MRI-assessed tumor-free distance to serosa predicts deep myometrial invasion and poor outcome in endometrial cancer.

OBJECTIVES: To explore the diagnostic accuracy of preoperative magnetic resonance imaging (MRI)-derived tumor measurements for the prediction of histopathological deep (≥ 50%) myometrial invasion (pDMI) and prognostication in endometrial cancer (EC). METHODS: Preoperative pelvic MRI of 357 included patients with histologically confirmed EC were read independently by three radiologists blinded to clinical information. The radiologists recorded imaging findings (T1 post-contrast sequence) suggesting deep (≥ 50%) myometrial invasion (iDMI) and measured anteroposterior tumor diameter (APD), depth of myometrial tumor invasion (DOI) and tumor-free distance to serosa (iTFD). Receiver operating characteristic (ROC) curves for the prediction of pDMI were plotted for the different MRI measurements. The predictive and prognostic value of the MRI measurements was analyzed using logistic regression and Cox proportional hazard model. RESULTS: iTFD yielded highest area under the ROC curve (AUC) for the prediction of pDMI with an AUC of 0.82, whereas DOI, APD and iDMI yielded AUCs of 0.74, 0.81 and 0.74, respectively. Multivariate analysis for predicting pDMI yielded highest predictive value of iTFD < 6 mm with OR of 5.8 (p < 0.001) and lower figures for DOI ≥ 5 mm (OR = 2.8, p = 0.01), APD ≥ 17 mm (OR = 2.8, p < 0.001) and iDMI (OR = 1.1, p = 0.82). Patients with iTFD < 6 mm also had significantly reduced progression-free survival with hazard ratio of 2.4 (p < 0.001). CONCLUSION: For predicting pDMI, iTFD yielded best diagnostic performance and iTFD < 6 mm outperformed other cutoff-based imaging markers and conventional subjective assessment of deep myometrial invasion (iDMI) for diagnosing pDMI. Thus, iTFD at MRI represents a promising preoperative imaging biomarker that may aid in predicting pDMI and high-risk disease in EC.

An MRI-Based Radiomic Prognostic Index Predicts Poor Outcome and Specific Genetic Alterations in Endometrial Cancer.

Integrative tumor characterization linking radiomic profiles to corresponding gene expression profiles has the potential to identify specific genetic alterations based on non-invasive radiomic profiling in cancer. The aim of this study was to develop and validate a radiomic prognostic index (RPI) based on preoperative magnetic resonance imaging (MRI) and assess possible associations between the RPI and gene expression profiles in endometrial cancer patients. Tumor texture features were extracted from preoperative 2D MRI in 177 endometrial cancer patients. The RPI was developed using least absolute shrinkage and selection operator (LASSO) Cox regression in a study cohort (n = 95) and validated in an MRI validation cohort (n = 82). Transcriptional alterations associated with the RPI were investigated in the study cohort. Potential prognostic markers were further explored for validation in an mRNA validation cohort (n = 161). The RPI included four tumor texture features, and a high RPI was significantly associated with poor disease-specific survival in both the study cohort (p < 0.001) and the MRI validation cohort (p = 0.030). The association between RPI and gene expression profiles revealed 46 significantly differentially expressed genes in patients with a high RPI versus a low RPI (p < 0.001). The most differentially expressed genes, COMP and DMBT1, were significantly associated with disease-specific survival in both the study cohort and the mRNA validation cohort. In conclusion, a high RPI score predicts poor outcome and is associated with specific gene expression profiles in endometrial cancer patients. The promising link between radiomic tumor profiles and molecular alterations may aid in developing refined prognostication and targeted treatment strategies in endometrial cancer.

Preoperative 18F-FDG PET/CT tumor markers outperform MRI-based markers for the prediction of lymph node metastases in primary endometrial cancer.

