Preoperative CA125 Significantly Improves Risk Stratification in High-Grade Endometrial Cancer.

Patients with high-grade endometrial carcinoma (EC) have an increased risk of tumor spread and lymph node metastasis (LNM). Preoperative imaging and CA125 can be used in work-up. As data on cancer antigen 125 (CA125) in high-grade EC are limited, we aimed to study primarily the predictive value of CA125, and secondarily the contributive value of computed tomography (CT) for advanced stage and LNM. Patients with high-grade EC (n = 333) and available preoperative CA125 were included retrospectively. The association of CA125 and CT findings with LNM was analyzed by logistic regression. Elevated CA125 ((>35 U/mL), (35.2% (68/193)) was significantly associated with stage III-IV disease (60.3% (41/68)) compared with normal CA125 (20.8% (26/125), [p < 0.001]), and with reduced disease-specific-(DSS) (p < 0.001) and overall survival (OS) (p < 0.001). The overall accuracy of predicting LNM by CT resulted in an area under the curve (AUC) of 0.623 (p < 0.001) independent of CA125. Stratification by CA125 resulted in an AUC of 0.484 (normal), and 0.660 (elevated). In multivariate analysis elevated CA125, non-endometrioid histology, pathological deep myometrial invasion ≥50%, and cervical involvement were significant predictors of LNM, whereas suspected LNM on CT was not. This shows that elevated CA125 is a relevant independent predictor of advanced stage and outcome specifically in high-grade EC.

Endometrial cancer after endometrial ablation: a systematic review.

OBJECTIVE: To investigate whether a previously performed endometrial ablation is associated with the development and diagnosis of endometrial cancer. METHODS: First, a systematic review was performed of the articles reporting the incidence of endometrial cancer in patients treated with endometrial ablation. Second, a systematic review was performed to identify all individual cases of endometrial cancer after ablation to evaluate presenting symptoms, diagnostic work-up, potential risk factors, and the type and stage of the endometrial cancer. A systematic search was performed, using Medline, EMBASE, and the Cochrane Library databases, from inception through February 24, 2022. RESULTS: Based on 11 included studies, the incidence of endometrial cancer in a population of 29 102 patients with a prior endometrial ablation ranged from 0.0% to 1.6%.A total of 38 cases of endometrial cancer after ablation were identified. In 71% of cases (17 of 24 cases), vaginal bleeding was the first presenting symptom. With transvaginal ultrasound it was possible to identify and measure the endometrial thickness in eight cases. Endometrium sampling was successful in 16 of 18 described cases (89%). In 18 of 20 cases (90%) pathologic examination showed early-stage endometrioid adenocarcinoma (International Federation of Gynecology and Obstetrics stage I). CONCLUSION: Previous endometrial ablation is not associated with the development of endometrial cancer. Diagnostic work-up is not impeded by previous endometrial ablation. In addition, endometrial cancers after endometrial ablation are not detected at an advanced stage.

Gene Promoter Methylation in Endometrial Carcinogenesis.

Up to 60% of untreated atypical hyperplastic endometrium will develop into endometrial carcinoma (EC), and for those who underwent a hysterectomy a coexisting EC is found in up to 50%. Gene promoter methylation might be related to the EC development. The aim of this study is to determine changes in gene promoter profiles in normal endometrium, atypical hyperplasia (AH) and EC in relation to K-Ras mutations. A retrospective study was conducted in patients diagnosed with endometrial hyperplasia with and without subsequent EC. Promoter methylation of APC, hMLh1, O6-MGMT, P14, P16, RASSF1, RUNX3 was analysed on pre-operative biopsies, and correlated to the final histological diagnosis, and related to the presence of K-Ras mutations. In the study cohort (n=98), differences in promoter methylation were observed for hMLH1, O6-MGMT, and P16. Promoter methylation of hMLH1 and O6-MGMT gradually increased from histologically normal endometrium to AH to EC; 27.3, 36.4% and 38.0% for hMLH1 and 8.3%, 18.2% and 31.4% for O6-MGMT, respectively. P16 promoter methylation was significantly different in AH (7.7%) compared to EC (38%). K-Ras mutations were observed in 12.1% of AH, and in 19.6% of EC cases. No association of K-Ras mutation with promoter methylation of any of the tested genes was found. In conclusion, hMLH1 and O6-MGMT promoter methylation are frequently present in AH, and thus considered to be early events in the carcinogenesis of EC, whereas P16 promoter methylation was mainly present in EC, and not in precursor lesions supporting a late event in the carcinogenesis.

