The presence of an endometrioid component does not alter the clinicopathologic profile or survival of patients with uterine serous cancer: A gynecologic oncology group (GOG/NRG) study of 934 women.

OBJECTIVE: While most cases of endometrial cancer can readily be classified as pure endometrioid, pure serous, or another type, others show an apparent mixture of serous and endometrioid components, or indeterminate serous versus endometrioid features. Since serous histology carries a worse prognosis than endometrioid, Gynecologic Oncology Group protocol GOG-8032 was established to examine whether the presence of a non-serous component is a favorable feature in an otherwise serous cancer. METHODS: 934 women with serous cancer were prospectively identified among a larger group enrolled in GOG-0210. Six expert gynecologic pathologists classified each case as pure serous (SER, n=663), mixed serous and endometrioid (SER-EM-M, n=138), or indeterminate serous v. endometrioid (SER-EM-I, n=133) by H&E morphology. Follow-up data from GOG-0210 were analyzed. RESULTS: The subgroups did not differ on BMI, race, ethnicity, lymphovascular invasion, cervical invasion, ovary involvement, peritoneal involvement, omental involvement, FIGO stage, or planned adjuvant treatment. SER-EM-M patients were younger (p=0.0001) and less likely to have nodal involvement (p=0.0287). SER patients were less likely to have myoinvasion (p=0.0002), and more likely to have adnexal involvement (p=0.0108). On univariate analysis, age, serous subtype, race, and components of FIGO staging predicted both progression-free and overall survival. On multiple regression, however, serous subtype (SER, SER-EM-M, or SER-EM-I) did not significantly predict survival. CONCLUSIONS: There were few clinicopathologic differences between cases classified as SER, SER-EM-M, and SER-EM-I. Cases with a mixture of serous and endometrioid morphology, as well as cases with morphology indeterminate for serous v. endometrioid type, had the same survival as pure serous cases. NCT#: NCT00340808.

Brain Metastases from Endometrial Cancer: Clinical Characteristics, Outcomes, and Review of the Literature.

BACKGROUND: Brain metastases from endometrial cancer are rare and poorly described. We aimed to estimate the proportion of brain metastases at our institution that arose from endometrial cancer, and to detail clinicopathologic features and survival outcomes. METHODS: We retrospectively identified and reviewed the charts of 30 patients with brain metastases from endometrial cancer seen at Stanford Hospital from 2008 to 2018. RESULTS: Among all patients with brain metastases, the proportion arising from endometrial cancer was 0.84%. The median age at diagnosis was 62 years (range, 39-79 years), and the median overall survival from brain metastasis diagnosis was 6.8 months (range, 1.0-58.2 months). Most patients harbored endometrioid histology (53.3%), and some had concurrent metastases to lung (50.0%), bone (36.7%), and liver (20.0%). The median time from endometrial cancer diagnosis to brain metastasis development was 20.8 months (range, 1.4 months to 11.2 years), and the median number of brain metastases was 2 (range, 1-20). Patients with non-endometrioid histologies had more brain metastases than those with endometrioid histology (6.21 vs. 2.44, P = 0.029). There was no difference in overall survival by histology. CONCLUSIONS: We describe the largest cohort to date of patients with brain metastases originating from endometrial cancer. These patients represent a small fraction of all patients with brain metastases and have poor prognoses. These data enable providers caring for patients with brain metastases from endometrial cancer to appropriately counsel their patients.

Immunohistochemical Profiles of Endometrioid Endometrial Carcinomas With and Without Metastatic Disease.

