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The prevalence and significance of programmed death-1 ligand (PD-L1) expression in different types of tubo-ovarian carcinoma have not been well defined. We evaluated PD-L1 expression and CD8 tumor-infiltrating lymphocyte (TIL) density in whole tissue sections of 189 cases of tubo-ovarian carcinoma, including high-grade serous carcinoma (HGSC, n=100), clear cell carcinoma (CCC, n=24), endometrioid carcinoma (EmC, n=40), and mucinous carcinomas (MC, n=25). Using the tumor proportion score (TPS) with a 1% cutoff, PD-L1 expression was present in 21% of HGSC, 16.7% of CCC, 2.5% of EmC, and 4% of MC. Using the combined positive score (CPS) with a cutoff of 1, PD-L1 expression was present in 48% of HGSC, 25% of CCC, 20% of EmC, and 24% of MC. HGSC demonstrated significantly higher CD8 TIL density than CCC (P=0.013238), EmC (P=0.01341), or MC (P=0.004556). In HGSC, CD8 TIL density was directly correlated with PD-L1 positivity using either TPS (P=0.0008) or CPS (P=0.00011). Survival analysis of patients with high stage (stage III to IV) HGSC revealed PD-L1 positivity by TPS to be associated with improved progression-free survival (adjusted hazard ratio: 0.4912 vs. 2.036, P=0.0378). Although not statistically significant, a similar trend was observed in overall survival (adjusted hazard ratio: 0.3387 vs. 2.953, P=0.0548). In contrast, with CPS, no significant difference was identified between PD-L1-positive and negative groups in either progression-free survival (P=0.5086) or overall survival (P=0.7823). Neoadjuvant chemotherapy was associated with higher PD-L1 expression by TPS (P=0.00407) but not CPS. No significant difference in PD-L1 expression was detected in tumors from patients with germline BRCA1/2 mutations compared with germline mutation-negative tumors by either TPS or CPS. In conclusion, the prevalence of PD-L1 expression is variable in different types of tubo-ovarian carcinoma and is highest in HGSC. In high-stage HGSC, PD-L1 positivity in tumor cells is associated with an increased immune response and improved survival.

Objective: Although racial disparities in treatment and outcome for endometrial cancer are well recognized, little work has explored disparities in young women. We performed a population-based analysis to compare survival between black and white women with endometrial cancer at <50years of age., Methods: We used the National Cancer Data Base to identify women <50years of age with endometrial cancer from 1998 to 2012. Clinical and demographic characteristics were compared between black and white women and survival by race analyzed using Kaplan-Meier curves and multivariable Cox proportional hazards models., Results: We identified a total of 35,850 women <50years of age including 31,947 (89.1%) white and 3903 (10.9%) black patients. Black women were more likely to have advanced stage, poorly differentiated, and non-endometrioid histology neoplasms (P<0.05 for all). In a multivariable model, survival was 19% worse for black patients than white patients (HR=1.19; 95% CI, 1.08-1.32). A similar effect was seen when limited to women with early-stage tumors (HR=1.24; 95% CI, 1.04-1.49), while among patients with advanced stage tumors, no association between race and survival was seen (HR=1.12; 95% CI, 0.89-1.41). Five-year survival rates were 90.6% (95% CI, 88.6-92.3%) for white and 81.5% (95% CI, 73.0-87.5%) for black women with stage IB tumors, and 75.1% (95% CI, 72.5-77.5%) and 63.3% (95% CI, 54.1-71.2%) for white and black women with stage III tumors, respectively., Conclusions: Young black women are more likely to present with pathologically aggressive, advanced stage tumors. Even after adjusting for these pathologic differences, young black women with endometrial cancer have higher mortality than white women., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: To investigate the 5-year relative survival rates in gynecological cancers diagnosed and treated in Turkey by year 2009 and to compare the results with developed countries., Methods: Data of patients diagnosed for ovarian, corpus uteri or cervix uteri cancer at year 2009 are collected from 9 national cancer registry centers. Date of deaths are retracted from governmental Identity Information Sharing System (KPS). In order to calculate relative survival rates, national general population mortality tables are obtained from Turkish Statistical Institute (TurkStat). Hakulinen method is used for computing curves by R program. Data for European, Asian and some developed countries were obtained from official web pages., Results: A total of 1,553 patients are evaluated. Among these, 713 (45.9%) are corpus uteri cancers, while remaining 489 (31.5%) are ovarian and 351 (22.6%) are cervix uteri. Five-year overall relative survival rates are 85%, 50%, and 62% for corpus uteri, ovarian, and cervix uteri, respectively. These figures are between 73%-87% for corpus uteri, 31%-62% for ovarian and 61%-80% for cervix uteri in developed countries. Stage is the most important factor for survival in all cancers. Five-year relative survival rates in corpus uteri cancers are 92%, 66%, and 38% for localized, regional, and distant metastatic disease, respectively. These figures are 77%, 57%, and 29% for ovarian; 80%, 50%, and 22% for cervix uteri., Conclusion: This is the first report from Turkey giving national overall relative survival for gynecological cancers from a population based cancer registry system., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright © 2017. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology)

