表浅性膀胱移行细胞癌中p53和Bcl-2同时表达的临床意义

目的 :探讨表浅性膀胱移行细胞癌中Bcl 2和 p5 3的同时表达与膀胱癌预后之间的关系。 方法 :应用免疫组化技术 (SABC法 )检测 4 2例表浅性膀胱癌蜡块标本中Bcl 2和p5 3的表达。患者术后平均随访 36个月 ,14例复发 ,其中复发 2次以上 9例 ,有转移者 4例。结果 :4 2例中 ,31例 (73.8% ) p5 3阳性表达 ,与G1(6 2 .5 % )和G2 (72 .2 % )相比较 ,G3 (81.2 % )更多见 ;pT1期 (78.6 % )p5 3阳性率较 pTa期 (6 4 .3% )高。 12例(2 8.6 % )发现有Bcl 2表达 ,Bcl 2表达阳性率G3 (37.5 % )明显高于G2 (2 2 .2 % )和G1(2 5 .0 % ) ,与分期无关 (P>0 .0 5 )。膀胱癌复发率p5 3基因表达阳性者高于阴性者 (P <0 .0 5 ) ,而Bcl 2基因表达阳性者与阴性者的差别无统计学意义 (P >0 .0 5 ) ,但 p5 3和Bcl 2同时呈阳性表达者 (8例 )明显高于其他患者 (P <0 .0 1)。Bcl 2和p5 3的阳性表达与肿瘤侵袭性和淋巴结及远处转移有关。结论 :p5 3和Bcl 2同时阳性表达的肿瘤患者预后较差 ,两者同时检测对判断膀胱癌复发及预后更具有指导意义。     

成纤维细胞生长因子受体3及p53蛋白表达与膀胱癌预后关系的研究

目的 探讨膀胱癌组织中成纤维细胞生长因子受体3(FGFR3)、p53蛋白表达及与膀胱癌预后的关系.方法 免疫组织化学法检测108例膀胱癌组织和8例正常膀胱黏膜中FGFR3和p53的表达.膀胱癌患者中男60例,女48例.年龄29～87岁.TNM分期Ta～T164例、T2～T4 44例.病理分级G130例,G249例、G329例.结合临床资料分析其与膀胱癌分期、分级、复发的相关性.Kaplan-Meier法和Cox回归分析法进行生存分析. 结果 108例膀胱癌组织FGFR3阳性表达59例(54.6%),其中Ta～T1肿瘤阳性表达率75.0%,T2～T425.0%;G1 70.0%、G2 57.1%、G334.5%;p53阳性表达48例(44.4%),其中Ta～T1 25.0%、T2～T4 72.7%;G1 36.7%、G2 34.7%、G369.0%.8例正常膀胱黏膜组织FGFR3、p53表达均为阴性.组间差异均有统计学意义(P＜0.01).Spearman等级相关分析表明FGFR3与p53表达不相关(P＞0.05).Kaplan-Meier法结果表明FGFR3阳性表达组较阴性表达组、p53阴性表达组较阳性表达组有较长的复发间期(P＜0.05).单因素Cox回归分析显示FGFR3表达缺失和p53过度表达与肿瘤分级分期显著相关(P＜0.05).多因素Cox回归分析表明,p53表达是膀胱癌预后的独立影响因素(OR=0.59,P=0.04).结论膀胱肿瘤组织中FGFR3蛋白过度表达及p53蛋白表达缺失提示患者预后较好.     

