Hormone replacement therapy and endometrial cancer risk: A meta-analysis

Objective

To assess the association of unopposed estrogen or estrogen plus progestin and the risk of developing endometrial cancer or dying of that disease.

Data Sources

A literature search of English-language studies was performed using MEDLINE, a review of bibliographies, and consultations with experts.

Methods of Study Selection

We identified 30 studies with adequate controls and risk estimates.

Data Extraction and Synthesis

Risk estimates were extracted by two authors and summarized using meta-analytic methods. The summary relative risk (RR) was 2.3 for estrogen users compared to nonusers (95% confidence interval [CI] 2.1–2.5), with a much higher RR associated with prolonged duration of use (RR 9.5 for 10 or more years). The summary RR of endometrial cancer remained elevated 5 or more years after discontinuation of unopposed estrogen therapy (RR 2.3). Interrupting estrogen for 5–7 days per month was not associated with lower risk than daily use. Users of unopposed conjugated estrogen had a greater increase in RR of developing endometrial cancer than users of synthetic estrogens. The risk for endometrial cancer death was elevated among unopposed estrogen users (RR 2.7, 95% CI 0.9–8.0). Among estrogen plus progestin users, cohort studies showed a decreased risk of endometrial cancer (RR 0.4), whereas case-control studies showed a small increase (RR 1.8).

Conclusions

Endometrial cancer risk increases substantially with long duration of unopposed estrogen use, and this increased risk persists for several years after discontinuation of estrogen. Although not statistically significant, the risk of death from endometrial cancer among unopposed estrogen users is increased, similar to the increased risk of developing the disease. Data regarding risk for endometrial cancer among estrogen plus progestin users are limited and conflicting. [1]

Risk of endometrial cancer after tamoxifen treatment of breast cancer

Since large trials have been set up to assess whether tamoxifen decreases the risk of breast cancer in healthy women, it has become important to investigate the drug’s potential adverse effects, including occurrence of endometrial cancer. We undertook a case-control study in the Netherlands to assess the effect of tamoxifen on the risk of endometrial cancer after breast cancer. Through the population-based Netherlands Cancer Registry and two older, hospital-based, registries, we identified 98 patients who had endometrial cancer diagnosed at least 3 months after a diagnosis of primary breast cancer. Detailed information about treatment was obtained for all these patients, and for 285 controls, who were matched to the cases for age, year of breast cancer diagnosis, and survival time with intact uterus. Tamoxifen had been used by 24% of patients with subsequent endometrial cancer and 20% of controls (relative risk 1·3 [95% Cl 0·7-2·4]). Women who had used tamoxifen for more than 2 years had a 2 3 (0 9-5 9) times greater risk of endometrial cancer than never users. There was a significant trend of increasing risk of endometrial cancer with duration of tamoxifen use (p=0 049), and also with cumulative dose (p=0·046). The duration-response trends were similar with daily doses of 40 mg or 30 mg and less. These findings support the hypothesis that tamoxifen use increases the risk of endometrial cancer. This oestrogenic effect on the endometrium was not related to the dose intensity. Physicians should be aware of the higher risk of endometrial cancer in tamoxifen users. [2]

Endovaginal Ultrasound to Exclude Endometrial Cancer and Other Endometrial Abnormalities
Context.— Postmenopausal vaginal bleeding is a common clinical problem. Endovaginal ultrasound (EVUS) is a noninvasive diagnostic test that may help determine which women should undergo endometrial biopsy.

Objective.— To determine the accuracy of EVUS in detecting endometrial disease in postmenopausal women with vaginal bleeding according to hormone replacement use.

Data Sources.— Literature search of English-language and non–English-language articles published from 1966 through November 1996 using MEDLINE and by a manual search of bibliographies of published articles.

Study Selection.— Studies were included if they prospectively collected EVUS measurements of endometrial thickness prior to obtaining endometrial tissue for histologic evaluation in postmenopausal women with vaginal bleeding. Of 85 studies that included data on EVUS and endometrial histology, 35 were included in the meta-analysis and included 5892 women.

Data Extraction.— Articles were reviewed and independently selected and abstracted by 2 reviewers. Disagreement was resolved by consensus.

Data Synthesis.— The overall summary mean weighted estimates of sensitivity and specificity were calculated for thresholds of endometrial thickness from 3 to 10 mm. Using a 5-mm threshold to define abnormal endometrial thickening, 96% (95% confidence interval [CI], 94%-98%) of women with cancer had an abnormal EVUS result, whereas 92% (95% CI, 90%-93%) of women with endometrial disease (cancer, polyp, or atypical hyperplasia) had an abnormal result. This did not vary by hormone replacement use. However, the number of women with normal histology who had an abnormal EVUS result did vary by hormone replacement use. In women who were not using hormone replacement therapy, 593 (8%) with normal histological findings had an abnormal EVUS result (specificity, 92%; 95% CI, 90%-94%), whereas 1544 (23%) using hormone replacement therapy had an abnormal EVUS result (specificity, 77%; 95% CI, 75%-79%). For a postmenopausal woman with vaginal bleeding with a 10% pretest probability of endometrial cancer, her probability of cancer is 1% following a normal EVUS result.

