Complex Atypical Endometrial Hyperplasia Research Articles

Diagnostic criteria for distinguishing endometrial adenocarcinoma from complex atypical endometrial hyperplasia

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).

Endometrial Intraepithelial Neoplasia (EIN) in Endometrial Biopsy Specimens Categorized by the 1994 World Health Organization Classification for Endometrial Hyperplasia

Our study is to determine the presence of endometrial intraepithelial neoplasia (EIN) in endometrial biopsy specimens classified by the 1994 World Health Organization (WHO) criteria for endometrial hyperplasia. Endometrial biopsy specimens that were stained with hematoxylin and eosin (HE) were examined and categorized by the WHO 1994 criteria and for the presence of EIN as defined by the International Endometrial Collaborative Group. β-catenin expression was examined by immunohistochemistry. A total of 474 cases of HE stained endometrial biopsy tissues were reviewed. There were 379 cases of simple endometrial hyperplasia, 16 with simple atypical endometrial hyperplasia, 48 with complex endometrial hyperplasia, and 31 with complex atypical endometrial hyperplasia. Among the 474 endometrial hyperplasia cases, there were 46 (9.7%) that were classified as EIN. Of these 46 cases, 11(2.9%) were classified as simple endometrial hyperplasia, 1 (6.3%) as simple atypical endometrial hyperplasia, 6 (12.5%) as complex endometrial hyperplasia, and 28 (90.3%) as complex atypical endometrial hyperplasia. EIN was associated with a higher rate of β-catenin positivity than endometrium classified as benign hyperplasia (72% vs. 22.5%, respectively, P < 0.001), but a lower rate than endometrial adenocarcinoma (72% vs. 96.2%, respectively, P < 0.001). In benign endometrial hyperplasia, high β-catenin expression was noted in the cell membranes, whereas in EIN and endometrial adenocarcinoma high expression was noted in the cytoplasm. In conclusion, EIN is more accurate than the WHO classification for the diagnosis of precancerous lesions of the endometrium.

Which Endometrial Pathologies Need Intraoperative Frozen Sections?

Endometrial cancers are the most common gynecologic cancers. Endometrial sampling is a preferred procedure for diagnosis of the endometrial pathology. It is performed routinely in many clinics prior to surgery in order to exclude an endometrial malignancy. We aimed to investigate the accuracy of endometrial sampling in the diagnosis of endometrial pathologies and which findings need intra-operative frozen sections. Three hundred nine women applying to a university hospital and undergoing endometrial sampling and hysterectomy between 2010 and 2012 were included to this retrospective study. Data were retrieved from patient files and pathology archives. There was 17 patients with malignancy but endometrial sampling could detect this in only 10 of them. The endometrial sampling sensitivity and specificity of detecting cancer were 58.8% and 100%, with negative and positive predictive values of 97.6%, and 100%, respectively. In 7 patients, the endometrial sampling failed to detect malignancy; 4 of these patients had a preoperative diagnosis of complex atypical endometrial hyperplasia and 2 patients had a post-menopausal endometrial polyps and 1 with simple endometrial hyperplasia. There is an increased risk of malignancy in post-menopausal women especially with endometrial polyps and complex atypia hyperplasia. Endometrial sampling is a good choice for the diagnosis of endometrial pathologies. However, the diagnosis should be confirmed by frozen section in patients with post-menopausal endometrial polyps and complex atypia hyperplasia.

Complication à long terme du morcellement utérin par voie cœlioscopique : les myomes parasitiques iatrogènes

Identify parasitic myomas following uterine laparoscopic morcellation and describe the circumstances of diagnosis, management, potential consequences and possible preventive measures. Retrospective study of observed cases in a university hospital between 2000 and 2012 and review of the literature. Five cases were identified in our department. Pelvic pain was the main symptom in three patients while one was asymptomatic and one consulted for a cystocele. The average time to diagnosis was 88 months (3-192). Surgical removal was performed in four cases by laparoscopy and vaginally for one case. Histological examination showed typical leiomyomas, but in one case, an atypical leiomyoma with limited experience for a typical primary lesion. In the literature, there are about 50 cases. One required a bowel resection and for another one, after subtotal hysterectomy, histological examination showed complex atypical endometrial hyperplasia for normal endometrium initially. This study should draw the attention of laparoscopic surgeon. It emphasizes, beyond a potential reoperation, a risk of atypical histological secondary processing. Surgical resection should be discussed even in case of asymptomatic lesions.