OBJECTIVES: To compare the diagnostic accuracy of preoperative 18F-FDG PET/CT and MRI tumor markers for prediction of lymph node metastases (LNM) and aggressive disease in endometrial cancer (EC). METHODS: Preoperative whole-body 18F-FDG PET/CT and pelvic MRI were performed in 215 consecutive patients with histologically confirmed EC. PET/CT-based tumor standardized uptake value (SUVmax and SUVmean), metabolic tumor volume (MTV), and PET-positive lymph nodes (LNs) (SUVmax > 2.5) were analyzed together with the MRI-based tumor volume (VMRI), mean apparent diffusion coefficient (ADCmean), and MRI-positive LN (maximum short-axis diameter ≥ 10 mm). Imaging parameters were explored in relation to surgicopathological stage and tumor grade. Receiver operating characteristic (ROC) curves were generated yielding optimal cutoff values for imaging parameters, and regression analyses were used to assess their diagnostic performance for prediction of LNM and progression-free survival. RESULTS: For prediction of LNM, MTV yielded the largest area under the ROC curve (AUC) (AUC = 0.80), whereas VMRI had lower AUC (AUC = 0.72) (p = 0.03). Furthermore, MTV > 27 ml yielded significantly higher specificity (74%, p < 0.001) and accuracy (75%, p < 0.001) and also higher odds ratio (12.2) for predicting LNM, compared with VMRI > 10 ml (58%, 62%, and 9.7, respectively). MTV > 27 ml also tended to yield higher sensitivity than PET-positive LN (81% vs 50%, p = 0.13). Both VMRI > 10 ml and MTV > 27 ml were significantly associated with reduced progression-free survival. CONCLUSIONS: Tumor markers from 18F-FDG PET/CT outperform MRI markers for the prediction of LNM. MTV > 27 ml yields a high diagnostic performance for predicting aggressive disease and represents a promising supplement to conventional PET/CT reading in EC. KEY POINTS: • Metabolic tumor volume (MTV) outperforms other 18F-FDG PET/CT and MRI markers for preoperative prediction of lymph node metastases (LNM) in endometrial cancer patients. • Using cutoff values for tumor volume for prediction of LNM, MTV > 27 ml yielded higher specificity and accuracy than VMRI> 10 ml. • MTV represents a promising supplement to conventional PET/CT reading for predicting aggressive disease in EC.

Preoperative tumor texture analysis on MRI predicts high-risk disease and reduced survival in endometrial cancer.

BACKGROUND: Improved methods for preoperative risk stratification in endometrial cancer are highly requested by gynecologists. Texture analysis is a method for quantification of heterogeneity in images, increasingly reported as a promising diagnostic tool in various cancer types, but largely unexplored in endometrial cancer. PURPOSE: To explore whether tumor texture parameters from preoperative MRI are related to known prognostic features (deep myometrial invasion, cervical stroma invasion, lymph node metastases, and high-risk histological subtype) and to outcome in endometrial cancer patients. STUDY TYPE: Prospective cohort study. POPULATION/SUBJECTS: In all, 180 patients with endometrial carcinoma were included from April 2009 to November 2013 and studied until January 2017. FIELD STRENGTH/SEQUENCES: Preoperative pelvic MRI including contrast-enhanced T1 -weighted (T1 c), T2 -weighted, and diffusion-weighted imaging at 1.5T. ASSESSMENT: Tumor regions of interest (ROIs) were manually drawn on the slice displaying the largest cross-sectional tumor area, using the proprietary research software TexRAD for analysis. With a filtration-histogram technique, the texture parameters standard deviation, entropy, mean of positive pixels (MPP), skewness, and kurtosis were calculated. STATISTICAL TESTS: Associations between texture parameters and histological features were assessed by uni- and multivariable logistic regression, including models adjusting for preoperative biopsy status and conventional MRI findings. Multivariable Cox regression analysis was used for survival analysis. RESULTS: High tumor entropy in apparent diffusion coefficient (ADC) maps independently predicted deep myometrial invasion (odds ratio [OR] 3.2, P lt 0.001), and high MPP in T1 c images independently predicted high-risk histological subtype (OR 1.01, P = 0.004). High kurtosis in T1 c images predicted reduced recurrence- and progression-free survival (hazard ratio [HR] 1.5, P lt 0.001) after adjusting for MRI-measured tumor volume and histological risk at biopsy. DATA CONCLUSION: MRI-derived tumor texture parameters independently predicted deep myometrial invasion, high-risk histological subtype, and reduced survival in endometrial carcinomas, and thus, represent promising imaging biomarkers providing a more refined preoperative risk assessment that may ultimately enable better tailored treatment strategies in endometrial cancer. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;48:1637-1647.

In vivo MR spectroscopy predicts high tumor grade in endometrial cancer.

