Non-endometrioid Adenocarcinoma Research Articles

Can the ADC Value Be Used as an Imaging “Biopsy” in Endometrial Cancer?

Background: The tumor histological grade is closely related to the prognosis of patients with endometrial cancer (EC). Multiparametric MRI, including diffusion-weighted imaging (DWI), provides information about the cellular density that may be useful to differentiate between benign and malignant uterine lesions. However, correlations between apparent diffusion coefficient (ADC) values and histopathological grading in endometrial cancer remain controversial. Material and methods: We retrospectively evaluated 92 patients with endometrial cancers, including both endometrioid adenocarcinomas (64) and non-endometrioid adenocarcinomas (28). All patients underwent DWI procedures, and mean ADC values were calculated in a region of interest. These values were then correlated with the tumor grading offered by the histopathological examination, which was considered the gold standard. In this way, the patients were divided into three groups (G1, G2, and G3). The ADC values were then compared to the results offered by the biopsy to see if the DWI sequence and ADC map could replace this procedure. We also compared the mean ADC values to the myometrial invasion (</>50%) and lymphovascular space invasion. Results: We have divided the ADC values into three categories corresponding to three grades: >0.850 × 10−3 mm2/s (ADC1), 0.730–0.849 × 10−3 mm2/s (ADC2) and <0.730 × 10−3 mm2/s (ADC3). The diagnostic accuracy of the ADC value was 85.71% for ADC1, 75.76% for ADC2, and 91.66% for ADC3. In 77 cases out of 92, the category in which they were placed using the ADC value corresponded to the result offered by the histopathological exam with an accuracy of 83.69%. For only 56.52% of patients, the biopsy result included the grading system. For each grading category, the mean ADC value showed better results than the biopsy; for G1 patients, the mean ADC value had an accuracy of 85.71% compared to 66.66% in the biopsy, G2 had 75.76% compared to 68.42%, and G3 had 91.66 compared to 75%. For both deep myometrial invasion and lymphovascular space invasion, there is a close, inversely proportional correlation with the mean ADC value. Conclusions: Mean endometrial tumor ADC on MR-DWI is inversely related to the histological grade, deep myometrial invasion and lymphovascular space invasion. Using this method, the patients could be better divided into risk categories for personalized treatment.

Endometrial Cancer-Adjacent Tissues Express Higher Levels of Cancer-Promoting Genes than the Matched Tumors.

Molecular alterations in tumor-adjacent tissues have recently been recognized in some types of cancer. This phenomenon has not been studied in endometrial cancer. We aimed to analyze the expression of genes associated with cancer progression and metabolism in primary endometrial cancer samples and the matched tumor-adjacent tissues and in the samples of endometria from cancer-free patients with uterine leiomyomas. Paired samples of tumor-adjacent tissues and primary tumors from 49 patients with endometrial cancer (EC), samples of endometrium from 25 patients with leiomyomas of the uterus, and 4 endometrial cancer cell lines were examined by the RT-qPCR, for MYC, NR5A2, CXCR2, HMGA2, LIN28A, OCT4A, OCT4B, OCT4B1, TWIST1, STK11, SNAI1, and miR-205-5p expression. The expression levels of MYC, NR5A2, SNAI1, TWIST1, and STK11 were significantly higher in tumor-adjacent tissues than in the matched EC samples, and this difference was not influenced by the content of cancer cells in cancer-adjacent tissues. The expression of MYC, NR5A2, and SNAI1 was also higher in EC-adjacent tissues than in samples from cancer-free patients. In addition, the expression of MYC and CXCR2 in the tumor related to non-endometrioid adenocarcinoma and reduced the risk of recurrence, respectively, and higher NR5A2 expression in tumor-adjacent tissue increased the risk of death. In conclusion, tissues proximal to EC present higher levels of some cancer-promoting genes than the matched tumors. Malignant tumor-adjacent tissues carry a diagnostic potential and emerge as new promising target of anticancer therapy.

Peritoneal metastases from endometrial cancer treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: a 13-case series and systematic literature review

