Early-stage Endometrial Carcinoma Research Articles

L1CAM and HER2 Expression in Early Endometrioid Uterine Cancer.

Recently L1CAM was shown to be a promising biomarker for early-stage endometrial carcinoma (EC). As L1CAM expression was found to be related to serous ECs and areas of serous differentiation in endometrioid carcinomas, there is evidence that L1CAM-positive cancers more likely resemble type II carcinomas. Furthermore, expression of growth factor receptor HER2 has been found to be closely associated with serous ECs. We conducted a retrospective study on 142 patients in FIGO stages I and II with endometrioid EC and analyzed L1CAM and HER2 expression by double-staining immunohistochemistry. The association between these 2 transmembrane molecules and their impact on patient outcome was analyzed. Both L1CAM and HER2 showed a significant association with recurrent disease (P<0.001 and P=0.007, respectively). We found 39 (27%) L1CAM-positive cases and 17 (12%) HER2-positive cases. About 6.3% of cases were positive for both biomarkers. Survival of L1CAM-positive patients showed a significant difference between HER2-positive and HER2-negative patients (P=0.019) regarding disease-free survival. The most unfavorable disease-free survival and overall survival was found for patients with L1CAM and HER2 double-positive tumors (P<0.001). Double immunostaining revealed a mutually exclusive staining pattern for L1CAM and HER2 expression on the level of tumor cells. In early endometrioid uterine carcinoma, an additional expression of HER2 to L1CAM seems to further worsen disease-free survival and overall survival. In terms of "personalized medicine," detection of these molecules in endometrioid ECs may open new avenues for targeted therapies with the newly available anti-HER2 drugs and/or with the upcoming humanized anti-L1CAM antibodies.

Evaluation and validation of the diagnostic value of the apparent diffusion coefficient for differentiating early-stage endometrial carcinomas from benign mimickers at 3T MRI.

Previous researchers obtained various apparent diffusion coefficient (ADC) cutoff values to differentiate endometrial carcinoma from benign mimickers with 1.5T magnetic resonance imaging (MRI). Few studies have used 3T MRI or validated the effectiveness of these cutoff ADC values prospectively. This study was designed in two stages to obtain a cutoff ADC value at 3T MRI and to validate prospectively the role of the ADC value. First, we conducted a retrospective study of 60 patients to evaluate the diagnostic value of ADC by obtain a theoretical cutoff ADC value for differentiating between benign and malignant endometrial lesions. Student's t test revealed that ADC values for stage I endometrial carcinomas were significantly lower than those for benign lesions. The area under the curve value of the receiver operating characteristic curve was 0.993, and the cutoff ADC value was 0.98 × 10−3 mm2/s. The sensitivity, specificity, and overall accuracy of diagnosing stage I endometrial carcinoma were 100%, 97.1%, and 98.3%, respectively. Second, we conducted a prospective study of 26 patients to validate the use of the cutoff ADC value obtained in the study's first stage. The sensitivity, specificity, and overall accuracy for differentiating malignant from benign endometrial lesions based on the cutoff ADC value obtained earlier were as follows: radiologist 1 attained 86.67%, 100.0%, and 92.31%, respectively; radiologist 2 attained 86.67%, 91.0%, and 88.5%, respectively. Our results suggest that ADC values could be a potential biomarker for use as a quantitative and qualitative tool for differentiating between early-stage endometrial carcinomas and benign mimickers.

Clinicopathological Features of Early and Late Recurrence of Endometrial Carcinoma After Surgical Resection.

The incidence of endometrial carcinoma has been increasing annually in developed nations; it is currently the second most common gynecological malignancy. Although the majority of patients are diagnosed at an early stage, 15% to 20% reportedly recur; consequently, patients are usually followed clinically for 3 years after the initial curative surgery. We therefore aimed to determine the incidence and clinicopathological features of early and late recurrences of endometrial carcinoma after surgical resection. This retrospective study was performed using the clinical records of 2233 patients who underwent surgical resection for endometrial carcinoma between January 1970 and December 2009 at a single cancer center. Tumor recurrences were classified as early (<5 years) and late (>5 years) after initial surgery. Clinicopathological variables and tumor recurrence patterns were compared between the early and late recurrence groups. Survival analysis was performed using the Kaplan-Meier method. Among 2233 study patients, 255 (11.4%) experienced endometrial carcinoma recurrence; of these, early and late recurrences occurred in 232 (91.0%) and 23 (9.0%) patients, respectively. Late recurrence was associated with invasion of less than half of the myometrium at diagnosis and the presence of histopathological features of endometrioid adenocarcinoma with low- or intermediate-grade histological subtype and absence of lymphovascular invasion. After recurrence, there was no significant difference in overall survival between the early and late recurrence groups (P = 0.437). Furthermore, surgical treatment was associated with a significantly improved prognosis in the late recurrence group (P = 0.044). The findings of this study indicated that patients who initially underwent successful treatment for low-grade and early-stage endometrial carcinoma should be followed clinically for more than 5 years. In cases of late recurrence, surgical management may improve prognosis.

