Endometrial (Uterus) Cancer
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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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Information for Patients and the Public
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Latest Research Publications

Information Patients and the Public (10 links)

Information for Health Professionals / Researchers (10 links)

Latest Research Publications

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

Xin G, Du J, Xu Y
Isolated sacral metastases as the initial presentation from an endometroid ovarian carcinoma: a case report.
Eur J Gynaecol Oncol. 2014; 35(5):589-91 [PubMed] Related Publications
Bone metastases are rarely in ovarian carcainoma. It usually occurrs only when the cancer is advanced or recurrent. A case of endometrioid carcinoma in right ovary with intact capsule is reported. The isolated sacral metastasis was found as the initial presentation, and no distant metastases were reported.

Related: Ovarian Cancer

Nakamura H, Takehara K, Samura O, Mizunoe T
Cytoreductive surgery for isolated para-aortic lymph node recurrence of endometrial cancer: report of four cases and a review of the literature.
Eur J Gynaecol Oncol. 2014; 35(5):535-8 [PubMed] Related Publications
Isolated para-arotic lymph node recurrence of endometrial cancer occurs occasionally, but management of such patients has been controversial. The authors performed cytoreductive surgery in four patients with isolated para-aortic lymph node metastasis of recurrent endometrial cancer. They resected metastatic foci by laparoscopic method for three cases and by laparotomy for one case. After the surgery, three cases underwent radiation therapy and one case was given chemotherapy as adjuvant therapy. After the treatment for recurrence, progression-free interval was from 64 to 127 months and all cases had no evidence of disease. Cytoreductive surgery may improve prognosis of isolated para-aortic lymph node metastasis of recurrent endometrial cancer. As laparoscopic surgery is superior to laparotomy in terms of less invasiveness, further examinations will reveal that it is feasible for such an isolated lymph node recurrence situation.

Baser E, Gungor T, Togrul C, et al.
Preoperative prediction of poor prognostic parameters and adjuvant treatment in women with pure endometrioid type endometrial cancer: what is the significance of tumor markers?
Eur J Gynaecol Oncol. 2014; 35(5):513-8 [PubMed] Related Publications
PURPOSE OF THE STUDY: The study was conducted to determine whether preoperative serum levels of cancer antigen (CA) 125, CA15- 3, CA19-9, carcinoembryonic antigen (CEA), and alpha-fetoprotein (AFP) are associated clinicopathologically with poor prognostic parameters and adjuvant treatment requirements in women with pure endometrioid endometrial cancer (EEC).
MATERIALS AND METHODS: The authors performed a retrospective review of EEC cases that were treated between January 2008 and January 2011. The association between preoperative tumor markers and prognostic parameters, recurrence risk, and adjuvant treatment requirements were investigated. Following univariate analyses, receiver-operating characteristic (ROC) curves were constructed for each marker to assess their capacity to predict prognostic parameters and need for adjuvant treatment.
RESULTS: A total of 166 EEC cases were identified. Mean CA125, CA15-3, and CA19-9 levels were higher in cases that required adjuvant treatment (p < 0.05). CA125 had significant power for prediction of extrauterine disease, tumor size > two cm, lymphovascular space invasion (LVSI), deep myometrial invasion, cervical involvement, adnexal involvement, positive cytology, lymph node metastasis, and adjuvant treatment requirement. CA15-3 was a significant marker for adjuvant treatment prediction. CA19-9 could predict deep myometrial invasion, cervical involvement, and adjuvant treatment requirement. However, CEA and AFP did not have adequate capacity to predict any of the poor prognostic parameters and adjuvant treatment requirements. CONCLUSIONs: CA125 is currently one of the most important preoperative markers for identifying EEC cases that exhibit postoperatively poor prognostic pathologic findings and a consequent need for adjuvant treatment. CA15-3 and CA19- 9 were also significant markers with limited capacity in detecting prognostic parameters.

Siufi DF, Siufi Neto J, Abrão MS, Favero G
Lymphadenectomy in early stage endometrial cancer: a critical review of the current literature.
Tumori. 2014 Sep-Oct; 100(5):477-85 [PubMed] Related Publications
To date there has been no consensus on the exact oncological importance of systematic lymphadenectomy in early stage endometrial cancer. In this scenario, the balance between potential therapeutic benefit and procedure-related morbidity plays a central role in the indication for the procedure since the likelihood of detecting a metastatic node is relatively low. Compared with laparotomy, laparoscopic lymphadenectomy has several clearly demonstrated advantages and is an important tool to reduce morbidity. Additionally, many authors have developed less invasive methods to selectively identify patients who are at increased risk of lymph node involvement. This paper aims to review the current literature evidence and guidelines regarding the role of lymphadenectomy in patients with early stage endometrial cancer. Alternatives such as lymphatic sampling or sentinel lymph node biopsy are possible solutions but must be further investigated through more comprehensive studies.

Logan M, Hawkins SM
Role of microRNAs in cancers of the female reproductive tract: insights from recent clinical and experimental discovery studies.
Clin Sci (Lond). 2015; 128(3):153-80 [PubMed] Related Publications
microRNAs (miRNAs) are small RNA molecules that represent the top of the pyramid of many tumorigenesis cascade pathways as they have the ability to affect multiple, intricate, and still undiscovered downstream targets. Understanding how miRNA molecules serve as master regulators in these important networks involved in cancer initiation and progression open up significant innovative areas for therapy and diagnosis that have been sadly lacking for deadly female reproductive tract cancers. This review will highlight the recent advances in the field of miRNAs in epithelial ovarian cancer, endometrioid endometrial cancer and squamous-cell cervical carcinoma focusing on studies associated with actual clinical information in humans. Importantly, recent miRNA profiling studies have included well-characterized clinical specimens of female reproductive tract cancers, allowing for studies correlating miRNA expression with clinical outcomes. This review will summarize the current thoughts on the role of miRNA processing in unique miRNA species present in these cancers. In addition, this review will focus on current data regarding miRNA molecules as unique biomarkers associated with clinically significant outcomes such as overall survival and chemotherapy resistance. We will also discuss why specific miRNA molecules are not recapitulated across multiple studies of the same cancer type. Although the mechanistic contributions of miRNA molecules to these clinical phenomena have been confirmed using in vitro and pre-clinical mouse model systems, these studies are truly only the beginning of our understanding of the roles miRNAs play in cancers of the female reproductive tract. This review will also highlight useful areas for future research regarding miRNAs as therapeutic targets in cancers of the female reproductive tract.