Intracrine Regulation of Estrogen and Other Sex Steroid Levels in Endometrium and Non-gynecological Tissues; Pathology, Physiology, and Drug Discovery.

Our understanding of the intracrine (or local) regulation of estrogen and other steroid synthesis and degradation expanded in the last decades, also thanks to recent technological advances in chromatography mass-spectrometry. Estrogen responsive tissues and organs are not passive receivers of the pool of steroids present in the blood but they can actively modify the intra-tissue steroid concentrations. This allows fine-tuning the exposure of responsive tissues and organs to estrogens and other steroids in order to best respond to the physiological needs of each specific organ. Deviations in such intracrine control can lead to unbalanced steroid hormone exposure and disturbances. Through a systematic bibliographic search on the expression of the intracrine enzymes in various tissues, this review gives an up-to-date view of the intracrine estrogen metabolisms, and to a lesser extent that of progestogens and androgens, in the lower female genital tract, including the physiological control of endometrial functions, receptivity, menopausal status and related pathological conditions. An overview of the intracrine regulation in extra gynecological tissues such as the lungs, gastrointestinal tract, brain, colon and bone is given. Current therapeutic approaches aimed at interfering with these metabolisms and future perspectives are discussed.

Blocking 17ß-hydroxysteroid dehydrogenase type 1 in endometrial cancer: a potential novel endocrine therapeutic approach.

The enzyme type 1 17ß-hydroxysteroid dehydrogenase (17ß-HSD-1), responsible for generating active 17ß-estradiol (E2) from low-active estrone (E1), is overexpressed in endometrial cancer (EC), thus implicating an increased intra-tissue generation of E2 in this estrogen-dependent condition. In this study, we explored the possibility of inhibiting 17ß-HSD-1 and impairing the generation of E2 from E1 in EC using in vitro, in vivo, and ex vivo models. We generated EC cell lines derived from the well-differentiated endometrial adenocarcinoma Ishikawa cell line and expressing levels of 17ß-HSD-1 similar to human tissues. In these cells, HPLC analysis showed that 17ß-HSD-1 activity could be blocked by a specific 17ß-HSD-1 inhibitor. In vitro, E1 administration elicited colony formation similar to E2, and this was impaired by 17ß-HSD-1 inhibition. In vivo, tumors grafted on the chicken chorioallantoic membrane (CAM) demonstrated that E1 upregulated the expression of the estrogen responsive cyclin A similar to E2, which was impaired by 17ß-HSD-1 inhibition. Neither in vitro nor in vivo effects of E1 were observed using 17ß-HSD-1-negative cells (negative control). Using a patient cohort of 52 primary ECs, we demonstrated the presence of 17ß-HSD-1 enzyme activity (ex vivo in tumor tissues, as measured by HPLC), which was inhibited by over 90% in more than 45% of ECs using the 17ß-HSD-1 inhibitor. Since drug treatment is generally indicated for metastatic/recurrent and not primary tumor, we next demonstrated the mRNA expression of the potential drug target, 17ß-HSD-1, in metastatic lesions using a second cohort of 37 EC patients. In conclusion, 17ß-HSD-1 inhibition efficiently blocks the generation of E2 from E1 using various EC models. Further preclinical investigations and 17ß-HSD-1 inhibitor development to make candidate compounds suitable for the first human studies are awaited. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

High mRNA levels of 17ß-hydroxysteroid dehydrogenase type 1 correlate with poor prognosis in endometrial cancer.