A minority of endometrial carcinomas present at an advanced stage with a poor prognosis, and should be identified to individualize treatment. Immunohistochemical markers have been studied, but most have not been directly linked to metastasis. This study analyzes the immunohistochemical profile of endometrioid endometrial carcinomas (EECs) with and without metastases, and corresponding metastases. Tissue microarray slides from stage I EECs, stage III-IV EECs, and corresponding metastases were stained and scored for expression of ß-catenin, E-cadherin, ER, PR, PTEN, p16, MLH1, PMS2, L1CAM, p53, p21, and MIB1. Scores were compared between primary stage I and III-IV EECs, stage III-IV EECs, and the corresponding metastases, and between intra-abdominal and distant metastases. Primary tumors with distant metastases had a significantly lower ER expression than those without metastases or with intra-abdominal metastases. Distant metastases had a significantly lower PR expression than the corresponding primary tumor and intra-abdominal metastases. In contrast, p16 and PTEN expression was significantly higher in intra-abdominal metastases compared with corresponding primary tumors. Immunohistochemistry predicts both presence and location of EEC metastases. Loss of ER and PR was related to distant spread, and increased expression of PTEN and p16 was related to intra-abdominal spread. Additional research should assess the use of these markers in the diagnostic workup as well as the possibility to target metastases through these markers.

Cell proliferation, measured as flow cytometric S-phase fraction, is a strong prognostic indicator in FIGO stage I endometrioid endometrial carcinoma: a population-based study.

INTRODUCTION: In early-stage endometrial carcinoma, there is controversy regarding the prognostic value of the flow cytometric variables DNA ploidy (diploid vs. aneuploid) and S-phase fraction. In Sweden, the former is included in national guidelines despite poor scientific support and the latter is not used clinically. This study investigates the prognostic properties of these variables, together with classical histopathological variables, in multivariate analysis in a stringently stratified material. MATERIAL AND METHODS: Consecutive, population-based patient material restricted to International Federation of Gynecology and Obstetrics (FIGO) 2009 stage I endometrioid endometrial carcinoma (n = 1140) was retrospectively collected from routinely reported data from medical records. Data on age, FIGO stage, degree of differentiation, S-phase fraction, DNA ploidy status, and adjuvant treatment were included in the study. Cumulative incidence curves with other causes of death as a competing risk were used for univariable analysis for the primary endpoint endometrial cancer death. Cox proportional hazards regression analysis was used for multivariate modeling of all endpoints, and for univariable analysis for the secondary endpoints overall survival and time to progression. RESULTS: An S-phase fraction value of >5.5% was associated with worse outcome (for endometrial cancer death: hazard ratio 2.25; 95% CI 1.38-3.67; p = 0.001, adjusted) and DNA ploidy status was not, for all endpoints tested. CONCLUSIONS: In FIGO stage I endometrioid endometrial carcinoma, DNA ploidy status had no prognostic value, whereas the S-phase fraction may be used to identify those with a higher risk of adverse clinical outcome.

Immediate repair of an incompletely transected obturator nerve during robotic-assisted pelvic lymphadenectomy.

Intraoperative injury of the obturator nerve may occur in gynecologic oncologic procedures when extensive pelvic side wall dissection is performed. In this case, we report an immediate repair of an incompletely transected obturator nerve during robotic-assisted pelvic lymphadenectomy. A 62-year-old gravida 3, para 3 woman was admitted to our clinic for postmenopausal bleeding. The result of an endometrial biopsy was complex endometrial hyperplasia with atypia, and a robotic-assisted laparoscopic hysterectomy was performed. A frozen section of the specimen revealed grade 1 endometrioid adenocarcinoma with >1/2 myometrial invasion. During the pelvic lymphadenectomy, the left obturator nerve was incompletely transected. The obturator nerve edges were oriented and reapproximated end-to-end with two 6/0 polypropylene sutures. The operation and console times were 244 and 223 minutes, respectively. The final pathologic finding was a stage IB endometrial adenocarcinoma. The number of the obtained lymph nodes was 38. Postoperatively, the patient did not exhibit any clinically apparent loss of adductor function or any other neurologic deficiency. Over 6 months of follow-up, the patient experienced no residual neuropathy or deficit in the left thigh. Robotic-assisted repair of a transected obturator nerve during surgery is feasible, and immediate repair of the damaged nerve may result in no neurologic deficit postoperatively.

Gonadotropin releasing hormone agonist and levonorgestrel-intrauterine device followed by in vitro fertilization program as management strategy for an infertile endometrial cancer patient: a case report.

