Clinicopathologic vs. Molecular Integrated Prognostication of Endometrial Carcinoma by European Guidelines

This was a retrospective study of 604 patients with endometrial carcinoma, classified into ESGO-ESTRO-ESP 2021 clinicopathologic and molecular integrated risk groups. The Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) and Leiden classifier were employed for molecular classification. Median follow-up time was 81 months. Clinicopathologic and molecular integrated risk groups were similarly associated with distinct prognoses (p < 0.001). Disease-specific survival was similar for all molecular subgroups within clinicopathologic intermediate-risk, high-risk, and advanced/metastatic groups. In contrast, the p53 abnormal subgroup (hazard ratio 9.1, 95% confidence interval 2.0–41; p = 0.004) and mismatch repair deficient subgroup (hazard ratio 3.5, 95% confidence interval 1.2–10; p = 0.024) were associated with disease-related death within clinicopathologic low-risk and high-intermediate-risk carcinomas, respectively. A risk-group shift occurred in 6.0% (36/604) and 7.4% (38/515) of patients classified by ProMisE and Leiden, respectively (p = 0.341). Of the 36 patients shifted in the ProMisE cohort, 27 were upshifted and 9 downshifted. Based on the Leiden classifier, polymerase-ϵ sequencing could be omitted in 60% (311/515) of patients without affecting the risk-group assessment. ESGO-ESTRO-ESP 2021 guidelines provide a platform for risk classification in future trials on molecularly directed treatment of endometrial carcinoma

Mismatch Repair Deficiency as a Predictive and Prognostic Biomarker in Molecularly Classified Endometrial Carcinoma

The aggressiveness of mismatch repair (MMR) deficient endometrial carcinomas was examined in a single institution retrospective study. Outcomes were similar for MMR proficient (n = 508) and deficient (n = 287) carcinomas, identified by immunohistochemistry. In accordance with molecular classification based on The Cancer Genome Atlas (TCGA), tumors with abnormal p53 staining or polymerase-ϵ exonuclease domain mutation were excluded from the MMR proficient subgroup, termed as “no specific molecular profile” (NSMP). Compared with NSMP (n = 218), MMR deficiency (n = 191) was associated with poor disease-specific survival (p = 0.001). MMR deficiency was associated with an increased risk of cancer-related death when controlling for confounders (hazard ratio 2.0). In the absence of established clinicopathologic risk factors, MMR deficiency was invariably associated with an increased risk of cancer-related death in univariable analyses (hazard ratios ≥ 2.0). In contrast, outcomes for MMR deficient and NSMP subgroups did not differ when risk factors were present. Lymphatic dissemination was more common (p = 0.008) and the proportion of pelvic relapses was higher (p = 0.029) in the MMR deficient subgroup. Our findings emphasize the need for improved triage to adjuvant therapy and new therapeutic approaches in MMR deficient endometrial carcinomas

Molecular classification of endometrial carcinoma : a clinically oriented review

The Cancer Genome Atlas research network performed a genome-wide analysis of endometrial carcinomas in 2013 and classified tumours into four distinct subgroups: polymerase-epsilon ultramutated, microsatellite unstable hypermutated, copy-number low and copy-number high. These molecular alterations are mostly mutually exclusive as only about 3% of tumours exhibit more than one molecular signature. Apart from the polymerase-epsilon ultramutated subgroup, molecular classification can be reproduced by using surrogate markers. This has facilitated the implementation of molecular diagnostics into routine patient care. Molecular subgroups are associated with different prognoses; thus, improved risk assessment is their most obvious clinical application. However, based on their unique molecular architectures, molecular subgroups should not be regarded simply as risk groups but rather as distinct diseases. This has prompted us and others to examine the role of molecular subgroups in modifying the prognostic effect of traditional risk factors, including clinical factors, uterine factors and tissue biomarkers, and in predicting the response to adjuvant therapies. In the following review, we summarise the current knowledge of molecularly classified endometrial carcinoma and present, based on our own experience, a proposal for implementing molecular classification into daily practice in pathology laboratories.Peer reviewe

