Two-dimensional and 3-dimensional transvaginal ultrasound with addition of power Doppler angiography and gel infusion sonography for diagnosis of endometrial malignancy. Margit Dueholm1, Julie Wulf Holm1, Stinne Rydbjerg1, Estrid Stær Hansen2, Gitte Ørtoft1 From Department of Obstetrics and Gynecology1 Department of pathology2 Aarhus University Hospital Brendstrupgaardsvej 100 8200 Aarhus N, Denmark
Corresponding author: Margit Dueholm Department of Obstetrics and Gynecology1 Aarhus University Hospital Brendstrupgaardsvej 100 8200 Aarhus N, Denmark Mail:[email protected] This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/uog.13421
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ABSTRACT Aim: To evaluate the diagnostic efficiency of 2-dimensional and 3-dimensional transvaginal ultrasonography (2D-TVS, 3D-TVS), power Doppler angiography (2D-PDA, 3D-PDA), and gel infusion sonography (2D-GIS, 3D-GIS) at offline analysis for recognition of malignant endometrium compared to live-scanning; and to determine optimal image parameters at 3Danalysis. Design: 169 consecutive women with postmenopausal bleeding and an endometrium thickness ≥ 5 mm had systematic evaluation of endometrial pattern(SEP) at live- and offline 2D- and 3D-analysis. Hysteroscopy or hysterectomy was reference standard. The efficiency of the different techniques for malignant diagnosis was calculated and compared. 3D image parameters, endometrial volume and 3D vascular indices were assessed. Optimal 3D image parameters were at logistic regression transformed into a risk of endometrial cancer(RECscore) capturing the scores for; Body Mass Index(BMI),endometrial thickness; endometrial morphology at grey-scale, Doppler and GIS. Results: Offline 2D and 3D-analysis had equivalent, but lower diagnostic performance than live scanning. Their diagnostic performance was not markedly improved by addition of PDA and GIS, but their efficiency was comparable with that of live 2D-GIS in offline examinations of good image quality. At logistic regression, the 3D-parameters from the REC-score system had the highest diagnostic efficiency. The area under the curve(AUC) of the REC-score system at 3D-GIS; 0.89, was not improved by vascular indices or endometrial volume calculations. Conclusion: Live scanning is most efficient, but offline 2D and 3D-analysis is useful for prediction of endometrial cancer when good image quality can be obtained. The diagnostic efficiency at 3D-analysis may be improved by use of REC-scoring systems, without calculation of vascular indices or endometrial volume. Keywords: endometrial neoplasms, ultrasonography, ultrasonography, Doppler color, post menopause, uterine hemorrhage Abbreviations: Area under the curve (AUC) Body mass index (BMI)
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Doppler score (DS) Endometrial volume (EV) Flow index (FI) Gel infusion sonography (GIS) Two dimensional gel infusion sonography (2D-GIS) Three dimensional gel infusion sonography (2D-GIS) Receiver-operating curve (ROC) Positive predictive value (PPV), Negative predictive value (NPV), Positive likelihood ratio (LR+), Negative likelihood ratio (LR-). Risk of endometrial cancer score (REC score) Saline infusion sonography (SIS) Subjective impression based on systematic evaluation of pattern (SEP) Transvaginal ultrasound (TVS) Two dimensional transvaginal ultrasound (2D-TVS) Three dimensional transvaginal ultrasound (3D-TVS) Power Doppler angiography (PDA) Two-dimensional transvaginal ultrasound with power Doppler angiography (2D-PDA) Three-dimensional transvaginal ultrasound with power Doppler angiography (3D-PDA) Vascularization index (VI) Vascularization-flow index (VFI) INTRODUCTION Transvaginal ultrasonography (TVS) is the most cost-effective first test in the diagnostic work-up of postmenopausal bleeding1-3and may identify patients at very low risk of endometrial cancer4;5. In patients with an increased endometrial thickness, identification of patients at high risk of endometrial cancer at the first TVS examination may allow high-risk patients to be referred for fast-track investigation and staging., This set-up could shorten the time from the first investigation to treatment. In experienced hands, evaluation of endometrial pattern at TVS, saline infusion sonography (SIS), and Doppler findings6-9 yield promising results for identification of patients at high risk of endometrial cancer6-12. First-line investigations should ideally be performed by experienced assessors to ensure fast-track
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referral, but experienced assessors are only rarely accessible for such procedures. Page: 5 Assessment at two-dimensional (2D) TVS usually takes place while scanning and demands diligence in image optimization and pathology recognition. Modern scanners and software have simplified image optimization, but recognition of pathology continues to demand considerable experience. Offline analysis of three-dimensional (3D) volumes is reliable for assessing adnexal masses13, and offline analysis of 3D volumes or 2D video recordings by experts could compensate for the lack of local experts and could hence be an efficient alternative. Evaluation of endometrial pattern based on a score system at live 2D-TVS and live 2D-GIS had a high diagnostic efficiency for diagnosis of malignancy14. The score system may be improved at 3D-volume assessment by inclusion of 3D-vascular indices and endometrial volume (EV) measurements10-12. Thus, we hypothesize that 3D ultrasound may increase the diagnostic performance of 2D ultrasound. We propose to rethink the diagnostic set-up so that the current practice of local first-line assessment is supplemented by a secondary evaluation of 3D volumes by non-local experienced assessors. The aim of the present study was to assess and compare the diagnostic efficiency of off-line and live analysis of 2D- and 3D-TVS, PDA, and GIS for discrimination between benign and malignant endometrial conditions in women with postmenopausal bleeding and a thickened endometrium. Moreover, the aim was to evaluate the most optimal image parameters at 3D.
METHODS Two investigators who were blinded to the results of all prior microscopic specimens and diagnoses performed TVS with Doppler and GIS in consecutive women with postmenopausal bleeding and an endometrial thickness of ≥ 5 mm referred to Aarhus University Hospital, Denmark, from October 2010 to February 2012. Both examiners had several years of experience in the staging of endometrial cancer. 2D clips and 3D volumes were stored after each examination (TVS, TVS with Doppler and GIS). The study group comprised patients with postmenopausal bleeding referred to our clinic. Some of the patients were unselected (n = 93), but a number of patients (n = 76) had been referred from other hospitals. The exclusion criteria used in the present study have been described elsewhere 14.