Most endometrial cancers (ECs) are diagnosed at an early stage and have a good prognosis. However, 20-30% develop recurrence and have poor survival. Recurrence-risk prediction at diagnosis is hampered by the scarcity of prognostic markers. Most ECs are estrogen related, and recent studies show that estrogen exposure in EC is controlled intracrinally. We aim at assessing any association between patient prognosis and the pathways controlling the intracrine estrogen generation in EC: (a) the balance between 17ß-hydroxysteroid-dehydrogenase-type 1 (HSD17B1), that generates active estrogens, and HSD17B2, converting active into poorly active compounds; (b) the balance between steroid sulphatase (STS, that activates estrogens) and estrogen-sulphotransferase (SULT1E1, that deactivates estrogens); (c) the levels of aromatase (ARO), that converts androgen into estrogens. mRNA levels of HSD17B1, HSD17B2, STS, SULT1E1 and ARO were determined among 175 ECs using cDNA microarray. Proteins were explored by immunohistochemistry. Patients with high mRNA of HSD17B1 had a poorer prognosis compared with those with low levels. Combining the expression of HSD17B1 and HSD17B2, patients with high tumour expression of HSD17B1 and low levels of HSD17B2 had the poorest prognosis. Contrarily, women that had high tumour levels of HSD17B2 and low of HSD17B1 had the best outcome. No differences were seen between mRNA level of other the genes analysed and prognosis. At the protein level, HSD17B2, STS and SULT1E1 were highly expressed, whereas HSD17B1 was low and ARO was almost absent. In conclusion, HSD17B1 is a promising marker to predict EC prognosis. Immunohistochemical detection of this protein in ECs has low sensitivity and should be improved for future clinical applications.

Overexpression of 17ß-hydroxysteroid dehydrogenase type 1 increases the exposure of endometrial cancer to 17ß-estradiol.

CONTEXT: The local interconversions between estrone (low activity) and 17ß-estradiol (potent compound) by 17ß-hydroxysteroid dehydrogenases (17ß-HSDs) can lead to high 17ß-estradiol generation in endometrial cancer (EC). OBJECTIVE: Examine the balance between the 17ß-HSDs reducing estrone to 17ß-estradiol (types 1, 5, 12, and 7) and those oxidizing 17ß-estradiol to estrone (2, 4, and 8), in EC. PATIENTS AND METHODS: Reducing and oxidizing 17ß-HSD activities (HPLC) and mRNA level (RT-PCR) were assessed in normal post-menopausal (n = 16), peritumoral endometrium (normal tissue beside cancer, n = 13), and 58 EC (29 grade 1, 18 grade 2, 11 grade 3). RESULTS: Grade 1 EC displayed a shifted estrone reduction/17ß-estradiol oxidation balance in favor of 17ß-estradiol compared with controls. This was more pronounced among estrogen receptor-α (ER-α)-positive biopsies. Type 1 17ß-HSD mRNA (HSD17B1 gene expression, real time PCR) and protein levels (immunohistochemistry) were higher in ER-α-positive grade 1 EC than controls. The mRNA coding for types 4, 5, 7, 8, and 12 17ß-HSD did not vary, whereas that coding for type 2 17ß-HSD was increased in high-grade lesions compared with controls. Three-dimensional ex vivo EC explant cultures demonstrated that 17ß-HSD type 1 generated 17ß-estradiol from estrone and increased tumor cell proliferation. Additional in vitro studies using EC cells confirmed that in the presence of 17ß-HSD type 1, estrone induced estrogen signaling activation similarly to 17ß-estradiol. Therefore, estrone was reduced to 17ß-estradiol. CONCLUSIONS: Type 1 17ß-HSD increases 17ß-estradiol exposure in grade 1 EC, thus supporting tumor growth. This enzyme represents a potential therapeutic target.