{"paper_id":"8f6afec9-af0a-495f-9381-5d6d5f9893e3","body_text":"ALMA MATER STUDIORUM UNIVERSITA’ DI BOLOGNA \n \nDOTTORATO DI RICERCA IN \nScienze Mediche Generali e Dei Servizi \n \nCiclo XXIX Secondo Bando \nSettore Concorsuale 06H1 \nSettore Scientifico-Disciplinare MED/40 \n \n \n \nACCURACY OF NEW SONOGRAPHIC MARKERS IN \nTHE DIAGNOSIS OF ADENOMYOSIS \n \n \n \n \n \nPresentata dalla Dott.ssa                                                  \nLETIZIA ZANNONI       \n                                                   \nCoordinatore Dottorato Chiar.mo Prof.                         Relatore Chiar.mo Prof.    \n                         \nLUIGI BOLONDI                                           RENATO SERACCHIOLI \n \n \nEsame finale anno 2017 \n\n 2\n \n   \n                                                  Index  \n \n \n \n \n \n \n \n Abstract                                                                                    3  \n Introduction                                                                              5 \n Patients  and Methods                                                               7              \n Results                                                                                    10 \n Discussion                                                                              13 \n Tables                                                                                      17                                                                   \n Image                                                                                      21                                                                   \n References                                                                              22                   \n\n 3\n                                              Abstract \n \nObjective : to evaluate the diagnostic accuracies of well-kno wn sonographic \nmarkers of adenomyosis and of two innovative ones, the question mark sign  \nand the transvaginal ultrasound uterine tenderness . \nMethods : 78 patients scheduled for hysterectomy for uterin e benign diseases \nunderwent preoperative transvaginal ultrasonography  to evaluate the criteria of \nsonographic diagnosis of adenomyosis as reported by  consensus statement \nMUSA. Adenomyosis was diagnosed in presence of two or more of the \nfollowing parameters: asymmetry of the uterine wall s, hyperechoic striae, \nanechoic myometrial cysts, hyperechogenic islands, echogenic subendometrial \nlines and buds, interruption/irregularities of the junctional zone and \ntranslesional vascular flow. In addition the question mark sign  and the \ntransvaginal ultrasound uterine tenderness  were evaluated, the first being  the \nlongitudinal section of the uterus with a morpholog y similar to a question mark \nand the other being the dynamic ultrasound evaluati on of uterine tenderness by \nthe pressure of the transvaginal probe. Sonographic  features were compared \nwith histological examination. \nResults : the prevalence of adenomyosis in the sample is 33 .3%. Sensitivity, \nspecificity, positive and negative predictive values and accuracy of transvaginal \nultrasound in the diagnosis of adenomyosis are 83%,  96%, 91%, 89% and 92%. \nAsymmetry, hyperechoic striae and interruption of t he junctional zone were the \n\n 4\nmost accurate markers for the diagnosis of adenomyo sis. Myometrial \nheterogeneity was the most frequently encountered f eature (100%), but showed \na low specificity (7%). The question mark sign  and the transvaginal ultrasound \nuterine tenderness  showed sensitivity, specificity, positive and nega tive \npredictive values and accuracy of 41%, 96%, 83%, 77 %, and 69% and 69%, \n65%, 66%, 81% and 67% respectively. \nConclusions : the sonographic markers proposed by consensus sta tement \nMUSA were confirmed accurate in the diagnosis of adenomyosis in our sample. \nThe question mark sign  and the transvaginal ultrasound uterine tenderness  \nshowed good diagnostic capacities and may be a usef ul complement in the \nsonographic diagnosis of adenomyosis.  \n \n\n 5\n      Introduction  \n \n \nAdenomyosis is a benign condition of the uterus def ined by the presence of \nendometrial glands and stroma within the myometrium . Adenomyosis affects \naround 20% of women during their fertile age and ma y be associated to \ndysmenorrhea, menorrhagia and infertility 1. \nA diagnosis of certainty can be posed only by histo logical examination. \nSeveral studies showed that transvaginal sonography  (TVS) can be considered \nthe first-line imaging modality for studying adenom yosis, because it is as \nsensitive and as specific as magnetic resonance, 2–6 nevertheless univocal \nultrasound parameters for the diagnosis of adenomyo sis are still lacking. 7 \nRecently the MUSA (Morphological Uterus Sonographic  Assessment) \nconsensus statement proposed terms, definitions and  measurements that may be \nused to describe and report the sonographic feature s of the myometrium using \ngray-scale sonography, color/power Doppler and thre e-dimensional ultrasound \nimaging, with particular regard to two conditions: adenomyosis and fibroids. 8 \nEven if many ultrasound features are supposed to be  associated with \nadenomyosis, the diagnostic weight of each one is n ot clear and some features \nmay be more relevant than others in order to formul ate a diagnosis. 8 A \nparticular shape of the uterine rime, called the question mark sign, has been \nrecently described as a typical sign of adenomyosis  associated with deep \n\n 6\ninfiltrating posterior endometriosis 9,10  and it was deliberately not included in \nthe MUSA statement. 8 Transvaginal ultrasound is a dynamic examination 11 , \npermitting to the operator to evaluate the tenderne ss of an examined anatomical \nstructures by a gentle pressure of the probe. An en larged and tender uterus, \npainful at mobilization may suggest adenomyosis 12 . The TVS uterine \ntenderness , that is the tenderness of the uterus during the g entle pressure with \nthe transvaginal probe, could be useful to rule out  the presence of adenomyosis, \noften associated to painful uterine mobilization. \n The aim of our study is to establish the diagnosti c accuracy of the \nultrasound features associated to adenomyosis accor ding to the MUSA \nstatement and of two new markers, the question mark sign , evaluated \nindependently from the presence of endometriosis, a nd the TVS uterine \ntenderness .\n\n 7\n                       Patients and methods  \n \n \nThis is a cross-sectional observational study enrol ling all consecutive \npremenopausal women with a diagnosis of a benign ut erine pathology, \ndiagnosed by ultrasound or by hysteroscopy, and sch eduled for hysterectomy \nfrom November 2014 to June 2016 in the Department o f Gynaecology and \nHuman Reproduction Pathophysiology, Sant’Orsola Hos pital, University of \nBologna. Postmenopausal women and those with a pre- surgical diagnosis of a \nreproductive tract cancer were excluded.  \n A data sheet with most relevant information on eac h patient’s medical \nhistory was filled in: age, BMI, last menstrual per iod, gravidity and parity, \nprevious pelvic surgery, previous diagnosis of endo metriosis, presence of \ndysmenorrhea, menorrhagia and dyspareunia. \nTransvaginal ultrasound examination was carried out  using a 4–9-MHz probe \nwith a three-dimensional (3D) facility (Voluson E8, GE Medical Systems, Zipf, \nAustria). All transvaginal ultrasound scans were pe rformed in a standardized \nfashion by a single operator with more than 7 years  of experience (L.Z.). \nPhotos, clips and 3D scans were saved and stored fo r further examinations. The \nstudy of the uterine corpus was carried out as indi cated by the MUSA \nstatement. \n8 In addition the sonographer evaluated subjectively the globular-\n\n 8\nshape of the uterus, the tenderness of the uterus a t the gentle pressure of the \ntransvaginal probe and the presence of the question mark sign (Figure 1) .9, 10  A \n3D volume of each uterus was stored following the m ethod of Exacoustos 13  in \norder to evaluate the junctional zone  (JZ). 