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Endometrial carcinoma is the most common malignancy of the female genital tract in developed countries and presents with postmenopausal bleeding in more than 95% of cases[1, 2]. In patients with postmenopausal bleeding, sonographic measurement of endometrial thickness is the first test to determine whether further investigations are needed to rule out malignancy. Guidelines recommend a cut-off value of 4 or 5 mm by transvaginal ultrasonography (TVS), below which endometrial cancer is unlikely[4-7]. When the endometrial thickness is below this cut-off, the probability of endometrial carcinoma is below 1%. In contrast to the clear guidelines on the management of women with postmenopausal bleeding, clinicians are faced with uncertainty when endometrial thickness is measured in asymptomatic postmenopausal women. Symptom-free women may undergo TVS for other indications, such as vaginal prolapse or abdominal complaints. Inevitably, the endometrium is then visualized and a thickened endometrium may incidentally be observed. It is not known how best to manage such patients in whom a thick endometrium is observed incidentally.
Based on a decision analysis in a theoretical cohort, Smith-Bindman et al. concluded that in asymptomatic postmenopausal women with an endometrial thickness of ≥ 11 mm an endometrial biopsy should be performed. They argued that women with an endometrial thickness above this threshold have a malignancy risk of 6.7%, which is comparable with the risk in patients with postmenopausal bleeding and an endometrial thickness of > 5 mm (7.3%), the latter being the widely accepted threshold for performing a biopsy in symptomatic patients.
Apart from the debate on the accuracy of endometrial thickness measurement in asymptomatic postmenopausal women, its potential value also depends on the prevalence of the disease searched for, i.e. endometrial carcinoma and/or its precursors. Since in asymptomatic women the prevalence of endometrial carcinoma is lower than in symptomatic women, the cut-off of endometrial thickness for abnormality in these women should be higher.
To address the abovementioned dilemmas, we reviewed the literature on asymptomatic postmenopausal women not using hormone replacement therapy (HRT). The aims of this review were to address in asymptomatic postmenopausal women: (1) normal endometrial thickness as measured with sonography, (2) the prevalence of serious endometrial pathology and (3) the sensitivity and specificity of endometrial thickness measurement by TVS for diagnosing premalignant and malignant endometrial disease.
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Our review shows that in a population of postmenopausal women without postmenopausal bleeding and not using HRT, the mean endometrial thickness is 2.9 mm and the prevalences of endometrial carcinoma and atypical endometrial hyperplasia are 0.62 and 0.59%, respectively. Positive predictive values for the three outcomes (endometrial carcinoma, atypical endometrial hyperplasia and both combined) for all reported endometrial thickness cut-offs were between 0 and 0.2. The negative predictive value of TVS was between 0.98 and 1.0 at all endometrial thickness cut-offs and for all three disease outcomes. However, the utility of a negative test in an asymptomatic postmenopausal population is limited because the absolute risk of disease is already low, as demonstrated in this review (prevalence of endometrial carcinoma 0.62% and atypical endometrial hyperplasia 0.59%). This contrasts with symptomatic postmenopausal women, in whom the pre-testing risk of endometrial cancer or atypical hyperplasia varies between 5 and 20%[43, 44]. Thus, TVS is only of value in postmenopausal women with vaginal bleeding because a clinically substantial reduction in the estimated probability of disease may be achieved by the observation of a normal endometrial thickness on TVS. This reduction is typically from around 10% to below 1% for endometrial carcinoma, a probability threshold where firstly, the majority of clinicians recommend reassurance and no need for further evaluation of the endometrium, and secondly, post-TVS probability is demonstrated to be equivalent to the prevalence in the asymptomatic postmenopausal female population[4-7].
The strength of our analysis is the complete overview of data combining endometrial thickness, endometrial carcinoma and atypical endometrial hyperplasia in asymptomatic postmenopausal women not using HRT. We describe mean endometrial thickness and the prevalence of endometrial (pre)malignancies in these women. Furthermore, we assessed the diagnostic accuracy of endometrial thickness measurements in this population. Efforts were made to identify all available publications on this subject and we used the most appropriate technique to summarize the sensitivity and specificity, to come to better estimates than the formerly applied summary receiver–operating characteristics curve (sROC) technique for meta-regression in diagnostic meta-analysis[10, 45-47]. To our knowledge, there is no previously published review or meta-analysis on this subject.
A limitation of our study is that despite the thousands of women included in our analysis, the estimates of sensitivity and specificity are very imprecise, especially those of sensitivity. Another limitation could be a bias because of the quality of the included studies. We tried to minimize this bias by performing quality assessment and applying strict criteria for inclusion of studies in the meta-analysis.
In a decision analysis performed by Smith-Bindman et al., an endometrial thickness cut-off of 11 mm for an incidentally measured increased endometrial thickness in an asymptomatic woman was proposed. In this decision analysis the risk of malignancy in a woman below the threshold is extremely low and the risk of malignancy above the threshold varies between 2.2 and 9.3%. In contrast to this analysis, which was a decision analysis in a theoretical cohort, we analyzed observational data. Unfortunately, we had insufficient data from the published studies to calculate an optimal threshold for endometrial thickness based on the sensitivity and specificity reported in the different studies. Because of the low prevalence of the disease, the 95% CI for the summary estimates of sensitivity are very wide, indicating a high degree of inaccuracy.
The use of TVS is not limited to women with postmenopausal bleeding. The portability and improved resolution of TVS have contributed to the ubiquity of the test in routine gynecological practice. Postmenopausal women undergo TVS for a variety of gynecological indications (e.g. pelvic pain, suspicion of a pelvic mass, uterine prolapse). During TVS for such non-bleeding indications, images of the endometrium are frequently obtained and a thickened endometrium may be observed. This situation of an apparently incidental finding of an abnormal endometrium will be familiar to all practicing sonologists. Faced with such a TVS finding, it is difficult for the physician to decide on the right management and this usually results in a decision to undertake further, more invasive testing with endometrial sampling and/or hysteroscopy, in keeping with current guidelines for postmenopausal bleeding. Therefore, the findings of this review, describing normative values for endometrial thickness, determining serious disease prevalence and estimating diagnostic accuracy at various TVS thresholds, in this non-bleeding postmenopausal population are clinically important. Our review has shown that the average TVS-derived endometrial thickness is 2.9 mm. However, the significance of an endometrial thickness beyond 4 mm is not the same as for a symptomatic postmenopausal bleeding population, and extrapolating protocols from postmenopausal bleeding to an asymptomatic population is not justifiable in view of the low overall disease prevalence and poor performance of TVS in detecting serious endometrial disease at all cut-offs.
Because the prevalence of the target disease in an unselected postmenopausal population without bleeding symptoms and not using HRT is very low, and endometrial thickness measurement in this population cannot achieve a sufficiently high sensitivity to provide additional reassurance to women with a negative test or achieve a sufficiently high specificity to justify further invasive testing in women with a positive test, endometrial thickness measurement has no value in this population. Furthermore, there is no evidence that patients in whom endometrial cancer was discovered while asymptomatic have a prognostic advantage over postmenopausal endometrial cancer patients who visited their gynecologist immediately after bleeding had occurred. Thus, 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 any asymptomatic postmenopausal woman not using HRT. Hence, the need for further diagnostic evaluation of the endometrium should be made by the clinician on an individual patient basis taking into account clinical signs (e.g. abnormal findings at physical examination, pelvic pain, distension, urinary and bowel complaints), risk factors for endometrial disease (e.g. abnormal BMI, medical comorbidities, family history) and patient preference[49-54].