BACKGROUND: A progressive delay in the age of first conception results in an increased frequency of endometrial cancer patients in reproductive age and desiring childbearing. CASE: A 38-year-old infertile woman with stage I endometrioid adenocarcinoma was treated with gonadotropin releasing hormone agonist (GnRHa) and levonorgestrel-releasing intrauterine device (LNG-IUD). After disease remission, she underwent a controlled ovarian stimulation for standard in vitro fertilization (IVF) program and had a pregnancy delivering a healthy male baby. Total laparoscopic hysterectomy with bilateral salpingo-oophorectomy was performed four months after delivery. The patient is free of disease after 3-year follow-up. CONCLUSION: GnRHa plus LNG-IUD followed by IVF program is a safe and effective fertility-sparing strategy to manage infertile patients with stage I endometrial cancer.

Discovery of serum biomarkers implicated in the onset and progression of serous ovarian cancer in a rat model using iTRAQ technique.

OBJECTIVE: Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy, and early tumor detection is the most promising approach for improving the EOC survival rate. The goal of this study was to identify the biomarkers underlying ovarian carcinogenesis. STUDY DESIGN: To mimic the onset and progression of human ovarian cancer, we established a rat model of ovarian neoplasm by implanting 7,12-dimethylbenz(a)anthracene (DMBA)-coated silk cloth strips onto the ovaries. Sera collected from rats bearing serous ovarian carcinoma (SOC) at baseline, 12 and 24 weeks after DMBA treatment and from controls were analyzed using iTRAQ combined with two-dimensional liquid chromatography and tandem mass spectrometry. The data were analyzed with ProteinPilot software for peptide matching, protein identification, and protein quantitation. Ingenuity pathway analysis software was used to identify the canonical pathways and biological interaction networks of differentially expressed proteins. RESULTS: The cumulative ovarian tumor incidence rate reached 75% at 32 weeks after DMBA treatment. Out of all tumors, 94% were EOC, and 51% of the EOC cases were SOC. A total of 225 unique, non-redundant proteins were identified with 95% confidence. Twenty-seven differentially expressed proteins were significantly up- or down-regulated during the early or advanced carcinogenesis of SOC. Fifteen proteins were previously reported to be involved in ovarian cancer, and 12 proteins, including MMRN1, SERPINC1, TLN1, AHSG, PLG, APOA2, HPX, APOC1, APOC2, FERMT3, FETUB and HBB, were identified for the first time in our study. CONCLUSION: The discovery of these differentially expressed proteins provides valuable clues for understanding the molecular mechanism underlying the dynamic carcinogenic process of ovarian cancer. These proteins could be used as diagnostic biomarkers for early detection, disease monitoring and therapeutic targets.

Endometrial hyperplasia - the dilemma of management remains: a retrospective observational study of 280 women.

OBJECTIVE: To quantify the rate of inconsistency in histopathological reporting between endometrial biopsy specimens (obtained by Pipelle endometrial sampler or curettage) and hysterectomy specimens using the World Health Organization classification criteria. STUDY DESIGN: A retrospective review of the records of 280 women with a histopathological diagnosis of endometrial hyperplasia treated in Ipswich Hospital NHS Trust, UK from 1 January 1998 to 31 May 2009. RESULTS: Discrepancy was found between the histopathological results of endometrial samples and hysterectomy specimens. The discrepancy was doubled for specimens obtained using a Pipelle endometrial sampler, with false-positive (i.e. overdiagnosis when the hysterectomy specimen showed a better diagnosis) and false-negative (i.e. underdiagnosis when the hysterectomy specimen showed a worse diagnosis) rates of 5.3% and 22.6%, respectively. For curettage specimens, the false-positive and false-negative rates were 1.8% and 13.2%, respectively. All cases of curettage were performed under general or regional anaesthesia, and were preceded by hysteroscopy. Apart from age, no risk factors were associated with a worse diagnosis. The association of age differed between types of endometrial hyperplasia and cancer; the strongest association was seen for cancer and the weakest association was seen for simple hyperplasia. CONCLUSION: Hysteroscopy and curettage may be considered when simple or complex hyperplasia is diagnosed from a specimen obtained with a Pipelle endometrial sampler. When a diagnosis of atypical hyperplasia is made, irrespective of the method of endometrial sampling, the gynaecologist must be concerned that endometrial carcinoma exists concomitantly within the uterus.

