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The present article summarises the relevant aspects of the S3 guidelines on endometrioid carcinomas. The recommendations include the processing rules of fractional currettings as well as for hysterectomy specimens and lymph node resections (including sentinel lymph nodes). Besides practical aspects, the guidelines consider the needs of the clinicians for appropriate surgical and radiotherapeutic treatment of the patients. Carcinosarcomas are assigned to the endometrial carcinoma as a special variant. For the first time, an algorithmic approach for evaluation of the tumour tissue for Lynch syndrome is given. Prognostic factors based on morphologic findings are summarised.

Purpose: The available literature on the treatment options for recurrent or metastatic endometrial cancer (EC) is full of controversies. Therefore, we explore the results of the AGO pattern of care studies from the years 2013, 2009 and 2006., Methods: A questionnaire was developed and sent to all 682 German gynecological departments in 2013 (775 in 2009, 500 in 2006, respectively). The results of the questionnaires were compared with each other using Fisher's exact test., Results: Responses were available in 40.0 % in 2013, 33.3 % in 2009 and 35.8 % in 2006. In 2013 the most preferred endocrine drug was progestin (79.8 %), followed by tamoxifen (42.8 %), aromatase inhibitor (19.8 %), fulvestrant (16.3 %) and a combination (3.9 %) (p < 0.001). 65.3, 59.8, 51.7 and 38.2 % of the participants used platinum, taxane, a combination of cytostatic drugs, anthracycline in metastatic EC, respectively (p = 0.215). 96.2, 92.7, 49.8 and 60.9 % of the participants performed an operation, radiotherapy, endocrine therapy and chemotherapy in 2013 because of a local recurrence, respectively (p < 0.001). Compared to 2009 and 2006 these rates remained stable (no p value <0.05). Because of a distant metastasis 50.4, 64.2, 78.5 and 90.8 % of the participants performed an operation, radiotherapy, endocrine therapy and chemotherapy in 2013, respectively (p < 0.001). Compared to 2009 and 2006 more participants performed an operation or radiotherapy and less an endocrine treatment., Conclusions: Whereas progestin was the favorite drug, the participants of this study did not prefer a specific cytostatic drug for metastatic EC in 2013. This might have reflected the available literature, which did not provide a real standard of care.

Purpose: In 2013, 2009 and 2006, the Arbeitsgemeinschaft Gynäkologische Onkologie evaluated the therapeutic approaches for endometrial carcinoma and the adherence to their guideline in Germany. Here, the adjuvant treatment decisions were presented., Methods: A questionnaire was developed and sent to all 682 German gynecological departments in 2013 (775 in 2009 and 500 in 2006, respectively). The results of the questionnaires were compared with the recommendations of the guideline and with each other using Fisher's exact test., Results: Responses were available in 40.0 % in 2013, 33.3 % in 2009 and 35.8 % in 2006. Participants recommended external beam radiotherapy (EBRT) in 13 out of 16 requested stages and vaginal brachytherapy (VBT) in only 10 out of 16 requested stages as suggested by the guideline. Comparing the results of 2013 with 2009, less participants used EBRT and VBT in 7 out of 16 and in 6 out of 16 requested stages, respectively. Conversely, more participants offered adjuvant chemotherapy (CT) in 2013 (90.4 %) compared to 61.9 % in 2009 (p < 0.001) and 48.8 % in 2006 (p < 0.001), respectively. However, the stage-adjusted recommendations of CT were not in line with the guideline in 11 out of 15 requested stages. In total, 77.3 % of the participants use a multiple drug schedule with a platinum and a taxane compound., Conclusions: The results suggest non-adherence to the guideline concerning the stage-adjusted use of VBT and CT in endometrial carcinoma. These findings emphasize great uncertainties and the need of more clarifying trials. Furthermore, a shift from radiotherapy toward CT is observable.

