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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Menu: Endometrial (Uterus) Cancer

Information for Patients and the Public
Information for Health Professionals / Researchers
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).

Nogami Y, Iida M, Banno K, et al.
Application of FDG-PET in cervical cancer and endometrial cancer: utility and future prospects.
Anticancer Res. 2014; 34(2):585-92 [PubMed] Related Publications
Positron-emission tomography (PET), a diagnostic imaging technique using an agent labeled with a positron-emitting radionuclide, may facilitate improved diagnosis and treatment in gynecological fields. A combined PET/computerized tomography (CT) scan can identify the precise anatomical location of a lesion based on accumulation of (18)F-fluoro-D-glucose (FDG). FDG-PET and PET/CT have been used for detecting metastatic lesions and predicting prognosis in uterine cancer. PET has higher reliability in diagnosing lymph node metastases of uterine cancer than CT or MRI, and is considered most useful among non-invasive diagnostic imaging methods. Accumulation of FDG in lesions is indicative of a poor prognosis. Due to its limited spatial resolution, PET is not suitable has lower utility for detecting small lesions, and is not suitable for early-stage screening, and diagnosing primary lesions. Further improvements in diagnostic technology, including PET/MRI, investigation of new positron tracers, and analysis of data from various combinations of tracers are likely to make PET particularly useful for diagnosis and therapeutic strategy planning.

Related: Cervical Cancer

Visnovsky J, Fiolka R, Kudela E, et al.
Hypermethylation of selected genes in endometrial carcinogenesis.
Neuro Endocrinol Lett. 2013; 34(7):675-80 [PubMed] Related Publications
OBJECTIVES: Endometrial cancer is one of the most common malignancies in women. The prevention has failed so far to develop an effective screening program and its incidence is rising in proportion to the incidence of cervical cancer. In recent years the investigation of malignancy genomics (genetic and epigenetic changes) has become the main focus of scientists because of its high sensitivity and specificity.
MATERIAL AND METHODS: We conducted a prospective longitudinal study at the Dpt. of Gynaecology and Obstetrics of the Jessenius Faculty of Medicine in Martin from 2010 to 2012, in collaboration with the Institute of Pathology of the University Hospital in Martin. We analysed paraffin blocks of endometrial tissue from 123 women with endometrial cancer, hyperplasia and normal endometrial findings. By the use of bisulphidic modification technique and nested methylation-specific PCR (MSP), we analysed the methylation patterns of three genes: GSTP1, E-cad, RASSF1.
RESULTS: We found a statistically significant increase of methylation of the RASSF1 gene in endometrial cancer compared to simplex hyperplasia and intact endometrial tissue (p<0.001). GSTP1 and E-cad did not show any relevant methylation pattern in various endometrial lesions.
CONCLUSION: According to the results of our study, RASSF1 gene methylation could serve as a prognostic factor of endometrial carcinogenesis and could help to predict the behaviour of endometrial hyperplasia.

Related: GSTP1 RASSF1

Faloppa CC, Baiocchi G, Cunha IW, et al.
NF-κB and COX-2 expression in nonmalignant endometrial lesions and cancer.
Am J Clin Pathol. 2014; 141(2):196-203 [PubMed] Related Publications
OBJECTIVES: To examine the immunohistochemical expression of cyclooxygenase-2 (COX-2) and nuclear factor-κB (NF-κB) in benign endometrial polyps (EPs), endometrial hyperplasia (EH), endometrial intraepithelial neoplasia (EIN), and endometrioid endometrial cancer (EC).
METHODS: The immunohistochemical expression of COX-2 and NF-κB was performed using an Aperio Scanscope XT automated system in 218 patients with endometrioid EC and 107 patients with nonmalignant endometrial lesions: 53 with benign EPs, 37 with EH, and 17 with EIN.
RESULTS: COX-2 and NF-κB p50 expression were significantly lower in EC compared with nonmalignant lesions. We observed significant decreased NF-κB p65 expression in EC vs EPs (P < .001) and EH (P = .014) as well as in EIN vs. EPs (P = .01). For patients with EC, COX-2 correlated positively with NF-κB p65 and NF-κB p50 (P < .001). Grade 3 tumors had a higher mean expression of NF-κB p65 (P = .03). NF-κB p50, NF-κB p65, and COX-2 expression had no impact on survival.
CONCLUSIONS: We conclude that COX-2 and NF-κB expression are lower in EC compared with nonmalignant endometrial lesions. COX-2 and NF-κB expression have no prognostic value in EC.

Related: PTGS2

Verma J, Sulman EP, Jhingran A, et al.
Dosimetric predictors of duodenal toxicity after intensity modulated radiation therapy for treatment of the para-aortic nodes in gynecologic cancer.
Int J Radiat Oncol Biol Phys. 2014; 88(2):357-62 [PubMed] Related Publications
PURPOSE: To determine the incidence of duodenal toxicity in patients receiving intensity modulated radiation therapy (IMRT) for treatment of para-aortic nodes and to identify dosimetric parameters predictive of late duodenal toxicity.
METHODS AND MATERIALS: We identified 105 eligible patients with gynecologic malignancies who were treated with IMRT for gross metastatic disease in the para-aortic nodes from January 1, 2005, through December 31, 2009. Patients were treated to a nodal clinical target volume to 45 to 50.4 Gy with a boost to 60 to 66 Gy. The duodenum was contoured, and dosimetric data were exported for analysis. Duodenal toxicity was scored according to Radiation Therapy Oncology Group criteria. Univariate Cox proportional hazards analysis and recursive partitioning analysis were used to determine associations between dosimetric variables and time to toxicity and to identify the optimal threshold that separated patients according to risk of toxicity.
RESULTS: Nine of the 105 patients experienced grade 2 to grade 5 duodenal toxicity, confirmed by endoscopy in all cases. The 3-year actuarial rate of any duodenal toxicity was 11.7%. A larger volume of the duodenum receiving 55 Gy (V55) was associated with higher rates of duodenal toxicity. The 3-year actuarial rates of duodenal toxicity with V55 above and below 15 cm(3) were 48.6% and 7.4%, respectively (P<.01). In Cox univariate analysis of dosimetric variables, V55 was associated with duodenal toxicity (P=.029). In recursive partitioning analysis, V55 less than 13.94% segregated all patients with duodenal toxicity.
CONCLUSIONS: Dose-escalated IMRT can safely and effectively treat para-aortic nodal disease in gynecologic malignancies, provided that care is taken to limit the dose to the duodenum to reduce the risk of late duodenal toxicity. Limiting V55 to below 15 cm(3) may reduce the risk of duodenal complications. In cases where the treatment cannot be delivered within these constraints, consideration should be given to other treatment approaches such as resection or initial chemotherapy.