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Ultrasound analysis was performed as follows: In the first round, live evaluation at TVS with Doppler (Live-PDA) and GIS (Live-GIS) was performed and 2D-clips and 3D-volumes were stored. In the second round, stored clips (2D-TVS, 2D-PDA, and 2D-GIS) were assessed. In a third round, 3D-volumes (3D-TVS, 3D-PDA, and 3D-GIS) were evaluated. In a fourth round, data on vascular indices and the EV at 3D-PDA were obtained. Each round of analysis was followed by systematic pattern evaluation which included completion of a standard systematic form with IETA parameters 15. A subjective impression of malignancy after systematic pattern evaluation (SEP) was formed at the end of each examination (Live-PDA, Live-GIS, 2D-TVS, 2D-PDA, 2D-GIS, 3D-TVS, 3D-PDA, and 3D-GIS). Included for analysis were all patients (169) for whom 2D clips or correctly stored 3D volumes obtained at any of the three examination (TVS, PDA or GIS) could be evaluated (3D-TVS(n=169), 3D-power Doppler(n=155), 3D-GIS(n=160)) (clips 2D-TVS (n=165), 2DPDA(n=153), and 2-D-GIS(n=159). A total of 1142 off-line 2D and 3D evaluations were undertaken at TVS, TVS with Doppler, and GIS. In addition, vascular indices and EVs were calculated in155 3D-PDA volumes. The Central Denmark Regional Ethics Committee approved the study protocol. As hysteroscopy was standard procedure in the department, the committee found that no informed consent for this procedure was needed. After ultrasound evaluation, a standard history with respect to clinical variables was obtained. The most optimal Doppler image parameters at 2D-live scanning and at 2D clips evaluation by two observers were evaluated, and a Doppler score (DS) was developed. The DS was obtained by simple addition of the following Doppler parameters: vessels, but no dominant single/double (DV) (1 point), multiple vessels (> 4-5) (1 point), large vessels (1 point), and splashed/densely packed vessels (1 point)14. A score system for evaluation of the risk of endometrial cancer (REC) was designed based on different 2D image parameters analyzed by logistic regression and the most optimal evaluation of live 2D in this population14. The REC score system included body mass index (BMI) exceeding or equal to 30 (30+ = score 1), total endometrial thickness exceeding or equal to 10mm (10+= score 1), total endometrial thickness exceeding or equal to 15mm (15+= score 1), vascularity, no single/double vessel (present = score 1), multiple (> 4-5) vessels (present= score 1), large vessels (present= score 1), splashed/densely packed vessels (present=score 1), interrupted endo-myometrial junction (present = score 1), and irregular surface at GIS (present = score 1). Simple addition of these values constituted the REC score This article is protected by copyright. All rights reserved
14
. Diagram of parameters in the REC-score system and accompanying ultrasound pictures is
shown in Figure 1.
Transvaginal ultrasound (TVS) Examinations were performed with a Voluson E8 expert (GE Healthcare, Milwaukee, WI) equipped with a multifrequency (5-12 MHz) endovaginal probe according to a predetermined scanning protocol. The endometrial structure, thickness, and analysis of vessels at power Doppler ultrasonography was evaluated using a standard form meeting the International Endometrial Tumor Analysis (IETA) criteria 15 as previously described 14; the form comprised the following elements: Internal endometrial echo structure: Hyper/hypo/iso -echogenic, cystic, (regular/irregular), homo/heterogeneity. Endomyometrial border, subendometrial halo (junctional zone (jz)): Visualization and interruption of subendometrial halo, regular/irregular, homo/heterogeneity, and bright line. A 2-D power Doppler gate was activated to assess vascularization from the myometrium and the endometrium. Power Doppler settings were set to achieve maximum sensitivity to detect low-velocity flow without noise using predetermined, standardized settings (frequency, 6 MHz; power Doppler gain, 50; dynamic range, 10 dB; edge, 1; persistence, 2; color map, 1; gate, 2; filter, 3; PRF 0.6). Analysis of the power Doppler ultrasonography included visual evaluation of the vessels15: Dominant (single or double); origin (focal or multifocal); number (few or multiple); large vessels (yes, no); branching (yes, no), if branching (regular); presence of: color splashes, densely packed vessels, circular flow. After the TVS and Doppler examinations, the evaluation of image parameters was entered on paper sheets. The main diagnoses of malignancy were interpreted subjectively after systematic evaluation of patterns (SEP): cystic endometrium with irregular or interrupted endo-myometrial junction; indistinct endo-myometrial border; multiple vessels at Doppler sonography.
Gel installation sonography (GIS) GIS was performed as previously described 14. A small flexible sterile catheter (infantfeeding tube Unometric no:227581, Abena A/S Aabenraa, Denmark) mounted with a 10-mL syringe with Instillagel® (E.Tjellesen A/S, Lynge, Denmark) was introduced into the uterine This article is protected by copyright. All rights reserved
cavity. During instillation of gel (GIS), the pressure was manually adjusted until sufficient for expansion of the uterine cavity. The distension was continuously observed by TVS, and distension was continued until the entire uterine cavity was clearly visible. The uterine cavity was evaluated in sagittal and coronal views. At GIS, the same parameters as at TVS were evaluated. Endometrial thickness was measured in the sagittal plane as the sum of the maximum endometrial thickness at the anterior and the posterior wall. A standardized coding sheet was used for registration of the additional parameters defined by the IETA system15 as previously described14: the structure of the endometrial surface (smooth, polyploidy, irregular), the size of localized and/or a non-localized lesions (i.e. a lesion < or > 25% of the surface), and the structure of the surface of the local lesion (regular or irregular). The findings were classified as present, not present or indefinite to avoid missing values. After systematic evaluation of patterns (SEP), the main diagnoses of malignancy at GIS were interpreted subjectively as follows: TVS findings of malignancy and/or irregular surface of a localized or diffuse lesion at GIS. 3-dimensional volume acquisition: With a sweeping angle of 90-120 degrees, an acquisition box of 3D volume was placed over the uterus. The patient was asked to remain as immobile as possible, and at least two 3D volume acquisitions were made. With addition of a power Doppler window, a 3D power Doppler angiography (3D-PDA) of the uterus was obtained with the previously defined fixed settings. Volume acquisition was repeated when artifacts appeared. 2D clips and 3D storage At each examination (TVS, Doppler, GIS), three 2D clips were obtained including two sweeps in the sagittal plane and one in the horizontal plane. Clips of 5-10 seconds (retrospective) were obtained. The system was set for retrospective storage of either the last ten seconds or the length of the last scanning section (most often used). Two 3D volumes at 3DTVS, 3D-PDA, and 3D-GIS, respectively, were stored and evaluated later in a personal computer using the VOCAL program (Kretz Technik, Zipf, Austria). Evaluation of stored 2D videos clips All patients were given an identity number. 2D clips obtained at the live investigations were stored in a separate file with this number by (SR). All examinations (n=169) (2D-TVS+ 2DPDA+2D-GIS) were given a new random identity number. Three months after the
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investigation was completed, all 2D clips were evaluated by (MD) in random order without knowledge of the patient’s identity and pathology. The patient’s age was noted on a standard form. The standard form was also used for entering data on the quality of the images (score 1 to 5) at examination, the same morphologic endometrial parameters as those obtained at the primary evaluation14;15; and, again, a diagnosis was given at the end of each evaluation, first at TVS, then at Doppler, and finally at GIS. All video clips were evaluated in the order 2D-TVS, 2D-PDA, and 2D-GIS. Again, after systematic evaluation of patterns (SEP), a subjective diagnosis of malignancy was given.
