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Endometrial (Uterus) Cancer

Endometrial cancer is a malignancy of the endometrium (the inner lining of the uterus, or womb) and is the most common gynaecological cancer, and accounts for 13% of all cancers in women. It is most frequently in women over age 50. A know risk factor is prior oestrogen-replacement therapy (however, oestrogen replacement also lowers risk of heart disease). Symptoms can include pelvic pain, and blood-soaked discharge - though these are also common symptoms related to menopausal changes.

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  • PubMed search for publications about Endometrial Cancer - Limit search to: [Reviews]

    PubMed Central search for free-access publications about Endometrial Cancer
    MeSH term: Endometrial Neoplasms
    International US National Library of Medicine
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Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Stampoliou A, Arapantoni-Dadioti P, Pavlakis K
Epigenetic mechanisms in endometrial cancer.
J BUON. 2016 Mar-Apr; 21(2):301-6 [PubMed] Related Publications
Purpose: Endometrial cancer is a very common type of cancer in females worldwide. Advances in diagnosis and treatment have not decreased the incidence of endometrial cancer. Lately, research has been focused on revealing the molecular and genetic characteristics of endometrial cancer in order to provide new insights in the biology of this entity, leading hopefully to innovating therapies. Research has revealed that epigenetic modifications govern endometrial carcinogenesis. In this review, the epigenetic mechanisms that are involved in endometrial cancer as well as the differences between the different types of endometrial cancer are discussed. The review also refers to the putative therapeutic benefits that hopefully can arise.

Kwack JY, Kwon YS, Im KS
Anti-adhesive film mimicking local recurrence during follow up after surgical treatment of gynecologic malignancy.
Eur J Gynaecol Oncol. 2016; 37(1):133-4 [PubMed] Related Publications
A 51-year-old woman received a laparoscopic surgical staging operation due to endometrial carcinoma. Adjuvant pelvic radiotherapy was performed when the endometrial carcinoma was staged at FIGO Stage IIIC1, adnexa metastasis. Three months completing adjuvant pelvic radiotherapy, a 2.5-cm vaginal stump mass was found by abdomino-pelvic computed tomography (AP-CT). To rule out local recurrence, diagnostic laparoscopic exploration was performed. The pathologic report revealed chronic inflammation due to the presence of a foreign body. To avoid unnecessary surgery during the follow-up of patients with gynecologic malignancies, anti-adhesive material should be avoided which can possibly cause a lesion mimicking local recurrence.

Su C, Fan M, Lu L, Li P
Effects of silencing MTA1 gene by RNA interference on invasion and metastasis of endometrial carcinoma.
Eur J Gynaecol Oncol. 2016; 37(1):59-62 [PubMed] Related Publications
OBJECTIVE: The study aimed at the silence effect of MAT1 gene and proteins in Ishikawa cell of human endometrial carcinoma cell line through RNAi mediated by siRNA and also discussed the effect of MTA1 gene silence on the invasion and metastasis of endometrial carcinoma.
MATERIALS AND METHODS: According to the principle of designing siRNA sequence, siRNA aiming at MTA1 gene (MTA1-siRNA) and siRNA used for negative control (Control-siRNA) were designed and synthesized and Ishikawa cell was transfected by transfection reagents. RT-PCR method as well as western blot was used, respectively, to detect the MTA1 mRNA and protein expression of stably transfected cells. Transwell method and scarification experiment were adopted to detect the invasion and metastasis of Ishikawa cells.
RESULTS: The expression results of MTA1 on the levels of mRNA and protein showed that the expression level in transfected MTA1-siRNA group was obviously lower than that in non-transfected group and transfected control-siRNA group (p <0.05), while there was no significant difference between non-transfected group and transfected control-siRNA group (p > 0.05). Effective interference on the expression of MTA1 gene remarkably lowered the invasion and metastasis of endometrial carcinoma Ishikawa cells.
CONCLUSION: RNAi aiming at MTA1 can effectively inhibit the expression of MTA1 in endometrial carcinoma Ishikawa cells and the effective silence of MTA1 can weaken the invasion and metastasis of Ishikawa cells, which provides a new strategy for gene therapy of endometrial carcinoma and an experimental basis for inhibiting the invasion and metastasis of endometrial carcinoma.

Sak ME, Alanbay I, Rodriguez A, et al.
The role of 15-lipoxygenase-1 expression and its potential role in the pathogenesis of endometrial hyperplasia and endometrial adenocarcinomas.
Eur J Gynaecol Oncol. 2016; 37(1):36-40 [PubMed] Related Publications
PURPOSE OF INVESTIGATION: To investigate the presence of 15-lipoxygenase-1 (15-LOX-1) expression and its potential role in the pathogenesis of endometrial hyperplasia and endometrial adenocarcinomas.
MATERIALS AND METHODS: The authors investigated the presence of 15-LOX-1 expression in samples from patients diagnosed with normal endometrium (n = 12), endometrial hyperplasia (n = 12), and endometrial cancer (n = 12). The immunohistochemical stainings were scored by three independent pathologists. A Western blot of 15- LOX-1 determined the presence of protein expression in normal endometrium. A Kolmogorov-Smirnov test was used to evaluate the data's distribution pattern. For pairwise comparisons of the combined scores between groups, the Mann-Whitney U test was used.
RESULTS: Based on the combined scores for 15-LOX-1 expression, strong immunochemistry staining was observed in samples diagnosed with normal endometrium. There was a significant difference in 15-LOX-1 expression between normal endometrium and endometrial adenocarcinoma (p = 0.03). Comparing tissues from normal endometrium and endometrial hyperplasia, there was a decline in the expression from normal endometrium to endometrial hyperplasia. However, the difference was not statistically significant.
CONCLUSION: The present results show that a decrease of 15-LOX-1 expression in the endometrial tumorigenesis process, starting from normal endometrium to hyperplasia and endometrial cancer, might be a trigger. Further studies are required to determine its potential use as a marker in a larger randomized multicenter study.

