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Background: To help BRCA1 and 2 mutation carriers make informed decisions regarding use of combined-type oral contraceptive preparation (COCP), absolute risk-benefit estimates are needed for COCP-associated cancer., Methods: For a hypothetical cohort of 10 000 women, we calculated the increased or decreased cumulative incidence of COCP-associated (breast, ovarian, endometrial) cancer, examining 18 scenarios with differences in duration and timing of COCP use, uptake of prophylactic surgeries, and menopausal hormone therapy., Results: COCP use initially increased breast cancer risk and decreased ovarian and endometrial cancer risk long term. For 10 000 BRCA1 mutation carriers, 10 years of COCP use from age 20 to 30 years resulted in 66 additional COCP-associated cancer cases by the age of 35 years, in addition to 625 cases expected for never users. By the age of 70 years such COCP use resulted in 907 fewer cancer cases than the expected 9093 cases in never users. Triple-negative breast cancer estimates resulted in 196 additional COCP-associated cases by age 40 years, in addition to the 1454 expected. For 10 000 BRCA2 mutation carriers using COCP from age 20 to 30 years, 80 excess cancer cases were estimated by age 40 years in addition to 651 expected cases; by the age of 70 years, we calculated 382 fewer cases compared with the 6156 cases expected. The long-term benefit of COCP use diminished after risk-reducing bilateral salpingo-oophorectomy followed by menopausal hormone therapy use., Conclusion: Although COCP use in BRCA1 and BRCA2 mutation carriers initially increases breast, ovarian, and endometrial cancer risk, it strongly decreases lifetime cancer risk. Risk-reducing bilateral salpingo-oophorectomy and menopausal hormone therapy use appear to counteract the long-term COCP-benefit., (© The Author(s) 2022. Published by Oxford University Press.)

Background: Laparoscopic hysterectomy is accepted worldwide as the standard treatment option for early-stage endometrial cancer. However, there are limited data on long-term survival, particularly when no lymphadenectomy is performed. We compared the survival outcomes of total laparoscopic hysterectomy (TLH) and total abdominal hysterectomy (TAH), both without lymphadenectomy, for early-stage endometrial cancer up to 5 years postoperatively., Methods: Follow-up of a multi-centre, randomised controlled trial comparing TLH and TAH, without routine lymphadenectomy, for women with stage I endometrial cancer. Enrolment was between 2007 and 2009 by 2:1 randomisation to TLH or TAH. Outcomes were disease-free survival (DFS), overall survival (OS), disease-specific survival (DSS), and primary site of recurrence. Multivariable Cox regression analyses were adjusted for age, stage, grade, and radiotherapy with adjusted hazard ratios (aHR) and 95% confidence intervals (95%CI) reported. To test for significance, non-inferiority margins were defined., Results: In total, 279 women underwent a surgical procedure, of whom 263 (94%) had follow-up data. For the TLH (n = 175) and TAH (n = 88) groups, DFS (90.3% vs 84.1%; aHR[recurrence], 0.69; 95%CI, 0.31-1.52), OS (89.2% vs 82.8%; aHR[death], 0.60; 95%CI, 0.30-1.19), and DSS (95.0% vs 89.8%; aHR[death], 0.62; 95%CI, 0.23-1.70) were reported at 5 years. At a 10% significance level, and with a non-inferiority margin of 0.20, the null hypothesis of inferiority was rejected for all three outcomes. There were no port-site or wound metastases, and local recurrence rates were comparable., Conclusion: Disease recurrence and 5-year survival rates were comparable between the TLH and TAH groups and comparable to studies with lymphadenectomy, supporting the widespread use of TLH without lymphadenectomy as the primary treatment for early-stage, low-grade endometrial