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. Although 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 1163 women aged ≥45 years were enrolled from February 2013 to 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 through transvaginal ultrasound). We also evaluated risks among women with postmenopausal bleeding according to baseline age (<60 vs 60+ years) as an alternative example. For this approach, biopsy would be conducted for all women aged 60+ years and those aged <60 years with an endometrial thickness of >4 mm. We assessed the clinical efficiency of each strategy by estimating the percentage of women who would be referred for endometrial biopsy, the percentage 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 endometrial cancer. Maximum risk was noted 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 for whom transvaginal ultrasound was recommended, endometrial thickness did not provide meaningful risk stratification: risks of endometrial cancer and endometrial intraepithelial neoplasia were nearly identical in women with an endometrial thickness of >4 mm (5.8%; 1.3%-10.3%) and ≤4 mm (3.6%; 0.9%-8.6%). In contrast, among those aged <60 years with an endometrial thickness of >4 mm, the risk of endometrial cancer and endometrial intraepithelial neoplasia was 8.4% (4.3%-12.5%), and in those with an endometrial thickness of ≤4 mm, the risk was 0% (0.0%-3.0%; P=.01). The most efficient strategy was to perform biopsy in all women aged 60+ years and among those aged <60 years with an endometrial thickness of >4 mm, with the lowest percentage referred to biopsy while still detecting all cases.

Conclusion: Existing clinical recommendations for endometrial cancer detection in women with abnormal bleeding are not consistent with the underlying risk. Endometrial cancer risk factors such as age can provide important risk stratification compared with 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.

Keywords: abnormal bleeding; endometrial biopsy; endometrial cancer; endometrial intraepithelial neoplasia; postmenopausal bleeding; risk assessment; transvaginal ultrasound.

Figure 1.

CONSORT Diagram of the study population

Figure 2.. Baseline Risk of Endometrial Cancer and Endometrial Intraepithelial Neoplasia according to bleeding type and endometrial thickness.

We evaluated the combined baseline risks of endometrial cancer and endometrial intraepithelial neoplasia combined following a sequential diagnostic process according to current guidelines from the American College of Obstetricians and Gynecologists. Bleeding type was characterized as either initial episode of bleeding or recurrent bleeding (any occurrence of bleeding after prior evaluation for PMB). Endometrial thickness was measured clinically using transvaginal ultrasound. The diamond markers are weighted according to the corresponding number of women within each stratum of diagnostic test results. A total of 22 women are missing bleeding type information; the risk of EC/EIN in these women is 4.6%. Abbreviations: EC, endometrial cancer; EIN, Endometrial Intraepithelial Neoplasia; PMB, postmenopausal bleeding; ET, endometrial thickness; TVUS, transvaginal ultrasound

Figure 3.. Baseline Risk of Endometrial Cancer and Endometrial Intraepithelial Neoplasia according to age and endometrial thickness.

We evaluated the combined baseline risks of endometrial cancer and endometrial intraepithelial neoplasia combined using age at a cutoff of 60 years (<60 and ≥60) as an initial risk stratifier. Endometrial thickness was measured clinically using transvaginal ultrasound. The diamond markers are weighted according to the corresponding number of women within each stratum of diagnostic test results. Abbreviations: EC, endometrial cancer; EIN, Endometrial Intraepithelial Neoplasia; PMB, postmenopausal bleeding; ET, endometrial thickness; TVUS, transvaginal ultrasound