Validation of ultrasound strategies to assess tumor extension and to predict high-risk endometrial cancer in women from the prospective IETA (International Endometrial Tumor Analysis)-4 cohort.

OBJECTIVES: To compare the performance of ultrasound measurements and subjective ultrasound assessment (SA) in detecting deep myometrial invasion (MI) and cervical stromal invasion (CSI) in women with endometrial cancer, overall and according to whether they had low- or high-grade disease separately, and to validate published measurement cut-offs and prediction models to identify MI, CSI and high-risk disease (Grade-3 endometrioid or non-endometrioid cancer and/or deep MI and/or CSI). METHODS: The study comprised 1538 patients with endometrial cancer from the International Endometrial Tumor Analysis (IETA)-4 prospective multicenter study, who underwent standardized expert transvaginal ultrasound examination. SA and ultrasound measurements were used to predict deep MI and CSI. We assessed the diagnostic accuracy of the tumor/uterine anteroposterior (AP) diameter ratio for detecting deep MI and that of the distance from the lower margin of the tumor to the outer cervical os (Dist-OCO) for detecting CSI. We also validated two two-step strategies for the prediction of high-risk cancer; in the first step, biopsy-confirmed Grade-3 endometrioid or mucinous or non-endometrioid cancers were classified as high-risk cancer, while the second step encompassed the application of a mathematical model to classify the remaining tumors. The 'subjective prediction model' included biopsy grade (Grade 1 vs Grade 2) and subjective assessment of deep MI or CSI (presence or absence) as variables, while the 'objective prediction model' included biopsy grade (Grade 1 vs Grade 2) and minimal tumor-free margin. The predictive performance of the two two-step strategies was compared with that of simply classifying patients as high risk if either deep MI or CSI was suspected based on SA or if biopsy showed Grade-3 endometrioid or mucinous or non-endometrioid histotype (i.e. combining SA with biopsy grade). Histological assessment from hysterectomy was considered the reference standard. RESULTS: In 1275 patients with measurable lesions, the sensitivity and specificity of SA for detecting deep MI was 70% and 80%, respectively, in patients with a Grade-1 or -2 endometrioid or mucinous tumor vs 76% and 64% in patients with a Grade-3 endometrioid or mucinous or a non-endometrioid tumor. The corresponding values for the detection of CSI were 51% and 94% vs 50% and 91%. Tumor AP diameter and tumor/uterine AP diameter ratio showed the best performance for predicting deep MI (area under the receiver-operating characteristics curve (AUC) of 0.76 and 0.77, respectively), and Dist-OCO had the best performance for predicting CSI (AUC, 0.72). The proportion of patients classified correctly as having high-risk cancer was 80% when simply combining SA with biopsy grade vs 80% and 74% when using the subjective and objective two-step strategies, respectively. The subjective and objective models had an AUC of 0.76 and 0.75, respectively, when applied to Grade-1 and -2 endometrioid tumors. CONCLUSIONS: In the hands of experienced ultrasound examiners, SA was superior to ultrasound measurements for the prediction of deep MI and CSI of endometrial cancer, especially in patients with a Grade-1 or -2 tumor. The mathematical models for the prediction of high-risk cancer performed as expected. The best strategies for predicting high-risk endometrial cancer were combining SA with biopsy grade and the subjective two-step strategy, both having an accuracy of 80%. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Ultrasound-based risk model for preoperative prediction of lymph-node metastases in women with endometrial cancer: model-development study.

OBJECTIVE: To develop a preoperative risk model, using endometrial biopsy results and clinical and ultrasound variables, to predict the individual risk of lymph-node metastases in women with endometrial cancer. METHODS: A mixed-effects logistic regression model for prediction of lymph-node metastases was developed in 1501 prospectively included women with endometrial cancer undergoing transvaginal ultrasound examination before surgery, from 16 European centers. Missing data, including missing lymph-node status, were imputed. Discrimination, calibration and clinical utility of the model were evaluated using leave-center-out cross validation. The predictive performance of the model was compared with that of risk classification from endometrial biopsy alone (high-risk defined as endometrioid cancer Grade 3/non-endometrioid cancer) or combined endometrial biopsy and ultrasound (high-risk defined as endometrioid cancer Grade 3/non-endometrioid cancer/deep myometrial invasion/cervical stromal invasion/extrauterine spread). RESULTS: Lymphadenectomy was performed in 691 women, of whom 127 had lymph-node metastases. The model for prediction of lymph-node metastases included the predictors age, duration of abnormal bleeding, endometrial biopsy result, tumor extension and tumor size according to ultrasound and undefined tumor with an unmeasurable endometrium. The model's area under the curve was 0.73 (95% CI, 0.68-0.78), the calibration slope was 1.06 (95% CI, 0.79-1.34) and the calibration intercept was 0.06 (95% CI, -0.15 to 0.27). Using a risk threshold for lymph-node metastases of 5% compared with 20%, the model had, respectively, a sensitivity of 98% vs 48% and specificity of 11% vs 80%. The model had higher sensitivity and specificity than did classification as high-risk, according to endometrial biopsy alone (50% vs 35% and 80% vs 77%, respectively) or combined endometrial biopsy and ultrasound (80% vs 75% and 53% vs 52%, respectively). The model's clinical utility was higher than that of endometrial biopsy alone or combined endometrial biopsy and ultrasound at any given risk threshold. CONCLUSIONS: Based on endometrial biopsy results and clinical and ultrasound characteristics, the individual risk of lymph-node metastases in women with endometrial cancer can be estimated reliably before surgery. The model is superior to risk classification by endometrial biopsy alone or in combination with ultrasound. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Ultrasound characteristics of endometrial cancer as defined by International Endometrial Tumor Analysis (IETA) consensus nomenclature: prospective multicenter study.