Utilization of unlabeled probes for the detection of fibroblast growth factor receptor 2 exons 7 and 12 mutations in endometrial carcinoma.

BACKGROUND: Endometrial adenocarcinomas are associated with a variety of molecular abnormalities including microsatellite instability, Kirsten rat sarcoma viral oncogene homolog mutations, and phosphatase and tensin homolog inactivation. Recently, mutations in fibroblast growth factor receptor 2 (FGFR2) have been described but their frequency and clinicopathologic characteristics are incompletely known. METHODS: To determine the frequency of mutations in FGFR2 exons 7 and 12, 43 adenocarcinomas of the endometrium were studied by high-resolution melting analysis utilizing unlabeled probes and sequencing. RESULTS: Three of 43 (7%) endometrial carcinomas harbored FGFR2 exon 7 mutations. All 3 mutations were S252W and occurred in endometrioid (type I) adenocarcinomas. Direct sequencing indicated that 2 of the S252W mutations were heterozygous, whereas 1 was presumably homozygous. No FGFR2 mutations were detected in exon 12. CONCLUSIONS: FGFR2 mutations occur in approximately 7% of adenocarcinomas of the endometrium. Only carcinomas of an endometrioid morphology contain FGFR2 mutations, and in our series all were S252W. FGFR2 exons 7 and 12 unlabeled DNA probes allow for easy screening of endometrial carcinoma for the 2 most common FGFR2 mutations (S252W and N550K). Identification of these mutations may have important implications in directed molecular therapy.

Clinical presentation of endometrioid epithelial ovarian cancer with concurrent endometriosis: a multicenter retrospective study.

BACKGROUND: Endometrioid epithelial ovarian cancer (EEOC) is frequently diagnosed in conjunction with endometriosis and is suggested to arise during the process of endometriosis. This study evaluates the clinical manifestations, including endometriosis-related symptoms and their relationships according to the coexistence of endometriosis. METHODS: Using medical records, a retrospective analysis was conducted on 221 patients treated for EEOC at four tertiary educational hospitals between 2000 and 2008. The initial presenting symptoms, particularly those related to endometriosis, were examined in relation to the coexistence of endometriosis or other clinical variables. RESULTS: Endometriosis was identified in 82 (37.1%) of the 221 patients with EEOC. The most common symptoms were pelvic pain followed by gastrointestinal symptoms, palpable mass, abdominal distension, vaginal bleeding, and newly developed or exacerbated dysmenorrhea (18.1%) and dyspareunia (13.6%). Notably, dysmenorrhea and dyspareunia were frequently observed in patients with endometriosis. Among 210 patients identified with pretreatment serum CA-125, 54 (25.7%) displayed normal CA-125 levels (<35 units/mL) and 23.3% and 29.9% of patients without and with endometriosis had normal CA-125 levels, respectively (P = 0.381). Additionally, 32.6% of the patients with early-stage EEOC displayed normal CA-125 levels. CONCLUSIONS: In this large series of patients with EEOC, the main presenting symptoms were pelvic pain followed by gastrointestinal symptoms, palpable mass, abdominal distension, vaginal bleeding, and newly developed or exacerbated dysmenorrhea and dyspareunia. Dyspareunia and dysmenorrhea were more frequently detected in patients with endometriosis. Normal CA-125 levels cannot be applied as a marker to exclude EEOC, particularly at the early stages.

Body mass index as a prognostic factor in epithelial ovarian cancer and correlation with clinico-pathological factors.