c-FLIP及突变p53蛋白表达与膀胱癌预后关系的研究

目的研究膀胱癌中细胞型Fas相关死亡域样白介素-1β转换酶抑制蛋白（c-FLIP）、突变p53蛋白的表达与膀胱癌预后的关系。方法采用免疫组织化学方法测定82例膀胱癌组织和10例正常膀胱黏膜中c-FLIP和突变p53蛋白的表达。膀胱癌患者中,男66例,女16例,年龄45～90岁。2002年TNM分期Ta～T129例、T2～T453例。WHO1973年病理分级G1级12例、G2级41例、G3级29例。结合临床资料分析其与膀胱癌分期、分级、复发的相关性。采用SPSS 13.0软件包分析其表达与肿瘤组织学性状的关系以及对患者预后的影响。结果82例膀胱癌组织中c-FLIP的阳性表达率为62.2%（51/82）,其中Ta～T1肿瘤阳性表达率为37.9%,T2～T4肿瘤阳性表达率为75.5%;突变p53蛋白的阳性表达率为45.1%（37/82）,其中Ta～T1肿瘤阳性表达率为24.1%,T2～T4肿瘤阳性表达率为56.6%。10例正常膀胱黏膜中c-FLIP和突变p53蛋白的表达均为阴性。c-FLIP与p53蛋白在不同的分期组间阳性表达差异均有统计学意义（P〈0.05）;生存分析发现c-FLIP与突变p53蛋白表达对生存具有明显影响（P〈0.05）。结论c-FLIP与突变p53蛋白对评价膀胱癌的侵袭性和预后都是一个重要的独立因素。膀胱肿瘤组织中的c-FLIP及突变p53蛋白表达缺失提示患者预后较好。     

p21~(WAF1)和p53基因在胆管癌组织中的表达研究

目的　探讨p2 1WAF1、p5 3基因与胆管癌发生发展的关系。方法　采用免疫组化方法 ,检测 48例胆管癌和 8例伴慢性炎症的胆管壁组织中p2 1WAF1、p5 3蛋白表达情况。结果　胆管癌中p2 1WAF1、p5 3阳性表达率分别为 2 5 %和 5 4% ,而伴炎症的胆管组织阳性表达率分别为 88%和 0。p2 1WAF1蛋白表达与胆管癌的分化程度、有无淋巴结转移或远处转移以及TNM分期呈显著相关性 ;而p5 3则与这些指标无关 ,与p2 1WAF1蛋白表达无相关性。结论　胆管癌的发生发展可能与p2 1WAF1、p5 3等多基因表达异常有关 ,p2 1WAF1基因异常表达是衡量胆管癌恶性行为的有用指标     

p53,CD34,E-钙粘蛋白在膀胱癌中的表达及判断预后的价值

目的　探讨 p5 3、CD3 4 、E 钙粘蛋白 (E cadherin)在膀胱移行细胞癌中的表达及判断膀胱癌预后的价值。　方法　采用免疫组化方法检测 4 6例膀胱移行细胞癌和 8例正常膀胱粘膜标本p5 3、CD3 4 、E cadherin的表达情况。　结果　 4 6例膀胱癌标本中p5 3、E cadherin的异常表达率分别为2 1.7%和 4 5 .6 %。p5 3异常表达在表浅型膀胱癌为 9.1% ,浸润型为 33.3% ,差别有显著性意义 (P <0 .0 5 ) ;病理Ⅰ～Ⅱ级异常表达 7.1% ,Ⅲ级 4 4 .4 % ,差别有显著性意义 (P <0 .0 0 5 ) ;复发组异常表达89 % ,未复发组 15 % ,差别有显著性意义 (P <0 .0 0 5 )。E Cadherin的异常表达率在浅表型膀胱癌为77.3% ,浸润型为 33.3% ,差别有显著性意义 (P <0 .0 0 5 ) ;在Ⅰ、Ⅱ级膀胱癌为 71.4 % ,Ⅲ级为2 7.8% ,差别有显著性意义 (P <0 .0 0 5 ) ;在复发组与未复发组分别为 18.0 %和 6 1.0 % ,差别有显著性意义 (P <0 .0 1)。CD3 4 在膀胱癌中的异常表达率为 4 1.3% ,在不同分期分级及复发与未复发组之间的表达差别均无显著性意义。　结论　p5 3和E Cadherin的异常表达与膀胱癌的恶性程度及复发密切相关 ,可作为判定肿瘤预后和复发的分子生物学指标     