Objectives: Endometrial cancer with peritoneal metastases may have similar biology to other cancers that respond to treatment with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). We present our experience and provide an extensive literature review of endometrial cancer treated with CRS/HIPEC. Methods: A review of a single-institution prospective database of 949 CRS/HIPEC patients and the English literature in PubMed was performed to identify cases of peritoneal metastases from endometrial origin treated with CRS/HIPEC. Perioperative variables and outcomes were analyzed. Patients at our center were selected for CRS/HIPEC based on feasibility of obtaining a complete cytoreduction (CC) (residual disease Results: Endometrial cancer was identified in 16 patients from 1994-2020. Three cases (19%) were aborted due to inability to achieve a CC. Of the 13 patients treated with CRS/HIPEC, histopathologic subtypes included 6 (46%) endometrioid adenocarcinomas, 4 (31%) endometrial carcinosarcomas, 2 (15%) mixed endometrioid/serous adenocarcinomas, and 1 (8%) clear cell carcinoma. Median age at CRS/HIPEC was 63 years (IQR: 53-66; range: 44-72). Seven (54%) underwent CRS/HIPEC as initial treatment and 6 (46%) underwent CRS/HIPEC for recurrence. Median PCI was 15 (IQR: 6-24; range: 3-36) with CC achieved in 12 (92%). Median hospital stay was 10 days (IQR: 8-11; range: 6-15). Only 1 (7%) grade III complication and no grade IV/V complications occurred. Adjuvant chemotherapy was administered in 5 (38%) patients. After median follow-up of 56.4 months (CI95% 49.0-63.8; range: 18.7-85.2), median overall (OS) and progression-free survival (PFS) were 33.9 and 14.4 months, respectively. Literature review revealed 8 reports with 107 cases of endometrial cancer treated with CRS/HIPEC, including 50% endometrioid adenocarcinomas, 14% serous carcinomas, 3% clear cell carcinomas, 3% carcinosarcomas, 2% mixed endometrioid/serous adenocarcinomas, 1% mesonephric, 1% squamous carcinomas, and 26% unspecified non-endometrioid adenocarcinomas. Age at HIPEC ranged from 26-73 years. Overall, 76% were treated for disease recurrence and 24% were newly diagnosed. CC was achieved in 92%. Length of hospital stay ranged from 6-90 days and 70% received adjuvant chemotherapy. Median OS and PFS ranged from 19.4-33.1 and 11.4-18 months, respectively. Conclusions: CRS/HIPEC seems to be a reasonable strategy to treat these challenging patients with PM from endometrial origin and may offer recurrence-free time off treatment in select patients whose alternative is continuous systemic therapy. Multicenter trials are indicated to evaluate survival and optimal patient selection criteria.

Metabolic syndrome affects the long-term survival of patients with non-endometrioid carcinoma of the uterine corpus.

To probe the influence of metabolic syndrome (MS) on the long-term survival of patients with non-endometrioid adenocarcinoma. Between January 2003 and December 2012, 139 Chinese patients with non-endometrial adenocarcinoma were analyzed in a retrospective study. Patients who had received any treatment before surgery were excluded. Survival times were compared between patients with and without MS. Overall, 41 (29.5%) patients had MS; the highest incidence of MS was observed in those with uterine serous carcinoma (19/45, 42.2%). For uterine serous carcinoma or adenosquamous carcinoma, MS was an independent predictive factor of morbidity (P=0.023 and 0.016, respectively). For the overall population, those with MS had a significantly lower survival rate than those without MS (P=0.008), and the median overall survival (mOS) was 15months versus 55months (P<0.001, hazard ratio [HR] 0.45, 95% confidence interval [CI] 0.29-0.69). Similarly, a lower survival rate (P=0.020) and shorter mOS (19months vs 55months, P=0.007, HR 0.41, 95% CI 0.20-0.83) were also found in the uterine serous carcinoma population with MS. Multivariate Cox regression analyses showed that disease stage (P=0.023) and MS (P=0.008) were independent prognostic factors for uterine serous carcinoma. The present study suggests that MS is a prognostic factor for non-endometrioid adenocarcinoma, especially uterine serous carcinoma.

Abstract 3344: Effect of anticoagulation on the cancer stage at time of diagnosis of endometroid adenocarcinoma in a cohort of postmenopausal patients

