雄激素受体在膀胱尿路上皮癌中的表达及其临床意义

目的 观察雄激素受体(AR)在膀胱癌中的表达及其与临床病理特征的关系,探讨其临床意义.方法 采用免疫组织化学SP法检测AR蛋白在123例膀胱尿路上皮癌和18例正常膀胱黏膜中的表达.结果 AR蛋白的阳性表达主要定位于细胞核中,其在膀胱癌组织中阳性表达率为46.3%,在正常膀胱黏膜组织阳性表达率为5.6%,差异有统计学意义(P＜0.05).AR的表达率随着膀胱癌病理分级和临床分期的升高而增高(P＜0.05),而与年龄和性别无明显相关(P＞0.05),有淋巴结转移者AR表达率也显著升高(P＜0.05).结论 AR在膀胱癌组织中有广泛表达,且与膀胱癌的分化和浸润性进展密切相关,提示AR蛋白可能在膀胱癌的发生发展中起重要作用.     

雌激素受体-β在膀胱尿路上皮癌中的表达及其临床意义

目的 观察雌激素受体β(ER-β)在膀胱癌中的表达及其与临床病理特征的关系,探讨其临床意义.方法 采用免疫组织化学SP法检测ER-β蛋白在146例膀胱尿路上皮癌和25例正常膀胱黏膜中的表达.结果 ER-β蛋白在膀胱癌组织中阳性表达率为44.5%,在正常膀胱黏膜组织阳性表达率为20.0%,差异有统计学意义(P＜0.05).ER-β的表达率随着膀胱癌病理分级和临床分期的升高而增高(P＜0.05),而且与患者性别明显相关,女性阳性率显著高于男性患者(P＜0.05).结论 ER-β在膀胱癌组织中表达有明显的性别差异,且与膀胱癌的分化和浸润性进展密切相关,提示ER-β蛋白可能在膀胱癌的发生发展中起重要作用.

Abstract：

Objective To investigate the expression of estrogen receptor beta (ER-β) in bladder urothelial carcinoma and to explore its clinical significance.Methods Immunohistochemical SP method was employed to detected the expression of ER-β in bladder cancer tissue ( 146 cases) and the normal controls (25 cases).In addition,clinicopathological data of them were analyzed.Results The positive expression rate of ER-β in bladder cancer tissue was 44.5%,but low positive expression rate (20.0% )was found in normal bladder tissue.The expression of ER-β was markedly associated with tumor pathological grade and clinical stage ( P＜0.05).Moreover,the expression of ER-β was observed more frequently in female (59.6%) than male (37.4%) (P＜0.05 ).Conclusion The sex difference in expression of ER-β is associated with differentiation and invasion in bladder urothelial carcinoma,it implies that ER-β might play important roles in the development and progression of bladder cancer.     

PTEN基因和FHIT基因在膀胱尿路上皮癌中的表达和意义

目的 探讨磷酸酶和张力蛋白同源(phosphatase and tensin homolog,PTEN)基因及脆性组氨酸三联体(fragile histindine triad,FHIT)基因在膀胱尿路上皮癌组织中的表达水平及临床意义. 方法 采用免疫组织化学S-P法检测14例正常膀胱黏膜及37例膀胱尿路上皮癌组织中的PTEN及FHIT基因的表达水平. 结果 在14例正常膀胱组织中PTEN与FHIT基因均表达阳性或强阳性.在37例膀胱尿路上皮癌组织中PTEN 基因阳性表达率为56.8%(21/37),其中阳性9例,强阳性12例,FHIT基因阳性表达率为48.6%(18/37),其中阳性8例,强阳性10例.随着肿瘤分期、分级的增加PTEN和FHIT基因表达均显著减少;PTEN基因的表达与FHIT基因的表达呈正相关(P＜0.01). 结论 PTEN与FHIT基因可能成为估计膀胱尿路上皮癌恶性程度及肿瘤侵袭性的一项有用的指标,联合检测PTEN和FHIT基因在膀胱尿路上皮癌中的表达,有助于对膀胱肿瘤的细胞分化程度及诊断做出正确评价.     

