Shagaf H. Bakour

Endometrial thickness measurement for detecting endometrial cancer in women with postmenopausal bleeding: a systematic review and meta-analysis

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.

The risk of premalignant and malignant pathology in endometrial polyps

OBJECTIVE To evaluate the risk of premalignant and malignant pathology among endometrial polyps. DESIGN Prospective cohort study. SETTING Minimal Access Surgical Training (MAST) center in a large teaching hospital. METHODS Among 248 patients seen in outpatient hysteroscopy clinic (1996-97), 62 had endometrial polyps. All patients had endometrial sampling for histological assessment. To determine the magnitude of malignant potential among polyps, we compared the pathological findings in polyps (cases) with non-polypoidal specimens (controls). RESULTS Out of 62 polyps, histologically 53 (85.5%) were benign, seven (11.3%) had hyperplasia, and two (3.2%) were associated with malignancy. Hyperplasia was more frequent in endometrial specimens with polyps than in those without (11.3% vs 4.3%, p=0.04), but the incidence of carcinoma in the two groups was the same (3.2% vs 3.2%, p= 1.0). CONCLUSION In abnormal uterine bleeding, hyperplasia was, but cancer was not, more common in women with endometrial polyps compared to those without polyps.

Controlled analysis of factors associated with insufficient sample on outpatient endometrial biopsy

We examined the relative significance of hysteroscopic and ultrasonographic evidence of endometrial atrophy in relation to insufficient sample on outpatient endometrial biopsy in women with abnormal uterine bleeding. Multivariate logistic regression modelling was used to evaluate the independent effects of age, menopausal status, hysteroscopic findings and sonographic endometrial thickness on outpatient endometrial sampling (sufficient or insufficient) used as the binary dependent variable. Insufficient sample on endometrial biopsy was associated with hysteroscopic finding of endometrial atrophy (OR 4.79, 95% CI 1.05–21.91, P= 0.04) and sonographic endometrial thickness below 5 mm (OR 0.19, 95% CI 0.07–0.53, P= 0.001). There was no association with patients age and menopausal status. In conclusion, when reassuring women with insufficient sample on outpatient endometrial biopsy, one can be confident about absence of pathology provided the hysteroscopic and sonographic endometrial assessment is consistent with endometrial atrophy.

Risk factors associated with endometrial polyps in abnormal uterine bleeding

Objectives: To evaluate the significance of various risk factors associated with endometrial polyps in women with abnormal uterine bleeding. Methods: A prospective cohort study of 248 consecutive patients evaluated for abnormal uterine bleeding in a Rapid Access Ambulatory Diagnostic (RAAD) clinic was carried out from 1996 to 1997. Endometrial polyps were diagnosed using outpatient hysteroscopy and their histological nature was confirmed in all patients by performing inpatient polypectomy. Multivariate logistic regression modeling was used to evaluate the effects of age, parity, menopausal status, hormone replacement therapy and tamoxifen treatment on the occurrence of polyps. Results: In an analysis adjusted for the effects of age, parity and menopausal status, tamoxifen treatment was associated with endometrial polyps (adjusted odds ratio 11.21, 95% confidence interval 2.70–46.46, P=0.0009) but hormone replacement therapy was not (adjusted odds ratio 1.48, 95% confidence interval 0.68–3.20, P=0.32). Conclusion: Our study confirmed that tamoxifen is associated with endometrial polyps. However, it rejects the hypothesis that hormone replacement therapy is a risk factor for endometrial polyps.

Evaluation of outpatient hysteroscopy and ultrasonography in the diagnosis of endometrial disease

OBJECTIVE To develop a multivariable approach to determine the added value of tests in routine practice where some diagnostic information is already available from clinical history. METHODS Multivariable logistic regression models were built in a stepwise fashion, considering the clinical sequence used in the rapid access ambulatory diagnosis clinic (clinical history followed by transvaginal ultrasonography and hysteroscopy). The reference standard for confirmation of diagnosis was endometrial biopsy. The diagnostic accuracy of the models was determined by the area under the receiver operating characteristic curve. RESULTS The area under the receiver operating characteristic curve for the model including historical features alone was 0.78. When hysteroscopy and ultrasonography were each added to the model, it increased to 0.81 (P = .008 for improvement) and 0.82 (P = .02 for improvement), respectively. CONCLUSION The type of stepwise analysis we have developed is crucial in facilitating meaningful clinical interpretation about the value of diagnostic technology. Our finding that hysteroscopy or ultrasonography marginally but significantly increased the prediction of serious endometrial pathology above that predicted from patient history alone needs validation in an independent data set. The use of this approach is recommended when evaluating strategies for diagnosis.