膀胱癌组织中nm23蛋白和p53蛋白的表达及其意义

目的　探讨肿瘤抑制基因nm2 3、p5 3蛋白在膀胱癌组织中的异常表达及其与肿瘤病理分级、浸润程度和淋巴结转移等肿瘤的病理特征的关系。方法　应用免疫组织化学ABC方法检测 4 0例膀胱癌组织标本中nm2 3、p5 3蛋白的表达水平。 结果　膀胱癌组织中nm2 3和 p5 3蛋白表达的阳性率分别为 5 0 .0 %和 4 7.3%。nm2 3蛋白表达与病理分级和浸润程度呈正相关 ,而与膀胱癌的淋巴结转移呈负相关 (P <0 .0 5 )。p5 3蛋白表达与膀胱癌的浸润程度和分化程度呈正相关 ,而与肿瘤的淋巴结转移无关(P >0 .0 5 )。结论　nm2 3、p5 3蛋白的表达在膀胱癌的浸润转移中起重要作用 ,p5 3表达与膀胱癌组织浸润、分化程度有关 ,膀胱癌的淋巴结转移可能与多基因异常改变有关。     

膀胱癌p53蛋白核蓄积的临床意义

为探讨不同病理分期膀胱癌p53蛋白核蓄积与肿瘤恶性进展的关系．采用免疫组织化学方法检测122例获随访结果的膀胱癌患者的p53表达，用多变量相关分析，Logistic回归分析和Kaplan-Meier法分析。发现p53蛋白核反应与肿瘤临床病理分期及淋巴结转移呈正相关(P=0.003)；Kaplan—Meier生存分析显示肿瘤局限于膀胱内(P1，P2和P3a)，p53蛋白阳性染色者复发率显著高于阴性者，5年生存率明显低于阴性者。本研究证明p53蛋白核蓄积表示肿瘤呈恶性进展，病人预后较差。     

VEGF,p53,P21WAF/CIP1和C-myc蛋白表达与肝细胞癌预后关系的研究

目的：探讨肝细胞癌（HCC）中VEGF,p53,p21WAF/CIP1和C-myc蛋白表达的情况及其与肝癌预后的关系。方法：用MaxvisionTM免疫组化法,检测61例HCC组织及其中52例癌旁组织VEGF,突变型p53,p21WAF/CIP1和C-myc蛋白的表达,观察相应的临床病理指标并进行统计学分析。结果：61例肝癌标本中,VEGF,p53,p21WAF/CIP1和C-myc蛋白阳性表达率分别为60.7%(37/61),39.3%(24/61),21.3%(13/61)和39.3%（24/61）;52例癌旁组织中上述4种蛋白阳性表达率依次为：38.5%(20/52),0%(0/52),5.8%(3/52)和59.6%（31/52）。两种组织中4种蛋白阳性表达率差异均有显著性(P<0.05)。肝癌组织中VEGF,p53蛋白表达与肿瘤门静脉癌栓的发生存在明显相关(P<0.05);Kaplan—Meier法生存分析发现VEGF,p53蛋白阳性表达患者肿瘤术后复发时间明显早于阴性表达者;多因素分析显示,肿瘤细胞分化、癌栓形成、VEGF及p53蛋白表达是HCC术后复发的风险因素。结论：肝癌组织中VEGF和p53蛋白的异常表达与肝癌的预后密切相关,可作为肝癌预后判断的参考指标。     