Objective: To compare the overall survival of non-Hispanic white and Hispanic women with endometrial cancer., Methods: We performed an observational retrospective cohort study of Hispanic and non-Hispanic women with endometrial cancer from the 2004-2014 National Cancer Database. Baseline characteristics were compared with the Chi-squared test for categorical variables or the Mann-Whitney U test for ordinal or continuous variables. The Kaplan-Meier method was used to estimate unadjusted survival times, which were compared with the log-rank test. Missing data was imputed using multiple imputation with chained equations. A multivariable parametric accelerated failure time model for survival was used. Sensitivity analyses were performed using matched cohort analyses of the overall cohort, and of subgroups based on stage or type., Results: 112,574 non-Hispanic and 6313 Hispanic women met inclusion criteria. Five-year survival was slightly higher for Hispanic women (83.1% (82.1-84.3%) versus 81.4% (81.2-81.7%), P=0.002). Hispanic women were younger, treated at lower volume hospitals, and more often diagnosed with a type II histology and stage II-IV disease compared to non-Hispanic women (all P<0.001). With multivariable adjustment for measured confounders, Hispanic women lived 8% longer than non-Hispanic women (time-ratio (95% CI) 1.08 (1.02-1.14), P=0.01). When bias-reducing matched cohort analyses were used for sensitivity analyses, Hispanic women did not have significantly different survival than non-Hispanic women., Conclusion: Hispanic ethnicity was not associated with a clinically meaningful difference in survival among women with endometrial cancer., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: Intraperitoneal (IP) chemotherapy (CT) for treatment of epithelial ovarian cancer (EOC) has been shown to provide a substantial OS advantage. This study aims to compare the toxicity and benefits of IP CT in patients ≥70 with those <70., Methods: We performed a single institution retrospective review of patients diagnosed with Stage IIA-IIIC EOC from 2000 to 2013 who received IP CT. Clinicopathologic characteristics were extracted, and survival was calculated., Results: 133 patients were included with 100 pts. <70years old and 33 pts. ≥70years old. Clinical trial enrollment was similar despite age. In trial enrolled patients, older patients received statistically fewer cycles of therapy (6.4 vs 5.8, p=0.002) but had similar dose delays (0.9 vs 0.7, p=0.72), and modifications (0.9 vs 0.36, p=0.11). Median PFS (27 vs 31months) and OS (71 and 62months) were not statistically different. Grade 3/4 neutropenia was significantly worse in the older patients (82% vs 100%, p=0.04). Neuropathy grade ≥2 and other non-hematologic toxicities were not different between age groups., Conclusions: Despite completing fewer cycles of IP CT, older EOC patients had comparable survival to younger patients. The population of older patients receiving IP CT in this study were on clinical trial and likely to be heartier than the general older population. IP CT appears well tolerated and effective among select older patients and is likely under-utilized outside of clinical trials., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: The morphological classification of high-risk endometrial cancer is of limited prognostic value. Recent attempts to stratify tumours according to molecular signatures have shown considerable promise. Here we attempted to further refine molecular classifications using markers of the p53 pathway., Methods: We analysed the expression of p53 as well as three downstream markers of the p53 pathway, p21, mdm2 and phospho-p63 (pp63), by immunohistochemistry in a series of 114 endometrial cancers (86 endometrioid, 28 non-endometrioid subtype) with high-risk features (such as high tumour grade and deep myometrial invasion) and correlated results with clinical outcome. The Cancer Genome Atlas (TCGA) data were used to analyse TP63 mutations and copy-number alterations using cBioPortal. TP53 was silenced in two endometrial cancer cell lines to study its effect on p21 and p63., Results: About half of the tumours showed a p53 mutant phenotype and there was a strong negative correlation with p21 expression. Being marker positive for pp63 or mdm2 was associated with a significantly increased likelihood of dying, [hazard ratios 5.93 (95% CI 2.37-7.27) and 7.48 (95% CI 3.04-9.39), respectively]. These findings were seen in both p53 wildtype and p53 mutant tumours. Only 11% of TCGA endometrial cancers had a functional TP63 alteration. Upon silencing of TP53, p21 expression was decreased in one cell line, but no effects on p63 were observed., Conclusion: Markers of the p53 pathway improve stratification of endometrial cancers and provide novel insights into the role of this pathway in the disease., (Copyright © 2017. Published by Elsevier Inc.)