Comparison among fertility-sparing therapies for well differentiated early-stage endometrial carcinoma and complex atypical hyperplasia.

ObjectiveTo compare fertility-sparing therapies including oral progestogens, hysteroscopic resection (HR), and the levonorgestrel- releasing intrauterine system (LNG-IUS) in achieving disease regression, recurrence and live birth rate in well differentiate early-stage endometrial carcinoma (eEC) and complex atypical hyperplasia(CAH).Study DesignThis was a meta-analysis of previous studies focus on the fertility-sparing therapy for well differentiate early-stage endometrial carcinoma (eEC) and complex atypical hyperplasia (CAH).Date SourcesMedline, the Cochrane Library and Embase was searched with the terms and Synonyms: words similar to eEC and CAH with therapies associated with fertility-sparing.Main Outcome MeasuresThe number of all patients accepted fertility sparing therapies, patients got regressed, relapsed and delivered were extracted from each study, and the regression, recurrence, and live birth rate of each study were calculated. The regression, recurrence and live birth rates between each two interventions were compared with the aid of meta-regression in packages of “meta” and ”meta for” written in R.ResultsFifty-four studies reported fertility sparing therapies in young women with eEC and CAH were included. Meta-analysis showed that HR followed by progestogens achieved a higher pooled regression (98.06% vs 77.20% P < 0.0001) and live birth rate (52.57% vs 33.38%, P = 0.0944) and a lower recurrence rate compared with oral progestogens alone (4.79% vs 32.17% P = 0.0004). At the same time, the pooled live birth rate (52.57% vs 18.09% P =0.0399) of HR followed by progestogens are significantly higher than the LNG-IUS alone. Which no statistical difference in regression (98.06% vs 94.24%; P = 0.4098) and recurrence rates (4.79% vs 3.90% P = 0.8561) was seen.ConclusionsOf the available fertility-sparing therapeutic options, HR followed by progestogens may be a more effective one.

Influence of Comorbidity on the Risk of Death: A Single Institution Study of 1132 Women With Early-stage Uterine Cancer.

The impact of competing medical comorbidity on survival endpoints in women with early stage endometrial carcinoma (EC) is not well studied. The study goal was to utilize a validated comorbidity scoring system to determine its impact on all-cause mortality as well as on recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival (OS) in patients with early-stage EC. For this IRB-approved study, we reviewed our prospectively maintained uterine cancer database of 1720 patients. We identified 1132 patients with EC FIGO stages I-II who underwent hysterectomy from 1984 to 2011. Age-adjusted Charlson Comorbidity Index (AACCI) at time of hysterectomy was retrospectively calculated by physician chart review. The cause of death (uterine cancer-related and unrelated) was correlated with AACCI. Univariate and multivariate modeling with Cox regression analysis was used to determine significant predictors of OS, DSS, and RFS. The Kaplan-Meier and the log-rank test methods were used to evaluate survival outcomes. After a median follow-up of 51 months, 262 deaths were recorded (42 from EC [16%], and 220 [84%] from other causes). Median AACCI score for the study cohort was 3 (range, 0 to 15). On the basis of AACCI, patients were grouped as follows: 0 to 2 (group 1, n=379), 3 to 4 (group 2, n=532), and ≥5 (group 3, n=221). By AACCI grouping, the 5-year RFS, DSS, and OS were 95%, 98%, and 97% for group 1, 89%, 95%, and 87% for group 2, and 86%, 95% and 72% for group 3 (P<0.0001). The cause of death in the first 10 years after hysterectomy in our study was mainly non-uterine cancer-related (78% vs. 22% for uterine cancer-related) causes. On multivariate analyses, higher AACCI, lymphovascular space invasion (LVSI), higher tumor grade, age, and involvement of the lower uterine segment were significant predictors of shorter OS. On multivariate analysis for DSS and RFS, only high tumor grade and LVSI were significant predictors. The cause of death for women with early stage EC is mainly nonuterine cancer-related. Comorbidity score is a significant predictor of OS in our study cohort. Comorbidity scores may be useful as a stratification factor in any prospective clinical trial for women with early-stage EC.

