Effector T Cells Abrogate Stroma-Mediated Chemoresistance in Ovarian Cancer.

Effector T cells and fibroblasts are major components in the tumor microenvironment. The means through which these cellular interactions affect chemoresistance is unclear. Here, we show that fibroblasts diminish nuclear accumulation of platinum in ovarian cancer cells, resulting in resistance to platinum-based chemotherapy. We demonstrate that glutathione and cysteine released by fibroblasts contribute to this resistance. CD8(+) T cells abolish the resistance by altering glutathione and cystine metabolism in fibroblasts. CD8(+) T-cell-derived interferon (IFN)γ controls fibroblast glutathione and cysteine through upregulation of gamma-glutamyltransferases and transcriptional repression of system xc(-) cystine and glutamate antiporter via the JAK/STAT1 pathway. The presence of stromal fibroblasts and CD8(+) T cells is negatively and positively associated with ovarian cancer patient survival, respectively. Thus, our work uncovers a mode of action for effector T cells: they abrogate stromal-mediated chemoresistance. Capitalizing upon the interplay between chemotherapy and immunotherapy holds high potential for cancer treatment.

Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy.

Epigenetic silencing including histone modifications and DNA methylation is an important tumorigenic mechanism. However, its role in cancer immunopathology and immunotherapy is poorly understood. Using human ovarian cancers as our model, here we show that enhancer of zeste homologue 2 (EZH2)-mediated histone H3 lysine 27 trimethylation (H3K27me3) and DNA methyltransferase 1 (DNMT1)-mediated DNA methylation repress the tumour production of T helper 1 (TH1)-type chemokines CXCL9 and CXCL10, and subsequently determine effector T-cell trafficking to the tumour microenvironment. Treatment with epigenetic modulators removes the repression and increases effector T-cell tumour infiltration, slows down tumour progression, and improves the therapeutic efficacy of programmed death-ligand 1 (PD-L1; also known as B7-H1) checkpoint blockade and adoptive T-cell transfusion in tumour-bearing mice. Moreover, tumour EZH2 and DNMT1 are negatively associated with tumour-infiltrating CD8(+) T cells and patient outcome. Thus, epigenetic silencing of TH1-type chemokines is a novel immune-evasion mechanism of tumours. Selective epigenetic reprogramming alters the T-cell landscape in cancer and may enhance the clinical efficacy of cancer therapy.

A Matched Analysis on the Prognostic Impact of Race on Survival Endpoints of Women with Early-Stage Endometrial Cancer.

OBJECTIVE: To compare survival endpoints between African American (AA) and non-AA (NAA) women with endometrial carcinoma (EC) stage I-II using a robust matching analysis. METHODS AND MATERIALS: Patients were matched by stage, grade, adjuvant management (surveillance, vaginal brachytherapy or pelvic radiation treatment), age, and year of hysterectomy. Recurrence-free survival (RFS), disease-specific survival (DSS) and overall survival (OS) were calculated. RESULTS: A total of 758 patients were included. Body mass index and Age-Adjusted Charlson comorbidity index was significantly higher in AA compared to NAA women. There were no significant differences between the AA and NAA groups in regard to 5-year RFS (94 vs. 93%), DSS (96 vs. 98%) or 5-year OS (90 vs. 92%). On multivariate analysis of survival endpoints for the entire study cohort, it was found that race (AA vs. NAA) was not a significant predictor of RFS, DSS, or OS. Grade 3 tumors and the presence of lymphovascular space invasion (LVSI) were the only 2 independent predictors of RFS and DSS, while age-adjusted Charlson comorbidity score, grade 3, stage II and the presence of LVSI were independent predictors of shorter OS. CONCLUSIONS: When matched based on the tumor stage, grade, adjuvant treatment, age, and year of surgery, our study suggests that there is no statistically significant difference in any survival endpoints between AA and NAA women with early-stage EC. Based on these data, disparities in outcome likely do not stem from uterine cancer-related causes. The increased comorbidity burden in AA women is likely a factor contributing to the racial disparity in endometrial cancer.

The role of adjuvant therapy in stage IA serous and clear cell uterine cancer: A multi-institutional pooled analysis.