Objective: Observational studies suggest that statin therapy for cardio-protection is associated with improved survival in cancer patients. We sought to evaluate the impact of statin treatment on ovarian cancer survival in a nationally representative elderly population., Methods: The linked Surveillance, Epidemiology, and End Results (SEER) registries and Medicare claims data on patients diagnosed with epithelial ovarian cancer in 2007-2009 were used to extract data on statin prescription fills, population characteristics, primary treatment, comorbidity and survival. Cox regression models were used to examine the association between statin treatment and overall survival., Results: Among the 1431 ovarian cancer patients who underwent surgical resection, 609 (42.6%) filled prescriptions for statin. The majority of statin-users (89%) were prescribed a lipophilic formulation. Mean overall survival among statin-users was 32.3months compared to 28.8months for non-users (p<0.0001). A 34% reduction in death was associated with statin therapy, independent of age, race, neighborhood median household income, stage, platinum therapy and comorbid conditions (HR=0.66, 95% CI 0.55-0.81). Improved overall survival with statin use was observed for both serous (HR=0.69, 95% CI 0.54-0.87) and non-serous (HR=0.63, 95% CI 0.44-0.90) histologies. When statin treatment was categorized by lipophilicity and intensity, a significant survival benefit was limited to lipophilic statin users and those who took statins of moderate intensity., Conclusions: This SEER-Medicare analysis demonstrates improvement in overall survival with lipophilic statin use after surgery in elderly patients with epithelial ovarian cancer. A clinical trial to evaluate the impact of statin treatment in ovarian cancer survival is warranted., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: To examine characteristics and survival outcomes of women with apparent early-stage endometrial cancer who had a supracervical hysterectomy., Methods: The Surveillance, Epidemiology, and End Results Program was used to identify women with presumed stage I endometrial cancer who underwent supracervical hysterectomy between 1983 and 2012. Propensity score matching was performed to adjust background difference between supracervical hysterectomy (n=1,339) and total hysterectomy (n=110,523) cases. Endometrial cancer-specific survival (CSS) was examined by multivariable analysis expressed with adjusted-hazard ratio [HR] and 95% confidence interval [CI]., Results: Supracervical hysterectomy was independently associated with younger age, low-grade disease, and small tumor size on multivariable analysis (all, P<0.001). After propensity score matching, supracervical hysterectomy remained an independent prognostic factor for decreased CSS compared to total hysterectomy (10-year rates, 91.0% versus 94.9%, adjusted-HR 1.72, 95%CI 1.20-2.47, P=0.003). Among women who received postoperative radiotherapy, 10-year CSS rates were similar between supracervical and total hysterectomy cases (84.7% versus 80.3%, P=0.40). Contrary, in the absence of postoperative radiotherapy, women undergoing supracervical hysterectomy had a significantly lower 10-year CSS rate compared to those undergoing total hysterectomy (92.1% versus 97.2%, P<0.001). Moreover, with lack of lymphadenectomy, supracervical hysterectomy was associated with decreased CSS compared to those who had total hysterectomy (91.6% versus 94.3%, P=0.018) but had similar CSS rates with lymphadenectomy (92.7% versus 91.8%, P=0.91)., Conclusion: Although rarely performed, supracervical hysterectomy is associated with decreased survival outcome among women with apparent stage I endometrial cancer supporting the importance of avoiding this procedure in women with or at risk of endometrial cancer., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Mixed endometrial carcinomas (MECs) refer to tumors characterized by 2 or more distinct histotypes mostly that comprised endometrioid (EC) and serous/clear cell carcinomas (SC/CC). The specific quantification of these distinct components represents a challenging and critical point for both prognosis and management. Herein, we analyze a large series of MEC and compare them with EC and SC/CC. We evaluated a series of 69 MECs between January 2002 and December 2015. We compared the MEC series with 186 ECs (including 117 endometrioid G3), 31 SCs, and 38 CCs. The prognostic implication of the percentage of each component was analyzed. Among the 69 MECs, those patients older than 45 years represent the significant population, with 52.2% of them with stage III-IV disease. A similar result was found among pure SC. The comparative analysis of some prognostic parameters (multifocality, vascular invasion, and lymph node metastasis) underlined that MECs with a type II component larger than 5% represent a more aggressive entity. However, relapse, disease-free survival, mortality, and overall survival are statistically significant (P<.05) in EC-SC (SC<5%or >5%) and in EC-CC (CC<5%or >5%), whereas they are not significant (P>.05) in SC-CC (SC/CC<%or >5%). MECs, including also cases with less than 5% of SC/CC, show features as aggressive as those of pure SC/CC. In this perspective, MEC should be followed by personalized and tailored managements. The presence of different components suggests different pathogenic and metastatic processes when compared with pure carcinomas., (Copyright © 2016. Published by Elsevier Inc.)