8 The diagnosis of adenomyosis was \nposed when at least two of the ultrasound features studied were present.  \n Each patient underwent laparoscopic, laparotomic o r vaginal \nhysterectomy according to her clinical condition wi thin one month from the \nultrasound examination. In each case the whole uter us was sent to histological \nexamination, except one for which morcellation was needed. \n All histopathological examinations were performed by the same \npathologist, skilled in gynaecologic pathology and blinded to the ultrasound \nfindings. For each uterus a series of samples were taken, including all the wall \nfrom the serosa to the endometrium. Of these, at le ast three samples were taken \nboth from the posterior and from the anterior wall.  The diagnosis of \nadenomyosis was posed if endometrial stroma and gla nds were present into the \nmyometrial layer. Adenomyosis was reported as diffu se or focal and evaluated \nby the grade of invasion: limited to the internal half of the myometrium (M1) or \nfull-thickness (M2). In case of doubt, an immunoche mical test with CD10 \nantibodies was performed in order to highlight the ectopical endometrium. 14  For \nthe purpose of this study, only the presence or abs ence of adenomyosis was \nconsidered, but not the depth of infiltration. \n\n 9\n All the data were recorded in an electronic databa se. Patients were \ndivided into two groups, according to the presence or absence of adenomyosis \nat the histological examination. Means and standard  deviations were calculated \nfor the continuous variables, using the Student's T -test. Relative frequencies \nwere calculated for the categorical variables using  the chi-squared test or \nFisher’s exact test. P value less than .05 was cons idered statistically significant. \nIn order to compare gravidity and parity of the two  groups, each one was \ndivided into three classes, considering the number of pregnancies and \ndeliveries. Agreement between TVS and histological diagnosis was measured \nwith Cohen’s Kappa coefficient. Sensitivity, specif icity, positive (PPV) and \nnegative (NPV) predictive values, positive (LH+) and negative (LH-) likelihood \nratios and accuracy (area under curve ROC) of each TVS variable were \ncalculated. Analyses were performed by using the St atistical Package for the \nSocial Sciences version 16 (SPSS Inc., Chicago, IL, USA). \nAll the patients signed an informed consent and the  study was approved by our \nlocal ethics committee (clinical trial ARC-ENDO n. 149/2014/O/Oss). \n\n 10 \n                                                                   Results  \n \nSeventynine patients were enrolled in this study an d one was excluded because \nthe uterus was morcellated during laparoscopic hyst erectomy, due to its great \nsize. The total number of patients considered in th e statistical analysis is 78. \nForty/78 (51.2%) patients were operated on for leyomyomatosis, 24/78 (30.8%) \nfor adenomyosis, 10/78 (12.8%) for uterine prolapse , 4/78 (0.5%) for fibroids \nwith atypical ultrasound appearance. Hysterectomy w as performed through \nlaparoscopy in 62/78 (79.5%) patients, laparotomy i n 6/78 (7.7%) and vaginal \napproach in 10/78 (12.8%) cases. \n Histology showed adenomyosis in 26/78 (33.3%) pati ents, among them \n16/26 (61.5%) presented fibroids and 6/26 (23.1%) p resented adenomyomas. \nAmong the 52/78 (66.6%) patients without adenomyosi s 41/78 (52.5%) had \nfibroids, 1/78 (1.2%) had a spindle-like cells neop lasia with myogenic \ndifferentiation and mitotic index <4 M/10 HPF, and 10/78 (12.8%) showed \nhysterocele not associated to myometrial pathology. \n Clinical features of patients are shown in Table 1 . There are no \nstatistically significant differences between the t wo groups with and without \nadenomyosis for age, BMI, gravidity and parity. Stu dent's T-test and linear \nregression shows an inverse correlation between the  uterine volume calculated \nby ultrasound and the diagnosis of adenomyosis. Nev ertheless, by dividing the \n\n 11 \ntwo populations into quartiles of volumes, no stati stically significant difference \nbetween the two groups can be found. \n Percentage frequencies of symptoms and association  with previous \npelvic surgeries or with endometriosis are summariz ed in Table 2. All the \ndiagnosis of endometriosis nodules suspected by TVS  were confirmed by \nhistology. Menorrhagia was significantly more frequ ent in patients with \nadenomyosis.  \n TVS diagnosed adenomyosis in 22/78 (28.2%) patient s: in 20/22 \n(90.9%) cases ultrasound diagnosis was confirmed by  the pathologist, while \n2/22 (9.1%) cases were false positives. Among the 5 6/78 (71.8%) patients \nwithout ultrasound features of adenomyosis, 4/56 (7 .1%) were false negatives, \nwhile 52/56 (92.9%) were true negatives. TVS diagnosed adenomyosis in 20/26 \n(76.9%) patients positives at histological examinat ion, with sensitivity, \nspecificity, PPV, NPV 83%, 96%, 91% e 89% respectiv ely. Positive and \nnegative likelihood ratio were 20 and 0.24. Global accuracy of TVS is 92.3%. \nKappa analysis showed a good accordance between his tology and TVS \n(kappa=0.760). \n Table 3 shows the statistical significance of each  ultrasound feature \nincluded in the study according to presence/absence  of adenomyosis at \nhistology. Hyperechoic islands and subendometrial l ines and buds were not \npresent in the examined sample. Table 4 shows diagn ostic capacities of each \nultrasound marker. Heterogeneous myometrium showed the highest sensitivity \nand PPV (both 100%). Most specific markers were JZm ax ≥8mm, fan-shaped \n\n 12 \nstriations and question-mark sign  (respectively 99%, 96% and 96%), with PPV \nrespectively 100%, 88% and 83%.  \n\n 13 \n                                                          Discussion  \n \n     This is the first study strictly applying the MUSA indications 8 to \nprospectively validate the importance of each of these ultrasound features in the \ndiagnosis of adenomyosis in a sample of 78 hysterec tomies. In addition it \nshowed two new ultrasound markers for the diagnosis  of adenomyosis: the \nquestion mark sign  and the TVS uterine tenderness , showing an accuracy of \n69% and 67% respectively.  \n      In this study 2D, 3D and power Doppler ultrasound features were associated \nin order to diagnose adenomyosis, obtaining diagnos tic capacities superior than \nKepkep  et al. \n15  and similar to those obtained in other studies, wh ich report \nsensitivity up to 89% and specificity up to 100%. 16-18  In accordance with Bazot \net al. 18  TVS is very specific, but prone to produce false n egatives, which is the \nbest condition for a test aiming to diagnose a beni gn pathology. In addition, our \ndata show that TVS diagnostic capacity is reduced i n the presence of \ncomorbidities, as it was already demonstrated 3,18 : all the diagnostic mistakes (4 \nfalse negatives, 2 false positives) were made in pa tients affected by fibroids. A \nrecent meta-analysis of 14 trials and 1985 particip ants reported sensitivity and \nspecificity of ultrasound-diagnosed adenomyosis to be as high as 82.5 and \n84.6%, respectively 19 . Our data showed a similar sensitivity but a great er \n\n 14 \nspecificity, maybe due to the presence of two new s onographic markers of \nendometriosis. \n      The q uestion mark sign  has been recently proposed by our group as a \nmarker of adenomyosis strongly associated with deep  infiltrating posterior \nendometriosis. \n10  In the present study the question mark sign  showed to be a \nmarker of adenomyosis independent from the presence  of endometriosis. Its \nstrong association with adenomyosis is in contrast with MUSA consensus \nstatement. 8 The question mark sign showed also great specifici ty (96%) and \nPPV (83%) with the best positive likelihood ratio among 2D ultrasound features. \nIn this sample, only 4 out of the ten patients affe cted by deep infiltrating \nposterior endometriosis showed an associated question mark sign and Fisher’s \nexact test excluded a correlation (p=0.245). These results suggest that question \nmark sign  might have a wider application in diagnosing adeno myosis than \npreviously thought.  \n     As far as we are aware this is the first prosp ective study proposing TVS \nuterine tenderness as a marker of adenomyosis, showing a NPV of 81% an d an \naccuracy of 67.3%. Original descriptions of adenomy osis reported an \nassociation between the disease and “a great deal o f pain” \n20 . Several later \nstudies reported similar findings 21-23 , but others have not shown significant \ndifferences in the prevalence of adenomyosis in wom en with and without a \nhistory of pain 24-26 . One possible confounder in the interpretation of pain could \nbe the coexisting presence of endometriosis, which is a common cause of pain \nin women of reproductive age. We believe that the u se of TVS, as a dynamic \n\n 15 \nexamination 11 , permits to show if the pain is related to the gen tle pressure and \nmobilization of the uterus and permits as well to f ind the tenderness related to \nother location of endometriosis, if present. \n        Among the ultrasound features of adenomyosi s the most specific were \nJZmax ≥8mm, fan-shaped striations and question-marked sign . Our results are \ncomparable to previous studies for the high specifi city of fan-shaped striation \n15-\n18  and  of myometrial cysts 27 , while Jzmax in our study showed better values \nthan previously shown 27 . Heterogeneous myometrium is once again the most \nsensitive marker, but with very low specificity 18 . The main problem with the \nuse of histology for the diagnosis of adenomyosis i s the heavy selection bias \nincurred 28 , indeed we had a very high percentage of leyomyomato sis, typically \nassociated to heterogeneous myometrium at TVS. \n    Prevalence of adenomyosis in the sample is 33.3 %, which is consistent with \nthe Literature, where a mean value of 20-30% is reported in patients undergoing \nhysterectomy for various indications \n29-31 . \n       Differently from Literature 5,6,8  an association between increased uterine \nvolume and adenomyosis was not found. Regarding thi s, it should be taken into \naccount that patients without adenomyosis were ofte n affected by \nleyomyomatosis, which also increases uterine volume . Nevertheless, \nExacoustos et al.  demonstrated a significant correlation between dec reased \nuterine volume and adenomyosis, in comparison with uterus without fibroids 13 .  \n     Several strengths add power to this study: the  use of histological \nconfirmation of the diagnosis, the fact that all ul trasound scans were performed \n\n 16 \nusing top-of-the-range equipment by a single operat or, thereby minimizing \ninterobserver variability and the fact that all the  demographic, ultrasound and \nanamnestic data were collected prospectively. In pa rticular it is remarkable that \nall the diagnosis of endometriotic nodules suspected by TVS were confirmed by \nhistology. Moreover the choice of using wide inclus ion criteria reduced the \nselection bias and allowed to evaluate adenomyosis in presence of numerous \npotentially confounding variables, as fibroids, tha t often reduce diagnostic \naccuracy 3,18 .  Wide inclusion criteria are also a potential weakne ss of this study, \nas confounding factors, such as fibroids and hormon al treatments prevented \nsome features from being detectable in several pati ents. Another main \nlimitation of this study is the only inclusion of p atients undergoing \nhysterectomy, creating a selection bias, as patient s who chose surgery are more \nsymptomatic than those who do not. \n    This study confirms TVS diagnostic accuracy in diagnosing adenomyosis, \nreinforcing TVS role as a first-line exam for its r eliability, safety and cheapness. \nComparing the ultrasound features considered curren tly to be typical of \nadenomyosis in a sample full of confounding factors demonstrates their validity \neven in less selected patients, providing an update d and realistic idea of TVS \ndiagnostic capacities that could be applied in ever yday clinical practice. The \ntwo new proposed features, the question mark sign  and the TVS uterine \ntenderness,  showed promising results and might prove to be use ful for the \ndiagnosis of adenomyosis. Further prospective studi es are needed in order to \nprove their efficacy in wider samples.  \n\n 17 \nTable 1. Population characteristic of 78 premenopausal patie nts according to \npresence/absence of adenomyosis at histology. Data are presented as mean ± \nstandard deviation, or as % frequencies.  \n                                         Adenomyosis at histology  \nCharacteristic Yes ( n=26) No ( n=52) P \n \n \nAge (years) \n \n48.2 ± 3.9 \n \n47.1 ± 3.9 \n \nn.s.  \nBMI 24.6 ± 1.1 25.5 ± 1.0 n.s.  \nParity   \n0 38.5% 23.1% n.s.  \n1 23.1% 30.8% n.s.  \n>1 38.4% 46.1% n.s.  \nGravidity   \n0 30.8% 19.2% n.s.  \n1 23.1% 26.9% n.s.  \n>1 46.1% 53.9% n.s.  \nUterine volume 230 ± 189 295 ± 306 n.s.  \n \n \n \n\n 18 \n \nTable 2.  Clinical symptoms and association with previous pe lvic surgeries and \nendometriosis according to presence/absence of aden omyosis at histology. Data \nare presented as frequencies.   \n \n                                                          Adenomyosis at histology  \n Yes (n=26) No (n=52) P \n    \nDysmenorrhea 77% 50% n.s. \nDyspareunia 46% 31% n.s. \nMenorrhagia 85% 50% 0.045 \nPrevious pelvic surgery 46% 46% n.s. \nPresence of endometriosis 30% 15% n.s. \n \n\n 19 \n \nTable 3. Ultrasound features according to presence/absence of adenomyosis at \nhistology.  Data are presented as n(%). N.e. not evaluable. \n                                                               Adenomyosis at histology   \nFeatures Yes (n=26) No (n=52) N.e. P \n \nGlobular shape \n \n \n10 (77%) \n \n14 (54%) \n \n0 \n \nn.s. \nHeterogeneus myometrium  \n \n13 (100%) \n \n24 (92%) \n \n0 n.s. \nFan-shaped striations \n \n7 (54%) 1 (4%) \n \n0 0.001 \nMyometrial cysts \n \n4 (31%) 2 (8%) 0 n.s. \nIll-defined interface 11 (85%) \n \n11 (42%) \n \n1 0.037 \nQuestion mark sign \n \n5 (38%) \n \n1 (4%) \n \n2 0.005 \nWalls asymmetry \n \n8 (62%) \n \n2 (8%) \n \n20 0.001 \nTVS uterine tenderness \n \n9 (69%) \n \n9 (35%) \n \n0 0.044 \nDoppler \n \n4 (31%) \n \n2 (8%) \n \n2 0.011 \nJZ max ≥ 8 mm \n \n4 (31%) \n \n0 (0%) \n \n13 0.015 \n∆ JZ ≥ 4 mm \n \n6 (46%) \n \n2 (8%) \n \n13 0.027 \nJZ interruption \n \n7 (54%) \n \n2 (8%) \n \n13 0.008 \n \n \n \n \n\n 20 \nTable 4. Diagnostic capacities of each ultrasound features associated to the \ndiagnosis of adenomyosis. \n \nFeature Sensibility \n Specificity  PPV NPV  LR+  LR- Accuracy  \n        \nGlobular shape \n \n77% 46% 42% 80% 1.43 0.5 61.5% \nAsimmetry \n \n80% 70% 72% 78% 2.67 0.29 \n 78.9% \nHeterogeneous myometrium  \n \n100% 7% 35% 100%  1.08 0 53.9% \nIll-defined interface \n \n85% 56% 50% 88% 1.9 0.27 \n 70.3% \nFan-shaped striations \n \n54% 96% 88% 81% 14 0.48 \n 75.0% \nMyometrial cysts \n \n30% 92% 67% 73% 4 0.75 \n 61.5% \nQuestion-mark sign \n \n41% 96% 83% 77% 10.42 \n 0.61  68.8% \nTVS uterine tenderness \n \n69% 65% 66% 81% 2 0.47  67.3% \nJZ max \n \n40% 99% 100% \n 73% 4 0.60  70.0% \nJZ interruption \n \n70% 88% 78% 82% 5.64 0.35 \n 78.8% \n∂JZ \n \n60% 87% 75% 76% 4.5 0.46  73.8% \nDoppler \n \n55% 88% 66% 82% 4.72 0.51 \n 71.5% \n \n\n 21 \nFigure 1.  Transvaginal sonography longitudinal section of a uterus showing the \nquestion mark sign  which is described when the corpus uteri is flexed  \nbackwards, the fundus uteri is facing the posterior  pelvic compartment and the \ncervix is directed frontally towards the urinary bl adder with the endometrial \nrhim resembling a question mark sign (a, b). Schema tic drawing of the question \nmark sign (c). \n \n \n \n \n \na \n \n \nc \n \n \nb \n \n \n \n \n \n \n    \n\n 22 \n \nReferences  \n \n1. Naftalin J, Hoo W, Pateman K, Mavrelos D, Hollan d T, Jurkovic D. \nHow common is adenomyosis? A prospective study of p revalence using \ntransvaginal ultrasound in a gynaecology clinic. Hu m Reprod. 2012; \n27(12):3432-3439.  \n2. Dueholm M, Lundorf E, Hansen ES, Sorensen JS, Le dertoug S, Olesen \nF. Magnetic resonance imaging and transvaginal ultrasonography for the \ndiagnosis of adenomyosis. Fertil Steril. 2001;76(3):588-594.  \n3. Bazot M, Cortez A, Darai E, et al. 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