Related: Ovarian Cancer Cervical Cancer

Elshaikh MA, Vance S, Suri JS, et al.
Improved survival endpoints with adjuvant radiation treatment in patients with high-risk early-stage endometrial carcinoma.
Int J Radiat Oncol Biol Phys. 2014; 88(2):351-6 [PubMed] Related Publications
PURPOSE/OBJECTIVE(S): To determine the impact of adjuvant radiation treatment (RT) on recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival (OS) in patients with high-risk 2009 International Federation of Gynecology and Obstetrics stage I-II endometrial carcinoma.
METHODS AND MATERIALS: We identified 382 patients with high-risk EC who underwent hysterectomy. RFS, DSS, and OS were calculated from the date of hysterectomy by use of the Kaplan-Meier method. Cox regression modeling was used to explore the risks associated with various factors on survival endpoints.
RESULTS: The median follow-up time for the study cohort was 5.4 years. The median age was 71 years. All patients underwent hysterectomy and salpingo-oophorectomy, 93% had peritoneal cytology, and 85% underwent lymphadenectomy. Patients with endometrioid histology constituted 72% of the study cohort, serous in 16%, clear cell in 7%, and mixed histology in 4%. Twenty-three percent of patients had stage II disease. Adjuvant management included RT alone in 220 patients (57%), chemotherapy alone in 25 patients (7%), and chemoradiation therapy in 27 patients (7%); 110 patients (29%) were treated with close surveillance. The 5-year RFS, DSS, and OS were 76%, 88%, and 73%, respectively. On multivariate analysis, adjuvant RT was a significant predictor of RFS (P<.001) DSS (P<.001), and OS (P=.017). Lymphovascular space involvement was a significant predictor of RFS and DSS (P<.001). High tumor grade was a significant predictor for RFS (P=.038) and DSS (P=.025). Involvement of the lower uterine segment was also a predictor of RFS (P=.049). Age at diagnosis and lymphovascular space involvement were significant predictors of OS: P<.001 and P=.002, respectively.
CONCLUSION: In the treatment of patients with high-risk features, our study suggests that adjuvant RT significantly improves recurrence-free, disease-specific, and overall survival in patients with early-stage endometrial carcinoma. Furthermore, adjuvant RT is an independent predictor for RFS, DSS, and OS in this group of patients. These findings need validation from a prospective randomized study.

Ciortea R, Mihu D, Mihu CM
Association between visceral fat, IL-8 and endometrial cancer.
Anticancer Res. 2014; 34(1):379-83 [PubMed] Related Publications
BACKGROUND/AIM: In endometrial cancer, visceral obesity, as a risk factor, is associated with a chronic inflammatory process, confirmed by the elevation of serum inflammatory markers in obese patients. The aim of the present study was to evaluate the correlation between visceral fat, assessed by ultrasonography, and the systemic levels of interleukin (IL)-8 in patients with endometrial cancer. This study also evaluated the usefulness of abdominal ultrasonography in assessing the visceral fat correlated with systemic inflammatory status, as an alternative method to identify patients at risk of endometrial cancer.
MATERIALS AND METHODS: The study was a case-control analysis including two groups of patients: Group I: 44 patients diagnosed with endometrial cancer; group II: 44 patients with no gynecological pathology. The diagnosis of endometrial cancer was performed following histopathological examination that evaluated the tissue material obtained through endometrial biopsy. These patients underwent ultrasound examination by which intraperitoneal fat was determined. IL-8 levels were determined for each patient. The Student's t-test was used for the comparison of the means and the Mann-Whitney test for rank comparison of two independent samples.
RESULTS: In patients diagnosed with endometrial cancer, the visceral fat area evaluated by ultrasound was significantly larger (p<0.0001) compared to that of the control group. The plasma levels of IL-8 in the endometrial cancer group were significantly elevated (p<0.001) compared to the control group. A positive linear correlation was also found between the visceral fat area and plasma levels of IL-8.
CONCLUSION: The plasma levels of IL-8 are positively linearly correlated with visceral fat. Determination of visceral fat in association with IL-8 levels may be a predictive factor for endometrial cancer.