cancer., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Endometrial cancer (EC) risk in BReast CAncer gene 1/2 (BRCA1/2) mutation carriers is uncertain; therefore, we assessed this in a large Dutch nationwide cohort study., Methods: We selected 5980 BRCA1/2 (3788 BRCA1, 2151 gBRCA2, 41 both BRCA1/BRCA2) and 8451 non-BRCA1/2 mutation carriers from the Hereditary Breast and Ovarian cancer study, the Netherlands cohort. Follow-up started at the date of the nationwide Dutch Pathology Registry coverage (January 1, 1989) or at the age of 25 years (whichever came last) and ended at date of EC diagnosis, last follow-up, or death (whichever came first). EC risk in BRCA1/2 mutation carriers was compared with 1) the general population, estimating standardized incidence ratios (SIRs) based on Dutch population-based incidence rates; and 2) non-BRCA1/2 mutation carriers, using Cox-regression analyses, expressed as hazard ratio (HR). Statistical tests were 2-sided., Results: Fifty-eight BRCA1/2 and 33 non-BRCA1/2 mutation carriers developed EC over 119 296 and 160 841 person-years, respectively (SIR = 2.83, 95% confidence interval [CI] = 2.18 to 3.65; and HR = 2.37, 95% CI = 1.53 to 3.69, respectively). gBRCA1 mutation carriers showed increased risks for EC overall (SIR = 3.51, 95% CI = 2.61 to 4.72; HR = 2.91, 95% CI = 1.83 to 4.66), serous-like EC (SIR = 12.64, 95% CI = 7.62 to 20.96; HR = 10.48, 95% CI = 2.95 to 37.20), endometrioid EC (SIR = 2.63, 95% CI = 1.80 to 3.83; HR = 2.01, 95% CI = 1.18 to 3.45), and TP53-mutated EC (HR = 15.71, 95% CI = 4.62 to 53.40). For BRCA2 mutation carriers, overall (SIR = 1.70, 95% CI = 1.01 to 2.87) and serous-like EC risks (SIR = 5.11, 95% CI = 1.92 to 13.63) were increased compared with the general population. Absolute risks by 75 years remained low (overall EC = 3.0%; serous-like EC = 1.1%)., Conclusions: BRCA1/2 mutation carriers have a two- to threefold increased risk for EC, with highest risk observed for the rare subgroups of serous-like and p53-abnormal EC in BRCA1 mutation carriers., (© The Author(s) 2021. Published by Oxford University Press.)

Introduction: Intraepithelial CD8+ tumour-infiltrating T-lymphocytes (TIL) are associated with a prolonged survival in endometrial cancer (EC). By contrast, stromal infiltration of CD8+ TIL does not confer prognostic benefit. A single marker to discriminate these populations would therefore be of interest for rapid assessment of the tumour immune contexture, ex vivo analysis of intraepithelial and stromal T-cells on a functional level and/or adoptive T-cell transfer. Here we determined whether CD103, the αE subunit of the αEβ7integrin, can be used to specifically discriminate the epithelial and stromal CD8+ TIL populations in EC., Methods: CD103+ TIL were quantified in a cohort of 305 EC patients by immunohistochemistry. Localization of CD103+ cells and co-expression of CD103 with CD3, CD8, CD16 and FoxP3 were assessed by immunofluorescence. Further phenotyping of CD103+ cells was performed by flow cytometry on primary endometrial tumour digests., Results: CD8+CD103+ cells were preferentially located in endometrial tumour epithelium, whereas CD8+CD103- cells were located in stroma. CD103+ lymphocytes were predominantly CD3+CD8+ T-cells and expressed PD1. The presence of a high CD103+ cell infiltration was associated with an improved prognosis in patients with endometrial adenocarcinoma (p = 0.035). Moreover, this beneficial effect was particularly evident in high-risk adenocarcinoma patients (p = 0.031)., Conclusions: Because of the restricted expression on intraepithelial CD8+ T-cells, CD103 may be a suitable biomarker for rapid assessment of immune infiltration of epithelial cancers. Furthermore, this intraepithelial tumour-reactive subset might be an interesting T-cell subset for adoptive T-cell transfer and/or target for checkpoint