OBJECTIVE: To describe the sonographic features of endometrial cancer in relation to tumor stage, grade and histological type, using the International Endometrial Tumor Analysis (IETA) terminology. METHODS: This was a prospective multicenter study of 1714 women with biopsy-confirmed endometrial cancer undergoing standardized transvaginal grayscale and Doppler ultrasound examination according to the IETA study protocol, by experienced ultrasound examiners using high-end ultrasound equipment. Clinical and sonographic data were entered into a web-based database. We assessed how strongly sonographic characteristics, according to IETA, were associated with outcome at hysterectomy, i.e. tumor stage, grade and histological type, using univariable logistic regression and the c-statistic. RESULTS: In total, 1538 women were included in the final analysis. Median age was 65 (range, 27-98) years, median body mass index was 28.4 (range 16-67) kg/m2 , 1377 (89.5%) women were postmenopausal and 1296 (84.3%) reported abnormal vaginal bleeding. Grayscale and color Doppler features varied according to grade and stage of tumor. High-risk tumors, compared with low-risk tumors, were less likely to have regular endometrial-myometrial junction (difference of -23%; 95% CI, -27 to -18%), were larger (mean endometrial thickness; difference of +9%; 95% CI, +8 to +11%), and were more likely to have non-uniform echogenicity (difference of +7%; 95% CI, +1 to +13%), a multiple, multifocal vessel pattern (difference of +21%; 95% CI, +16 to +26%) and a moderate or high color score (difference of +22%; 95% CI, +18 to +27%). CONCLUSION: Grayscale and color Doppler sonographic features are associated with grade and stage of tumor, and differ between high- and low-risk endometrial cancer. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Prospective temporal validation of mathematical models to calculate risk of endometrial malignancy in patients with postmenopausal bleeding.

OBJECTIVES: To validate prospectively five mathematical models published in 2007 for calculating the risk of endometrial malignancy in a defined high-risk group of patients with postmenopausal bleeding and sonographic endometrial thickness ≥ 4.5 mm. METHODS: Of 1012 consecutive patients, 379 fulfilled our inclusion criteria, which were the same as those of the original study in which the models were created (endometrial thickness ≥ 4.5 mm, no fluid in the uterine cavity, detectable Doppler signals in the endometrium). A standardized history was taken, and clinical and transvaginal grayscale and power Doppler ultrasound examinations were performed following the study protocol. All data were collected prospectively and the five models were applied prospectively to the study patients' data to assess their risk of endometrial malignancy. Using the histological diagnosis of the endometrium as gold standard, we calculated the area under the receiver-operating characteristics curve (AUC), and sensitivity, specificity and likelihood ratios when using the same cut-offs as in the original study, for each of the five models. RESULTS: Ninety-three (25%) patients had malignant endometrium. The performance of the models was similar to that in the original study, with AUCs ranging from 0.86 to 0.90. The model with the best diagnostic performance included endometrial thickness, heterogeneous endometrial echogenicity and areas of densely packed vessels on power Doppler (AUC, 0.90; sensitivity, 81%; specificity, 84% at preselected cut-off). The models were well calibrated. CONCLUSIONS: On temporal validation, the five models for calculating the risk of endometrial malignancy in a defined high-risk group of patients retained their good diagnostic performance and were well calibrated. The models make it possible to reclassify high-risk patients as having a low or relatively low risk, moderately high risk or very high risk of endometrial cancer, and so can be used for individualized patient management. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Prediction of endometrial malignancy in women with postmenopausal bleeding and sonographic endometrial thickness ≥ 4.5 mm.