Related: MicroRNAs Ovarian Cancer Cervical Cancer

Abid N, Mnif H, Mellouli M, et al.
Uterine tumour resembling ovarian sex cord tumours presenting as multiple endometrial and cervical uterine polyps: a case report.
Pathologica. 2014; 106(2):73-6 [PubMed] Related Publications
BACKGROUND: Uterine tumours resembling ovarian sex-cord tumours (UTROSCT) are very rare, benign uterine tumours, composed solely of sex cord elements. These tumours have a polyphenotypic immunophentype that favours a derivation from uterine mesenchymal stem cells.
CASE REPORT: A 43-year-old female presented with recurrent vaginal bleeding. On hysteroscopy, she had multiple endometrial and cervical polyps that were removed endoscopically. Histologically, the specimen contained epithelioid cells arranged in tubules, trabeculae and anastomosing cords, without significant cellular atypia or mitotic activity. Immunohistochemical studies were performed. The tumour was found to be diffusely positive for vimentin, calretinin and desmin, focally positive for cytokeratin, CD99 and inhibin and negative for chromogranin and CD10. A subsequent total hysterectomy was performed and revealed neoplastic infiltration of the myometrium.
CONCLUSION: A polyphenotypic immunophenotype is a characteristic feature of UTROSCT, and may be helpful in diagnosis and in exclusion of other lesions. Familiarity with this tumour by gynaecologists and pathologists is essential to avoid misdiagnosis:correct diagnosis of this neoplasm is important in patient management.

Related: Ovarian Cancer Cervical Cancer

Zygouris D, Pouliakis A, Margari N, et al.
Classification of endometrial lesions by nuclear morphometry features extracted from liquid-based cytology samples: a system based on logistic regression model.
Anal Quant Cytopathol Histpathol. 2014; 36(4):189-98 [PubMed] Related Publications
OBJECTIVE: To investigate the potential of a computerized system for the discrimination of benign from malignant endometrial nuclei and lesions.
STUDY DESIGN: A total of 228 histologically confirmed liquid-based cytological smears were collected: 117 within normal limits cases, 66 malignant cases, 37 hyperplasias without atypia, and 8 cases of hyperplasia with atypia. From each case we extracted nuclear morphometric features from about 100 nuclei using a custom image analysis system. Initially we performed feature selection, and subsequently we applied a logistic regression model that classified each nucleus as benign or malignant. Based on the results of the nucleus classification process, we constructed an algorithm to discriminate endometrium cases as benign or malignant.
RESULTS: The proposed system had an overall accuracy for the classification of endometrial nuclei equal to 83.02%, specificity of 85.09%, and sensitivity of 77.01%. For the case classification the overall accuracy was 92.98%, specificity was 92.86%, and sensitivity was 93.24%.
CONCLUSION: The proposed computerized system can be applied for the classification of endometrial nuclei and lesions as it outperformed the standard cytological diagnosis. This study highlights interesting diagnostic features of endometrial nuclear morphology, and the proposed method can be a useful tool in the everyday practice of the cytological laboratory.

Touboul C, Piel B, Koskas M, et al.
Factors predictive of endometrial carcinoma in patients with atypical endometrial hyperplasia on preoperative histology.
Anticancer Res. 2014; 34(10):5671-6 [PubMed] Related Publications
AIM: To identify predictive factors of endometrial cancer in patients with atypical endometrial hyperplasia (AEH).
PATIENTS AND METHODS: This was a retrospective cohort study of 79 patients diagnosed with AEH. Clinicopathological characteristics of patients and final histology on hysterectomy were reviewed and univariate and multivariate analyses were performed.
RESULTS: Nineteen cases of endometrial cancer (24%) were diagnosed at final histology. Most patients had IA (n=15, 79%) grade 1 (n=15, 79%) cancer, but two had FIGO stage IIIC (10.5%). The predictive factors of endometrial cancer on final histology in univariate analysis were: hysteroscopic sampling, older age, post-menopausal status, suspicion of cancer on hysteroscopy and suspicion of cancer at histology. In multivariable analysis, the only predictive factors of endometrial cancer were older age and the suspicion of cancer on hysteroscopy.
CONCLUSION: In patients with AEH on biopsy, our results showed that hysteroscopy could be performed both to assess macroscopic features of malignancy and to orient biopsy.

Čermáková P, Melichar B, Tomšová M, et al.
Prognostic significance of CD3+ tumor-infiltrating lymphocytes in patients with endometrial carcinoma.
Anticancer Res. 2014; 34(10):5555-61 [PubMed] Related Publications
AIM: The aim of the present study was to investigate tumor-infiltrating leukocytes in patients with endometrial carcinoma.
PATIENTS AND METHODS: Cluster of differentiation (CD)3(+), CD8(+) and C20(+) tumor-infiltrating lymphocytes (TILs) and CD68(+) tumor-associated macrophages (TAMs) were evaluated retrospectively by immunohistochemistry in tumor specimen from 124 patients with endometrial carcinoma.
RESULTS: A significant decrease of CD3(+) TILs and an increase of CD68(+) TAM count was associated with higher tumor stage. In patients with early-stage, high-risk tumors, low intraepithelial CD3(+) TIL counts were associated with significantly inferior survival. In multivariate analysis of patients with early-stage tumors, intraepithelial CD3(+) TIL counts were an independent predictor of survival.
CONCLUSION: In patients with endometrial carcinoma a decrease of intraepithelial CD3(+) TIL counts is associated with advanced stage and high risk group. Intraepithelial CD3(+) TIL counts are an independent predictor of survival in patients with early tumors.