Background In vivo magnetic resonance spectroscopy (MRS) enables non-invasive measurements of tumor metabolites. Choline-containing metabolites play a key role in tumor metabolism. Purpose To explore whether preoperative MRS-derived tumor choline levels are associated with clinical and histological features in endometrial carcinomas. Material and Methods Preoperative pelvic magnetic resonance imaging (MRI) (1.5T), including structural and diffusion-weighted imaging and localized multivoxel proton MR (1H-MR) spectroscopy, was performed in 77 prospectively included patients with histologically confirmed endometrial carcinomas. Relative levels of total choline-containing metabolites (tCho) in tumor and myometrium were measured using the ratios: tCho/Creatine; tCho/Water; and tCho/Noise. MRS parameters were analyzed in relation to histological subtype and grade, surgicopathological staging parameters, MRI-measured tumor volume, and tumor apparent diffusion coefficient (ADC) value and clinical outcome. Results Tumor tissue had significantly higher ratios for tCho/Creatine, tCho/Water, and tCho/Noise than normal myometrial tissue ( P < 0.001 for all). High tumor tCho/Water ratio was significantly associated with high tumor grade in endometrioid tumors ( P = 0.02). Tumor tCho/Creatine ratio was positively correlated to MRI-measured tumor volume (rs = 0.25; P = 0.03). Conclusion High choline levels in tumor are associated with high-risk features. In vivo MRS may potentially aid in the preoperative risk stratification in endometrial cancer.

Preoperative quantitative dynamic contrast-enhanced MRI and diffusion-weighted imaging predict aggressive disease in endometrial cancer.

Background Quantitative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and diffusion-weighted imaging (DWI) may yield preoperative tumor biomarkers relevant for prognosis and therapy in cancer. Purpose To explore the value of preoperative DCE-MRI and DWI for the prediction of aggressive disease in endometrial cancer patients. Material and Methods Preoperative MRI (1.5-T) from 177 patients were analyzed and imaging parameters reflecting tumor microvasculature (from DCE-MRI) and tumor microstructure (from DWI) were estimated. The derived imaging parameters were explored in relation to clinico-pathological stage, histological subtype and grade, molecular markers, and patient outcome. Results Low tumor blood flow (Fb) and low rate constant for contrast agent intravasation (kep) were associated with high-risk histological subtype ( P ≤ 0.04 for both) and tended to be associated with poor prognosis ( P ≤ 0.09). Low tumor apparent diffusion coefficient (ADC) value and large tumor volume were both significantly associated with deep myometrial invasion ( P < 0.001 for both) and were also unfavorable prognostic factors ( P = 0.05 and P < 0.001, respectively). Conclusion DCE-MRI and DWI represent valuable supplements to conventional MRI by providing preoperative imaging biomarkers that predict aggressive disease in endometrial cancer patients.

High visceral fat percentage is associated with poor outcome in endometrial cancer.

Despite evidence of increased endometrial cancer (EC) risk in obese women, the impact of obesity on clinical and histological phenotype is poorly understood. This study explored abdominal fat volumes and fat distribution quantified by computed tomography (CT), in relation to tumor characteristics and outcome. 227 EC patients with preoperative abdominal CT scans were included. Total abdominal fat volume (TAV), subcutaneous abdominal fat volume (SAV) and visceral abdominal fat volume (VAV) were quantified, and visceral fat percentage calculated (VAV%=[VAV/TAV]x100). Waist circumference (WC) and liver density (LD) were measured, and body mass index (BMI) calculated. Data for estrogen, progesterone and androgen receptor (ERα/PR/AR) expression by immunohistochemistry were available for 149 tumors, and global gene expression data for 105 tumors. High BMI, TAV, SAV, VAV and WC, and low LD, were associated with low grade endometrioid tumors and PR and AR positivity (all p≤0.03). High VAV% was associated with high age (p<0.001), aneuploidy (p=0.01) and independently predicted reduced disease-specific survival (HR 1.05, 95% CI 1.00-1.11, p=0.041). Tumors from patients with low VAV% showed enrichment of gene sets related to immune activation and inflammation. In conclusion, high VAV% independently predicts reduced EC survival. Tumors arising in patients with low VAV% show enrichment of immune and inflammation related gene sets, suggesting that the global metabolic setting may be important for tumor immune response.

Preoperative imaging markers and PDZ-binding kinase tissue expression predict low-risk disease in endometrial hyperplasias and low grade cancers.