Presl J, Novotny Z, Topolcan O, et al.
CA125 and HE4 levels in a Czech female population diagnosed with endometrial cancer in preoperative management.
Anticancer Res. 2014; 34(1):327-31 [PubMed] Related Publications
AIM: The aim of the present study was to compare the use of cancer antigen 125 (CA125) and human epididymis protein 4 (HE4) biomarkers in patients with endometrial cancer for preoperative management and to particularly focus on relationship between CA125 and HE4 and disease stage in predicting myometrial invasion or intrauterine tumor spread.
PATIENTS AND METHODS: Thirty-four patients diagnosed with endometrial cancer and 32 healthy controls were enrolled into the pilot study in the period between May 2012 and March 2013. Blood from all the females was collected and examined for CA125 and HE4. Based on standardized ultrasound examination, including gynecological examination, the clinical disease stage was determined.
RESULTS: We found a significant difference (p<0.0001) for means of serum levels of HE4: females with endometrial cancer, 75.5 pmol/l, versus healthy females, 40.0 pmol/l. A non-significant statistical difference was found for mean serum CA125 levels (p=0.4442): females with endometrial cancer 19.0 IU/l, versus healthy females, 15 IU/l. A significant correlation with histopathological disease stage was found for both biomarkers (Spearman correlation). Sensitivity and specificity, and the related cut-off for HE4 suggest that HE4 would be a more appropriate biomarker for differential diagnosis between benign and malignant states.
CONCLUSION: Based on our pilot study, we found that parallel examination of HE4 and CA125 may support endometrial ultrasound finding verification prior to biopsy. This study is ongoing and we expect that results on a larger population may enable HE4 measurement to be implemented in routine practice.

Nassir M, Roth A, Gasimli K, et al.
Is endometrial cancer really a neurophobic tumor? A case report and review of the literature.
Anticancer Res. 2014; 34(1):249-57 [PubMed] Related Publications
Brain metastases due to endometrial cancer are rare and usually occur in the context of widespread disease. We present a rare case of a 74-year-old woman with recurrent endometrial cancer in terms of a solitary brain lesion two years after initial diagnosis. She was treated with local resection of the brain metastasis and subsequent whole-brain radiotherapy. She then experienced relapse twice, presenting two solitary metastases at two different time points at the same location as at initial diagnosis, but never showed any signs of extracranial widespread disease. The patient has been alive for 13 months after detection of her initial brain metastasis. Despite the identification of some risk factors, there is still very limited knowledge why some patients develop brain metastases as the only sign of distant spread. Our review of the literature revealed that the combination of two treatment modalities yields higher survival rates than single treatment-alone, as was the case in the presented patient. Further case reports, as well as large and prospective studies, may contribute to a better understanding of the etiology and dynamics of this disease and allow better evaluation of treatment options.

Watrowski R, Möckel J, Venzke T, et al.
Anaplastic pelvic carcinoma secondary to low-grade endometrial carcinoma.
Anticancer Res. 2014; 34(1):239-42 [PubMed] Related Publications
BACKGROUND: Low-grade endometrial carcinoma has an excellent prognosis. The risk of secondary cancer after endometrial carcinoma is moderately increased and is mostly related to the field of postoperative radiation (small intestine, colon, vagina, and urinary bladder). Anaplastic (undifferentiated) pelvic carcinoma (APC) is rare and probably under-reported. To date, only one publication has reported six cases of APC that were secondary to low-grade endometrial carcinoma. Case Report: We have analyzed the fulminant course of APC-preceded by paraneoplastic arthritis-four months after hysterectomy and adnexectomy for low-grade endometrial carcinoma (endometrioid type, moderately differentiated, tumor diameter: 2 cm, infiltration depth 3 of 15 mm). The 73-year-old patient died five weeks after the diagnosis of the second malignancy.
CONCLUSION: The prognosis of APC is poor and the limitations of the therapy result from aggressive tumor biology and rapid deterioration of the patients' general condition. Rheumatological symptoms can precede cancer diagnosis. Immunohistochemistry facilitates the differentiation between primary and secondary carcinoma.

Eifel PJ
The value of pelvic radiation therapy after hysterectomy for early endometrial cancer.
Oncology (Williston Park). 2013; 27(10):990-9 [PubMed] Related Publications
Although endometrial carcinoma is one of the most common cancers affecting women, most cases are detected at an early stage and are cured with hysterectomy alone. Most recurrences occur in the relatively small subset of patients whose surgical specimens reveal multiple risk factors. Clinicians have sought to define adjuvant treatments that can improve the outcome of treatment for these higher-risk patients. Although randomized trials have demonstrated that radiation therapy improves local control, they have failed to demonstrate an improvement in survival with radiation therapy. In this review, the results and limitations of studies concerning adjuvant radiation therapy and chemotherapy for endometrial cancer will be discussed, focusing on evidence that can help to guide treatment decisions.

Stemme S, Ghaderi M, Carlson JW
Diagnosis of endometrial stromal tumors: a clinicopathologic study of 25 biopsy specimens with identification of problematic areas.
Am J Clin Pathol. 2014; 141(1):133-9 [PubMed] Related Publications
OBJECTIVES: To assess the difficulties associated with diagnosing endometrial stromal tumors (ESTs) on endometrial biopsy.
METHODS: We examined 25 endometrial biopsy specimens from 19 consecutive women diagnosed with either endometrial stromal nodule (n = 3) or endometrial stromal sarcoma (n = 16).
RESULTS: Rereview of the biopsy specimens revealed a stromal fragment suspicious for an EST in 16, of which eight had received a benign diagnosis on initial review. Most ESTs had an aglandular stromal fragment that was 5 mm or larger. Stromal fragments of this size were not encountered in the control material. Problematic areas included highly cellular leiomyoma and a lack of attention to the stromal compartment.
CONCLUSIONS: Most endometrial stromal tumors present with large aglandular stromal fragments (≥5 mm). These fragments are large enough that difficulties in diagnosis appear to be due to a lack of attention to the stromal compartment.