Abstract Objectives: We sought to determine whether postmenopausal women on chronic anticoagulation were diagnosed with endometrial cancer at an earlier stage. Methods: A retrospective case-control study of women at a tertiary care medical center with a diagnosis of Endometrioid Adenocarcinoma on chronic anticoagulation at time of diagnosis in comparison with patients not on anticoagulation was performed. Patients with personal history of cancer, including breast cancer, non-postmenopausal bleeding, and non-Endometrioid Adenocarcinoma histopathology were excluded. Anticoagulation was defined as use of Enoxaparin, Warfarin, Apixaban, Rivaroxaban or Clopidogrel. Indications for anticoagulation included atrial fibrillation, deep vein thrombosis/pulmonary embolism, or stroke. The primary outcome was Endometrioid Cancer stage (I, II, III/IV and X). The secondary outcomes were duration of bleeding to presentation and presentation to diagnosis. Statistical analysis was performed using Wilcoxan-Rank Sum Test and Cochran-Armitage Trend Test. Results: 25 postmenopausal patients met the inclusion criteria for being treated in the last 10 years. 100 controls not on anticoagulation (non-AC) were identified for a 4:1 comparison to obtain a 2-sided alpha level of 0.05. Results were divided into 3 groups: 1) All patients, 2) Non-white patients, 3) White patients. Subjects were controlled for age (P&amp;lt;0.001) and BMI (P&amp;lt;0.049). The results indicated that non-AC patients were more likely to be diagnosed at Stage 1 when compared to the AC patients in all 3 categories. The trend was not statistically significant for the non-white patients (p=0.133), but was statistically significant in the overall population (p&amp;lt;0.001) and White patients (p&amp;lt;0.001). No statistical significance was detected for duration from bleeding to presentation and presentation to diagnosis between the AC and non-AC groups. However, median days from bleeding to presentation are considerably larger for the non-AC than AC (Group 1: 42 vs 14 days, Group 2: 75 vs 33 days Group 3: 30 vs 14 days, respectively). Conclusion: Non-anticoagulated patients had an earlier cancer stage at diagnosis. Although anticoagulated patients may present earlier, they have advanced cancer stage. These findings should prompt immediate evaluation of patients on chronic anticoagulation to optimize oncologic management and prognosis. Citation Format: Ghadear Shukr, Tra Pham, Thomas Buekers. Effect of anticoagulation on the cancer stage at time of diagnosis of endometroid adenocarcinoma in a cohort of postmenopausal patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3344.

Expression and clinical significance of MMR protein and MLH1 promoter methylation testing in endometrial cancer

Objective: To explore the expression and clinical significance of mismatch repair (MMR) protein and MLH1 promoter methylation testing in endometrial cancer (EC) . Methods: A total of 420 cases with EC diagnosed by the surgical pathology examination from the Department of Pathology of PLA General Hospital, MLH1, MSH2, MSH6 and PMS2 protein in EC were detected by immunohistochemistry and methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) testing. Results: (1) Of the 420 tumor cases, the total expression loss rate of MMR protein was 34.5% (145/420) , the expression loss rates of MLH1, MSH2, MSH6 and PMS2 protein were respectively 17.1% (72/420) , 8.1% (34/420) , 7.4% (31/420) , 26.2% (110/420) and loss rates of MLH1 and PMS2, MSH2 and MSH6 were16.7% (70/420) , 6.2% (26/420). When there was a loss of MMR protein expression, any one or more protein expression deletions in MLH1, PMS2, MSH2 and MSH6, it could be Lynch syndrome related endometrial carcinoma (LS-EC). The expression loss rate of MMR protein in the poorly differentiated endometrioid adenocarcinoma was higher than that in the well differentiated endometrioid adenocarcinoma (P<0.05). (2) The expression loss rate of MMR and PMS2 protein had statistically significant between the endometrioid adenocarcinoma and non-endometrioid adenocarcinoma (P<0.01). The expression loss rate of MSH2 protein had statistically significant in the stage Ⅲ (P<0.01). Moreover, there were also significant differences in depth of myometrial invasion and lymph node metastasis between the expression loss rate of MMR protein (P<0.05). (3) The expression loss rate of MLH1 protein was 72 cases and 57 cases had MLH1 promoter methylation testing (excluding those who were not qualified for DNA testing). The positive rate was 47.4% (27/57). Therefore, these patients were sporadic endometrial cancer, not non-LS-EC. Conclusions: MMR protein may be play an important role in the development of endometrial cancer and be indicated poor prognosis. Immunohistochemical staining and MLH1 promoter methylation detection may be play an important role in the screening of the LS-EC.

A Comparative Survival Analysis of Adjuvant Vaginal Cylinder Brachytherapy versus External Beam Radiation Therapy for Stage I Non-endometrioid Adenocarcinomas Treated with Multi-Agent Chemotherapy

A Comparative Survival Analysis of Adjuvant Vaginal Cylinder Brachytherapy versus External Beam Radiation Therapy for Stage I Non-endometrioid Adenocarcinomas Treated with Multi-Agent Chemotherapy

Can the apparent diffusion coefficient differentiate the grade of endometrioid adenocarcinoma and the histological subtype of endometrial cancer?

