P. Sladkevicius

Prospective geographical and temporal validation of three published mathematical models to calculate risk of endometrial malignancy in patients with postmenopausal bleeding

The Risk of Endometrial Malignancy and Other Endometrial Pathology in Women with Abnormal Uterine Bleeding: An Ultrasound-Based Model Development Study by the IETA Group

<b><i>Objectives:</i></b> The aim of this study was to develop a model that can discriminate between different etiologies of abnormal uterine bleeding. <b><i>Design:</i></b> The International Endometrial Tumor Analysis 1 study is a multicenter observational diagnostic study in 18 bleeding clinics in 9 countries. Consecutive women with abnormal vaginal bleeding presenting for ultrasound examination (<i>n</i> = 2,417) were recruited. The histology was obtained from endometrial sampling, D&C, hysteroscopic resection, hysterectomy, or ultrasound follow-up for >1 year. <b><i>Methods:</i></b> A model was developed using multinomial regression based on age, body mass index, and ultrasound predictors to distinguish between: (1) endometrial atrophy, (2) endometrial polyp or intracavitary myoma, (3) endometrial malignancy or atypical hyperplasia, (4) proliferative/secretory changes, endometritis, or hyperplasia without atypia and validated using leave-center-out cross-validation and bootstrapping. The main outcomes are the model’s ability to discriminate between the four outcomes and the calibration of risk estimates. <b><i>Results:</i></b> The median age in 2,417 women was 50 (interquartile range 43–57). 414 (17%) women had endometrial atrophy; 996 (41%) had a polyp or myoma; 155 (6%) had an endometrial malignancy or atypical hyperplasia; and 852 (35%) had proliferative/secretory changes, endometritis, or hyperplasia without atypia. The model distinguished well between malignant and benign histology (<i>c</i>-statistic 0.88 95% CI: 0.85–0.91) and between all benign histologies. The probabilities for each of the four outcomes were over- or underestimated depending on the centers. <b><i>Limitations:</i></b> Not all patients had a diagnosis based on histology. The model over- or underestimated the risk for certain outcomes in some centers, indicating local recalibration is advisable. <b><i>Conclusions:</i></b> The proposed model reliably distinguishes between four histological outcomes. This is the first model to discriminate between several outcomes and is the only model applicable when menopausal status is uncertain. The model could be useful for patient management and counseling, and aid in the interpretation of ultrasound findings. Future research is needed to externally validate and locally recalibrate the model.

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

ABSTRACTObjectiveTo 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.MethodsA 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).ResultsLymphadenectomy 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.ConclusionsBased 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.

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

ABSTRACTObjectivesTo 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).MethodsThe 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.ResultsIn 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.ConclusionsIn 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.

Vessel morphology depicted by three‐dimensional power Doppler ultrasound as second‐stage test in adnexal tumors that are difficult to classify: prospective diagnostic accuracy study

ABSTRACTObjectivesTo assess whether vessel morphology depicted by three‐dimensional (3D) power Doppler ultrasound improves discrimination between benignity and malignancy if used as a second‐stage test in adnexal masses that are difficult to classify.MethodsThis was a prospective observational international multicenter diagnostic accuracy study. Consecutive patients with an adnexal mass underwent standardized transvaginal two‐dimensional (2D) grayscale and color or power Doppler and 3D power Doppler ultrasound examination by an experienced examiner, and those with a ‘difficult’ tumor were included in the current analysis. A difficult tumor was defined as one in which the International Ovarian Tumor Analysis (IOTA) logistic regression model‐1 (LR‐1) yielded an ambiguous result (risk of malignancy, 8.3% to 25.5%), or as one in which the ultrasound examiner was uncertain regarding classification as benign or malignant when using subjective assessment. Even when the ultrasound examiner was uncertain, he/she was obliged to classify the tumor as most probably benign or most probably malignant. For each difficult tumor, one researcher created a 360° rotating 3D power Doppler image of the vessel tree in the whole tumor and another of the vessel tree in a 5‐cm3 spherical volume selected from the most vascularized part of the tumor. Two other researchers, blinded to the patient's history, 2D ultrasound findings and histological diagnosis, independently described the vessel tree using predetermined vessel features. Their agreed classification was used. The reference standard was the histological diagnosis of the mass. The sensitivity of each test for discriminating between benign and malignant difficult tumors was plotted against 1 – specificity on a receiver‐operating‐characteristics diagram, and the test with the point furthest from the reference line was considered to have the best diagnostic ability.ResultsOf 2403 women with an adnexal mass, 376 (16%) had a difficult mass. Ultrasound volumes were available for 138 of these cases. In 79/138 masses, the ultrasound examiner was uncertain about the diagnosis based on subjective assessment, in 87/138, IOTA LR‐1 yielded an ambiguous result and, in 28/138, both methods gave an uncertain result. Of the masses, 38/138 (28%) were malignant. Among tumors that were difficult to classify as benign or malignant by subjective assessment, the vessel feature ‘densely packed vessels’ had the best discriminative ability (sensitivity 67% (18/27), specificity 83% (43/52)) and was slightly superior to subjective assessment (sensitivity 74% (20/27), specificity 60% (31/52)). In tumors in which IOTA LR‐1 yielded an ambiguous result, subjective assessment (sensitivity 82% (14/17), specificity 79% (55/70)) was superior to the best vascular feature, i.e. changes in the diameter of vessels in the whole tumor volume (sensitivity 71% (12/17), specificity 69% (48/70)).ConclusionVessel morphology depicted by 3D power Doppler ultrasound may slightly improve discrimination between benign and malignant adnexal tumors that are difficult to classify by subjective ultrasound assessment. For tumors in which the IOTA LR‐1 model yields an ambiguous result, subjective assessment is superior to vessel morphology as a second‐stage test. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Imaging in gynecological disease (24): clinical and ultrasound characteristics of ovarian mature cystic teratomas