Supernat A, Lapinska-Szumczyk S, Majewska H, et al.
Epithelial-mesenchymal transition and cancer stem cells in endometrial cancer.
Anticancer Res. 2013; 33(12):5461-9 [PubMed] Related Publications
BACKGROUND/AIM: Epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs) are presumed to be key conditions for malignancy. Data concerning their role in endometrial cancer (EC) are scarce. We aimed to investigate the possible link between EMT and CSCs markers in EC samples.
MATERIALS AND METHODS: The study encompassed 156 primary tumour samples. Using RT-qPCR, we analyzed the expression of EMT-related genes, SNAIL and SLUG, and the CSCs marker CD133.
RESULTS: SNAIL and SLUG correlated with each other (R=0.33; p=0.00003). All the studied genes were expressed in both normal and malignant endometrial tissue. Decreased SNAIL expression was found to correlate with post-menopausal status (p=0.002). Decreased SLUG expression was associated with shorter overall survival (p=0.01).
CONCLUSION: SLUG expression could serve as a prognostic factor in EC. No correlation between the expression of EMT and CSCs markers was found, suggesting there to be no association between the EMT and CSC phenotype in endometrial cancer.

Buchanan DD, Tan YY, Walsh MD, et al.
Tumor mismatch repair immunohistochemistry and DNA MLH1 methylation testing of patients with endometrial cancer diagnosed at age younger than 60 years optimizes triage for population-level germline mismatch repair gene mutation testing.
J Clin Oncol. 2014; 32(2):90-100 [PubMed] Related Publications
PURPOSE: Clinicopathologic data from a population-based endometrial cancer cohort, unselected for age or family history, were analyzed to determine the optimal scheme for identification of patients with germline mismatch repair (MMR) gene mutations.
PATIENTS AND METHODS: Endometrial cancers from 702 patients recruited into the Australian National Endometrial Cancer Study (ANECS) were tested for MMR protein expression using immunohistochemistry (IHC) and for MLH1 gene promoter methylation in MLH1-deficient cases. MMR mutation testing was performed on germline DNA of patients with MMR-protein deficient tumors. Prediction of germline mutation status was compared for combinations of tumor characteristics, age at diagnosis, and various clinical criteria (Amsterdam, Bethesda, Society of Gynecologic Oncology, ANECS).
RESULTS: Tumor MMR-protein deficiency was detected in 170 (24%) of 702 cases. Germline testing of 158 MMR-deficient cases identified 22 truncating mutations (3% of all cases) and four unclassified variants. Tumor MLH1 methylation was detected in 99 (89%) of 111 cases demonstrating MLH1/PMS2 IHC loss; all were germline MLH1 mutation negative. A combination of MMR IHC plus MLH1 methylation testing in women younger than 60 years of age at diagnosis provided the highest positive predictive value for the identification of mutation carriers at 46% versus ≤ 41% for any other criteria considered.
CONCLUSION: Population-level identification of patients with MMR mutation-positive endometrial cancer is optimized by stepwise testing for tumor MMR IHC loss in patients younger than 60 years, tumor MLH1 methylation in individuals with MLH1 IHC loss, and germline mutations in patients exhibiting loss of MSH6, MSH2, or PMS2 or loss of MLH1/PMS2 with absence of MLH1 methylation.

Related: Australia Cancer Screening and Early Detection MSH6 MSH2

Kir G, Yilmaz MS, Çetiner H, et al.
Significance of foamy histiocytes in cervical smears from postmenopausal women.
Acta Cytol. 2014; 58(1):42-6 [PubMed] Related Publications
OBJECTIVE: To determine the significance of the presence of foamy histiocytes (FH) in postmenopausal cervicovaginal smears for the detection of endometrial carcinomas (EC).
STUDY DESIGN: Endometrial sampling was performed over 6 months in 53 of 102 cases that presented with postmenopausal FH, benign endometrial cells (BEC), FH with BEC (FH + BEC), and atypical endometrial cells (AEC), resulting in a total of 41,150 cervicovaginal smears. The control group consisted of 58 cases with a cytologic diagnosis of a normal smear (NS).
RESULTS: There were 0 (0%), 1 (4.54%), 2 (13.33%), 2 (33.33%), and 5 (50.00%) cases of EC diagnosed on histopathologic evaluation in patients with NS (n = 58), BEC (n = 22), FH (n = 15), FH + BEC (n = 6), and AEC (n = 10), respectively. The sensitivities and specificities of the cytologic diagnoses of FH, FH + BEC, and AEC for the detection of EC were 81.7 and 100%, 93.6 and 100%, and 92.1 and 100%, respectively.
CONCLUSION: The cytologic diagnoses of FH and FH + BEC had reasonably high sensitivities and specificities for the diagnosis of EC by cervicovaginal smear. Additional studies are needed.

Wimmer JL, Coffey DM, Kaplan AL, et al.
Tumor-to-tumor metastasis with endometrial carcinoma metastatic to squamous cell carcinoma of vulva: the first reported case.
Arch Pathol Lab Med. 2013; 137(12):1825-8 [PubMed] Related Publications
Endometrial carcinoma metastasizing to the vulva is a rare occurrence, with only 15 reported cases in the literature. To our knowledge, no cases of tumor-to-tumor metastasis involving endometrial carcinoma as a donor tumor have ever been published. We report the first case of an endometrial carcinoma as a donor tumor metastasizing to a squamous cell carcinoma of the vulva, a recipient tumor. A 79-year-old woman with a history of endometrioid adenocarcinoma of the uterus presented with a vulvar lesion. Pathologic examination of the excised lesion confirmed the presence of metastatic endometrioid adenocarcinoma; however, it was found within a well-differentiated squamous cell carcinoma of the vulva. Surrounding the squamous cell carcinoma was a background of a high-grade vulvar intraepithelial lesion (vulvar intraepithelial neoplasia 3), and immunohistochemistry confirmed the presence of 2 separate tumors involved in a tumor-to-tumor metastasis. This unique case highlights the importance of awareness of the phenomenon, and expands the current spectrum of tumor-to-tumor metastases.