Background: Recent data suggest that the use of nonsteroidal anti-inflammatory drugs (NSAIDs) may be associated with reductions in endometrial cancer risk, yet very few have examined whether their use is related to prognosis among endometrial cancer patients., Methods: Study subjects comprised 4374 participants of the NRG Oncology/Gynecology Oncology Group 210 Study with endometrial carcinoma who completed a presurgical questionnaire that assessed history of regular prediagnostic NSAID use and endometrial cancer risk factors. Recurrences, vital status, and causes of death were obtained from medical records and cancer registries. Fine-Gray semiproportional hazards regression estimated adjusted subhazard ratios (HRs) and 95% confidence intervals (CIs) for associations of NSAID use with endometrial carcinoma-specific mortality and recurrence. Models were stratified by endometrial carcinoma type (ie, type I [endometrioid] vs type II [serous, clear cell, or carcinosarcoma]) and histology., Results: Five hundred fifty endometrial carcinoma-specific deaths and 737 recurrences occurred during a median of five years of follow-up. NSAID use was associated with 66% (HR = 1.66, 95% CI = 1.21 to 2.30) increased endometrial carcinoma-specific mortality among women with type I cancers. Associations were statistically significant for former and current users, and strongest among former users who used NSAIDs for 10 years or longer (HR = 2.23, 95% CI = 1.19 to 4.18, two-sided P trend = .01). NSAID use was not associated with recurrence or endometrial carcinoma-specific mortality among women with type II tumors., Conclusions: In this study, use of NSAIDs was associated with increased endometrial carcinoma-specific mortality, especially in patients with type I tumors. Barring a clear biologic mechanism by which NSAIDs would increase the risk of cause-specific mortality, cautious interpretation is warranted., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: The incidence of endometrial cancer increases with age and is associated with medical comorbidities such as obesity and diabetes. Although a few cohort studies of <500 patients showed an association between comorbidity and survival in patients with endometrial cancer, the degree of association must be better described. The Adult Comorbidity Evaluation 27 is a validated comorbidity instrument that provides a score of 0-3 based on the number of and severity of medical comorbidities., Objective: This study was performed to explore the association between medical comorbidities and survival of patients with endometrial cancer., Study Design: Patients who were diagnosed with endometrial cancer from 2000-2012 were identified from the prospectively maintained Siteman Cancer Center tumor registry. Patients who underwent primary surgical treatment for endometrioid, serous, and clear cell endometrial carcinoma were included. Patients who primarily were treated with radiation, chemotherapy, or hormone therapy were excluded. Patients with uterine sarcomas or neuroendocrine tumors were excluded. Patients with missing Adult Comorbidity Evaluation 27 scores were also excluded from analysis. Information that included patient demographics, Adult Comorbidity Evaluation 27 score, tumor characteristics, adjuvant treatment, and survival data were extracted from the database. The association of Adult Comorbidity Evaluation 27 and overall and recurrence-free survival was explored in a multivariable Cox regression analysis after being controlled for variables that have been found to be associated significantly with survival in univariable analysis., Results: A total of 2073 patients with a median age of 61 years (range, 20-94 years) at diagnosis were identified. The Adult Comorbidity Evaluation 27 score was 0, 1, 2, and 3 in 22%, 38%, 28%, and 12% of patients, respectively. Stage distribution was I (73%), II (5%), III (15%), and IV (7%), and grade distribution was 1 (52%), 2 (23%), and 3 (25%). Most patients had endometrioid histologic condition (87%) followed by serous (11%) and clear cell (3%) endometrial carcinoma. The median overall survival time for the entire cohort was 54 months (95% confidence interval, 3-154 months), and the median recurrence-free survival was 50 months (95% confidence interval, 2-154 months). On univariable analysis, age, race, marital status, stage, grade, histologic condition, and treatment type were associated significantly with overall survival and recurrence-free survival. After adjustment for these covariates, patients with an Adult Comorbidity Evaluation 27 score of 2 had a 52% higher risk of death (95% confidence interval, 1.16-2.00); patients with an Adult Comorbidity Evaluation 27 score of 3 had a 2.35-fold increased risk of death (95% confidence interval, 1.73-3.21) compared with patients with an Adult Comorbidity Evaluation 27 score of 0. Similarly, patients with an Adult Comorbidity Evaluation 27 score of 2 had a 38% higher risk of recurrence (95% confidence interval, 1.07-1.78); patients with Adult Comorbidity Evaluation 27 score of 3 had a 2.05-fold increased risk of recurrence (95% confidence interval, 1.53-2.75) compared with patients with an Adult Comorbidity Evaluation 27 score of 0. We found no interaction between Adult Comorbidity Evaluation 27 score and age, stage, or treatment type., Conclusion: Our findings demonstrate the importance of comorbidities in the estimation of the prognosis of patients with endometrial cancer, even after adjustment for age and known tumor-specific prognostic factors such as stage, grade, histologic condition, and adjuvant treatment., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: Long non-coding RNAs (lncRNAs) are a class of non-protein coding transcripts that has gained significant attention lately due to their important biological actions and potential involvement in cancer. Ovarian cancer is a devastating disease with poor prognosis, and our understanding of lncRNA's involvement in the malignancy is limited. To further our knowledge, we measured the expression of three lncRNAs, ASAP1-IT1, FAM215A, and LINC00472, in tumor samples, and analyzed their associations with disease characteristics and patient survival., Methods: Two hundred sixty-six patients diagnosed with primary epithelial ovarian cancers were recruited for the study. Fresh-frozen tumor samples were obtained from the patients at tumor resection and analyzed by RT-qPCR for expression of ASAP1-IT1, FAM215A, and LINC00472. Associations of lncRNA expression with patient survival were determined using Cox proportional hazards regression models., Results: We observed high expression of ASAP1-IT1, FAM215A and LINC00472 more frequently in low grade tumors and early stage disease compared to high grade tumors and late stage disease, respectively. High expression of ASAP1-IT1 and FAM215A were associated with favorable overall survival, and the survival association with ASAP1-IT1 was independent of