Purpose: In 2013, 2009, and 2006, the Arbeitsgemeinschaft Gynäkologische Onkologie evaluated the therapeutic approaches and the adherence to their guidelines for endometrial carcinoma (EC) in Germany. Here, we present the results concerning the surgical procedures., Methods: A questionnaire was developed and sent to 682 German gynecological departments in 2013 (775 in 2009 and 500 in 2006). The results were compared with the recommendations of the guideline and with each other., Results: Responses were available in 40.0 % in 2013, 33.3 % in 2009, and 35.8 % in 2006, respectively. Pelvic lymphadenectomy (LAN) was performed in accordance with the guidelines with some exceptions in 2013, 2009, and 2006, whereas paraaortic LAN was performed in accordance with the guideline only in 2009. Histological high-risk subtypes of EC received pelvic and paraaortic LAN in 2013, 2009, and 2006 in accordance with the guidelines with small exceptions. LAN for Patients, who were postoperatively upstaged or upgraded, was not conducted in accordance with the guidelines in 2013, 2009, and 2006. In 2013, 84.6 % of the participants offered the laparoscopic approach (LSA) for hysterectomy and bilateral salpingo-oophorectomy, 63.3 % for pelvic LAN, and 49.1 % for paraaortic LAN, respectively. More participants offered the LSA in 2013 compared to 2009 and 2006 (p values <0.014)., Conclusions: The paraaortic LAN, the LSA as well as the second operation on patients who had postoperatively been upstaged were not conducted in accordance with the guideline [CORRECTED]. Improvements concerning surgical treatment are possible and might lead to higher survival rates and a reduction of morbidity in patients with EC in Germany.

Objective: In 2009 and 2006, the Arbeitsgemeinschaft Gynäkologische Onkologie evaluated therapeutic approaches for endometrial carcinoma (EC) in Germany., Methods and Materials: A questionnaire was developed and sent to 775 German gynecologic departments in 2009 (500 in 2006). The results of the questionnaires were compared with each other and with the recommendations of the Arbeitsgemeinschaft Gynäkologische Onkologie's guideline. Subgroup analyses were performed, dividing the participating centers into small and large centers and into centers with less and more experience with EC., Results: Responses were available in 33.3% in 2009 and 35.8% in 2006. Comparing 2009 with 2006, it became apparent that peritoneal washing cytology was performed in 94.6% versus 86.9% (P = 0.008), pelvic lymphadenectomy (LAN) in 98.3% versus 95.3%, and paraaortic LAN in 90.2% versus 73.8% (P < 0.001) for endometrioid EC, and LAN for histologic high-risk subtypes of EC in 99.6% versus 94.2% (P = 0.001), respectively. In 2009, all these criteria met the recommendation of the guidelines. Reoperation for LAN after postoperative upstaging was performed in 66.1% versus 50.6% (P = 0.002), and adjuvant systemic treatment with chemotherapy and endocrine therapy was performed in 63.7% versus 48.8% (P = 0.003) and 25.7% versus 15.4% (P = 0.014), respectively. This showed nonadherence to the guidelines. Laparoscopic approach was performed in 30.4% versus 19.7% (P = 0.014) of the participating centers, respectively. In subgroup analysis, laparoscopic approach showed a significant difference between small centers (11.5%) and large centers (27.3%) in 2006 (P = 0.012)., Conclusions: German hospitals increasingly follow the guidelines concerning LAN and peritoneal washing cytology. However, recommendations concerning reoperating in upstaged patients and adjuvant treatment decisions do not meet the guidelines, thus underlining great uncertainties in this field of gynecologic oncology.