Bogani G, Dowdy SC, Cliby WA, et al.
Management of endometrial cancer: issues and controversies.
Eur J Gynaecol Oncol. 2016; 37(1):6-12 [PubMed] Related Publications
Although endometrial cancer (EC) is the most common gynecologic cancer in developed countries, several aspects of its management are still controversial. In particular, the need to perform lymphadenectomy represents an important matter of discussion. Because of the discordant results in the literature, it is still not possible to draft any definitive conclusions regarding the therapeutic value of lymph node dissection. The present review discusses the role of lymphadenectomy in the setting of EC, risk factors for lymphatic spread, identification of patients at risk for lymph node dissemination, and the current evidence for adjuvant therapies in patients with positive nodes. Reasons for the difficulty in demonstrating any therapeutic value of pelvic and para-aortic lymphadenectomy are also discussed.

Milicić V, Matić TS, Martinek V, et al.
Does Cytological Laboratory Holds the Responsibility for the Low Sensitivity of the PAP Test in Detecting Endometrial Cancer?
Coll Antropol. 2015; 39(3):713-7 [PubMed] Related Publications
Endometrial cancer is the most common gynecological cancer but there is no economically justified screening method. Although we can detect endometrial cells in the sample using PAP test, many studies show low sensitivity and positive predictive value of PAP test for the diagnosis of endometrial cancer. The goal of this research was to determine significance of PAP test for the diagnostics of endometrial carcinoma. Sensitivity and specificity were analyzed with statistical parameters. VCE (vaginal, cervical, endocervical) smears of patients with histologically proven endometrial carcinoma were re-examined in order to determine the proportion of false negative results for endometrial cancer cells in the VCE samples. Study group consisted of all consecutive patients with PAP test performed at the Department of Clinical Cytology of the University Hospital Center Osijek from 2002 until the end of 2014. There was one inclusion criteria: subsequent hysterectomy or curettage within the six month after the PAP test, regardless of histological finding. From a total of 263 patients with previous PAP test and histologically proven endometrial cancer, endometrial cancer was cytologicaly diagnosed in 24.7% (including suspicious and positive findings), while 66.2% patients had normal cytological findings. The diagnostic value of PAP test in detection of endometrial cancer was statistically revealed with 25% sensitivity and 99% specificity. To determine false negative rate VCE samples were reviewed for patients with histologically proven endometrial cancer and negative VCE findings. There were a total of five negative results. In one case revision did not changed the original negative diagnosis, but benign endometrial cells, a lot of blood and inadequate cytohormonal status were found. In three out of four reviewed samples there were missed cells of endometrial adenocarcinoma. Review of remaining VCE sample upgraded the diagnosis from negative to suspicious for endometrial cancer. Proportion of error in the detection of endometrial cancer using cytological findings was 3.4% (true false negatives). Negative rate of the cytological findings in the detection of endometrial cancer was 66.2%. PAP test is not a suitable method for detection of endometrial carcinoma due to low sensitivity (25%). The main cause of negative findings in PAP test was lack of diagnostic cells in the sample.

Zhou Q, Tang C, Zhao KW, et al.
Clinical assessment of 252Californium neutron intracavitary brachytherapy using a two-channel Y applicator combined with external beam radiotherapy for endometrial cancer.
Clinics (Sao Paulo). 2016; 71(1):10-6 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: The aim of this study was to determine the efficacy of 252Californium neutron intracavitary brachytherapy using a two-channel Y applicator combined with external beam radiotherapy for the treatment of endometrial cancer.
METHODS: Thirty-one patients with stage I-III endometrial cancer were recruited for this study. The stage I patients received only 252Californium neutron intracavitary brachytherapy with a two-channel applicator. The stage II and III patients received both 252Californium neutron intracavitary brachytherapy using a two-channel applicator and parallel-opposed whole pelvic radiotherapy.
RESULTS: The five-year local control rate was 80.6% (25/31), the overall survival rate was 51.6% (16/31), and the disease-free survival rate was 54.8% (17/31). The incidence of serious late complications was 12.9% (4/31).
CONCLUSIONS: 252Californium neutron intracavitary brachytherapy using a two-channel applicator combined with external beam radiotherapy was effective for treating endometrial cancer and the incidence of serious late complications related to this combination was within an acceptable range.

Wright JD, Tergas AI, Hou JY, et al.
Trends in Periodic Surveillance Testing for Early-Stage Uterine Cancer Survivors.
Obstet Gynecol. 2016; 127(3):449-58 [PubMed] Article available free on PMC after 01/03/2017 Related Publications
OBJECTIVE: To examine the use of periodic surveillance testing for early-stage endometrial cancer survivors.
METHODS: We performed a population-based analysis using the Surveillance, Epidemiology, and End Results-Medicare database, which was used to identify patients with stage I-II endometrioid endometrial cancer treated from 1992 to 2011. Three surveillance periods (7-18, 19-30, 31-42 months) after hysterectomy were examined. Use of vaginal cytology and imaging were quantified.
RESULTS: We identified 17,638 patients. From 1992 to 2011, the use of chest radiography decreased (46.3-34.2%) during the first surveillance period, whereas imaging with chest computed tomography (CT) (0.9-12.6%), abdominopelvic CT (11.7-24.8%), and positron emission tomography (0-2.9%) increased (P<.001 for all). The use of cytology increased from 68.5% in 1992 to 72.3% in 2007 and then decreased to 66.9% in 2011 (P=.02). The mean number of cytologic samples obtained per patient increased from 1.3 in 1992 to 1.6 in 2008 and then declined to 1.3 in 2011, whereas the mean per patient number of chest CTs (0.02-0.2), abdominopelvic CTs (0.2-0.4), and positron emission tomographies (0-0.03) rose from 1992 to 2011. In 2011, 49.3% underwent radiologic surveillance 7-18 months after diagnosis, whereas 11.9% underwent two or more radiologic assessments in combination with cytology. These findings were similar for surveillance periods 2 and 3.
CONCLUSION: The use of chest radiography has decreased and use of cytology has started to decline. However, the use of more costly imaging modalities is increasing despite a lack of evidence for the efficacy of these tests for early-stage endometrial cancer survivors.