膀胱尿路上皮癌中LRIG3基因的表达及其临床意义

目的：探讨富含亮氨酸重复序列和免疫球蛋白样多肽3（LRIG3）基因与膀胱尿路上皮癌（BUC）生物学行为的关系。方法：采用免疫组织化学SP法和逆转录-聚合酶链反应（RT-PCR）法检测64例膀胱尿路上皮癌组织和12例正常膀胱黏膜中LRIG3蛋白及mRNA的表达情况，并结合临床资料进行分析。结果：膀胱癌组织中LRIG3蛋白和mRNA的表达水平显著低于正常膀胱黏膜组织，且分级和分期越高，LRIG3蛋白和mRNA的表达水平越低。结论：LRIG3基因在膀胱癌组织中存在表达缺失和低表达，提示LRIG3基因在膀胱癌的发生发展中可能具有抑癌基因的作用，有可能成为肿瘤基因治疗的又一靶点。     

抑癌基因P16在膀胱肿瘤中的表达及意义

应用Ｓ－Ｏ５３例膀胱肿瘤中抑癌基因Ｐ１６进行了研究。结果显示：４９例膀胱移行细胞癌Ｐ１６表达的阳性率为４４．９０％，其阳性率在肿瘤的病理分级、临床分期及预后等方面差异有显著性。提示Ｐ１６在抑制膀胱肿瘤的发生、发展中起重要作用。     

MDM2、p53基因在膀胱癌中的表达及其临床价值

目的　探讨癌基因ＭＤＭ２ 和抑癌基因ｐ５３ 在膀胱癌中的表达及其临床价值。　方法　采用免疫组织化学方法对２３ 例膀胱癌标本进行检测。　结果　ＭＤＭ２ 、ｐ５３ 基因蛋白在肿瘤中阳性表达为３９ ％ 和４８ ％ ,与肿瘤分级分期,肿瘤复发性相关,两者异常表达呈负相关（ｒ＝ － ０ ．２ ９４６ ,Ｐ＜０ ．０５）。两者在癌旁组织中亦有一定表达率。　结论　ＭＤＭ２ 、ｐ５３ 基因的异常表达是膀胱癌中的基因事件,与膀胱癌发生发展密切相关,可作为临床判断肿瘤进展及可能预后的瘤标。     

自噬相关基因 LC3、Beclin-1与凋亡相关基因BCL-2在膀胱尿路上皮癌中的表达

目的 检测自噬相关基因LC3、Beclin-1与凋亡相关基因BCL-2在膀胱尿路上皮癌和膀胱正常组织中的表达情况,探讨其与膀胱尿路上皮癌发生、发展的相关性。 方法 应用免疫组化SP法检测10例正常膀胱组织及56例膀胱尿路上皮癌组织中LC3、Beclin-1及BCL-2 蛋白的表达水平,并结合临床病理因素进行分析。结果 LC3在膀胱癌的阳性表达率高于正常膀胱组织( P＜0. 05),且与膀胱尿路上皮癌的组织学分化程度及肿瘤分期相关( P ＜0. 05)。Beclin-1在膀胱尿路上皮癌组织中的表达高于正常膀胱组织( P ＜0. 05),且与膀胱尿路上皮癌的组织学分化程度相关（P＜0.01）。BCL-2在膀胱癌组织中的表达显著高于正常膀胱组织( P＜0. 01),且与膀胱尿路上皮癌淋巴结转移相关( P＜0. 05)。经Spearman秩相关检验,LC3蛋白、Beclin-1蛋白的表达均与BCL-2蛋白的表达呈正相关,相关系数分别为0.3436（P＜0. 05)和0.3593（P＜0. 01)。结论 在膀胱尿路上皮癌中,自噬活性的上调与凋亡能力的下调并存,自噬相关基因LC3、Beclin-1与凋亡相关基因BCL-2在膀胱尿路上皮癌的发生、发展中起协调作用,对其联合检测有助于判断膀胱尿路上皮癌的进展程度及患者的预后情况。     