Evaluation of stored 3D volumes 3D volumes at 3D-TVS, 3D-PDA, and 3D-GIS were evaluated 3 month after the 2D-video evaluation had been completed using the VOCAL program. We evaluated the morphologic criteria, image quality, and diagnosis (maximum of two prioritized diagnoses). Each examination consisted of six to ten volume determinations in the order 3D-TVS, 3D-PDA, and 3D-GIS. Again, all examinations were given a new random number and they were performed randomly in an order blinded to the previous date of examination and the patient’s identity. At each examination, we opened all stored volumes, and used the volume with highest quality for measurement. All volumes were evaluated in the order 3D-TVS, 3DPDA, and 3D-GIS. Again at each evaluation (3D-TVS.3D-PDA and 3D-GIS, respectively), 3D-volumes were evaluated according to the criteria stated above, and the results were entered into a standard form a diagnosis of malignancy was based on subjective impression after systematic evaluation of pattern (SEP) and stated at the end of each examination.
3D-power Doppler indices analysis: Four months later, 3D-PDAs were analyzed for 3D power Doppler indices. Using the virtual organ computer-aided analysis (VOCAL) program, we evaluated the endometrial area manually in the coronal or C plane. Using a rotational technique with a 9-degree step as previously described 11;16, 20 endometrial slices were obtained that outlined the endometrium at the myometrial-endometrial junction from the fundus to the internal cervical opening. The VOCAL program was used to calculate the EV and three 3D power Doppler indices: vascularization index (VI), flow index (FI), and vascularization-flow index (VFI). VI measures the number of color voxels in the volume. It may represent the vessels in the tissue and is expressed as a percentage. FI is the mean color value in the color voxels. It indicates the average intensity of blood flow and is expressed as a number from 0-100. VFI is the mean This article is protected by copyright. All rights reserved
color value in all the voxels in the volume. It represents both vascularization and blood flow and is also expressed as a number from 0-100. Pathology All patients had hysteroscopy and/or hysterectomy; and microscopic pathology was the reference standard at these examinations14. All focal changes were attempted removed at hysteroscopy; and in cases of large, diffuse or localized changes, resectoscopic biopsies were taken from the area of the endometrium with the largest changes. Three to five biopsies were sampled. In cases of normal hysteroscopic findings, one biopsy was taken from the anterior wall of the uterine cavity, one from the posterior wall of the uterine cavity, and curettage was performed at the end of hysteroscopy. Two pathologists specialized in gynecological oncology evaluated all specimens. Statistics and analysis Data were analyzed using STATA (Statistic Data Analysis, STATA Corp, TX, USA). Continuous data and normally distributed data are expressed as mean ± standard deviation. Wilcoxon signed rank test and McNemar’s test were used for comparison of the scored quality of the examination. •
We evaluated and compared the diagnostic performance of Live-PDA, with addition of GIS (Live-GIS), off line video evaluation (2D-TVS) with addition of Doppler (2DPDA), and GIS(2D-GIS) and 3D-TVS with addition of Doppler(3D-PDA) and GIS (3D-GIS).
•
The diagnostic performance with regard to discrimination between a benign and a malignant endometrium of the different techniques was evaluated in terms of the areas under the curve (AUC), sensitivity, specificity, positive likelihood ratios (LR+), and negative likelihood ratios (LR-). Receiver-operator characteristic (ROC) curve analyses were performed to evaluate and compare the diagnostic performance of the different techniques.
•
ROC analysis was performed for all parameters measured by 3D (pattern variables and parameters calculated by vocal program (index and volume). The sensitivity, the specificity, and the LR+ and LH- of the most optimal cut points were calculated.
•
Stepwise multivariate logistic regression was performed to build a model that could be used to predict malignancy at 3D evaluation. A maximum of four fitting variables were allowed into the model. Optimal cut points were calculated using a 45-degree tangent line intersection or the smallest sum of residual sensitivity and specificity.
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•
The most optimal ROC curve calculated by logistic regression was compared to the REC score developed at live-2D-evaluation, χ2 tests were used for discrete data. Statistical tests were two-tailed; P < 0.05 was considered statistically significant.
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RESULTS The mean age (range) of patients was 64.1(45-89) years. Endometrial cancer was present in 69 (40.8%) of the patients, hyperplasia in 20 (11.8%), and endometrial polyps in 51(30.2%). Overall diagnostic efficiency of live 2D, 2D clips, and 3D evaluations. Table 1 shows the diagnostic efficiency of the evaluation of 2D-Live, 2D clips, and 3D volumes. Sensitivities were from 70-89% and specificities close to 90% at the different offline 3D and 2D evaluations. Addition of Doppler and GIS did not markedly change the diagnostic efficiency. Live scanning GIS (153 patients) obtained better diagnostic efficiency than both 3D-GIS and 2D-GIS clips (p splashed/densely packed p vesseels (presentt=score 1), iinterrupted endo-myom e metrial juncttion o these (presentt = score 1)), and irreguular surfacee at GIS (preesent = scorre 1). Simplle addition of 14 values cconstituted the REC score . Diaggram A) shoows REC sccores for BM MI (30+), endomeetrial thicknness(10+), (115+), interruupted endo-m myometrial junction(1+ +) and irreggular surface at GIS (1+). ) Accompannying ultrassound picturres illustratee interrupted d endo-myoometrial junctionn B) and irregular endoometrial surrface at 2D and a 3DGIS C) and D). Diagram E) E illustratte vascularitty, no singlee/double veessel (1+), multiple m (> 4-5) 4 vesselss (1+), largee vessels (1+), spplashed/densely packedd vessels. A single vesssel (3D endo ometrial pollyp) is demonsstrated in F)) densely paacked vessels G) and multiple m andd large vesssels in H).