tumor grade and disease stage. Analyses of online data also demonstrated similar survival associations with ASAP1-IT1 and FAM215A, suggesting that these lncRNAs may be involved in ovarian cancer progression., Conclusions: LncRNAs may play appreciable roles in ovarian cancer and more research is needed to elucidate their biological mechanisms and clinical implications in tumor characterization as well as disease prognosis and treatment., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: To determine overall survival (OS) and factors associated with OS after pelvic exenteration for uterine cancer., Methods: Women with uterine cancer who underwent exenteration (n=1160) were identified from the 1998-2011 National Cancer Data Base. Kaplan-Meier and multivariate Cox proportional-hazards survival analyses were performed to test for associations of potential explanatory variables with OS. Analyzed confounders included age, comorbidity score, insurance status, income, distance from home to treatment center, stage, distant and nodal metastasis, tumor size, surgical margin status, exenteration type, and treatment with radiation and/or chemotherapy., Results: Among women with follow-up data (n=652), median (IQR) OS was 63.1 (42.2-107.2) and 17.6 (14.7-23.9) months for women with node-negative versus node-positive disease, respectively. Histology (p=1.5×10 -4 ), grade (p=7.9×10 -14 ), race (p=0.0002), lymph node status (p=1.0×10 -14 ), surgical node evaluation (p=2.8×10 -8 ), surgery for distant metastasis (p=0.004), distant metastasis at diagnosis (p=1.3×10 -10 ), positive surgical margins (p=1.6×10 -9 ), radiotherapy (p=0.004), and insurance status (p=6.5×10 -6 ) were significantly associated with differential, unadjusted Kaplan-Meier OS estimates. Exenteration type was not associated with OS (p=0.357). By multivariate regression, increased age, positive surgical margins, nodal metastasis or unknown nodal status, higher histologic grade, and black race were associated with increased hazards for death., Conclusion: Exenteration may be curative for well-selected women with uterine cancer, particularly among women with pathologically negative lymph nodes., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: We sought to analyze the clinicopathologic features, recurrence patterns and survival outcomes of women with high-grade uterine cancer (UC) enrolled on The Gynecologic Oncology Group (GOG) LAP2 trial., Methods: This is a post-hoc analysis of LAP-2 patients with grade 3 endometrioid adenocarcinoma (ENDO), uterine serous (USC), clear cell (CC) and carcinosarcoma (CS). Demographics, clinicopathologic features, and recurrence patterns, were compared by histology and surgical approach. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method., Results: Of the 2600 patients enrolled in LAP-2, 753 patients had high-grade UC: 350 had ENDO, 289 had USC, 42 had CC and 72 had CS. Compared with the ENDO cohort, those with other high-grade subtypes were older (p<0.001) and were more likely to have positive peritoneal cytology (p<0.001), positive lymph nodes (p=0.05) and higher disease stage on final pathology (p<0.001). With a median follow-up time of 60months, compared to patients with ENDO, those with USC, CCC and CS subtypes had higher recurrence rates (p<0.001), extra-pelvic recurrences (p<0.001) and poorer PFS (p<0.001) and OS (p<0.001). Those diagnosed with USC and CS experienced the worst survival outcomes (p=0.003). Patterns of recurrence and survival were not different in those staged with LSC vs LAP. On multivariable analysis, age, stage, pelvic washings and Type II histology were independently and adversely associated with survival., Conclusions: Women with apparent early-stage, USC and CS histologies have poorer outcomes than women with grade 3 endometrioid adenocarcinoma. Patterns of recurrence and survival were not impacted by surgical approach., Competing Interests: Dr. Nick Spirtos receives per capita reimbursement to the Women's Cancer Center, travel supplement as Gyn Onc Committee Chair, co-operative research funding on a per capita basis from GOG Foundation, Inc., and royalties from Wiley Health Services for Bonney's Gynaecological Surgery. Dr. Michael Pearl receives grant money from the GOG/NRG. He also serves as a consultancy for Ethicon, provided expert testimony for legal expert review, and has grants/grants pending from NIH, small foundations, as well as royalties from VitaTex. Dr. David O'Malley serves as a consultant for Yondelis on the Sarcoma Advisory Board, AstraZeneca on the Ovarian Cancer Advisory Board, Clovis on the Ovarian Cancer Advisory Board, Genentech/Roche on the Ovarian Cancer Advisory Board and Eisai on the Advisory Board. Dr. Robert Mannel receives grant monies from GOG-LAP2 grant. He also serves on the Advisory Board as a consultant for Medimmune, Oxigene, Endocyte, Bayer and Clovis. All other coauthors have no conflicts of interest to declare., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Study Objective: To evaluate the oncologic outcomes of patients with early-stage ovarian cancer (eOC) managed by laparoscopy or laparotomy in a single high-volume gynecologic cancer center., Design: Retrospective case-control study (Canadian Task Force classification II-2)., Setting: Catholic University of the Sacred Hearth, Rome, Italy., Patients: Data of consecutive women with eOC undergoing comprehensive laparoscopic staging between 2007 and 2013 were matched with a cohort of patients undergoing open surgery between 2000 and 2011. Four-year survival outcomes were analyzed using the Kaplan-Meier method., Measurements and Results: Sixty women undergoing staging via laparoscopy were compared with a cohort of 120 patients undergoing open surgery. Baseline characteristics were similar between groups. Seventy percent of patients underwent adjuvant platinum based chemotherapy without differences between the 2 groups. Operative time (p = .01), estimated blood loss (p = .032), and median hospital stay (p = .001) were higher in patients submitted to laparotomic versus laparoscopic staging. As of October 2015, median duration of follow-up was 38 months (range, 24 -48), recurrent disease was documented in 16 patients (13.3%) in the laparotomic group and in 5 patients (8.3%) in the laparoscopic group (p = .651), without differences in the pattern of recurrence presentation. Four-year progression-free survival (PFS) and overall survival (OS) rates were 89% and 92% in the laparoscopic group, respectively, and 81% and 91% in the laparotomic group, without any statistical significant difference between the groups (4-year PFS p = .651; 4-year OS p = .719)., Conclusion: The findings of the present study suggests that in the surgical treatment of FIGO stage I ovarian cancer, laparoscopy is associated with equivalent oncologic outcome compared with a conventional abdominal approach., (Copyright © 2016 AAGL. Published by Elsevier Inc. All rights reserved.)