MMP-9和CyclinE在膀胱尿路上皮癌中的表达及其临床意义

目的：探讨和CyclinE在膀胱癌组织和正常膀胱黏膜组织中的表达,并结合ll缶床病理特征进行分析。结果：MMP一9在膀胱癌组织中的阳性表达率为70．9％,显著高于正常膀胱黏膜中的阳性表达率11．1％,差异有统计学意义（P〈0．05）。MMP一9的表达与膀胱癌患者性别和年龄无关（P〉0．05）,与膀胱癌患者肿瘤的大小、肿瘤的多少以及肿瘤的恶性程度密切相关（P〈O．05）。CyclinE在膀胱癌组织和正常膀胱黏膜中的阳性表达率分别为64．6％和16．7％,差异有统计学意义（P〈O．05）。CyclinE的表达与膀胱癌的大小、肿瘤的多少以及肿瘤的病理分级和临床分期密切相关（P〈0．05）,与膀胱癌患者的年龄和性别无关（P〉0．05）。结论：MMP一9和CyclinE在膀胱癌组织中的表达均升高,提示它们共同参与了膀胱癌的发生和发展,MMP一9和CyclinE有协同表达关系。同时检测膀胱癌组织中MMP一9和CyclinE的表达对判断预后和指导治疗有一定意义。     

p73基因在膀胱尿路上皮癌中的表达及临床意义

目的研究p73基因在膀胱尿路上皮癌组织中的表达及其与临床病理特征的关系。方法应用免疫组织化学SP法检测60例膀胱尿路上皮癌中p73基因的表达,统计分析其与肿瘤临床病理特征的关系。结果膀胱癌组织中p73阳性表达率为38.3%（23/60）,明显低于癌旁组织（78.3%,47/60,P〈0.01）及正常膀胱组织（86.7%,13/15,P〈0.01）。p73蛋白的表达与膀胱尿路上皮癌组织分化程度有关（P〈0.05）,且与临床分期、浸润及转移也密切相关（P〈0.05）。结论p73基因在膀胱尿路上皮癌的发生和发展中起抑制作用,p73蛋白的表达可能是预判膀胱癌预后的重要指标之一。     

错配修复基因hMLH1在膀胱移行细胞癌中的表达及其意义

目的 观察错配修复基因hMLH1在膀胱移行细胞癌中的表达,探讨hMLH1与膀胱移行细胞癌的关系.方法 通过免疫组织化学方法 测定hMLH1在80例膀胱移行细胞癌中及20例正常膀胱组织中的表达.结果 hMLH1在膀胱移行细胞癌中的低表达率(32.5%)明显高于在正常膀胱组织中的低表达率(0%),差异有统计学意义(P＜0.05),且hMLH1在膀胱移行细胞癌中的低表达与肿瘤的分期分级有关(P＜0.05).结论 hMLH1的低表达与膀胱移行细胞癌的发生有关,与肿瘤的高分期和高分级有关,hMLH1的低表达在浸润性及分化差的膀胱移行细胞癌多见.     

FHIT及Ki67在膀胱尿路上皮癌中的表达及与意义

目的:观察FHIT及Ki67蛋白在膀胱尿路上皮癌组织中的表达及相关性。方法:采用免疫组织化SP法检测66例膀胱癌和42例正常膀胱组织中FHIT及Ki67蛋白表达情况,利用Spearman相关性分析对FHIT与Ki67蛋白进行相关性分析。结果:FHIT蛋白在正常膀胱组织中的阳性率为92.85%,在膀胱尿路上皮癌中的阳性表达率为39.39%;而Ki67则相反;在膀胱尿路上皮癌中的表达率为90.91%;在正常膀胱组织中表达率为11.90%;FHIT和Ki67蛋白的异常表达与膀胱尿路上皮癌临床分期、分化程度有关。Spearman相关性分析显示,FHIT与Ki67蛋白表达呈负相关。结论:联合检测FHIT和Ki67,有助于提高膀胱尿路上皮癌侵袭能力的评估,有助于膀胱尿路上皮癌临床预后判断。     