OBJECTIVE: As the optimal adjuvant management of stage IA serous or clear cell endometrial cancer is controversial, a multi-institutional review was conducted with the objective of evaluating the appropriateness of various strategies including observation. METHODS: Retrospective chart reviews for 414 consecutive patients who underwent hysterectomy for FIGO stage IA endometrial cancer with serous, clear cell or mixed histology between 2004 and 2015 were conducted in 6 North American centers. Time-to-event outcomes were analyzed by Kaplan-Meier estimates, log-rank test, univariable and multivariable cox proportional hazard regression models. RESULTS: Post-operative management included observation (50%), chemotherapy and radiotherapy (RT) (27%), RT only (16%) and chemotherapy only (7%). The 178 RT patients received external beam (EBRT, 16%), vaginal vault brachytherapy (VVB, 56%) or both (28%). Among patients without any adjuvant treatment, 5-year local control (LC), disease free survival (DFS) and cancer-specific survival (CSS) were 82% (95% confidence interval: 74-88), 70% (62-78) and 90% (82-94), respectively. CSS in patients without adjuvant treatment was improved with adequate surgical staging (100% vs. 87% (77-92), log-rank p=0.022). Adjuvant VVB was associated with improved LC (5-year 96% (91-99) vs. 84% (76-89), log-rank p=0.007) and DFS (5-year 79% (66-88) vs. 71% (63-77), log-rank p=0.033). Adjuvant chemotherapy was associated with better LC (5-year 96% (90-98) vs. 84% (77-89), log-rank p=0.014) and DFS (5-year 84% (74-91) vs. 69% (61-76), log-rank p=0.009). On multivariable analysis, adjuvant chemotherapy and VVB were associated with improved LC while adjuvant chemotherapy and age were significant for DFS. CONCLUSIONS: In stage IA serous or clear cell uterine cancer, adjuvant RT and chemotherapy were associated with better LC and DFS. Observation may be appropriate in patients who have had adequate surgical staging.

Does Age-Adjusted Charlson Comorbidity Score Impact Survival Endpoints in Women with Federation of Gynecology and Obstetrics-Stage III Endometrial Cancer?

OBJECTIVES: We sought to evaluate the impact of age-adjusted Charlson comorbidity index (AACCI) score on survival endpoints for women with advanced stage endometrial carcinoma (EC). METHODS AND MATERIALS: We identified 238 women with stage III EC. AACCI score was calculated and 3 groups were created accordingly; group 1 with a score of 0-2, group 2 with score 3-4, and group 3 with score ≥5. Significant predictors of recurrence-free (RFS), disease-specific (DSS) and overall survival (OS) were analyzed. RESULTS: Median follow-up was 54 months and median age was 65 years. Stage IIIC was the most common stage (69%). The 3 groups were well-balanced except for less utilization of adjuvant chemotherapy in group 3 (p = 0.01). Five-year OS was significantly lower in group 3 compared to groups 1 and 2 (23 vs. 65 and 51%, respectively). Similarly, 5-year RFS was 54, 41, and 33% and DSS was 65, 54, and 35% for groups 1, 2, and 3 respectively. On multivariate analyses, AACCI group 3, cervical stromal involvement, positive peritoneal cytology, and higher tumor grade were predictors for shorter OS. Cervical stromal involvement and higher grade were independent predictors for worse RFS and DSS. Additionally, positive cytology, lymphovascular space invasion, and stage IIIC2 were significantly detrimental for RFS. CONCLUSIONS: Our study suggests that comorbidity burden is a strong predictor of worse OS in women with stage III EC. Women with higher AACCI are less likely to receive adjuvant chemotherapy. Comorbidity score can significantly impact survival endpoints for women with advanced EC.

Synergistic effect of MEK inhibitor and metformin combination in low grade serous ovarian cancer.