Ovarian endometrioid carcinomas (OEC) of low grade have characteristic morphologic features, but high-grade tumors can mimic high-grade serous and undifferentiated carcinomas. We reviewed tumors initially diagnosed as OEC to determine whether a combination of pathologic and immunohistochemical features can improve histologic subclassification. Tumors initially diagnosed as OEC were reviewed using World Health Organization criteria. We also noted the presence of associated confirmatory endometrioid features (CEFs): (i) squamous metaplasia; (ii) endometriosis; (iii) adenofibromatous background; and (iv) borderline endometrioid or mixed Mullerian component. A tissue microarray was constructed from 27 representative tumors with CEF and 14 without CEF, and sections were stained for WT-1, p16, and p53. Of 109 tumors initially diagnosed as OEC, 76 (70%) tumors were classified as OEC. The median patient age was 55 years, and 75% of patients were younger than 60 years. Ninety-two percent presented with disease confined to the pelvis, and 87% of tumors were unilateral. The median tumor size was 11.8 cm. Only 3% of tumors were high grade (grade 3of 3). Eighty percent of cases had at least 1 CEF, and 59% had at least 2 CEFs. Eleven percent overexpressed p16, 0% overexpressed p53, and 3% expressed WT-1. Only 10% of patients died of disease at last follow-up. Thirty-three (33) tumors, or 30% of tumors originally classified as endometrioid, were reclassified as serous carcinoma (OSC). The median patient age was 54.5 years, and 59% of patients were younger than 60 years of age. Only 27% had disease confined to the pelvis at presentation, 52% of tumors were unilateral, and the median tumor size was 8 cm. Associated squamous differentiation, endometrioid adenofibroma, and endometrioid or mixed Mullerian borderline tumor (CEFs) were not present in any case, but 6% of patients had endometriosis. Approximately one half of the reclassified OSC demonstrated SET-pattern morphology (combinations of glandular, cribriform, solid, and transitional cell-like architecture) and were immunophenotypically indistinguishable from OSCs with papillary architecture. Sixty percent of OSC overexpressed p16, 50% overexpressed p53, and 82% expressed WT-1. At last follow-up, 52% had died of disease. Compared with OSC, OEC patients more frequently presented below 60 years of age (P=0.046), had low-stage tumors (P<0.001), were more frequently unilateral (P<0.001), more frequently had synchronous endometrial endometrioid carcinomas (P<0.001); and had no evidence of disease at last follow-up (P<0.001). Their tumors were of lower grade (P<0.001), had more CEFs (P<0.001), and less frequently overexpressed p16 and p53 (P=0.003 and P<0.001, respectively) and less frequently expressed WT-1 (P<0.001). This analysis emphasizes the diagnostic value of CEFs, the presence of a low-grade gland-forming endometrioid component, and WT-1 negativity, as valid, clinically relevant criteria for a diagnosis of OEC. Glandular and/or cribriform architecture alone may be seen in both OECs and OSCs and are therefore not informative of diagnosis. Further study is needed to elaborate the characteristics of the exceedingly rare high-grade OEC.

Purpose of Investigation: Vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX 2) are markers of angiogenesis and potential therapeutic targets. Previous studies demonstrate that VEGF is upregulated in some ovarian cancers. The purpose of this study was to determine the correlation of VEGF and COX 2 staining with survival in ovarian cancer patients., Materials and Methods: One hundred forty-three consecutive patients with ovarian carcinoma underwent primary staging or cytoreduction prior to platinum-based chemotherapy. Their tumors were immunohistochemically stained for expression of VEGF and COX 2. FIGO stage, grade, cytoreduction status, and histology were also analyzed as prognostic factors., Results: Twenty-seven patients had Stage I tumors, three Stage II, 87 Stage III, and 26 Stage IV. Median follow-up was 74 months (mean 79 months). One hundred nineteen patients (83.2%) had tumors that were positive for VEGF and 110 patients (76.9%) had tumors that were positive for COX 2. Patients with tumors staining positive for both VEGF and COX 2 (68.5%) had a significantly increased risk of dying from their ovarian cancer (Chi-square p = 0.011, Log rank p = 0.037). Multivariate logistic regression analysis revealed FIGO stage, grade, cytoreduction status, and VEGF/COX 2 expression to be independent prognostic indicators of survival. Conclusion: VEGF and COX 2 staining are frequently positive in ovarian cancer. Patients whose tumors are positive for both VEGF and COX 2 have a decreased survival. These patients may benefit from anti-angiogenesis targeted therapy.