Laskey RA, McCarroll ML, von Gruenigen VE
Obesity-related endometrial cancer: an update on survivorship approaches to reducing cardiovascular death.
BJOG. 2016; 123(2):293-8 [PubMed] Related Publications
As the rate of obesity increases worldwide, so will the number of women diagnosed with obesity-related malignancy. The strongest correlation between obesity and cancer is endometrial cancer (EC). Obesity is the most significant modifiable risk factor for development of EC and also contributes to the most common cause of death in EC survivors-cardiovascular disease (CVD). Most cancer survivors after diagnosis do not implement lifestyle changes aimed at weight-loss and CVD risk reduction. This selective review highlights recent novel and unique approaches for managing CVD co-morbidities in EC survivorship.

Sponholtz TR, Palmer JR, Rosenberg L, et al.
Body Size, Metabolic Factors, and Risk of Endometrial Cancer in Black Women.
Am J Epidemiol. 2016; 183(4):259-68 [PubMed] Article available free on PMC after 15/02/2017 Related Publications
Total and abdominal obesity, as well as metabolic factors such as type 2 diabetes, have been associated with a higher risk of endometrial cancer in white women. It remains unclear to what extent these factors influence the risk of endometrial cancer in black women. We followed 47,557 participants from the Black Women's Health Study for incident endometrial cancer from 1995 through 2013 (n = 274). We used Cox regression models to estimate incidence rate ratios and 95% confidence intervals while accounting for potential confounders. Incidence rate ratios for body mass indices (weight (kg)/height (m)(2)) of 25.0-29.9, 30.0-34.9, 35.0-39.9, and ≥40.0 versus those <25.0 were 1.00 (95% confidence interval (CI): 0.67, 1.48), 1.49 (95% CI: 0.97, 2.30), 2.16 (95% CI: 1.34, 3.49), and 3.60 (95% CI: 2.24, 5.78), respectively (Ptrend <0.0001). A high weight-to-height ratio was also associated with a higher risk (for the highest quartile vs. the lowest, incidence rate ratio = 2.83, 95% CI: 1.77, 4.53), as was type 2 diabetes mellitus (incidence rate ratio = 1.52, 95% CI: 1.04, 2.21). Positive associations with measures of central adiposity (waist circumference, waist-to-hip ratio, and waist-to-height ratio) and hypertension were attenuated after we controlled for body mass index. Total adiposity was an independent risk factor for endometrial cancer among black women and appeared to explain most of the associations seen with other adiposity measures and metabolic factors.

Billingsley CC, Cansino C, O'Malley DM, et al.
Survival outcomes of obese patients in type II endometrial cancer: Defining the prognostic impact of increasing BMI.
Gynecol Oncol. 2016; 140(3):405-8 [PubMed] Related Publications
OBJECTIVE: To investigate the role of obesity as a risk factor for type II endometrial cancer (EC), as well as the prognostic significance of increasing body mass index (BMI) on survival.
METHODS: A single institution retrospective analysis of 154 type II EC cases from 1987 to 2010 was conducted. Patients were categorized into cohorts by BMI (normal (<25), overweight (25-29.9), obese class I (30-34.9), and obese class II-III (≥35)). Descriptive, regression and ANOVA analyses were performed. Kaplan-Meier curves were compared with log rank tests.
RESULTS: The BMI distribution was 22.8% normal BMI; 24% overweight; 17.5% class I; and 35.7% class II-III. The median follow up was 41 months. The median progression-free survival (PFS) was 45.4, 36.0, 35.3 and 42.0 months and overall survival (OS) was 54.7, 44.7, 44.8 and 49.7 months, among the respective groups. There was no association between BMI and PFS (p=0.71), OS (p=0.72), or time to recurrence (p=0.71). There were no differences among the increasing BMI groups compared to normal weight women for the risk of death.
CONCLUSIONS: Our analysis did not reveal any differences in outcomes by BMI group. Our data reveals that obesity is highly prevalent in type II ECs, though obesity has not historically been described as a risk factor. While BMI as a single variable may not be prognostic for survival outcomes, the role of obesity as a risk factor for type II EC should be further investigated, given the increasing prevalence of obesity in type II ECs.

Sivalingam VN, Kitson S, McVey R, et al.
Measuring the biological effect of presurgical metformin treatment in endometrial cancer.
Br J Cancer. 2016; 114(3):281-9 [PubMed] Article available free on PMC after 15/02/2017 Related Publications
BACKGROUND: Preclinical studies in endometrial cancer (EC) show that metformin reduces cellular proliferation by PI3K-AKT-mTOR inhibition. We tested the hypothesis that short-term presurgical metformin reduces cellular proliferation in atypical endometrial hyperplasia (AEH) and endometrioid EC, and assessed the feasibility of using phosphorylated PI3K-AKT-mTOR proteins as tissue end points.
METHODS: Women with AEH or EC received metformin 850 mg twice a day or no drug in the presurgical window between diagnosis and hysterectomy. Before and after the window, tissue samples were obtained; serum markers of insulin resistance (e.g. homeostasis model of assessment of insulin resistance index) were determined; and anthropometrics measured (e.g. BMI). Cell proliferation (Ki-67) and PI3K-AKT-mTOR phosphostatus were assessed by immunohistochemistry and scored blinded to treatment.
RESULTS: Twenty-eight metformin-treated and 12 untreated patients, well matched for age and BMI, completed the study. Metformin treatment (median 20 days, range 7-34) was associated with a 17.2% reduction in tumour Ki-67 (95% CI -27.4, -7.0, P=0.002), in a dose-dependent manner. Tumour PI3K-AKT-mTOR protein phosphostatus varied but the effects were not significant after adjusting for changes in controls.
CONCLUSIONS: Short-term metformin was associated with reduced Ki-67 expression in EC. Changes in tumour PI3K-AKT-mTOR protein phosphostatus were seen in both groups. Future studies should address the variability attributed to different sampling techniques including devascularisation of the uterus at hysterectomy.