OBJECTIVE: Low-grade serous ovarian cancer (LGSOC) constitutes 5-8% of epithelial ovarian cancers and is refractory to chemotherapy. We and others have shown metformin to cause significant growth inhibition in high-grade ovarian cancer both in vitro and in vivo. Here, we aimed to analyze if metformin was effective in inhibiting proliferation of LGSOC alone and in combination with MEK inhibitor. METHODS: Three LGSOC lines (VOA1056, VOA1312 and VOA5646) were treated with metformin, trametinib or 2-deoxyglucose (2DG) alone or in combination with metformin. Proliferation was measured by MTT assay over a period of four days. Protein expression was measured by western blotting. Seahorse Analyzer was used to measure effect of metformin on glycolysis and mitochondrial respiration. RESULTS: All LGSOC cell lines showed significant inhibition with metformin in a dose- and time-dependent manner. Trametinib significantly inhibited the growth of Ras mutated LGSOC lines (VOA1312 and VOA1056), while VOA5646 cells without RAS mutation did not show any response. Metformin and trametinib combination showed synergistic inhibition of RAS mutated VOA1312 and VOA1056 cells, but not for non-Ras mutated VOA5646 cells. Metformin and trametinib increased phosphorylated AMPK expression in LGSOC lines with combination showing stronger expression. Trametinib decreased 42/44 mitogen activated kinase phosphorylation in all cell lines, while metformin and combination had no significant effect. 2-DG significantly inhibited glycolysis in all LGSOC lines and combination with metformin showed synergistic inhibitory effect. CONCLUSIONS: Metformin alone or in combination with MEK and glycolytic inhibitors may be a potential therapy for LGSOC, a cancer that is indolent but chemo-resistant.

Clear Cell Carcinoma of the Endometrium: Evaluation of Prognostic Parameters in a Multi-institutional Cohort of 165 Cases.

OBJECTIVES: Clear cell carcinoma (CCC) comprises a rare yet an aggressive subtype, accounting for less than 5% of all uterine carcinomas. Several clinicopathologic features have been predictive of poor prognosis; however, data remain controversial. The aim of this study was to evaluate the clinicopathologic features of a multi-institutional cohort of endometrial CCC in order to identify which, if any, have prognostic significance. METHODS: Retrospective review of endometrial CCC diagnosed between 1995 and 2012 at 3 institutions was conducted to evaluate clinicopathologic parameters: age, race, tumor size, stage, myometrial invasion (MI), lymphovascular invasion, lymph node and adnexal involvement, adjuvant therapy, and outcomes. Data were analyzed using Fisher exact, Cox regression, and Kaplan-Meier analyses. RESULTS: Patients' ages ranged from 36 to 90 years (median, 67 years). The median tumor size was 3.6 cm. Inner-half MI was present in 44%, lymphovascular invasion in 34%, adnexal involvement in 16%, and lymph node metastasis in 30% of cases. Fifty-eight percent of the patients presented with early-stage disease. The 5-year overall survival (OS) was 58%. Shorter disease-free interval (DFI) was significantly associated with older age at diagnosis (>70 years), advanced-stage disease, adnexal involvement, and deep MI (P = 0.005, P = 0.001, P = 0.001, and P = 0.003, respectively). Patients who received adjuvant chemotherapy had a significantly worse DFI and 5-year OS (P = 0.001 and P = 0.001, respectively). A significantly shorter 5-year OS was noted with advanced stage (III-IV) and presence of adnexal involvement (P = 0.001 and P = 0.021, respectively). On Cox regression analysis, advanced-stage disease, older age, and adnexal involvement were significant independent predictors of worse DFI (P = 0.001, P = 0.005, and P = 0.019, respectively), whereas inner-half MI was a significant independent predictor of longer DFI (P = 0.004). Adjuvant radiotherapy alone was a significant independent predictor of better 5-year OS (P = 0.012). CONCLUSIONS: In our series of endometrial CCC, older age at diagnosis, advanced stage, deep MI, and adnexal involvement were independent poor prognostic factors. Adjuvant radiotherapy had a significant positive impact on 5-year OS.

Folic acid tagged nanoceria as a novel therapeutic agent in ovarian cancer.

BACKGROUND: Nanomedicine is a very promising field and nanomedical drugs have recently been used as therapeutic agents against cancer. In a previous study, we showed that Nanoceria (NCe), nanoparticles of cerium oxide, significantly inhibited production of reactive oxygen species, cell migration and invasion of ovarian cancer cells in vitro, without affecting cell proliferation and significantly reduced tumor growth in an ovarian cancer xenograft nude model. Increased expression of folate receptor-α, an isoform of membrane-bound folate receptors, has been described in ovarian cancer. To enable NCe to specifically target ovarian cancer cells, we conjugated nanoceria to folic acid (NCe-FA). Our aim was to investigate the pre-clinical efficacy of NCe-FA alone and in combination with Cisplatin. METHODS: Ovarian cancer cell lines were treated with NCe or NCe-FA. Cell viability was assessed by MTT and colony forming units. In vivo studies were carried in A2780 generated mouse xenografts treated with 0.1 mg/Kg NCe, 0.1 mg/Kg; NCe-FA and cisplatinum, 4 mg/Kg by intra-peritoneal injections. Tumor weights and burden scores were determined. Immunohistochemistry and toxicity assays were used to evaluate treatment effects. RESULTS: We show that folic acid conjugation of NCe increased the cellular NCe internalization and inhibited cell proliferation. Mice treated with NCe-FA had a lower tumor burden compared to NCe, without any vital organ toxicity. Combination of NCe-FA with cisplatinum decreased the tumor burden more significantly. Moreover, NCe-FA was also effective in reducing proliferation and angiogenesis in the xenograft mouse model. CONCLUSION: Thus, specific targeting of ovarian cancer cells by NCe-FA holds great potential as an effective therapeutic alone or in combination with standard chemotherapy.

