      • Tuncay Y.A.
      • Göynümer G.
      • et al.
      Transvaginal sonography in the diagnosis of adenomyosis: which findings are most accurate?.
      ,
      • Sun Y.L.
      • Wang C.B.
      • Lee C.Y.
      • et al.
      Transvaginal sonographic criteria for the diagnosis of adenomyosis based on histopathologic correlation.
      ,
      • Exacoustos C.
      • Brienza L.
      • Di Giovanni A.
      • et al.
      Adenomyosis: three-dimensional sonographic findings of the junctional zone and correlation with histology.
      ,
      • Hanafi M.
      Ultrasound diagnosis of adenomyosis, leiomyoma, or combined with histopathological correlation.
      ,
      • Di Donato N.
      • Bertoldo V.
      • Montanari G.
      • et al.
      Question mark form of uterus: a simple sonographic sign associated with the presence of adenomyosis.
      ,
      • Luciano D.E.
      • Exacoustos C.
      • Albrecht L.
      • et al.
      Three-dimensional ultrasound in diagnosis of adenomyosis: histologic correlation with ultrasound targeted biopsies of the uterus.
      ,
      • Acar S.
      • Millar E.
      • Mitkova M.
      • et al.
      Value of ultrasound shear wave elastography in the diagnosis of adenomyosis.
      ]. Only 1 study also included patients submitted to myomectomy [
      • Hanafi M.
      Ultrasound diagnosis of adenomyosis, leiomyoma, or combined with histopathological correlation.
      ]. The prevalence of histologically confirmed adenomyosis and myomas in the included studies ranged from 34.0% to 73.6% and 23.6% to 94.3%, respectively.
      Table 1Included studies on TVUS imaging tools to access adenomyosis in the last 10 years
      TVUS typeStudyStandard testTotal no. of patientsAdenomyosis

      n (%)
      Myomas

      n (%)
      Quality ratingResults characteristics
      2DKepkep, 2007
      • Kepkep K.
      • Tuncay Y.A.
      • Göynümer G.
      • et al.
      Transvaginal sonography in the diagnosis of adenomyosis: which findings are most accurate?.
      Hysterectomy7026 (37.1)20 (28.6)GoodPathologist blinded
      2DSun, 2010
      • Sun Y.L.
      • Wang C.B.
      • Lee C.Y.
      • et al.
      Transvaginal sonographic criteria for the diagnosis of adenomyosis based on histopathologic correlation.
      Hysterectomy21385 (39.9)93 (43.7)GoodPathologist blinded
      2DHanafi, 2013
      • Hanafi M.
      Ultrasound diagnosis of adenomyosis, leiomyoma, or combined with histopathological correlation.
      Hysterectomy (130), myomectomy (33)163110 (67.5)134 (82.2)FairNot blinded; uninterpretable or intermediate results were not reported
      2DDi Donato, 2015
      • Di Donato N.
      • Bertoldo V.
      • Montanari G.
      • et al.
      Question mark form of uterus: a simple sonographic sign associated with the presence of adenomyosis.
      Hysterectomy5024 (48.0)NRFairNot blinded; uninterpretable or intermediate results were not reported
      2D/3DExacoustos, 2011
      • Exacoustos C.
      • Brienza L.
      • Di Giovanni A.
      • et al.
      Adenomyosis: three-dimensional sonographic findings of the junctional zone and correlation with histology.
      Hysterectomy7232 (44.4)17 (23.6)GoodPathologist blinded
      3DLuciano, 2013
      • Luciano D.E.
      • Exacoustos C.
      • Albrecht L.
      • et al.
      Three-dimensional ultrasound in diagnosis of adenomyosis: histologic correlation with ultrasound targeted biopsies of the uterus.
      Hysterectomy5436 (66.7)NRFairNot blinded; uninterpretable or intermediate results were not reported
      3D/color DopplerSharma, 2015
      • Sharma K.
      • Bora M.K.
      • Venkatesh B.P.
      • et al.
      Role of 3D ultrasound and Doppler in differentiating clinically suspected cases of leiomyoma and adenomyosis of uterus.
      Hysterectomy8830 (34.0)53 (60.2)FairNot blinded; uninterpretable or intermediate results were not reported
      ElastographyAcar, 2016
      • Acar S.
      • Millar E.
      • Mitkova M.
      • et al.
      Value of ultrasound shear wave elastography in the diagnosis of adenomyosis.
      Hysterectomy5339 (73.6)50 (94.3)FairNot blinded; uninterpretable or intermediate results were not reported
      NR = not reported.
      Quality of included studies evaluated using QUADAS scoring for included studies and evaluated imaging tools. All included studies were accuracy studies.