Background Diffusion-weighted imaging (DWI) provides useful information for the identification of benign and malignant uterine lesions. However, the use of the apparent diffusion coefficient (ADC) for histopathological grading of endometrial cancer is controversial. Purpose To explore the use of ADC values in differentiating the preoperative tumor grading of endometrioid adenocarcinomas and investigate the relationship between the ADC values of endometrial cancer and the histological tumor subtype. Material and Methods We retrospectively evaluated 98 patients with endometrial cancers, including both endometrioid adenocarcinomas (n = 80) and non-endometrioid adenocarcinomas (n = 18). All patients underwent DWI procedures and ADC values were calculated. The Kruskal-Wallis test and the independent samples Mann-Whitney U test were used to compare differences in the ADC values between different tumor grades and different histological subtypes. Results The mean ADC values (ADCmean) for high-grade endometrioid adenocarcinomas were significantly lower than the values for low-grade tumors (0.800 versus 0.962 × 10-3 mm2/s) ( P = 0.002). However, no significant differences in ADCmean and minimum ADC values (ADCmin) were found between tumor grades (G1, G2, and G3) of endometrial cancer. Compared with endometrioid adenocarcinomas, the adenocarcinoma with squamous differentiation showed lower ADC values (mean/minimum = 0.863/0.636 versus 0.962/0.689 × 10-3 mm2/s), but the differences were not significant ( Pmean = 0.074, Pmin = 0.441). Moreover, ADCmean for carcinosarcomas was significantly higher than the value for G3 non-carcinosarcoma endometrial cancers (1.047 versus 0.823 × 10-3 mm2/s) ( P = 0.001). Conclusion The ADCmean was useful for identifying high-grade and low-grade endometrioid adenocarcinomas. Additionally, squamous differentiation may decrease ADCmean and ADCmin of endometrioid adenocarcinoma, and carcinosarcomas showed relatively high ADCmean.

Drug screening and grouping by sensitivity with a panel of primary cultured cancer spheroids derived from endometrial cancer.

Several molecular targeting drugs are being evaluated for endometrial cancer; selecting patients whose cancers are sensitive to these agents is of paramount importance. Previously, we developed the cancer tissue‐originated spheroid method for primary cancer cells taken from patients’ tumors as well as patient‐derived xenografts. In this study, we successfully prepared and cultured cancer tissue‐originated spheroids from endometrial cancers. Characteristics of the original tumors were well retained in cancer tissue‐originated spheroids including morphology and expression of p53 or neuroendocrine markers. We screened 79 molecular targeting drugs using two cancer tissue‐originated spheroid lines derived from endometrioid adenocarcinoma grade 3 and serous adenocarcinoma. Among several hits, we focused on everolimus, a mammalian target of rapamycin complex 1 inhibitor, and YM155, a survivin inhibitor. When sensitivity to everolimus or YM155 was assessed in 12 or 11 cancer tissue‐originated spheroids, respectively, from different endometrial cancer patients, the sensitivity varied substantially. The cancer tissue‐originated spheroids sensitive to everolimus showed remarkable suppression of proliferation. The phosphorylation status of the mammalian target of rapamycin complex 1 downstream molecules before and after everolimus treatment did not predict the effect of the drug. In contrast, the cancer tissue‐originated spheroids sensitive to YM155 showed remarkable cell death. The effect of YM155 was also confirmed in vivo. The histological type correlated with YM155 sensitivity; non‐endometrioid adenocarcinomas were sensitive and endometrioid adenocarcinomas were resistant. Non‐canonical autophagic cell death was the most likely cause of cell death in a sensitive cancer tissue‐originated spheroid. Thus, sensitivity assays using cancer tissue‐originated spheroids from endometrial cancers may be useful for screening drugs and finding biomarkers.

Survival by surgical approach in patients with endometrial adenocarcinoma treated in Navarra in the 2001-2009

Endometrial adenocarcinoma is the most frequent gynaecological neoplasia after breast cancer and represents 6% of cancers in women. The treatment for this disease is surgery. The majority of cases are diagnosed in their initial stages and surgery is curative; on other occasions it is necessary to add radiotherapy and chemotherapy. The classical treatment for endometrial adenocarcinoma is hysterectomy with double adnexectomy by laparotomy, with the addition of pelvic and para-aortic lymphadenectomy and omentectomy according to the characteristics of the case. During the last 10-15 years laparoscopy has been introduced in the surgical treatment of endometrial adenocarcinoma. The main aim of this study is to analyze the cases of endometrial adenocarcinoma treated surgically in the former Virgen de Camino Hospital (nowadays the Hospital Complex of Navarra) during 2001-2009. Historical cohort of 444 patients with endometrial adenocarcinoma during 2001-2009 who received surgical treatment, followed four years. The results confirm that laparoscopy is a safe alternative to classical laparotomy as it does not affect either survival or time free of disease, in both endometrioid adenocarcinoma and non-endometrioid adenocarcinoma.

Outpatient-based high-dose-rate interstitial brachytherapy for gynecologic malignancies.