Targeting of free fatty acid receptor 1 in EOC: A novel strategy to restrict the adipocyte-EOC dependence.

OBJECTIVES: Adipocyte derived free fatty acids (FFA) promote epithelial ovarian cancer (EOC) by acting as a fuel source to support the energy requirement of the cancer cells. FFA may also exert biological effects through signaling pathways. Recently, a family of FFA activated G-protein coupled receptors (FFAR/GPCRs) was identified. Our objective was to investigate the role of FFAR/GPCRs in EOC and assess their potential as therapeutic targets. METHODS: The mRNA (RT-PCR) expression of FFAR/GPCR family members (FFAR1/GPR40; FFAR2/GPR43, FFAR3/GPR41, FFAR4/GPR120 and GPR84) was examined in: (1) a syngeneic mouse model of EOC fed high energy diet (60% fat) or regular diet (30% fat), (2) EOC cell lines exposed to free fatty acids and (3) specimens from 13 histologically normal ovaries and 28 high grade ovarian serous carcinomas. The GPR 40 antagonist, GW1100, was used to inhibit FFAR1/GPR40 and cell survival was assayed by MTT in various cell lines. RESULTS: High Grade Serous carcinoma specimens expressed significantly increased GPR40 compared to normal ovaries (p=0.0020). Higher expression was noted in advanced stage disease. ID8 ovarian tumors from mice fed with high fat diet also showed higher GPR40 expression. Exposing EOC cells to FFAs, increased GPR40 expression. Treatment of EOC cell lines with GW100 resulted in growth inhibition and was associated with an alteration in their energy metabolism. CONCLUSION: FFA-induced cancer cell growth may be partly mediated through FFAR1/GPR40. Targeting of FFAR1/GPR40 may be an attractive treatment strategy in EOC, and possibly offers a targeted treatment for a subset of EOC patients.

Cancer and the world's poor: What's a gynecologic cancer specialist to do?

Women in low- and middle-income countries (LMICs) face a drastically increased burden of cervical cancer and the same burden of other gynecologic cancers as do women in high-income countries, yet there are few resources or specialists to meet their needs. 85% of deaths from cervical cancer occur in LMICs. As the population of these regions age, and as death from infectious diseases decrease, this burden will increase further without strong intervention. There are few cancer specialists in LMICs and training in gynecologic cancer care is rare. Gynecologic cancer specialists are uniquely positioned to meet this challenge as advocates, educators and experts. On behalf of the SGO International Committee, we call on our colleagues to meet this historic challenge.

Predictors of Survival After Recurrence in Women With Early-Stage Endometrial Carcinoma.

OBJECTIVE: Factors predictive of survival after recurrent early-stage endometrial carcinoma have not been thoroughly investigated. The purpose of this study was to explore factors that impact disease-specific survival (DSS) and overall survival (OS) after recurrence in women with early-stage endometrial carcinoma. MATERIALS AND METHODS: After institutional review board approval, we identified 104 women with 2009 International Federation of Gynecology and Obstetrics stage I to II uterine endometrioid carcinoma who developed disease recurrence between January 1990 and December 2014. The Kaplan-Meier approach and Cox regression analysis were used to assess DSS and OS after recurrence and to determine factors influencing these survival end points. RESULTS: Median age of the study cohort was 65 years with a median follow-up time of 42.8 months after hysterectomy. Median time to recurrence was 15.8 months. Recurrences were diagnosed in 60 patients (57.7%) who were originally managed with observation after hysterectomy and in 44 patients (42.3%) who were initially managed with adjuvant radiation treatment. Fifty-six patients (54%) had pelvic recurrence (vaginal and/or pelvic), whereas 48 (46%) had extrapelvic recurrence. Five-year DSS and OS for the entire study population was 44% and 37%, respectively. Five-year DSS and OS were longer for patients with pelvic recurrence compared with patients with extrapelvic recurrence (66% vs 18% and 55% vs 17%, P < 0.0001). Five-year DSS was also longer for radiation-naive patients than for radiation-treated patients (51% vs 34%, P = 0.023). On multivariate analysis of DSS and OS, pelvic recurrence (P < 0.001) was the only significant predictor of longer DSS and OS. CONCLUSIONS: In women with recurrent early-stage endometrioid carcinoma, our study suggests that site of recurrence (pelvic vs extra pelvic) is the only predictor of survival. In addition, we found that radiation naivete and pelvic recurrence correlated with longer DSS and OS.