Relapse of endometrial hyperplasia after conservative treatment: a cohort study with long-term follow-up

What is the risk of relapse for women with endometrial hyperplasia treated with levonorgestrel-releasing intrauterine system (LNG-IUS) or oral progestogens? Relapse of complex endometrial hyperplasia after initial regression occurs often and it occurs less often in women treated with LNG-IUS than with oral progestogens. The LNG-IUS and oral progestogens are used to treat women with endometrial hyperplasia and achieve regression. There is uncertainty over whether further surveillance for these women is necessary as the risk for relapse is unknown. A cohort study of 219 women with complex non-atypical or atypical endometrial hyperplasia who were treated and achieved initial regression with LNG-IUS (n = 153) or oral progestogens (n = 66) from August 1998 until December 2007 and followed up for >5 years. The mean length of follow-up was 74.7 ± SD 31.8 months for the LNG-IUS versus 87.6 ± SD 42.2 months for the oral progestogen group. We evaluated the proportion of women who relapsed or had hysterectomy after initial regression with LNG-IUS compared with oral progestogens by logistic regression and adjusting for confounding. The time from regression to relapse was explored through a survival analysis. Relapse of hyperplasia occurred in 13.7% (21/153) of women treated with LNG-IUS compared with 30.3% (20/66) of women treated with oral progestogens [adjusted odds ratio (OR) = 0.34, 95% confidence interval (CI): 0.17-0.7, P = 0.005]. Relapse rates over long-term follow-up were lower for complex non-atypical hyperplasia compared with atypical hyperplasia for both LNG-IUS (12.7%, 18/142 versus 27.3%, 3/11, respectively; P ≤ 0.001) and oral progestogens (28.3%, 17/60 versus 50%, 3/6, respectively; P ≤ 0.001). The survival analysis indicates that relapse occurred less often with LNG-IUS at 12, 24, 36, 48, 60 and >60 months of follow-up (hazard ratio 0.37, 95% CI: 0.2-0.7, P = 0.0013). There were no events of relapse after 48 months from regression with oral progestogens, but 5 women treated with LNG-IUS relapsed after 60 months when treatment was discontinued. Hysterectomy rates were lower in the LNG-IUS than oral progestogen group during follow-up (19.6%, 30/153 versus 31.8%, 21/66, respectively, OR = 0.52, 95% CI: 0.27-1, P = 0.05). Endometrial cancer was diagnosed in 2 (11.8%) women who had hysterectomy (n = 17) because of relapse. We are unable to accurately estimate the cancer risk in women who relapse during follow-up as only 17 out of 41 who relapsed underwent hysterectomy. Relapse of endometrial hyperplasia after initial regression occurs often and long-term follow-up is advised. Ioannis D. Gallos and this study were funded through a grant from Wellbeing of Women (ELS022). No competing interests.

The Influence of Infertility Treatment on the Prognosis of Endometrial Cancer and Atypical Complex Endometrial Hyperplasia

Many patients with endometrial cancer have no children when diagnosed, and thus are reluctant to undergo hysterectomy, hoping to preserve their fertility. Their requirement is met, at least partially, with high-dose medroxyprogesterone acetate that brings good response rate in the treatment of endometrial cancer in the early stage and atypical complex endometrial hyperplasia (EC/ACEH). Actually, a number of successful pregnancies after the conservative treatment have been reported. To conceive, many of them need infertility treatment because of ovulation disorders which might have induced the cancer with unopposed estrogens. However, on the other side, hyperestrogenic status caused by ovulation induction or controlled ovarian stimulation might promote the progression and the recurrence of the disease. This study aimed to assess the effectiveness and safety of infertility treatment after conservative therapy for EC/ACEH, to confirm the significance of fertility-sparing therapy. The patients with EC/ACEH who achieved complete response after high-dose medroxyprogesterone acetate were eligible for this retrospective study. Characteristics of the patients, whether they underwent infertility treatment, conceived, or relapsed, and the interval from complete response to conception or recurrence were retrospectively analyzed. The clinical outcomes of 36 patients were investigated. Twenty-six of them desired to conceive soon after complete response. All of them underwent infertility treatment, and 16 women delivered healthy babies. Kaplan-Meyer curve and log-rank test analysis revealed that women who achieved live birth had a significantly lower risk of recurrence than those without live birth. There was not a significant difference between the patients with and without infertility treatment. Use of ovulation induction drugs after conservative treatment of endometrial cancer did not increase the recurrence of the disease. Moreover, resulting pregnancy seems to have an advantageous effect on the oncologic outcome.