Elit LM, O'Leary EM, Pond GR, Seow HY
Impact of wait times on survival for women with uterine cancer.
J Clin Oncol. 2014; 32(1):27-33 [PubMed] Related Publications
PURPOSE: To determine whether wait time from histologic diagnosis of uterine cancer to time of definitive surgery by hysterectomy had an impact on all-cause survival.
PATIENTS AND METHODS: Women in Ontario with a confirmed histopathologic diagnosis of uterine cancer between April 1, 2000, and March 31, 2009, followed by surgery were identified in the Ontario Cancer Registry. Survival was calculated by using the Kaplan-Meier method. Factors were evaluated for their prognostic effect on survival by using Cox proportional hazards regression. Wait time was evaluated in a multivariable model after adjusting for other significant factors.
RESULTS: The final study population included 9,417 women; 51.9% had surgery by a gynecologist, and 69.9% had endometrioid adenocarcinoma. Five-year survival for women with wait times of 0.1 to 2, 2.1 to 6, 6.1 to 12, or more than 12 weeks was 71.1%, 81.8%, 79.5%, and 71.9%, respectively. Wait times of ≤ 2 weeks were adversely prognostic for survival after adjusting for other significant factors in the multivariable model, and patients with wait times of more than 12 weeks had worse survival than those who had wait times between 2.1 and 12.0 weeks.
CONCLUSION: To the best of our knowledge, this is the first report in a large population-based cohort demonstrating that longer wait times from diagnosis of uterine cancer to definitive surgery have a negative impact on overall survival.

Moon HS, Mantzoros CS
Regulation of cell proliferation and malignant potential by irisin in endometrial, colon, thyroid and esophageal cancer cell lines.
Metabolism. 2014; 63(2):188-93 [PubMed] Related Publications
OBJECTIVE: Irisin is a novel hormone that has been proposed to mediate the beneficial effects of exercise on metabolism, including body weight regulation and insulin resistance. No previous studies have evaluated whether irisin may regulate cell proliferation and malignant potential of obesity-related cancer cell lines.
MATERIALS/METHODS: Cell proliferation and malignant potential i.e. cell adhesion and colony formation were studied in vitro using human and mouse obesity-related cancer cell lines i.e. endometrial (KLE and RL95-2), colon (HT29 and MCA38), thyroid (SW579 and BHP7) and esophageal (OE13 and OE33).
RESULTS: We observed that, in contrast to metformin, cell proliferation is not regulated by irisin in a dose-dependent manner in human and mouse obesity-related cancer cell lines. Specifically, physiological (5 to 10 nmol/L) and high physiological/pharmacological (50 to 100 nmol/L) concentrations of irisin had no effect on cell proliferation when compared to control in human and mouse endometrial, colon, thyroid and esophageal cancer cell lines. Also, we observed that, in contrast to metformin, neither physiological nor high physiological/pharmacological concentrations of irisin regulate cell adhesion and/or colony formation in human and mouse endometrial, colon, thyroid and esophageal cancer cell lines.
CONCLUSIONS: Our data suggest that irisin, in physiological and high physiological/pharmacological concentrations, has no in vitro effect on cell proliferation and malignant potential of obesity-related cancer cell lines. Future work is needed to determine the regulation of irisin levels and any physiological effects it may have on obesity-related cancers in vivo in animals and humans.

Related: Cancer of the Esophagus Esophageal Cancer Thyroid Cancer

Kaizu H, Ogino I, Hata M, et al.
Chemoradiation as a definitive treatment for cervical lymph node metastases from unknown primary cancer.
Anticancer Res. 2013; 33(11):5187-92 [PubMed] Related Publications
AIM: To assess the treatment outcomes of chemoradiation for cervical lymph node metastases from an unknown primary site (CUP), and to identify for prognostic factors.
PATIENTS AND METHODS: Thirty patients diagnosed as having CUP, and receiving chemoradiation as a definitive treatment were included in the analysis. Locoregional control (LRC), disease-free survival (DFS), and overall survival (OS) rates were estimated, and the factors affecting treatment outcomes were analyzed.
RESULTS: After a median follow-up period of 25 months for surviving patients, the two- and five-year LRC, DFS, and OS rates were 56%/45%, 46%/36%, and 69%/52%, respectively. On univariate analysis, lower performance status (PS; p=0.001), and limitation of disease to level 2 or 3 lymph nodes (p=0.009) were significantly associated with better DFS. Low PS (p=0.002) was significantly associated with better LRC. No late toxicity of grade 3 or greater was observed.
CONCLUSION: Definitive chemoradiation for CUP was well-tolerated, with improvement of DFS/LRC for those with good PS and disease limited to level 2 or 3 lymph nodes.