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Legend Figure 2. Area under the curve (AUC) of 2-dimensional and 3-dimensional transvaginal ultrasonography (2DTVS, 3DTVS), power Doppler angiography (2DPDA, 3DPDA), and gel infusion sonography (2DGIS,3DGIS) at offline analysis and live-scanning(LiPDA, LiGIS). The figure include only patients(n=136) in whom all evaluations by all techniques were completed.
.95
AUC
.9
.85
.8
.75 AUC 95% CI LiPDA
2DTVS LiGIS
2DGIS 2DPDA
3DPDA 3DTVS
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3DGIS
Table 1: Diagnostic efficiency for diagnosis of malignancy at live and offline analysis of 3D-TVS, 3D-PDA, 3DGIS, 2D-TVS, 2D-PDA, and 2D-GIS. Subjective impression based on systematic evaluation of pattern (SEP) was used.
N
Live evaluation Live 16 PDA 9 Live GIS 15 8 2D-offline
Sensitivity
Specificity
% (CI95% n/N )
% (CI95% n/N )
LR+ (CI%95 )
LR (CI%95 - )
N=158 87. (77-94) 60/6 0 9 88. (79-95) 62/7 6 0
88. (80-94) 88/10 0 0 95. (89-99) 84/88 5
7.3 (4.212.4 ) 19. (7.55 50.9)
.1 5 .1 2
2D-TVS 16 5
80. (69-89) 54/6 6 7
88. (81-94) 87/98 8
7.2 (4.112.6)
2D-PDA 15 3
79. (67-89) 47/5 7 9
89. (81-95) 84/94 4
2D-GIS
84. (74-92) 59/7 3 0
83. (74-90) 74/89 1
15 9
Patients who had all tests AU (CI%95 AUC C ) (CI%95)
(.08.27) (.06.23)
.87 5 .92 0
(.82.93) (.8896)
.879(.83 -.93) .920(.88 -96) N=142
.2 (.132 .36)
.84 (.797 .90)
.838(.78 -.90)
7.5 (4.113.6)
.2 (.143 .38)
.84 (.795 .91)
.838(.78 -.90)
5.0 (3.18.0)
.1 (.119 .33)
.83 (.787 .90)
.839(.78 -.90)
3D-volume 3D-TVS 16 69. (57-80) 9 6 3D-PDA 15 72. (60-83) 5 6 3D-GIS 16 78. (67-88) 0 6 Investigation with agreement at 2D and 3D (offline analysis) TVS 13 82. (69-92) 7 4 Dopple 14 83. (71-92) r 3 3 GIS 14 88. (77-95) 0 1 Image quality 1-3 (offline analysis) 3D-GIS 12 81. (68-91) 4 1 2D-GIS 13 89. (78-96) 5 1
N=145 48/6 9 45/6 2 55/7 0
92. (85-97) 92/10 0 0 89. (81-95) 83/93 1 87. (79-94) 79/90 8
8.7 (4.417.2) 6.8 (3.712.4) 6.4 (3.711.3)
.3 3 .3 1 .2 4
(.23.48) (.20.46) (.16.39)
.80 8 .80 9 .83 2
(.75.87) (.74.87) (.77.89)
.803(.74 -.87) .809(.74 -.87) .832(.77 -.89) N=120
42/5 1 45/5 4 52/5 9
97. (92-98) 84/86 7 94. (87-98) 84/89 4 90. (82-96) 73/81 1
35. 4 14. 8 8.9
(9.0140) (6.335) (4.617.3)
.1 8 .1 8 .1 3
(.10.33) (.10.32) (.07.27)
.90 0 .88 9 .89 1
(.85.96) (.83.94) (.84.94)
.921(.87 -.97) .925(.88 -.98) .916(.86 -.97) N=115
43/5 3 49/5 5
90. (81-96) 64/71 1 86. (77-93) 69/80 3
8.2 (4.016.8) 6.5 (3.711.3)
.2 1 .1 3
(.12.37) (.06.27)
.85 6 .87 7
(.79.92) (.82.93)
.879(.82 -.94) .878(.82 -.94)
Evaluation of transvaginal ultrasound at the performance (live-TVS). 2- and 3-dimensional offline transvaginal ultrasound (2D-TVS, 3D-TVS); 2- and 3-dimensional offline power Doppler angiography(2D-PDA, 3D-PDA) and 2- and 3-dimensional offline and live gel infusion sonography This article is protected by copyright. All rights reserved
(2D-GIS, live GIS, 3D-GIS). Reference standard was histopathology at hysteroscopy or hysterectomy.Positive likelihood ratios (LR+) and negative likelihood ratios (LR-). Image quality 1-3 (excellent to intermediate) at 3D or 2D clips. Comparison of AUC: 3D-TVS vs. 2D-TVSoffline vs. 2DTVS live (n=163) NS; 3D-PDA, 2D-PDA offline, 2D-TVS live (n=151) NS. 3D-GIS vs. 2D-GIS offline vs. live 2D-GIS (n=153) (p 10%)
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Table 2: Mean endometrial thickness (ET), endometrial volume (EV ) (cm3), vascular index (VI), vascular flow index (VFI), and flow index (FI) for patients with endometrial cancer, hyperplasia, benign uterine polyps, and the remaining patients (Other).(n=169) N
ET (CI95%)
EV (CI95%)
VI (CI95%)
VFI (CI95%)
FI (CI95%)
Cancer
69 18.4 (15.521.3)
20.5 (7.733.2)
13.81 (9.018.6)
4.09 (2.65.6)
27.73 (25.729.8)
Hyperplasia
20 12.3 (9.515.2)
5.47 (3.17.8)
4.85 (2.17.6)
1.42 (.582.3)
24.28 (20.827.8)
Polyps
51
9.9 (8.811.1)
5.88 (3.18.6)
5.85 (2.79.1)
1.13 (.651.6)
22.39 (20.424.3)
Other
29
8.1 (6.7-9.6) 5.62 (.1011.1)
3.83 (1.56.2)
1.02 (.351.7)
21.63 (19.024.2)
P
Corresponding author: Margit Dueholm Department of Obstetrics and Gynecology1 Aarhus University Hospital Brendstrupgaardsvej 100 8200 Aarhus N, Denmark Mail:[email protected] This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/uog.13421
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ABSTRACT Aim: To evaluate the diagnostic efficiency of 2-dimensional and 3-dimensional transvaginal ultrasonography (2D-TVS, 3D-TVS), power Doppler angiography (2D-PDA, 3D-PDA), and gel infusion sonography (2D-GIS, 3D-GIS) at offline analysis for recognition of malignant endometrium compared to live-scanning; and to determine optimal image parameters at 3Danalysis. Design: 169 consecutive women with postmenopausal bleeding and an endometrium thickness ≥ 5 mm had systematic evaluation of endometrial pattern(SEP) at live- and offline 2D- and 3D-analysis. Hysteroscopy or hysterectomy was reference standard. The efficiency of the different techniques for malignant diagnosis was calculated and compared. 