Predictive Capacity of 3 Comorbidity Indices in Estimating Survival Endpoints in Women With Early-Stage Endometrial Carcinoma.

OBJECTIVE: The negative impact of comorbidity on survival in women with endometrial carcinoma (EC) is well-known. Few validated comorbidity indices are available for clinical use, such as the Charlson Comorbidity Index (CCI), the Age-Adjusted CCI (AACCI), and the Adult Comorbidity Evaluation-27 (ACE-27). The aim of the study is to determine which index best correlates with survival endpoints in women with EC. MATERIALS AND METHODS: We identified 1132 women with early-stage EC treated at an academic center. Three scores were calculated for each patient using CCI, AACCI, and ACE-27 at the time of hysterectomy. Univariate and multivariable modeling was used to determine predictors of survival. RESULTS: For each of the studied comorbidity indices, the highest scores were significantly correlated with poorer overall survival. The hazard ratio of death from any cause was 3.92 for AACCI, 2.25 for CCI, and 1.57 for ACE-27. All 3 indices were independent predictors of overall survival with a P value of less than 0.001 on multivariate analysis. In addition, lymphovascular space invasion, lower uterine segment involvement, and tumor grade were predictors of overall survival. Lymphovascular space invasion, grade (P < 0.001), and high AACCI score were the only significant predictors of recurrence-free survival (RFS). Lymphovascular space invasion and tumor grade were the only 2 predictors of disease-specific survival. CONCLUSIONS: Although all 3 studied comorbidity indices were significant predictors of overall survival in women with early-stage EC, AACCI showed a stronger association. It should be considered for evaluating comorbidity in women with early-stage EC.

Protective effect of bisphosphonates on endometrial cancer incidence in data from the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial.

BACKGROUND: Preclinical studies have demonstrated antitumor effects of bisphosphonates. The objective of the current study was to determine the effect of exposure to bisphosphonate on the incidence of endometrial cancer. METHODS: The authors used data from the National Cancer Institute's Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, which collected data on all cancers. In year 5, all participants were asked to complete a self-administered supplemental questionnaire (SQX) that included questions regarding bone medication use. For women without a cancer diagnosis at the time of the SQX, the authors identified whether a woman reported current or former use of a nitrogenous bisphosphonate (NBP), defined as ever-use, and compared them with women never exposed to an NBP. Women with missing information were excluded as were women who reported undergoing a hysterectomy. Incidence rates and rate ratios were calculated with 95% confidence intervals (95% CIs). Cox proportional hazard ratios were also calculated and adjusted for covariates. RESULTS: A total of 29,254 women were included in the current analysis; an additional 77 cases of endometrial cancer have been diagnosed since the SQX. The incidence rate for endometrial cancer among women exposed to NBPs was 8.7 per 10,000 person-years versus 17.7 per 10,000 person-years among never-exposed women (rate ratio, 0.49; 95% CI, 0.30-0.80). The effect was similar after adjusting for all the covariates in the Cox proportional hazards analysis, with a hazard ratio of 0.56 (95% CI, 0.34-0.93). CONCLUSIONS: The results of the current study suggest that use of NBPs may have a protective effect on the incidence of endometrial cancer. However, additional studies are needed that include other potential confounders and a larger sample.

Recurrence patterns and survival endpoints in women with stage II uterine endometrioid carcinoma: a multi-institution study.

