Microsatellite Instability and Epigenetic Inactivation of MLH1 and Outcome of Patients With Endometrial Carcinomas of the Endometrioid Type

Purpose Most studies of microsatellite instability (MSI) and outcomes in endometrial cancer patients have included varied histologic subtypes. Nonetheless, MSI occurs almost exclusively in endometrioid tumors. The impact of MSI on outcomes in patients with endometrial cancer is controversial. We sought to determine whether MSI and MLH1 methylation are associated with clinicopathologic variables and survival outcomes in a large series of patients with endometrial carcinomas of the endometrioid type. Patients and Methods Tumor samples, blood, and clinicopathologic data were prospectively collected and analyzed for 446 patients with endometrioid carcinomas. MSI was determined using five National Cancer Institute (NCI) consensus panel markers, and the methylation status of the MLH1 promoter was determined by combined bisulfite restriction analysis (COBRA). Associations with clinicopathologic variables and survival outcomes were evaluated. Results MSI was identified in 147 cases (33%). MSI was associated with higher International Federation of Gynecology and Obstetrics (FIGO) grade (P < .0001). MSI+ tumors without MLH1 methylation were associated with younger age (P < .001). MSI was not associated with overall survival (OS; hazard ratio [HR], 1.011; 95% CI, 0.688 to 1.484; P = .96) or disease-free survival (DFS; HR 0.951; 95% CI, 0.554 to 1.635; P = .86). The combined MSI/MLH1 methylation status (treating MSI− as the reference) did not predict OS (MSI+/MLH1-U: HR, 0.62; 95% CI, 0.27 to 1.44; P = .26; MSI+/MLH1-M: HR, 0.95; 95% CI, 0.62 to 1.46; P = .82) or DFS (MSI+/MLH1-U: HR, 0.51; 95% CI, 0.22 to 1.19; P = .12; MSI+/MLH1-M: HR, 0.93; 95% CI, 0.62 to 1.40; P = .72). Conclusion MSI is not associated with survival in patients with endometrioid endometrial cancer.

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The Prognosis of Stage IA Mixed Endometrial Carcinoma

American Journal of Clinical Pathology ◽

10.1093/ajcp/aqz083 ◽

2019 ◽

Vol 152 (5) ◽

pp. 616-624 ◽

Cited By ~ 3

Author(s):

Wenhui Li ◽

Lei Li ◽

Ming Wu ◽

Jinghe Lang ◽

Yalan Bi

Keyword(s):

Overall Survival ◽

Endometrial Cancer ◽

Endometrial Carcinoma ◽

Disease Free Survival ◽

Survival Outcomes ◽

Group A ◽

Stage Ia ◽

Definition Of ◽

Group B ◽

Endometrial Carcinomas

AbstractObjectivesTo explore the survival and definition of stage IA mixed endometrial carcinoma.MethodsFrom June 1, 2010, to June 1, 2017, cases with stage IA endometrial cancer were included in this study. The survival outcomes were compared among patients with endometrioid (group A), nonendometrioid (group B), and mixed subtypes (group C) and among patients with different proportions of nonendometrioid components (<5%, >50%, and others).ResultsIn total, 890 cases were included, comprising 808 (90.8%), 33 (3.7%), and 47 (5.3%) cases in groups A, B, and C, respectively. After a median follow-up of 55.9 months, groups B and C had significantly more inferior disease-free survival, overall survival, and cancer-specific overall survival. Patients with a nonendometrioid proportion of more than 50% and serous subtype also had a significantly more inferior prognosis. Adjuvant therapy could improve the prognosis in mixed endometrial carcinomas.ConclusionsPatients with endometrial cancer of mixed subtypes had inferior survival outcomes.

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Myoinvasive Pattern as a Prognostic Marker in Low-Grade, Early-Stage Endometrioid Endometrial Carcinoma

Cancers ◽

10.3390/cancers11121845 ◽

2019 ◽

Vol 11 (12) ◽

pp. 1845 ◽

Cited By ~ 2

Author(s):

Ignacio Ruz-Caracuel ◽

Jorge L Ramón-Patino ◽

Álvaro López-Janeiro ◽

Laura Yébenes ◽

Alberto Berjón ◽

...