       Quality Assessment

      Three studies [
      • Kepkep K.
      • Tuncay Y.A.
      • Göynümer G.
      • et al.
      Transvaginal sonography in the diagnosis of adenomyosis: which findings are most accurate?.
      ,
      • Sun Y.L.
      • Wang C.B.
      • Lee C.Y.
      • et al.
      Transvaginal sonographic criteria for the diagnosis of adenomyosis based on histopathologic correlation.
      ,
      • Exacoustos C.
      • Brienza L.
      • Di Giovanni A.
      • et al.
      Adenomyosis: three-dimensional sonographic findings of the junctional zone and correlation with histology.
      ] were of good quality, whereas 5 [
      • Sharma K.
      • Bora M.K.
      • Venkatesh B.P.
      • et al.
      Role of 3D ultrasound and Doppler in differentiating clinically suspected cases of leiomyoma and adenomyosis of uterus.
      ,
      • Hanafi M.
      Ultrasound diagnosis of adenomyosis, leiomyoma, or combined with histopathological correlation.
      ,
      • Di Donato N.
      • Bertoldo V.
      • Montanari G.
      • et al.
      Question mark form of uterus: a simple sonographic sign associated with the presence of adenomyosis.
      ,
      • Luciano D.E.
      • Exacoustos C.
      • Albrecht L.
      • et al.
      Three-dimensional ultrasound in diagnosis of adenomyosis: histologic correlation with ultrasound targeted biopsies of the uterus.
      ,
      • Acar S.
      • Millar E.
      • Mitkova M.
      • et al.
      Value of ultrasound shear wave elastography in the diagnosis of adenomyosis.
      ] were of fair quality using QUADAS scoring (Table 1). In the 3 studies rated as good [
      • Kepkep K.
      • Tuncay Y.A.
      • Göynümer G.
      • et al.
      Transvaginal sonography in the diagnosis of adenomyosis: which findings are most accurate?.
      ,
      • Sun Y.L.
      • Wang C.B.
      • Lee C.Y.
      • et al.
      Transvaginal sonographic criteria for the diagnosis of adenomyosis based on histopathologic correlation.
      ,
      • Exacoustos C.
      • Brienza L.
      • Di Giovanni A.
      • et al.
      Adenomyosis: three-dimensional sonographic findings of the junctional zone and correlation with histology.
      ], pathologists were blinded to the imaging results. All other studies rated as fair included evaluators who were not blinded for both the standard and index tests, which may have created a review bias. Also, only 1 study [
      • Exacoustos C.
      • Brienza L.
      • Di Giovanni A.
      • et al.
      Adenomyosis: three-dimensional sonographic findings of the junctional zone and correlation with histology.
      ] reported the uninterpretable/intermediate results, which were excluded, whereas in all other studies this information was not reported.