OBJECTIVE: There is paucity of data in regard to prognostic factors and outcome of women with 2009 FIGO stage II disease. The objective of this study was to investigate prognostic factors, recurrence patterns and survival endpoints in this group of patients. METHODS: Data from four academic institutions were analyzed. 130 women were identified with 2009 FIGO stage II. All patients underwent hysterectomy, oophorectomy and lymph node evaluation with or without pelvic and paraaortic lymph node dissections and peritoneal cytology. The Kaplan-Meier approach and Cox regression analysis were used to estimate recurrence-free (RFS), disease-specific (DSS) and overall survival (OS). RESULTS: Median follow-up was 44months. 120 patients (92%) underwent simple hysterectomy, 78% had lymph node dissection and 95% had peritoneal cytology examination. 99 patients (76%) received adjuvant radiation treatment (RT). 5-year RFS, DSS and OS were 77%, 90%, and 72%, respectively. On multivariate analysis of RFS, adjuvant RT, the presence of lymphovascular space invasion (LVSI) and high tumor grades were significant predictors. For DSS, LVSI and high tumor grades were significant predictors while older age and high tumor grade were the only predictors of OS. CONCLUSIONS: In this multi-institutional study, disease-specific survival for women with FIGO stage II uterine endometrioid carcinoma is excellent. High tumor grade, lymphovascular space invasion, adjuvant radiation treatment and old age are important prognostic factors. There was no significant difference in the outcome between patients who received vaginal cuff brachytherapy compared to those who received pelvic external beam radiation treatment.

Impact of adjuvant chemotherapy and pelvic radiation on pattern of recurrence and outcome in stage I non-invasive uterine papillary serous carcinoma. A multi-institution study.

OBJECTIVES: To determine the impact of adjuvant chemotherapy or pelvic radiation on risk of recurrence and outcome in stage IA non-invasive uterine papillary serous carcinoma (UPSC). METHODS: This is a multi-institutional retrospective study for 115 patients with stage IA non-invasive UPSC (confined to endometrium) treated between 2000 and 2012. Kaplan-Meier and multivariable Cox proportional hazards regression modeling were used. RESULTS: Staging lymphadenectomy and omentectomy were performed in 84% and 57% respectively. Recurrence was seen in 26% (30/115). Sites of recurrences were vaginal in 7.8% (9/115), pelvic in 3.5% (4/115) and extra-pelvic in 14.7% (17/115). Adjuvant chemotherapy did not impact risk of recurrence (25.5% vs. 26.9%, p=0.85) even in subset of patients who underwent lymphadenectomy (20% vs. 23.5%, p=0.80). These findings were consistent for pattern of recurrence. Among those who underwent lymphadenectomy, adjuvant chemotherapy did not impact progression-free survival (p=0.34) and overall survival (p=0.12). However among patients who did not have lymphadenectomy, adjuvant chemotherapy or pelvic radiation was associated with longer progression-free survival (p=0.04) and overall survival (p=0.025). In multivariable analysis, only staging lymphadenectomy was associated with improved progression-free survival (HR 0.34, 95% CI 0.12-0.95, p=0.04) and overall survival (HR 0.35, 95% CI 0.12-1.0, p=0.05). Neither adjuvant chemotherapy nor pelvic radiation were predictors of progression-free or overall survivals. CONCLUSION: In stage IA non-invasive UPSC, staging lymphadenectomy was significantly associated with recurrence and outcome and therefore, should be performed in all patients. Adjuvant chemotherapy or pelvic radiation had no impact on outcome in surgically staged patients but was associated with improved outcome in unstaged patients.

Adjuvant vaginal brachytherapy decreases the risk of vaginal recurrence in patients with stage I non-invasive uterine papillary serous carcinoma. A multi-institutional study.