Is Older Age a Real Adverse Prognostic Factor in Women With Early-Stage Endometrial Carcinoma? A Matched Analysis.

The aim of this study was to evaluate if older age alone negatively impacts survival endpoints in women with early-stage uterine endometrioid carcinoma (EC), or its reported prognostic impact is due to an interaction with other well-known adverse factors using matched-analysis methodology. We identified 1254 patients with International Federation of Gynecology and Obstetrics stage I-II EC who underwent hysterectomy at our institution. We created 2 matched groups based on International Federation of Gynecology and Obstetrics stage, tumor grade, lymph node dissection status, and the type of adjuvant management. Recurrence-free (RFS), disease-specific (DSS) and overall survival (OS) were calculated. A total 297 women 70 years or older were matched with 297 women younger than 70 years. The 2 groups were well balanced except for age and higher body mass index in younger patients. There were no significant difference between older and younger patients in regard to 5-year RFS (85% vs 87%; P = 0.52) or DSS (93% for both groups with P = 0.77). Five-year OS was shorter in older patients (76% vs 88% with P < 0.001). On multivariate analysis for RFS and DSS, high tumor grade and the presence of lymphovascular space invasion (LVSI) were the only 2 predictors of shorter RFS and DSS (P = 0.01 and P = 0.02, and P = 0.01 and P = 0.01, respectively). Tumor grade and LVSI also were predictors of shorter OS. Our study suggests that when older patients with EC are matched with younger patients based on tumor stage, grade, and adjuvant management the prognostic impact of old age disappears. High tumor grade and LVSI remained as independent predictors of survival endpoints.

Survival endpoints for young women with early stage uterine endometrioid carcinoma: a matched analysis

ObjectivesYounger age is thought to be a favorable prognostic factor in women with endometrial carcinoma (EC). Survival endpoints were compared between two matched groups of patients with early stage EC: women 45 years or younger and women older than 45 years. Methods and materialsTwo matched groups of patients were created based on stage, grade, lymph node dissection and adjuvant management. Recurrence-free (RFS), disease-specific (DSS) and overall survival (OS) were calculated. ResultsA total of 525 patients (88 younger patients and 437 older patients, matched 1:5) were included in this study. The two groups were well balanced except for less myometrial invasion in the younger patients. There were no significant differences between younger and older patients in regards to 5-year RFS (94% vs. 91%, p=0.6902). Similarly, there was no significant difference in regards to DSS (96% vs. 97%, p=0.9000). While 5-year OS was similar for both groups (89% vs. 89%, p=0.9942), 10-year OS was longer in the younger group (83% vs. 68% with p=0.13). On multivariate analysis for RFS, the presence of lymphovascular space invasion was the only predictor of shorter RFS (p=0.0007). Tumor grade (p=0.0002) and lower uterine segment involvement (p=0.0141) were independent predictors of shorter DSS. Older age (p<0.001) and stage II (p=0.01) were the only predictors of shorter OS. ConclusionsWhen matched based on tumor stage, grade and adjuvant management, our study suggests that there is no difference in survival endpoints between younger and older patients with early stage endometrial carcinoma.

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

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. 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. 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. 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.

Improved Risk Assessment by Integrating Molecular and Clinicopathological Factors in Early-stage Endometrial Cancer-Combined Analysis of the PORTEC Cohorts.