Schiavone MB, Bielen MS, Gardner GJ, et al.
Herniation formation in women undergoing robotically assisted laparoscopy or laparotomy for endometrial cancer.
Gynecol Oncol. 2016; 140(3):383-6 [PubMed] Article available free on PMC after 01/03/2017 Related Publications
OBJECTIVE: To compare the incidence of trocar site hernia in women who underwent robotically assisted laparoscopic surgery (RBT) for endometrial cancer staging with the incidence of ventral hernia formation in patients who underwent laparotomy (LAP) for the same indication. To analyze risk factors for hernia formation in women undergoing RBT for endometrial cancer.
METHODS: We retrospectively identified all patients who underwent surgical staging for endometrial cancer via RBT or LAP from 2009-2012. Clinicopathologic data were analyzed. Appropriate statistical tests were used.
RESULTS: 738 patients were staged via RBT (n=567) or LAP (n=171). Overall median age was 61 years (RBT range, 33-90; LAP range,28-86; p=0.4). Median BMI was 29.5 kg/m(2) (range, 17.9-66) and 30.3 kg/m(2) (range, 16.8-67.2), respectively (p=1.0). Eleven (1.9%) of 567 patients in the RBT cohort developed a trocar site hernia compared with 11 (6.4%) of 171 LAP patients who developed a ventral hernia (p=0.002). Median time to diagnosis was 18 months (range, 3-49) and 17 months (range, 7-30), respectively (p=0.7). Of the 11 RBT patients who developed a trocar site hernia, 10 (91%) were midline defects and 1 (9%) was a lateral defect of a prior inferior epigastric port site. No hernias required emergent operative intervention. Four (0.7%) of 567 RBT patients compared with 2 (1.2%) of 171 LAP patients required surgical hernia repair (p=0.4).
CONCLUSIONS: Trocar site herniation after RBT staging for endometrial cancer is uncommon and less likely to occur than ventral hernia formation with LAP staging. Furthermore, surgical revision rates are low.

Bleu G, Arsène E, Merlot B, et al.
How to improve the preoperative staging of presumed early-stage endometrioid endometrial cancer?
Eur J Gynaecol Oncol. 2015; 36(6):698-702 [PubMed] Related Publications
PURPOSE OF INVESTIGATION: Accurate preoperative staging of early-stage endometrioid endometrial cancer (EEC) is necessary to avoid under or over surgical treatment. The objective is to determine the rate of understaging and to evaluate the accuracy of different methods: hysteroscopy-curettage versus endometrial biopsy in predicting the final stage.
MATERIALS AND METHODS: This retrospective single-centre study led from 2000 to 2010, included women with EEC preoperatively assessed at low- or intermediate-risk. Understaging was defined as a postoperative FIGO Stage > 1 or a determination of high risk after the final histopathologic diagnosis.
RESULTS: The study included 101 women (75 low-risk and 26 intermediate-risk). Final diagnosis was upstaged for 26 of them, more frequently in the presumed intermediate-risk group (57.7% vs 14.7%, p < 0.001). The rate of preoperative understaging was higher in the women with endometrial biopsies than those with curettage (34.5% vs 15.2%, p = 0.04).
CONCLUSIONS: Hysteroscopy-curettage combined with magnetic resonance imaging (MRI) may improve preoperative staging of early-stage EEC, especially for presumed intermediate-risk disease.

Gungor T, Cetinkaya N, Ozdal B, et al.
Endometrial adenocarcinoma in young-aged women: a Turkish population study.
Eur J Gynaecol Oncol. 2015; 36(6):667-71 [PubMed] Related Publications
PURPOSE OF INVESTIGATION: The present study aims to investigate the incidence, clinicopathological features, and experience of treat- ment outcomes of patients with endometrial adenocarcinoma (EC) at ≤ 40 years of age in a gynecologic oncology reference center in Ankara, Turkey.
MATERIALS AND METHODS: This retrospective study included 577 patients with EC, diagnosed and treated between 2007 and 2013.
RESULTS: The incidence of EC ≤ 40 years of age was 5.1% (n: 30). The mean age at diagnosis was 35.5 (range: 27-40). Most of the patients with EC were overweight or obese. However, 23% had normal body mass index (BMI). Infertility was seen as a risk factor in 38.4%. The mean duration of postoperative follow-up was 38.3 months with rates of disease persistence and recurrence 14.2% and 28.5%, respectively.
CONCLUSION: The disease is diagnosed usually in its early stage and has a good prognosis. Appropriately selected patients with fertility desire have the opportunity to conceive with conservative management.

Valha P, Kucera E, Sak P, et al.
Intraoperative subserosal approach to label sentinel nodes in intermediate and high-risk endometrial cancer.
Eur J Gynaecol Oncol. 2015; 36(6):643-6 [PubMed] Related Publications
DESIGN: prospective experimental study.
PURPOSE OF INVESTIGATION: The purpose of this study was to evaluate feasibility and reliabil- ity of in vivo sentinel lymph node (SLN) mapping in patients with endometrial cancer and to verify a modified method of application of subserosal blue dye. Detection substance was applied subserosally in the uterine edges vicinity the round ligament of uterus and uterine vessels in the isthmic portion of the uterus.
MATERIALS AND METHODS: Eighteen patients with intermediate and high-risk endome- trial cancer Stages I-II were subjected to staging laparotomy with intraoperative detection of SLNs and subsequent completion of the pelvic and para-aortic lymphadenectomies. Harvested SLN was routinely examined by classical haematoxylin eosin staining and in case of negativity, immunohistochemistry with anti-keratin antibodies AEl/AE3 was applied.
RESULTS: Total of 773 lymph nodes were removed in 18 patients: pelvic 420 (54%) and para-aortic 353 (46%). SLNs were detected in 16 of 18 patients totalling 59 nodes (7.6% of all nodes). Forty-eight were identified in the pelvic area (81%) and 11 nodes (19%) in the para-aortic area. Three metastatic SLNs were found in two patients (11%). No false negative nodes were demonstrated.
CONCLUSION: Experimental study results indicate that the proposed modified approach to label SLNs is applicable. The presented modified approach brings the highest added value namely in women with a myomatous uterus and scars from previous surgical procedures on the uterus.