膀胱癌错配修复基因hMSH2表达的研究

目的 探讨错配修复基因hMSH2在膀胱移行细胞癌中的表达情况及其与肿瘤细胞增殖、凋亡的关系.方法 采用免疫组化法检测101例膀胱移行细胞癌错配修复基因hMSH2以及细胞增殖抗原Ki-67的表达情况,原位末端标记(TUNEL)法检测肿瘤细胞凋亡情况.结果 hMSH2表达于非膀胱肿瘤尿路上皮及部分膀胱移行细胞癌的细胞核,膀胱移行细胞癌组低表达率较非膀胱肿瘤膀胱组织组高(P=0.004,＜0.05);膀胱移行细胞癌pT2-pT4组中hMSH2的低表达率比pTis-pT1组的低表达率高(P=0.016,＜0.05);G1、G2、G3三组间低表达率的总体差别有统计学意义(P=0.033,＜0.05),G1+G2组与G3组之间差别有统计学意义(P=0.036＜0.05);有无淋巴结转移组差别无统计学意义(P=0.317).hMSH2弱表达组与强表达组间凋亡指数(AI)均值差异非常显著(P＜0.01),Ki-67标记指数(Ki-67 LI)均值差异不显著(P＞0.05),AI/KI值差异经统计学分析具有统计学意义(P＜0.05).结论 hMSH2基因突变或功能缺失与膀胱移行细胞癌的发生有关,可能系肿瘤发生过程中的重要事件,并可能与肿瘤细胞凋亡有关,而与增殖活性无关.     

错配修复基因hMLH1,hMSH2在肝门部胆管癌中的表达和意义

目的 检测肝门部胆管癌中错配修复基因hMLH1,hMSH2失表达情况,研究其与肝门部胆管癌临床特征的关系,并探讨其与预后的相关性.方法 用免疫组织化学技术检测54例肝门部胆管癌组织、25例正常胆管中hMLH1,hMSH2表达,结合临床病理学资料及随访统计资料进行统计学处理分析.结果 (1)在54例肝门部胆管癌组织中,hMLH1蛋白阳性表达24例,其阳性率44.4%;25例正常胆管组织中,hMLH1蛋白阳性表达23例,其阳性率92.0%;hMSH2蛋白癌组织阳性表达21例,其阳性率38.9%;hMSH2蛋白在正常胆管组织阳性表达21例,其阳性率84.0%.hMLH1,hMSH2在肝门部胆管癌组织中的表达明显减少,二者比较差异具有统计学意义(P＜0.05).(2)根据统计学检验,hMLH1,hMSH2表达与肝门部胆管癌Bismuth分型(P＞0.05)、病人性别(P＞0.05)、年龄(P＞0.05)、肿瘤大小(P＞0.05)无关,但与病理分级(P＜0.05)和淋巴结转移(P＜0.05)具有显著相关性.(3)hMLH1表达阴性组术后2年生存率明显低于表达阳性组(15%VS 45.4%,P＜0.05).hMSH2表达阴性组术后2年生存率明显低于表达阳性组(23.5%VS44%,P＜0.05).结论 hMLH1,hMSH2在肝门胆管癌中的失表达在肿瘤的发生、发展及转移中起重要作用,是判断预后有价值的指标.     