Keyword(s):

Prognostic Factor ◽

Microsatellite Instability ◽

Endometrial Carcinoma ◽

Early Stage ◽

Disease Free Survival ◽

Figo Stage ◽

Low Grade ◽

Gynecology And Obstetrics ◽

Endometrioid Endometrial Carcinoma ◽

Endometrial Carcinomas

Low-grade and early Federation for Gynecology and Obstetrics (FIGO) stage endometrioid endometrial carcinomas (EEC) have an excellent prognosis. However, approximately 10% of patients develop recurrence, which cannot be correctly predicted at diagnosis. We evaluated myoinvasive patterns as a prognostic factor of relapse in low-grade, early-stage EEC. Two-hundred and fifty-eight cases were selected according to the following inclusion criteria: (i) endometrioid endometrial carcinomas, (ii) grade 1 or 2 with (iii) FIGO stage I or II, and (iv) clinical follow-up. Slides were reviewed to annotate the myoinvasive pattern present in each case (infiltrative glands, microcystic, elongated and fragmented –MELF-, broad front, adenomyosis-like and adenoma malignum). Microsatellite instability was studied by immunoexpression of mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6). There were 29 recurrences (11.2%) among the 258 cases analysed. A predominant broad front myoinvasive pattern was significantly associated with tumour relapse (p = 0.003). The presence of a pattern of infiltrative glands (p = 0.001) and microsatellite instability (p = 0.004) were associated with lower disease-free survival, without having an impact on overall survival. Our observations suggest the potential value of the pattern of myoinvasion as a prognostic factor in low-grade, early-stage endometrioid endometrial carcinoma.

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Mismatch repair protein and MLH1 methylation status as predictors of response to adjuvant therapy in endometrial cancer

Cancer Medicine ◽

10.1002/cam4.3691 ◽

2021 ◽

Vol 10 (3) ◽

pp. 1034-1042

Author(s):

Mikko Loukovaara ◽

Annukka Pasanen ◽

Ralf Bützow

Keyword(s):

Endometrial Cancer ◽

Adjuvant Therapy ◽

Mismatch Repair ◽

Methylation Status ◽

Predictors Of Response ◽

Repair Protein ◽

Mlh1 Methylation ◽

Mismatch Repair Protein

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Efficacy of different surgical approaches on survival outcomes in patients with early-stage cervical cancer: protocol for a multicentre longitudinal study in China

BMJ Open ◽

10.1136/bmjopen-2020-038020 ◽

2020 ◽

Vol 10 (8) ◽

pp. e038020

Author(s):

Xiaopei Chao ◽

Ming Wu ◽

Shuiqing Ma ◽

Xianjie Tan ◽

Sen Zhong ◽

...

Keyword(s):

Cervical Cancer ◽

Radical Hysterectomy ◽

Early Stage ◽

Disease Free Survival ◽

Learning Curves ◽

Surgical Approaches ◽

Survival Outcomes ◽

Link Type ◽

Gynecology And Obstetrics ◽

Early Stage Cervical Cancer

IntroductionRecent studies have revealed that the oncological survival outcomes of minimally invasive radical hysterectomy (MIRH) are inferior to those of abdominal radical hysterectomy (ARH) in early-stage cervical cancer, but the potential reasons are unclear.Methods and analysisEach expert from 28 study centres participating in a previously reported randomised controlled trial (NCT03739944) will provide successive eligible records of at least 100 patients who accepted radical hysterectomy for early-stage cervical cancer between 1 January 2009 and 31 December 2015. Inclusion criteria consist of a definite pathological evaluation of stages IA1 (with positive lymphovascular space invasion), IA2 and IB1 according to the International Federation of Gynecology and Obstetrics 2009 staging system and a histological subtype of squamous cell carcinoma, adenocarcinoma or adenosquamous carcinoma. The primary endpoint is 5-year disease-free survival between the MIRH and ARH groups. The secondary endpoints include the MIRH learning curves of participating surgeons, 5-year overall survival between the MIRH and ARH groups, survival outcomes according to surgical chronology, surgical outcomes and sites of recurrence and potential risk factors that affect survival outcomes. A subgroup analysis in patients with tumour diameter less than 2 cm will follow the similar flow diagram.Ethics and disseminationThis study has been approved by the Institutional Review Board of Peking Union Medical College Hospital (registration no. JS-1711), and is also filed on record by all other 27 centres. The results will be disseminated through community events and peer-reviewed journals.Trial registration numberNCT03738969

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Endometrial Cancer Lymphadenectomy Trial (ECLAT) (pelvic and para-aortic lymphadenectomy in patients with stage I or II endometrial cancer with high risk of recurrence; AGO-OP.6)

International Journal of Gynecological Cancer ◽

10.1136/ijgc-2021-002703 ◽

2021 ◽

Vol 31 (7) ◽

pp. 1075-1079

Author(s):

Günter Emons ◽

Jae-Weon Kim ◽

Karin Weide ◽

Nikolaus de Gregorio ◽

Pauline Wimberger ◽

...

