Longitudinal effects of adjuvant chemotherapy and lymph node staging on patient-reported outcomes in endometrial cancer survivors: a prospective cohort study.

BACKGROUND: Most patients with endometrial cancer with localized disease are effectively treated and survive for a long time. The primary treatment is hysterectomy, to which surgical staging procedures may be added to assess the need for adjuvant therapy. Longitudinal data on patient-reported outcomes comparing different levels of primary treatment are lacking, especially when adjuvant radiotherapy is omitted. OBJECTIVE: We assessed the impact of lymphadenectomy and adjuvant chemotherapy on patient-reported symptoms, function, and quality of life. We hypothesized that these treatment modalities would substantially affect patient-reported outcomes at follow-up. STUDY DESIGN: We prospectively included patients with endometrial cancer enrolled in the ongoing MoMaTEC2 study (ClinicalTrials.gov Identifier: NCT02543710). Patients were asked to complete the patient-reported outcome questionnaires European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire EN24 preoperatively and at 1 and 2 years of follow-up. Functional domains and symptoms were analyzed for the whole cohort and by treatment received. To assess the effect of the individual treatment modifications, we used mixed regression models. RESULTS: Baseline data were available for 448 patients. Of these patients, 339 and 219 had reached 1-year follow-up and 2-year follow-up, respectively. Treatment included hysterectomy (plus bilateral salpingo-oophorectomy) alone (n=177), hysterectomy and lymph node staging without adjuvant therapy (n=133), or adjuvant chemotherapy irrespective of staging procedure (n=138). Overall, patients reported improved global health status and quality of life (+9 units; P<.001), increased emotional and social functioning, and increased sexual interest and activity (P<.001 for all) from baseline to year 1, and these outcomes remained stable at year 2. Means of functional scales and quality of life were similar to age- and sex-weighted reference cohorts. Mean tingling and numbness and lymphedema increased after treatment. The group who received adjuvant chemotherapy had a larger mean reduction in physical functioning (-6 vs +2; P=.002) at year 1, more neuropathy (+30 vs +5; P<.001; year 1) at years 1 and 2, and more lymphedema at year 1 (+11 vs +2; P=.007) than the group treated with hysterectomy and salpingo-oophorectomy only. In patients not receiving adjuvant chemotherapy, patient-reported outcomes were similar regardless of lymph node staging procedures. Adjuvant chemotherapy independently increased fatigue, lymphedema, and neuropathy in mixed regression models. CONCLUSION: Patients with endometrial cancer receiving adjuvant chemotherapy reported significantly reduced functioning and more symptoms up to 2 years after treatment. For patients treated by surgery alone, surgical staging did not seem to affect the quality of life or symptoms to a measurable degree at follow-up. Therefore, subjecting patients to lymph node removal to tailor adjuvant therapy seems justified from the patient's viewpoint; however, efforts should increase to find alternatives to traditional chemotherapy.

Data Set for the Reporting of Endometrial Cancer: Recommendations From the International Collaboration on Cancer Reporting (ICCR).

Endometrial cancer is one of the most common cancers among women. The International Collaboration on Cancer Reporting (ICCR) developed a standardized endometrial cancer data set in 2011, which provided detailed recommendations for the reporting of resection specimens of these neoplasms. A new data set has been developed, which incorporates the updated 2020 World Health Organization Classification of Female Genital Tumors, the Cancer Genome Atlas (TCGA) molecular classification of endometrial cancers, and other major advances in endometrial cancer reporting, all of which necessitated a major revision of the data set. This updated data set has been produced by a panel of expert pathologists and an expert clinician and has been subject to international open consultation. The data set includes core elements which are unanimously agreed upon as essential for cancer diagnosis, clinical management, staging, or prognosis and noncore elements which are clinically important, but not essential. Explanatory notes are provided for each element. Adoption of this updated data set will result in improvements in endometrial cancer patient care.

Impact of hormonal biomarkers on response to hormonal therapy in advanced and recurrent endometrial cancer.

