Lymphatic Metastasis Prediction For Endometrial Cancer: Implication Of Clinical Methods And Combined Molecular Markers

Purpose:To investigate the clinicopathological characteristics,treatment,survival rate and prognostic factors of endometrial cancer and to explore the value of clinical methods and combined molecular markers in predicting lymphatic metastasis of endometrial cancer.To investigate the role of systematic lymphadenectomy in the treatment strategy of endometrial cancer and the feasibility in carrying out the surgery, to evaluate the predictive value of serum CA125 levels,MRI,curettage pathologic findings and molecular markers in the assessment of lymph nodes metastasis.Materials and methods:Retrospectively analyzed the clinicopathologic parameters and prognosis of endometrial cancer patients in Department of Gyneocologic Oncology,Fudan University Cancer Hospital between 1996 and 2006. The status of lymphadenetomy and the complications associated with the procedure of the 186 patients of endometrial cancer underwent systematic retroperitoneal lymphadenectomy between 2005 and 2008 were analyzed retrospectively.Collecting serum CA125 levels,MRI and histologic type and grade by curettage of endometrial cancer patients between 2004 and 2008,and evaluating their predictive value of lymphatic metastasis.An analysis group of 120 patients with endometrial cancer treated between 2000 and 2008 were explored the predictive value of immunohistochemical proteins,including ER,PR,pS2,p53,p21,E-cadherin,β-catenin,VEGF and PIK3CA. Multivariate analysis was performed to study the relationship between proteinic markers and lymphatic metastasis,proteinic signature of integrated risk factor was simulated and analyzed for a better prediction model.Results:PartⅠ:Mean age of patients is 55.9 years old,62.2%patients were postmenopausal. 576 patients included 509 endometrioid adenocarcinoma cases and 67 non-endometrioid adenocarcinoma cases.Patients were followed up with the median period 36 months,21 patients experienced local relapse,19 patients were found distant metastases and 52 cases died.The 3-year overall survival was 89.6%,3-year and 5-year disease free survival rate was 84.4%and 82.5%.Three-year OS and 3-year and 5-year DFS had significant difference in FIGO stages,histologic types and grades(P＜0.001). Patients treated between 2004 and 2005 had a higher 3-year OS rate(92.2%) than patients between 1996 and 2003(85.0%,P=0.0355),but two groups had no significant difference in 3-year DFS(86.4%vs.79.9%,P=0.1934).COX regression analysis showed postmenopausal,FIGO stage and histological grade were prognostic factors.PartⅡ:Totally 4376 lymph nodes(3679 pelvic lymph nodes,697 lymph nodes) with mean of 23.5 were dissected in 186 patients underwent systematic lymphadenectomy,including 105 positive lymph nodes.Twenty-two patients(11.8%) had lymph node metastases:both pelvic and para-aortic in 10 patients,only pelvic in 8 patients,and exclusively isolated to the para-aortic area in 4 patients.Adjuvant radiotherapy and/or chemotherapy were needed by 17 patients upstaged by lymph-nodal invasion,whiles 69 patient with intermediate/intermediate-high risk exempt from adjuvant therapy by systematic lymphadenectomy.Histological type, histological grade,depth of myometrial invasion,and LVSI were associated with lymph node metastasis,multivariate analyses showed myometrial invasion and LVSI were independent predictive factors of lymphatic metastasis(P=0.006 and 0.007, respectively).The median time of the procedure was 150 minutes,median blood loss was 300ml,38 patients received blood transfusion,and 17(9.1%) patients had postoperative complications.PartⅢ:In this retrospective study,248 patients with preoperative serum CA125 levels were enrolled.The median value of the total patients was 21.88 U/ml,while 41.53 U/ml of patients with lymphatic metastasis.Univariate analysis showed preoperative CA125 serum levels had significant difference in patients with negative and positive lymph nodes(P=0.003),but it couldn't predict lymphatic metastasis independently(P=0.073).The area under CA125 serum level ROC was 0.753(95%CI: 0.635～0.870),when using 20U/ml as the critical value,the sensitivity and specificity of preoperative CA125 serum level in predicting lymph nodes metastasis were 83.33% and 48.21%respectively,while PPV and NPV were 14.71%and 96.43%respectively. One hundred and sixty-eight patients undertook prepoperative enhancement MRI scanning,MRI had an accuracy at 97.02%in diagnosis of endometrial cancer,and the diagnostic accuracy of myometrial invasion,cervical involvement and adnexa involvement were 69.64%,83.93%and 94.05%respectively.The lymphatic metastasis was accurately determined in 97.02%petients,but its sensitivity and specificity were 23.53%and 98.68%respectively,PPV and NPV were 66.67%and 91.98%,respectively. Evaluation of the histologic type and tumor grade of 564 patients with endometrial cancer by curettage were compared with the final pathologic findings.The coincidence of disease diagnosis was 91.5%,however,only 59.7%patients has the correct diagnosis in tumor grade.About 32.1%patients had to be upgraded after evaluation of the uterine specimens,whereas 8.1%downgraded.PartⅣ:Univariate analysis revealed among 9 molecular markers,PR,pS2 and p21protein expression had significant difference in patients with negative and positive lymph nodes(P=0.003,0.011 and 0.037,respectively),and also were indepentive predictive factors for lymphatic metastasis.A 3-marker proteinic signature of integrated risk factor was simulated and analyzed for a better prediction model.Multivariate analyses revealed the score of proteinic signature was independent predictive factor for lymphatic metastasis.ROC also proved the integrated risk factor had the best value of predicting lymphatic metastasis,compared to sole-use of above molecular markers, when using 1.5 as the critical value,the sensitivity and specificity in predicting lymph nodes metastasis were 65.0%and 76.3%respectively,PPV and NPV were 57.8%and 81.3%respectively.Conclusions:PartⅠ:For endometrial cancer,lymphadenectomy comes to be an importantst part of routine operation gradually,and with the development of standard treatment modality, patients with endometrial cancer might obtain a long-term survival.PartⅡ:Systematic retroperitoneal lymphadenectomy conduces to identfing the FIGO stage,directing the postoperative adjuvant therapy,and might have survival advantage,but also increases the surgical time and complication incidence.PartⅢ:Preoperative serum CA125 level might have the value in lymphatic metastasis prediction,but MRI and curettage pathologic findings have limited value in predicting lymphatic metastasis and its risk factors of endometrial cancer.PartⅣ:PR,pS2 and p21 protein expression were independent predictive factors for lymphatic metastasis of endometrial cancer.The score of proteinic signature, derived from 3-marker signature,was another independent predictive factor.The integrated risk factor was an more valuable predictive factor than sole-use of molecular markers.