To evaluate outpatient-based high-dose-rate (HDR) interstitial brachytherapy (ISBT) in the treatment of gynecologic malignancies. Between December 2006 and July 2012, 50 patients were treated with twice-daily outpatient-based HDR iridium-192 ISBT at our institution. Thirty-two patients had vaginal cancers, 13 vulvar, 3 urethral, and 2 cervical cancers. The most common histologies were squamous cell carcinoma (58%) and endometrioid adenocarcinoma (26%). Twenty-six patients were treated with definitive radiation therapy with or without platinum-based chemotherapy, 16 were treated for recurrent disease, 5 were treated in the postoperative setting, and 3 were treated palliatively. Forty patients received external beam radiation therapy before ISBT. Median followup was 13.7 months. Median interstitial dose was 18 Gy in 2.25 Gy twice-daily fractions prescribed to the implant volume. Median external beam dose was 50.4 Gy in 1.8 Gy daily fractions prescribed to the primary disease site. Eight patients (16%) were seen in the emergency room or were admitted to the hospital during treatment. Six patients (17%) experienced significant complications after treatment (3 ulcerations at the primary site, 1 vaginal necrosis, 1 vaginal abscess, and 1 patient with urinary obstruction). Larger volume encompassing 100% of the prescribed dose was correlated with significant complications on multivariate analysis (p = 0.039). Actuarial local control at 1 year was 72%, with univariate analysis demonstrating worse local control for nonendometrioid adenocarcinoma compared with squamous cell carcinoma (20% vs. 84%, p = 0.044). Outpatient-based HDR ISBT is feasible and safe, with toxicity and local control rates consistent with historical outcomes.

Prognosis for endometrial cancer patients treated with systematic pelvic and para-aortic lymphadenectomy followed by platinum-based chemotherapy.

The purpose of this study was to analyze the prognosis for endometrial cancer patients treated with systematic pelvic and para-aortic lymphadenectomy (PLA and PALA) followed by platinum-based chemotherapy. From 1994 to 2004, in the Cancer Institute Hospital, 502 patients who were surgically treated with systematic PLA and PALA were enrolled in this study. Their prognosis and clinicopathological features were retrospectively reviewed. One hundred ninety-one (38.0%) patients received adjuvant platinum-based chemotherapy. Lymph node (LN) metastasis was observed in 80 (15.9%) patients, pelvic-only LN metastasis in 27 (5.4%), para-aortic-only LN metastasis in 15 (3.0%), and both pelvic and para-aortic LN metastasis in 38 (7.6%). The median number of metastatic LNs was 2 (range, 1-57), 1 (range, 1-4), and 6 (range, 2-50) in patients with pelvic-only, para-aortic-only, and both pelvic and para-aortic LN metastasis, respectively (P < 0.001). Only 2.6% (2/76) of patients with no myometrial invasion had LN metastasis, and no less than 8.9% (22/247) of patients with myometrial invasion (limited to the inner half) had LN metastasis. Five-year overall survival (OS) for LN metastasis-negative and -positive patients was 96.7% and 76% (P < 0.001), respectively. Five-year OS for patients with metastasis in 1 or 2 LNs was 84.8% and was significantly higher than that for patients with metastasis in 3 or more LNs (57.8%; P = 0.011). In patients with LN metastasis, 5-year OS of endometrioid adenocarcinoma and non-endometrioid adenocarcinoma cell types was 90.2% and 56.7% (P = 0.0016), respectively. Under the settings of thorough PLA and PALA followed by intensive platinum-based chemotherapy for endometrial cancer, metastasis in 1 or 2 LNs seems to have little effect on survival, although para-aortic LNs are involved. This therapeutic strategy could not improve the prognosis of patients with metastasis in 3 or more LNs or patients with non-endometrioid adenocarcinoma cell types along with LN involvement.

Significance of phosphoinositide 3 kinase/AKT pathway alterations in endometrial carcinoma