BACKGROUND: Approximately 20% of women with endometrial cancer have advanced-stage disease or suffer from a recurrence. For these women, prognosis is poor, and palliative treatment options include hormonal therapy and chemotherapy. Lack of predictive biomarkers and suboptimal use of existing markers for response to hormonal therapy have resulted in overall limited efficacy. OBJECTIVE: This study aimed to improve the efficacy of hormonal therapy by relating immunohistochemical expression of estrogen and progesterone receptors and estrogen receptor pathway activity scores to response to hormonal therapy. STUDY DESIGN: Patients with advanced or recurrent endometrial cancer and available biopsies taken before the start of hormonal therapy were identified in 16 centers within the European Network for Individualized Treatment in Endometrial Cancer and the Dutch Gynecologic Oncology Group. Tumor tissue was analyzed for estrogen and progesterone receptor expressions and estrogen receptor pathway activity using a quantitative polymerase chain reaction-based messenger RNA model to measure the activity of estrogen receptor-related target genes in tumor RNA. The primary endpoint was response rate defined as complete and partial response using the Response Evaluation Criteria in Solid Tumors. The secondary endpoints were clinical benefit rate and progression-free survival. RESULTS: Pretreatment biopsies with sufficient endometrial cancer tissue and complete response evaluation were available in 81 of 105 eligible cases. Here, 22 of 81 patients (27.2%) with a response had estrogen and progesterone receptor expressions of >50%, resulting in a response rate of 32.3% (95% confidence interval, 20.9-43.7) for an estrogen receptor expression of >50% and 50.0% (95% confidence interval, 35.2-64.8) for a progesterone receptor expression of >50%. Clinical benefit rate was 56.9% for an estrogen receptor expression of >50% (95% confidence interval, 44.9-68.9) and 75.0% (95% confidence interval, 62.2-87.8) for a progesterone receptor expression of >50%. The application of the estrogen receptor pathway test to cases with a progesterone receptor expression of >50% resulted in a response rate of 57.6% (95% confidence interval, 42.1-73.1). After 2 years of follow-up, 34.3% of cases (95% confidence interval, 20-48) with a progesterone receptor expression of >50% and 35.8% of cases (95% confidence interval, 20-52) with an estrogen receptor pathway activity score of >15 had not progressed. CONCLUSION: The prediction of response to hormonal treatment in endometrial cancer improves substantially with a 50% cutoff level for progesterone receptor immunohistochemical expression and by applying a sequential test algorithm using progesterone receptor immunohistochemical expression and estrogen receptor pathway activity scores. However, results need to be validated in the prospective Prediction of Response to Hormonal Therapy in Advanced and Recurrent Endometrial Cancer (PROMOTE) study.

Impact of MDM2 promoter SNP55 (rs2870820) on risk of endometrial and ovarian cancer.

BACKGROUND: While large GWAS analyses have not found convincing associations between MDM2 promoter SNP55 and gynaecological cancers, SNP55 is in linkage disequilibrium with two other functional SNPs in the same promoter, likely to obscure associations between single SNPs and cancer risk. Here, we assessed the impact of SNP55 on risk of endometrial and ovarian cancer, including sub-analyses stratified for other functional SNPs in the region. MATERIAL AND METHODS: Using a custom LightSNiP assay, we genotyped SNP55 in two large hospital-based cohorts of patients with ovarian (n = 1,332) and endometrial (n = 1,363) cancer and compared genotypes to healthy female controls (n = 1,858). RESULTS: Among individuals harbouring the SNP309TT genotype, the minor SNP55T-allele was associated with a reduced risk of endometrial (dominant model: OR = 0.63; CI = 0.45-0.88; p = 0.01). Regardless of the genotype in neighbouring SNPs, the SNP55T-allele was also associated with a reduced risk of endometrial cancer before 50 years of age (dominant model: OR = 0.56; CI = 0.34-0.90; p = 0.02). No association between SNP55 status and ovarian cancer risk was observed. CONCLUSIONS: MDM2 SNP55T-allele may correlate with reduced risk for endometrial cancer in a SNP309T-, but not SNP309G, context.

Development of prediction models for lymph node metastasis in endometrioid endometrial carcinoma.