3D image parameters, endometrial volume and 3D vascular indices were assessed. Optimal 3D image parameters were at logistic regression transformed into a risk of endometrial cancer(RECscore) capturing the scores for; Body Mass Index(BMI),endometrial thickness; endometrial morphology at grey-scale, Doppler and GIS. Results: Offline 2D and 3D-analysis had equivalent, but lower diagnostic performance than live scanning. Their diagnostic performance was not markedly improved by addition of PDA and GIS, but their efficiency was comparable with that of live 2D-GIS in offline examinations of good image quality. At logistic regression, the 3D-parameters from the REC-score system had the highest diagnostic efficiency. The area under the curve(AUC) of the REC-score system at 3D-GIS; 0.89, was not improved by vascular indices or endometrial volume calculations. Conclusion: Live scanning is most efficient, but offline 2D and 3D-analysis is useful for prediction of endometrial cancer when good image quality can be obtained. The diagnostic efficiency at 3D-analysis may be improved by use of REC-scoring systems, without calculation of vascular indices or endometrial volume. Keywords: endometrial neoplasms, ultrasonography, ultrasonography, Doppler color, post menopause, uterine hemorrhage Abbreviations: Area under the curve (AUC) Body mass index (BMI)
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Doppler score (DS) Endometrial volume (EV) Flow index (FI) Gel infusion sonography (GIS) Two dimensional gel infusion sonography (2D-GIS) Three dimensional gel infusion sonography (2D-GIS) Receiver-operating curve (ROC) Positive predictive value (PPV), Negative predictive value (NPV), Positive likelihood ratio (LR+), Negative likelihood ratio (LR-). Risk of endometrial cancer score (REC score) Saline infusion sonography (SIS) Subjective impression based on systematic evaluation of pattern (SEP) Transvaginal ultrasound (TVS) Two dimensional transvaginal ultrasound (2D-TVS) Three dimensional transvaginal ultrasound (3D-TVS) Power Doppler angiography (PDA) Two-dimensional transvaginal ultrasound with power Doppler angiography (2D-PDA) Three-dimensional transvaginal ultrasound with power Doppler angiography (3D-PDA) Vascularization index (VI) Vascularization-flow index (VFI) INTRODUCTION Transvaginal ultrasonography (TVS) is the most cost-effective first test in the diagnostic work-up of postmenopausal bleeding1-3and may identify patients at very low risk of endometrial cancer4;5. In patients with an increased endometrial thickness, identification of patients at high risk of endometrial cancer at the first TVS examination may allow high-risk patients to be referred for fast-track investigation and staging., This set-up could shorten the time from the first investigation to treatment. In experienced hands, evaluation of endometrial pattern at TVS, saline infusion sonography (SIS), and Doppler findings6-9 yield promising results for identification of patients at high risk of endometrial cancer6-12. First-line investigations should ideally be performed by experienced assessors to ensure fast-track
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referral, but experienced assessors are only rarely accessible for such procedures. Page: 5 Assessment at two-dimensional (2D) TVS usually takes place while scanning and demands diligence in image optimization and pathology recognition. Modern scanners and software have simplified image optimization, but recognition of pathology continues to demand considerable experience. Offline analysis of three-dimensional (3D) volumes is reliable for assessing adnexal masses13, and offline analysis of 3D volumes or 2D video recordings by experts could compensate for the lack of local experts and could hence be an efficient alternative. Evaluation of endometrial pattern based on a score system at live 2D-TVS and live 2D-GIS had a high diagnostic efficiency for diagnosis of malignancy14. The score system may be improved at 3D-volume assessment by inclusion of 3D-vascular indices and endometrial volume (EV) measurements10-12. Thus, we hypothesize that 3D ultrasound may increase the diagnostic performance of 2D ultrasound. We propose to rethink the diagnostic set-up so that the current practice of local first-line assessment is supplemented by a secondary evaluation of 3D volumes by non-local experienced assessors. The aim of the present study was to assess and compare the diagnostic efficiency of off-line and live analysis of 2D- and 3D-TVS, PDA, and GIS for discrimination between benign and malignant endometrial conditions in women with postmenopausal bleeding and a thickened endometrium. Moreover, the aim was to evaluate the most optimal image parameters at 3D.
METHODS Two investigators who were blinded to the results of all prior microscopic specimens and diagnoses performed TVS with Doppler and GIS in consecutive women with postmenopausal bleeding and an endometrial thickness of ≥ 5 mm referred to Aarhus University Hospital, Denmark, from October 2010 to February 2012. Both examiners had several years of experience in the staging of endometrial cancer. 2D clips and 3D volumes were stored after each examination (TVS, TVS with Doppler and GIS). The study group comprised patients with postmenopausal bleeding referred to our clinic. Some of the patients were unselected (n = 93), but a number of patients (n = 76) had been referred from other hospitals. The exclusion criteria used in the present study have been described elsewhere 14.