膀胱移行细胞癌中DNA错配修复基因hMLH1、hMSH2和hMSH3启动子区甲基化状态研究

目的探讨DNA错配修复基因启动子区CpG岛甲基化状态及其在膀胱移行细胞癌（BTCC）中的表达。方法应用MSP技术检测膀BTCC中hMLH1、hMSH2和hMSH3基因启动子区甲基化状态,RT-PCR法检测其mRNA表达水平。结果36例BTCC组织中hMSH1、hMSH2的甲基化阳性率分别为38.9％（14／36）、52.8％（19／36）,所有标本中均未发现有hMSH3启动子甲基化。hMLH1、hMSH2、hMSH3 mRNA在BTCC中表达率分别为47.2％（17／36）、38.9％（14／36）、16.7％（6／36）,在正常组织中分别为22.2％（8／36）、63.9％（23／36）、0％（0／36）,差异均有统计学意义（P〈0.01）,并且随肿瘤病理分级的增加呈下降趋势（P〈0.05）,均与临床分期不相关（P〉0.05）。结论hMLH1、hMSH2和hMSH3基因启动子异常甲基化可能导致该基因转录表达失活,使其mRNA表达减少甚至缺失,这可能是导致BTCC发生、发展的原因之一。     

Papillary Urothelial Bladder Carcinoma Associated with Osteoclast-Like Giant Cells

We report the case of a papillary urothelial carcinoma associated with osteoclast-like giant cells. A 60-year old woman presented with hematuria. A papillary neoplasm was detected by cystoscopy and removed transurethrally. Histological examination revealed a papillary urothelial carcinoma (grade I) associated with multiple stromal giant cells, which displayed morphological, ultrastructural and immunohistochemical characteristics of osteoclast-like giant cells. The formation of osteoclast-like giant cells in association with urothelial bladder carcinoma is a rare event, of which only six cases have been reported in the Anglo-American literature. It may cause diagnostic problems because primary giant cell tumor, giant cell carcinoma and foreign body stromal reaction have to be considered. Immunohistochemistry and electron microscopy may help to rule out these differential diagnoses.     

ICUD-EAU International Consultation on Bladder Cancer 2012: Radical Cystectomy and Bladder Preservation for Muscle-Invasive Urothelial Carcinoma of the Bladder

Context

New guidelines of the International Consultation on Urological Diseases for the treatment of muscle-invasive bladder cancer (MIBC) have recently been published.

Objective

To provide a comprehensive overview of the current role of radical cystectomy (RC) in MIBC.

Evidence acquisition

A detailed Medline analysis was performed for original articles addressing the role of RC with regard to indication, timing, surgical extent, perioperative morbidity, oncologic outcome, and follow-up. The analysis also included radiation-based bladder-preserving strategies.

Evidence synthesis

The major findings are presented in an evidence-based fashion and are based on large retrospective unicenter and multicenter series with some prospective data.

Conclusions

Open RC is the standard treatment for locoregional control of MIBC. Delay of RC is associated with reduced cancer-specific survival. In males, standard RC includes the removal of the bladder, prostate, seminal vesicles, and distal ureters; in females, RC includes an anterior pelvic exenteration including the bladder, entire urethra and adjacent vagina, uterus, and distal ureters. A procedure sparing the urethra and the urethra-supplying autonomous nerves can be performed in case of a planned orthotopic neobladder. Further technical variations (ie, seminal-sparing or vaginal-sparing techniques) aimed at improving functional outcomes must be weighed against the risk of a positive margin. Laparoscopic surgery is promising, but long-term data are required prior to accepting it as an option equivalent to the open procedure. Lymphadenectomy should remove all lymphatic tissue around the common iliac, external iliac, internal iliac, and obturator region bilaterally. Complications after RC should be reported according to the modified Clavien grading system. In selected patients with MIBC, bladder-preserving therapy with cystectomy reserved for tumor recurrence represents a safe and effective alternative to immediate RC.     