OBJECTIVE: To find out if body mass index (BMI) was associated with clinico-pathological features and prognosis in epithelial ovarian cancer (EOC). DESIGN: Retrospective cohort study. SETTING: Patients with EOC, who underwent primary surgery and postoperative chemotherapy in the Orebro Medical Region, Sweden, 1994-2003. SAMPLE: A total of 446 patients with stage I-IV EOC, who underwent primary surgery and chemotherapy with information of values of height and weight at the start of chemotherapy were eligible. METHODS: Patients were stratified by BMI according to guidelines set forth by the World Health Organization. Pearson's chi-squared test was used for univariate analyses. The level of statistical significance was p < 0.05. MAIN OUTCOME MEASURES: The survival curves were generated by using the Kaplan-Meier method, and in multivariate analyses the Cox regression model was used with cancer-specific survival as the end point. RESULTS. Of the patients, 5% were underweight (BMI < 18.5), 55% were of ideal body weight (BMI 18.5-25), 25% were overweight (BMI 25-30) and 15% were obese (BMI > 30). Among patients with serous tumors a significant (p = 0.01) worse survival was found in the subgroup of underweight (BMI < 18.5) patients compared with patients in the other BMI groups. In multivariate analysis only FIGO-stage and age were independent and significant prognostic factors. CONCLUSION: Overweight and obese patients did not have worse survival than normal weight and underweight patients. The prognostic impact of BMI on survival was only noted for underweight patients with serous tumors.

The reduction in pigment epithelium-derived factor is a sign of malignancy in ovarian cancer expressing low-level of vascular endothelial growth factor.

BACKGROUND: Angiogenesis is a critical factor in the progression of solid tumors and metastasis. The aim of this study was to characterise the roles of angiogenic and anti-angiogenic factors on ovarian cancer. METHODS: The expression levels of vascular endothelial growth factor (VEGF, angiogenic factor) and pigment epithelial growth factor (PEDF, anti-angiogenic factor) were measured by real-time polymerase chain reaction and Western blotting in ovarian tumors. Microvessel density (MVD) was evaluated by the total microvessel length in high-power field of tumor tissue preparations. RESULTS: MVD correlated with tumor malignancy. The tissues with the highest expression levels of VEGF (VEGF-H) were malignant tumors. The VEGF expression levels in some malignant tumors (VEGF-L) were as low as that in benign tumors. Therefore, the expression of PEDF was examined. The PEDF expression levels in VEGF-L malignant tumors were significantly lower than those in benign tumors. On the other hand, the PEDF expression levels in VEGF-H malignant tumor tissues were not significantly different from those in benign tumors. CONCLUSION: The reduction in PEDF expression levels may be, in part, responsible for tumor malignancy in VEGF-L ovarian tumors. Furthermore, PEDF may be a useful marker of malignancy in VEGF-L ovarian tumors.

Neoangiogenesis and expression of hypoxia-inducible factor 1alpha, vascular endothelial growth factor, and glucose transporter-1 in endometrioid type endometrium adenocarcinomas.

OBJECTIVE: Hypoxia Inducible Factor-1alpha (HIF-1alpha) is a transcriptional factor that activates multiple genes including Vascular Endothelial Growth Factor (VEGF) and glucose transporter-1 (GLUT-1) in response to hypoxia and promotes neoangiogenesis. METHODS: Expression of HIF-1alpha VEGF, and GLUT-1 were analyzed by immunohistochemistry and microvessel density (MVD) was determined by CD 34 immunostaining in 100 endometrioid type endometrial adenocarcinoma, FIGO Stages I-IV. RESULTS: High expression of HIF-1alpha, VEGF and GLUT-1 were significantly more prevalent in advanced stages than early stages (p<0.001). High expression of HIF-1alpha was found in 100% of Stage III-IV patients, whereas 50% of Stage II and 9% of Stage I patients had high HIF-1alpha expression. Similarly, high VEGF expression was determined in 4% of Stage I and 30% of Stage II patients, however 90% of Stage III-IV patients had high expression of VEGF. Comparing the GLUT-1 scores, it was found that increasing stages correlated with high GLUT-1 expression. Additionally, a statistically significant difference was also noted in MVD between stages (p<0.001). The average MVD of Stage I patients was 31.87+/-7.73. It was found 49.24+/-7.60 in Stage II, and 78.74+/-14.48 in Stage III-IV patients. On analyzing expression of HIF-1alpha, VEGF and GLUT-1 and MVD in pairs, statistically significant correlations were found between each other (p<0.001). CONCLUSION: HIF-1alpha was increasingly expressed from early stages through advance stages of endometrioid adenocarcinoma, paralleled by activation of its downstream genes such as GLUT-1, VEGF and increased angiogenesis. These results highlight the importance of hypoxia and related pathways in progression of endometrial carcinoma.