Evidence-based obstetric and gynaecologic diagnosis: the STARD checklist for authors, peer-reviewers and readers of test accuracy studies

In obstetrics and gynaecology, the technology behind existing tests is continuously improving and new tests are developing at a fast rate. The question of whether these developments lead to improved diagnosis is addressed in test accuracy studies. The BJOG covered proper evaluation of clinical tests in 2001 with two commentaries, which provided the basis for improvement in reporting and peer-review. Recently, an international initiative on the Standards for Reporting of Diagnostic accuracy called STARD has been reported. In this commentary, we introduce this to authors, peer-reviewers and readers. Evaluation of research depends on transparent, complete and accurate reporting. This allows the reader to detect the potential for bias in the study and to evaluate the applicability of the results in their practice. Hence, guidelines on reporting randomised trials (CONSORT) and systematic reviews (QUORUM and MOOSE) have been developed and widely accepted by both journal editors and authors. STARD is an initiative on similar lines. It is aimed at studies of diagnostic accuracy comparing ‘new’ tests with existing reference standards. STARD consists of a 25-item checklist (Table 1) and flow diagram (Fig. 1) and an explanatory document that describes the background, rationale and evidence for each of the 25 items. Checklist and flow diagram are available from http://www. consort-statement.org/stardstatement.htm. The explanatory document is available from the websites of Clinical Chemistry (http://www.clinchem.org) and the Annals of Internal Medicine (http://www.annals.org). STARD was developed after a search for published guidelines about diagnostic research, which had yielded 33 previously published checklists. From these, a list of 75 potential items was developed. At an international consensus meeting of researchers, editors and members of professional organisations, participants short-listed 25 items, considering empirical evidence of bias whenever available. The flow diagram provides information about the method of recruitment of participants, the order of tests and the numbers of participants undergoing the test under evaluation and the reference standard. This flow diagram communicates vital information about the study design and the flow of participants in a transparent matter. It is anticipated that the use of this checklist, in combination with the flow diagram, will enhance the quality of reporting of studies on diagnostic accuracy. In studies of test accuracy, the information from one or more tests under evaluation is compared with a reference standard as measured in the same subjects suspected of the condition of interest. The word ‘test’ refers to any method for obtaining additional information on a patient’s health status (e.g. history, physical examination, laboratory tests, imaging tests, function tests and histopathology). The ‘condition of interest’ is usually a particular disease or diagnosis. The ‘reference standard’ is the best available method for verifying the presence or absence of the diagnosis, which may consist of one or more methods including laboratory tests, imaging tests, histopathology and also clinical follow up of subjects. A complete description of independence and blinding of comparison of the test under scrutiny with reference standard among an appropriate patient group is required by STARD. The term ‘accuracy’ refers to the amount of agreement between the information from the test under evaluation and the reference standard. Test accuracy can be expressed as sensitivity and specificity, likelihood ratios, diagnostic odds ratio, the area under a ROC curve etc. Details of how to estimate these have been previously provided. To comprehend and use the results of test accuracy studies, readers must be able to understand the design, conduct, analysis and results. If readers have to speculate, there could be errors in interpretation with undesired clinical consequences. Critical appraisal, a key step in evidencebased practice, is only possible if the design, conduct and analysis of test accuracy studies is thoroughly described in published articles. Inadequate methodological approaches are often associated with erroneous conclusions. Authors themselves have a tendency to exaggerate conclusions about test accuracy. Biased and exaggerated inferences can trigger premature dissemination and mislead decision making in health care for individual patients as well as for regional and national policies. A rigorous evaluation of test accuracy studies could help limit health care costs by preventing unnecessary testing and by reducing the number of unwanted clinical consequences related to false test results. One of the issues deliberately left out from the STARD list at present is that of sample size. It is possible to perform a sample size (power) calculation at the start, but there is no consensus on methods of sample size estimation for

Transvaginal ultrasonography and endometrial histology in peri‐ and postmenopausal women on hormone replacement therapy