Sun L, Sheng XG, Wei L, et al.
Which is the appropriate surgical procedure for Stage I endometrial carcinoma?
Eur J Gynaecol Oncol. 2015; 36(6):637-42 [PubMed] Related Publications
OBJECTIVE: To study the appropriate surgical procedure for Stage I endometrial carcinoma (EC), the clinical and pathological features and prognosis factors, as well as types were analyzed retrospectively.
MATERIALS AND METHODS: This is a retrospective study of 277 patients with early-stage EC in clinical Stages I that received surgery between January 2000 and March 2008. The appropriate surgical procedures were divided into three types (procedure I-III: hysterectomy with or without ovary preservation, subradical hysterectomy plus pelvic lymph node biopsy, and radical hysterectomy pelvic plus lymphadenectomy) according to the clinical stage.
RESULTS: Tumor invasion of the cervix and deep muscularis as well as the parametrium, EC Stage Ib, grade 3 and ascites had carcinoma cells, were high-risk factors of EC metastasis to the retroperitoneum (p < 0.05). The ovarian preservation of EC Stage Ia had no effect on overall survival. The three types of procedure for the EC Stage Ia were not correlated significantly to the three-year and five-year survival rates. The three-year and five-year survival rates of three surgical procedures for the EC Stage Ib were significantly correlated. The survival rates of surgical procedures II and III were significantly higher than that of procedure I (P < 0.05).
CONCLUSION: Subradical hysterectomy plus pelvic lymph node biopsy was recommended for EC Stage 1b with high-risk factors. There was no evidence of benefit in terms of overall or recurrence-free survival for radical hysterectomy plus pelvic lymphadenectomy in women with Stage I EC.

Helder-Woolderink JM, Blok EA, Vasen HF, et al.
Ovarian cancer in Lynch syndrome; a systematic review.
Eur J Cancer. 2016; 55:65-73 [PubMed] Related Publications
OBJECTIVE: The aim was to systematically review the characteristics of ovarian cancer in women with Lynch syndrome (LS) and evaluate the role of surveillance in detection of ovarian cancer in LS.
METHODS: All studies between 1979 and 2015 of women with ovarian cancer and LS or at 50% risk of LS were evaluated. Two reviewers independently evaluated eligible studies and extracted data on age at diagnosis, histological type, FIGO stage, and way of detection according to pre-specified criteria. The studies were assessed for quality using the Newcastle-Ottawa quality assessment scales.
RESULTS: The quality score of the 49 identified studies was at least 6 out of 8 and provide clinical information on 747 LS women with ovarian cancer. The mean age at diagnosis was 45.3 (range 19-82) years. Most frequent mutations were MSH2 (47%) and MLH1 (38%). Histopathological data were available for 445 women. The most frequently reported histological type was mixed type (mucinous/endometrioid/clear cell carcinomas) (n = 136; 31%). Most tumours (281, 65%) were diagnosed at an early stage (FIGO I/II). Six studies evaluating the effect of surveillance of ovarian cancer, reported that seven of 22 (32%) ovarian cancers were found during surveillance, 6/7 (86%) were detected at an early stage.
CONCLUSION: This systematic review describes that ovarian cancer in women with LS has a wide age-range of onset, is often diagnosed at an early stage with frequently endometrioid/clear cell histology. Data about the role of surveillance in detection of ovarian cancer in women with LS are scarce however detection at an early stage seems possible.

Jorge S, Hou JY, Tergas AI, et al.
Magnitude of risk for nodal metastasis associated with lymphvascular space invasion for endometrial cancer.
Gynecol Oncol. 2016; 140(3):387-93 [PubMed] Article available free on PMC after 01/03/2017 Related Publications
OBJECTIVES: While lymphvascular space invasion (LVSI) is a risk factor for nodal metastasis in endometrial cancer, the magnitude of risk is poorly described. We examined the risk of nodal metastasis associated with LVSI for various combinations of tumor grade and depth of invasion and examined the effect of LVSI on survival.
METHODS: We identified patients with T1A (<50% myoinvasion) and T1B (>50% myoinvasion) endometrioid adenocarcinomas of the endometrium diagnosed between 2010 and 2012 and recorded in the National Cancer Database. The risk of nodal metastasis associated with LVSI stratified by grade and stage is reported. The association of LVSI and survival was examined using Kaplan-Meier analyses and Cox proportional hazards models.
RESULTS: We identified 25,907 patients, including 3928 (15.2%) with LVSI. Among patients with LVSI, 21.0% had positive lymph nodes, compared to 2.1% in patients without LVSI (P<0.0001). In analyses stratified by stage and grade, LVSI was associated with increased risks of LN metastasis by a magnitude of 3 to over 10-fold. In a multivariable model controlling for clinical and demographic characteristics, the risk ratio of nodal disease with LVSI was 9.29 (95% CI, 7.29-11.84) for T1A tumors and 4.64 (95% CI 3.99-5.39) for T1B tumors. LVSI was associated with decreased survival even after adjustment for the presence of lymph node metastases (HR=1.92, 95% CI 1.56-2.36).
CONCLUSIONS: LVSI is independently associated with lymph node metastases in women with apparent early-stage endometrial cancer and an independent predictor of survival even after adjustment for the presence of lymph node metastases.