BACKGROUND: In endometrioid endometrial cancer (EEC), current clinical algorithms do not accurately predict patients with lymph node metastasis (LNM), leading to both under- and over-treatment. We aimed to develop models that integrate protein data with clinical information to identify patients requiring more aggressive surgery, including lymphadenectomy. METHODS: Protein expression profiles were generated for 399 patients using reverse-phase protein array. Three generalised linear models were built on proteins and clinical information (model 1), also with magnetic resonance imaging included (model 2), and on proteins only (model 3), using a training set, and tested in independent sets. Gene expression data from the tumours were used for confirmatory testing. RESULTS: LNM was predicted with area under the curve 0.72-0.89 and cyclin D1; fibronectin and grade were identified as important markers. High levels of fibronectin and cyclin D1 were associated with poor survival (p = 0.018), and with markers of tumour aggressiveness. Upregulation of both FN1 and CCND1 messenger RNA was related to cancer invasion and mesenchymal phenotype. CONCLUSIONS: We demonstrate that data-driven prediction models, adding protein markers to clinical information, have potential to significantly improve preoperative identification of patients with LNM in EEC.

What Is the Role of Imaging at Primary Diagnostic Work-Up in Uterine Cervical Cancer?

PURPOSE OF REVIEW: For uterine cervical cancer, the recently revised International Federation of Gynecology and Obstetrics (FIGO) staging system (2018) incorporates imaging and pathology assessments in its staging. In this review we summarize the reported staging performances of conventional and novel imaging methods and provide an overview of promising novel imaging methods relevant for cervical cancer patient care. RECENT FINDINGS: Diagnostic imaging during the primary diagnostic work-up is recommended to better assess tumor extent and metastatic disease and is now reflected in the 2018 FIGO stages 3C1 and 3C2 (positive pelvic and/or paraaortic lymph nodes). For pretreatment local staging, imaging by transvaginal or transrectal ultrasound (TVS, TRS) and/or magnetic resonance imaging (MRI) is instrumental to define pelvic tumor extent, including a more accurate assessment of tumor size, stromal invasion depth, and parametrial invasion. In locally advanced cervical cancer, positron emission tomography-computed tomography (PET-CT) or computed tomography (CT) is recommended, since the identification of metastatic lymph nodes and distant metastases has therapeutic consequences. Furthermore, novel imaging techniques offer visualization of microstructural and functional tumor characteristics, reportedly linked to clinical phenotype, thus with a potential for further improving risk stratification and individualization of treatment. Diagnostic imaging by MRI/TVS/TRS and PET-CT/CT is instrumental for pretreatment staging in uterine cervical cancer and guides optimal treatment strategy. Novel imaging techniques may also provide functional biomarkers with potential relevance for developing more targeted treatment strategies in cervical cancer.

Asparaginase-like protein 1 is an independent prognostic marker in primary endometrial cancer, and is frequently lost in metastatic lesions.

OBJECTIVE: Loss of Asparaginase-like protein 1 (ASRGL1) has been suggested as a prognostic biomarker in endometrial carcinoma. Our objective was to validate this in a prospectively collected, independent patient cohort, and evaluate ASRGL1 expression in endometrial carcinoma precursor lesion and metastases. METHODS: 782 primary endometrial carcinomas, 90 precursor lesions (complex atypical hyperplasia), and 179 metastases (from 87 patients) were evaluated for ASRGL1 expression by immunohistochemistry in relation to clinical and histopathological data. ASRGL1 mRNA level was investigated in 237 primary tumors and related to survival and ASRGL1 protein expression. RESULTS: Low expression of ASRGL1 protein and ASRGL1 mRNA predicted poor disease specific survival (P<0.001). In multivariate survival analyses ASRGL1 had independent prognostic value both in the whole patient cohort (Hazard ratio (HR): 1.53, 95% confidence interval (CI): 1.04-2.26, P=0.031) and within the endometrioid subgroup (HR: 2.64, CI: 1.47-4.74, P=0.001). Low ASRGL1 expression was less frequent in patients with low grade endometrioid primary tumors compared to high grade endometrioid and non-endometrioid primary tumors, and ASRGL1 was lost in the majority of metastatic lesions. CONCLUSIONS: In a prospective setting ASRGL1 validates as a strong prognostic biomarker in endometrial carcinoma. Loss of ASRGL1 is associated with aggressive disease and poor survival, and is demonstrated for the first time to have independent prognostic value in the entire endometrial carcinoma patient population.