inhibition therapy., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Serous endometrial intraepithelial carcinoma has been proposed to be a potential precursor lesion of pelvic high-grade serous carcinoma. If true, an increased incidence of uterine papillary serous carcinomas would be expected in BRCA1 and BRCA2 mutation carriers, who are at high-risk of developing pelvic high-grade serous carcinoma. This study explored particularly the occurrence of uterine papillary serous carcinoma, as well as other endometrial cancers, following risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 germline mutation attending a tertiary multidisciplinary clinic. A consecutive series of women with a BRCA1 or BRCA2 mutation who had undergone risk-reducing salpingo-oophorectomy without hysterectomy at the University Medical Center Groningen from January 1996 until March 2012 were followed prospectively. They were crossed with the histopathology list of endometrial cancer diagnoses reported by the Dutch nationwide pathology database PALGA. To assess the risk of endometrial cancer, a standardized incidence ratio was calculated comparing the observed with the expected number of endometrial cancer cases. Overall, 201 BRCA1 and 144 BRCA2 mutation carriers at a median age of 50 years (range, 32-78) were analyzed. After a median follow-up period of 6 years, after risk-reducing salpingo-oophorectomy, two cases of endometrial cancer were diagnosed, whereas the expected number was 0.94 cases (standardized incidence ratio 2.13; 95% confidence interval 0.24-7.69; P=0.27). Both endometrial cancer cases were of the endometrioid histological subtype. We showed that the incidence of endometrial cancer following risk-reducing salpingo-oophorectomy, especially uterine papillary serous carcinoma, in women at high-risk of developing pelvic high-grade serous carcinoma is not increased. On the basis of our data, the hypothesis of serous endometrial intraepithelial carcinoma being an important precursor lesion of pelvic high-grade serous carcinoma seems unlikely. There is no need to add a prophylactic hysterectomy to risk-reducing salpingo-oophorectomy in BRCA1 or BRCA2 mutation carriers.

Tumor cells can escape from cytotoxic T-cell responses by downregulation of human leukocyte antigen (HLA) class I molecules expressed at the cell surface which has been associated with a deficient mismatch repair (MMR) system in colorectal carcinomas. Our study investigated the association between expression of MMR proteins and HLA class I in sporadic endometrioid endometrial carcinomas (EC). In a consecutively selected cohort of 486 EC patients, MMR proteins (MLH1, MSH2 and MSH6) and HLA class I (HLA-A, -B, -C or β(2) m) were investigated by immunohistochemistry. Expression levels of MMR proteins and HLA class I were compared between low-grade and high-grade ECs. HLA class I expression was compared between tumors with loss (negative immunostaining of ≥1 MMR protein) and expression of MMR proteins. Associations between previously determined numbers of intratumoral CD8(+) T-lymphocytes and expression of MMR proteins and HLA class I and the influence on survival was determined. ECs with loss of MMR protein expression (33.5%) more frequently have loss of HLA-B/C (37.3%), compared to ECs with MMR protein expression (25.5%, p = 0.007). Patients with loss of MMR proteins have a worse disease-specific survival compared to patients with expression (p = 0.039). CD8(+) T-lymphocytes have a positive influence on disease-free and disease-specific survival in the total EC cohort but not in patients with loss of MMR protein expression. In conclusion, our results indicate that loss of MMR protein expression is related to selective downregulation of HLA class I which contributes to immune escape in EC with an abnormal MMR system., (Copyright © 2012 UICC.)