Objectives: The objective of this study is to analyze the clinical behavior of endometrial carcinomas by high risk(HR) histotype, including stage, overall survival, recurrence free survival and patterns of failure., Methods: This is a retrospective multi-institutional cohort study performed at 7 tertiary care centers across Canada between 2000 and 2012 and included: grade 3 endometrioid (EC3), endometrial serous cancer (ESC), clear cell carcinomas (CCC) and carcinosarcoma (CS). Clinicopathological and outcome data was collected., Results: 1260 women with endometrial carcinoma with 1013 having staging procedures were identified; 398 EC3, 449 ESC, 236 CS and 91 CCC. 51.8% had lymphovascular space invasion (LVSI) and 18.5% had omental involvement with a statistically significant difference between tumor types (p=0.0005 and 0.0047 respectively); ESC had a significantly greater rate of omental involvement compared to EC3 (22% to 9%, p=0.0005). Within the entire cohort 49.3% were stage 1, 10.6% were stage 2, 27.4% were stage 3 and 12.7% were stage 4. Overall survival and recurrence free survival were significantly different between histotypes (p<0.0001) with CS having the worst outcome. Overall 31.5% of patients recurred. CS and ESC had a higher distant recurrence rate compared to EC3 (29.6%, 31.0% compared to 16.4%, p=0.0002 and p<0.001)., Conclusion: This study is one of the largest clinical cohorts of HR endometrial cancers. We have further clarified the impact of histotype and stage on recurrence and survival, and the high likelihood of distant recurrence. However, the differences are modest and risk prediction models will require additional molecular markers., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: In contrast with the decreasing incidence seen for most cancers, endometrial cancer has been increasing in the United States. We examined whether the increasing incidence and mortality from endometrial cancer are equally distributed by race/ethnicity and tumor histologic subtype., Methods: Surveillance, Epidemiology, and End Results (SEER) endometrial cancer incidence and mortality data were obtained from 2000 to 2011. Age-adjusted incidence and incidence-based mortality rates, 95% confidence intervals, and annual percent changes (APC) were calculated. Rate ratios were calculated to compare racial/ethnic groups. Five-year relative survival rates were presented to explore survival by stage at diagnosis., Results: Incidence rates for endometrial cancers are rising across all racial/ethnic groups, with the greatest APC seen among non-Hispanic black (NHB) and Asian women (APC, 2.5 for both). NHB women have significantly higher incidence rates of aggressive endometrial cancers (clear cell, serous, high-grade endometrioid, and malignant mixed Mullerian tumors) compared with non-Hispanic white (NHW) women. Hispanic and Asian women have incidence rates equal to or lower than NHW women for all tumor subtypes. For nearly every stage and subtype, the 5-year relative survival for NHB women is significantly less than NHW women, whereas Hispanic and Asian women have the same or better survival., Conclusions: Endometrial cancer incidence is increasing for all women, particularly the aggressive subtypes. The disparity associated with excess incidence for these aggressive histologic subtypes and poorer survival is limited to NHB women., Impact: Increasing rates of aggressive endometrial cancers may widen the survival disparity between NHW and NHB women., (©2015 American Association for Cancer Research.)

Objective: To describe the incidence of thromboembolic events (venous thromboembolism) before and after the diagnosis of epithelial endometrial cancer and to evaluate the effects of these events on survival., Methods: We used the National Cancer Institute's Surveillance, Epidemiology, and End Results cancer registries linked to Medicare claim files to identify patients with epithelial endometrial cancer diagnosed between 1992 and 2009. To identify venous thromboembolism events 3 months before diagnosis and up to 24 months after diagnosis, we used International Classification of Diseases, 9th Revision, and Healthcare Common Procedure Coding System codes., Results: A total of 23,122 patients were included; of them 1,873 (8.1%) developed a venous thromboembolism. Patients with low-grade (grades 1 and 2) endometrioid adenocarcinoma had a significantly lower rate of venous thromboembolism 3 months before and 6 months after the diagnosis of cancer (3.6%; 95% confidence interval [CI] 3.3-3.9%) compared with carcinosarcoma (9.2%; 95% CI 7.8-10.8%), clear cell (6.9%; 95% CI 4.8-9.7%), uterine serous cancer (8.1%; 95% CI 7.01-9.3%), and grade 3 endometrioid adenocarcinoma (6.1%; 95% CI 5.4-6.9%) (P<.001). On multivariate analysis during the same time period, most recent time periods of diagnosis, carcinosarcoma histology compared with lower grade endometrial cancer, higher stage, African American race, marital status, chemotherapy delivery, and lymph node dissection were associated with increased risk of venous thromboembolism. The median overall survival for women who experienced a venous thromboembolism 3 months before the diagnosis of endometrial cancer was 31 months (95% CI 20-48 months); in women diagnosed with venous thromboembolism 6 months after the cancer diagnosis was 37 months (95% CI 31-44), and in women who did not experienced a venous thromboembolism was 111 months (95% CI 109-114). After adjusting for prognostic factors, there was an association between venous thromboembolism diagnosed 3 months before endometrial cancer (hazard ratio 1.69, 95% CI 1.34-2.13) or 6 months after the diagnosis (hazard ratio 1.57, 95% CI 1.44-1.71) and lower survival., Conclusion: Patients with uterine serous cancer, carcinosarcoma, clear cell carcinoma, and grade 3 endometrioid adenocarcinoma had a higher rate of venous thromboembolism than patients with low-grade endometrioid adenocarcinoma. A diagnosis of venous thromboembolism was associated with decreased survival in elderly patients with endometrial cancer., Level of Evidence: II.

