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Postmenopausal bleeding (PMB) can be the first sign of endometrial cancer. In case of thickened endometrium, endometrial sampling is often used in these women. In this systematic review, we studied the accuracy of endometrial sampling for the diagnoses of endometrial cancer, atypical hyperplasia and endometrial disease (endometrial pathology, including benign polyps). We systematically searched the literature for studies comparing the results of endometrial sampling in women with postmenopausal bleeding with two different reference standards: blind dilatation and curettage (D&C) and hysteroscopy with histology. We assessed the quality of the detected studies by the QUADAS-2 tool. For each included study, we calculated the fraction of women in whom endometrial sampling failed. Furthermore, we extracted numbers of cases of endometrial cancer, atypical hyperplasia and endometrial disease that were identified or missed by endometrial sampling. We detected 12 studies reporting on 1029 women with postmenopausal bleeding: five studies with dilatation and curettage (D&C) and seven studies with hysteroscopy as a reference test. The weighted sensitivity of endometrial sampling with D&C as a reference for the diagnosis of endometrial cancer was 100% (range 100-100%) and 92% (71-100) for the diagnosis of atypical hyperplasia. Only one study reported sensitivity for endometrial disease, which was 76%. When hysteroscopy was used as a reference, weighted sensitivities of endometrial sampling were 90% (range 50-100), 82% (range 56-94) and 39% (21-69) for the diagnosis of endometrial cancer, atypical hyperplasia and endometrial disease, respectively. For all diagnosis studied and the reference test used, specificity was 98-100%. The weighted failure rate of endometrial sampling was 11% (range 1-53%), while insufficient samples were found in 31% (range 7-76%). In these women with insufficient or failed samples, an endometrial (pre) cancer was found in 7% (range 0-18%). In women with postmenopausal bleeding, the sensitivity of endometrial sampling to detect endometrial cancer and especially atypical hyperplasia and endometrial disease, including endometrial polyps, is lower than previously thought. Therefore, further diagnostic work-up for focal pathology is warranted, after a benign result of endometrial sampling., (Copyright © 2015. Published by Elsevier Ireland Ltd.)

Background: Heavy menstrual bleeding (HMB) and post-menopausal bleeding (PMB) together constitute the commonest gynaecological presentation in secondary care and impose substantial demands on health service resources. Accurate diagnosis is of key importance to realising effective treatment, reducing morbidity and, in the case of PMB, reducing mortality. There are many tests available, including transvaginal scan (TVS), endometrial biopsy (EBx), saline infusion sonography and outpatient hysteroscopy (OPH); however, optimal diagnostic work-up is unclear., Objectives: To determine the most cost-effective diagnostic testing strategy for the diagnosis and treatment of (i) HMB and (ii) PMB., Data Sources: Parameter inputs were derived from systematic quantitative reviews, individual patient data (IPD) from existing data sets and focused searches for specific data. In the absence of data estimates, the consensus view of an expert clinical panel was obtained., Methods: Two clinically informed decision-analytic models were constructed to reflect current service provision for the diagnostic work-up of women presenting with HMB and PMB. The model-based economic evaluation took the form of a cost-effectiveness analysis from the perspective of the NHS in a contemporary, 'one-stop' secondary care clinical setting, where all indicated testing modalities would be available during a single visit., Results: Two potentially cost-effective testing strategies for the initial investigation of women with HMB were identified: OPH alone or in combination with EBx. Although a combination testing strategy of OPH + EBx was marginally more effective, the incremental cost-effectiveness ratio (ICER) was approximately £21,000 to gain one more satisfied patient, whereas for OPH it was just £360 when compared with treatment with the levonorgestrel intrauterine system (LNG-IUS) without investigation. Initial testing with OPH was the most cost-effective testing approach for women wishing to preserve fertility and for women with symptoms refractory to empirical treatment with a LNG-IUS. For the investigation of PMB, selective use of TVS based on historical risk prediction for the diagnostic work-up of women presenting with PMB generated an ICER compared with our reference strategy of 'no initial work-up' of £129,000 per extra woman surviving 5 years. The ICERs for the two other non-dominated testing strategies, combining history and TVS or combining OPH and TVS, were over £2M each., Limitations: In the absence of IPD, estimates of accuracy for test combinations presented some uncertainty where test results were modelled as being discordant., Conclusions: For initial investigation of women presenting to secondary care with HMB who do not require preservation of their fertility, our research suggests a choice between OPH alone or a combination of OPH and EBx. From our investigation, OPH appears to be the optimal first-line diagnostic test used for the investigation of women presenting to secondary care with HMB wishing to preserve their fertility or refractory to previous medical treatment with the LNG-IUS. We would suggest that the current recommendation of basing the initial investigation of women with PMB on the universal TVS measurement of endometrial thickness at a 5-mm threshold may need to be replaced by a strategy of restricting TVS to women with risk factors (e.g. increasing age-raised body mass index, diabetes or nulliparity), obtained from the preceding clinical assessment., Funding: The National Institute for Health Research Health Technology Assessment programme.