       2D TVUS

      Five studies with a total of 568 patients addressed the accuracy of 2D TVUS in the diagnosis of adenomyosis and were included for quantitative analysis [
      • Kepkep K.
      • Tuncay Y.A.
      • Göynümer G.
      • et al.
      Transvaginal sonography in the diagnosis of adenomyosis: which findings are most accurate?.
      ,
      • Sun Y.L.
      • Wang C.B.
      • Lee C.Y.
      • et al.
      Transvaginal sonographic criteria for the diagnosis of adenomyosis based on histopathologic correlation.
      ,
      • Exacoustos C.
      • Brienza L.
      • Di Giovanni A.
      • et al.
      Adenomyosis: three-dimensional sonographic findings of the junctional zone and correlation with histology.
      ,
      • Hanafi M.
      Ultrasound diagnosis of adenomyosis, leiomyoma, or combined with histopathological correlation.
      ,
      • Di Donato N.
      • Bertoldo V.
      • Montanari G.
      • et al.
      Question mark form of uterus: a simple sonographic sign associated with the presence of adenomyosis.
      ]. Three studies [
      • Kepkep K.
      • Tuncay Y.A.
      • Göynümer G.
      • et al.
      Transvaginal sonography in the diagnosis of adenomyosis: which findings are most accurate?.
      ,
      • Sun Y.L.
      • Wang C.B.
      • Lee C.Y.
      • et al.
      Transvaginal sonographic criteria for the diagnosis of adenomyosis based on histopathologic correlation.
      ,
      • Di Donato N.
      • Bertoldo V.
      • Montanari G.
      • et al.
      Question mark form of uterus: a simple sonographic sign associated with the presence of adenomyosis.
      ] considered the diagnosis of adenomyosis when at least 1 sonographic criteria was present and 2 studies [
      • Exacoustos C.
      • Brienza L.
      • Di Giovanni A.
      • et al.
      Adenomyosis: three-dimensional sonographic findings of the junctional zone and correlation with histology.
      ,
      • Hanafi M.
      Ultrasound diagnosis of adenomyosis, leiomyoma, or combined with histopathological correlation.
      ] when 2 sonographic criteria were present. The reported sensitivity and specificity of 2D TVUS in these separate studies varied greatly, ranging from 75% to 85% and 43% to 90%, respectively (Fig. 4). A meta-analysis was performed, and the overall pooled sensitivity and specificity of all combined imaging characteristics of 2D TVUS evaluation of adenomyosis were 83.8% and 63.9%, respectively (Fig. 4).
      Fig. 4
      Fig. 4Pooled sensitivity and specificity off all combined imaging characteristics of 2D TVUS evaluation of adenomyosis.
      Multiple 2D TVUS imaging characteristics were used in these studies. Asymmetry of myometrial wall, myometrial cysts, hypoechoic linear striations, and heterogeneous myometrium were evaluated in 3 studies; globular-appearing uterus and poor definition of the endometrial–myometrial zone in 2; and the question mark sign in only 1 study (Table 2).
      Table 2
      Table thumbnail jmig3259-fig-5001
      The sensitivity and specificity of each 2D TVUS characteristic reported in the 5 studies varied greatly. For presence of myometrial cysts, sensitivity ranged from 53.1% to 82.4% and specificity from 45.3% to 97.5%. For hypoechoic linear striations, sensitivity ranged from 30.8% to 91.8% and specificity from 71.1% to 95.5%. Asymmetry of the myometrial wall was found to have sensitivity ranging from 46.9% to 61.5% and specificity from 63.6% to 80% (Table 2). A meta-analysis was performed for each of the ultrasound characteristics (summarized in Table 2). The overall pooled sensitivity for 355 patients for heterogeneous myometrium with 2D TVUS was highest (86.0%), whereas the overall pooled specificity for 283 patients was highest for globular uterus (78.1%).
      The efficacy of the use of the question mark sonographic sign for the presence of adenomyosis was first reported in a 2015 study [
      • Di Donato N.
      • Bertoldo V.
      • Montanari G.
      • et al.
      Question mark form of uterus: a simple sonographic sign associated with the presence of adenomyosis.
      ]. This study reported that the overall sensitivity and specificity of 2D TVUS was 83% and 88%, respectively. After including the question mark sign with other ultrasound features in the imaging diagnosis, higher sensitivity and specificity, 92% and 88%, respectively, were noted.

       3D TVUS

      Three studies with a total of 214 patients addressed the accuracy of 3D TVUS in the diagnosis of adenomyosis [
      • Sharma K.
      • Bora M.K.
      • Venkatesh B.P.
      • et al.
      Role of 3D ultrasound and Doppler in differentiating clinically suspected cases of leiomyoma and adenomyosis of uterus.
      ,
      • Exacoustos C.
      • Brienza L.
      • Di Giovanni A.
      • et al.
      Adenomyosis: three-dimensional sonographic findings of the junctional zone and correlation with histology.
      ,
      • Luciano D.E.
      • Exacoustos C.
      • Albrecht L.
      • et al.
      Three-dimensional ultrasound in diagnosis of adenomyosis: histologic correlation with ultrasound targeted biopsies of the uterus.
      ]. The diagnosis of adenomyosis was defined by the presence of 1 sonographic feature in 1 study [
      • Sharma K.
      • Bora M.K.
      • Venkatesh B.P.
      • et al.
      Role of 3D ultrasound and Doppler in differentiating clinically suspected cases of leiomyoma and adenomyosis of uterus.
      ] and by 2 features in 2 studies [
      • Exacoustos C.
      • Brienza L.
      • Di Giovanni A.
      • et al.
      Adenomyosis: three-dimensional sonographic findings of the junctional zone and correlation with histology.
      ,
      • Luciano D.E.
      • Exacoustos C.
      • Albrecht L.
      • et al.
      Three-dimensional ultrasound in diagnosis of adenomyosis: histologic correlation with ultrasound targeted biopsies of the uterus.
      ]. The sensitivity was similar between 3D TVUS studies, ranging from 86.7% to 91.7%. However, specificity of 3D TVUS varied greatly, ranging from 44.4% to 86.7%. When all 3 studies were subjected for quantitative analysis, the overall pooled sensitivity and specificity of all combined imaging characteristics of 3D TVUS evaluation of adenomyosis were 84.7% and 81.0% (Fig. 5).
      Fig. 5
      Fig. 5Pooled sensitivity and specificity off all combined imaging characteristics of 3D TVUS evaluation of adenomyosis.
      The imaging characteristics evaluated in all 3D TVUS studies were presence of myometrial cysts, heterogeneous myometrial areas, asymmetry of the myometrial wall, and poor definition of the endometrial–myometrial junction. Poor definition of junctional zone was noted when the sonographer was unable to visualize a clear distinction between the endometrial–myometrial layers. This last criterion showed the highest pooled sensitivity (86%) and the highest pooled specificity (56.0%) for the diagnosis of adenomyosis with 3D TVUS. However, its specificity varied greatly among the studies, from 22.5% to 82.8%. Similarly, accuracy of the use of myometrial cysts varied greatly between studies, with sensitivity ranging from 33.3% to 83.3% and specificity from 5% to 88.9%. Hypoechoic linear striations were evaluated by only 1 study [
      • Luciano D.E.
      • Exacoustos C.
      • Albrecht L.
      • et al.
      Three-dimensional ultrasound in diagnosis of adenomyosis: histologic correlation with ultrasound targeted biopsies of the uterus.
      ], showing a sensitivity and specificity of 52.8% and 61.1%.