Recommendations for adjuvant treatment for women with early-stage endometrial carcinoma are based on clinicopathologic features. Comprehensive genomic characterization defined four subgroups: p53-mutant, microsatellite instability (MSI), POLE-mutant, and no specific molecular profile (NSMP). We aimed to confirm the prognostic capacity of these subgroups in large randomized trial populations, investigate potential other prognostic classifiers, and integrate these into an integrated molecular risk assessment guiding adjuvant therapy. Analysis of MSI, hotspot mutations in 14 genes including POLE, protein expression of p53, ARID1a, β-catenin, L1CAM, PTEN, ER, and PR was undertaken on 947 available early-stage endometrioid endometrial carcinomas from the PORTEC-1 and -2 trials, mostly high-intermediate risk (n = 614). Prognostic value was determined using univariable and multivariable Cox proportional hazard models. AUCs of different risk stratification models were compared. Molecular analyses were feasible in >96% of the patients and confirmed the four molecular subgroups: p53-mutant (9%), MSI (26%), POLE-mutant (6%), and NSMP (59%). Integration of prognostic molecular alterations with established clinicopathologic factors resulted in a stronger model with improved risk prognostication. Approximately 15% of high-intermediate risk patients had unfavorable features (substantial lymphovascular space invasion, p53-mutant, and/or >10% L1CAM), 50% favorable features (POLE-mutant, NSMP being microsatellite stable, and CTNNB1 wild-type), and 35% intermediate features (MSI or CTNNB1-mutant). Integrating clinicopathologic and molecular factors improves the risk assessment of patients with early-stage endometrial carcinoma. Assessment of this integrated risk profile is feasible in daily practice, and holds promise to reduce both overtreatment and undertreatment. Clin Cancer Res; 22(16); 4215-24. ©2016 AACR.

Trends in the utilization of adjuvant vaginal brachytherapy in women with early-stage endometrial carcinoma: Results of an updated period analysis of SEER data

PurposeAdjuvant vaginal brachytherapy (VB) is a well-established and effective radiation treatment modality in women with early-stage endometrial carcinoma. We sought to evaluate and update published trends in the utilization of VB vs. other radiation therapy modalities (pelvic external beam radiation therapy (EBRT) or the combination of VB and pelvic EBRT using the National Cancer Institute's Surveillance, Epidemiology, and End Results database. Methods and MaterialsThe Surveillance, Epidemiology, and End Results database was queried for adult females with histologically confirmed International Federation of Gynecology and Obstetrics 1988 Stage I–II endometrial carcinoma diagnosed from 1995 to 2012 and treated definitively with hysterectomy and adjuvant radiation therapy. Chi-square tests were used to assess differences by radiation type (VB, EBRT, and VB + EBRT) and various demographic and clinical variables. ResultsWe identified 15,201 patients that met inclusion criteria. There was a significant overall increase in the use of VB was observed from 17.1% in 1995–2000 compared to 57.1% in 2007–2012 (p < 0.0001). Similarly, there was a proportional decrease in the use of EBRT from 54.0% to 25.5% (p < 0.0001) as well as in the use of VB + EBRT from 28.9% to 17.4% during the same period (p < 0.0001). The observed increase in utilization of VB was not limited to any variables (age, race, histological type, International Federation of Gynecology and Obstetrics stage, and the status of lymph node dissection [yes or no]) or the number of dissected lymph nodes. ConclusionsIn this large national database set, there continues to be an increasing trend for the use of VB in the adjuvant setting in women with early-stage endometrial carcinoma.

Combined modality adjuvant therapy for high-risk endometrial cancer

Combined modality adjuvant therapy for high-risk endometrial cancer

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

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. 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. 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. 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.

Surgery for early stage endometrial carcinoma in the obese patient

AbstractObese patients have increased risk of developing endometrial cancer proportional to the excess in body mass index. In this review, we explored the latest information on surgical management and its adaptation to the obese condition. Mini-invasive treatments (laparoscopic, robotic, vaginal, or combinations) should be systematically considered. Prevention and active treatment of obesity seem an interesting approach to reduce incidence and severity of the disease.

Influence of robotic-assisted laparoscopic hysterectomy on vaginal cuff healing and brachytherapy initiation in endometrial carcinoma patients