PURPOSE: Distinguishing complex atypical hyperplasia (CAH) from grade 1 endometrioid endometrial cancer (EECG1) preoperatively may be valuable in order to prevent surgical overtreatment, particularly in patients wishing preserved fertility or in patients carrying increased risk of perioperative complications. MATERIAL AND METHODS: Preoperative histological diagnosis and radiological findings were compared to final histological diagnosis in patients diagnosed with CAH and EECG1. Imaging characteristics at preoperative magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography/computer tomography (FDG-PET/CT) were compared with tumor DNA oligonucleotide microarray data, immunohistochemistry findings and clinicopathological annotations. RESULTS: MRI assessed tumor volume was higher in EECG1 than in CAH (p=0.004) whereas tumor apparent diffusion coefficient value was lower in EECG1 (p=0.005). EECG1 exhibited increased metabolism with higher maximum and mean standard uptake values (SUV) than CAH (p≤0.002). Unsupervised clustering of EECG1 and CAH revealed differentially expressed genes within the clusters, and identified PDZ-binding kinase (PBK) as a potential marker for selecting endometrial lesions with less aggressive biological behavior. CONCLUSION: Both PBK expression and preoperative imaging yield promising biomarkers that may aid in the differentiation between EECG1 and CAH preoperatively, and these markers should be further explored in larger patient series.

Tissue and imaging biomarkers for hypoxia predict poor outcome in endometrial cancer.

Hypoxia is frequent in solid tumors and linked to aggressive phenotypes and therapy resistance. We explored expression patterns of the proposed hypoxia marker HIF-1α in endometrial cancer (EC) and investigate whether preoperative functional imaging parameters are associated with tumor hypoxia. Expression of HIF-1α was explored both in the epithelial and the stromal tumor component. We found that low epithelial HIF-1α and high stromal HIF-1α expression were significantly associated with reduced disease specific survival in EC. Only stromal HIF-1α had independent prognostic value in Cox regression analysis. High stromal HIF-1α protein expression was rare in the premalignant lesions of complex atypical hyperplasia but increased significantly to invasive cancer. High stromal HIF-1α expression was correlated with overexpression of important genes downstream from HIF-1α, i.e. VEGFA and SLC2A1 (GLUT1). Detecting hypoxic tumors with preoperative functional imaging might have therapeutic benefits. We found that high stromal HIF-1α expression associated with high total lesion glycolysis (TLG) at PET/CT. High expression of a gene signature linked to hypoxia also correlated with low tumor blood flow at DCE-MRI and increased metabolism measured by FDG-PET. PI3K pathway inhibitors were identified as potential therapeutic compounds in patients with lesions overexpressing this gene signature. In conclusion, we show that high stromal HIF-1α expression predicts reduced survival in EC and is associated with increased tumor metabolism at FDG-PET/CT. Importantly; we demonstrate a correlation between tissue and imaging biomarkers reflecting hypoxia, and also possible treatment targets for selected patients.

High Diagnostic Value of 18F-FDG PET/CT in Endometrial Cancer: Systematic Review and Meta-Analysis of the Literature.

UNLABELLED: The aim of this study was to evaluate the diagnostic performance of (18)F-FDG PET/CT for the preoperative assessment of lymph node metastases (LNM) in endometrial cancer patients and for the assessment of endometrial cancer recurrence (ECR) after primary surgical treatment. METHODS: A comprehensive search was performed on Pubmed/MEDLINE databases for studies reporting the diagnostic performance of (18)F-FDG PET/CT for assessment of LNM and ECR published up to August 15, 2015. Twenty-one studies (13 for LNM and 8 for ECR) were included in the systematic review and meta-analysis. Pooled estimates of sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio of the (18)F-FDG PET/CT were calculated along with 95% confidence intervals (CIs). A summary receiver-operating-characteristics curve (SROC) was constructed, and the area under the SROC curve (AUC) was determined along with Q* index. RESULTS: The overall pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, and AUC (with 95% CI) of (18)F-FDG PET/CT for detection of LNM were 0.72 (95% CI, 0.63-0.80), 0.94 (95% CI, 0.93-0.96), 10.9 (95% CI, 7.9-15.1), 0.36 (95% CI, 0.27-0.48), 39.7 (95% CI, 21.4-73.6), and 0.94 (95% CI, 0.85-0.99), respectively, whereas the corresponding numbers for detection of ECR were 0.95 (95% CI, 0.91-0.98), 0.91 (95% CI, 0.86-0.94), 8.8 (95% CI, 6.0-12.7), 0.08 (95% CI, 0.05-0.15), 171.7 (95% CI, 67.9-434.3), and 0.97 (95% CI, 0.95-0.98), respectively. The overall diagnostic accuracy (Q* index) in LNM and ECR were 0.88 and 0.93, respectively. CONCLUSION: (18)F-FDG PET/CT has an excellent diagnostic performance for detecting LNM preoperatively and disease recurrence postoperatively in endometrial cancer patients.

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.