【作者】 靳秀平；

【导师】 梁建芳； 郑绘霞；

【作者基本信息】 山西医科大学 ， 病理学与病理生理学， 2009， 硕士

【摘要】 背景和目的:恶性肿瘤的病理分级和临床分期是比较认可的预后指标,但对于具有异质性及多向分化潜能的肿瘤,用它们来估计预后仍是比较困难的事。近年来,神经内分泌分化(NED)对预后是否产生影响受到人们的关注。传统的观点认为只有类癌存在神经内分泌细胞,研究发现在前列腺癌、肺非小细胞癌中存在与肺小细胞癌相似的NED。这些伴NED的前列腺癌、肺非小细胞癌(NSCLC)在生物学行为上与其它肿瘤有很大的差别,其形态相似于肺的小细胞癌,但常伴有前列腺腺癌、肺腺、鳞癌的成分,这可能与患者的预后有关。本研究检测胃泌素释放肽前体31-98片段在前列腺癌、肺非小细胞癌组织中的表达,探讨NED对前列腺癌、肺非小细胞癌患者生存的影响方法:1.收集2002年6月至2007年12月手术切除前列腺癌标本60例,对有完整随访记录的43例采用免疫组织化学Polymer conjugate法检测胃泌素释放肽前体(Progrp31-98)、嗜铬素A(CgA)、神经特异性烯醇化酶(NSE)在前列腺癌中的表达,电镜观察前列腺癌神经内分泌分化颗粒。采用Spearman分析Progrp与Gleason分级的相关性。术后病例随访7-70个月。log-rank检验比较NED阳性与阴性患者术后总体生存率,Cox模型多因素分析影响患者预后显著因素。2.收集2003年1月至2008年6月手术切除肺非小细胞癌标本46例,其中鳞癌26例,腺癌20例,采用免疫组织化学Polymer conjugate法检测Progrp31-98片段、NSE及突触素(SYN)的表达,并分析三种标记物的表达与临床病理参数的关系,病例术后随访5-66个月。用log-rank法比较肺非小细胞癌神经内分泌分化阳性(NSCLC-NED)与阴性患者生存曲线间的差异。采用单因素分析肺非小细胞癌神经内分泌分化与患者术后生存的关系,统计分析均应用SPSS13.0统计软件包进行,以p<0.05为检验水准。结果:1.有完整随访资料的43例前列腺癌病例中Progrp阳性28例(65.1%) ,CgA阳性9例(20.9%),NSE阳性12例(27.9%)。两两比较χ~2检验Progrp分别与CgA、NSE比较差异有统计学意义(P <0.01、P <0.05),而NSE、CgA两者比较差异无统计学意义(P >0.05)。电镜观察到前列腺癌NED特异性颗粒18例(41.86%),其中14例与Progrp阳性表达一致,Progrp的阳性表达与前列腺癌Gleason积分呈正相关(r=0.30,P <0.05)。2.log-rank检验比较前列腺癌NED阳性与阴性患者术后总体生存率发现前列腺癌NED阳性者生存率明显低于NED阴性的患者(P <0.05)。Cox模型多因素分析表明前列腺癌NED阳性者术后生存时间明显缩短(P <0.05),生存时间与Gleason积分(P <0.05)、NED阳性密切相关(P <0.05),但与血清PSA水平、年龄无明显关系(P >0.05)。3. 46例N-SCLC中Progrp阳性率为47.8%(22/46),NSE阳性表达率为17.4%(8/46),SYN阳性表达率为23.9%(11/46),log-rank分析结果表明NSCLC-NED分化病例术后生存时间明显缩短(P <0.05),CoX模型单因素分析表明术后生存与肺癌细胞分化程度(P <0.05 )、病理分期(P <0.05)、NED表达有密切关系。结论:1. Progrp是检测前列腺癌NED、NSCLC-NED的敏感指标,有望用于患者预后判断。2.神经内分泌分化与Gleason积分和前列腺癌患者术后生存有关,是影响前列腺癌患者预后的独立因素。3.神经内分泌分化与肿瘤细胞分化和NSCLC患者术后生存有关,采用NED标志物标记肿瘤,对预后评估具有重要的参考意义,可作为临床判断患者预后指标之一。更多还原

