M. C. Breijer

Diagnostic evaluation of the endometrium in postmenopausal bleeding: An evidence-based approach

Postmenopausal bleeding (PMB) is a common complaint in general gynecological practice. Women with PMB have around a 10% chance of having endometrial carcinoma and therefore PMB always needs further evaluation. This article summarizes the reviews on the subject and provides an overview of the use of diagnostic tools in patients with PMB. Four types of diagnostic test are described: sonographic measurement of endometrial thickness, endometrial sampling, hysteroscopy and saline infusion sonography. All four have been independently shown to be accurate in excluding endometrial cancer. However, neither in systematic reviews nor in international guidelines is consensus found regarding the sequence in which these methods should be employed in women with PMB. For measurement of endometrial thickness in symptomatic women, a cut-off value of 3mm is recommended, but the cost-effectiveness of this strategy has yet to be shown. Research should now focus on the incorporation of individual patient characteristics and pre-test probabilities for cancer in algorithms for the investigation of PMB, and the most cost-effective sequenced combination of the four types of test.

Capacity of endometrial thickness measurement to diagnose endometrial carcinoma in asymptomatic postmenopausal women: a systematic review and meta-analysis

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.

Diagnostic Strategies for Postmenopausal Bleeding

Postmenopausal bleeding (PMB) is a common clinical problem. Patients with PMB have 10%–15% chance of having endometrial carcinoma and therefore the diagnostic workup is aimed at excluding malignancy. Patient characteristics can alter the probability of having endometrial carcinoma in patients with PMB; in certain groups of patients the incidence has been reported to be as high as 29%. Transvaginal sonography (TVS) is used as a first step in the diagnostic workup, but different authors have come to different conclusions assessing the accuracy of TVS for excluding endometrial carcinoma. Diagnostic procedures obtaining material for histological assessment (e.g., dilatation and curettage, hysteroscopy, and endometrial biopsy) can be more accurate but are also more invasive. The best diagnostic strategy for diagnosing endometrial carcinoma in patients with PMB still remains controversial. Future research should be focussed on achieving a higher accuracy of different diagnostic strategies.

Factors attributing to the failure of endometrial sampling in women with postmenopausal bleeding

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.

Diagnostic strategies for endometrial cancer in women with postmenopausal bleeding: cost-effectiveness of individualized strategies

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.

Diagnostic workup for postmenopausal bleeding: a randomised controlled trial

To evaluate the effectiveness of hysteroscopy for the detection and treatment of endometrial polyps versus expectant management in women with postmenopausal bleeding (PMB), a thickened endometrium and benign endometrial sampling.

A Structured Assessment to Decrease the Amount of Inconclusive Endometrial Biopsies in Women with Postmenopausal Bleeding.

Objective. To determine whether structured assessment of outpatient endometrial biopsies decreases the number of inconclusive samples. Design. Retrospective cohort study. Setting. Single hospital pathology laboratory. Population. Endometrial biopsy samples of 66 women with postmenopausal bleeding, collected during the usual diagnostic work-up and assessed as insufficient for a reliable histological diagnosis. Methods. Endometrial biopsy samples were requested from the pathology laboratories. The retrieved samples were systematically reassessed by a single pathologist specialized in gynecology. Main Outcome Measure. Disagreement between initial assessment and conclusion after structured reassessment. Results. We retrieved 36 of 66 endometrial biopsy samples from six different pathology laboratories. Structured reassessment of the retrieved samples by a single pathologist specialized in gynecology did not change the conclusion in 35 of the 36 samples. The remaining sample contained a large amount of endometrial tissue and the diagnosis at reassessment was endometrial hyperplasia without atypia. All other samples contained insufficient material for a reliable diagnosis. Conclusion. A structured reassessment of endometrial biopsies samples, which were classified as inconclusive due to insufficient material, did not change the conclusion. Although it might be helpful for pathologists to have diagnostic criteria for adequacy and/or inadequacy of an endometrial biopsy sample, the gain in efficiency is likely to be small.

Transvaginal ultrasound measurement of the endometrium remains the first line test for investigating postmenopausal bleeding but integration of patient characteristics into testing may further improve diagnostic algorithms.