Related: Cancer of Unknown Primary

González-Rodilla I, Aller L, Llorca J, et al.
The E-Cadherin expression vs. tumor cell proliferation paradox in endometrial cancer.
Anticancer Res. 2013; 33(11):5091-5 [PubMed] Related Publications
BACKGROUND: E-Cadherin is a putative marker of good prognosis in endometrial cancer. Paradoxically, in a previous study of endometrial carcinoma we found that E-Cadherin is significantly co-expressed with molecular markers of proliferation, usually associated with a worse prognosis in most tumor types.
PATIENTS AND METHODS: The expression of estrogen (ER) and progesterone receptors (PR), Ki67, Human Epidermal Growth Factor Receptor 2 (HER-2, c-ERB-B2), p53 and E-Cadherin was studied by means of immunohistochemistry in 126 endometrial carcinoma samples. The results were correlated with patient survival and included in a multivariate model, in order to identify factors independently associated with the patient outcome.
RESULTS: E-Cadherin overexpression was associated with a significantly better overall survival in the whole group of patients with endometrial carcinoma (p=0.012), as well as in the group of patients exclusively harboring endometrioid tumors (p=0.004). In a restricted multivariate model, only tumor stage and E-Cadherin expression retained their independent prognostic power, both for the whole group of tumors (p=0.04), as well as for the subgroup of endometrioid carcinomas (p=0.05).
CONCLUSION: E-Cadherin is an independent predictor of survival in endometrial carcinoma, regardless of histological variety. Proliferation, on the other hand, does not seem to play a prominent role in this same context. This may explain why E-Cadherin retains its prognostic power, despite being significantly co-expressed with all tested molecular proliferation markers.

Related: MKI67 TP53

Elshaikh MA, Ruterbusch J, Cote ML, et al.
Improved survival of baby boomer women with early-stage uterine cancer: A Surveillance, Epidemiology and End Results (SEER) Study.
Anticancer Res. 2013; 33(11):4983-7 [PubMed] Related Publications
AIM: To study the prognostic impact of baby boomer (BB) generation on survival end-points of patients with early-stage endometrial carcinoma (EC).
PATIENTS AND METHODS: Data were obtained from the SEER registry between 1988-2009. Inclusion criteria included women who underwent hysterectomy for stage I-II EC. Patients were divided into two birth cohorts: BB (women born between 1946 and 1964) and pre-boomers (PB) (born between 1926 and 1945).
RESULTS: A total of 30,956 patients were analyzed. Considering that women in the PB group were older than those of the BB generation, the statistical analysis was limited to women 50-59 years of age at the time of diagnosis (n=11,473). Baby boomers had a significantly higher percentage of endometrioid histology (p<0.0001), higher percentage of African American women (p<0.0001), lower tumor grade (p<0.0001), higher number of dissected lymph nodes (LN) (p<0.0001), and less utilization of adjuvant radiation therapy (p=0.0003). Overall survival was improved in women in the BB generation compared to the PB generation (p=0.0003) with a trend for improved uterine cancer-specific survival (p=0.0752). On multivariate analysis, birth cohort (BB vs. PB) was not a significant predictor of survival end-points. Factors predictive of survival included: tumor grade, FIGO stage, African-American race, and increased number of dissected LN.
CONCLUSION: Our study suggests that the survival of BB women between 50-60 years of age is better compared to women in the PB generation. As more BB patients are diagnosed with EC, further research is warranted.

Tirumani SH, Shanbhogue AK, Prasad SR
Current concepts in the diagnosis and management of endometrial and cervical carcinomas.
Radiol Clin North Am. 2013; 51(6):1087-110 [PubMed] Related Publications
Cross-sectional imaging modalities play a pivotal role in the diagnosis and multidisciplinary management of patients with endometrial and cervical carcinomas. Ultrasonography, including sonohysterography, permits evaluation of endometrial abnormalities and characterization of adnexal masses. Computed tomography, particularly in conjunction with (18)(F)-fluorodeoxyglucose positron emission tomography, is increasingly used to stage the cancers and to detect disease recurrence. Magnetic resonance imaging plays a major role in accurate locoregional staging of these cancers, and significantly influences treatment decisions and outcomes. This article discusses the role of imaging modalities in the diagnosis, management, and surveillance of these cancers.

Related: Cervical Cancer

Kim TM, Laird PW, Park PJ
The landscape of microsatellite instability in colorectal and endometrial cancer genomes.
Cell. 2013; 155(4):858-68 [PubMed] Article available free on PMC after 07/11/2014 Related Publications
Microsatellites-simple tandem repeats present at millions of sites in the human genome-can shorten or lengthen due to a defect in DNA mismatch repair. We present here a comprehensive genome-wide analysis of the prevalence, mutational spectrum, and functional consequences of microsatellite instability (MSI) in cancer genomes. We analyzed MSI in 277 colorectal and endometrial cancer genomes (including 57 microsatellite-unstable ones) using exome and whole-genome sequencing data. Recurrent MSI events in coding sequences showed tumor type specificity, elevated frameshift-to-inframe ratios, and lower transcript levels than wild-type alleles. Moreover, genome-wide analysis revealed differences in the distribution of MSI versus point mutations, including overrepresentation of MSI in euchromatic and intronic regions compared to heterochromatic and intergenic regions, respectively, and depletion of MSI at nucleosome-occupied sequences. Our results provide a panoramic view of MSI in cancer genomes, highlighting their tumor type specificity, impact on gene expression, and the role of chromatin organization.

Related: Colorectal (Bowel) Cancer

Tafe LJ, Riggs ER, Tsongalis GJ
Lynch syndrome presenting as endometrial cancer.
Clin Chem. 2014; 60(1):111-21 [PubMed] Related Publications
BACKGROUND: Lynch syndrome (LS) is the most common form of the hereditary colon cancer syndromes. Because of its high prevalence, a nationwide campaign has begun to screen all colorectal cancers for the genetic abnormalities associated with LS.
CONTENT: Next to colorectal cancer, endometrial cancer is the most common form of malignancy found in women with LS. Identifying individuals who harbor the well-characterized mismatch-repair gene mutations via immunohistochemistry, microsatellite instability analysis, or direct gene sequencing is critical to managing the LS patient and to surveillance for the development of other associated tumor types.
SUMMARY: Although many institutions have begun screening all colorectal tumors for LS, the evidence is sufficient to warrant the testing of all endometrial cancers for LS as well. Various testing algorithms, along with genetic-counseling efforts, can lead to a cost-efficient and beneficial screening program.