Conclusion.— Endovaginal ultrasound has a high sensitivity for detecting endometrial cancer and other endometrial disease and can reliably identify postmenopausal women with vaginal bleeding who are highly unlikely to have significant endometrial disease so that endometrial sampling may be unnecessary. [3]

Role of Diffusion Weighted Magnetic Resonance Imaging at 3-T in Staging of Endometrial Cancer and Correlation to Histopathology

Aim: To investigate the value of diffusion weighted imaging (DWI) at 3-T MR in staging of endometrial cancer and the correlation to histopathology.

Study Design: A retrospective study.

Place and Duration of Study: CT-MR Division, Qianfoshan Hospital Affiliated to Shandong University. Department of Radiology, Affiliated Hospital of Jining Medical College. From June 2013 to June 2014

Methodology: 30 patients with histologically proved endometrial cancers were analyzed retrospectively. The staging diagnosis of DWI was compared with pathologic results. The ADC values in different histologic types and different differentiated of endometrial cancers were also compared. P<0.05 was considered statistically significant.

Results: The staging accuracy of DWI was 83.3%. The ADC value in 30 patients of endometrial cancer was (0.856±0.080) ×10-3 mm2/s. There was no statistically significant difference in different histologic types (t=1.093，P=0.284). In different differentiated endometrial cancers, there was significant difference (F=97.246，P=0.000).

Conclusion: DWI has considerable value in staging of endometrial cancer. The ADC values can demonstrate the grade malignancy of tumors initially. So diffusion weighted sequences can be included in routine MR protocols for tumor assessment. [4]

Assessment of Mean Vessel Density and Angiogenesis in Endometrial Carcinomas

Objective: To evaluate the role of angiogenesis in tumor growth by the assessment of mean vessel density and to quantify angiogenesis as an important variable in endometrial cancers.

Material and Methods: 53 cases of endometrial malignancies (epithelial tumors-36 cases and metastatic tumors-17 cases), were analysed for histological types, grades and features like depth of invasion and vascular invasion. Microvessel counts were performed by examining the microvessels thoroughly in terms of count, morphology and density after staining the tissues by hematoxylin & eosin stain, reticulin and immunostain (Antifactor VIII Ag).

Results: On H&E stain – Microvessel density (MVD) in endometrial malignancy ranged from 3.0 – 13.5 and mean MVD was 8.78. On Reticulin stain – MVD ranged from 3.5 – 15.2 and mean MVD was 9.76.  Antifactor VIII sections showed very small microvessels or even single endothelial cells with the highest total counts and the MVD ranged from 6.5-16.8 with Mean MVD of 11.7. The counts increased with the grade of the tumor in the absence of necrosis or haemorrhage. MVD counts also increased with the stage, being 8.12 in Stage I disease, 8.65 in Stage II and 10.8 in stage III disease. Atypical hyperplasia was found to be associated with epithelial tumors in 8 cases, making it a significant finding.

Conclusion: Role of angiogenesis assumes greater significance with increasing severity of lesions, higher grade and stage of the tumor and seems to have an important diagnostic and prognostic significance. [5]

Reference

[1] Grady, D., Gebretsadik, T., Kerlikowske, K., Ernster, V. and Petitti, D., 1995. Hormone replacement therapy and endometrial cancer risk: a meta-analysis. Obstetrics & Gynecology, 85(2), pp.304-313.

[2] van Leeuwen, F.E., Van den Belt-Dusebout, A.W., Benraadt, J., Diepenhorst, F.W., Van Tinteren, H., Coebergh, J.W.W., Kiemeney, L.A.L.M., Gimbrère, C.H.F., Otter, R., Schouten, L.J. and Damhuis, R.A.M., 1994. Risk of endometrial cancer after tamoxifen treatment of breast cancer. The Lancet, 343(8895), pp.448-452.

[3] Smith-Bindman, R., Kerlikowske, K., Feldstein, V.A., Subak, L., Scheidler, J., Segal, M., Brand, R. and Grady, D., 1998. Endovaginal ultrasound to exclude endometrial cancer and other endometrial abnormalities. Jama, 280(17), pp.1510-1517.

[4] Dong, G.-Q., Wei, J.-C., Deng, K. and Shi, H. (2015) “Role of Diffusion Weighted Magnetic Resonance Imaging at 3-T in Staging of Endometrial Cancer and Correlation to Histopathology”, Journal of Advances in Medicine and Medical Research, 10(11), pp. 1-7. doi: 10.9734/BJMMR/2015/20400.

[5] K. Sherwani, R., Akhtar, K., Gupta, D., Mehdi, G. and Akhtar, N. (2014) “Assessment of Mean Vessel Density and Angiogenesis in Endometrial Carcinomas”, Cardiology and Angiology: An International Journal, 2(4), pp. 230-237. doi: 10.9734/CA/2014/7531.