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.publishedVersio

Functional imaging to promote individualized and targeted therapy in endometrial cancer

Background: Endometrial carcinoma is the most common pelvic malignancy in the Western world and the incidence is increasing. Endometrial carcinomas are surgically staged according to FIGO 2009 criteria, and the lack of robust preoperative staging methods results in overtreatment of this patient population, mostly by unnecessary invasive surgery and lymphadenectomy in patients with localized disease. New imaging methods are highly warranted to aid more accurate preoperative staging and thus potentially reduce unwanted post-operative side effects, decrease the amount of unnecessary resource-demanding surgery and to provide better individualized therapy for this patient group. Aims: Promote individualized treatment, reduce morbidity and facilitate implementation of targeted therapy among endometrial carcinoma patients by investigating functional and structural imaging biomarkers in pre-operatively acquired MRI and FDG-PET/CT. Methods: All patients with histologically confirmed endometrial carcinoma at Haukeland University Hospital were consecutively referred to pre-operative MRI and/or FDG-PET/CT for a period of four years. Images were individually read by two to four radiologists and nuclear medicine physicians conducting staging and image quantifications in a standard imaging report. Results were compared to the results of surgical staging regarding the tumors depth of myometrial invasion, cervical stromal involvement and the presence of lymph node metastases, these three criteria being well-established parameters predicting aggressiveness of disease and survival in endometrial cancer. Main Results: The evaluation of the staging criteria depth of myometrial invasion, cervical stromal involvement and the presence of lymph node metastases on pre- operative 1.5T MRI are prone to considerable inter-observer variability (κ=0.4, 0.5 and 0.6, respectively), and the staging accuracy is variable with a sensitivity (specificity) of 80%, 63% and 38% respectively (53%, 94% and 100%, respectively). For image quantifications, the inter-observer agreement is good (ICC=0.56-0.98) and the measured parameters show significant correlations to established staging criteria. Tumor apparent diffusion coefficient (ADC) value on diffusion-weighted imaging (DWI) is significantly lower in tumors with deep myometrial invasion (ADC = 0.75 × 10-3mm2/s) compared with tumors with superficial or no myometrial invasion (ADC = 0.85 × 10-3mm2/s; p < 0.001), and the ADC value is negatively correlated to tumor size (p=0.007). Large tumor size measured on preoperative MRI is associated with reduced progression/recurrence free survival (p ≤ 0.005 for all size parameters), and CC diameter has an independent impact on survival (adjusted hazards ratio, 1.04; p = 0.009). FDG-PET/CT is excellent in ruling out lymph node metastases (NPV=97%) and SUVmax, SUVmean, MTV and TLG are significantly related to deep myometrial invasion, presence of lymph node metastases and high histological grade (p<0.015 for all). Calculated optimal cut-off values for MTV in predicting deep myometrial invasion (20 ml) and presence of lymph node metastases (30 ml), yield ORs of 7.8 (p<0.001) and 16.5 (p=0.001), respectively, outperforming the current pre-operative ground for decision-making based on pathology findings in endometrial biopsies. Conclusion: Functional and structural imaging biomarkers from MRI and FDG- PET/CT are promising for preoperative identification of high-risk patients in endometrial carcinoma

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

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

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