Mittal K, Salem A, Lo A
Diagnostic criteria for distinguishing endometrial adenocarcinoma from complex atypical endometrial hyperplasia.
Hum Pathol. 2014; 45(1):98-103 [PubMed] Related Publications
Morphologic criteria for distinguishing endometrial adenocarcinoma from complex atypical endometrial hyperplasia have been described previously, but they have not been examined extensively for their individual ability for predicting endometrial adenocarcinoma as determined by subsequent hysterectomy. We examined endometrial biopsies diagnosed in the spectrum of complex atypical endometrial hyperplasia to well-differentiated endometrial adenocarcinoma for various morphologic features that may be predictive for the presence of myoinvasive endometrial adenocarcinoma in subsequent hysterectomy. Cases diagnosed as FIGO grade I endometrial adenocarcinoma or complex atypical endometrial hyperplasia in endometrial biopsies seen at New York University Medical Center from 2003 to 2006 were analyzed for the presence of various morphologic features without the knowledge of hysterectomy findings. Only those cases with subsequent hysterectomy were included in the study. The data were analyzed to identify features with high specificity for a finding of myoinvasive endometrial adenocarcinoma in subsequent hysterectomy. Extreme glandular crowding (95% or greater area with glands, aggregate size 3 mm or greater) and cribriform foci of any size were found to have high sensitivity and specificity for the finding of myoinvasive carcinoma in subsequent hysterectomy (P < .0001).

Fisher C, Mo A, Warrillow S, et al.
Utility of thromboelastography in managing acquired Factor VIII inhibitor associated massive haemorrhage.
Anaesth Intensive Care. 2013; 41(6):799-803 [PubMed] Related Publications
Disorders of clotting and coagulation are common in the intensive care unit. Diagnosis, treatment and monitoring of these disorders are traditionally based on conventional coagulation tests such as activated partial thromboplastin time (APTT) and international normalised ratio (INR). We present here a patient who developed massive postoperative haemorrhage secondary to an acquired factor VIII inhibitor. The case highlights the utility and sensitivity of thromboelastography (TEG) in the diagnosis of the condition and monitoring the response to therapy.

Haldorsen IS, Stefansson I, Grüner R, et al.
Increased microvascular proliferation is negatively correlated to tumour blood flow and is associated with unfavourable outcome in endometrial carcinomas.
Br J Cancer. 2014; 110(1):107-14 [PubMed] Article available free on PMC after 07/01/2015 Related Publications
BACKGROUND: We aimed to study the angiogenic profile based on histomorphological markers in endometrial carcinomas in relation to imaging parameters obtained from preoperative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and diffusion-weighted imaging (DWI) and to explore the potential value of these markers to identify patients with poor outcome.
METHODS: In fifty-four surgically staged endometrial carcinoma patients, immunohistochemical staining with factor VIII and Ki67 allowed assessment of microvessel density (MVD) and microvascular proliferation reflecting tumour angiogenesis. In the same patients, preoperative pelvic DCE-MRI and DWI allowed the calculation of parameters describing tumour microvasculature and microstructure in vivo.
RESULTS: Microvascular proliferation was negatively correlated to tumour blood flow (Fb) (r=-0.36, P=0.008), capillary permeability surface area product (PS) (r=-0.39, P=0.004) and transfer from the blood to extravascular extracellular space (EES) (Ktrans) (r=-0.40, P=0.003), and was positively correlated to tumour volume (r=0.34; P=0.004). High-tumour microvascular proliferation, low Fb and low Ktrans were all significantly associated with reduced progression/recurrence-free survival (P<0.05).
CONCLUSION: Disorganised angiogenesis with coexisting microvascular proliferation and low tumour blood flow is a poor prognostic factor supporting that hypoxia is associated with progression and metastatic spread in endometrial carcinomas.

Related: Angiogenesis and Cancer

Cardenas-Goicoechea J, Shepherd A, Momeni M, et al.
Survival analysis of robotic versus traditional laparoscopic surgical staging for endometrial cancer.
Am J Obstet Gynecol. 2014; 210(2):160.e1-160.e11 [PubMed] Related Publications
OBJECTIVE: The purpose of this study was to compare the survival of women with endometrial cancer managed by robotic- and laparoscopic-assisted surgery.
STUDY DESIGN: This was a retrospective study conducted at 2 academic centers. Primary outcomes were overall survival, disease-free survival (DFS), and disease recurrence.
RESULTS: From 2003 through 2010, 415 women met the study criteria. A total of 183 women had robotic and 232 women had laparoscopic-assisted surgery. Both groups were comparable in age, body mass index, comorbid conditions, histology, surgical stage, tumor grade, total nodes retrieved, and adjuvant therapy. With a median follow-up of 38 months (range, 4-61 months) for the robotic and 58 months (range, 4-118 months) for the traditional laparoscopic group, there were no significant differences in survival (3-year survival 93.3% and 93.6%), DFS (3-year DFS 83.3% and 88.4%), and tumor recurrence (14.8% and 12.1%) for robotic and laparoscopic groups, respectively. Univariate and multivariate analysis showed that surgery is not an independent prognostic factor of survival.
CONCLUSION: Robotic-assisted surgery yields equivalent oncologic outcomes when compared to traditional laparoscopic surgery for endometrial adenocarcinoma.