OBJECTIVE: To build mathematical models for evaluating the individual risk of endometrial malignancy in women with postmenopausal bleeding and sonographic endometrial thickness ≥ 4.5 mm using clinical data, sonographic endometrial thickness and power Doppler ultrasound findings. METHODS: Of 729 consecutive patients with postmenopausal bleeding, 261 with sonographic endometrial thickness ≥ 4.5 mm and no fluid in the uterine cavity were included. They underwent transvaginal two-dimensional gray-scale and power Doppler ultrasound examination of the endometrium. The ultrasound image showing the most vascularized section through the endometrium as assessed by power Doppler was frozen, the endometrium was outlined and the percentage vascularized area (vascularity index) was calculated using computer software. The ultrasound examiner also estimated the color content of the endometrial scan on a visual analog scale (VAS) graded from 0 to 100 (VAS score). A structured history was taken to collect clinical information. Multivariate logistic regression analysis was used to create mathematical models to predict endometrial malignancy. RESULTS: There were 63 (24%) malignant and 198 (76%) benign endometria. Women with a malignant endometrium were older (median age 74 vs. 65 years; P = 0.0005) and fewer used hormone replacement therapy and warfarin. Women with a malignant endometrium had a thicker endometrium (median thickness 20.8 vs. 10.2 mm; P = 0.0005) and higher values for vascularity index and VAS score. When using only clinical data to build a model for estimating the risk of endometrial malignancy, a model including the variables age, use of warfarin and use of hormone replacement therapy had the largest area under the receiver-operating characteristics curve (AUC), with a value of 0.74 (95% confidence interval (CI), 0.67-0.81). A model including age, use of warfarin and endometrial thickness had an AUC of 0.82 (95% CI, 0.76-0.87), and one including age, use of hormone replacement therapy, endometrial thickness and vascularity index had an AUC of 0.91 (95% CI, 0.87-0.95). Using a risk cut-off of 11%, the latter model had sensitivity 90%, specificity 71%, positive likelihood ratio 3.14 and negative likelihood ratio 0.13. CONCLUSIONS: The diagnostic performance of models predicting endometrial cancer increases substantially when sonographic endometrial thickness and power Doppler information are added to clinical variables. The models are likely to be clinically useful but need to be prospectively validated.

Three-dimensional ultrasound imaging for discrimination between benign and malignant endometrium in women with postmenopausal bleeding and sonographic endometrial thickness of at least 4.5 mm.

OBJECTIVES: To determine whether endometrial volume or power Doppler indices as measured by three-dimensional (3D) ultrasound imaging can discriminate between benign and malignant endometrium, to compare their diagnostic performance with that of endometrial thickness measurement using two-dimensional (2D) ultrasound examination, and to determine whether power Doppler indices add any diagnostic information to endometrial thickness or volume. METHODS: Sixty-two patients with postmenopausal bleeding and endometrial thickness > or = 4.5 mm underwent transvaginal 2D gray-scale and 3D power Doppler ultrasound examination of the corpus uteri. The endometrial volume was calculated, along with the vascularization index (VI), flow index and vascularization flow index (VFI) in the endometrium and in a 2-mm 'shell' surrounding the endometrium. The 'gold standard' was the histological diagnosis of the endometrium obtained by hysteroscopic resection of focal lesions, dilatation and curettage or hysterectomy. Receiver-operating characteristics (ROC) curves were drawn for all measurements to evaluate their ability to distinguish between benign and malignant endometrium. Multivariate logistic regression analysis was used to create mathematical models to estimate the risk of endometrial malignancy. RESULTS: There were 49 benign and 13 malignant endometria. Endometrial thickness and volume were significantly larger in malignant than in benign endometria, and flow indices in the endometrium and endometrial shell were significantly higher. The area under the ROC curve (AUC) of endometrial thickness was 0.82, that of endometrial volume 0.78, and that of the two best power Doppler variables (VI and VFI in the endometrium) 0.82 and 0.82. The best logistic regression model for predicting malignancy contained the variables endometrial thickness (odds ratio 1.2; 95% CI, 1.04-1.30; P = 0.004) and VI in the endometrial 'shell' (odds ratio 1.1; 95% CI, 1.02-1.23; P = 0.01). Its AUC was 0.86. Using its mathematically optimal risk cut-off value (0.22), the model correctly classified seven more benign cases but two fewer malignant cases than the best endometrial thickness cut-off (11.8 mm). Models containing endometrial volume and flow indices performed less well than did endometrial thickness alone (AUC, 0.79 vs. 0.82). CONCLUSIONS: The diagnostic performance for discrimination between benign and malignant endometrium of 3D ultrasound imaging was not superior to that of endometrial thickness as measured by 2D ultrasound examination, and 3D power Doppler imaging added little to endometrial thickness or volume.

Two- and three-dimensional saline contrast sonohysterography: interobserver agreement, agreement with hysteroscopy and diagnosis of endometrial malignancy.

