Risk assessment of endometrial cancer and endometrial intraepithelial neoplasia in women with abnormal bleeding and implications for clinical management algorithms

Abstract Background Most endometrial cancer cases are preceded by abnormal uterine bleeding, offering a potential opportunity for early detection and cure of endometrial cancer. While clinical guidelines exist for diagnostic workup of abnormal uterine bleeding, consensus is lacking regarding optimal management for women with abnormal bleeding to diagnose endometrial cancer. Objective We report the baseline data from a prospective clinical cohort study of women referred for endometrial evaluation at the Mayo Clinic, designed to evaluate risk stratification in women at increased risk for endometrial cancer. Here, we introduce a risk-based approach to evaluate diagnostic tests and clinical management algorithms in a population of women with abnormal bleeding undergoing endometrial evaluation at the Mayo Clinic. Study Design A total of 1,163 women aged ≥45 years were enrolled from February 2013-May 2019. We evaluated baseline absolute risks and 95% confidence intervals of endometrial cancer and endometrial intraepithelial neoplasia according to clinical algorithms for diagnostic workup of women with postmenopausal bleeding (assessment of initial vs. recurrent bleeding episode and endometrial thickness measured via transvaginal ultrasound). We also evaluated risks among women with postmenopausal bleeding according to baseline age ( 4mm. We assessed the clinical efficiency of each strategy by estimating the percent of women who would be referred for endometrial biopsy, the percent of cases detected and missed, and the ratio of biopsies per case detected. Results Among the 593 women with postmenopausal bleeding, 18 (3.0%) had endometrial intraepithelial neoplasia and 47 (7.9%) had endometrial cancer and among the 570 premenopausal women with abnormal bleeding, 8 (1.4%) had endometrial intraepithelial neoplasia and 7 (1.2%) had EC. Risks were highest in women aged 60+ years 17.7% (13.0-22.3%), followed by those with recurrent bleeding (14.7%, 11.0-18.3%). Among women with an initial bleeding episode in whom transvaginal ultrasound is recommended, endometrial thickness did not provide meaningful risk stratification: risks of endometrial cancer/endometrial intraepithelial neoplasia were nearly identical in women with an endometrial thickness of >4mm (5.8%; 1.3-10.3%) and ≤4mm (3.6%; 0.9-8.6%). In contrast, among those aged 4mm, the risk of endometrial cancer/endometrial intraepithelial neoplasia was 8.4% (4.3-12.5%) and in those with an endometrial thickness of ≤4mm, the risk was 0% (0.0-3.0%; p=0.010). The most efficient strategy was to perform biopsy in all women aged 60+ years and among those aged 4mm, with the lowest percentage referred to biopsy while still detecting all cases. Conclusions Current clinical recommendations for endometrial cancer detection in women with abnormal bleeding are not consistent with underlying risk. Endometrial cancer risk factors such as age can provide important risk stratification compared to the assessment of recurrent bleeding. Future research will include a formal assessment of clinical and epidemiologic risk prediction models in our study population as well as validation of our findings in other populations.