Complex atypical endometrial hyperplasia in a 22-year-old woman

A 22-year-old woman presented with a 6-month history of heavy, painful periods. An ultrasound scan suggested thickened endometrium. Hysteroscopic examination was unsatisfactory because of heavy ble...

β-Catenin signaling regulates Foxa2 expression during endometrial hyperplasia formation

The Wnt/β-catenin signaling is essential for various organogenesis and is often implicated during tumorigenesis. Dysregulated β-catenin signaling is associated with the formation of endometrial adenocarcinomas (EACs), which is considered as the common form of endometrial cancer in women. In the current study, we investigate the downstream target of Wnt/β-catenin signaling in the uterine epithelia and the mechanism leading to the formation of endometrial hyperplasia. We report that conditional ablation and activation of β-catenin in the uterine epithelia lead to aberrant epithelial structures and endometrial hyperplasia formation, respectively. We demonstrate that β-catenin regulates Foxa2 with its candidate upstream region for the uterine epithelia. Furthermore, knockdown of Foxa2 leads to defects in cell cycle regulation, suggesting a possible function of Foxa2 in the control of cell proliferation. We also observe that β-catenin and Foxa2 expression levels are augmented in the human specimens of complex atypical endometrial hyperplasia, which is considered to have a greater risk of progression to EACs. Thus, our study indicates that β-catenin regulates Foxa2 expression, and this interaction is possibly essential to control cell cycle progression during endometrial hyperplasia formation. Altogether, the augmented expression levels of β-catenin and Foxa2 are essential features during the formation of endometrial hyperplasia.

Predicting the Coexistence of an Endometrial Adenocarcinoma in the Presence of Atypical Complex Hyperplasia: Immunohistochemical Analysis of Endometrial Samples

This study aimed to determine whether immunohistochemical markers in complex atypical endometrial hyperplasia could predict the presence of a concurrent endometrial carcinoma. Endometrial biopsies of 39 patients with complex atypical hyperplasia were selected retrospectively between 1999 and 2006. Only patients who underwent a hysterectomy were included. A coexisting endometrial carcinoma was present in 25 patients (64%). Immunohistochemical analysis was performed on formalin-fixed paraffin-embedded sections of the endometrial biopsies, using antibodies for MIB-1, β-catenin, E-cadherin, p53, PTEN, CD44, HER2-neu, survivin, COX-2, tenascin, and bcl-2. To evaluate the potential utility of these markers, a prediction model was constructed. In the univariate analysis, expressions of both PTEN and HER2-neu were significantly different between the groups with and without a coexisting endometrial carcinoma (P < 0.05). Loss of PTEN staining was found in 13 (54%) and 1 (7%) of the patients with and without a coexistent carcinoma, respectively (odds ratio, 16.55; 95% confidence interval [CI], 1.87-146.65). HER2-neu expression was found in only 2 (8.6%) and 6 (43%) patients with and without a coexistent carcinoma, respectively, and was excluded from further analysis because of its low expression. A prediction model containing PTEN expression only showed an area under the curve of 73.4% (95% CI, 57.3%-89.6%). After adding MIB-1 and p53, discriminative power improved to 87.2% (95% CI, 75.1%-99.3%). This study showed that PTEN expression in complex endometrial hyperplasia is a promising factor for the prediction of the presence of a coexisting endometrial carcinoma, and prediction may even better when MIB-1 and p53 expressions are considered simultaneously.