OBJECTIVES: The aims of our study were to compare the interobserver reproducibility of two-dimensional (2D) and three-dimensional (3D) saline contrast sonohysterography (SCSH) and agreement of these techniques with hysteroscopy, and to determine which SCSH findings best discriminate between benign and malignant endometrium. METHODS: Consecutive women with postmenopausal bleeding and endometrial thickness > or = 4.5 mm underwent 2D and 3D SCSH; the results were videotaped and stored electronically, respectively, for analysis by two independent experienced examiners who were blinded to each other's results. A histological diagnosis was obtained by dilatation and curettage, hysteroscopic resection or hysterectomy. The hysteroscopist was blinded to the ultrasound results and used the same standardized research protocol to describe the uterine cavity as the ultrasound examiners. RESULTS: Of 170 consecutive women with postmenopausal bleeding and endometrial thickness > or = 4.5 mm, 84 (14 with endometrial malignancy) fulfilled our inclusion criteria. Hysteroscopy findings in 54 women (one with endometrial malignancy) were used to determine agreement with SCSH. Interobserver agreement of 2D and 3D SCSH was 95% (80/84) vs. 89% (75/84) with regard to presence of focal lesions, 89% (75/84) vs. 88% (74/84) for presence of focal lesions with irregular surface, 67% (54/81) vs. 63% (51/81) for number of focal lesions, and 77% (46/60) vs. 70% (42/60) for location of focal lesions. The agreement between 2D and 3D SCSH and hysteroscopy was 94% (51/54) vs. 93% (50/54) with regard to presence of focal lesions, 74% (40/54) vs. 76% (41/54) for presence of focal lesions with irregular surface, 63% (34/54) vs. 54% (29/54) for number of focal lesions, and 66% (29/44) vs. 64% (28/44) for location of focal lesions. The SCSH finding that best discriminated between benign and malignant endometrium was the presence of focal lesion(s) with irregular surface (for 2D SCSH: sensitivity 71%, specificity 97%, positive likelihood ratio 25, negative likelihood ratio 0.3; for 3D SCSH: sensitivity 43%, specificity 97%, positive likelihood ratio 15, negative likelihood ratio 0.6). CONCLUSIONS: 3D SCSH does not seem to be superior to 2D SCSH when performed by experienced ultrasound examiners either with regard to reproducibility, agreement with hysteroscopy findings or diagnosis of endometrial malignancy. The presence of focal lesion(s) with irregular surface is the best SCSH variable for discrimination between benign and malignant endometrium.

Ultrasound assessment of endometrial morphology and vascularity to predict endometrial malignancy in women with postmenopausal bleeding and sonographic endometrial thickness >or= 4.5 mm.

OBJECTIVES: To determine which endometrial morphology characteristics as assessed by gray-scale ultrasound and which endometrial vessel characteristics as assessed by power Doppler ultrasound are useful for discriminating between benign and malignant endometrium in women with postmenopausal bleeding (PMB) and sonographic endometrial thickness >or= 4.5 mm and to develop logistic regression models to calculate the individual risk of endometrial malignancy in women with PMB, endometrial thickness >or= 4.5 mm, good visibility of the endometrium and detectable Doppler signals in the endometrium. METHODS: Of 223 consecutive patients with PMB and sonographic endometrial thickness >or= 4.5 mm, 120 fulfilled our inclusion criteria. They underwent transvaginal gray-scale and power Doppler ultrasound examination, which was videotaped for later analysis by two examiners with more than 15 years' experience in gynecological ultrasonography. They independently assessed endometrial morphology and vascularity using predetermined criteria. Their agreed-upon description was compared with the histological diagnosis. Univariate and multivariate logistic regression analyses were used. The best diagnostic test was defined as the one with the largest area under the receiver-operating characteristics curve (AUC). RESULTS: Thirty (25%) endometria were malignant. Inter-observer agreement for the description of endometrial morphology and vascularity was moderate to good (Kappa 0.49-0.78). The best ultrasound variables to predict malignancy were heterogeneous endometrial echogenicity (AUC 0.83), endometrial thickness (AUC 0.80), and irregular branching of endometrial blood vessels (AUC 0.77). A logistic regression model including endometrial thickness and heterogeneous endometrial echogenicity had an AUC of 0.91. Its mathematically best risk cut-off yielded a positive likelihood ratio of 4.4, and a negative likelihood ratio of 0.1. Adding Doppler information to the model improved diagnostic performance marginally (AUC 0.92). CONCLUSIONS: In selected high-risk women with PMB and an endometrial thickness of >or= 4.5 mm, calculation of the individual risk of endometrial malignancy using regression models including gray-scale and Doppler characteristics can be used to tailor management. These models would need to be tested prospectively before introduction into clinical practice.