Purpose of Investigation: Ovarian cancer is associated with poor prognosis and altered protein expression patterns may be useful for identifying patients likely to have poor disease outcomes. The impact of altered INPP4B protein expression on prognosis is unclear. The aim of this study was to evaluate the implication of INPP4B expression changes in a large series of ovarian cancer tissue samples., Materials and Methods: Tissue microarrays were constructed from 599 epithelial ovarian tumors and stained with antibodies for INPP4B, p53, and PTEN. Proportional hazard models were used to estimate survival hazard ratios (HRs) associated with altered protein expression., Results: Seventy-nine percent of the ovarian cancers demonstrated loss of INPP4B, whereas 53% showed aberrant p53 expression (i.e., complete loss of p53 or over-expression of p53) and 8% showed loss of PTEN. INPP4B was frequently lost in serous and endometrioid cancer subtypes, aberrant p53 expression was most common among serous subtype, and loss of PTEN was most common among endometrioid tumors (p for all three proteins across histologic subtypes ≤ 0.0001). INPP4B loss or aberrant p53 expression were both associated with increased mortality (HR = 1.84; 95% CI 1.27 - 2.68 and HR = 3.10; 95% CI 2.33 - 4.11, respectively); however, in multivariate models, only the relationship with p53 achieved statistical significance (HR = 1.20; 95% CI 0.82 - 1.76 for INPP4B and HR = 1.73; 95% CI 1.28 - 2.34 for p53). Conclusion: The INPP4B protein is frequently lost in serous and endometrioid subtypes of ovarian cancer. A possible prognostic role of INPP4B for endometrioid ovarian tumors requires further evaluation.

The aim of this study was to determine impact of lymph vascular space involvement (LVSI) on recurrence and survival in early stage of endometrial cancer. From 1991 through 2010, all endometrial cancer patients at University Hospital of Bari, Italy were identified. The Log-rank test and Kaplan-Meyer methods were used for time-to-event analysis to evaluate the effects of on lymph vascular space involvement recurrence rate and survival time. Of the 560 endometrial cancer patients, 525 underwent primary surgery. Of those, 399 had early stage disease. Three hundred and forty women were not found to have LVSI, whereas 59 were found to have lymph vascular space involvement. Forty-nine (12%) patients developed a recurrence and 20 of them showed lymph vascular space involvement. The statistical analysis demonstrated that LVSI was strongly associated with a poor survival (P < 0.0001). Lymph vascular space involvement is associated with a high risk of recurrence and poor overall survival in early stage of endometrial cancer; therefore, the clinical decision to decide whether or not a patient with early stage endometrial cancer should receive adjuvant therapy should be included the evaluation of lymph vascular space involvement., (© 2013 John Wiley & Sons Ltd.)

Purpose: Alteration of CyclinD1 was suggested to relate with development of endometrial carcinogenesis before, however CyclinD1 expression is not well defined in endometrial hyperplasia lesions. We checked the relationship between its expression and clinic-pathological variables of endometrial lesions to explore the possibility for CyclinD1 as a potential diagnostic and prognostic marker., Methods: Cyclin D1 immunohistochemical analysis (IHC) was used to evaluate 201 fixed, paraffin-embedded endometrial samples which included simple hyperplasia (n = 27), atypical complex hyperplasia (ACH) (n = 41), endometrioid carcinoma (n = 103), endometrial serous carcinoma (ESC) (n = 21) and clear cell carcinoma (CCC) (n = 9). A breast cancer with known CyclinD1 expression was selected as a positive control in each immunohistochemistry run. We also performed follow-up study to estimate patients' prognosis., Results: CyclinD1 was significantly overexpressed in atypical complex hyperplasia (ACH), endometrioid carcinoma and clear cell carcinoma (CCC). The positive signaling of CyclinD1 was showed less than 40% in simple hyperplasia and endometrial serous carcinoma (ESC). The high expression of CyclinD1 was observed in metastasis carcinoma group more significantly than non-metastasis carcinoma group. Kaplan Meier analysis demonstrated that patients with high CyclinD1 expression had an obviously poor prognosis than patients without CyclinD1 staining (p < 0.05). Moreover, according to multivariate Cox regression analysis, CyclinD1 expression, as crucial as metastasis, was a risk marker for overall survival rate., Conclusion: CyclinD1 exhibited a promising potential to predict the prognosis of patients with endometrial carcinoma. However, the statistical analysis demonstrated that CyclinD1 exhibited a poor ability to differentiate neoplastic lesions from non-neoplastic lesions; thus, the application of CyclinD1 only is not so credible for differentiation between benign and malignant lesions., Virtual Slides: The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1871063048950173.