OBJECTIVES: To investigate the impact of adjuvant vaginal brachytherapy on vaginal recurrence in stage I non-invasive uterine papillary serous carcinoma (UPSC). METHODS: This is a retrospective multi-institutional study from 2000-2012. 103 patients who underwent surgical treatment with non-invasive stage IA UPSC were included. RESULTS: 85% and 55% underwent staging lymphadenectomy and omentectomy respectively. 28.2% (29/103) developed recurrence. Vaginal, pelvic and extra-pelvic recurrences developed in 7.8% (8/103), 3.9% (4/103) and 16.5% (17/103) respectively. Among patients who were observed or received only chemotherapy, the rate of vaginal recurrence was 10.9% (7/64) compared to 2.6% (1/39) among those who received vaginal brachytherapy +/- chemotherapy (p=0.035). The rate of vaginal recurrence was not different between those who were observed and those who received only chemotherapy (9.3% vs. 14.3%, p=0.27). The 5-year progression free survival (PFS) and overall survival (OS) for the entire cohort were 88.3% and 90.6%. Patients who underwent surgical staging had longer PFS (p=0.001) and OS (p=0.0005) compared to those who did not. In multivariable analysis controlling for age, histology, chemotherapy, brachytherapy, and staging lymphadenectomy, only lymphadenectomy was an independent predictor of PFS (HR 0.28, 95% CI 0.11-0.71, p=0.0037) and OS (HR 0.27, 95% CI 0.10-0.71, p=0.0035). Neither chemotherapy nor brachytherapy were predictors of PFS or OS. CONCLUSIONS: This is the largest study reported in stage I non-invasive UPSC. The majority of recurrences were extra-pelvic. Vaginal brachytherapy has a significant role in reducing the risk of vaginal recurrence and surgical staging was the only predictor of outcome. Therefore, both should be considered in these patients.

The prognostic significance of histologic type in early stage cervical cancer - A multi-institutional study.

BACKGROUND: Cervical adenocarcinomas (ADC) have been viewed as more aggressive than squamous cell carcinoma (SCC). We analyzed an international cohort of early stage cervical cancer to determine the impact of histologic type. METHODS: Retrospective analysis of patients with SCC (148 patients) and ADC (130 patients) stages IA1-IB2 who underwent surgery at our three institutions (two from Detroit, one from Mexico) from 2000-2010 was performed for: age, stage, tumor size, lymphovascular invasion (LVI), invasion depth, lymph node status (LN), recurrence and survival. Pathologic review proceeded inclusion. RESULTS: In the Latino population, ADC's tended to be higher grade (p=0.01), while SCC's were larger with deeper invasion (p<0.001). LVI and LN were not significantly different. Recurrence rate (RR) was 8% (8/101) in ADC and 11.8% (9/76) in SCCs. 5 year survival (OS) was equivalent (98.2% and 95.2% for ADC and SCC respectively, p=0.369). In the Detroit cohort, we noted no difference in size, grade, depth of invasion, LVI, LN. RR was 8/72 (13.7%) for SCC and 4/29 (13.7%) but not statistically different between the tumor types (p=0.5). 5 year survival was 91% and 92% for ADC and SCC, respectively. In this population 33% of the patients with SCC and 34% of the patients with ADC received adjuvant chemo-radiation (p=0.4). Histologic type demonstrated no significant outcome difference for any type of adjuvant therapy. CONCLUSION: Comparing early stage disease cervical ADC and SCC suggests equivalent recurrence and survival. Therefore, the paradigm of more aggressive management of early stage cervical ADC warrants further investigation.

Significance of lymphovascular space invasion in uterine serous carcinoma: what matters more; extent or presence?

To analyze the clinical significance of the extent of lymphovascular space invasion (LVI) in patients with uterine serous carcinoma. After IRB approval, 232 patients with uterine serous carcinoma from the pathology databases of 4 large academic institutions were included. Patients were divided into 3 groups based on extent of LVI. Extensive LVI (E-LVI) was defined as ≥3 vessel involvement; low LVI (L-LVI) was defined <3 vessel involvement; and the third group consisted of tumors with no LVI (A-LVI). The association between LVI and myometrial invasion, cervical involvement, lower uterine segment involvement, positive peritoneal washings, lymph node involvement, stage, and survival were analyzed. Of 232 patients, 47 had E-LVI (20.3%), 83 had L-LVI (35.8%), and 102 had A-LVI (44%). A total of 9.8% of the patients with A-LVI had lymph node involvement as compared with 18.1% in the L-LVI group and 55.4% in the E-LVI group (P<0.0001). Fifty-nine percent of the patients in A-LVI, 85% in L-LVI, and 100% in the E-LVI group demonstrated myometrial invasion (P<0.0001). Cervical involvement was noted in 23%, 43%, 66% (P<0.0001) and lower uterine segment involvement involvement in 31%, 43%, and 42% of A-LVI, L-LVI, and E-LVI (P<0.0001), respectively. Stage III and IV disease were seen in 29%, 38%, and 79% of the patients with A-LVI, L-LVI, and E-LVI, respectively (P<0.0001). The median overall survival was 172, 95, and 39 mo for the A-LVI, L-LVI, and E-LVI groups, respectively (P<0.0001). The racial distribution was significant with African American patients demonstrating significantly more L-LVI (27.8%) and E-LVI (40.4%) when compared with A-LVI (19.6%) (P=0.040). In a subgroup analysis including patients with Stage I and II (n=123) revealed median survivals of 172, 169, and 38 mo in the A-LVI, L-LVI, and E-LVI groups, respectively (P<0.0001). Fifty percent of these patients with E-LVI, 20% in L-LVI group, and 15% in A-LVI group had disease recurrence (P=0.040). The extent of LVI was associated with multiple pathologic factors and was found to be a negative prognostic factor for overall survival and disease recurrence.