       TVUS with Color Doppler

      One study [
      • Sharma K.
      • Bora M.K.
      • Venkatesh B.P.
      • et al.
      Role of 3D ultrasound and Doppler in differentiating clinically suspected cases of leiomyoma and adenomyosis of uterus.
      ] compared 100 patients with adenomyosis with patients with myoma using TVUS with color Doppler. The lesions were evaluated for morphology, vascularity, pulsatility index, resistive index, and maximum velocity.
      For adenomyosis lesions, a central vascular pattern was observed in 93% of cases compared with a peripheric vascular pattern in 89% of patients with myoma. Doppler pulsatility index (9.0 ± .20 vs 1.5 ± .20), resistive index (.50 ± .15 vs .9 ± .15), and maximum velocity (12.0 ± 2.5 vs 7.0 ± 2.5 cm/sec) were significantly different between adenomyosis and myoma groups. Using a cut-off value of a pulsatility index > 1.2 and a resistive index > .7, sensitivity for the diagnosis of adenomyosis with TVUS with color Doppler was 95.6%, specificity was 93.4%, positive predictive value was 88.6%, and negative predictive value was 97.6%. This study suggested benefit with the use of TVUS with color Doppler in differentiating adenomyosis from myomas, with an overall diagnostic accuracy of the use of TVUS with color Doppler for adenomyosis of 93.8%.

       TVUS Elastography

      Acar et al [
      • Acar S.
      • Millar E.
      • Mitkova M.
      • et al.
      Value of ultrasound shear wave elastography in the diagnosis of adenomyosis.
      ] evaluated 53 patients submitted to hysterectomy for menorrhagia with TVUS elastography. Adenomyosis was confirmed in 39 cases. Color and numerical values of Young's modulus in the areas of maximum myometrial stiffness was measured. TVUS elastography imaging (color window) with adenomyosis was characterized by red, green, and yellow colors (showing predominately heterogeneous staining due to high stiffness), whereas unremarkable myometrium was mapped by blue color. Comparing the mean value of Young's modulus in patients with and without adenomyosis, significant difference was noted (72.7 kPA vs 28.3 kPA; p < .05). Also, when Young's modulus value higher than 34.6 kPa was used as the threshold, the sensitivity and specificity of TVUS elastography in adenomyosis diagnosis were 89.7% and 82.9%, respectively.