Keyword(s):

Overall Survival ◽

Endometrial Cancer ◽

High Risk ◽

Controlled Trial ◽

Left Renal Vein ◽

Stage I ◽

Open Label ◽

Risk Of Recurrence ◽

Gynecology And Obstetrics ◽

The Impact

BackgroundThe impact of comprehensive pelvic and para-aortic lymphadenectomy on survival in patients with stage I or II endometrial cancer with a high risk of recurrence is not reliably documented. The side effects of this procedure, including lymphedema and lymph cysts, are evident.Primary ObjectiveEvaluation of the effect of comprehensive pelvic and para-aortic lymphadenectomy in the absence of bulky nodes on 5 year overall survival of patients with endometrial cancer (International Federation of Gynecology and Obstetrics (FIGO) stages I and II) and a high risk of recurrence.Study HypothesisComprehensive pelvic and para-aortic lymphadenectomy will increase 5 year overall survival from 75% (no lymphadenectomy) to 83%, corresponding to a hazard ratio of 0.65.Trial DesignOpen label, randomized, controlled trial. In arm A, a total hysterectomy plus bilateral salpingo-oophorectomy is performed. In arm B, in addition, a systematic pelvic and para-aortic lymphadenectomy up to the level of the left renal vein is performed. For all patients, vaginal brachytherapy and adjuvant chemotherapy (carboplatin/paclitaxel) are recommended.Major Inclusion CriteriaPatients with histologically confirmed endometrial cancer stages pT1b–pT2, all histological subtypes, and pT1a endometrioid G3, serous, clear cell, or carcinosarcomas can be included when bulky nodes are absent. When hysterectomy has already been performed (eg, for presumed low risk endometrial cancer), study participation is also possible.Exclusion CriteriaPatients with pT1a, G1 or 2 of type 1 histology or uterine sarcomas (except for carcinosarcomas), endometrial cancers of FIGO stage III or IV (except for microscopic lymph node metastases) or visual extrauterine disease.Primary EndpointOverall survival calculated from the date of randomization until death.Sample Size640 patients will be enrolled in the study.Estimated Dates for Completing Accrual and Presenting ResultsAt present, 252 patients have been recruited. Based on this, accrual should be completed in 2025. Results should be presented in 2031.Trial RegistrationNCT03438474.

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Universal endometrial cancer tumor typing: How much has immunohistochemistry, microsatellite instability, and MLH1 methylation improved the diagnosis of Lynch syndrome across the population?

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e17119 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e17119-e17119

Author(s):

Ryan Kahn ◽

Sushmita Gordhandas ◽

Brandon Paul Maddy ◽

Becky Baltich Nelson ◽

Gulce Askin ◽

...

Keyword(s):

Endometrial Cancer ◽

Lynch Syndrome ◽

Microsatellite Instability ◽

Large Scale ◽

Screening Method ◽

Cochrane Library ◽

Predictive Values ◽

Msi Analysis ◽

Weighted Prevalence ◽

Mlh1 Methylation

e17119 Background: Universal tumor testing for defective DNA mismatch repair (MMR) is recommended for all women diagnosed with endometrial cancer (EC) to identify those with underlying Lynch syndrome (LS). However, since its implementation in 2013, the effectiveness of this screening method on identifying individuals with LS across the population has not been well studied. The aim of this study was to evaluate outcomes of MMR immunohistochemistry (IHC), MLH1 methylation, and microsatellite instability (MSI) analysis among EC patients. Methods: We conducted a complete systematic search of online databases PubMed, Embase, Medline, and Cochrane Library between 1990-2018. A DerSimonian–Laird random-effects model meta-analysis was utilized to estimate the weighted prevalence of LS diagnoses. Results: The comprehensive search produced 3,427 publications. 29 peer-review studies met the inclusion criteria. 6,649 EC patients were identified, 206 (3%) were confirmed to have LS following positive universal tumor molecular screening.5,917 patients underwent tumor IHC, 28% had abnormal staining. 3,140 patients underwent MSI analysis, 31% had MSI instability. Among EC patients with deficient IHC staining or positive MSI analysis, the weighted prevalence of LS was 15% and 19% respectively. 1159 patients exhibited loss of MLH1 staining, 143 (13.7%) were found to be MLH1 methylation negative, 32 demonstrated a germline MLH1 mutation (2.8% of all MLH1 absent staining; 22.4% of all MLH1 methylation negative). 43% of EC patients diagnosed with LS via tumor typing would have been missed by family history-based screening alone. Conclusions: Despite widespread implementation of universal tumor testing in EC, data regarding results have previously been limited. For the first time, this study provides large-scale predictive values that will help practitioners evaluate abnormal results in the context of LS and aid in patient counseling. [Table: see text]