To investigate the clinicopathologic and prognostic implications of phosphoinositide 3 kinase (PI3K)/AKT pathway alterations in endometrial cancers of Chinese women. The expression of PTEN, p-AKT, and ER/PR was assessed in 71 cases of endometrial carcinoma by immunohistochemistry (EnVision method). The PIK3CA mutation at exon 9 and exon 20 was analyzed by PCR and direct sequencing in 34 tumors. (1) Of the 71 cases of endometrial carcinoma, 65 cases were endometrioid adenocarcinoma (EEC) and 6 cases were nonendometrioid adenocarcinoma (NEEC). PTEN loss of expression was found in 63.4% (45/71) of tumors, and more commonly occurred in EEC (66.2%, 43/65) than that in NEEC (2/6, P = 0.18). Patients with PTEN loss in their tumors (45 cases) had a better survival than those without (26 cases, P = 0.07). In ER negative subgroup, the patients with PTEN loss of expression (12 cases) had longer survival than those with normal PTEN expression (7 cases; P = 0.04). (2) The frequency of PIK3CA mutation was 41.2% (14/34) with a hot mutation spot at T544 in exon 9. PIK3CA mutations more commonly occurred in EEC (44.8%, 13/29) than in NEEC (1/5, P > 0.05). The mutations at exon 9 more commonly occurred in EEC, well- and moderately-differentiated EEC, and tumors at early stage (P > 0.05). On the contrary, in tumors at early stages, the frequency of mutations in exon 20 (14.3%, 4/28) was significantly lower than that at late stages (4/6, P = 0.01). (3) p-AKT was positive in 59.2% (42/71) of tumors that were more frequently found in EEC (60.0%, 39/65) than that in NEEC (3/6, P = 0.68). However, the significant difference of p-AKT expression was found between well- and moderately-differentiated EEC (75.0%, 21/28; 53.6%, 15/28) and poorly-differentiated EEC (3/9, P = 0.02). Moreover, p-AKT expression was significantly correlated with positive ER (r = 0.339, P = 0.00). Endometrial carcinoma patients with loss of PTEN and p-AKT positivity have a favorable prognosis. PIK3CA mutations at exon 9 or 20 may have different impact on the prognosis. The function of PTEN loss and p-AKT expression may vary according to different hormone status.

Stage 1C grade 3 endometrial cancer: the KK Hospital gynaecological oncology group experience.

It is our standard of care to include pelvic lymph node dissection (PLND) in the staging of endometrial cancer, followed by adjuvant vaginal vault brachytherapy. We report our experience and outcome of patients with stage 1C grade 3 endometrial cancer from KK Hospital Singapore. Records of patients with a diagnosis of stage 1C grade 3 endometrial cancer (based on the 1988 FIGO [International Federation of Gynecology and Obstetrics] staging system) from 1995 to 2008 were retrospectively reviewed. Details of surgery, chemotherapy, and radiotherapy were recorded, as were prognostic factors such as histological subtype and number of lymph nodes removed. Dates and sites of relapses were noted. A total of 31 cases were reviewed; 29 had sufficient records to be analyzed, of which one was excluded as she had a second primary cancer (breast). Median follow-up was 50.1 months (15.5-154 months). All cases underwent total hysterectomy and bilateral salpingo-oophorectomy; the majority (22 [76%]) had PLND as well. Those who did not undergo PLND received external beam radiotherapy instead. All but 1 case received postoperative vaginal vault brachytherapy. Eight of 10 patients with nonendometrioid adenocarcinoma (eg, clear cell) histology also received adjuvant chemotherapy. There were 5 systemic relapses (17.9%) and 1 pelvic recurrence (3.6%). The 5-year disease-free survival is 78.6%. No serious (grade 3 or 4) adverse effects were recorded. Pelvic lymph node dissection and vaginal vault brachytherapy seem to be effective in preventing locoregional recurrences, with few associated adverse effects. However, the rate of systemic relapse is relatively high. Adjuvant chemotherapy should also be considered for cases with poor prognostic factors.

Expression and its clinical significance of hsa-miR-155 in serum of endometrial cancer

to investigate the expression of the hsa-miR-155 in serum of endometrial cancer and its clinical significance. collected 44 cases blood specimens before surgery operation from Sep. 2008 to Dec. 2009, and collected 12 cases blood specimens from the health of volunteers in comparison. Real time quantity PCR was used to detect the expression of hsa-miR-155 in those specimens and analyzed clinical pathological with the expression of hsa-mir-155 in endometrial cancer. the expression of hsa-miR-155 was (3.9 ± 0.7) in endometrial cancer, which was significantly higher than that in control group (P < 0.01). The expressions of hsa-miR-155 were (3.7 ± 0.6), (3.9 ± 0.6) and (3.7 ± 0.6) times in well, moderately and poorly differentiated endometrial cancer, respectively, while there were not significant difference (P > 0.05). The expressions were (3.8 ± 0.6) and (3.9 ± 0.6) times between endometrioid adenocarcinoma and non-endometrioid adenocarcinoma, and there were significant difference (P > 0.05). The expressions were (2.1 ± 0.4) and (5.6 ± 0.8) times in stage I - II and III - IV endometrial cancer, respectively, in which there were significant difference (P < 0.05). The expressions of hsa-miR-155 were (5.5 ± 0.5) and (1.9 ± 0.2) times between lymph node metastasis and without lymph node metastasis in endometrial cancer, in which there were significant difference (P < 0.01). Hsa-miR-155 may play an important role in the proliferation, and metastasis of endometrial cancer, which may be a indicator in the diagnosis and prognosis of endometrial cancer and may be used as a predictive biomarker.