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Ultrasound analysis was performed as follows: In the first round, live evaluation at TVS with Doppler (Live-PDA) and GIS (Live-GIS) was performed and 2D-clips and 3D-volumes were stored. In the second round, stored clips (2D-TVS, 2D-PDA, and 2D-GIS) were assessed. In a third round, 3D-volumes (3D-TVS, 3D-PDA, and 3D-GIS) were evaluated. In a fourth round, data on vascular indices and the EV at 3D-PDA were obtained. Each round of analysis was followed by systematic pattern evaluation which included completion of a standard systematic form with IETA parameters 15. A subjective impression of malignancy after systematic pattern evaluation (SEP) was formed at the end of each examination (Live-PDA, Live-GIS, 2D-TVS, 2D-PDA, 2D-GIS, 3D-TVS, 3D-PDA, and 3D-GIS). Included for analysis were all patients (169) for whom 2D clips or correctly stored 3D volumes obtained at any of the three examination (TVS, PDA or GIS) could be evaluated (3D-TVS(n=169), 3D-power Doppler(n=155), 3D-GIS(n=160)) (clips 2D-TVS (n=165), 2DPDA(n=153), and 2-D-GIS(n=159). A total of 1142 off-line 2D and 3D evaluations were undertaken at TVS, TVS with Doppler, and GIS. In addition, vascular indices and EVs were calculated in155 3D-PDA volumes. The Central Denmark Regional Ethics Committee approved the study protocol. As hysteroscopy was standard procedure in the department, the committee found that no informed consent for this procedure was needed. After ultrasound evaluation, a standard history with respect to clinical variables was obtained. The most optimal Doppler image parameters at 2D-live scanning and at 2D clips evaluation by two observers were evaluated, and a Doppler score (DS) was developed. The DS was obtained by simple addition of the following Doppler parameters: vessels, but no dominant single/double (DV) (1 point), multiple vessels (> 4-5) (1 point), large vessels (1 point), and splashed/densely packed vessels (1 point)14. A score system for evaluation of the risk of endometrial cancer (REC) was designed based on different 2D image parameters analyzed by logistic regression and the most optimal evaluation of live 2D in this population14. The REC score system included body mass index (BMI) exceeding or equal to 30 (30+ = score 1), total endometrial thickness exceeding or equal to 10mm (10+= score 1), total endometrial thickness exceeding or equal to 15mm (15+= score 1), vascularity, no single/double vessel (present = score 1), multiple (> 4-5) vessels (present= score 1), large vessels (present= score 1), splashed/densely packed vessels (present=score 1), interrupted endo-myometrial junction (present = score 1), and irregular surface at GIS (present = score 1). Simple addition of these values constituted the REC score This article is protected by copyright. All rights reserved
14
. Diagram of parameters in the REC-score system and accompanying ultrasound pictures is
shown in Figure 1.
Transvaginal ultrasound (TVS) Examinations were performed with a Voluson E8 expert (GE Healthcare, Milwaukee, WI) equipped with a multifrequency (5-12 MHz) endovaginal probe according to a predetermined scanning protocol. The endometrial structure, thickness, and analysis of vessels at power Doppler ultrasonography was evaluated using a standard form meeting the International Endometrial Tumor Analysis (IETA) criteria 15 as previously described 14; the form comprised the following elements: Internal endometrial echo structure: Hyper/hypo/iso -echogenic, cystic, (regular/irregular), homo/heterogeneity. Endomyometrial border, subendometrial halo (junctional zone (jz)): Visualization and interruption of subendometrial halo, regular/irregular, homo/heterogeneity, and bright line. A 2-D power Doppler gate was activated to assess vascularization from the myometrium and the endometrium. Power Doppler settings were set to achieve maximum sensitivity to detect low-velocity flow without noise using predetermined, standardized settings (frequency, 6 MHz; power Doppler gain, 50; dynamic range, 10 dB; edge, 1; persistence, 2; color map, 1; gate, 2; filter, 3; PRF 0.6). Analysis of the power Doppler ultrasonography included visual evaluation of the vessels15: Dominant (single or double); origin (focal or multifocal); number (few or multiple); large vessels (yes, no); branching (yes, no), if branching (regular); presence of: color splashes, densely packed vessels, circular flow. After the TVS and Doppler examinations, the evaluation of image parameters was entered on paper sheets. The main diagnoses of malignancy were interpreted subjectively after systematic evaluation of patterns (SEP): cystic endometrium with irregular or interrupted endo-myometrial junction; indistinct endo-myometrial border; multiple vessels at Doppler sonography.
Gel installation sonography (GIS) GIS was performed as previously described 14. A small flexible sterile catheter (infantfeeding tube Unometric no:227581, Abena A/S Aabenraa, Denmark) mounted with a 10-mL syringe with Instillagel® (E.Tjellesen A/S, Lynge, Denmark) was introduced into the uterine This article is protected by copyright. All rights reserved
cavity. During instillation of gel (GIS), the pressure was manually adjusted until sufficient for expansion of the uterine cavity. The distension was continuously observed by TVS, and distension was continued until the entire uterine cavity was clearly visible. The uterine cavity was evaluated in sagittal and coronal views. At GIS, the same parameters as at TVS were evaluated. Endometrial thickness was measured in the sagittal plane as the sum of the maximum endometrial thickness at the anterior and the posterior wall. A standardized coding sheet was used for registration of the additional parameters defined by the IETA system15 as previously described14: the structure of the endometrial surface (smooth, polyploidy, irregular), the size of localized and/or a non-localized lesions (i.e. a lesion < or > 25% of the surface), and the structure of the surface of the local lesion (regular or irregular). The findings were classified as present, not present or indefinite to avoid missing values. After systematic evaluation of patterns (SEP), the main diagnoses of malignancy at GIS were interpreted subjectively as follows: TVS findings of malignancy and/or irregular surface of a localized or diffuse lesion at GIS. 3-dimensional volume acquisition: With a sweeping angle of 90-120 degrees, an acquisition box of 3D volume was placed over the uterus. The patient was asked to remain as immobile as possible, and at least two 3D volume acquisitions were made. With addition of a power Doppler window, a 3D power Doppler angiography (3D-PDA) of the uterus was obtained with the previously defined fixed settings. Volume acquisition was repeated when artifacts appeared. 2D clips and 3D storage At each examination (TVS, Doppler, GIS), three 2D clips were obtained including two sweeps in the sagittal plane and one in the horizontal plane. Clips of 5-10 seconds (retrospective) were obtained. The system was set for retrospective storage of either the last ten seconds or the length of the last scanning section (most often used). Two 3D volumes at 3DTVS, 3D-PDA, and 3D-GIS, respectively, were stored and evaluated later in a personal computer using the VOCAL program (Kretz Technik, Zipf, Austria). Evaluation of stored 2D videos clips All patients were given an identity number. 2D clips obtained at the live investigations were stored in a separate file with this number by (SR). All examinations (n=169) (2D-TVS+ 2DPDA+2D-GIS) were given a new random identity number. Three months after the
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investigation was completed, all 2D clips were evaluated by (MD) in random order without knowledge of the patient’s identity and pathology. The patient’s age was noted on a standard form. The standard form was also used for entering data on the quality of the images (score 1 to 5) at examination, the same morphologic endometrial parameters as those obtained at the primary evaluation14;15; and, again, a diagnosis was given at the end of each evaluation, first at TVS, then at Doppler, and finally at GIS. All video clips were evaluated in the order 2D-TVS, 2D-PDA, and 2D-GIS. Again, after systematic evaluation of patterns (SEP), a subjective diagnosis of malignancy was given.