Ravid Y, Formanski M, Smith Y, et al.
Uterine leiomyosarcoma and endometrial stromal sarcoma have unique miRNA signatures.
Gynecol Oncol. 2016; 140(3):512-7 [PubMed] Related Publications
OBJECTIVE: To compare the microRNA (miRNA) profiles of uterine endometrial stromal sarcoma (ESS) and leiomyosarcoma (LMS), and to compare the miRNA signatures of primary and metastatic uterine LMS.
METHODS: Eight primary LMS, 9 primary ESS and 8 metastatic LMS were analyzed for miRNA profiles using TaqMan Human miRNA Array Cards. Findings for 20 differentially expressed miRNAs were validated in a series of 44 uterine sarcomas (9 primary uterine ESS, 17 primary uterine LMS, 18 metastatic LMS) using qPCR. Frizzled-6 protein expression was analyzed in 30 LMS (15 primary, 15 metastases). Frizzled-6 was silenced in SK-LMS-1 uterine LMS cells using siRNA and the effect on invasion, wound healing and matrix metalloproteinase-2 (MMP2) activity was assessed.
RESULTS: Ninety-four miRNAs were significantly differentially expressed in ESS and LMS, of which 76 were overexpressed in ESS and 18 overexpressed in LMS. Forty-nine miRNAs were differentially expressed in primary and metastatic LMS, of which 45 were overexpressed in primary LMS and 4 in metastases. Differential expression was confirmed for 10/20 miRNA analyzed using qPCR. Frizzled-6 silencing in SK-LMS-1 cells significantly inhibited cellular invasion, wound healing and MMP-2 activity.
CONCLUSIONS: Differential miRNA signatures of ESS and LMS provide novel data regarding transcriptional regulation in these cancers, based on which new potential diagnostic markers, prognostic biomarkers and therapeutic targets may be explored. Differences in miRNA profiles of primary and metastatic LMS may improve our understanding of disease progression in this aggressive malignancy.

Brasky TM, Sponholtz TR, Palmer JR, et al.
Associations of Dietary Long-Chain ω-3 Polyunsaturated Fatty Acids and Fish Consumption With Endometrial Cancer Risk in the Black Women's Health Study.
Am J Epidemiol. 2016; 183(3):199-209 [PubMed] Article available free on PMC after 01/02/2017 Related Publications
Dietary long-chain (LC) ω-3 polyunsaturated fatty acids (PUFAs), which derive primarily from intakes of fatty fish, are thought to inhibit inflammation and de novo estrogen synthesis. This study prospectively examined the associations of dietary LC ω-3 PUFAs and fish with endometrial cancer risk in 47,602 African-American women living in the United States, aged 21-69 years at baseline in 1995, and followed them until 2013 (n = 282 cases). Multivariable-adjusted Cox regression models estimated hazard ratios and 95% confidence intervals for associations of LC ω-3 PUFA (quintiled) and fish (quartiled) intake with endometrial cancer risk, overall and by body mass index (BMI; weight (kg)/height (m)(2)). The hazard ratio for quintile 5 of total dietary LC ω-3 PUFAs versus quintile 1 was 0.79 (95% confidence interval (CI): 0.51, 1.24); there was no linear trend. Hazard ratios for the association were smaller among normal-weight women (BMI <25: hazard ratio (HR) = 0.53, 95% CI: 0.18, 1.58) than among overweight/obese women (BMI ≥ 25: HR = 0.88, 95% CI: 0.54, 1.43), but these differences were not statistically significant. Fish intake was also not associated with risk (quartile 4 vs. quartile 1: HR = 0.86, 95% CI: 0.56, 1.31). Again hazard ratios were smaller among normal-weight women (HR = 0.65) than among overweight/obese women (HR = 0.94). While compatible with no association, the hazard ratios observed among leaner African-American women are similar to those from recent prospective studies conducted in predominantly white populations.

Zhang Y, Luo L, Luo Q
Identification of benign and malignant endometrial cancer with transvaginal ultrasonography combined with elastography and tissue hardness analysis.
J Biol Regul Homeost Agents. 2015 Oct-Dec; 29(4):905-12 [PubMed] Related Publications
This study was designed to explore tissue hardness and distinguish benign and malignant endometrial cancer with the use of transvaginal ultrasonography combined with elastography. Color Doppler ultrasonic diasonograph was used to carry out transvaginal ultrasonography and elastography. Once the nidus was observed, features of the 2D image were analyzed. Then features of elasticity of the uterine cavity in different states were analyzed by elastography, and strain rate ratio was measured. Finally, elasticity scoring (0~5 points) was made. Receiver operating characteristic (ROC) curve was drawn based on elasticity score and strain rate ratio. The area under the elasticity score curve and strain rate ratio curve was 0.761 and 0.852, respectively, and there was no statistically significant difference between them (c2= 4.663, P>0.05). Then 2.98 was confirmed as the diagnostic cut-off value of benign and malignant lesions, based on strain rate ratio. Ultrasonic elastography as an effective assistance for transvaginal ultrasonography provides more valuable information for confirmation of lesions and offers more accurate evidence for diagnosis of disease in the uterine cavity.