Expression profiling of 22 genes involved in the PI3K–AKT pathway identifies two subgroups of high-grade endometrial carcinomas with different molecular alterations

Previously, we showed that PIK3CA and p53 alterations in uterine endometrial carcinomas correlate with poor prognosis. However, the contribution of phosphatidylinositol 3-kinase (PI3K) –AKT deregulation to endometrial carcinogenesis is not completely understood. The purpose of this study was to analyze alterations of this pathway in endometrial carcinomas and correlate them with the most common genetic abnormalities. Expression profiling of 22 genes involved in PI3K–AKT signaling pathway was analyzed in 38 endometrial carcinomas using TaqMan low-density array (TLDA) analysis. The gene expression pattern was analyzed by hierarchical clustering analysis. Unsupervised clustering divided the high-grade endometrial carcinomas into two clusters. One cluster identified tumors with alterations in the PI3K–AKT signaling pathway (exon 20 PIK3CA mutations and/or PTEN mutations 9/15; 60%), and p16 protein overexpression (8/13; 62%). Almost all non-endometrioid adenocarcinomas (serous and clear cell adenocarcinomas) were segregated into this cluster. In contrast, the other cluster identified tumors with p53 alterations (6/6; 100%), p16 protein overexpression (5/5; 100%), and exon 9 PIK3CA mutations (2/6; 33%). Exon 20 PIK3CA and PTEN mutations were not found in this subgroup. Low-grade endometrial carcinomas clustered in a third subgroup characterized by high frequency of PTEN mutations (10/17; 59%) and microsatellite instability (6/17; 35%). Our results show that gene expression profile differences in the PI3K–AKT signaling pathway identify two subgroups of high-grade endometrial carcinomas with different molecular alterations (PI3K–AKT pathway vs p53 alterations) that may have distinct roles in endometrial carcinogenesis. Identification of these subgroups can provide insight into the biology of these tumors and may facilitate the development of future treatments.

Concomitant PI3K–AKT and p53 alterations in endometrial carcinomas are associated with poor prognosis

The status of p53 and the phosphatidylinositol 3-kinase–AKT (PI3K–AKT) signaling pathway was investigated in 132 endometrial carcinomas, including endometrioid endometrial carcinomas, non-endometrioid endometrial carcinomas, and mixed endometrioid adenocarcinomas-non-endometrioid adenocarcinomas. Results were compared with the clinicopathologic parameters associated with prognosis, patients' follow-up, and other genetic alterations found frequently in these tumors. Molecular genetic differences between low-grade and high-grade endometrioid adenocarcinomas were encountered; ie, PIK3CA mutations were detected in 26 and 34% of cases, respectively. We found p53 alterations in only 17% of high-grade endometrioid adenocarcinomas. In contrast, non-endometrioid adenocarcinomas had a higher frequency of p53 alterations (54%), PIK3CA mRNA overexpression (45%), and exon 20 PIK3CA mutations (21%). In the mixed endometrioid adenocarcinomas-non-endometrioid adenocarcinomas, the most frequent alterations were p53 (50%) and PIK3CA (44%) mutations, followed by PTEN mutations (38%). In some cases, p53 and PIK3CA alterations coexisted, but they rarely coexisted with the PTEN mutations. Our findings suggest that the PIK3CA mutations are frequent events in endometrial carcinomas of any histological type. However, location of the PIK3CA mutations, either in exon 9 or exon 20, varies significantly according to the histologic grade and type of carcinoma. Carcinomas with exon 20 PIK3CA mutations or PIK3CA mRNA overexpression were often high-grade carcinomas associated with myometrial invasion; in contrast, tumors that carried exon 9 mutations were more likely to be low-grade carcinomas. The Kaplan–Meier analysis suggested that p53 alterations (strong immunoexpression or mutations) conferred a worse prognosis (P=0.000). Although alterations in the PI3K–AKT signaling pathway alone did not influence overall survival, patients with deregulated PI3K–AKT pathway (PIK3CA and/or PTEN alterations) and p53 alterations had shorter survival (P=0.000) than patients with only p53 alterations. Such a relationship was lost when we considered exon 9 PIK3CA mutations. Our results contribute to further characterize the molecular genetic model for endometrial carcinogenesis.