【Abstract】 Background and Objective: Malignant tumor pathological grade and clinical stage were more recognized prognostic indicators, but with heterogeneous and multi-differentiati on potential of tumor, estimating the prognosis is still relatively difficult. In recent years, neuroendocrine differentiation (NED) have an impact on the prognosis. Traditional view believed that only the carcinoid had the neuroendocrine cells, the study found that in prostate cancer, non-small-cell lung carcinoma (N-SCLC) had existing NED, too. Prostate cancer, N-SCLC with NED had a lot of difference with the others in a variety of biological behavior of tumor. Its shape was equivalent to the small cell lung cancer, but had often accompanied the composition with prostate cancer, lung adeno-, squamous cell carcinoma ,which may be related to patient’s prognosis.In this study we evaluate the application of Progast rinreleasing peptide 31-98(Progrp 31-98)as a marker in the diagnosis of prostate cancer and N-SCLC, and observe the relationship between neuroendocrine differentiation and patients’postoperative survival.Methods: 1.During June 2002 to December 2007, patients with prostate cancer who were surgical treated were enrolled in this study. The tumor specimens were stained by NED markers : Progastrinreleasing peptide(Progrp31-98), neuron specific enolase(NSE) and chromogranin(CgA),These patients were positive for NED stain were also examined by electronmicroscope for the specific neuroendocrine granule. All enrolled patients were followed up to 7 months, and the maximum follow-up time was 70 months. Patients’postoperative survival for the NED positive expression and negative expression had been analyzed by the logistic analysis .The Cox proportional hazard model multivariate analysis was applied to observe the relationship among the prostate cancer with neuroendocrine differentiation and other prognostic factors .2. During January 2003 to June 2008, patients with non-small cell lung cancer who were surgical treated were enrolled in this study. To investigate the percent of neuroendocrine differentiation by NED markers: Progastrinreleasing peptide ( Progrp) 31-98 ,neuron specific enolase (NSE) and synaptophysin(SYN).All enrolled patients were followed up 5 - 66 months. The logistic analysis was applied to observe the NED positive expression and negative expression among the patients’postoperative survival. The Univariate Cox proportional hazard regression analysis was applied to observe the relationship among the non-small cell lung cancer with neuroendocrine differentiation and other prognostic factors .Results:1. In complete follow-up data of 43 cases,twenty -eight cases (28/43)were diagnosed as positive for NED stain. Among them ,65.1% (28/43) Progrp were positive ,20.9%(9/ 43) were CgA positive and 27.9%(12/43) were NSE positive .Progrp compared with CgA, NSE separately byχ2 test has statistically significant difference(P <0.01, P <0.05), the comparison between NSE and CgA was no significant difference (P >0.05). The specific NED granules were found by the electron microscope examination in 41.9 %(18/43) ,among them 14 cases are consistent with the Progrp positive expression.2. The logistic analysis showed that the prostate cancer with neuroendocrine differentiation patients’survival was significantly reduced (P<0.05).The Cox proportional hazard model multivariate analysis showed that the prostate patients’survival with neuroendocrine differentiation was significantly reduced (P <0.05) .The following factors were related to prostate patients’survival : the different Gleason score of the cancer (P <0.05) , and the NED markers reaction (P <0.05).No correlation with serum PSA and age of prostate cancer(P >0.05).3. Among forty-six N-SCLC cases ,47.8%(22/46) Progrp were positive ,23.9%(11/46)SYN were positive and 17.4%(8/46) NSE were positive.The logistic analysis was showed that the non-small cell lung cancer with neuroendocrine differentiation patients’survival was significantly reduced (P <0.05).The Cox proportional hazard model Univariate analysis was showed the following factors were related to the non-small cell lung cancer patients’survival: lung cancer cell differentiation (P <0.05),stages of the cancer (P <0.05 ),and the NED markers reaction(P <0.05) .Conclusion:1. Prostate cancer with neuroendocrine differentiation and the different Gleason score of the cancer are significantly related to the patients’postoperative survival.2.Progrp should be applied clinically as one of prognostic factors to evaluate the postoperative survival for prostate cancer patients.3.NSCLC-NED and the cancer cell differentiation are significantly related to the patients’postoperative survival. The NED markers should be applied clinically as one of prognostic factors to evaluate the postoperative survival for N-SCLC patients.更多还原