T1G3膀胱尿路上皮癌预后评估系统的建立

目的 统计分析T1 G3膀胱尿路上皮癌复发、进展、死亡的预后风险因素,尝试制订相对客观准确的预后评估模型.方法 收集1998年1月至2006年10月诊断为T1 G3膀胱尿路上皮癌患者187例,回顾患者临床资料,进行临床流行病学调查并随访患者预后情况.187例患者的石蜡标本分别进行p53、成纤维细胞生长因子受体3(FGFR3)、E-钙黏素、CD-34标记的微血管密度(MVD)、增殖细胞核抗原(Ki-67)免疫组化染色,分析其表达情况.寿命表法估算本组患者复发、进展及死亡各时点的累积概率.纳入年龄、性别、出现症状到就诊时间、肾积水、手术方式、术后即刻灌药、膀胱灌注药物种类、肿瘤最大径、肿瘤数量、肿瘤形态、原位癌、复发次数、初次复发时间≤6个月、p53、FGFR3、E-钙黏素、MVD计数、Ki-67共18个因素作为拟评估的预后风险因素,分别进行肿瘤复发、疾病进展、死亡的Kaplan-Meier单因素及Cox多因素生存分析.得到T1 G3膀胱尿路上皮癌预后最佳比例风险模型后,以各预后因素的偏回归系数作为风险积分权重,计算得到T1 G3膀胱尿路上皮癌复发、进展的预后评估积分系统.结果 本组患者随访12 ～111个月(中位随访时间39个月).随访期内肿瘤复发100例(53.5％),进展61例(32.6％),死亡37例(19.8％).本组患者1、2、3、5年肿瘤复发率分别为35.0％、60.0％、63.0％、65.0％;1、2、3、5年疾病进展率分别为12.0％、27.0％、34.0％、38.0％;1、2、3、5年死亡率分别为0、11.0％、17.0％、26.0％.肿瘤最大径、肿瘤数量、即刻灌注、初次复发时间≤6个月、p53、FGFR3是T1 G3膀胱尿路上皮癌复发的危险因素,计算患者复发风险总积分并分为-3 ～6、7～19、20～32三组,其1年复发率分别为3％、35％、81％,5年复发率分别为20％、65％、100％.肿瘤形态、原位癌、初次复发时间≤6个月、复发次数、p53、E-钙黏素是T1 G3膀胱尿路上皮癌进展的危险因素,计算患者疾病进展风险总积分并分为6 ～ 14、15 ～ 23、24～30三组,其1年进展概率分别为2％、19％、56％,2年进展概率分别为7％、33％、88％.肿瘤进展是患者死亡的危险因素(RR= 324.70,95％ CI:9.848 ～ 10707.800).结论 根据T1 G3膀胱尿路上皮癌肿瘤复发、疾病进展的各项风险因素定量计算各因素对预后的影响,为T1G3膀胱尿路上皮癌预后评估模型的建立做了初步尝试,有利于为T1G3膀胱尿路上皮癌患者的个体化治疗提供决策依据.     

膀胱癌转化生长因子β1过表达的临床意义

目的　探讨膀胱移行细胞癌TGFβ1蛋白及mRNA异常表达的临床意义。 　方法　采用SP法检测 74例膀胱癌组织中TGFβ1蛋白的表达 ;QRT PCR方法检测 43例膀胱癌TGFβ1mRNA转录水平。　结果　膀胱癌TGFβ1蛋白表达阳性率为 89.2 % ,T2 ～T4 浸润性膀胱癌TGFβ1过表达率为 83.8% ,明显高于Ta～T1表浅性膀胱癌 (33.3% ) ,P <0 .0 5 ;复发转移组 30例中TGFβ1过表达 2 9例 ,而无瘤存活组 44例中过表达 30例 ,P <0 .0 0 5 ;膀胱癌组织TGFβ1mRNA含量明显高于正常膀胱组织。　结论　TGFβ1过表达与膀胱癌浸润生长方式和预后等有密切关系 ,可能成为评价膀胱癌预后的有效指标之一。     

Prognostic significance of histopathological grading and immunoreactivity for p53 and p21/WAF1 in grade 2 pTa transitional cell carcinoma of the urinary bladder