Prognostic factors of stage III endometrial carcinoma

To investigate the prognostic factors of surgery-pathological stage III endometrial cancer. The clinical data of 102 patients with stage III endometrial cancer, aged 54.9 (27-79), 71 with endometrioid adenocarcinoma, 31 with non-endometrioid adenocarcinoma, 9 undergoing simple surgical treatment, and 42 receiving radiation, 16 receiving chemotherapy, and 35 receiving chemoradiation after surgery, were analyzed retrospectively. Follow-up was conducted for 56 (3-192) months. Cox risk model analysis showed that the risk factors for the prognosis of stage III endometrial cancer were pathological types, method of treatment, vascular thrombosis, and age (all P < 0.05). The average survival time of stage III a endometrial cancer patients purely positive in peritoneal cytology was 74.4 months, significantly longer than that of the patients with serosa and/or annex involvement (53.8 months, P < 0.05). The independent prognostic factors of stage III endometrial cancer are pathological type, method of treatment, vascular thrombosis, and age. The patients with, the prognosis of stage III a endometrial cancer simply positive in peritoneal cytology is better than that with serous and/or annex involvement.

Non-Endometrioid Adenocarcinoma of the Uterine Corpus: A Review of Selected Histological Subtypes

Understanding the etiology, presentation, evaluation, and management of selected non-endometrioid endometrial adenocarcinomas of the uterine corpus is needed to define optimal treatment regimens. The pathology and treatment of selected non-endometrioid endometrial adenocarcinomas of the uterus are reviewed and summarized. The most common non-endometrioid histology is papillary serous (10%), followed by clear cell (2% to 4%), mucinous (0.6% to 5%), and squamous cell (0.1% to 0.5%). Some non-endometrioid endometrial carcinomas behave more aggressively than the endometrioid cancers such that even women with clinical stage I disease often have extrauterine metastasis at the time of surgical evaluation. Therefore, when technically and medically feasible, comprehensive surgical staging is helpful for women with non-endometrioid endometrial cancer histology. Comprehensive surgical staging includes hysterectomy, bilateral salpingo-oophorectomy, pelvic and para-aortic lymphadenectomy, and cytological evaluation of the abdominal cavity. While whole abdominal radiotherapy has a limited role in early-stage uterine papillary serous carcinoma (UPSC) and clear cell carcinoma (CC), there may be a role for postoperative chemotherapy and volume-directed radiotherapy in both early-stage UPSC and CC. In the setting of optimally debulked advanced-stage disease, a combination of radiation and chemotherapy may be indicated. In the setting of recurrent disease or in women with residual disease after surgery, a platinum-based regimen or enrollment in a clinical trial is recommended. UPSC and CC are managed similarly since sufficient data to separate treatment recommendations are lacking. Because both histologies are associated with a high rate of recurrence, adjuvant therapy is recommended even in women with early-stage disease. The remaining cell types should be treated similar to endometrioid or other low-grade histologies.

Pathological Characteristics of Cervical Adenocarcinoma in a Multi-center U.S.-based Study

Although human papillomavirus infection plays a role in the development of both cervical adenocarcinoma (AC) and squamous-cell carcinoma (SCC) of the cervix, cytological screening has been less effective in lowering the incidence of AC and its mortality rate in the United States. In contrast to SCC, only the immediate precursor of AC, adenocarcinoma in situ (AIS), has been clearly defined. In addition, the microscopic findings in AC are more diverse, and pathologists have less experience in diagnosing AC and AIS compared with SCC and its preceding lesions. The investigators undertook a detailed pathological review of subtypes of cervical AC. The study population consisted of 154 women ranging in age from 18 to 69 years who, when seen at one of six US medical centers in the years 1992-1996, received a diagnosis of in situ or invasive AC, adenosquamous (AS) tumor, or other rare cervical glandular tumors. Three pathologists jointly carried out a microscopic review of these tumors, and risk factors were identified from questionnaires administered by interviewers. In general, there were no substantial epidemiological differences between women with different histopathological subtypes. Nearly one-fourth of the 154 cervical glandular tumors (23%) were AIS; the remaining 77% were invasive neoplasms. Of the invasive cancers, 45% were AC; 19% were AS; and 20 were unusual types such as adenoid basal, small cell, and undifferentiated carcinomas. A majority of AIS lesions and invasive ACs exhibited endocervical or endometrioid differentiation. Nearly 80% of AS cases were grade 2 or 3, whereas 80% of ACs was grade 1 lesions. Invasive AS tumors were much likelier than ACs to exhibit vascular invasion (42% vs. 10%). AIS was likelier to be present in AC than in AS cases (71% vs. 39%). Approximately two-thirds of carcinomas of any type were stage IB when diagnosed. Both AIS and cribriform patterns were more common in ACs exhibiting cervical intraepithelial neoplasia (CIN). Nonendometrioid ACs were higher-grade tumors than endometrioid lesions. There was no evidence that microglandular hyperplasia was associated with the use of oral contraceptives. These findings show that cervical AS tumors have more aggressive characteristics than do ACs. In addition, AIS may not be a common precursor of AS tumors, making it less likely that screening for AIS or CIN will detect these tumors an early stage.