Added Value of Estrogen Receptor, Progesterone Receptor, and L1 Cell Adhesion Molecule Expression to Histology-Based Endometrial Carcinoma Recurrence Prediction Models: An ENITEC Collaboration Study.

OBJECTIVES: Endometrial carcinoma mortality is mainly caused by recurrent disease, and various immunohistochemical markers to predict recurrences have been studied. Loss of the estrogen receptor (ER) and progesterone receptor (PR) and the presence of the L1 cell adhesion molecule (L1CAM) are promising markers, but their combined value has not been studied. MATERIALS AND METHODS: Expression of ER, PR, and L1CAM was immunohistochemically determined in 293 endometrial carcinomas from 11 collaborating European Network for Individualized Treatment of Endometrial Cancer centers. Estrogen receptor, PR, or L1CAM staining was considered positive or negative when expressed by greater than or equal to 10% or less than 10% of the tumor cells, respectively. The association between these markers and clinicopathological markers, and their combined value in predicting survival were calculated, both in the entire cohort and in a selected groups of stage I endometrioid and low-risk stage I endometrioid carcinomas. RESULTS: Estrogen receptor and PR were negative in 19% and 28% of the cases, respectively, and L1CAM was positive in 18%. All 3 were associated with advanced stage, high-grade, nonendometrioid histology, lymphovascular space invasion (LVSI), and reduced disease-free survival. Only advanced stage, loss of PR, and LVSI were associated with reduced disease-free survival in multivariate analysis. A prognostic model including these 3 markers was superior to 1 including only the 3 immunohistochemical markers, which was superior to the traditional model. In both the stage I endometrioid and the low-risk stage I endometrioid groups, only loss of PR was associated with reduced disease-free survival. CONCLUSIONS: Loss of ER and PR, and the presence of L1CAM are associated with high risk characteristics, and loss of PR is the strongest predictor of recurrent disease. Although a combination of these 3 markers is slightly superior to the traditional histological markers, a prognostic model including stage, PR expression, and LVSI is the most promising model in the identification of high risk carcinomas. In the stage I endometrioid carcinomas, PR immunohistochemistry appears to be of additional value in predicting recurrences.

Candidate locus analysis of the TERT-CLPTM1L cancer risk region on chromosome 5p15 identifies multiple independent variants associated with endometrial cancer risk.

Several studies have reported associations between multiple cancer types and single-nucleotide polymorphisms (SNPs) on chromosome 5p15, which harbours TERT and CLPTM1L, but no such association has been reported with endometrial cancer. To evaluate the role of genetic variants at the TERT-CLPTM1L region in endometrial cancer risk, we carried out comprehensive fine-mapping analyses of genotyped and imputed SNPs using a custom Illumina iSelect array which includes dense SNP coverage of this region. We examined 396 SNPs (113 genotyped, 283 imputed) in 4,401 endometrial cancer cases and 28,758 controls. Single-SNP and forward/backward logistic regression models suggested evidence for three variants independently associated with endometrial cancer risk (P = 4.9 × 10(-6) to P = 7.7 × 10(-5)). Only one falls into a haplotype previously associated with other cancer types (rs7705526, in TERT intron 1), and this SNP has been shown to alter TERT promoter activity. One of the novel associations (rs13174814) maps to a second region in the TERT promoter and the other (rs62329728) is in the promoter region of CLPTM1L; neither are correlated with previously reported cancer-associated SNPs. Using TCGA RNASeq data, we found significantly increased expression of both TERT and CLPTM1L in endometrial cancer tissue compared with normal tissue (TERT P = 1.5 × 10(-18), CLPTM1L P = 1.5 × 10(-19)). Our study thus reports a novel endometrial cancer risk locus and expands the spectrum of cancer types associated with genetic variation at 5p15, further highlighting the importance of this region for cancer susceptibility.

Preoperative tumor size at MRI predicts deep myometrial invasion, lymph node metastases, and patient outcome in endometrial carcinomas.