Background: Total laparoscopic hysterectomy (TLH) is safe and cost effective in early stage endometrial cancer when compared to total abdominal hysterectomy (TAH). In non-randomised data it is often hypothesised that older and obese patients benefit most from TLH. Aim of this study is to analyse whether data support this assumption to advice patients, clinicians and policy makers., Methods: Data of 283 patients enrolled in a randomised controlled trial comparing TAH versus TLH in early stage endometrial cancer were re-analysed. Randomisation by sequential number generation was done centrally, with stratification by trial centre. Using multivariate analysis, predictors of major complications and conversions to laparotomy were assessed. For the cost effectiveness analysis, subgroups of patients were constructed based on age and body mass index (BMI). For each subgroup, costs per major complication-free patient were estimated, using incremental cost effect ratios (extra costs per additional effect)., Results: Older (odds ratio (OR): 1.05; 1.01-1.09) and obese (OR: 1.05; 1.01-1.10) patients had a higher risk to develop complications, for both groups. In obese (OR: 1.17; 1.09-1.25) patients and patients with a previous laparotomy (OR: 3.45; 1.19-10.04) a higher risk of conversion to laparotomy was found. For patients>70 years of age and patients with a BMI over 35 kg/m2, incremental costs per major complication-free patients were €16 and €54 for TLH compared to TAH, respectively., Conclusion: In general, TLH should be recommended as the standard surgical procedure in early stage endometrial cancer, also in patients>70 years of age. In obese patients with a BMI>35 kg/m2 TLH is not cost effective because of the high conversion rate. A careful consideration of laparoscopic treatment is needed for this subgroup. Surgeon experience level may influence this choice., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Tamoxifen has been a very effective treatment for breast cancer for several decades, however, at the same time increases the risk of endometrial cancer, especially after prolonged exposure. In addition, tamoxifen has been associated with a higher proportion of unfavorable uterine tumor subtypes (carcinosarcomas and serous adenocarcinomas) with worse survival. We investigated whether endometrial tumors, which developed after prolonged tamoxifen treatment for breast cancer, are genetically different from endometrial tumors without preceding tamoxifen exposure. Array CGH was used on archival formalin-fixed paraffin embedded endometrial tumors to determine genomic aberrations. We compared the genomic profiles of 52 endometrial tumors from breast cancer patients after long-term (>or=2 years) tamoxifen use (endometrioid adenocarcinomas, n = 26; carcinosarcomas, n = 14; and serous adenocarcinomas, n = 12) with endometrial tumors from unexposed breast cancer patients (n = 45). Genomic profiles were correlated with tamoxifen exposure, tumor subtypes, and histopathological characteristics of the endometrial tumors. The common uterine corpus cancers of the endometrioid subtype show few genomic aberrations. Tumors with many genomic aberrations were in general ER-negative. In contrast, carcinosarcomas and serous adenocarcinomas showed many aberrations; however, they were indistinguishable from each other. Tumors that developed after prolonged tamoxifen use did not show more or different aberrations than unexposed tumors. This was true for all tumor subtypes. Thus, endometrial carcinomas that develop after prolonged tamoxifen use cannot be distinguished from nonusers on basis of their tumor genomic profile.

Background: The standard surgery for early-stage endometrial cancer is total abdominal hysterectomy (TAH) and bilateral salpingo-oophorectomy, which is associated with substantial morbidity. Total laparoscopic hysterectomy (TLH) and bilateral salpingo-oophorectomy is less invasive and is assumed to be associated with lower morbidity, particularly in obese women. This study investigated the complication rate of TLH versus TAH in women with early-stage endometrial cancer., Methods: This randomised trial was done in 21 hospitals in The Netherlands, and 26 gynaecologists with proven sufficient skills in TLH participated. 283 patients with stage I endometrioid adenocarcinoma or complex atypical hyperplasia were randomly allocated (2:1) to the intervention group (TLH, n=187) or control group (TAH, n=96). Randomisation by sequential number generation was done centrally in alternate blocks of six and three participants, with stratification by trial centre. After assignment, the study coordinators, patients, gynaecologists, and members of the panel were not masked to intervention. The primary outcome was major complication rate, assessed by an independent panel. Data were analysed by a modified intention-to-treat analysis, since two patients in both groups were excluded from the main analysis. This trial is registered with the Dutch trial registry, number NTR821., Findings: The proportion of major complications was 14.6% (27 of 185) in the TLH group versus 14.9% (14 of 94) in the TAH group, with a difference of -0.3% (95% CI -9.1 to 8.5; p=0.95). The proportion of patients with an intraoperative major complication (nine of 279 [3.2%]) was lower than the proportion with a postoperative major complication (32 of 279 [11.5%]) and did not differ between TLH (five of 185 [2.7%]) and TAH (four of 94 [4.3%]; p=0.49). The proportion of patients with a minor complication was 13.0% (24 of 185) in the TLH group and 11.7% (11 of 94) in the TAH group (p=0.76). Conversion to laparotomy occurred in 10.8% (20 of 185) of the laparoscopic procedures. TLH was associated with significantly less blood loss (p<0.0001), less use of pain medication (p<0.0001), a shorter hospital stay (p<0.0001), and a faster recovery (p=0.002), but the procedure took longer than TAH (p<0.0001)., Interpretation: Our results showed no evidence of a benefit for TLH over TAH in terms of major complications, but TLH (done by skilled surgeons) was beneficial in terms of a shorter hospital stay, less pain, and quicker resumption of daily activities., Funding: The Dutch Organization for Health Research and Development (ZonMw), programme efficacy., (2010 Elsevier Ltd. All rights reserved.)