OBJECTIVE: At present, there are no predictors of tumour behaviour for grade (G) 2 pTa transitional cell carcinomas (TCC) of the bladder. Here we analyse the prognostic relevance of histopathological grading and the immunohistochemical detection of p53 and p21/WAF1. METHODS: 70 patients were newly diagnosed with G2 pTa TCC of the bladder based on transurethral resection specimens. Two pathologists, blinded with respect to the clinical outcome, confirmed the initial grade and subclassified the G2 lesions into G2a and G2b carcinomas based on the degree of nuclear atypia and the number of mitoses. Immunoreactivity for p53 and p21/WAF1 was evaluated semiquantitatively. RESULTS: There were 52 G2a and 18 G2b tumours, mean follow-up was 49.2 months. Of all patients, 31.4% remained tumour-free, 48.6% recurred with the same tumour grade and stage, and 20.0% showed tumour progression. Patients with G2a tumours developed tumour progression in 13% in contrast to 39% with G2b lesions (p = 0.037). Of 21 p53-positive tumours, 33% (7/21) developed progressive disease, whereas 14% (7/49) of p53-negative patients showed tumour progression (p = 0.102). Neither p21/WAF1 expression alone nor the combination of p53 and p21/WAF1 correlated with clinical outcome. CONCLUSION: The more detailed grading system but not p53 or p21/WAF1 immunohistochemistry was found to be an independent prognostic factor for tumour progression.     

p53 expression predicts progression and poor survival in T1 bladder tumours

OBJECTIVES: Histological grade (G) is the only parameter proved to have prognostic value for progression in T1 transitional cell carcinoma (TCC) of the bladder, although it is considered inaccurate to make clinical decisions on individuals. The aim of the present study was to evaluate the prognostic relevance of p53 expression in T1 TCC of the bladder. METHODS: Clinical records of 207 patients with T1 TCC of the bladder were reviewed for clinical parameters reported to influence the evolution of superficial bladder cancer. Among these 207 patients, 40 developed muscle-invasive disease (20 G2 and 20 G3). A retrospective case-control study was then carried out comparing the latter 40 tumours with 40 control tumours matched by grade, sex, age, number and size of the tumours, chemical exposure and presence of carcinoma in situ. p53 immunostaining with monoclonal antibody was performed in these two groups. RESULTS: Histological grade was the only clinical parameter that influenced evolution. p53 expression correlated with tumour progression, since it was observed in 21 out of 24 p53-positive tumours and in only 20 of 56 p53-negative tumours (p<0.0001), showing a specificity of 93. 5% and a sensitivity of 53%. p53 expression correlated as well with patient survival, being 39% in patients with p53-positive tumours and 80% in patients with p53-negative tumours at 60 months (p<0. 0001). CONCLUSIONS: p53 protein expression has prognostic value for survival and progression in T1 bladder tumours and can be used for early detection of poor-prognosis T1 bladder tumours.     

p53, p21 and mdm2 expression vs the response to radiotherapy in transitional cell carcinoma of the bladder

OBJECTIVE: To identify, in a retrospective study, possible molecular markers predictive of radioresponsiveness in patients with transitional cell carcinoma (TCC) of the bladder. PATIENTS AND METHODS: Patients with T2-T4a TCC treated with preoperative radiotherapy and cystectomy were included in the study if their cystectomy specimen was pT3b (in 42) or pT0 (in 17). Because treatment schedules changed over time, radiotherapy was given either as 2 Gy x 23 over 4-5 weeks with cystectomy 4-5 weeks later (in 23), or as 4 Gy x 5 during 1 week with cystectomy in the following week (in 36 patients). Protein expression of p53, mdm2 and p21 (CDKN1 A/WAF1/CIP1/SDI1) was assessed immunohistochemically in biopsies taken before radiotherapy. RESULTS: There was no difference in protein expression when comparing all patients with pT0 and pT3b. However, for patients receiving 46 Gy, increased p53 expression (but not p21 or mdm2) predicted the absence of residual tumour (P = 0.005): six of seven patients with > 50% p53 expression had pT0 in the cystectomy specimen, whereas 10 of 12 patients with < or = 5% expression had pT3b. Over-expression of p53 correlated with longer overall (P = 0.045) and cancer-specific survival (P = 0.020). CONCLUSION: The expression of mdm2 or p21 did not predict radioresponsiveness in patients with TCC of the bladder. The role of p53 remains unclear; the view that p53 over-expression confers radioresistance in bladder cancer is not supported.     