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

Background: Mismatch repair (MMR) system has been implicated in the response of mammalian cells to ionizing radiation and DNA damaging agents. We investigated the value of the MMR system in predicting response to adjuvant therapy in endometrial cancer. Methods: This was a single institution retrospective study. MMR protein status of endometrial carcinomas was assessed by immunohistochemistry. MMR deficient (MMR-D) tumors were identified as MLH1 methylated or nonmethylated by methylation-specific multiplex ligation-dependent probe amplification. Tumors with abnormal p53 staining or polymerase epsilon exonuclease domain mutation were excluded from the MMR proficient subgroup, which was termed as "no specific molecular profile" (NSMP). Disease-specific survival analyses were adjusted for age, stage, histology and grade, depth of myometrial invasion, and lymphovascular space invasion. Results: A total of 505 patients were included in the study. Median follow-up time was 81 months (range 1-136). Whole pelvic radiotherapy (adjusted hazard ratio [HR] 0.092 vs. no adjuvant therapy) and chemotherapy combined with radiotherapy (adjusted HR 0.18) were associated with improved disease-specific survival in the NSMP subgroup (n = 218). In contrast, adjuvant therapies showed no effect on disease-specific survival in the full MMR-D cohort (n = 287) or in MLH1 methylated tumors (n = 154). Whole pelvic radiotherapy (adjusted HR 25 vs. no adjuvant therapy/vaginal brachytherapy) and chemotherapy combined with whole pelvic radiotherapy (adjusted HR 32) were associated with poor disease-specific survival in MMR-D nonmethylated tumors (n = 70). Conclusion: MMR protein and MLH1 methylation status predict the response to adjuvant therapy in endometrial cancer. The MMR system could be utilized for selection of patients who most likely benefit from adjuvant therapy.Peer reviewe

Clinicopathologic vs. Molecular Integrated Prognostication of Endometrial Carcinoma by European Guidelines

This was a retrospective study of 604 patients with endometrial carcinoma, classified into ESGO-ESTRO-ESP 2021 clinicopathologic and molecular integrated risk groups. The Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) and Leiden classifier were employed for molecular classification. Median follow-up time was 81 months. Clinicopathologic and molecular integrated risk groups were similarly associated with distinct prognoses (p < 0.001). Disease-specific survival was similar for all molecular subgroups within clinicopathologic intermediate-risk, high-risk, and advanced/metastatic groups. In contrast, the p53 abnormal subgroup (hazard ratio 9.1, 95% confidence interval 2.0–41; p = 0.004) and mismatch repair deficient subgroup (hazard ratio 3.5, 95% confidence interval 1.2–10; p = 0.024) were associated with disease-related death within clinicopathologic low-risk and high-intermediate-risk carcinomas, respectively. A risk-group shift occurred in 6.0% (36/604) and 7.4% (38/515) of patients classified by ProMisE and Leiden, respectively (p = 0.341). Of the 36 patients shifted in the ProMisE cohort, 27 were upshifted and 9 downshifted. Based on the Leiden classifier, polymerase-ϵ sequencing could be omitted in 60% (311/515) of patients without affecting the risk-group assessment. ESGO-ESTRO-ESP 2021 guidelines provide a platform for risk classification in future trials on molecularly directed treatment of endometrial carcinoma

Mismatch Repair Deficiency as a Predictive and Prognostic Biomarker in Molecularly Classified Endometrial Carcinoma

The aggressiveness of mismatch repair (MMR) deficient endometrial carcinomas was examined in a single institution retrospective study. Outcomes were similar for MMR proficient (n = 508) and deficient (n = 287) carcinomas, identified by immunohistochemistry. In accordance with molecular classification based on The Cancer Genome Atlas (TCGA), tumors with abnormal p53 staining or polymerase-ϵ exonuclease domain mutation were excluded from the MMR proficient subgroup, termed as “no specific molecular profile” (NSMP). Compared with NSMP (n = 218), MMR deficiency (n = 191) was associated with poor disease-specific survival (p = 0.001). MMR deficiency was associated with an increased risk of cancer-related death when controlling for confounders (hazard ratio 2.0). In the absence of established clinicopathologic risk factors, MMR deficiency was invariably associated with an increased risk of cancer-related death in univariable analyses (hazard ratios ≥ 2.0). In contrast, outcomes for MMR deficient and NSMP subgroups did not differ when risk factors were present. Lymphatic dissemination was more common (p = 0.008) and the proportion of pelvic relapses was higher (p = 0.029) in the MMR deficient subgroup. Our findings emphasize the need for improved triage to adjuvant therapy and new therapeutic approaches in MMR deficient endometrial carcinomas