Regression, relapse, and live birth rates with fertility-sparing therapy for endometrial cancer and atypical complex endometrial hyperplasia: a systematic review and metaanalysis

The objective of the study was to evaluate the regression, relapse, and live birth rates of early-stage endometrial cancer (EC) and atypical complex hyperplasia (ACH) with fertility-sparing treatment. This was a metaanalysis of the proportions from observational studies with a random-effects model and a meta-regression to explore for heterogeneity. Thirty-four observational studies, evaluating the regression, relapse, and live birth rates of early-stage EC (408 women) and ACH (151 women) with fertility-sparing treatment. Fertility-sparing treatment for EC achieved a pooled regression rate of 76.2%, a relapse rate of 40.6%, and a live birth rate of 28%. For ACH the pooled regression rate was 85.6%, a relapse rate of 26%, and a live birth rate of 26.3%. Twenty women were diagnosed with ovarian cancer (concurrent or metastatic) during follow-up (3.6%) and 10 progressed to higher than stage I EC (1.9%) from which 2 women died. Fertility-sparing treatment of EC and ACH is feasible and selected women can satisfy their reproductive wishes.

Accuracy of Frozen Sections for Intraoperative Diagnosis of Complex Atypical Endometrial Hyperplasia

The purpose of this study was to correlate the histological diagnosis made during intraoperative frozen section (FS) examination of hysterectomy samples with complex atypical endometrial hyperplasia (CAEH) diagnosed with definitive paraffin block histology. FS pathology results of 125 patients with a pre- operative biopsy showing CAEH were compared retrospectively with paraffin block pathology findings. Paraffin block results were consistent with FS in 78 of 125 patients (62.4%). The FS sensitivity and specificity of detecting cancer were 81.1% and 97.9%, with negative and positive predictive values of 76.7%, and 98.4%, respectively. Paraffin block results were reported as endometrial cancer in 77 of 125 (61.6%) patients. Final pathology was endometrial cancer in 45.3% patients diagnosed at our center and 76.9% for patients who had their diagnosis at other clinics (p=0.018). Paraffin block results were consistent with FS in 62.4% of all cases Consistence was 98.4% in patients who had endometrial cancer in FS. FS does not exclude the possibility of endometrial cancer in patients with the preoperative diagnosis of CAEH. In addition, sufficient endometrial sampling is important for an accurate diagnosis.

The Value of Additional Pathology Comments Indicating Suspicion of Adenocarcinoma Among Women Diagnosed Preoperatively With Complex Atypical Endometrial Hyperplasia

Over 40% of women with a preoperative diagnosis of complex atypical hyperplasia (CAH) will have endometrial cancer at hysterectomy. CAH diagnoses are often qualified by comments indicating suspicion of cancer. We examine whether these comments correlate with cancer found at hysterectomy. Pathology reports for 824 women with CAH diagnoses who underwent hysterectomy were reviewed to identify those qualified by comments indicating concern for cancer. The rate of cancer, severity of disease, and effects of endometrial sampling method and age were determined. Comments indicating suspicion of cancer qualified 219 of 824 (27%) CAH diagnoses and were associated with a significantly higher cancer rate at hysterectomy (69% versus 40%; P<0.0001), regardless of whether sampling consisted of curettage or biopsy. Cancer severity correlated independently with age. Comments indicating concern for underlying cancer frequently qualify CAH diagnoses and are associated with a high likelihood of cancer and with more extensive disease, especially for older women.