Sakane R, Tsubamoto H, Sakata K, et al.
Expression of chemokine ligand 18 in stage IA low-grade endometrial cancer.
Anticancer Res. 2014; 34(10):5331-6 [PubMed] Related Publications
BACKGROUND/AIM: The identification of novel molecules associated with endometrial cancer (EC) development might offer less invasive surgery, better fertility preservation, and avoidance of unnecessary adjuvant therapy.
MATERIALS AND METHODS: Microarray analysis was conducted using fresh surgically-obtained specimens from five EC patients and five cases with benign tumours. Additionally, immunohistochemical studies of the most highly expressed molecules were performed on paraffin-embedded tissues from these patients and others with stage IA, grade 1-2 EC (n=3) with or without (n=7) recurrent disease.
RESULTS: The most highly expressed gene in EC was chemokine ligand 18 (CCL18), with a 35.6-fold change compared to benign tumors. CCL18 expression was observed in tumor cells at the myometrial invasive front in 9 out of 11 tested samples.
CONCLUSION: CCL18 expression was positively correlated with malignancy in EC. Further investigation with a larger number of samples or examination of serum CCL18 levels is warranted.

Schwab CL, Bellone S, English DP, et al.
Afatinib demonstrates remarkable activity against HER2-amplified uterine serous endometrial cancer in vitro and in vivo.
Br J Cancer. 2014; 111(9):1750-6 [PubMed] Related Publications
BACKGROUND: Uterine serous carcinomas (USCs) are an aggressive form of uterine cancer that may rely on HER2/neu amplification as a driver of proliferation. The objective of this paper is to assess the sensitivity of USC cell lines with and without HER2/neu gene amplification to afatinib, an irreversible ErbB tyrosine kinase inhibitor, and to test the efficacy of afatinib in the treatment of HER2-amplified USC xenografts.
METHODS: Eight of fifteen primary USC cell lines (four with HER2 amplification and four without) demonstrating similar in vitro growth rates were treated with scalar concentrations of afatinib. Effects on cell growth, signalling and cell cycle distribution were determined by flow cytometry assays. Mice harbouring xenografts of HER2/neu-amplified USC were treated with afatinib by gavage to determine the effect on tumour growth and overall survival.
RESULTS: Primary chemotherapy-resistant USC cell lines harbouring HER2/neu gene amplification were exquisitely sensitive to afatinib exposure (mean ± s.e.m. IC50=0.0056 ± 0.0006 μM) and significantly more sensitive than HER2/neu-non-amplified USC cell lines (mean ± s.e.m. IC50=0.563 ± 0.092 μM, P<0.0001). Afatinib exposure resulted in abrogation of cell survival, inhibition of HER2/neu autophosphorylation and S6 transcription factor phosphorylation in HER2/neu overexpressing USC and inhibited the growth of HER2-amplified tumour xenografts improving overall survival (P=0.0017).
CONCLUSIONS: Afatinib may be highly effective against HER2/neu-amplified chemotherapy-resistant USC. The investigation of afatinib in patients harbouring HER2/neu-amplified USC is warranted.

Related: Apoptosis FISH Signal Transduction

Mills AM, Liou S, Ford JM, et al.
Lynch syndrome screening should be considered for all patients with newly diagnosed endometrial cancer.
Am J Surg Pathol. 2014; 38(11):1501-9 [PubMed] Related Publications
Lynch syndrome (LS) is an autosomal dominant inherited disorder caused by germline mutations in DNA mismatch repair (MMR) genes. Mutation carriers are at substantially increased risk of developing cancers of the colorectum and endometrium, among others. Given recent recommendations for universal, cost-effective screening of all patients with newly diagnosed colorectal cancer using MMR protein immunohistochemistry, we evaluated MMR protein expression in a series of endometrial cancers in the general population. A total of 605 consecutive cases of primary endometrial cancer at a single institution (1997 to 2013) were evaluated regardless of age, family history, or histologic features. Evaluation methods consisted of immunohistochemistry for the MMR proteins MLH1, MSH2, MSH6, and PMS2, followed by DNA methylation analysis for cases with MLH1/PMS2 deficiency. Germline mutation testing was performed on a subset of cases. Forty MMR-deficient, nonmethylated endometrial cancers were identified: 3 MLH1/PMS2 and 37 MSH6/MSH2 protein deficiencies. Only 25% occurred in women below 50 years of age (range, 39 to 88 y), 1 of which was in a risk-reducing hysterectomy specimen. Only 15% of patients had a prior history of carcinoma, including only 2 patients with prior colorectal carcinoma. Most (80%) of the endometrial cancers were purely endometrioid; there were 2 mixed endometrioid/mucinous, 1 mucinous, 1 serous, 2 clear cell, and 2 carcinosarcoma cases. When grading was applicable, 40% of the endometrial malignancies were FIGO grade 1, 34% grade 2, and 26% grade 3. Thirteen percent arose in the lower uterine segment, and 23% had tumor-infiltrating lymphocytes. Of the tumors with known germline testing, 41% with a LS-associated germline mutation were not associated with any of the traditional indicators that have been recommended for LS screening (ie, age 50 y or younger, personal/family cancer pedigree that meets Bethesda guideline criteria, presence of MMR-associated tumor morphology, or location in the lower uterine segment). These data suggest that a significant number of LS-associated endometrial carcinomas are missed using clinical, histologic, and locational screening parameters and provide support for universal screening of all newly diagnosed endometrial cancers.