Zahl Eriksson AG, Ducie J, Ali N, et al.
Comparison of a sentinel lymph node and a selective lymphadenectomy algorithm in patients with endometrioid endometrial carcinoma and limited myometrial invasion.
Gynecol Oncol. 2016; 140(3):394-9 [PubMed] Article available free on PMC after 01/03/2017 Related Publications
OBJECTIVES: To assess clinicopathologic outcomes between two nodal assessment approaches in patients with endometrioid endometrial carcinoma and limited myoinvasion.
METHODS: Patients with endometrial cancer at two institutions were reviewed. At one institution, a complete pelvic and para-aortic lymphadenectomy to the renal veins was performed in select cases deemed at risk for nodal metastasis due to grade 3 cancer and/or primary tumor diameter>2cm (LND cohort). This is a historic approach at this institution. At the other institution, a sentinel lymph node mapping algorithm was used per institutional protocol (SLN cohort). Low risk was defined as endometrioid adenocarcinoma with myometrial invasion <50%. Macrometastasis, micrometastasis, and isolated tumor cells were all considered node-positive.
RESULTS: Of 1135 cases identified, 642 (57%) were managed with an SLN approach and 493 (43%) with an LND approach. Pelvic nodes (PLNs) were removed in 93% and 58% of patients, respectively (P<0.001); para-aortic nodes (PANs) were removed in 14.5% and 50% of patients, respectively (P<0.001). Median number of PLNs removed was 6 and 34, respectively; median number of PANs removed was 5 and 16, respectively (both P<0.001). Metastasis to PLNs was detected in 5.1% and 2.6% of patients, respectively (P=0.03), and to PANs in 0.8% and 1.0%, respectively (P=0.75). The 3-year disease-free survival rates were 94.9% (95% CI, 92.4-97.5) and 96.8% (95% CI, 95.2-98.5), respectively.
CONCLUSIONS: Our findings support the use of either strategy for endometrial cancer staging, with no apparent detriment in adhering to the SLN algorithm. The clinical significance of disease detected on ultrastaging and the role of adjuvant therapy is yet to be determined.

Mobit PN, Nguyen A, Packianathan S, et al.
Dosimetric comparison of brachytherapy sources for high-dose-rate treatment of endometrial cancer: (192)Ir, (60)Co and an electronic brachytherapy source.
Br J Radiol. 2016; 89(1059):20150449 [PubMed] Related Publications
OBJECTIVE: To compare high-dose-rate (HDR) brachytherapy systems with (192)Ir, (60)Co and electronic brachytherapy source (EBS) for treatment of endometrial cancers.
METHODS: Two additional plans were generated per patient fraction using a (60)Co source and Xoft-EBS on 10 selected patients, previously treated with a vaginal cylinder applicator using a (192)Ir source. Dose coverage of "PTV_CYLD", a 5-mm shell surrounding the cylinder, was evaluated. Doses to the following organs at risk (OARs) the rectum, bladder and sigmoid were evaluated in terms of V35% and V50%, the percentage volume receiving 35% and 50% of the prescription dose, respectively, and D2cm(3), the highest dose to a 2-cm(3) volume of an OAR.
RESULTS: Xoft-EBS reduces doses to all OARs in the lower dose range, but it does not always provide better sparing of the rectum in higher dose range as does evaluation using D2cm3. V150% and V200% for PTV_CYLD was up to four times greater for Xoft-EBS plans than for plans generated with (192)Ir or (60)Co. Surface mucosal (vaginal cylinder surface) doses were also 23% higher for Xoft-EBS than for (192)Ir or (60)Co plans.
CONCLUSION: Xoft-EBS is a suitable HDR source for vaginal applicator treatment with advantages of reducing radiation exposure to OARs in the lower dose range, while simultaneously increasing the vaginal mucosal dose.
ADVANCES IN KNOWLEDGE: This work presents newer knowledge in dosimetric comparison between (192)Ir or (60)Co and Xoft-EBS sources for endometrial vaginal cylinder HDR planning.

Kataoka F, Susumu N, Yamagami W, et al.
The importance of para-aortic lymph nodes in sentinel lymph node mapping for endometrial cancer by using hysteroscopic radio-isotope tracer injection combined with subserosal dye injection: Prospective study.
Gynecol Oncol. 2016; 140(3):400-4 [PubMed] Related Publications
OBJECTIVE: The objective of this study is to evaluate the detection rate and diagnostic accuracy of sentinel lymph node (SN) mapping using hysteroscopic sub-endometrial injection of 99m-Technetium labeled phytate (Radio-isotope; RI method) and subserosal Indocyanine green (ICG) injection (Dye method) in patients with endometrial cancer.
METHODS: From April 2009 to December 2012, prospective evaluation of 57 Japanese endometrial cancer patients undergoing SN mapping using RI method combined with Dye method was done. To combine RI method or no was determined by a status of RI supply of the tracer injection day. As for 32 cases, both (RI+Dye) methods were used and 23 cases were performed only in Dye method. The primary endpoint was estimation of sensitivity and negative predictive value (NPV) of SN, and analysis of the distribution of SNs with metastasis.
RESULTS: At least one SN was detected in 100% and average number of detected SNs was 6.0 in RI+Dye method. Sensitivity and NPV were 100%, 100%, respectively. From results of SN mapping, 62.8% of SNs were present in pelvic and 37.1% in para-aortic lymph nodes (PAN). Total 56.3% of lymph nodes with metastasis were present in pelvic and 43.8% in PAN, and the distribution has no difference with SN mapping results (P=0.602). Among 13 cases with metastatic SNs, 76.9% cases showed metastasis in PAN.
CONCLUSIONS: This SN mapping procedure for endometrial cancer patients revealed high detection rate, sensitivity, NPV, and also indicated the importance of the SN exploration in PAN area.

Guy MS, Qamar L, Behbakht K, et al.
Progestin treatment decreases CD133+ cancer stem cell populations in endometrial cancer.
Gynecol Oncol. 2016; 140(3):518-26 [PubMed] Related Publications
OBJECTIVES: Endometrial cancer is a hormonally responsive malignancy. Response to progestins is associated with estrogen receptor (ER) and progesterone receptor (PR) status. CD133 is a marker of endometrial cancer stem cells. We postulated that CD133+ cells express ER and PR and that progestin therapy differentially regulates CD133+ cells.
METHODS: The Ishikawa (ER/PR positive) and KLE (ER/PR negative) cell lines were examined for the presence of CD133 populations. Cell lines were treated with 30.4μM medroxyprogesterone 17-acetate (MPA) for 6days. After treatment, cell counts, apoptosis assays and CD133+ populations were examined. In a clinical project, we identified 12 endometrial cancer patients who were treated with progestin drugs at our institution. Using immunohistochemistry, CD133, ER, PR, and androgen receptor (AR) expression was scored and evaluated for change over time on serial biopsies.
RESULTS: CD133+ populations were identified in Ishikawa and KLE cell lines. MPA treatment resulted in a significant reduction in the percentage of live cells (Ishikawa, P=0.036; KLE, P=0.0002), significant increase in apoptosis (Ishikawa, P=0.01; KLE, P=0.0006) and significant decrease in CD133+ populations (Ishikawa, P<0.0001; KLE, P=0.0001). ER, PR, AR and CD133 were present in 96.4%, 96.4%, 89.3% and 100% of patient samples respectively. Paralleling the in vitro results, CD133 expression decreased in patients who had histologic response to progestin treatment.
CONCLUSION: CD133+ populations decreased after treatment with MPA in an in vitro model and in patients responding to treatment with progestins. Progestin treatment differentially decreases CD133+ cells.