Trachelectomy Following Supracervical Hysterectomy

Objective: The purpose of this study was to assess the reasons for trachelectomy following supracervical hysterectomy. Methods: A retrospective chart review was performed for all women undergoing trachelectomy following supracervical hysterectomy between January 1999 and October 2009 at Northwestern University's Prentice Women's Hospital. Data collected included demographics, indications, and pathology for both the supracervical hysterectomy and trachelectomy, as well as surgical modalities used and complications for each procedure. Results: Over a 10-year period, 27 trachelectomies were performed. The preoperative indications for supracervical hysterectomy in these 27 patients were: leiomyomata (16), abnormal uterine bleeding (4), pelvic pain (3), pelvic mass (2), prolapse (1), and complex atypical endometrial hyperplasia (1). The indications for trachelectomy were: pathologic evidence of uterine malignancy in 9 patients (33%), including 5 endometrial cancers, 3 stromal sarcomas, and 1 leiomyosarcoma; interval diagnosis of cervical malignancy in 2 patients (7%); interval development of cervical dysplasia in 5 patients (19%); and various benign conditions, such as pain (2), bleeding (5), prolapse (2), cervical fibroid (1), and pelvic mass (1), in 11 patients (41%). Conclusions: A small, but clinically important proportion of patients undergoing supracervical hysterectomy for apparent benign disease will require trachelectomy because of the pathologic finding of uterine malignancy in the hysterectomy specimen or the subsequent development of cervical intraepithelial neoplasia or cancer. (J GYNECOL SURG 28:9)

Risk for Advanced-Stage Endometrial Cancer in Surgical Specimens from Patients with Complex Endometrial Hyperplasia with Atypia

Objectives: To determine the incidence of endometrial cancer in patients undergoing hysterectomy for atypical complex endometrial hyperplasia and to study the risk of advanced endometrial cancer that may be associated with extra-uterine disease. Methods: A retrospective chart review was performed of the records of all women who underwent hysterectomy for a preoperative diagnosis of complex hyperplasia with atypia from two teaching hospitals between 1999 and 2006. Demographic and clinical variables were collected and analyzed for the 80 patients identified by the initial screening methods. Results: After screening and exclusions, 66 women with a preoperative diagnosis of atypical complex hyperplasia who subsequently underwent a hysterectomy were identified. Eleven of the 66 patients with atypical complex hyperplasia had a diagnosis of endometrial carcinoma in the hysterectomy specimens (17%). No endometrial cancer patient was staged greater than stage 1B or had greater than grade 2 disease. The patients with endometrial cancer were older (p < 0.05). Evidence of myometrial invasion was found in 63% (7/11) of the cancer cases, but all were less than 50% of the myometrium. Conclusion: Endometrial cancer found at the time of hysterectomy for complex hyperplasia with atypia may be associated with less advanced disease.

Abstract A13: AdipoR1 overexpression and AMPK signaling in histologically normal endometrium from obese women and in endometrial tumorigenesis

Abstract Background: Obesity is a significant risk factor for the development of endometrial cancer (EC). Epidemiological studies indicate that adiponectin is significantly decreased in the obese woman and in women with EC. Adiponectin is an insulin-sensitizing, anti-inflammatory cytokine produced in adipose that has pleiotropic effects on numerous physiologic processes and peripheral tissues. In normal metabolic tissues, adiponectin acts through the adiponectin receptor 1 (AdipoR1) to activate the AMPK pathway. Adiponectin stimulates AMPK by promoting the formation of AdipoR1-APPL1 complexes. APPL2 antagonizes AdipoR1 signaling by blocking the formation of these complexes. AdipoR1-APPL1 complexes activate AMPK signaling which can negatively regulate the mTOR pathway, an important contributor to the development of endometrial complex atypical hyperplasia (CAH) and EC, to inhibit protein synthesis and cell growth during times of cellular starvation. The goal of these studies was to assess adiponectin signaling pathway components (AdipoR1, APPL1 and APPL2) expression and activation of AMPK and mTOR signaling in histologically normal endometrium from lean and obese women and in endometrial CAH and EC from obese women. Methods: We quantitated transcript levels of AdipoR1 by qRT-PCR in timed endometrial biopsies obtained from lean women (BMI &amp;lt; 25.0kg/m2) and obese women (BMI &amp;gt; 30.0kg/m2) that were histologically confirmed to have normal proliferative phase endometrium and compared to biopsies from obese women with endometrial CAH and grade 1 endometrioid endometrial adenocarcinoma. Protein expression of AdipoR1 and the adaptor proteins APPL1/L2 was evaluated by immunohistochemistry. We assessed functional activation of AMPK (phosphorylation of S35 of ACC) and mTOR (phosphorylation of S235 of S6 ribosomal protein) pathways by immunohistochemistry. Results: There was a significant stepwise increase in the expression of AdipoR1 in normal obese endometrium and endometrial CAH as compared to normal lean endometrium. However, the expression of AdipoR1 was not significantly increased in EC (confirmed at the protein level). Overexpression of APPL2, but not APPL1 was evident in EC as compared to normal lean endometrium, normal obese endometrium and endometrial CAH. Consistent with normal physiology, phosphorylation of ACC was higher in normal lean endometrium as compared to normal obese endometrium. This data indicates that AMPK signaling was activated in normal lean endometrium as compared to normal obese endometrium, although there was no difference in mTOR activation. Endometrial CAH showed low expression of phosphorylated ACC and overexpression of phosphorylated S6 indicating that AMPK signaling is not activated and mTOR signaling is increased. Surprisingly, phosphorylation of ACC was significantly increased in EC with concomitant overexpression of phosphorylated S6 indicating that both AMPK and mTOR signaling were activated. Conclusions: Under conditions of obesity and we identified overexpression of AdipoR1 which is known in metabolic tissues to signal to AMPK. Upregulation of AdipoR1 occurs despite decreased serum levels of adiponectin in obesity and may indicate that receptor overexpression is compensatory to decreased levels of ligand. However, in the setting of EC we identified upregulation of AMPK signaling with low expression of AdipoR1 and upregulation of mTOR signaling. In addition, overexpression of APPL2, which is thought to inhibit AdipoR1-APPL1 complex formation did not effect activation of AMPK signaling in EC. Overall, these studies suggest that in EC there is a defect in the ability of AMPK to engage TSC2 and inhibit mTOR. Citation Information: Cancer Prev Res 2011;4(10 Suppl):A13.