Related: Lynch Syndrome - HNPCC MSH6 MLH1 MSH2

Liu Y, Patel L, Mills GB, et al.
Clinical significance of CTNNB1 mutation and Wnt pathway activation in endometrioid endometrial carcinoma.
J Natl Cancer Inst. 2014; 106(9) [PubMed] Article available free on PMC after 01/09/2015 Related Publications
BACKGROUND: Endometrioid endometrial carcinoma (EEC) is the most common form of endometrial carcinoma. The heterogeneous clinical course of EEC is an obstacle to individualized patient care.
METHODS: We performed an integrated analysis on the multiple-dimensional data types including whole-exome and RNA sequencing, RPPA profiling, and clinical data from 271 EEC cases in The Cancer Genome Atlas (TCGA) to identify molecular fingerprints that may account for this clinical heterogeneity. Significance analysis of microarray was used to identify marker genes of each subtype that were subject to pathway analysis. Association of molecular subtypes with clinical features and mutation data was analyzed with the Mann Whitney, Chi-square, Fisher's exact, and Kruskal-Wallis tests. Survival analysis was evaluated with log-rank test. All statistical tests were two-sided.
RESULTS: Four transcriptome subtypes with distinct clinicopathologic characteristics and mutation spectra were identified from the TCGA dataset and validated in an independent sample cohort of 184 EEC cases. Cluster II consisted of younger, obese patients with low-grade EEC but diminished survival. CTNNB1 exon 3 mutations were present in 87.0% (47/54) of Cluster II (P < .001) that exhibited a low overall mutation rate; this was statistically significantly associated with Wnt/β-catenin signaling activation (P < .001). High expression levels of CTNNB1 (P = .001), MYC (P = .01), and CCND1 (P = .01) were associated with poorer overall survival in low-grade EEC tumors.
CONCLUSIONS: CTNNB1 exon 3 mutations are likely a driver that characterize an aggressive subset of low-grade and low-stage EEC occurring in younger women.

Related: CTNNB1 gene

Byrne FL, Poon IK, Modesitt SC, et al.
Metabolic vulnerabilities in endometrial cancer.
Cancer Res. 2014; 74(20):5832-45 [PubMed] Related Publications
Women with metabolic disorders, including obesity and diabetes, have an increased risk of developing endometrial cancer. However, the metabolism of endometrial tumors themselves has been largely understudied. Comparing human endometrial tumors and cells with their nonmalignant counterparts, we found that upregulation of the glucose transporter GLUT6 was more closely associated with the cancer phenotype than other hallmark cancer genes, including hexokinase 2 and pyruvate kinase M2. Importantly, suppression of GLUT6 expression inhibited glycolysis and survival of endometrial cancer cells. Glycolysis and lipogenesis were also highly coupled with the cancer phenotype in patient samples and cells. To test whether targeting endometrial cancer metabolism could be exploited as a therapeutic strategy, we screened a panel of compounds known to target diverse metabolic pathways in endometrial cells. We identified that the glycolytic inhibitor, 3-bromopyruvate, is a powerful antagonist of lipogenesis through pyruvylation of CoA. We also provide evidence that 3-bromopyruvate promotes cell death via a necrotic mechanism that does not involve reactive oxygen species and that 3-bromopyruvate impaired the growth of endometrial cancer xenografts.

Yoneyama K, Shibata R, Igarashi A, et al.
Proteomic identification of dihydrolipoamide dehydrogenase as a target of autoantibodies in patients with endometrial cancer.
Anticancer Res. 2014; 34(9):5021-7 [PubMed] Related Publications
BACKGROUND/AIM: Accumulating evidence shows that various types of cancers induce a specific immune response, resulting in the production of antibodies against self-components (autoantibodies). The aim of the present study was to identify antigens for autoantibodies in sera from endometrial cancer patients as novel diagnostic markers for the disease.
MATERIALS AND METHODS: The reactivity of individual sera from patients was examined by 2-dimensional (2-D) immunoblotting using HeLa cell lysates as antigens to identify autoantigens. ELISA was established to quantitatively measure autoantibody titer of patients' sera.
RESULTS: A mitochondrial protein, dihydrolipoamide dehydrogenase (DLD), was identified as an autoantigen specific to endometrial cancer patients. The levels of immunoglobulin (Ig)A but not IgG autoantibody to DLD were significantly increased in the sera of endometrial cancer patients.
CONCLUSION: IgA autoantibody against DLD could be a novel diagnostic marker for endometrial cancer.

Related: Cervical Cancer

Nagao S, Nishikawa T, Hanaoka T, et al.
Feasibility study of combination chemotherapy with paclitaxel, doxorubicin and cisplatin without prophylactic granulocyte colony-stimulating factor injection for intermediate-to-high risk or recurrent endometrial cancer.
Jpn J Clin Oncol. 2014; 44(11):1040-4 [PubMed] Related Publications
OBJECTIVE: We evaluated the feasibility of combination chemotherapy with paclitaxel, doxorubicin and cisplatin without prophylactic granulocyte colony-stimulating factor injection for intermediate-to-high-risk or recurrent endometrial cancer.
METHODS: Women with histologically confirmed FIGO Stages I-II with >1/2 myometrial invasion, Stage III/IV or recurrent endometrial cancer were enrolled. Patients received intravenous doxorubicin (45 mg/m(2)), followed by cisplatin (50 mg/m(2)) on Day 1 and intravenous paclitaxel (160 mg/m(2)) on Day 2. Granisetron (75 µg) was administered depending on neutrophil counts on Days 3 and 8. Treatment was repeated every 21 days for six cycles or until disease progression or unacceptable toxicity. The primary endpoint was the completion rate of the scheduled chemotherapy; secondary endpoints were Grade 3/4 toxicity and response rate in patients with measurable lesions.
RESULTS: From September 2010 to December 2012, 35 women, including 7 with FIGO Stage I, 4 with Stage II, 13 with Stage III, 10 with Stage IV and 1 with recurrent endometrial cancer, were enrolled. There were 26 endometrial carcinomas (Grade 1, 16; Grade 2, 6; Grade 3, 4), 4 carcinosarcomas, 2 serous adenocarcinomas, 1 neuroendocrine carcinoma, 1 poorly differentiated carcinoma and 1 mixed carcinoma. Twenty-five patients (71%) completed six chemotherapy cycles. Grade 3/4 hematological toxicities included neutrocytopenia (97%), thrombocytopenia (6%) and anemia (34%). Three patients (9%) experienced neutropenic fever. Grade 3/4 non-hematological toxicities were observed in 13 patients. In 15 patients with evaluable lesions, the response rate was 80%.
CONCLUSIONS: Combination chemotherapy with paclitaxel, doxorubicin and cisplatin without prophylactic granulocyte colony-stimulating factor injection is feasible.