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A KRAS hot spot mutation correlates with MLH1 methylation in endometrial carcinomas with microsatellite instability: A potential triage tool for Lynch syndrome evaluation

Gynecologic Oncology ◽

10.1016/j.ygyno.2014.03.214 ◽

2014 ◽

Vol 133 ◽

pp. 79-80

Author(s):

J.G. Cohen ◽

R. Wiedemeyer ◽

B.Y. Karlan ◽

C. Walsh

Keyword(s):

Lynch Syndrome ◽

Microsatellite Instability ◽

Hot Spot ◽

Endometrial Carcinomas ◽

Mlh1 Methylation

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Tissue Infiltrating Immune Cells as Prognostic Biomarkers in Endometrial Cancer: A Meta-Analysis

Disease Markers ◽

10.1155/2020/1805764 ◽

2020 ◽

Vol 2020 ◽

pp. 1-11

Author(s):

Fang Guo ◽

Yishan Dong ◽

Qingqing Tan ◽

Jing Kong ◽

Bin Yu

Keyword(s):

Endometrial Cancer ◽

T Cell ◽

Cell Density ◽

Immune Cells ◽

Statistical Power ◽

Meta Analysis ◽

Disease Free Survival ◽

Free Survival ◽

Gynecology And Obstetrics ◽

The Relationship

Background. The association between tumour-infiltrating immune cells and the prognosis of endometrial cancer (EC) is controversial due to the smaller sample sizes and limited statistical power of the extant studies. We carried out a meta-analysis of the relationship between tumour-infiltrating immune cells and EC survival outcomes. Methods. A literature search in multiple databases was carried out up to December 2019. Pooled hazard ratio (HRs) and 95% confidence intervals (CIs) were calculated by the Z-test to assess the association between infiltrating immune cells and overall survival (OS), progression-free survival (PFS), relapse-free survival (RFS), disease-specific survival (DSS), and disease-free survival (DFS). A subgroup analysis was performed based on the localisation of immune cells in tumour parenchyma or stroma, immune markers, and the International Federation of Gynecology and Obstetrics stage. Heterogeneity and publication bias between studies were evaluated by Cochran’s Q-test and Egger regression test, respectively. Results. Seventeen studies were included in the analysis. The pooled HR of OS, PFS, DSS, and DFS indicated that a high CD8+ T cell density was associated with a favorable prognosis in EC patients. A significant relationship was found between a high density of CD45RO+ T cells and a favorable OS in EC patients, but the FoxP3+ T cell density was not associated with either OS or RFS. A high TAM density was associated with a worse PFS. However, a sensitivity analysis indicated that the findings of PFS and DSS in CD8+ T cell and PFS in TAM were not robust results. Conclusion. This is the first meta-analysis of the relationship between tumour-infiltrating immune cells and the prognosis of EC. High CD8+ and CD45RO+ T cell densities in tumours were associated with favorable outcomes in EC patients.

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Clinicopathologic Significance of Mismatch Repair Defects in Endometrial Cancer: An NRG Oncology/Gynecologic Oncology Group Study

Journal of Clinical Oncology ◽

10.1200/jco.2016.67.8722 ◽

2016 ◽

Vol 34 (25) ◽

pp. 3062-3068 ◽

Cited By ~ 69

Author(s):

D. Scott McMeekin ◽

David L. Tritchler ◽

David E. Cohn ◽

David G. Mutch ◽

Heather A. Lankes ◽

...