Loss of BAF250a (ARID1A) is frequent in high‐grade endometrial carcinomas

Mutation of the ARID1A gene and loss of the corresponding protein BAF250a has recently been described as a frequent event in clear cell and endometrioid carcinomas of the ovary. To determine whether BAF250a loss is common in other malignancies, immunohistochemistry (IHC) for BAF250a was performed on tissue microarrays (TMAs) in more than 3000 cancers, including carcinomas of breast, lung, thyroid, endometrium, kidney, stomach, oral cavity, cervix, pancreas, colon and rectum, as well as endometrial stromal sarcomas, gastrointestinal stromal tumours, sex cord-stromal tumours and four major types of lymphoma (diffuse large B cell lymphoma, primary mediastinal B cell lymphoma, mantle cell lymphoma and follicular lymphoma). We found that BAF250a loss is frequent in endometrial carcinomas but infrequent in other types of malignancies, with loss observed in 29% (29/101) of grade 1 or 2 and 39% (44/113) of grade 3 endometrioid carcinomas of the endometrium, 18% (17/95) of uterine serous carcinomas and 26% (6/23) of uterine clear cell carcinomas. Since endometrial cancers showed BAF250a loss, we stained whole tissue sections for BAF250a expression in nine cases of atypical hyperplasia and 10 cases of atypical endometriosis. Of the nine cases of complex atypical endometrial hyperplasia, all showed BAF250a expression; however, of 10 cases of atypical endometriosis (the putative precursor lesion for ovarian clear cell and endometrioid carcinoma), one case showed loss of staining for BAF250a in the atypical areas, with retention of staining in areas of non-atypical endometriosis. This was the sole case that recurred as an endometrioid carcinoma, indicating that BAF250a loss may be an early event in carcinogenesis. Since BAF250a loss is seen in endometrial carcinomas at a rate similar to that seen in ovarian carcinomas of clear cell and endometrioid type, and is uncommon in other malignancies, we conclude that loss of BAF250a is a particular feature of carcinomas arising from endometrial glandular epithelium.