Related: Cisplatin Doxorubicin Paclitaxel

Kato E, Orisaka M, Kurokawa T, et al.
Relation between outcomes and expression of estrogen receptor-α phosphorylated at Ser(167) in endometrioid endometrial cancer.
Cancer Sci. 2014; 105(10):1307-12 [PubMed] Related Publications
Both ligand-dependent and ligand-independent activation of estrogen receptor (ER)α is modulated by receptor phosphorylation and results in activation of the ERα-dependent pathways that are involved in endometrioid endometrial cancer (EEC) pathogenesis. It is also known that the mammalian target of rapamycin (mTOR)/p70 S6 kinase 1 (S6K1) and MAPK/p90 ribosomal S6 kinase (RSK) signaling pathways coordinately regulate phosphorylated-ERα at Ser(167) (p-Ser(167) -ERα). However, the expression of p-Ser(167) -ERα in EEC and its prognostic role in ECC is largely unexplored. The purpose of the present study was to investigate the expression of p-Ser(167) -ERα in ECC and its relationship with prognosis. Immunohistochemical staining of primary EEC surgical specimens (n = 103) was carried out using antibodies specific for p-Ser(167) -ERα and for p-mTOR/p-S6K1 and p-MAPK/p-RSK. The correlation of p-Ser(167) -ERα expression with clinicopathological features and survival of ECC was studied. Patients that were positive for nuclear p-Ser(167) -ERα had significantly shorter relapse-free survival, and although the result was not significant, levels of nuclear p-Ser(167) -ERα tended to be higher in advanced-stage ECC patients. Nuclear p-Ser(167) -ERα was significantly positively correlated with p-MAPK and p-S6K1, and with significantly shorter relapse-free survival in EEC.

Related: AKT1 ESR1

Nebgen DR, Lu KH, Rimes S, et al.
Combined colonoscopy and endometrial biopsy cancer screening results in women with Lynch syndrome.
Gynecol Oncol. 2014; 135(1):85-9 [PubMed] Related Publications
OBJECTIVE: Endometrial biopsy (EMBx) and colonoscopy performed under the same sedation is termed combined screening and has been shown to be feasible and to provide a less painful and more satisfactory experience for women with Lynch syndrome (LS). However, clinical results of these screening efforts have not been reported. The purpose of this study was to evaluate the long-term clinical outcomes and patient compliance with serial screenings over the last 10.5 years.
METHODS: We retrospectively analyzed the data for 55 women with LS who underwent combined screening every 1-2 years between 2002 and 2013. Colonoscopy and endometrial biopsy were performed by a gastroenterologist and a gynecologist, with the patient under conscious sedation.
RESULTS: Out of 111 screening visits in these 55 patients, endometrial biopsies detected one simple hyperplasia, three complex hyperplasia, and one endometrioid adenocarcinoma (FIGO Stage 1A). Seventy-one colorectal polyps were removed in 29 patients, of which 29 were tubular adenomas. EMBx in our study detected endometrial cancer in 0.9% (1/111) of surveillance visits, and premalignant hyperplasia in 3.6% (4/111) of screening visits. No interval endometrial or colorectal cancers were detected.
CONCLUSIONS: Combined screening under sedation is feasible and less painful than EMBx alone. Our endometrial pathology detection rates were comparable to yearly screening studies. Our results indicate that screening of asymptomatic LS women with EMBx every 1-2 years, rather than annually, is effective in the early detection of (pre)cancerous lesions, leading to their prompt definitive management, and potential reduction in endometrial cancer.

