【作者】 孙织；

【导师】 蔡三军； 王华英； 顾雅佳； 涂小予；

【作者基本信息】 复旦大学 ， 肿瘤学， 2009， 博士

【摘要】 目的:探讨子宫内膜癌的临床病理特点、治疗方法、生存情况及影响预后的因素,并从临床和分子标志物蛋白表达水平对子宫内膜癌淋巴结转移及其预测方法进行研究分析,探讨系统性后腹膜淋巴结清扫在子宫内膜癌治疗决策中的价值以及手术的可行性;探讨术前血清CA125水平、MRI检查和术前分段诊刮病理在判断淋巴结转移及其高危因素中的价值:寻找预测淋巴结转移的蛋白分子标志物,探讨其在预测子宫内膜癌淋巴结转移中的应用价值。方法:回顾性分析复旦大学附属肿瘤医院1996年1月至2006年12月间收治的子宫内膜癌初治患者的临床病理资料和预后,全面了解子宫内膜癌的临床病理特点、治疗方法、生存情况及影响预后的因素。对2005年1月～2008年12月在我院行系统性腹膜后淋巴结清扫的186例子宫内膜癌患者进行回归性分析,明确子宫内膜癌淋巴结转移情况,分析系统性腹膜后淋巴结清扫的价值和可行性。回顾性分析2004年1月～2008年12月间在我院初治的子宫内膜癌患者术前血清CA125水平、MRI检查及术前分段诊刮病理结果,寻找并评价预测子宫内膜癌淋巴结转移的临床病理方法。采用免疫组化法检测子宫内膜癌石蜡组织ER、PR、pS2、p53、p21、E-cadherin、β-catenin、VEGF、PIK3CA的蛋白表达情况,寻找预测淋巴结转移的蛋白分子标志物,并通过数学模型构建子宫内膜癌淋巴结转移联合预测因子。结果:第一部分:所有576例子宫内膜癌患者,平均年龄55.9岁,绝经后患者占62.2%;其中子宫内膜样腺癌509例,非内膜样腺癌67例。经过中位随访期36个月,局部复发21例,复发率为4.45%(阴道残端复发率为2.02%,盆腔复发率为2.43%);远处转移19例,转移率为4.05%。死亡52例,带瘤生存23例,3年总生存率为89.6%,3年和5年无病生存率分别为84.4%和82.5%。早期(Ⅰ、Ⅱ期)与Ⅲ期、Ⅳ期患者间、内膜样腺癌和非内膜样腺癌患者间、不同分化程度的子宫内膜癌患者间在3年总生存率和3年、5年无病生存率上差异均有统计学意义(P值均＜0.001)。2004年～2005年间收治患者的3年总生存率高于1996年～2003年治疗组(92.2%和85.0%,P=0.0355),但二者在3年无病生存率上差异无统计学意义(86.4%和79.9%,P=0.1934)。多因素分析显示绝经(P=0.001)、手术病理分期(P＜0.001)、组织学分级(P=0.006)与预后相关。第二部分:186例行系统性腹膜后淋巴结清扫的子宫内膜癌患者共清扫淋巴结4376枚(盆腔3679枚,腹主动脉旁697枚),平均为23.5枚;其中阳性105枚(盆腔63枚,腹主动脉旁42枚)。22例患者出现淋巴结转移,转移率为11.8%,其中盆腔淋巴结转移18例,腹主动脉旁淋巴结转移14例,10例患者同时出现盆腔及腹主动脉旁淋巴结转移,4例患者仅有腹主动脉旁淋巴结转移。17例患者因淋巴结转移分期升级,术后需要给予辅助放疗和/或化疗;另69例中危、中高危早期患者因手术排除子宫外转移而免去术后辅助治疗。单因素分析发现不同病理类型、分化程度、肌层浸润深度和LVSI之间淋巴结转移率的差异有统计学意义(P值均＜0.001),多因素分析结果提示肌层浸润深度(P=0.006)和LVSI(P=0.007)是子宫内膜癌淋巴结转移的独立的预测因素。中位手术时间为150分钟,中位手术出血量为300ml,其中38例(20.4%)患者接受输血治疗。无患者发生术中并发症,手术死亡率为0%,术后17例(9.1%)患者出现手术并发症,其中淋巴囊肿9例,盆腔感染3例,阴道残端出血2例,不全性低位肠梗阻、深静脉血栓伴淋巴囊肿和腔隙性脑梗塞各1例。