Le Gallo M, Bell DW
The emerging genomic landscape of endometrial cancer.
Clin Chem. 2014; 60(1):98-110 [PubMed] Related Publications
BACKGROUND: Endometrial cancer is responsible for approximately 74 000 deaths annually among women worldwide. It is a heterogeneous disease comprising multiple histologic subtypes. In the US, the majority of deaths from endometrial carcinoma are attributed to the serous and endometrioid subtypes. An understanding of the fundamental genomic alterations that drive serous and endometrioid endometrial carcinomas lays the foundation for the identification of molecular markers that could improve the clinical management of patients presenting with these tumors.
CONTENT: We review the current state of knowledge regarding somatic genomic alterations that occur in serous and endometrioid endometrial tumors. We present this knowledge in a historical context by reviewing the genomic alterations that studies of individual genes and proteins have identified over the past 2 decades or so. We then review very recent comprehensive and systematic surveys of genomic, exomic, transcriptomic, epigenomic, and proteomic alterations in serous and endometrioid endometrial carcinomas.
SUMMARY: The recent mapping of the genomic landscape of serous and endometrioid endometrial carcinomas has produced the first comprehensive molecular classification of these tumors, which has distinguished 4 molecular subgroups: a POLE [polymerase (DNA directed), ε, catalytic subunit] ultramutated subgroup, a hypermutated/microsatellite-unstable subgroup, a copy number-low/microsatellite-stable subgroup, and a copy number-high subgroup. This molecular classification may ultimately serve to refine the diagnosis and treatment of women with endometrioid and serous endometrial tumors.

Wei JJ, Paintal A, Keh P
Histologic and immunohistochemical analyses of endometrial carcinomas: experiences from endometrial biopsies in 358 consultation cases.
Arch Pathol Lab Med. 2013; 137(11):1574-83 [PubMed] Related Publications
CONTEXT: Uterine serous carcinoma is biologically more aggressive than the endometrioid carcinoma. Because uterine serous carcinoma has a high propensity for lymphovascular invasion and intraperitoneal and extra-abdominal spread, accurate diagnosis of this tumor type in endometrial biopsies/curettings is critical for appropriate clinical management.
OBJECTIVE: To share our experience in the evaluation of endometrial biopsy specimens in type I and type II endometrial adenocarcinoma.
DESIGN: We retrospectively reviewed 358 biopsies containing endometrial carcinoma during a recent 3 year period of our consultation records. In cases in which our interpretation differed from the submitting diagnosis, a panel of immunostains was performed. The performance characteristics of each antibody in our panel was calculated in this group of challenging cases.
RESULTS: Among the endometrial carcinomas we examined, a diagnosis of type I carcinoma accounted for 91% of cases (327 of 358) and type II carcinoma for 9% of cases (31 of 358); 41 cases (11.5%) were ambiguous or discordant (differing from submitted diagnoses and reviewed) based on histology alone. All 41 ambiguous and discordant cases were further evaluated with a battery of immunohistochemical markers. Of the 41 cases, 36 (88%) were ultimately classified (10 cases [24%] were endometrioid carcinoma; 18 cases [44%] were uterine serous carcinoma; 8 cases [20%] resulted in various other outcomes) and 5 cases (12%) remained indeterminate.
CONCLUSIONS: Making the distinction between type I and II endometrial carcinoma remains a common problem in general practice. Although no one biomarker provides excellent statistical performance, a panel of immunohistochemical markers is often useful in difficult cases.

Related: TP53

Kang MY, Sykes P, Herbison PY, Petrich S
Retrospective analysis on timeframes of referral, diagnosis and treatment of patients with endometrial carcinomas in Dunedin Hospital, 2008-2011.
N Z Med J. 2013; 126(1384):84-95 [PubMed] Related Publications
AIM: To quantify time taken for patients diagnosed and treated for endometrial cancer in Dunedin Hospital in context of Ministry of Health New Zealand (MoHNZ) best practice indicators for cancer diagnosis and treatment, and to identify factors which could potentially cause delays if present.
METHOD: Retrospective audit was carried out based on patients discussed at a Gynaecology-Oncology Multi-Disciplinary Meeting (GOMDM) at Dunedin Hospital during 2008-2011 for primary endometrial cancer. Median time taken between referral dates, first specialist appointment, date of histological diagnosis, staging scan, date when patients were waitlisted for surgery, and date of first treatment were calculated. Possible factors which could contribute to delay if present were identified and further explored.
RESULT: 44 eligible patients were identified. Compared to MoHNZ recommendations delays were present from initial referral to first treatment (93 days actual timeframe vs. 62 days recommended timeframe) and some delays present from initial referral to first specialist assessment (21 days vs. 14 days), with only 20% and 32% of patients being seen and treated within the best practice timeframes respectively. Patients were treated within the recommended time once they were wait-listed for first definitive treatment (19 days vs. 31 days) with 75% of patients being treated within the recommended timeframe. Waiting time for hysteroscopy and dilatation and curettage was seen to contribute towards considerably longer delays in diagnosis and treatment of endometrial cancers. Other potential factors contributing to delay identified were patients not attending clinic appointments and difficulty in obtaining a conclusive histological sample through pipelle biopsy at the initial clinic visit.
CONCLUSION: Currently the practice in Dunedin Hospital does not meet the planned MoHNZ standards, and significant changes in practice and reallocation of resource will be required to meet the MOH standards for women with endometrial cancer. Training of General Practitioners in pipelle biopsy, better patient education about post-menopausal bleeding, reducing the time taken for radiological scans, and expediting referrals to the first specialist appointment and hysteroscopy for patients with high suspicion, could reduce delays.

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