OBJECTIVE: The aim of this study was to explore the relation between preoperative tumor size based on magnetic resonance imaging (MRI) and the surgical pathologic staging parameters (deep myometrial invasion, cervical stroma invasion, and metastatic lymph nodes) and to assess the prognostic impact of tumor size in endometrial carcinomas. Interobserver variability for the different tumor size measurements was also assessed. METHODS/MATERIALS: Preoperative pelvic MRI of 212 patients with histologically confirmed endometrial carcinomas was read independently by 3 radiologists. Maximum tumor diameters were measured in 3 orthogonal planes (anteroposterior, transverse, and craniocaudal planes [CC]), and tumor volumes were estimated. Tumor size was analyzed in relation to surgical staging results and patient survival. The multivariate analyses were adjusted for preoperative risk status based on endometrial biopsy. Intraclass correlation coefficients and receiver operating characteristics curves for the different tumor measurements were also calculated. RESULTS: Anteroposterior tumor diameter independently predicted deep myometrial invasion (P < 0.001), whereas CC tumor diameter tended to independently predict lymph node metastases (P = 0.06). Based on receiver operating characteristic curves, the following tumor size cutoff values were identified: anteroposterior diameter greater than 2 cm predicted deep myometrial invasion (unadjusted odds ratio [OR], 12.4; P < 0.001; adjusted OR, 6.7; P < 0.001) and CC diameter greater than 4 cm predicted lymph node metastases (unadjusted OR, 6.2; P < 0.001; adjusted OR, 4.9; P = 0.009). Large tumor size was associated with reduced progression/recurrence-free survival (P ≤ 0.005 for all size parameters), and CC diameter had an independent impact on survival (adjusted hazards ratio, 1.04; P = 0.009). The interobserver variability for the different size measurements was very low (intraclass correlation coefficient, 0.78-0.85). CONCLUSIONS: Anteroposterior tumor diameter greater than 2 cm predicts deep myometrial invasion, and CC tumor diameter greater than 4 cm predicts lymph node metastases. Tumor size is a strong prognostic factor in endometrial carcinomas. Preoperative tumor measurements based on MRI may potentially improve preoperative risk stratification models and thus enable better tailored surgical treatment in endometrial cancer.

Molecular determinants of outcome with mammalian target of rapamycin inhibition in endometrial cancer.

BACKGROUND: Targeting the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is of increasing interest as a therapeutic strategy in many tumors. The aim of this study was to identify molecular markers associated with mTOR inhibitor activity in women with metastatic endometrial cancer. METHODS: Archival tumor samples were collected from 94 women with recurrent or metastatic endometrial cancer who participated in 3 National Cancer Insitute of Canada Clinical Trials Group phase 2 trials investigating single-agent mTOR inhibitors: IND160A and IND160B (temsirolimus) and IND192 (ridaforolimus). Analyses included mutational profiling using the OncoCarta Panel version 1.0 and immunohistochemical expression of the tumor suppressor gene PTEN (phosphatase and tensin homologue) and stathmin, a marker of PI3K activation. Associations between biomarker results and clinical outcomes were assessed. RESULTS: Mutations were found in 32 of 73 analyzed tumors, PIK3CA (21 patients) was the most common mutated gene. Co-mutations were seen in 8 tumors, most frequently KRAS and PIK3CA (4 cases). PTEN loss was observed in 46 of 85 samples analyzed and increased stathmin expression was observed in 15 of 65 analyzed samples. No correlation was observed between biomarkers and response or progression. In patients taking concurrent metformin, there was a trend toward lower progression, of 11.8% versus 32.5% (P = .14). CONCLUSIONS: No predictive biomarker or combination of biomarkers for mTOR inhibitor activity were identified in this study. Restriction and enrichment of study entry, especially based on archival tumor tissue, should be undertaken with caution in trials using these agents.

Hormone Receptor Expression and Activity for Different Tumour Locations in Patients with Advanced and Recurrent Endometrial Carcinoma.