Metastasis from primary tumors remains a major problem for tumor therapy. In the search for markers of metastasis and more effective therapies, the tumor metabolome is relevant because of its importance to the malignant phenotype and metastatic capacity of tumor cells. Altered choline metabolism is a hallmark of cancer. More specifically, a decreased glycerophosphocholine (GPC) to phosphocholine (PC) ratio was reported in breast, ovarian, and prostate cancers. Improved strategies to exploit this altered choline metabolism are therefore required. However, the critical enzyme cleaving GPC to produce choline, the initial step in the pathway controlling the GPC/PC ratio, remained unknown. In the present work, we have identified the enzyme, here named EDI3 (endometrial differential 3). Purified recombinant EDI3 protein cleaves GPC to form glycerol-3-phosphate and choline. Silencing EDI3 in MCF-7 cells decreased this enzymatic activity, increased the intracellular GPC/PC ratio, and decreased downstream lipid metabolites. Downregulating EDI3 activity inhibited cell migration via disruption of the PKCα signaling pathway, with stable overexpression of EDI3 showing the opposite effect. EDI3 was originally identified in our screening study comparing mRNA levels in metastasizing and nonmetastasizing endometrial carcinomas. Both Kaplan-Meier and multivariate analyses revealed a negative association between high EDI3 expression and relapse-free survival time in both endometrial (P < 0.001) and ovarian (P = 0.029) cancers. Overall, we have identified EDI3, a key enzyme controlling GPC and choline metabolism. Because inhibition of EDI3 activity corrects the GPC/PC ratio and decreases the migration capacity of tumor cells, it represents a possible target for therapeutic intervention.

Objective: P53 tumor suppressor gene plays a role in endometrial carcinogenesis. Former studies described correlations between p53 protein overexpression in endometrial cancer and prognostic factors, measured by immunohistochemistry. But data is still controversial. The aim of this study was to measure p53 and phospho-p53 overexpression by Western blot and evaluate correlations between overexpression and prognostic and clinical factors. Phospho-p53 seems to be the functional p53 protein and was examined for the first time in endometrial cancer., Methods: 40 patients with endometrial cancer were included in the study. A control group of 20 patients with normal endometrial tissue samples was used. Western blot was performed for detection of p53 and phospho-p53. Clinical and pathological parameters were obtained from medical records. Statistical analysis was performed using the log-rank test, the Mann-Whitney test for two independent groups and the Fisher's exact test for dichotomous groupings., Results: In 17.5% of the patients with endometrial cancer a p53 overexpression could be evaluated. There was a correlation between a p53 overexpression and recurring disease (p: 0.014), a negative progesterone receptor status (p: 0.021) and a low BMI (p: 0.022). Only one of 40 patients had a phospho-p53 expression., Conclusion: Western blot is a valid method for the detection of p53 overexpression. As other authors described before, p53 overexpression seems to correlate with negative prognostic factors. The correlation between p53 overexpression and a low BMI may underline the relationship between p53 alterations and biological aggressive endometrial carcinomas., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (PAI-1) contribute to the invasiveness of many carcinomas. Here, we studied a possible association between cytosolic uPA and PA-1 concentrations in tumor tissue with prognosis in patients with endometrial cancer., Methods: Cytosolic concentrations of uPA and PAI-1 were determined in 69 primary endothelial adenocarcinomas using an enzyme-linked immunoassay (ELISA). A possible influence of uPA and PAI-1 was studied by multivariate Cox regression adjusting for the established clinical prognostic factors FIGO-stage, grading, depth of invasion, diabetes mellitus and age., Results: Both uPA (p=0.011) and PAI-1 (p=0.003) were associated with relapse free time using the multivariate proportional hazards model. Association with overall survival was less pronounced with p=0.021 for uPA and p=0.358 for PAI-1. Concentrations of PAI-1 increased with FIGO stage (p=0.003) and with histological grading (p=0.005). Both uPA and PAI-1 concentrations were negatively correlated with estrogen and progesterone receptor levels., Conclusion: The combination of high cytosolic concentrations of uPA (>5 ng/mg total protein) and high PAI-1 (>20 ng/mg total protein) may reveal a group of patients with increased risk of progression.