Related: Lynch Syndrome - HNPCC Cancer Screening and Early Detection

Sciallis AP, Bedroske PP, Schoolmeester JK, et al.
High-grade endometrial stromal sarcomas: a clinicopathologic study of a group of tumors with heterogenous morphologic and genetic features.
Am J Surg Pathol. 2014; 38(9):1161-72 [PubMed] Related Publications
The existence of a "high-grade endometrial stromal sarcoma" category of tumors has been a controversial subject owing to, among other things, the difficulty in establishing consistent diagnostic criteria. Currently, the recommended classification for such tumors is undifferentiated uterine/endometrial sarcoma. Interest in this subject has recently increased markedly with the identification of recurrent molecular genetic abnormalities. At Mayo Clinic, a group of neoplasms has been observed that morphologically resemble, either cytologically or architecturally, classic "low-grade" endometrial stromal sarcoma but feature obvious deviations, specifically, 17 tumors with unequivocally high-grade morphology. These high-grade tumors displayed 3 morphologic themes: (1) tumors with a component that is identical to low-grade ESS that transitions abruptly into an obviously higher-grade component; (2) tumors composed exclusively of high-grade cells with uniform nuclear features but with a permeative pattern of infiltration; (3) tumors similar to the second group but with a different, yet characteristic, cytomorphology featuring enlarged round to ovoid cells (larger than those found in low-grade ESS) with smooth nuclear membranes and distinct chromatin clearing but lacking prominent nucleoli. We collected clinicopathologic data, applied immunohistochemical studies, and also tested tumors by fluorescence in situ hybridization for abnormalities in JAZF1, PHF1, YWHAE, and CCND1. Tumors from these 3 groups were found to be immunohistochemically and genetically distinct from one another. Most notable was the fact that category 3 contained all the cases that tested positive for YWHAE rearrangement, did not show any classic translocations for JAZF1, PHF1, or CCND1, often presented at a high stage, and behaved aggressively. This study demonstrates the morphologic, immunophenotypic, and molecular genetic heterogeneity that exists within "undifferentiated endometrial sarcomas" as currently defined and lends credence to the effort of subclassifying some tumors as truly "high-grade endometrial stromal sarcomas." Our study also shows that, in the context of undifferentiated endometrial sarcomas, recognition of cytomorphologic features on routine hematoxylin and eosin-stained sections may be used to select tumors with specific molecular genetic changes-that is, translocations involving YWHAE. Our conclusions will help further efforts towards proper sub-classification of these tumors which will aid in diagnosis and potentially affect clinical management.

Related: FISH

Hrzenjak A, Dieber-Rotheneder M, Moinfar F, et al.
Molecular mechanisms of endometrial stromal sarcoma and undifferentiated endometrial sarcoma as premises for new therapeutic strategies.
Cancer Lett. 2014; 354(1):21-7 [PubMed] Related Publications
Endometrial stromal sarcoma (ESS) and undifferentiated endometrial sarcoma (UES) are very rare gynecologic malignancies. Due to the rarity and heterogeneity of these tumors, little is known about their epidemiology, pathogenesis, and molecular pathology. Our previous studies have described deregulation of histone deacetylases expression in ESS/UES samples. Some of these enzymes can be inhibited by substances which are already approved for treatment of cutaneous T-cell lymphoma. On the basis of published data, they may also provide a therapeutic option for ESS/UES patients. Our review focuses on molecular mechanisms of ESS/UES. It describes various aspects with special emphasis on alteration of histone deacetylation and its possible relevance for novel therapies.

Related: Cutaneous T-cell lymphoma

Bosse T, Nout RA, Stelloo E, et al.
L1 cell adhesion molecule is a strong predictor for distant recurrence and overall survival in early stage endometrial cancer: pooled PORTEC trial results.
Eur J Cancer. 2014; 50(15):2602-10 [PubMed] Related Publications
BACKGROUND: L1 cell adhesion molecule (L1CAM) expression has been implicated as risk factor for disease recurrence in endometrial cancer (EC), most likely due to its role in promoting tumour cell motility. We tested the performance of L1CAM expression in predicting the risk of recurrence in the randomised post operative radiation therapy in endometrial carcinoma (PORTEC)-1 and -2 trials.
METHODS: In the PORTEC trials, stage I EC patients were randomised to external beam radiotherapy (EBRT) versus no additional treatment (PORTEC-1, n=714), or to EBRT versus vaginal brachytherapy (PORTEC-2, n=427). Tumour samples of 865 (75.8%) patients were available for L1CAM expression analysis by immunohistochemistry. An established scoring system for EC was used, with >10% L1CAM staining defined as positive.
RESULTS: Positive L1CAM expression was significantly correlated with risk of distant recurrence, with a hazard ratio (HR) of 5.1 (95% confidence interval (CI) 3.1-8.7) but not with vaginal relapse, while a trend for pelvic nodal relapse was found. Tumours with the highest expression levels (>50% positive) had the strongest risk of distant recurrence (HR 5.3, CI 2.7-10.4). In multivariate Cox analysis with the risk factors age, depth of invasion, grade, lympho-vascular space invasion (LVSI) and treatment, L1CAM expression remained an independent prognostic factor for distant recurrence (HR 3.5, CI 1.92-6.30) and overall survival (HR 2.1, CI 1.41-2.98).
CONCLUSION: L1CAM expression is a strong independent predictor for distant recurrence and overall survival in stage I endometrial cancer. These results warrant prospective validation of L1CAM as marker for selecting patients who could benefit from more extensive diagnostic and/or therapeutic procedures.

Pichatechaiyoot A, Buhachat R, Boonyapipat S, Kanjanapradit K
Radiation, chemotherapy or combined modality therapy in adjuvant treatment for stage III endometrial carcinoma in lower southern Thailand: disease recurrence and overall survival.
J Med Assoc Thai. 2014; 97(3):274-82 [PubMed] Related Publications
OBJECTIVE: To survey disease-free survival (DFS) and overall survival (OS) of patients with stage III endometrial carcinoma treated with post-operative radiation and/or chemotherapy
MATERIAL AND METHOD: The medical records of patients with surgical stage III endometrial carcinoma, and receiving adjuvant treatment between January 2003 and December 2012 were reviewed DFS and OS were analyzed using the Kaplan-Meier method and Cox proportional hazards model.
RESULTS: Of the 54 eligible patients, 61% underwent radiation, 19% chemotherapy, and 20% chemotherapy with radiation. The median DFS was 36.7 months. The 3-year DFS and OS was 51.9% (95% CI 36.3-74.1%) and 70.6% (95% CI 57.4-86.8%), respectively. There was no significant difference in DFS and OS among treatment groups. Cox regression analysis showed grade 2-3 tumors and menopause were associated with poor DFS and OS.
CONCLUSION: The DFS and OS in stage III endometrial carcinoma receiving postoperative adjuvant therapy were quite good and were not different among radiation therapy, chemotherapy, and combined treatment groups. The multi-center randomized prospective study was needed to determine the standard modality.

