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.

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). 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. 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. 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.

Verbakel JY ，Mascilini F ，Wynants L ，Fischerova D ，Testa AC ，Franchi D ，Frühauf F ，Cibula D ，Lindqvist PG ，Fruscio R ，Haak LA ，Opolskiene G ，Alcazar JL ，Mais V ，Carlson JW ，Sladkevicius P ，Timmerman D ，Valentin L ，Bosch TVD ，Epstein E ... -  《-》

Dynamic contrast-enhanced ultrasound improves diagnostic performance in endometrial cancer staging.

To compare the sensitivity and specificity of conventional two-dimensional transvaginal ultrasound/power Doppler (2D-TVU/PD) alone and 2D-TVU/PD combined with dynamic contrast-enhanced ultrasound (DCE-US) in diagnosing deep myometrial invasion (MI) and cervical stromal involvement (CSI) in women with endometrial cancer (EC), and to assess the association of DCE-US semiquantitative and qualitative variables with International Federation of Gynecology and Obstetrics (FIGO) Stage ≥ IB and 'high-risk' cancer. This was a prospective study of 101 consecutive women with biopsy-confirmed EC, undergoing expert ultrasound examination at Karolinska University Hospital, a tertiary referral center. All consenting women underwent DCE-US using a 1.5-2.5-mL intravenous bolus of SonoVue contrast agent, as well as conventional 2D-TVU/PD examination. DCE-US videoclips were analyzed with regard to filling (global or focal), wash-in (prior, simultaneous or after) and wash-out (global or focal) patterns of the contrast agent in the tumor compared with the surrounding tissue, as well as semiquantitative DCE-US parameters (wash-in slope, time-to-peak, peak intensity and area under the time-intensity curve (TIC)) obtained from a TIC. The study cohort was compared with a control cohort of women with EC examined at our center according to the International Endometrial Tumor Analysis protocol using 2D-TVU/PD only, matched at a ratio of 3:1 for FIGO stage and grade. The sensitivity and specificity of 2D-TVU/PD alone in the control cohort and in combination with DCE-US in the study cohort in the diagnosis of deep MI, CSI and high-risk cancer (defined as FIGO Stage ≥ IB and/or Grade 3 endometrioid and/or non-endometrioid histology) were compared, using pathological evaluation after hysterectomy as the 'gold standard'. After exclusions, 93 women were included in the study cohort and were matched to 279 women in the control cohort. The prevalence of FIGO Stage IA, Grade 1-2 EC was 52% in both cohorts. The sensitivity of 2D-TVU/PD with DCE-US in the study cohort was higher than that of 2D-TVU/PD alone in the control cohort in diagnosing both deep MI (0.74 vs 0.62; P = 0.036) and CSI (0.75 vs 0.51; P < 0.001), whereas the specificity was not significantly different (0.87 vs 0.85 and 0.96 vs 0.95, respectively). Compared with 2D-TVU/PD alone, the specificity of 2D-TVU/PD with DCE-US was higher in detecting high-risk cancer (0.94 vs 0.85; P = 0.024) but the sensitivity did not differ (0.73 vs 0.71). High-risk cancer and FIGO Stage ≥ IB were characterized by a 'focal' filling pattern, with a 'prior' wash-in pattern and a 'focal' wash-out pattern on subjective assessment of DCE-US videoclips. All semiquantitative DCE-US parameters were significantly predictive of FIGO Stage ≥ IB but not of high-risk cancer, despite a clear trend. Compared with 2D-TVU/PD alone, combining 2D-TVU/PD with DCE-US can significantly improve the detection of deep MI and CSI in women with EC, without increasing the false-positive rate. It can also improve the correct classification of high-risk disease, mainly by increasing specificity, thereby possibly reducing the number of unnecessarily extensive surgeries by almost 10%. Semiquantitative DCE-US parameters, as well as a 'focal' filling pattern, endometrial wash-in prior to the myometrium and a 'focal' wash-out pattern, are all associated with more advanced disease. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Green RW ，Epstein E 《-》

Evaluating myometrial and cervical invasion in women with endometrial cancer: comparing subjective assessment with objective measurement techniques.