Evaluation of stored 3D volumes 3D volumes at 3D-TVS, 3D-PDA, and 3D-GIS were evaluated 3 month after the 2D-video evaluation had been completed using the VOCAL program. We evaluated the morphologic criteria, image quality, and diagnosis (maximum of two prioritized diagnoses). Each examination consisted of six to ten volume determinations in the order 3D-TVS, 3D-PDA, and 3D-GIS. Again, all examinations were given a new random number and they were performed randomly in an order blinded to the previous date of examination and the patient’s identity. At each examination, we opened all stored volumes, and used the volume with highest quality for measurement. All volumes were evaluated in the order 3D-TVS, 3DPDA, and 3D-GIS. Again at each evaluation (3D-TVS.3D-PDA and 3D-GIS, respectively), 3D-volumes were evaluated according to the criteria stated above, and the results were entered into a standard form a diagnosis of malignancy was based on subjective impression after systematic evaluation of pattern (SEP) and stated at the end of each examination.
3D-power Doppler indices analysis: Four months later, 3D-PDAs were analyzed for 3D power Doppler indices. Using the virtual organ computer-aided analysis (VOCAL) program, we evaluated the endometrial area manually in the coronal or C plane. Using a rotational technique with a 9-degree step as previously described 11;16, 20 endometrial slices were obtained that outlined the endometrium at the myometrial-endometrial junction from the fundus to the internal cervical opening. The VOCAL program was used to calculate the EV and three 3D power Doppler indices: vascularization index (VI), flow index (FI), and vascularization-flow index (VFI). VI measures the number of color voxels in the volume. It may represent the vessels in the tissue and is expressed as a percentage. FI is the mean color value in the color voxels. It indicates the average intensity of blood flow and is expressed as a number from 0-100. VFI is the mean This article is protected by copyright. All rights reserved
color value in all the voxels in the volume. It represents both vascularization and blood flow and is also expressed as a number from 0-100. Pathology All patients had hysteroscopy and/or hysterectomy; and microscopic pathology was the reference standard at these examinations14. All focal changes were attempted removed at hysteroscopy; and in cases of large, diffuse or localized changes, resectoscopic biopsies were taken from the area of the endometrium with the largest changes. Three to five biopsies were sampled. In cases of normal hysteroscopic findings, one biopsy was taken from the anterior wall of the uterine cavity, one from the posterior wall of the uterine cavity, and curettage was performed at the end of hysteroscopy. Two pathologists specialized in gynecological oncology evaluated all specimens. Statistics and analysis Data were analyzed using STATA (Statistic Data Analysis, STATA Corp, TX, USA). Continuous data and normally distributed data are expressed as mean ± standard deviation. Wilcoxon signed rank test and McNemar’s test were used for comparison of the scored quality of the examination. •
We evaluated and compared the diagnostic performance of Live-PDA, with addition of GIS (Live-GIS), off line video evaluation (2D-TVS) with addition of Doppler (2DPDA), and GIS(2D-GIS) and 3D-TVS with addition of Doppler(3D-PDA) and GIS (3D-GIS).
•
The diagnostic performance with regard to discrimination between a benign and a malignant endometrium of the different techniques was evaluated in terms of the areas under the curve (AUC), sensitivity, specificity, positive likelihood ratios (LR+), and negative likelihood ratios (LR-). Receiver-operator characteristic (ROC) curve analyses were performed to evaluate and compare the diagnostic performance of the different techniques.
•
ROC analysis was performed for all parameters measured by 3D (pattern variables and parameters calculated by vocal program (index and volume). The sensitivity, the specificity, and the LR+ and LH- of the most optimal cut points were calculated.
•
Stepwise multivariate logistic regression was performed to build a model that could be used to predict malignancy at 3D evaluation. A maximum of four fitting variables were allowed into the model. Optimal cut points were calculated using a 45-degree tangent line intersection or the smallest sum of residual sensitivity and specificity.
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•
The most optimal ROC curve calculated by logistic regression was compared to the REC score developed at live-2D-evaluation, χ2 tests were used for discrete data. Statistical tests were two-tailed; P < 0.05 was considered statistically significant.
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RESULTS The mean age (range) of patients was 64.1(45-89) years. Endometrial cancer was present in 69 (40.8%) of the patients, hyperplasia in 20 (11.8%), and endometrial polyps in 51(30.2%). Overall diagnostic efficiency of live 2D, 2D clips, and 3D evaluations. Table 1 shows the diagnostic efficiency of the evaluation of 2D-Live, 2D clips, and 3D volumes. Sensitivities were from 70-89% and specificities close to 90% at the different offline 3D and 2D evaluations. Addition of Doppler and GIS did not markedly change the diagnostic efficiency. Live scanning GIS (153 patients) obtained better diagnostic efficiency than both 3D-GIS and 2D-GIS clips (p splashed/densely packed p vesseels (presentt=score 1), iinterrupted endo-myom e metrial juncttion o these (presentt = score 1)), and irreguular surfacee at GIS (preesent = scorre 1). Simplle addition of 14 values cconstituted the REC score . Diaggram A) shoows REC sccores for BM MI (30+), endomeetrial thicknness(10+), (115+), interruupted endo-m myometrial junction(1+ +) and irreggular surface at GIS (1+). ) Accompannying ultrassound picturres illustratee interrupted d endo-myoometrial junctionn B) and irregular endoometrial surrface at 2D and a 3DGIS C) and D). Diagram E) E illustratte vascularitty, no singlee/double veessel (1+), multiple m (> 4-5) 4 vesselss (1+), largee vessels (1+), spplashed/densely packedd vessels. A single vesssel (3D endo ometrial pollyp) is demonsstrated in F)) densely paacked vessels G) and multiple m andd large vesssels in H).