Related: Thailand

Seki T, Yanaihara N, Hirata Y, et al.
Uterine endometrial carcinoma with trophoblastic differentiation: a case report with literature review.
Eur J Gynaecol Oncol. 2014; 35(4):461-4 [PubMed] Related Publications
Choriocarcinoma is categorized as either gestational or nongestational depending on its origin. Nongestational choriocarcinoma originated in the trophoblastic differentiation is a rare but an aggressive tumor. This article reports a nongestational case of a uterine endometrial carcinoma with trophoblastic differentiation. A 54-year-old woman with a history of atypical genital bleeding that underwent semi-radical hysterectomy, bilateral salpingo-oophrectomy, and pelvic lymph nodes dissection. Pathological investigation showed that the tumor had endometrioid adenocarcinoma and choriocarcinomatous components. Although a series of multimodality treatments including craniotomy were performed, she died of aggressive lung and brain metastases one year after the primary surgery.

Rossi A, Forzano L, Romanello I, et al.
Comparison of pelvic masses score (PMS) and Risk of Malignancy Index (RMI 3) in the evaluation of pelvic masses.
Eur J Gynaecol Oncol. 2014; 35(4):421-4 [PubMed] Related Publications
PURPOSE: Ovarian cancer is the fourth cause of death from cancer in women worldwide and the majority of its diagnoses is made in an advanced stage of the disease. Several sonographic scoring systems have been created for a better preoperative discrimination between benign and malignant pelvic masses. The aim of this study was to evaluate the performances of the Risk of the Malignancy Index 3 (RMI 3) and the Pelvic Masses Score (PMS).
MATERIALS AND METHODS: This retrospective study was performed in 55 women admitted to the department of Obstetrics and Gynecology of University of Udine for surgical exploration of pelvic masses between 2009 and 2012. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated for both the scores.
RESULTS: PMS showed a sensitivity of 100%, a specificity of 93.8%, a PPV of 70%, and a NPV of 100%, while RMI 3 yielded a sensitivity of 85%, a specificity of 91%, a PPV of 60%, and a NPV of 97.8%.
CONCLUSION: The authors found that, in discriminating between benign and malignant pelvic disease, the PMS method was more reliable than RMI3. PMS is a simple scoring system which can be used in clinical practice.

Related: Ovarian Cancer

Litta P, Di Giuseppe J, Moriconi L, et al.
Predictors of malignancy in endometrial polyps: a multi-institutional cohort study.
Eur J Gynaecol Oncol. 2014; 35(4):382-6 [PubMed] Related Publications
PURPOSE OF INVESTIGATION: The risk of endometrial cancer in women with endometrial polyps (EPs) has been reported to vary between 0.3% and 4.8%. There is a lack of data about the management of asymptomatic women with incidental diagnosis of EPs. In the present study the authors correlated demographic and clinical characteristics with histopathological features of the EPs hysteroscopically removed.
MATERIALS AND METHODS: An observational multi-institutional cohort study was conducted from February 2010 to December 2012 to identify all the premenopausal and postmenopausal women consecutively undergoing hysteroscopic polypectomy. The data of women were reviewed and clinical features were related to histopathologic results.
RESULTS: The patients recruited were 813. The mean age was 52.5 years (range 22-87). The results showed a correlation between older age, high body mass index (BMI) and obesity, postmenopausal state, abnormal uterine bleeding (AUB), hypertension, and risk of malignant EPs. On multivariable analysis, the correlation remained only for age (OR 1.08, 95% CI 1.03 - 1.14) and AUB (OR 3.53, 95% CI 1.87 - 6.65).
CONCLUSION: Older patients in postmenopausal status with AUB, a high BMI, and hypertension are at higher risk for premalignant and malignant polyps. In these patients a surgical approach should be used, consisting in hysteroscopical removing of the polyp.

Davis R, Batur P, Thacker HL
Risks and effectiveness of compounded bioidentical hormone therapy: a case series.
J Womens Health (Larchmt). 2014; 23(8):642-8 [PubMed] Related Publications
After the publication of the Women's Health Initiative, attitudes towards management of menopausal symptoms changed dramatically. One alternative that has received much media attention is the use of bioidentical hormone therapy (BHT). The media and celebrity endorsements have promoted a number of misconceptions about the risks and benefits associated with the various forms of BHT. This article will review the available evidence regarding the safety and efficacy of BHT in comparison to conventional hormone therapy. We will also review several cases seen in our midlife women's referral clinics, which demonstrate concerns for the safety and efficacy of BHT, including unexplained endometrial cancer in otherwise healthy BHT users. Due to the lack of sufficient data to support the efficacy or safety of BHT, we recommend the use of United States Food and Drug Administration-approved regimens in the management of menopausal symptoms.