BACKGROUND: Response to hormonal therapy in advanced and recurrent endometrial cancer (EC) can be predicted by oestrogen and progesterone receptor immunohistochemical (ER/PR-IHC) expression, with response rates of 60% in PR-IHC > 50% cases. ER/PR-IHC can vary by tumour location and is frequently lost with tumour progression. Therefore, we explored the relationship between ER/PR-IHC expression and tumour location in EC. METHODS: Pre-treatment tumour biopsies from 6 different sites of 80 cases treated with hormonal therapy were analysed for ER/PR-IHC expression and classified into categories 0-10%, 10-50%, and >50%. The ER pathway activity score (ERPAS) was determined based on mRNA levels of ER-related target genes, reflecting the actual activity of the ER receptor. RESULTS: There was a trend towards lower PR-IHC (33% had PR > 50%) and ERPAS (27% had ERPAS > 15) in lymphogenic metastases compared to other locations (p = 0.074). Hematogenous and intra-abdominal metastases appeared to have high ER/PR-IHC and ERPAS (85% and 89% ER-IHC > 50%; 64% and 78% PR-IHC > 50%; 60% and 71% ERPAS > 15, not significant). Tumour grade and previous radiotherapy did not affect ER/PR-IHC or ERPAS. CONCLUSIONS: A trend towards lower PR-IHC and ERPAS was observed in lymphogenic sites. Verification in larger cohorts is needed to confirm these findings, which may have implications for the use of hormonal therapy in the future.

ARID1A loss is prevalent in endometrial hyperplasia with atypia and low-grade endometrioid carcinomas.

ARID1A (AT-rich interactive domain 1A) has recently been identified as a tumor suppressor gene in various, predominantly gynecological cancers. We wanted to investigate the distribution of ARID1A in endometrial hyperplasia, carcinomas and metastatic lesions to elucidate the timing of expression loss of its protein ARID1A in the course of endometrial cancer carcinogenesis. In addition, we wanted to assess the relationship between the loss of ARID1A and clinicopathological variables in endometrial cancer in general and the endometrioid subtype in particular. We analyzed a prospectively collected series of 535 primary endometrial cancers, 77 metastatic lesions, as well as 38 retrospectively collected endometrial hyperplasias with evaluable immunohistochemical staining for ARID1A. Fresh frozen tissue was available for mRNA microarray analysis in 122 primary tumors in parallel. Loss of ARID1A protein expression was noted in none of the hyperplasias without atypia, 16% of hyperplasias with atypia, 19% of primary endometrioid tumors and 28% of metastatic lesions. Loss of ARID1A in primary tumor was significantly associated with endometrioid grade 1 or 2 and clear-cell histology, diploid tumor cells, younger patient age and deeper myometrial infiltration, but not survival. ARID1A RNA expression was significantly correlated with ARID1A protein loss. Thus, loss of ARID1A appears to be an early event in the carcinogenesis of endometrioid uterine carcinomas and the association with deep myometrial infiltration may suggest an importance for invasiveness.

Preoperative anemia, leukocytosis and thrombocytosis identify aggressive endometrial carcinomas.

OBJECTIVES: The objective of this study is to investigate preoperative hematological parameters for anemia, leukocytosis and thrombocytosis in relation to established prognostic factors and survival in endometrial cancer. METHODS: 557 patients treated for endometrial carcinoma were prospectively included in a study focusing on the relationship between preoperative hemoglobin, leukocyte and platelet counts, and a panel of clinicopathological characteristics and outcome. RESULTS: Preoperative anemia was present in 15.8%, leukocytosis in 11.2% and thrombocytosis in 12.1%. Among patients with localized disease (FIGO stage I/II), 18.1% had anemia and/or thrombocytosis at diagnosis. Patients with advanced disease (high FIGO stage and lymph-node metastasis) had significantly lower hemoglobin count, higher leukocyte count and higher platelet count (all p<0.008). Patients with anemia, leukocytosis and thrombocytosis had significantly shorter 5-year disease-specific survival of 61.3%, 66.0% and 61.0% respectively, compared to 87.7%, 86.3% and 87.3% for patients with normal counts (all p<0.001). In multivariate Cox regression analysis, lower hemoglobin counts and higher platelet counts were independently associated with poor outcome adjusted for the standardly applied prognostic markers (p<0.033). CONCLUSION: Preoperative anemia, leukocytosis or thrombocytosis in women with endometrial carcinoma is associated with advanced disease and poor disease-specific survival.