Postmenopausal bleeding (PMB) is a frequent medical problem that accounts for approximately 5% of all gynaecological consultations. In 10% of women with PMB, endometrial cancer is the underlying cause, which makes endometrial cancer the most common malignancy of the female genital tract in developed countries (Moodley & Roberts, J Obstet Gynaecol 2004;24:736–41). Adoption of transvaginal ultrasound (TVS) measurement of endometrial thickness as the first line diagnostic test in PMB algorithms has minimised the need for more invasive endometrial evaluation with endometrial sampling and hysteroscopy. However, the endometrial thickness cutoff to exclude endometrial cancer and the need for further testing remains the subject of debate. Four systematic reviews and meta-analyses have been published on this subject with differing conclusions (Gupta et al. Acta Obstet Gynecol Scand 2002;81:799–816, Smith-Bindman et al. JAMA 1998;280:1510–7, Tabor et al. Obstet Gynecol 2002;99: 663–70, Timmermans et al. Obstet Gynaecol 2010;116:160–7]. Some of these meta-analyses suffer from the fact that authors of smaller studies titrated an optimal cut-off, thereby maximising the specificity for a sensitivity of almost 100%, whereas others suffer from partial verification bias because the need for endometrial biopsy was conditional upon the endometrial thickness measurement by TVS. The study by Wong et al. published in this issue of the journal is unique because it describes the largest cohort of women presenting with PMB where invasive assessment of the endometrium has been done in all women independent from the results of the preceding TVS endometrial thickness measurement. Indeed, the optimal threshold that combines an almost perfect sensitivity with an acceptable specificity appears to be 3 mm. At this cut-off point, positive and negative predictive values were 6.5 and 0.26%. Higher cut-off values, e.g. 5 mm, would result in positive predictive values of over 10% but a negative predictive value of 0.35%. Awareness of these trade-offs can inform decision making. The prevalence of endometrial cancer among women with PMB in this cohort from Hong Kong was 3.7%, which is much lower than the previously assumed 10%. Whether this is due to the large unselected population or due to differences in the incidence of endometrial cancer in an Asian population is unclear and requires further study. Although strategies for investigating PMB based upon TVS endometrial thickness thresholds are well established, further refinement is possible by integrating patient characteristics and thereby the individual risk of endometrial cancer, into decisions about the need and type of testing required. Other studies have shown that increasing age, older age at menopause, BMI, nulliparity, diabetes and recurrent bleeding increase the risk of endometrial cancer. These data of Wong et al. can help further refine and validate existing prediction models. In this way, preand post-test probabilities of endometrial cancer could be maximised, which in turn will reduce the harm done and wasting of resources arising from unnecessary testing.

Long-term Risk of Endometrial Cancer Following Postmenopausal Bleeding and Reassuring Endometrial Biopsy

ABSTRACT Women with postmenopausal bleeding who present with an endometrial thickness 4 mm or less are at a very low risk of endometrial cancer, and therefore refraining from endometrial sampling in these women is considered justified. If the endometrial thickness is more than 4 mm, endometrial sampling is indicated to exclude endometrial cancer. Although women with a histological finding of endometrial hyperplasia without atypia have a slightly increased risk of developing endometrial cancer, this finding is generally regarded as a reassuring histology without the need for further follow-up. A recently published prospective cohort study reported that in 84 (29.8%) of 356 women presenting with postmenopausal bleeding and endometrial thickness of more than 4 mm, outpatient endometrial sampling failed because the amount of tissue was insufficient for a reliable histopathologic diagnosis. When endometrial sampling fails, there is currently no consensus on what to do. No long-term follow-up studies have reported the incidence of endometrial cancer after failure of endometrial sampling. The aim of this long-term cohort follow-up study was to investigate the relative risk of developing endometrial cancer after initial workup for postmenopausal bleeding shows reassuring histology or insufficient endometrial sampling. The authors hypothesized that women with postmenopausal bleeding and failure of endometrial sampling have an increased risk of endometrial (pre)malignancies. Participants were women with postmenopausal bleeding presenting at 3 hospitals in the Netherlands between January 2009 and April 2011. Long-term follow-up data were collected from the patient charts of the 3 participating hospitals and from PALGA, the Dutch Pathology Registry. Standardized incidence ratios were calculated to estimate the risk of endometrial cancer, relative to the general population. A total of 668 women presented with postmenopausal bleeding; of these, 568 were available for follow-up. Median follow-up time was 47 months (range, 7–63 months). Women with postmenopausal bleeding, endometrial thickness of more than 4 mm, and hyperplasia without atypia on biopsy at the first presentation had a 17 times increased risk of developing endometrial cancer during the first 4 years of follow-up compared with the age-specific population; the standardized incidence ratio was 17.15, with a 95% confidence interval of 1.96 to 61.93. All women who developed endometrial cancer after initial reassuring histology presented with recurrent postmenopausal bleeding. During follow-up, no endometrial cancer was diagnosed in women with endometrial thickness of more than 4 mm and no or insufficient histology at initial presentation. Despite an initial reassuring histological finding of endometrial hyperplasia without atypia, women with postmenopausal bleeding and endometrial thickness of more than 4 mm had a significantly increased risk of endometrial cancer during 4 years of follow-up compared with the age-specific population. Further studies are needed to determine whether additional diagnostics or a more stringent follow-up regimen would be cost-effective.

Authors' reply re: Diagnostic work up for postmenopausal bleeding: a randomised controlled trial

11.6% of evaluated patients. These findings, which include an endometrial thickness >5 mm as assessed by sonographic evaluation and an irregular endometrial echo, have been found in five of 43 women who were postmenopausal for at least 1 year. Although our data are from a single centre andwere obtained in a retrospective study of a small number of patients, they nonetheless suggest that in PMW increased endometrial thickness should be further evaluated to rule out malignancy. Finally, the data of Timmerman also highlight the challenges for the gynaecologist regarding outpatient hysteroscopy; however, we do not agree with their conclusions regarding bleeding or abnormal ultrasonography in PMW. Rather, in this group of patients, bleeding and abnormal ultrasonographic findings should be considered indications for biopsy to rule out malignancy. Again, hysteroscopic examination in the outpatient setting is not, in our opinion, appropriate because of the stiff cervix of PMW. These observations should be of interest to gynaecologists when deciding whether to perform a hysteroscopy in PMW.&