The aim of this study was to investigate classical MHC class I and nonclassical MHC (human leukocyte antigen-G [HLA-G]) expression in a large cohort of patients with endometrial cancer, to determine the prognostic value of these cell surface markers and their relation with clinicopathological variables. Tissue microarrays containing epithelial endometrial carcinoma tissue from 554 patients were stained for classical and nonclassical MHC class I using the following monoclonal antibodies: 4H84 (anti-HLA-G), beta2-m (anti-beta-2-microglobulin) and HC-10 (MHC class I antigen heavy chain). Expression data were linked to known clinicopathological characteristics and survival. HLA-G upregulation and MHC class I downregulation in neoplastic cells was observed in 40% and 48%, respectively. Nonendometrioid tumor type, advanced stage disease (FIGO stage > or = II) and poorly or undifferentiated tumors were associated with MHC class I downregulation. Absence of HLA-G expression was independently associated with MHC class I downregulation. In univariate analysis, MHC class I downregulation was a predictor of worse disease-specific survival. Prognostic unfavorable tumor characteristics were correlated with downregulation of MHC class I expression in endometrial cancer cells. Furthermore, downregulated MHC class I has a negative impact on disease-specific survival, observed in a large cohort of patients with endometrial cancer. As there seems to be a relation between classical and nonclassical MHC class I molecules (HLA-G), further research is warranted to unravel this regulatory mechanism.

Objective: The presence of cervical involvement is important to establish a rational treatment for endometrial cancer patients. We investigated the value of preoperative endocervical curettage (ECC) in predicting cervical involvement., Methods: Preoperative ECC of 290 patients with clinical stage I epithelial endometrial cancer was compared with histopathology of the uterus., Results: Amongst all ECCs, 245 (84.5%) were negative and 45 (15.5%) were positive for endometrial cancer. In the uterine specimen, cervical involvement was found in 20% (58/290). PPV and NPV of ECC were 86.7% and 92.2%. False negative and false positive ECC occurred in 6.6% and 2.1%. Of all patients with positive ECC, 46.7% had FIGO stage II disease and 46.7% had extra uterine tumor spread (FIGO III, IV)., Conclusion: ECC is an acceptable diagnostic tool to predict the presence or absence of cervical involvement in early stage endometrial cancer patients.

Background: Traditionally standard treatment for patients with early stage endometrial cancer (EC) is total abdominal hysterectomy and bilateral salpingo oophorectomy (TAH+BSO) with or without lymph node dissection through a vertical midline incision. While TAH is an accepted effective treatment, it is highly invasive, visibly scarring and associated with morbidity. An alternative treatment is the same operation by laparoscopy. Though in several studies total laparoscopic hysterectomy (TLH+ BSO) seems a safe and feasible alternative approach in early stage endometrial cancer patients, there are no randomized data available yet. Furthermore, a randomized controlled trial with surgeons trained in laparoscopy is warranted in order to implement this technique in a safe manner. The aim of this study is to compare the treatment related morbidity, cost-effectiveness and quality of life in early stage endometrial cancer patients treated by laparoscopy versus the standard open approach., Methods: A multi centre randomized clinical phase 3 trial, including 5 university hospitals and 15 regional hospitals in the Netherlands. Only gynecologists trained in performing a TLH are allowed to participate., Inclusion Criteria: Patients with a clinical stage I endometrioid adenocarcinoma or complex atypical hyperplasia are randomized in a 2:1 allocation to receive TLH or TAH. The main outcome measure is the rate of major complications, as assessed by an independent clinical review board. In total, 275 patients are required to have 80% power at alpha-0.05 to detect a significant difference of 15% complication rate. Secondary outcome measures are 1) costs and cost-effectiveness, 2) minor complications, and 3) quality of life. All data from this multi center study are reported using case record forms. Data regarding quality of life, pain, body Image, sexuality and additional homecare are assessed with self reported questionnaires., Discussion: A randomized multi center study in early stage endometrial cancer patients with inclusion criteria for patients and surgeons is designed and ongoing. Results will be presented at the end of 2009., Trial Registration: Dutch trial register number NTR821.