Dynamic contrast-enhanced MRI in endometrial carcinoma identifies patients at increased risk of recurrence.

OBJECTIVES: To study the feasibility of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for assessment of tumour microvasculature in endometrial carcinoma patients, and to explore correlations with histological subtype, clinical course and microstructural characteristics based on apparent diffusion coefficient (ADC) values. METHODS: Diffusion-weighted imaging (DWI) and three-dimensional DCE-MRI (1.5 T) with high temporal resolution (2.49 s) were acquired preoperatively in 55 patients. Quantitative modelling allowed the calculation of four independent parameters describing microvasculature: blood flow (Fb), extraction fraction (E), capillary transit time (Tc) and transfer constant from the extravascular extracellular space [EES] to blood (Kep); and four derived parameters: blood volume (Vb), volume of EES (Ve), capillary permeability surface area product (PS) and transfer from blood to EES (Ktrans). RESULTS: Endometrial carcinoma tissue exhibited reduced Fb, E, Vb, Ve, PS and Ktrans compared with normal myometrium. Non-endometrioid carcinomas (n = 12) had lower Fb, and E than endometrioid carcinomas (n = 43; P < 0.05). Tumour Ve positively correlated with tumour ADC value (r = 0.29, P = 0.03). Reduced survival was observed in patients with low tumour Fb and high tumour Tc (P < 0.05). CONCLUSIONS: We demonstrate the feasibility of DCE-MRI in reflecting histological subtype and clinical course in primary endometrial carcinomas. DCE-MRI may potentially provide future biomarkers for preoperative risk stratification in endometrial carcinomas. KEY POINTS: • Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) offers new information about endometrial carcinoma. • Pelvic DCE-MRI with subsequent quantitative modelling seems feasible in endometrial carcinoma patients. • Low tumour perfusion is a feature of a more aggressive tumour subtype. • DCE-MRI provides potential biomarkers for preoperative risk stratification in endometrial carcinoma patients.

The impact of adipose tissue distribution on endometrial cancer: a systematic review.

Introduction: Endometrial cancer (EC) is the most common gynecological cancer with a rising incidence, attributed to advanced life expectancy and obesity. Adipose tissue (AT) is an important endocrine organ, and its metabolic activity is affected by the different anatomical distribution or locations. AT distribution influences a number of diseases. In EC, it remains unclear whether the type of AT distribution affects development or prognosis. This systematic review aimed to determine whether AT distribution is associated with patient characteristics, disease characteristics, and patient prognosis in EC. Materials and methods: A search was conducted in Medline, MEDLINE EMBASE, and Cochrane Library. We included studies that enrolled patients with EC with any histological subtype and that distinguished between the visceral and subcutaneous AT compartment. In eligible studies, correlative analyses were performed for all outcome measures and AT distribution. Results: Eleven retrospective studies were included, with a wide range of measurements for the visceral and subcutaneous AT compartments. AT distribution was found to be significantly correlated to a number of relevant (disease) characteristics including obesity measures, histological subtype, lymph node metastasis, and sex steroid levels. Five studies reported on survival parameters including overall survival, progression-free survival and disease-specific survival, and they found that increased VAT volume was statistically significantly associated with a worse survival. Discussion/conclusion: This review demonstrates that there are significant correlations between AT distribution and prognosis, body mass index, sex steroid levels, and disease characteristics like histology. Well-designed, prospective, and larger-scale studies are needed to pinpoint these differences more specifically and understand how it can add in prediction and even therapy in EC.

Improved survival related to changes in endometrial cancer treatment, a 30-year population based perspective.