Emons G, Kurzeder C, Schmalfeldt B, et al.
Temsirolimus in women with platinum-refractory/resistant ovarian cancer or advanced/recurrent endometrial carcinoma. A phase II study of the AGO-study group (AGO-GYN8).
Gynecol Oncol. 2016; 140(3):450-6 [PubMed] Related Publications
OBJECTIVES: To evaluate activity and toxicity of mTOR inhibitor temsirolimus in patients with platinum-refractory/resistant ovarian cancer (OC) or advanced/recurrent endometrial carcinoma (EC).
METHODS: Women with epithelial ovarian, fallopian tube or primary peritoneal cancer were eligible, when they had progression during treatment with a platinum based regimen or within 6 months after receiving a platinum based regimen and a previous taxane treatment. Women with advanced/recurrent EC, no longer amenable to curative surgery and/or radiotherapy were eligible when they had no previous or only adjuvant chemotherapy. Preceding endocrine therapy for metastatic/recurrent disease was allowed. Patients received weekly IV infusions of 25mg temsirolimus. Primary endpoint was progression free survival rate after 4 months (OC) or 6 months (EC). A two stage design was applied.
RESULTS: Forty-four patients (OC: n=22; EC: n=22) were enrolled and received temsirolimus treatment. Median age was 56 years (OC) or 63 years (EC). After eight weeks of treatment, 10 of 21 evaluable patients in the OC cohort and 8 of 20 evaluable patients in the EC cohort had progressive disease. Thus efficacy did not meet the predefined levels during the first stage of recruitment and the trial was stopped. Some patients in both cohorts had long lasting PFS (>7 months). Toxicity of temsirolimus was mild.
CONCLUSIONS: Temsirolimus treatment was well tolerated in our patients, but did not meet the predefined efficacy criteria. In our study as in other trials on rapalogs in OC or EC, a few patients had long lasting disease stabilisations.

Tsubamoto H, Sakata K, Sakane R, et al.
Gremlin 2 is Repressed in Invasive Endometrial Cancer and Inhibits Cell Growth In Vitro.
Anticancer Res. 2016; 36(1):199-203 [PubMed] Related Publications
BACKGROUND: There exist limited therapeutic opportunities regarding the treatment of endometrial cancer (EC), and novel therapies based on the molecular profiling of EC cells are required.
MATERIALS AND METHODS: We used microarray analysis of EC tumour samples in order to identify tumour-specific changes regarding gene expression.
RESULTS: It was found that gremlin 2, an inhibitor of bone morphogenetic protein (BMP) signaling, was repressed in EC samples, and that gremlin 2 inhibited tumour cell growth.
CONCLUSION: Down-regulation of gremlin 2 may lead to carcinogenesis and progression of EC. We suggest that re-activation of gremlin 2-associated pathways could suppress EC progression and should thus be explored as a potential novel therapeutic approach.

Inoue K, Tsubamoto H, Sakata K, et al.
Expression of Hedgehog Signals and Growth Inhibition by Itraconazole in Endometrial Cancer.
Anticancer Res. 2016; 36(1):149-53 [PubMed] Related Publications
BACKGROUND: There exist limited therapeutic opportunities for the treatment of endometrial cancer (EC). Itraconazole, a common anti-fungal agent and a potent inhibitor of the Hedgehog pathway, has been shown to be clinically effective for various types of cancers, but its clinical efficacy for EC is unknown. Herein, we evaluated the efficacy of itraconazole in treating EC.
MATERIALS AND METHODS: We performed immunohistochemistry on EC tumour samples including serous endometrial intraepithelial carcinoma (SEIC). We further evaluated the in vitro efficacy of itraconazole for inhibiting proliferation and migration of EC cell lines.
RESULTS: Sonic Hedgehog and glioma-associated oncogene homolog 1 (GLI1) were expressed in SEIC and endometrioid adenocarcinoma. We found that itraconazole significantly inhibited tumour cell growth in both dose-dependent and time-dependent manners and inhibited migration of HEC-1A cells.
CONCLUSION: Hedgehog signaling plays a role in carcinogenesis and malignant progression in EC. Itraconazole at a physiological dose may suppress progression of EC.

Buhtoiarova TN, Brenner CA, Singh M
Endometrial Carcinoma: Role of Current and Emerging Biomarkers in Resolving Persistent Clinical Dilemmas.
Am J Clin Pathol. 2016; 145(1):8-21 [PubMed] Related Publications
OBJECTIVES: Type II and other high-grade endometrial carcinomas may challenge conventional treatment due to recurrence and metastatic spread and therefore are a persistent clinical dilemma. Effective targeted therapy for these is a goal for clinicians and researchers alike.
METHODS: An extensive review of the literature has been performed for obtaining an in-depth understanding of the clinicopathological characteristics, etiologic factors, and molecular profile of these subsets of endometrial carcinoma. Progress made with current and emerging biomarkers for prognosis assessment and therapeutic targeting has been summarized.
RESULTS: There has been a significant increase in research on potential biomarkers of endometrial cancer, and beneficial targeted therapies have been identified.
CONCLUSIONS: Clinical trials are leading the charge for substantial gains toward personalized treatment of aggressive endometrial carcinoma subtypes.

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