To compare the diagnostic accuracy of subjective ultrasound assessment with that of objective measurement techniques in the evaluation of myometrial and cervical invasion in women with endometrial cancer. This was a prospective multicenter study including 144 women with endometrial cancer undergoing transvaginal ultrasound. Myometrial and cervical invasion was evaluated subjectively, as well as objectively measured in different ways: endometrial thickness, tumor/uterine anteroposterior (AP) diameter ratio, minimal tumor-free margin, minimal tumor-free margin/uterine AP diameter ratio, tumor volume (three-dimensional (3D)), tumor/uterine volume (3D) ratio, and distance from outer cervical os to lower margin of tumor (Dist-OCO). Histological assessment following hysterectomy was the gold standard. The sensitivity (72%) and specificity (76%) of tumor/uterine AP diameter (at cut-off, 0.53) were not significantly different from those of subjective evaluation (sensitivity, 77% (P = 0.44); specificity, 81% (P = 0.32)) for the prediction of deep myometrial invasion; all other objective measurement techniques had either a significantly lower sensitivity or a lower specificity. For all objective measurement techniques, except minimal tumor-free margin/uterine AP diameter ratio, fixing the sensitivity at the same level as that of subjective evaluation (i.e. 77%) gave a significantly lower specificity. Dist-OCO was the only parameter that might have potential to predict cervical invasion; it had a non-significantly higher sensitivity than did subjective evaluation (73% vs 54%, P = 0.06), but a significantly lower specificity (63% vs 93%, P < 0.001). Subjective assessment of cervical and myometrial invasion is as good as or better than any objective measurement technique. The tumor/uterine AP diameter ratio and minimal tumor-free margin/uterine AP diameter ratio seem to be the best objective measurement techniques to predict deep myometrial invasion. It remains to be shown if objective measurements are useful to predict cervical invasion.

Mascilini F ，Testa AC ，Van Holsbeke C ，Ameye L ，Timmerman D ，Epstein E ... -  《-》

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

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. 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). 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. 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.

Eriksson LSE ，Epstein E ，Testa AC ，Fischerova D ，Valentin L ，Sladkevicius P ，Franchi D ，Frühauf F ，Fruscio R ，Haak LA ，Opolskiene G ，Mascilini F ，Alcazar JL ，Van Holsbeke C ，Chiappa V ，Bourne T ，Lindqvist PG ，Van Calster B ，Timmerman D ，Verbakel JY ，Van den Bosch T ，Wynants L ... -  《-》

Development and external validation of new ultrasound-based mathematical models for preoperative prediction of high-risk endometrial cancer.

To develop and validate strategies, using new ultrasound-based mathematical models, for the prediction of high-risk endometrial cancer and compare them with strategies using previously developed models or the use of preoperative grading only. Women with endometrial cancer were prospectively examined using two-dimensional (2D) and three-dimensional (3D) gray-scale and color Doppler ultrasound imaging. More than 25 ultrasound, demographic and histological variables were analyzed. Two logistic regression models were developed: one 'objective' model using mainly objective variables; and one 'subjective' model including subjective variables (i.e. subjective impression of myometrial and cervical invasion, preoperative grade and demographic variables). The following strategies were validated: a one-step strategy using only preoperative grading and two-step strategies using preoperative grading as the first step and one of the new models, subjective assessment or previously developed models as a second step. One-hundred and twenty-five patients were included in the development set and 211 were included in the validation set. The 'objective' model retained preoperative grade and minimal tumor-free myometrium as variables. The 'subjective' model retained preoperative grade and subjective assessment of myometrial invasion. On external validation, the performance of the new models was similar to that on the development set. Sensitivity for the two-step strategy with the 'objective' model was 78% (95% CI, 69-84%) at a cut-off of 0.50, 82% (95% CI, 74-88%) for the strategy with the 'subjective' model and 83% (95% CI, 75-88%) for that with subjective assessment. Specificity was 68% (95% CI, 58-77%), 72% (95% CI, 62-80%) and 71% (95% CI, 61-79%) respectively. The two-step strategies detected up to twice as many high-risk cases as preoperative grading only. The new models had a significantly higher sensitivity than did previously developed models, at the same specificity. Two-step strategies with 'new' ultrasound-based models predict high-risk endometrial cancers with good accuracy and do this better than do previously developed models.

Van Holsbeke C ，Ameye L ，Testa AC ，Mascilini F ，Lindqvist P ，Fischerova D ，Frühauf F ，Fransis S ，de Jonge E ，Timmerman D ，Epstein E ... -  《-》