第三部分:248例患者中位术前血清CA125为21.88U/mL,其中的24例淋巴结转移患者中位血清CA125为41.53 U/mL。单因素分析显示淋巴结转移与否患者间的术前血清CA125水平存在统计学差异(P=0.003),但多因素分析显示血清CA125水平不能独立预测子宫内膜癌的淋巴结转移(P=0.073)。其预测淋巴结转移的ROC曲线下面积为0.753(95%CI:0.635～0.870),当术前血清CA125临界值取20U/mL时,其灵敏度和特异度分别为83.33%和48.21%,阳性预测值和阴性预测值分别为14.71%和96.43%。MRI(增强扫描)检查诊断子宫内膜癌宫腔内病灶的诊断符合率为97.02%(163/168),诊断肌层浸润深度、颈管侵犯和附件累及的符合率69.64%、83.93%和94.05%。MRI检查术前判断淋巴结转移的诊断符合率高达91.07%,但其灵敏度仅23.53%,特异度为98.68%,阳性预测值和阴性预测值分别为66.67%和91.98%。术前分段诊刮病理诊断子宫内膜癌的疾病性质的符合率为91.5%(516/564),病理类型的诊断符合率为92.1%(475/516),而在分化程度方面,40.3%的患者术前、术后组织学分级不符,其中32.1%的患者出现术后分化升级。第四部分:单因素分析发现9个分子标志物中,PR、pS2和p21的蛋白表达情况在分析组淋巴结阴性和阳性患者之间的差异具有统计学意义(P=0.003,0.011和0.037)。多因素分析显示PR(P=0.002)、pS2(P=0.047)和p21(P=0.044)均为阴性淋巴结的独立预测因子,其预测阴性淋巴结相应ROC曲线下面积分别为PR 0.694(95%CI:0.597-0.792)、pS2 0.653(95%CI:0.552-0.755)和p21 0.634(95%CI:0.532-0.736)。利用免疫组化染色强度和回归系数计算上述3个分子标志物的蛋白表达指数,Logistic回归分析显示联合预测因子蛋白表达指数是子宫内膜癌阴性淋巴结的独立预测因子,P＜0.001:其曲线下面积为0.761(95%CI:0.673-0.850),均大于各独立预测因子。当联合预测因子蛋白表达指数的临界值取1.5时,预测淋巴结转移的灵敏度和特异度分别为65.0%和76.3%,阳性预测值和阴性预测值分别为57.8%和81.3%,假阳性率和假阴性率分别为23.8%和35.0%。对验证组患者进行独立样本检验,发现联合预测因子蛋白表达指数预测淋巴结转移的灵敏度和特异度分别为73.3%和71.1%,阳性预测值和阴性预测值分别为45.8%和88.9%。结论:第一部分:淋巴结清扫逐渐成为子宫内膜癌常规手术的重要组成部分,子宫内膜癌的治疗也取得了较好的疗效,日趋规范的子宫内膜癌治疗方式将可能进一步提高患者长期生存。第二部分:系统性腹膜后淋巴结清扫有助于明确子宫内膜癌的手术病理分期,指导辅助治疗的选择,并可能具有生存优势,但在一定程度上增加了手术时间以及手术相关并发症。第三部分:术前血清CA125水平在预测淋巴结转移中有一定的价值;但MRI检查和术前分段诊刮病理在预测子宫内膜癌淋巴结转移及其高危因素中的价值有限。第四部分:PR、pS2和p21在预测独立预测子宫内膜癌阴性淋巴结中均有一定的价值;利用生物信息学模型构建上述3个分子标志物的联合预测因子蛋白表达指数是独立的阴性淋巴结预测因子,其预测价值高于各独立预测因子,将可能为今后个体化治疗提供依据。更多还原

【Abstract】 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.更多还原