PurposeThe purpose of this study was to examine the impact of robotic-assisted laparoscopic hysterectomy (RALH) compared with total abdominal hysterectomy by laparotomy (TAH) on vaginal cuff healing in early-stage endometrial carcinoma patients receiving adjuvant intravaginal brachytherapy (IVBT). Methods and materialsWe included 137 consecutive patients who underwent adjuvant IVBT without external beam radiation therapy or chemotherapy for stage I-II endometrial carcinoma. All patients underwent either RALH or TAH. Vaginal cuff healing status as assessed by inspection and palpation at initial evaluation by radiation oncology (VC1) was the primary outcome, with secondary outcomes including vaginal cuff healing status at first scheduled IVBT (VC2), time interval from hysterectomy to initiation of IVBT, and local recurrence. ResultsAmong 137 patients, 74 (54.0%) underwent RALH and 63 (46.0%) underwent TAH. There was no significant difference in mean time from hysterectomy to initial radiation oncology evaluation between RALH and TAH patients (approximately 30 days in both groups). RALH was the only covariate associated with protracted vaginal cuff healing time at both VC1 (P = .003) and VC2 (P = .038). There was a significantly increased mean interval between hysterectomy and start of IVBT for patients undergoing RALH from 47.7 to 55.0 days (P < .001). Vaginal cuff healing was more likely to contribute to delay in delivery of IVBT in RALH patients, whereas abdominal or other nonvaginal wound healing was more likely to contribute to delay in TAH patients. There were no vaginal cuff recurrences detected after 16 months median follow-up. ConclusionsRALH for early-stage endometrial carcinoma was associated with longer vaginal cuff healing time and a mean increase in interval from hysterectomy to IVBT of 1 week compared with TAH.

Endometrial cancer: Not your grandmother's cancer.

Worldwide, the incidence of endometrial carcinoma (EC) is rapidly increasing, and the highest disease burden is reported in North America and Western Europe. Although the prognosis remains good for patients with are diagnosed with early stage EC, for those with recurrent or metastatic disease, the options are few, and the median overall survival is short. It is imperative to gain a greater understanding of all aspects of EC, limit its effect on scarce health care resources and, more importantly, prevent this cancer from significantly impacting future generations of women. An exciting new era of endometrial cancer research and clinical management has begun that incorporates biologically and clinically relevant genomic and clinicopathologic parameters. Continued collaborative research efforts and funding are essential if we are to advance our understanding of this disease and improve clinical outcomes. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2787-2798. © 2016 American Cancer Society.

Older age is no longer an adverse prognostic factor in women with early-stage endometrial carcinoma: A matched analysis

Older age is no longer an adverse prognostic factor in women with early-stage endometrial carcinoma: A matched analysis

Predictive capacity of 3 comorbidity indices in estimating survival endpoints in women with early-stage endometrial carcinoma

Predictive capacity of 3 comorbidity indices in estimating survival endpoints in women with early-stage endometrial carcinoma

Predictors of survival after recurrence in women with early-stage endometrial carcinoma

Predictors of survival after recurrence in women with early-stage endometrial carcinoma

Use of next-generation sequencing (NGS) panels to predict recurrence in low-grade, early-stage endometrioid endometrial carcinoma.

5580Background: Predicting recurrence in low grade, early stage endometrial cancer (EC) is both difficult and important, as recurrence outside the pelvis is typically incurable. We sought to determ...

Clusterin immunoexpression is associated with early stage endometrial carcinomas

Clusterin has anti-apoptotic, regeneration and migration stimulating effects on tumor cells. This study investigates the relation between clusterin expression and the clinicopathological parameters in endometrial carcinomas. Seventy one cases of previously diagnosed endometrial carcinoma (including 59 endometrioid adenocarcinoma, 9 serous adenocarcinoma, 1 clear cell adenocarcinoma, and 2 malignant mixed Mullerian tumor) and 30 tissue samples of non-cancerous endometrium (including 16 proliferative endometrium, 10 secretory endometrium and 4 endometrial polyps) were employed for clusterin detection using tissue microarrays and immunostaining. A total number of 23 (32.4%) cases were positive for clusterin immunostaining. Brown granular cytoplasmic expression of clusterin was detected in 33.9% of endometrioid adenocarcinomas, 22.2% papillary serous endometrial carcinomas. Three (10%) control cases showed granular cytoplasmic expression. Positive clusterin immunostaining was found more frequent in well differentiated and stage I endometrial carcinomas, showing significant statistical association (p-value=0.036 and p-value=0.002 respectively). Significant difference in clusterin expression was observed between tumor cases and control group (P-Value=0.019), i.e., endometrial carcinoma cases are more than four times likely to show positive clusterin immunostaining (odds ratio 4.313 with 95% confidence interval 1.184–15.701). This study did not find relation between clusterin expression and disease recurrence, survival or any of the other clinicopathological parameters in endometrial tumors. The results of our study confirms the diagnostic values of clusterin in supporting the diagnosis of endometrioid carcinoma. When clusterin is expressed in endometrial tumors, it is associated with lower stage. The correlation of clusterin with tumor stage suggests involvement of this molecule in endometrial tumor progression.