Purpose of Investigation: To evaluate whether lymphvascular space involvement (LVSI) is a risk factor for relapse of disease and lymph node metastasis in endometrial cancer., Methods: From 1978 till 2003, 609 patients with epithelial endometrial cancer were treated at the Groningen University Medical Center. The association of LVSI and relapse of disease was evaluated in the total group of 609 patients and in a 'low' and 'high' risk stage I endometrial cancer group. In 239 surgically staged patients, the relation of LVSI and lymph node metastasis was investigated., Results: The median age at diagnosis was 63 years (range 27-92 years) with a median follow-up of 58 months (range 0-236 months). More than half of the patients (56%) received adjuvant radiotherapy. LVSI was present in 123 patients (25,6%), and a prognostic factor for relapse of disease (multivariate analysis, P < 0.0001). In the 'low' and 'high' risk stage I endometrial cancer patients an increase of 2.6 times in relapse of disease was observed in the presence of LVSI. LVSI positive tumors were more likely to have metastasized to the pelvic lymph nodes (multivariate analysis, P = 0.001). In patients with proven negative nodes, LVSI was a prognostic factor for relapse of disease (univariate analysis, P = 0.02)., Conclusion: LVSI is a predictor of nodal disease and an independent prognostic factor for relapse of disease in all stages of endometrial cancer. Patients with stage I endometrial cancer with positive LVSI are at risk for relapse of disease and might therefore benefit from adjuvant therapy., Content: The presence of lymphvascular space involvement (LVSI) in endometrial cancer is significantly and independently associated with an increased risk of pelvic lymph node metastases and/or relapse of disease.

Purpose: To determine the frequency of mismatch repair (MMR) gene germline mutations in endometrial cancer patients who were diagnosed at less than 50 years of age; to relate the presence of mutations to family history, histopathologic data, presence of tumor microsatellite instability (MSI), and immunostaining; and to formulate criteria for genetic testing in these patients., Patients and Methods: Endometrial cancer patients (N = 58), who were diagnosed at less than 50 years of age, were included and questioned about their family history. Mutation analysis of the MLH1, MSH2, and MSH6 genes was performed (denaturing gradient gel electrophoresis and sequence analysis to detect small mutations and multiplex ligation-dependent probe amplification to detect large deletions or duplications). For MSI analysis, five consensus markers were used, and immunostaining of the three MMR proteins was performed., Results: In five of 22 patients with a positive first-degree family history for hereditary nonpolyposis colorectal cancer (HNPCC)-related cancers, pathogenic germline mutations were found (one MLH1, three MSH2, and one MSH6). Four mutation carriers belonged to families fulfilling the revised Amsterdam criteria. No mutations were found in the 35 patients without such family history (P =.006). MSI was detected in 20 of 57 cancers, among which four were from mutation carriers. In 23 of 51 cancers, one or more MMR protein was absent; in all five mutation carriers, immunostaining indicated the involved MMR gene., Conclusion: In 23% of the young endometrial cancer patients with at least one first-degree relative with an HNPCC-related cancer, an MMR gene mutation was detected. Therefore, presence of an HNPCC-related cancer in a first-degree relative seems to be an important selection criterion for mutation analysis. Subsequent immunostaining of MMR proteins will point to the gene(s) that should be analyzed.