ABSTRACTObjectiveTo describe the clinical and ultrasound features of ovarian mature cystic teratomas (MCTs).MethodsThis was a retrospective study. From the International Ovarian Tumor Analysis (IOTA) database, we identified patients with a histologically confirmed diagnosis of MCT who had undergone transvaginal ultrasound examination between 1999 and 2016 (IOTA phases 1, 2, 3 and 5) in one of five centers. Ultrasound was performed by an experienced examiner who used the standardized IOTA examination technique and terminology. In addition to extracting data from the IOTA database, available two‐dimensional grayscale and color or power Doppler images were reviewed retrospectively to identify typical ultrasound features of MCT described previously and detect possible new features using pattern recognition. All images were reviewed by two independent examiners and further discussed with two ultrasound experts to reach consensus.ResultsIncluded in the study were 454 patients with histologically confirmed MCT. Median age was 33 (range, 8–90)  years and 66 (14.5%) patients were postmenopausal. Most MCTs were described by the original ultrasound examiner as unilocular (262/454 (57.7%)) or multilocular (70/454 (15.4%)) cysts with mixed echogenicity of cystic fluid (368/454 (81.1%)), acoustic shadowing (328/454 (72.2%)) and no or little vascularization on color Doppler (color score 1, 240/454 (52.9%); color score 2, 123/454 (27.1%)). The median largest lesion diameter was 66 (range, 15–310)  mm. A correct preoperative diagnosis of MCT was suggested by the original ultrasound examiner in 372/454 (81.9%) cases. On retrospective review of ultrasound images of 334 MCTs that had quality sufficient for assessment, ‘dots and/or lines’ and/or ‘echogenic white ball’ (typical features according to the literature) were present in 271/334 (81.1%) masses. We identified four new ultrasound features characteristic of MCT: ‘cotton wool tufts’, ‘mushroom cap sign’, ‘completely hyperechogenic lesion’ and ‘starry sky sign’. At least one classical or novel ultrasound feature was present in 315/334 (94.3%) MCTs. Twenty‐nine (8.7%) MCTs manifested vascularized solid tissue, of which seven exhibited no typical features.ConclusionWe provide a comprehensive overview of conventional and newly described ultrasound features of MCTs. Only a small proportion of MCTs did not manifest any of the typical features. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Imaging in gynecological disease (23): clinical and ultrasound characteristics of ovarian carcinosarcoma

ABSTRACTObjectiveTo describe the clinical and ultrasound characteristics of ovarian carcinosarcoma.MethodsThis was a retrospective multicenter study. Patients with a histological diagnosis of ovarian carcinosarcoma, who had undergone preoperative ultrasound examination between 2010 and 2019, were identified from the International Ovarian Tumor Analysis (IOTA) database. Additional patients who were examined outside of the IOTA study were identified from the databases of the participating centers. The masses were described using the terms and definitions of the IOTA group. Additionally, two experienced ultrasound examiners reviewed all available images to identify typical ultrasound features using pattern recognition.ResultsNinety‐one patients with ovarian carcinosarcoma who had undergone ultrasound examination were identified, of whom 24 were examined within the IOTA studies and 67 were examined outside of the IOTA studies. Median age at diagnosis was 66 (range, 33–91) years and 84/91 (92.3%) patients were postmenopausal. Most patients (67/91, 73.6%) were symptomatic, with the most common complaint being pain (51/91, 56.0%). Most tumors (67/91, 73.6%) were International Federation of Gynecology and Obstetrics (FIGO) Stage III or IV. Bilateral lesions were observed on ultrasound in 46/91 (50.5%) patients. Ascites was present in 38/91 (41.8%) patients. The median largest tumor diameter was 100 (range, 18–260) mm. All ovarian carcinosarcomas contained solid components, and most were described as solid (66/91, 72.5%) or multilocular‐solid (22/91, 24.2%). The median diameter of the largest solid component was 77.5 (range, 11–238) mm. Moderate or rich vascularization was found in 78/91 (85.7%) cases. Retrospective analysis of ultrasound images and videoclips using pattern recognition in 73 cases revealed that all tumors had irregular margins and inhomogeneous echogenicity of the solid components. Forty‐seven of 73 (64.4%) masses appeared as a solid tumor with cystic areas. Cooked appearance of the solid tissue was identified in 28/73 (38.4%) tumors. No pathognomonic ultrasound sign of ovarian carcinosarcoma was found.ConclusionsOvarian carcinosarcomas are usually diagnosed in postmenopausal women and at an advanced stage. The most common ultrasound appearance is a large solid tumor with irregular margins, inhomogeneous echogenicity of the solid tissue and cystic areas. The second most common pattern is a large multilocular‐solid mass with inhomogeneous echogenicity of the solid tissue. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.