Objective: The aim of this phase II multicenter study was to evaluate the safety, toxicity and efficacy of docetaxel administered weekly as first line chemotherapy in patients with recurrent or metastatic endometrial cancer., Patients and Methods: Thirty five patients with recurrent or metastatic endometrial cancer without previous chemotherapy were enrolled to receive three 6-week cycles of docetaxel 35 mg/m(2)/week with 2-week breaks between the cycles. Therapy response was evaluated after every 6-week cycle, and therapy was continued in case of at least stable disease. Final therapy response was evaluated after three 6-week cycles of docetaxel., Results: Thirty five patients with a median age of 65 years (range, 37-80 years) were evaluable for toxicity assessment, one patient presented with severe anaphylactic reaction during the second application of docetaxel and therapy was discontinued. Subsequently, this patient received doxorubicin-cisplatin combination chemotherapy. Another patient was initially documented with uterine papillary serous cancer but secondarily confirmed as uterine carcinosarcoma. Thus, 33 patients were assessable for response. Overall response rate was 21% (3 PR and 4 CR). Three patients showed stable disease. Median TTP and OAS were 12 weeks and 43 weeks, respectively. Therapy with weekly docetaxel was well tolerated; in particular, no grade 3 or 4 hematological toxicities occurred., Conclusion: Docetaxel weekly has a favorable toxicity profile, is well tolerated and shows encouraging activity in patients with advanced endometrial cancer.

Objective: The aim of this study was to analyse the influence of diabetes mellitus as a prognostic factor for overall survival in endometrial cancer., Materials and Methods: Charts were reviewed from patients with endometrial carcinoma from 1985 to 2003. Data on clinicopathologic variables, adjuvant treatment, site of recurrence and survival were collected. The chi-square test was used to examine associations between variables. The Kaplan-Meier method was used for survival analysis and Cox's proportional hazards model for multiple regression analysis., Results: Multivariate analysis revealed that diabetes mellitus, FIGO stage and depth of myometrial invasion were significantly associated with overall survival.

Objective: The aim of this study was to describe the relationships between the distribution of nodal disease, clinico-pathological patterns and recurrence and survival in surgically staged cases of endometrial cancer., Methods: Charts were abstracted from patients with endometrial carcinoma from 1985 to 1995. Data on clinicopathologic variables, adjuvant treatment, site of recurrence and survival were collected. The chi square test was used to test associations between variables. The Kaplan-Meier method was used for survival analysis and Cox's proportional hazards model for multiple regression analysis., Results: Sixty-nine out of 181 patients underwent lymph node dissection. Twenty-three had pelvic lymph node dissection, 23 underwent pelvic and paraaortic lymph node dissection and 20 patients had lymph node sampling. The median count of removed lymph nodes was 22.4. Fifty-four lymph node dissections showed negative lymph nodes and in 15 cases there was a minimum of one positive lymph node. Overall survival was in correlation to nodal involvement with a p value of 0.0017. Patients with lymph node involvement showed significantly more recurrence than patients with negative lymph nodes (p = 0.003). The depth of myometrial invasion correlated with lymph node metastasis (p = 0.01) and patients with additional diabetes mellitus showed significantly more nodal involvement (p = 0.02)., Conclusion: Endometrial cancer showed pelvic lymph node (PLN) and paraaortic lymph node (PALN) involvement. Under-diagnosis of the disease might result if there was only a PLN, but with or without PALN involvement there was no significant difference in overall survival or recurrence. There was an univariate correlation between lymph node involvement and diabetes.

In addition to the loss of function, mutant p53 can possess a dominant-negative effect on wild-type p53 and may also exert gain-of-function activity. It is not clear whether the functional status of p53 mutation contributes to differences in outcome in endometrial cancer. We collected a total of 92 RNA samples of high quality from endometrial cancer tissues, and the samples were subjected to yeast functional assay and sequencing for p53 mutations. The detected mutant p53 genes were further investigated for their dominant-negative activity using a yeast-based transdominance assay. p53 mutation was found in 24 out of 92 (26.1%) tumors, of which 10 exhibited no dominant-negative activity (recessive mutation) and 14 showed dominant-negative activity. Dominant-negative p53 mutation was related to advanced stages (p = 0.01), nonendometrioid type tumors (p = 0.01) and grade 3 tumors (p = 0.04). The patients with dominant-negative mutation had significantly shorter survival than patients with no mutation (p < 0.0001) and those with a recessive mutation (p = 0.01) in the p53 gene. No difference in survival was found between the patients with tumors harboring a recessive p53 mutation and those with tumors harboring a wild-type p53. Multivariate analysis revealed that dominant-negative p53 mutation (p = 0.019), FIGO stage (p = 0.0037) and histologic subtype (p = 0.014) were independently related to patient survival. Dominant-negative p53 mutation was the most important prognostic factor for stage III/IV endometrial cancer (p = 0.0023). In conclusion, dominant-negative p53 mutation is often found in advanced stages and aggressive histologic subtypes of endometrial cancer and it is a strong predictor of survival of patients with advanced endometrial cancer. To elucidate further the role of p53 mutation in endometrial cancer, it is necessary to investigate gain-of-function activity involving dominant-negative p53 mutant proteins., ((c) 2005 Wiley-Liss, Inc.)