Sir; We read with interest the observational study by Lindgren et al. (Vol 106, May 1999)’ concerning the association between ultrasonographicall y determined endometrial thickness and endometrial pathology in a large sample of women using hormone replacement therapy. We agree with their conclusion that no association could be found because the test (endometrial thickness 5 4 nun) was only marginally accurate with a sensitivity of 75%, a specificity of 47%, and positive and negative predictive values of 2% and 99%, respectively. In comparison, our own data from a prospective cohort study in two UK teaching hospitals2, showed that the sensitivity to detect premalignant and malignant endometrial lesions at endometrial thickness 5 4 mm was 92.9%, the specificity was 50%, and the positive and negative predictive values were 21.4% and 97.6%, respectively. We would, however, like to suggest that the interpretation of these measures of diagnostic accuracy is difficult. Most clinicians are unable to take home the essential message from such data presentation. We have found that using Bayesian analysis with likelihood ratios allows more meaningful interpretation, which improves the ability of a clinician to understand diagnostic data. In fact, analysis without likelihood ratios leads to misleading inferences’. We would suggest that all diagnostic papers should now be encouraged to present results using likelihood ratios. Based on recommendations of the Evidence-based Medicine Working group4, we have developed a diagram for interpreting likelihood ratios which has been very helpful in conveying the concept of diagnostic test accuracy to audiences at several conferences (Fig. 1). The likelihood ratio indicates by how much a given endometrial thickness will raise or lower the probability of having endometrial pathology. Analysis of our data’, using Bayesian analysis for detecting endometrial hyperplasia or cancer by ultrasound scan, reveals that likelihood ratio was 0.14 (95% CI 0.02-0.64) for endometrial thickness < 4 mm, 0.94 (95% CI 0.37-1.99) for endometrial thickness 4.1-9.0 mm, and 3.3 (95% CI 1.73-5.73) for endometrial thickness > 9 mm. Interpreted according to our diagram, this means that ultrasound

Successful conservative management of cervical ectopic pregnancy with combination of methotrexate, mifepristone, surgical evacuation and tamponade using a double balloon three-way catheter

ovulation induction today (Lehmann et al. 1991). Raziel et al. (2004) reported an incidence of 2.7% of all ectopic pregnancies, 1:3,000 of all live births leading to a mean ovarian pregnancy per year of 1.6. This increased incidence may be assumed to be a reflection of rising incidence of ectopic pregnancy, in general. However, to consider this assumption, there must be similarities between the main aetiological or risk factors of ovarian and tubal pregnancy. Risk factors for tubal pregnancy include tubal disease or surgery, failed IUCD, previous ectopic pregnancy and assisted conception. This seems to be more complicated in ovarian ectopics. The relation between IUD use and ovarian pregnancies is still strong (Raziel et al. 2004). In a review of seven ovarian pregnancies occurring during an 11-year period (1976 – 1986) in Barcelona, four of these cases presented in actual users of IUD and one in an infertile woman previously diagnosed of endometriosis (Cabero et al. 1989). The aetiology is unknown but said to occur more commonly in parous women (Vasilev and Sauer 1990). This apparently increased incidence may be partly due to routine and meticulous histological examination of the excised tissues, plus increased awareness of this unusual condition (Onon and Allen 1997). The diagnosis is often suspected at the time of surgery as the main clinical presentation is almost the same as tubal pregnancy (as in our case). However, an index of suspicion is becoming more valuable with the advancement in resolution of transvaginal ultrasound. Therefore a high index of suspicion is needed when any pelvic/ovarian lesion is seen at laparoscopy, especially in normal looking fallopian tubes with raised bhCG values and empty uterus on scan. Cases have been delayed diagnosis during laparoscopy on the assumption of ruptured corpus luteum to be confirmed on later follow-up (Sinha 2004). The main pathological criteria of Spiegelberg’s are used for the diagnosis of ovarian pregnancy. These include (1) normal fallopian tubes and separate from the ovary; (2) the conceptus is in the normal location of the ovary; (3) it is connected to the uterus by the ovarian ligament; (4) ovarian tissue must be demonstrable histologically within the wall of the gestation sac. Laparoscopic wedge resection has been described as the treatment of choice. Conservative laparoscopic treatment and methotrexate have also been reported. However, in ruptured ovarian ectopic pregnancy, oophorectomy is the treatment of choice as increased vascularity may lead to massive haemorrhage (Sinha 2004). In comparison with tubal pregnancy, recurrence of ovarian ectopic pregnancy is virtually non-existent (Adeniran and Stanek 2003). Apart from the known postoperative adhesion after ovarian surgery, patients who have ovarian pregnancy will have excellent prognosis for future fertility.

Latest evidence on using hormone replacement therapy in the menopause

Hormone replacement therapy (HRT) is the most effective treatment for symptoms of estrogen deficiency. When HRT is individually tailored women gain maximum advantages and the risks are minimised. Several types and regimens of HRT and different routes of delivery exist. Results from studies using only one type and route may not therefore apply to all users. The use of HRT is an individual decision, which a woman can only make once she has been given correct information and advice from healthcare professionals. HRT should be recommended in women with premature ovarian insufficiency with advice to continue until the average age of the menopause at 51.4 years.

Management of women with postmenopausal bleeding: evidence‐based review

Patients with postmenopausal bleeding (PMB) have a 10–15% chance of having endometrial carcinoma; they should therefore be seen within 2 weeks of referral. Cervical and vulval cancers remain important components of the differential diagnosis and can only be assessed by clinical examination. There are well‐developed and evidence‐based strategies on how best to investigate women with PMB. These strategies are formulated in several guidelines.