Related: USA

Todo Y, Okamoto K, Minobe S, Kato H
Clinical significance of surgical staging for obese women with endometrial cancer: a retrospective analysis in a Japanese cohort.
Jpn J Clin Oncol. 2014; 44(10):903-9 [PubMed] Related Publications
OBJECTIVE: In patients with endometrial cancer, obesity is associated with a well-differentiated histological grade but not with prolonged survival. It is possible that this lack of survival advantage is caused by incomplete surgical staging.
METHODS: In total, 716 patients with endometrial cancer were retrospectively reviewed. Obesity was defined as body mass index of ≥30 kg/m(2). The relationships between clinicopathological factors and disease-specific survival were analyzed by Cox regression analysis.
RESULTS: Older age (hazard ratio, 1.6; 95% confidence interval, 1.1-2.4), advanced stage (hazard ratio, 11.2; 95% confidence interval, 7.2-17.5), high-risk histology (hazard ratio, 2.7; 95% confidence interval, 1.8-4.0), no hysterectomy (hazard ratio, 3.1; 95% confidence interval, 1.7-5.8) and no lymphadenectomy (hazard ratio, 2.0; 95% confidence interval, 1.3-3.0) were independently associated with poor disease-specific survival. Survival was similar in obese and non-obese women (hazard ratio, 0.9; 95% confidence interval, 0.5-1.6) despite the fact that obesity was significantly associated with younger age and a well-differentiated histological grade. Although there was no difference in the distribution of disease stage between the two groups, obesity was associated with lower rates of hysterectomy (3.6 vs. 6.1%, P = 0.23) and lymphadenectomy (25.0 vs. 36.4%, P = 0.017). Obese patients who underwent hysterectomy had a significantly better disease-specific survival than those who did not (P = 0.002). The 5-year disease-specific survival rate in obese patients who underwent lymphadenectomy was 6.2% better than that in those who did not [86.0 vs. 79.8%, P = 0.36 (not statistically significant)].
CONCLUSION: Poor-quality surgical staging in obese women may result in worse than expected survival outcomes.

Günyeli I, Bozkurt KK, Yalçın Y, et al.
Granulosa cell tumor and concurrent endometrial cancer with (18)F-FDG uptake.
Hell J Nucl Med. 2014 May-Aug; 17(2):153-5 [PubMed] Related Publications
The findings and the role of fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) for the diagnosis of ovarian granulosa cell tumor (OG) are described. We present the pre-operative findings of (18)F-FDG PET/CT scan of a case of OG concurrent with endometrium cancer and endometrial hyperplasia, which revealed a 48mm mass demonstrating mild increased metabolic activity on the right ovary. Total abdominal hysterectomy and bilateral salpingo-oophorectomy was performed. Frozen and paraffin-enbeded sections showed an encapsulated OG. There were few mitoses. There was concurrent atypical endometrial hyperplasia. In conclusion, we reported a case of an encapsulated OG, which showed mild uptake of the (18)F-FDG with concurrent endometrial cancer. There has been only one report of (18)F-FDG findings in primary ovarian granulosa cell tumor, similar to ours.

Vierkoetter KR, Ayabe AR, VanDrunen M, et al.
Lynch Syndrome in patients with clear cell and endometrioid cancers of the ovary.
Gynecol Oncol. 2014; 135(1):81-4 [PubMed] Related Publications
OBJECTIVE: Patients with Lynch Syndrome are at an increased risk for a variety of malignancies, including ovarian cancer. Ovarian cancers associated with Lynch Syndrome are predominantly clear cell or endometrioid in histology. Lynch Syndrome is characterized by germline mutations in mismatch repair (MMR) genes. The current study aims to assess the prevalence of loss of MMR expression in patients with endometrioid and clear cell ovarian carcinoma.
METHODS: A retrospective review identified 90 patients with endometrioid and/or clear cell carcinomas. Slides made from tumor tissue microarray blocks were evaluated using immunohistochemical stains with antibodies against MLH1, PMS2, MSH2, and MSH6. Statistical analysis was performed.
RESULTS: Seven of the 90 cases (7.8%) had loss of MMR expression. The mean age of patients with loss of MMR expression (47 years) was significantly younger than those with retained MMR expression (p=0.014). Loss of MMR expression was present in 20% of patients under the age of 53 with clear cell or endometrioid cancers. Genetic studies found that 3 of the 5 patients with loss of MMR expression carried mutations consistent with Lynch Syndrome; acquired hypermethylation of MLH1 was noted in one patient. Six of 7 patients (86%) whose tumors lacked MMR expression had synchronous or metachronous primary malignancies, a significantly greater prevalence than those with retained MMR expression (p<0.001).
CONCLUSION: Patients under the age of 53 with clear cell or endometrioid ovarian carcinomas are at a clinically significant risk for loss of MMR expression and Lynch Syndrome; routine screening with immunohistochemical staining should be considered.

Related: Lynch Syndrome - HNPCC Ovarian Cancer

Worley MJ, Davis M, Berhie SH, et al.
Mucinous differentiation does not impact stage or risk of recurrence among patients with grade 1, endometrioid type, endometrial carcinoma.
Gynecol Oncol. 2014; 135(1):54-7 [PubMed] Related Publications
OBJECTIVE: To evaluate whether the presence of mucinous differentiation influences histopathologic findings, stage distribution, or rate of recurrence among women with grade 1, endometrioid type, endometrial carcinoma.
METHODS: This was a retrospective cohort study of all patients with grade 1, endometrioid type, endometrial carcinoma between January 2005 and December 2012. Patients were separated by the presence or absence of mucinous differentiation and then compared.
RESULTS: Of 655 patients, mucinous differentiation was present in 137 (20.9%) and absent in 518 (79.1%) patients. Compared to the group without mucinous differentiation, the group containing mucinous differentiation was older at diagnosis (mean: 61.1 vs. 58.5 years, OR, 95% CI; 1.03, 1.01-1.05) and more likely to have myometrial invasion (61.3% vs. 51.5%, OR, 95% CI; 1.49, 1.01-2.19). Additional histopathologic findings including: tumor size, cervical stromal invasion, adnexal involvement, LVI and/or the presence of positive lymph nodes were similar between groups. Mucinous differentiation did not affect stage distribution, as most patients were stage 1A (85.4% vs. 86.3%). The median PFS for the entire group has yet to be reached. The mean PFS for the entire study sample was 94.7 months. There was no difference in mean PFS when comparing the group with mucinous differentiation to the group without mucinous differentiation (98 vs. 93.4 months, p=0.07).
CONCLUSIONS: In the setting of grade 1, endometrioid type, endometrial carcinoma, mucinous differentiation is more common in older patients and is associated with an increased likelihood of myometrial invasion. However, stage distribution and risk of recurrence are not affected.

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