Stromal Deletion of the APC Tumor Suppressor in Mice Triggers Development of Endometrial Cancer

The contribution of the stromal microenvironment to the progression of endometrial cancer has not been well explored. We have conditionally expressed a mutant allele of adenomatous polyposis coli (APC(cKO)) in murine uterine stroma cells to study its effect on uterine development and function. In addition to metrorrhagia, the mice develop complex atypical endometrial gland hyperplasia that progresses to endometrial carcinoma in situ and endometrial adenocarcinoma as evidenced by myometrial invasion. Stromal cells subjacent to the carcinoma cells express alpha-smooth muscle actin (αSMA) with fewer cells expressing platelet-derived growth factor α compared with normal stromal cells, suggesting that the mutant stromal cells have acquired a more myofibroblastic phenotype, which have been described as cancer-associated fibroblasts and have been shown to induce carcinogenesis in other organ systems. Analyses of human endometrial cancer specimens showed substantial αSMA expression in the stroma compared with normal endometrial stroma cells. We also show that APC(cKO) mutant uteri and human endometrial cancer have decreased stromal levels of transforming growth factor β and bone morphogenetic protein activities and that the mutant uteri failed to respond to exogenous estradiol stimulation. The mutant stroma cells also had higher levels of vascular endothelial growth factor and stromal derived factor signaling components and diminished expression of estrogen receptor α and progesterone receptor, which is common in advanced stages of human endometrial cancer and is an indicator of poor prognosis. Our results indicate that de novo mutation or loss of heterozygosity in stromal APC is sufficient to induce endometrial hyperplasia and endometrial carcinogenesis by mechanisms that are consistent with unopposed estrogen signaling in the endometrial epithelium.

Progression of Pelvic Implants to Complex Atypical Endometrial Hyperplasia After Uterine Morcellation

Supracervical hysterectomy, a surgical technique that involves removal of the uterus while preserving the cervix, places women at an increased risk for future morbidity. The patient presented 7 years after laparoscopic supracervical hysterectomy for benign disease, with pelvic pain, urinary frequency, abdominal bloating, and tenderness. Surgical exploration revealed myometrial implants, along with a larger mass on the mesentery of the sigmoid composed of endometrium with complex atypical hyperplasia in a patient without a prior history of complex atypical hyperplasia. The patient was symptom-free 6 months postoperatively. Histology found during reoperation after laparoscopic supracervical hysterectomy includes endometriosis, residual endometrium, and leiomyomas. In this case, a woman with no prior history of endometrial atypia later developed complex adenomatous endometrial hyperplasia in a peritoneal implant. This finding adds to the list of possible complications after laparoscopic-assisted supracervical hysterectomy and uterine morcellation.

Abstract 2929: Adipokine receptor dysregulation and AMPK signaling in histologically normal endometrium from obese women and in endometrial tumorigenesis

Abstract Background: Obesity is a significant risk factor for the development of endometrial cancer (EC). Endometrial tissue biomarkers of risk would be useful in identifying obese women at particular risk for developing EC. Excess adipose tissue produces inflammatory cytokines, called adipokines that are thought to regulate proliferation in the endometrium and promote the development of EC. Epidemiological studies indicate that the adipokines adiponectin, leptin, IL-6 and TNFα are dysregulated in the obese woman and in women with EC. Activation of the mTOR pathway is an important contributor to the development of endometrial complex atypical hyperplasia (CAH), the precursor to EC. In normal metabolic tissues, adipokines act through their receptors to activate pathways including AMPK that crosstalk with the mTOR pathway to either promote activation (leptin, IL-6) or cause inhibition (adiponectin, TNFα). The goal of these studies was to assess adipokine receptor (AdipoR1, AdipoR2, Ob-Rb, IL-6Rα, IL6-Rβ TNFαR1 and TNFαR2) expression and activation of AMPK and mTOR signaling in histologically normal endometrium from lean and obese women and in endometrial CAH and EC. Methods: We quantitated adipokine receptor transcript levels by qRT-PCR in timed endometrial biopsies obtained from lean women (BMI &amp;lt; 25.0kg/m2) and obese women (BMI &amp;gt; 30.0kg/m2) that were histologically confirmed to have normal proliferative phase endometrium. These biopsies were compared to biopsies from obese women with CAH and EC. We assessed functional activation of AMPK (phosphorylation of T172 of AMPKα) and mTOR (phosphorylation of S235 of S6 ribosomal protein) pathways by immunohistochemistry. Results: There was a significant stepwise increase in the expression of AdipoR1, TNFαR1 and TNFαR2 in normal obese endometrium and endometrial CAH as compared to normal lean endometrium. The increased expression of AdipoR1, TNFαR1 and TNFαR2 seen in obese endometrium and CAH was not seen in EC. We identified increased expression of the Ob-Rb in EC as compared to normal endometrium and CAH. Surprisingly, AMPKα phosphorylation was increased in the normal obese endometrium compared to normal lean endometrium. AMPK phosphorylation was absent in the majority of CAH which showed activation of mTOR signaling. However, in the majority of EC with activated mTOR, AMPK was activated. Conclusions: Under conditions of obesity and tumorigenesis we identified up-regulation of receptors known in metabolic tissues to signal to AMPK. However, in the setting of tumorigenesis of the endometrium we identified upregulation of mTOR suggesting that there is a defect in the ability of AMPK to engage TSC2 and inhibit mTOR. These studies suggest that there may be a defect in AMPK regulation of mTOR signaling in obese women at risk for this disease. In addition, adipokine receptor expression may be a good biomarker of EC risk in obese women. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2929.