      Discussion

      The prevalence of adenomyosis is considerable in women of reproductive age, ranging from 20% to 35%. The prevalence of adenomyosis is likely underestimated because of the lack of standardized criteria in both imaging and histologic confirmation [
      • Abbott J.A.
      Adenomyosis and abnormal uterine bleeding (AUB-A)—pathogenesis, diagnosis, and management.
      ]. To illustrate, it has been estimated that histologic confirmation of adenomyosis ranges from 5% to 70% of patients who undergo hysterectomy [
      • Bazot M.
      • Cortez A.
      • Darai E.
      • et al.
      Ultrasonography compared with magnetic resonance imaging for the diagnosis of adenomyosis: correlation with histopathology.
      ].
      The availability of better imaging tools and determination of the best diagnostic feature(s) for adenomyosis would provide greater understanding of the disease. Studies evaluating multiple TVUS imaging characteristics have suggested different types of adenomyosis to be associated with other conditions and with varying clinical presentations [
      • Alabiso G.
      • Alio L.
      • Arena S.
      • et al.
      Adenomyosis: what the patient needs.
      ]. To illustrate, external adenomyosis has been associated with deep endometriosis in 49% to 60% of cases [
      • Gonzales M.
      • Matos L.A.
      • Gonçalves M.O.
      • et al.
      Patients with adenomyosis are more likely to have deep endometriosis.
      ]. Diffuse adenomyosis was noted to be more frequently associated with menorrhagia compared with nodular adenomyosis (84% vs 37%; p = .001) [
      • Pistofidis G.
      • Makrakis E.
      • Koukoura O.
      • et al.
      Distinct types of uterine adenomyosis based on laparoscopic and histopathologic criteria.
      ]. Indeed, more recent findings showed that the presence of more ultrasound features of adenomyosis in the patient was positively associated with more severe menstrual pain scores [
      • Naftalin J.
      • Hoo W.
      • Nunes N.
      • et al.
      Association between ultrasound features of adenomyosis and severity of menstrual pain.
      ,
      • Pinzauti S.
      • Lazzeri L.
      • Tosti C.
      • et al.
      Transvaginal sonographic features of diffuse adenomyosis in 18–30-year-old nulligravid women without endometriosis: association with symptoms.
      ].
      In the present systematic review 8 qualified studies showed that, overall, 2D TVUS and 3D TVUS are effective methods for diagnosis of adenomyosis with pooled sensitivity of 84% and 89% and pooled specificity of 64% and 56%, respectively. Improved diagnostic performance was noted when the question mark sign was used in addition to the other imaging characteristics. For all other imaging characteristics, accuracy varied greatly between studies, with the greatest variability observed in presence of myometrial cysts and hypoechoic linear striations for both 2D TVUS and 3D TVUS studies. This finding highlights the fact that further studies comparing each of these features for diagnosis performed by larger and multiple centers would be helpful. Future studies should also determine if characterization of the extent of disease (such as depth of myometrial infiltration, amount of myometrial cysts, or even amount of discrepancy between anterior and posterior myometrial thickness) may improve on diagnostic performance.
      In this review, specificity of 2D TVUS for adenomyosis was significantly enhanced with the use of 3D TVUS (64% vs 81%, respectively), whereas the sensitivity was not affected (84% vs 85%). Also, the pooled sensitivity and specificity for each of the imaging characteristics used in 3D TVUS were similar to those used in 2D TVUS, with the exception of the use of poor definition of junctional zone where greater sensitivity was noted when used in 3D TVUS compared with 2D TVUS (sensitivity 87.8% vs 58.6%, specificity 56.0% vs 71.5%, respectively).
      The use of color Doppler to differentiate adenomyosis from malignancies and uterine leiomyoma has been suggested previously [
      • Sharma K.
      • Bora M.K.
      • Venkatesh B.P.
      • et al.
      Role of 3D ultrasound and Doppler in differentiating clinically suspected cases of leiomyoma and adenomyosis of uterus.
      ,
      • Kepkep K.
      • Tuncay Y.A.
      • Göynümer G.
      • et al.
      Transvaginal sonography in the diagnosis of adenomyosis: which findings are most accurate?.
      ]. In this review 1 study was conducted showing the potential of the use of color Doppler in identifying the vascular pattern of adenomyomas, showing a high accuracy in differentiating these lesions from myomas. Because only 1 study has shown a difference in vascular pattern compared with myomas, larger comparative studies are needed to further delineate the role of the use of TVUS with color Doppler and other enhancement tools such as TVUS elastography for the differentiation between myomas and adenomyosis.
      This systematic review confirms that 2D TVUS is effective and should be considered as the first-line ultrasound imaging method for the diagnosis of adenomyosis. Enhancing tools such as 3D TVUS improved on sensitivity when used with poor definition of junctional zone, whereas no improvement was noted in the overall sensitivity compared with 2D TVUS. A lack of consensus remains in the imaging criteria used for nonhistologic confirmation of adenomyosis. More robust comparative studies are needed to advance our understanding of the disease and, ultimately, to expand the nonsurgical treatment options for patients with adenomyosis.

      Acknowledgment

      We thank Manoel Orlando Gonçalves, Leandro Accardo de Mattos, and Ana Luiza Marques for the ultrasound imaging figures.

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