Keyword(s):

Endometrial Cancer ◽

Mismatch Repair ◽

Gynecologic Oncology ◽

Progression Free Survival ◽

Prognostic Indicators ◽

Gynecologic Oncology Group ◽

Free Survival ◽

Gynecology And Obstetrics ◽

Mlh1 Methylation ◽

Lymphovascular Space Invasion

Purpose The clinicopathologic significance of mismatch repair (MMR) defects in endometrioid endometrial cancer (EEC) has not been definitively established. We undertook tumor typing to classify MMR defects to determine if MMR status is prognostic or predictive. Methods Primary EECs from NRG/GOG0210 patients were assessed for microsatellite instability (MSI), MLH1 methylation, and MMR protein expression. Each tumor was assigned to one of four MMR classes: normal, epigenetic defect, probable mutation (MMR defect not attributable to MLH1 methylation), or MSI-low. The relationships between MMR classes and clinicopathologic variables were assessed using contingency table tests and Cox proportional hazard models. Results A total of 1,024 tumors were assigned to MMR classes. Epigenetic and probable mutations in MMR were significantly associated with higher grade and more frequent lymphovascular space invasion. Epigenetic defects were more common in patients with higher International Federation of Gynecology and Obstetrics stage. Overall, there were no differences in outcomes. Progression-free survival was, however, worse for women whose tumors had epigenetic MMR defects compared with the MMR normal group (hazard ratio, 1.37; P < .05; 95% CI, 1.00 to 1.86). An exploratory analysis of interaction between MMR status and adjuvant therapy showed a trend toward improved progression-free survival for probable MMR mutation cases. Conclusion MMR defects in EECs are associated with a number of well-established poor prognostic indicators. Women with tumors that had MMR defects were likely to have higher-grade cancers and more frequent lymphovascular space invasion. Surprisingly, outcomes in these patients were similar to patients with MMR normal tumors, suggesting that MMR defects may counteract the effects of negative prognostic factors. Altered immune surveillance of MMR-deficient tumors, and other host/tumor interactions, is likely to determine outcomes for patients with MMR-deficient tumors.

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Stage IB Endometrioid Type Endometrial Cancer: The Role of Lymphadenectomy and Adjuvant Radiation Therapy

Gynecology Obstetrics and Reproductive Medicine ◽

10.21613/gorm.2017.704 ◽

2018 ◽

Vol 24 (3) ◽

pp. 156

Author(s):

Osman Turkmen ◽

Tolga Tasci ◽

Derman Basaran ◽

Gunsu Comert Kimyon ◽

Alper Karalök ◽

...

Keyword(s):

Overall Survival ◽

Endometrial Cancer ◽

Adjuvant Radiotherapy ◽

Survival Rates ◽

Disease Free Survival ◽

Adjuvant Radiation ◽

Free Survival ◽

Stage Ib ◽

Gynecology And Obstetrics ◽

Disease Free

Objective: Both performances of lymphadenectomy and benefit of adding adjuvant radiotherapy are controversial for patients with International Federation of Gynecology and Obstetrics stage IB endometrioid type endometrial cancer. We aimed to identify the role of lymphadenectomy and adjuvant radiation therapy as well as clinicopathological prognostic factors for this group of patients. Study Design: Records of all patients (n=132) with stage IB endometrioid endometrial cancer who were referred to or treated in our institution between Jan 1992 and Dec 2013 were retrospectively reviewed. Cox Proportional Hazard Regression Analysis was used to determine the effects of lymphadenectomy and adjuvant radiation as well as other clinicopathological factors on disease free survival and overall survival.Results: Mean age was 59.9 years (range, 45-82). Lymphadenectomy didn't perform in 36 (27.3%) patients and 23 (17.4%) patients did not have any kind of adjuvant treatment. Mean lymph node count was 18.8 (range, 3-67). Federation of Gynecology and Obstetrics grade, lymphovascular space invasion, lymphadenectomy, receiving adjuvant treatment and type of received adjuvant therapy were not associated with disease free survival and overall survival for the entire cohort. In a subgroup of patients with grade1&2 tumor, 5-year disease free survival rates were 80% and 50% (p=0.4), respectively and overall survival rates were 94.8% and 93.8% (p=0.2), respectively for patients who had or didn't have adjuvant radiotherapy. While performance of lymphadenectomy was not significantly associated with disease free survival in this subgroup (p=0.56), this association was statistically significant for overall survival (97.9% vs. 86.4%, p=0.04) Conclusion: Benefit of adjuvant radiotherapy in regard to prevention of recurrence needs to be confirmed by further studies. Lymphadenectomy had a survival benefit for patients with myometrial invasion greater than a half of myometrial thickness.

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