Abstract A13: Overexpression of adipokine receptors and dysregulation of AMPK signaling in normal and hyperplastic endometrium from obese women

Abstract Background: Excess adipose tissue in the obese woman produces inflammatory cytokines, called adipokines, that are thought to regulate proliferation in peripheral tissues such as the endometrium to promote the development of cancer. Epidemiological studies indicate that the adipokines IL-6, leptin, TNFα and adiponectin are dysregulated in the obese woman and in women with endometrial cancer (EC). Activation of the IGF-IR/PI3K/mTOR pathway is an important contributor to the development of endometrial complex atypical hyperplasia (CAH), the precursor to endometrioid-type endometrial cancer. Adipokines act through their receptors to activate pathways that exhibit signal transduction crosstalk with the IGF-IR/PI3K/mTOR pathway that is thought to either promote activation (IL-6, leptin) or inhibit this pathway (TNFα, adiponectin). The goal of these studies was to assess the corresponding adipokine receptors (IL-6Rα, IL6-Rβ, Ob-Rb, AdipoR1, AdipoR2, TNFαR1 and TNFαR2) expression and activation of AMPK and IGF-IR/PI3K/mTOR signaling pathways in normal endometrium from lean and obese women and in endometrial hyperplasia from obese women. Methods: We quantitated adipokine receptor transcript levels of the receptors by qRT-PCR in timed endometrial biopsies obtained from lean women (BMI &amp;lt; 25 kg/m2) and obese women (BMI &amp;gt; 30 kg/m2) that were histologically confirmed to have normal proliferative phase endometrium. These biopsies were compared to biopsies from obese women with endometrial CAH. We assessed functional activation of AMPK and mTOR pathways by immunohistochemistry. Results: There was a significant stepwise increase in the expression of AdipoR1, TNFαR1 and TNFαR2 in normal lean endometrium, normal obese endometrium and obese endometrial CAH. In addition, IL-6Rβ transcripts were significantly increased in obese endometrial CAH as compared to both lean and obese normal endometrium. Phosphorylation of AMPK was increased in obese normal endometrium compared to lean normal endometrium. Surprisingly, in endometrial CAH mTOR signaling was activated and activation of AMPK was lost compared to lean and obese normal endometrium. Conclusions: The stepwise increase in the expression of AdipoR1, TNFαR1 and TNFαR2 in the obese endometrium and endometrial CAH as compared to normal lean endometrium suggests that dysregulation of adipokine receptor expression is an early event and may be predictive of women at risk of developing endometrial CAH and EC. The overexpression of AdipoR1 in obese endometrium may contribute to activation of AMPK. The overexpression of AdipoR1 and activation of AMPK in obese endometrium may be a compensatory mechanism to dampen growth factor signaling through the IGF-IR/PI3K/mTOR pathway. In endometrial CAH there is upregulation of IL-6Rβ which may contribute to activation of mTOR by activating PI3K upstream. Activation of mTOR and loss of AMPK activation may contribute to the abnormal proliferation seen in endometrial CAH. These studies suggest that overexpression of adipokine receptor expression may be an important contributor to the risk of endometrial hyperplasia and cancer in obese women. Citation Information: Cancer Prev Res 2010;3(1 Suppl):A13.