The aim of this study was to evaluate the biologic outcome of endometrial carcinomas as compared to clinical and pathologic parameters and to identify multivariate independent prognostic factors. Charts were abstracted from patients with endometrial carcinoma from 1985 to 1995. Data on clinicopathologic variables, adjuvant treatment, site of recurrence, and survival were collected. chi2 test was used to test association between variables. Kaplan-Maier method was used for survival analysis and Cox proportional hazards model for multiple regression analysis. Univariate analysis revealed that FIGO stage, tumor grade, depth of myometrial invasion, biochemical analysis of progesterone receptor status, age, additional diabetes mellitus, lymph node metastasis, and type of tumor were significantly associated with the overall-survival. For disease-free interval, FIGO stage, tumor grade, depth of myometrial invasion, biochemical analysis of progesterone receptor status, lymph node metastasis, and type of tumor were also significantly associated. Multivariate analysis revealed that FIGO stage, tumor grading, tumor type, depth of myometrial invasion, and biochemically measured progesterone receptor status were associated significantly with overall survival. A significant correlation as independent prognostic factors were also seen for recurrence free interval for FIGO stage, tumor grade, and biochemical progesterone receptor status. In multivariate statistical analysis we identified FIGO stage, tumor type, tumor grade, biochemical analysis of progesterone receptor status, and depth of myometrial invasion as independent prognostic factors for overall survival, and FIGO stage, biochemical analysis of progesterone receptor status, and tumor grade as independent prognostic factors for recurrence-free interval.

Objective: We compared immunohistological examination of endometrium biopsy specimen with the results of the immunohistological examination of tumor specimen to analyse the valence of this preoperative examination according to the clinico-pathological findings and overall-survival., Material and Method: Between 1985 and 1995 193 women were treated of an endometrial carcinoma at the University hospital Mainz. In this group we evaluated 41 patients with enough preoperative endometrial biopsy material for a retrospective immunohistochemical analysis and complete follow-up data. The materials from diagnostic curettage were stained and analysed for oestrogen and progesterone receptor status and for MiB-1. The results were statistically analysed using Logrank-test for overall survival., Results: The mean follow-up time was 49 months. We found a significant correlation between staining results of oestrogen (p-value = 0.0005) and progesterone (p-value=0.0003) receptor status with overall survival as well as for MiB-1 (p-value=0.05). The correlation of staining results between biopsy specimen results and tumor material from hysterectomy was 84-85 %., Conclusion: These well known prognostic factors are measurable on biopsy specimen material in same quality and high valence as on hysterectomy material.

Objective: The purposes of this study were to analyze the relationship between clinical and pathological risk factors in endometrial cancer and additional diabetes mellitus and to clarify the correlation between additional diabetes mellitus and survival of patients with this disease. -, Material and Methods: This analyze included 181 patients with endometrial carcinoma who were treated between 1985 and 1995 at the University hospital Mainz. Patients with sarcoma were excluded. For statistical analysis a chi(2)-test was performed for univariat analysis. A Kaplan-Meier procedure was performed for over all survival and disease free interval and COX-Regression for multivariate analysis of independence. -, Results: The mean follow-up period was 49 months. The mean age was 65 years. 21.8 % of the patients had an additional diabetes mellitus. These patients had a significantly deeper infiltration of the Myometrium (p-value = 0.004) and were more likely to have lymphonode metastasis (p-value = 0.02). -, Conclusion: Our results show a correlation between Diabetes mellitus and adverse prognostic factors witch affects by the rate of lymphonode spread and overall survival.