Tumor size is an independent predictor of lymph node metastasis and survival in early stage endometrioid endometrial cancer.

OBJECTIVE(S): To analyze the impact of tumor size (TS) on risk of lymph node metastasis (PLN) and prognosis in endometrioid endometrial cancer grossly confined to the uterus (EEC). METHOD(S): Patients with EEC grossly confined to the uterus were identified from Surveillance, Epidemiology, and End Results dataset from 1988 to 2007. Only surgically treated patients were included. TS was analyzed as a continuous and categorical variable (TS ≤ 2 cm, >2-5 cm and >5 cm). Multivariable logistic regression and Cox proportional hazards models were used. RESULT(S): 19,692 patients met the inclusion criteria. In patients with TS ≤ 2 cm, only 2.7 % (88/3,244) had PLN; this increased to 5.8 % (372/6,355) with TS > 2-5 cm and 11.1 % (195/1,745) with TS > 5 cm. The odds of PLN increased by 14 % for each 1 cm increase in TS after controlling for age, race, depth of myometrial invasion and grade (HR 1.14, 95 % CI 1.10-1.19, p < 0.001). Further, TS was an independent predictor of disease-specific survival (DSS) even after adjusting for age, race, grade, depth of myometrial invasion, lymph node status and adjuvant radiation therapy (HR 1.13 for each 1 cm increment in TS, 95 % 1.08-1.18, p < 0.001). In multivariable analysis, larger TS (>5 cm) was significantly associated with worse DSS (HR 2.09, 95 % 1.31-3.35, p = 0.002); however, there was no significant difference between TS > 2-5 cm versus ≤2 cm (HR 1.25, 95 % 0.85-1.83, p = 0.25). The impact of TS remained significant on DSS in subset of patients who underwent lymphadenectomy with negative lymph nodes. CONCLUSION(S): TS was an independent predictor of lymph node metastasis and disease-specific survival in patients with EEC grossly confined to the uterus. Tumor >5 cm was a predictor of disease-specific survival but no difference in outcome was noted between tumor >2-5 cm and tumor ≤2 cm.

Is the two-tier ovarian serous carcinoma grading system potentially useful in stratifying uterine serous carcinoma? A large multi-institutional analysis.

OBJECTIVE: A subset of uterine serous carcinoma (USC) may have better clinical behavior bringing up the possibility that there may be morphologic features, which would help in their categorization. The aim of this study is to evaluate the potential use of the MD Anderson Cancer Center 2-tier grading system for ovarian carcinoma in USC. METHODS: Tumors assigned a combined score included in this analysis were 1) low-grade: tumors without marked atypia and 12 mitoses/10 high power field (HPF) and 2) high grade: tumors with severe nuclear atypia and >12 mitoses/10 HPF. Clinicopathologic parameters evaluated included patients' age, tumor size, myometrial invasion (MI), lymphovascular invasion (LVI), lymph node (LN), FIGO stage, and patient outcome. RESULTS: 140 patients with USC were included, 30 low grade uterine serous carcinoma (LGUSC) and 110 high grade uterine serous carcinoma (HGUSC). Of all parameters only 2 (MI and stage IA) reached statistical significance. 67% of LGUSC cases showed myometrial invasion versus 93.6% HGUSC cases (p = 0.003). A higher percentage of LGUSC (63.3%) versus HGUSC (32.7%) were in stage IA (p = 0.01). However, by multivariate analysis including age, LVI, stage and tumor grade only stage was an independent prognostic factor. CONCLUSION: The presence of atypia and mitosis across a uterine serous carcinoma is notoriously variable in magnitude and extent, potentially making evaluation of these features difficult and subsequent grading subjective. Our findings thus show that actual prognostic utility of application of MDACC two-tier grading system to uterine serous carcinoma may not be applicable.