Tight junction formation in epithelial ovarian adenocarcinoma.

BACKGROUND: Epithelial cells are characterised by their ability to form polarised cell sheets with barriers between two tissue compartments. Epithelial tightness and apical/basolateral orientation are maintained through adherens and tight junctions (TJs). Alterations in junction formation and function could promote tumorigenesis via increased access to growth factors and cytokines. The etiology and development of epithelial ovarian cancer (EOC) are far from understood. The ovarian surface epithelium (OSE), regarded as progenitor cells of EOC, form weak functional TJs in culture without expressing typical junction proteins. However, these integral membrane epithelial proteins, E-cadherin, claudin-3 and claudin-4, are often found in EOC. METHODS: To clarify whether EOC can form functional TJs, 4 different ovarian cancer cell lines of various histology were analysed for their expression of TJ (claudin-1, claudin-3, claudin-4 and zonola occludens-1 (ZO-1)) and adherens junction (AJ) (E-cadherin and N-cadherin) proteins, and the ability to build up trans-epithelial resistance (TER) in culture was measured. RESULTS: We found expression for all cell-junction proteins with a typical honeycomb-staining pattern in the serous adenocarcinomas indicating proper junction formation. Clear-cell and endometrioid adenocarcinomas showed a different expression pattern. By measuring TER, including Ca(2+) switch experiments, functional TJs were shown to build up only in serous adenocarcinomas. CONCLUSION: Serous adenocarcinomas formed functional TJs in vitro. The presence of claudin-4 might be essential for the function of TJs in ovarian cancer.

The power Doppler velocity index, pulsatility index, and resistive index can assist in making a differential diagnosis of primary ovarian carcinoma and Krukenberg tumors: a preliminary study.

OBJECTIVE: The aim of this study was to compare the effectiveness of transvaginal power Doppler sonography with spectral Doppler analysis as an aid in preoperatively distinguishing primary ovarian carcinoma and metastatic carcinoma to the ovary (Krukenberg tumors). METHODS: Fifty women with ovarian disease were preoperatively examined with transvaginal power Doppler sonography. Six basic parameters were measured, including intratumoral peak systolic velocity, end-diastolic velocity, time-averaged maximum velocity, pulsatility index (PI), resistive index (RI), and velocity index (VeI). Blood flow analyses were detectable in all patients. Twelve patients with metastatic carcinoma to the ovary were classified as group 1; 38 patients with primary ovarian carcinoma were classified as group 2. Comparison of intratumoral blood flow analyses between the two groups was performed. RESULTS: The PI, RI, and VeI were significantly lower in patients with metastatic carcinoma to the ovary than those with primary ovarian carcinoma (P < .05). There were no significant differences in the peak systolic velocity (P = .871), end-diastolic velocity (P = .508), and time-averaged maximum velocity (P = .850) between the two groups. CONCLUSIONS: Transvaginal power Doppler sonography with spectral Doppler analysis is an effective method in evaluating intratumoral blood flow of Krukenberg tumors. Low impedance (PI, RI, and VeI) might assist us in making differential diagnoses between primary ovarian carcinoma and Krukenberg tumors according to our preliminary results.

Immunohistochemical expression of PTEN in normal, hyperplastic and malignant endometrium and its correlation with hormone receptors, bcl-2, bax, and apoptotic index.