Objective: To determine which doctor- and patient-related factors affect failure of outpatient endometrial sampling in women with postmenopausal bleeding, and to develop a multivariable prediction model to select women with a high probability of failed sampling., Design: Prospective multicenter cohort study., Setting: Three teaching hospitals in the Netherlands., Population: Women presenting with postmenopausal bleeding with an indication for endometrial sampling., Methods: Multivariable logistic regression was performed to evaluate the impact of doctor's training level and patient's characteristics on failure of sampling., Main Outcome Measures: Failure of endometrial sampling, classified as technical failure or insufficient tissue for diagnosis., Results: In 74 (20.8%) of the 356 included women, sampling technically failed, and in 84 (29.8%) the amount of tissue was insufficient for diagnosis. Nulliparity [odds ratio (OR) 3.8, 95% confidence interval (CI) 1.8-7.9] and advanced age (OR 1.03 per year, 95% CI 1.00-1.06) were associated with technical failure. Advanced age was associated with insufficient sampling (OR 1.04 per year, 95% CI 1.01-1.07), and endometrial thickness >12 mm decreased the chance of insufficient sampling (OR 0.3, 95%CI 0.1-0.8). The prediction model for total failure had an area under the ROC curve of 0.64 (95% CI 0.58-0.70)., Conclusions: In women with postmenopausal bleeding, the failure rate of endometrial sampling is relatively high and is associated with nulliparity and advanced age. Endometrial thickness >12 mm decreased the chance of failure. A multivariable prediction model for total failure based on patient characteristics has a moderate capacity to discriminate between women at high or low risk of failure., (© 2013 Nordic Federation of Societies of Obstetrics and Gynecology.)

Objectives: Measurement of endometrial thickness is an important tool in the assessment of women with postmenopausal bleeding, but the role of endometrial thickness measurement by ultrasound in asymptomatic women is unclear. The aims of this study were to determine: (1) the normal endometrial thickness measured by ultrasonography, (2) the prevalence of serious endometrial pathology and (3) the sensitivity and specificity of endometrial thickness measurement by transvaginal ultrasonography (TVS) for diagnosing premalignant and malignant endometrial disease in asymptomatic postmenopausal women., Methods: A MEDLINE and EMBASE search (from inception to January 2011) was performed. Articles reporting on endometrial thickness measurement in the diagnosis of endometrial carcinoma and atypical hyperplasia in asymptomatic postmenopausal women not using hormone replacement therapy (HRT) were selected. Endometrial thickness and the prevalence of endometrial (pre)malignancies were recorded. If possible, 2 × 2 tables were extracted., Results: Thirty-two studies reporting on 11100 women were included. The estimated mean endometrial thickness was 2.9 mm (95% CI, 2.6-3.3 mm). The pooled estimated prevalences of endometrial carcinoma and atypical endometrial hyperplasia were 0.62% (95% CI, 0.42-0.82%) and 0.59% (95% CI, 0.22-0.96%), respectively. Summary estimates for sensitivity and specificity of TVS endometrial thickness measurement in the prediction of endometrial carcinoma were 0.83 (95% CI, 0.19-1.00) and 0.72 (95% CI, 0.23-0.95) for a 5-mm cut-off and 0.33 (95% CI, 0.04-0.85) and 0.94 (95% CI, 0.92-0.96) for a 6-mm cut-off., Conclusions: The results from this systematic review do not justify the use of endometrial thickness as a screening test for endometrial carcinoma and atypical endometrial hyperplasia in asymptomatic postmenopausal women not using HRT., (Copyright © 2012 ISUOG. Published by John Wiley & Sons, Ltd.)