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Legend Figure 2. Area under the curve (AUC) of 2-dimensional and 3-dimensional transvaginal ultrasonography (2DTVS, 3DTVS), power Doppler angiography (2DPDA, 3DPDA), and gel infusion sonography (2DGIS,3DGIS) at offline analysis and live-scanning(LiPDA, LiGIS). The figure include only patients(n=136) in whom all evaluations by all techniques were completed.
.95
AUC
.9
.85
.8
.75 AUC 95% CI LiPDA
2DTVS LiGIS
2DGIS 2DPDA
3DPDA 3DTVS
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3DGIS
Table 1: Diagnostic efficiency for diagnosis of malignancy at live and offline analysis of 3D-TVS, 3D-PDA, 3DGIS, 2D-TVS, 2D-PDA, and 2D-GIS. Subjective impression based on systematic evaluation of pattern (SEP) was used.
N
Live evaluation Live 16 PDA 9 Live GIS 15 8 2D-offline
Sensitivity
Specificity
% (CI95% n/N )
% (CI95% n/N )
LR+ (CI%95 )
LR (CI%95 - )
N=158 87. (77-94) 60/6 0 9 88. (79-95) 62/7 6 0
88. (80-94) 88/10 0 0 95. (89-99) 84/88 5
7.3 (4.212.4 ) 19. (7.55 50.9)
.1 5 .1 2
2D-TVS 16 5
80. (69-89) 54/6 6 7
88. (81-94) 87/98 8
7.2 (4.112.6)
2D-PDA 15 3
79. (67-89) 47/5 7 9
89. (81-95) 84/94 4
2D-GIS
84. (74-92) 59/7 3 0
83. (74-90) 74/89 1
15 9
Patients who had all tests AU (CI%95 AUC C ) (CI%95)
(.08.27) (.06.23)
.87 5 .92 0
(.82.93) (.8896)
.879(.83 -.93) .920(.88 -96) N=142
.2 (.132 .36)
.84 (.797 .90)
.838(.78 -.90)
7.5 (4.113.6)
.2 (.143 .38)
.84 (.795 .91)
.838(.78 -.90)
5.0 (3.18.0)
.1 (.119 .33)
.83 (.787 .90)
.839(.78 -.90)
3D-volume 3D-TVS 16 69. (57-80) 9 6 3D-PDA 15 72. (60-83) 5 6 3D-GIS 16 78. (67-88) 0 6 Investigation with agreement at 2D and 3D (offline analysis) TVS 13 82. (69-92) 7 4 Dopple 14 83. (71-92) r 3 3 GIS 14 88. (77-95) 0 1 Image quality 1-3 (offline analysis) 3D-GIS 12 81. (68-91) 4 1 2D-GIS 13 89. (78-96) 5 1
N=145 48/6 9 45/6 2 55/7 0
92. (85-97) 92/10 0 0 89. (81-95) 83/93 1 87. (79-94) 79/90 8
8.7 (4.417.2) 6.8 (3.712.4) 6.4 (3.711.3)
.3 3 .3 1 .2 4
(.23.48) (.20.46) (.16.39)
.80 8 .80 9 .83 2
(.75.87) (.74.87) (.77.89)
.803(.74 -.87) .809(.74 -.87) .832(.77 -.89) N=120
42/5 1 45/5 4 52/5 9
97. (92-98) 84/86 7 94. (87-98) 84/89 4 90. (82-96) 73/81 1
35. 4 14. 8 8.9
(9.0140) (6.335) (4.617.3)
.1 8 .1 8 .1 3
(.10.33) (.10.32) (.07.27)
.90 0 .88 9 .89 1
(.85.96) (.83.94) (.84.94)
.921(.87 -.97) .925(.88 -.98) .916(.86 -.97) N=115
43/5 3 49/5 5
90. (81-96) 64/71 1 86. (77-93) 69/80 3
8.2 (4.016.8) 6.5 (3.711.3)
.2 1 .1 3
(.12.37) (.06.27)
.85 6 .87 7
(.79.92) (.82.93)
.879(.82 -.94) .878(.82 -.94)
Evaluation of transvaginal ultrasound at the performance (live-TVS). 2- and 3-dimensional offline transvaginal ultrasound (2D-TVS, 3D-TVS); 2- and 3-dimensional offline power Doppler angiography(2D-PDA, 3D-PDA) and 2- and 3-dimensional offline and live gel infusion sonography This article is protected by copyright. All rights reserved
(2D-GIS, live GIS, 3D-GIS). Reference standard was histopathology at hysteroscopy or hysterectomy.Positive likelihood ratios (LR+) and negative likelihood ratios (LR-). Image quality 1-3 (excellent to intermediate) at 3D or 2D clips. Comparison of AUC: 3D-TVS vs. 2D-TVSoffline vs. 2DTVS live (n=163) NS; 3D-PDA, 2D-PDA offline, 2D-TVS live (n=151) NS. 3D-GIS vs. 2D-GIS offline vs. live 2D-GIS (n=153) (p 10%)
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Table 2: Mean endometrial thickness (ET), endometrial volume (EV ) (cm3), vascular index (VI), vascular flow index (VFI), and flow index (FI) for patients with endometrial cancer, hyperplasia, benign uterine polyps, and the remaining patients (Other).(n=169) N
ET (CI95%)
EV (CI95%)
VI (CI95%)
VFI (CI95%)
FI (CI95%)
Cancer
69 18.4 (15.521.3)
20.5 (7.733.2)
13.81 (9.018.6)
4.09 (2.65.6)
27.73 (25.729.8)
Hyperplasia
20 12.3 (9.515.2)
5.47 (3.17.8)
4.85 (2.17.6)
1.42 (.582.3)
24.28 (20.827.8)
Polyps
51
9.9 (8.811.1)
5.88 (3.18.6)
5.85 (2.79.1)
1.13 (.651.6)
22.39 (20.424.3)
Other
29
8.1 (6.7-9.6) 5.62 (.1011.1)
3.83 (1.56.2)
1.02 (.351.7)
21.63 (19.024.2)
P