PTEN is a tumor suppressor gene that is frequently mutated in type I endometrioid endometrial carcinomas (EECs), and is involved in the control of cell proliferation, differentiation, and apoptosis. In this study, we aimed to assess the relationship between PTEN expression and estrogen, progesterone receptors (PRs), other apoptosis-related proteins, such as bcl-2 and bax, and apoptotic index (AI) in EEC, its precursor lesion hyperplasia, and cyclical endometrium. We also evaluated the relationship between PTEN expression and clinicopathologic parameters. PTEN, estrogen receptor (ER), PR, and bcl-2 and bax expressions were evaluated immunohistochemically, and AI was evaluated in hematoxylin and eosin (HE)-stained slides in 23 cyclical and 37 hyperplastic endometria and in 35 EECs. PTEN expression was higher in cyclical endometrium than in the carcinomas (p<0.05). The PTEN expression level was significantly higher in non-atypical hyperplasias than in EEC, but there were no differences between atypical complex hyperplasia (ACH) and EEC and between hyperplasias. In the carcinomas, there was a negative correlation between grade and PTEN expression (r=-0.338, p=0.047). In conclusion, we presume that PTEN is involved in the early phases of endometrial tumorigenesis, and it can be speculated that decreased PTEN expression with loss of differentiation in carcinoma can contribute to the emergence of tumors with a more aggressive phenotype.

Body mass index as a prognostic factor in endometrioid adenocarcinoma of the endometrium.

OBJECTIVE: To determine if body mass index (BMI) influences tumor expression of HER-2/neu, estrogen and progesterone receptors (ER/PR), and survival in women with endometrial adenocarcinoma. METHODS: Patients diagnosed between January 1992 and December 2001 with endometrioid adenocarcinoma of the uterus were identified. Clinical and pathologic data were retrospectively collected. HER-2/neu, estrogen and progesterone receptor expression were determined by immunohistochemistry. Differences in these variables and other prognostic factors were analyzed and correlated with effect on survival. RESULTS: One-hundred-sixty-five patients were included in this analysis. Lower BMI was associated with high stage (p=0.04) and HER-2/neu expression (p=0.04). Black race, high grade, high stage and lack of ER/PR expression were all associated with decreased survival. Despite having better prognostic factors, women with a BMI >25 had a lower survival than women with a BMI <25 (p=0.36). When five-year survival rates were calculated for BMI category and stratified by prognostic factors, for almost every high risk factor, survival was lower in overweight patients. CONCLUSION: In patients with endometrioid adenocarcinoma, low BMI is associated with high stage and tumor expression of HER-2/neu. Despite better prognostic factors, overweight women experience poorer survival.

Molecular and pathologic aspects of endometrial carcinogenesis.

Endometrial cancer is the most common gynecological malignancy, with 41,000 new cases projected in the United States for 2006. Two different clinicopathologic subtypes are recognized: the estrogen-related (type I, endometrioid) and the non-estrogen-related types (type II, nonendometrioid such as papillary serous and clear cell). The morphologic differences in these cancers are mirrored in their molecular genetic profile with type I showing defects in DNA-mismatch repair and mutations in PTEN, K-ras, and beta-catenin, and type II showing aneuploidy and p53 mutations. This article reviews the genetic aspects of endometrial carcinogenesis and progression. We will define the precursor lesion of type I endometrioid cancer and the role of genetics and estrogen in its progression.

Molecular pathology of endometrial carcinoma: transcriptional signature in endometrioid tumors.

A dualistic model, which has been established on a morphological basis and that differentiates type I endometrioid from type II non-endometrioid endometrial cancer, is widely accepted. Molecular genetics have provided us with data supporting the dualistic model of endometrial tumorigenesis and with some clues to speculate about the sequence of the molecular alterations defining the tumorigenesis pathways. In type I endometrioid endometrial cancer, PTEN gene silencing, microsatellite instability associated with defects in DNA mismatch repair genes, or mutations in the K-ras gene are the known major alterations defining the progression from normal endometrium to hyperplasia and then on to carcinoma. Recently, cDNA microarray technology for identifying the differences in gene expression patterns between the histological types of endometrial cancer have permitted the identification of differentially expressed genes that could help us to understand differences in the biology and the clinical outcome between histiotypes. Genes involved in the mitotic checkpoint as a major mechanism of carcinogenesis in non-endometrioid endometrial cancer, or altered genes associated with the initial steps of myometrial infiltration in endometrioid endometrial cancer, represent examples of how useful large genetic screenings can be for understanding the tumorigenesis process and the future directions in the molecular pathogenesis of endometrial cancer.