Objective: To evaluate the cost-effectiveness of diagnostic strategies incorporating the diagnostic value of patient characteristics for endometrial carcinoma using prediction models., Study Design: A decision analytic model was created to compare four diagnostic strategies for women with postmenopausal bleeding: the main outcome measures were 5 year survival, costs, and cost-effectiveness of three model based strategies compared to the strategy reflecting current practice., Results: A strategy selecting women for endometrial biopsy based on their history only, dominated all other strategies (more effective, less cost). In a clinical scenario where transvaginal sonography (TVS) was assumed to be an integral part of the consultation without additional costs, a strategy selecting high-risk women for TVS became the most cost-effective strategy., Conclusions: Strategies taking into account the individual probability based on a prognostic model are less costly than the currently applied strategy for a similar effectiveness. The most cost-effective strategy depends on the clinical setting: in areas where TVS is performed by the consulting gynecologist without extra costs, selective TVS based on history is the most cost-effective strategy. When TVS is not readily available and therefore incurs extra costs, a risk selection based on patient characteristics is most cost-effective., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Postmenopausal bleeding is associated with an elevated risk of having endometrial cancer. The aim of this review is to give an overview of existing prediction models on endometrial cancer in women with postmenopausal bleeding. In a systematic search of the literature, we identified nine prognostic studies, of which we assessed the quality, the different phases of development and their performance. From these data, we identified the most important predictor variables. None of the detected models completed external validation or impact analysis. Models including power Doppler showed best performance in internal validation, but Doppler in general gynecological practice is not easily accessible. We can conclude that we have indications that the first step in the approach of women with postmenopausal bleeding should be to distinguish between women with low risk versus high risk of having endometrial carcinoma and the next step would be to refer patients for further (invasive) testing.

Objective: To estimate the accuracy of endometrial thickness measurement in the detection of endometrial cancer among women with postmenopausal bleeding with individual patient data using different meta-analytic strategies., Data Sources: Original data sets of studies detected after reviewing the included studies of three previous reviews on this subject. An additional literature search of published articles using MEDLINE databases was preformed from January 2000 to December 2006 to identify articles reporting on endometrial carcinoma and sonographic endometrial thickness measurement in women with postmenopausal bleeding., Methods of Study Selection: We identified 90 studies reporting on endometrial thickness measurements and endometrial carcinoma in women with postmenopausal bleeding., Tabulation, Integration, and Results: We contacted 79 primary investigators to obtain the individual patient data of their reported studies, of which 13 could provide data. Data on 2,896 patients, of which 259 had carcinoma, were included. Several approaches were used in the analyses of the acquired data. First, we performed receiver operator characteristics (ROC) analysis per study, resulting in a summary area under the ROC curve (AUC) calculated as a weighted mean of AUCs from original studies. Second, individual patient data were pooled and analyzed with ROC analyses irrespective of study with standardization of distributional differences across studies using multiples of the median and by random effects logistic regression. Finally, we also used a two-stage procedure, calculating sensitivities and specificities for each study and using the bivariate random effects model to estimate summary estimates for diagnostic accuracy. This resulted in rather comparable ROC curves with AUCs varying between 0.82 and 0.84 and summary estimates for sensitivity and specificity located along these curves. These curves indicated a lower AUC than previously reported meta-analyses using conventional techniques., Conclusion: Previous meta-analyses on endometrial thickness measurement probably have overestimated its diagnostic accuracy in the detection of endometrial carcinoma. We advise the use of cutoff level of 3 mm for exclusion of endometrial carcinoma in women with postmenopausal bleeding.

We describe the design of a randomised controlled trial to evaluate the efficacy of endometrial polyp removal in women with postmenopausal bleeding. We designed a trial in which patients with postmenopausal bleeding and endometrial thickness >4 mm undergo hysteroscopy. If during hysteroscopy an endometrial polyp was diagnosed, patients were asked to participate in this trial and after informed consent allocated to immediate removal of the polyp or expectant management. This trial suffered from lack of recruitment related both to doctors seeking for informed consent as well as to patients' unwillingness to participate in this trial. However, a randomised controlled trial on this subject is still necessary to evaluate the efficacy of uterine cavity evaluation in the diagnostic work-up of women with postmenopausal bleeding, focussing on benign pathology. Therefore, we propose an alternative design, which might be more feasible.