OBJECTIVE: Age adjusted incidence rate for uterine cancers in Norway has increased over last three decades from 12.2/100.000 (1981-90) to 16.0 (2001-2010). Corresponding 5-year survival increased nationally from 76.3% to 83.3%. METHODS: We wanted to investigate how changes in therapeutic strategies during a 30-year period are reflected in survival changes through careful characterization of a population-based series of 1077 endometrial carcinoma patients from Hordaland County, Norway. RESULTS: In concordance with increase in endometrial cancer nationally, the number of patients treated from Hordaland County rose from 286 (1981-1990) through 307 (1991-2000) to 484 (2001-2010). Main treatment changes included increase in routine pelvic lymphadenectomy from 0% through 9% to 77%, adjuvant chemotherapy from 0% through 3% to 9% and a dramatic reduction in adjuvant radiotherapy from 75% through 48% to 12% (all P<0.001). Body mass index increased significantly during this 30-year period, as did the 5-year disease-specific survival: from 75.8 through 80.2 to 86.9% (P=0.002) and overall survival from 67.8 through 71.7 to 77.8% (P=0.03). CONCLUSION: Improved overall and disease specific survival for endometrial carcinoma patients over the last 30 years is demonstrated in a population-based setting. Increasing BMI among patients and a change in treatment strategy with reduction in adjuvant radiotherapy and more extensive surgery is demonstrated for the same period.

Magnetic resonance imaging performs better than endocervical curettage for preoperative prediction of cervical stromal invasion in endometrial carcinomas.

OBJECTIVE: Preoperative identification of cervical stromal invasion in endometrial carcinoma is important to select patients for primary radical hysterectomy. The objective of this prospective implementation study was to assess if introduction of magnetic resonance imaging (MRI) in addition to the standardly applied endocervical curettage (ECC), improved the preoperative prediction of cervical stromal invasion. METHODS: Over a six-year period, a total of 338 patients were surgically staged after preoperative assessment of the uterine cervix by ECC (years 1 through 3), and a combination of MRI and ECC (years 4 through 6). Suggested presence of cervical stromal invasion based on ECC (n=321) and MRI (n=146) were compared for diagnostic performance applying surgical FIGO stage 2009 as reference standard. RESULTS: For assessment of cervical stromal invasion sensitivity (specificity) [accuracy] values were 65% (79%) [77%] for ECC and 59% (91%) [84%] for MRI. Among patients diagnosed with both preoperative tests (n=129), MRI yielded significantly higher specificity (p=0.001) and accuracy (p=0.005) than ECC. MRI independently predicted cervical stromal invasion with an odds ratio (OR) of 11.2 (p<0.001) compared to OR of 2.7 (p=0.07) for ECC. CONCLUSIONS: The diagnostic performance of MRI compares favorably to that of ECC for preoperative assessment of cervical stromal invasion in endometrial carcinoma. Thus, the findings in this prospective implementation study support the value of preoperative MRI for assessment of cervical stromal invasion before radical hysterectomy.

Standard 1.5-T MRI of endometrial carcinomas: modest agreement between radiologists.

OBJECTIVES: To evaluate pelvic magnetic resonance imaging (MRI) interobserver agreement for the detection of deep myometrial invasion, cervical stroma invasion and lymph node metastases in endometrial carcinoma patients in relation to surgical staging. METHODS: Fifty-seven patients with histologically confirmed endometrial carcinoma were prospectively included in a study of preoperative 1.5-T MRI. Four radiologists, blinded to patient data, independently reviewed the images for the presence of deep myometrial invasion, cervical stroma invasion and lymph node metastases. Kappa coefficients for interobserver agreement and diagnostic performances for each observer were calculated using final surgical staging results (FIGO 09) as reference standard. RESULTS: Overall agreement among all observers was moderate for cervical stroma invasion (κ = 0.50 [95% CI 0.27-0.73]) and lymph node metastases (κ = 0.56 [0.09-0.80]) and fair for deep myometrial invasion (κ = 0.39 [0.26-0.55]). Sensitivity (specificity) values for the four observers were 72-92% (44-63%) for deep myometrial invasion, 38-63% (82-94%) for cervical stroma invasion and 25-38% (90-100%) for lymph node metastases. CONCLUSIONS: Conventional MRI showed only modest interobserver agreement and diagnostic accuracy for detection of deep myometrial invasion, cervical stroma invasion and lymph node metastases. Improved methods are needed for preoperative imaging in the staging of endometrial carcinomas. KEY POINTS: MRI is an important tool for preoperative endometrial cancer staging. • Staging agreement based on pelvic MRI was modest among different observers. • Preoperative MRI alone was suboptimal in identifying high-risk patients. • Improved imaging and biomarkers may refine preoperative risk stratification in endometrial cancer.