Comprehensive Assessment of Immuno-oncology Biomarkers in Adenocarcinoma,Urothelial Carcinoma,and Squamous-cell Carcinoma of the Bladder

BackgroundIn patients with rare histologies of bladder cancer, including adenocarcinoma of the bladder (ACB) and squamous-cell carcinoma (SCC), there are limited standard therapy options, defining an unmet medical need.ObjectiveIn this comparative comprehensive genomic profiling (CGP) study, genomic alterations (GAs), and immuno-oncology (IO) biomarkers have been analyzed.Design, setting, and participantsWithin the Foundation Medicine database, 143 cases with centrally reviewed pure ACB, 2142 with pure urothelial carcinoma (UC), and 83 with pure SCC were subjected to CGP. All patients developed advanced disease following a primary diagnosis of bladder cancer.InterventionCGP using a hybrid capture–based assay and immunohistochemistry (IHC).Outcome measurements and statistical analysisTumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA, and microsatellite instability (MSI) was determined on 114 loci. Programmed cell-death ligand-1 (PD-L1) expression was determined by IHC (Ventana SP-142 assay), with >1% tumor cells (TCs) or tumor-infiltrating lymphocytes (TILs) scoring positive.Results and limitationsPure ACB patients were younger and more often female than pure UC and pure SCC patients. UC and SCC had a significantly higher median TMB than ACB (p < 0.001). Rare CD274 (PD-L1) amplification cases were more frequently seen in SCC than in UC (5% vs 1%), and were not seen in ACB. MSI high status was very uncommon in all tumor types (0–1%). The frequencies of PD-L1 expression in both TCs and TILs was higher in UC and SCC (both 30%) than in ACB (18%). The results are limited by their retrospective nature and lack of clinical data annotation.ConclusionsDeep sequencing revealed significant differences in IO biomarkers among the three major subtypes of bladder carcinomas. UC and SCC revealed higher frequencies of PD-L1 expression and higher TMB than ACB, and SCC has the highest frequency of CD274 amplification. The presence of pure SCC features should not disqualify patients for inclusion in IO trials.Patient summaryTumor samples from patients diagnosed with advanced pure adenocarcinoma of the bladder (ACB) or pure squamous-cell carcinoma (SCC) have been analyzed in terms of frequency of putative immunotherapy biomarkers. The results indicated that pure SCC of the bladder was characterized by genomic features that portend similar response possibilities to immunotherapy compared with the classical pure urothelial carcinoma. Conversely, for pure ACB there might be different therapeutic opportunities, such as targeted therapies against peculiar genomic alterations in selected patients.     

膀胱移行细胞癌EGFr的表达与预后相关性的研究

应用免疫组织化学方法对50例膀膛移行细胞癌中表皮生长因子受体(EGFr)表达进行研究。50例中EGFr表达阳性率为44％(22/50)。结果表明:浸润性肿瘤EGFr的阳性表达明显高于浅表性肿瘤;复发性肿瘤EGFr的阳性表达显著增高。结论;膀胱移行细胞癌EGFr的阳性表达与肿瘤临床分期和复发有相关性(P<0.05)。     

膀胱癌患者Ⅱ型环氧合酶和血管内皮生长因子的表达及意义

目的:探讨Ⅱ型环氧合酶(Cox-2)和血管内皮生长因子(VEGF)的表达与膀胱移行细胞癌(BTCC)生物学行为的关系。方法:应用免疫组化方法对139例BTCC以及36例正常膀胱组织中的Cox-2和VEGF进行检测。结果:Cox-2的阳性率在T_(a～1)和T_(2～4)分别为34.3%和75.0%(P0.001);Ⅰ级和Ⅲ级的表达率分别为33.9%和81.8%(P0.001)。VEGF的阳性表达率在T_(a～1)和T_(2～4)分别为23.9%和79.2%(P0.001);Ⅰ级和Ⅲ级的表达率分别为32.2%和84.8%(P0.001)。BTCC组织中COX-2与VEGF表达呈正相关(r=0.607,P0.05)。结论:Cox-2和VEGF可以作为了解BTCC生物学行为的有效指标。