Preoperative Risk Stratification of Endometrial Carcinoma : L1CAM as a Biomarker

Objective Preoperative or intraoperative risk assessment models are used to stratify patients with endometrial carcinoma to lymphadenectomy. Our aim was to determine whether preoperative analysis of L1 cell adhesion molecule (L1CAM) can improve risk assessment. Methods Immunohistochemical L1CAM staining was performed on endometrial biopsies of 241 patients and paired hysterectomy samples of 75 patients. Risk assessment models based on preoperative histologic type and grade, myometrial invasion, and/or tumor diameter and alternative models incorporating preoperative L1CAM were compared with regard to their capability of predicting lymph nodal or distant metastasis. Soluble L1 levels were measured by enzyme-linked immunosorbent assay in serum samples of 40 patients with endometrial carcinoma. Results The concordance rate between L1CAM staining results of preoperative and hysterectomy samples was moderate ( = 0.586, P <0.0001). Preoperative L1CAM expression was associated with nonendometrioid histology, lymph node involvement, advanced stage, and positive peritoneal cytology. Receiver operating characteristic curve analyses showed that L1CAM did not significantly improve risk stratification algorithms based on traditional risk factors. Intraoperative tumor diameter was an effective surrogate for myometrial invasion. There was no statistical difference between L1 serum levels of patients with an L1CAM-positive or L1CAM-negative endometrial carcinoma (P = 0.786). Conclusions L1 cell adhesion molecule expression in endometrial biopsy correlates with high-risk features of endometrial carcinoma but does not significantly improve risk stratification algorithms based on traditional factors. Soluble L1 detected in the serum of patients with endometrial carcinoma does not correlate with tumoral L1CAM expression.Peer reviewe

Major or minor placenta previa : Does it make a difference?

Introduction: Placenta previa is a severe pregnancy complication with considerable maternal and neonatal morbidity. Placenta previa can be defined as major or minor by location. Major placenta previa is associated with higher complication rates. Management of women with minor placenta previa has not been well defined. The primary goal of the study was to evaluate the accuracy of our existing screening protocol for placenta previa. Secondly, we wanted to compare pregnancy and delivery outcomes by the type of placenta previa. Methods: The study was conducted at the Helsinki University Hospital between June 2010 and September 2014. The study population consisted of all women with the antenatal ultrasound diagnosis of placenta previa during delivery. Data were retrospectively collected and analysed. Results: Altogether 176 women had placenta previa at delivery (major 129, minor 47). Placenta previa remained undiagnosed at second trimester screening ultrasound in 32 women (18.2%). Twenty (62.5%) of these cases had minor placenta previa and 12 (37.5%) had major placenta previa. Five (15.6%) of the undiagnosed cases developed life-threatening hemorrhage (>= 2500 ml) during the delivery and two had abnormally invasive placenta followed by hysterectomy. Women with major placenta previa had significantly more blood loss and delivered earlier than women with minor placenta previa. The groups were otherwise similar, including the rate of abnormally invasive placenta. Discussion: The existing protocol for placenta previa missed almost one fifth of cases. Both major and minor placenta previa are risk factors for abnormally invasive placenta and should be treated as severe conditions.Peer reviewe

Prediction of lymphatic dissemination in endometrioid endometrial cancer : Comparison of three risk-stratification models in a single-institution cohort

Objectives. To compare the performance characteristics of 3 risk-stratification models, referred to as Mayo, Helsinki and Milwaukee models, in predicting lymphatic dissemination in endometrial cancer. Methods. A total of 1052 patients with stage I-Ill endometrioid endometrial cancer were included in the study. The areas under curve were compared with the receiver operating characteristic curve area comparison test Chi-square and Fisher exact test were used for comparing categorical variables. The Kaplan-Meier method and multivariable Cox regression models were used for survival analyses. The median follow-up time was 55 months (range 1-108). Results. Areas under curve were 0.781, 0.830 and 0.829 for the Mayo, Helsinki (P = 0.285 vs. Mayo) and Milwaukee (P = 0.292 vs. Mayo) models, respectively, in predicting lymphatic dissemination. The rates of false negatives and false positives were similar for all models. The lymphadenectomy rate decreased in the order of Mayo model (71.5%) > Helsinki model (62.4%) > Milwaukee model (48.8%). In patients with stage I cancer, disease specific survival was better for those who satisfied low-risk criteria according to any of the models. In patients with stage II-III cancer, this difference in survival was significant only for the Milwaukee model, Both lymphatic dissemination and high-risk tumor features as per the risk models were independent predictors of survival. Conclusions. The studied models had a similar accuracy in predicting lymphatic dissemination in endometrial cancer. Lymphadenectomy rate was lowest for the Milwaukee model. Survival analyses suggest that variables included in the models predict patient outcome independently of tumor stage. (C) 2017 Elsevier Inc. All rights reserved.Peer reviewe