Objective: To assess the accuracy of the cervical smear in the diagnosis of endometrial cancer in women with postmenopausal bleeding, with an emphasis on the diagnostic relevance of normal endometrial cells., Study Design: Women presenting with abnormal postmenopausal bleeding, not using hormone replacement therapy, were included prospectively. Cervical cytology was coded according to both the Papanicolaou (Pap) classification and the Dutch coding system (CISOE-A), which classifies endometrial and other cell types separately. For both classification systems, likelihood ratios (LR) for the presence of (pre) malignancy of the endometrium were calculated., Results: We included 543 women with postmenopausal bleeding. A (pre) cancerous endometrial lesion was present in 64 women (11.7%). A Pap III increased the probability of (pre) malignancy (LR 3.5), whereas Pap IV and Pap V virtually proved the presence of carcinoma. The CISOE-A classification showed similar results. The presence of normal endometrial cells did not increase the probability of endometrial (pre) malignancy., Conclusion: Adding the results of the cervical smear to endometrial thickness could detect incidental endometrial cancers that are missed by transvaginal sonography (< 5 mm). In women with postmenopausal bleeding the presence of normal endometrial cells is not predictive of endometrial cancer.

The objective is to assess among women with postmenopausal bleeding the relationship of age and time since menopause on one hand and the presence of endometrial cancer and atypical hyperplasia on the other hand. In a multicenter prospective cohort study, 614 women presenting with postmenopausal bleeding were included. Women underwent transvaginal sonography and, in cases where the endometrial thickness was >4 mm, endometrial sampling. Splines were used to assess the association between each of the continuous variables and (pre)malignancy of the endometrium. Subsequently, univariate and multivariate analysis were performed. The average age for women without (pre)malignancy was 61.7 years (SD 9.8). As malignant and premalignant cases were found to have similar age, these subgroups were merged in the analyses. Age was an independent predictor of (pre)malignancy. In women younger than 55 years, the odds ratio was 1.9 (95% CI: 1.1-3.3) for each year under 55 years of age and 1.03 (95% CI: 1.00-1.06) for each year over 55 years of age. The risk of (pre)malignancy of the endometrium was 4.9% in women less than 3 years postmenopausal versus 19.7% in women more than 20 years postmenopausal. However, in a multivariate analysis only age contributed to the prediction of risk. This study demonstrates that, in postmenopausal women with vaginal bleeding, the risk of (pre)malignancy of the endometrium is low in women under 50 years of age, increases considerably until 55 years of age, and rises only modestly with further advancing age. Future studies should explore whether these findings can be incorporated in the diagnostic work-up of women with postmenopausal bleeding.

Objectives: The aim of this study was to evaluate whether the efficiency of the current diagnostic work up following postmenopausal bleeding could be improved by diagnostic strategies that take into account characteristics of the women in addition to the currently recommended transvaginal measurement of endometrial thickness to determine for subsequent histological assessment., Design: Multicenter, prospective cohort study., Setting: A university hospital and seven teaching hospitals in the Netherlands., Sample: Consecutive women not using hormone replacement therapy, presenting with postmenopausal bleeding., Methods: Five hundred and forty women underwent transvaginal sonography, and in case of endometrial thickness (double layer) above 4 mm, subsequent endometrial sampling was performed. Presence of carcinoma was ruled out by the absence of abnormalities in histological specimen or by an uneventful follow up of at least 6 months., Main Outcome Measures: Probability of endometrial carcinoma was estimated by multivariable logistic regression models. For each diagnostic strategy, we calculated diagnostic accuracy (area under receiver operating characteristic curve [AUC]), negative predictive value (NPV) and the number of diagnostic procedures., Results: A strategy with transvaginal sonography alone with a fixed threshold incorrectly classified 0.7% of the women as nonmalignant (NPV: 99.3% [98.5-100%]), with 97% sensitivity and 56% specificity. A strategy integrating characteristics of the women with transvaginal sonography could result in less false reassurances (NPV: 99.6% [99.2-100%]), with only marginal decrease in diagnostic procedures, or a minor increase in false reassurances (NPV: 99.0% [98.3-100%]), with a substantial reduction (15-20%) in the procedures. AUCs associated with these strategies could improve from 0.76 (0.73-0.79) for transvaginal sonography alone to 0.90 (0.87-0.93) for the integrated strategy., Conclusion: Taking into account the characteristics of the women could increase the efficiency of the diagnostic work up for postmenopausal bleeding.