T1G3 bladder cancer--indications for early cystectomy

OBJECTIVES: To review our experience with early radical cystectomy in patients with T1G3 Transitional Cell Carcinoma of bladder (TCC). PATIENTS AND METHODS: Thirty patients, who underwent early radical cystectomy over a 10-year period for clinical stage T1G3 TCC bladder, were studied. Of these 21 (70%) had radical cystectomy without treatment with intravesical chemo/immunotherapy. The number of tumours, presence or absence of Carcinoma In-Situ (CIS) and the pathological stage of the cystectomy specimen were recorded in each patient. Disease specific survival was determined in the subgroups using Kaplan-Meier estimates. RESULTS: Seventeen patients underwent radical surgery for a single tumour without concomitant CIS (Group A). The other 13 had multiple tumours with or without concomitant CIS or a single tumour with CIS (Group B). The disease was upstaged after cystectomy in 1 (6%) patient in Group A compared to 7 (55%) in Group B, (p = 0.009). Nine (53%) had pT0 disease in Group A compared to 0% in Group B, (p = 0.0017). The 5-year cancer specific survival rates were 92% in Group A and 82% in Group B. CONCLUSIONS: In patients with multiple T1G3 tumours with or without associated CIS, or in those with single T1G3 tumour with associated CIS the incidence of the disease being already muscle invasive at the time of clinical diagnosis is 55%. Early radical cystectomy should be advocated in this group. Conversely, for a single T1G3 tumour without associated CIS, conservative bladder preserving strategy with immuno-chemotherapy and close surveillance is justified.     

Growth inhibitory effect of p21 and p53 containing adenoviruses on transitional cell carcinoma cell lines in vitro and in vivo

Altered p53 expression has been demonstrated in the majority of advanced transitional cell carcinoma (TCC) of the bladder tumors. The objective of this investigation was to examine the effect of the introduction of a p53 or p21^(WAF1/CIP1) adenovirus on the proliferation and apoptosis of various human TCC cell lines in vitro and in vivo. Proliferation was measured by ³H-thymidine incorporation. Apoptosis was measured by DNA fragmentation and bax expression. We also examined the effect of ex vivo introduction of the p21^(WAF1/CIP1) or the p53 gene on growth of the T24 TCC cells and UMUC-3 TCC cells introduced subcutaneously into athymic nude mice. We found that although the effect of the p21-adenovirus on the proliferation of various TCC lines varied with each individual cell line, there was a substantial growth inhibition observed (greater than 80% growth inhibition) in seven of the eight TCC cell lines at the highest viral dosage. In contrast, after 24 h, the highest dosage of the p53-adenovirus produced only a heterogeneous decrease in proliferation compared to the highest dose of the p21^(WAF1/CIP1)-adenovirus (40–90%). In ex vivo experiments, no tumors were found in nude mice injected subcutaneously with either TCC cell line exposed in vitro to the AdSCMV-p21^(WAF1/CIP1) or AdSCMV-p53 viruses before three weeks. There was a threefold decrease in tumor square area at week 5 in the Ad5CMV-p21^(WAF1/CIP1) or Ad5CMV-p53 TCC cells injected mice (p<0.001, p<0.009) compared to either mock or Ad5CMVLacZ TCC bladder tumor cells. These data suggest that significant portion of the effect of altered p53 on TCC phenotype may be mediated through the p21^(WAF1/CIP1) pathway. Thus, the restoration of p21^(WAF1/CIP1) function in this tumor system may be a beneficial therapeutic strategy.     

Prospective evaluation of p53 as a prognostic marker in T1 transitional cell carcinoma of the bladder

OBJECTIVE: To prospectively evaluate p53 overexpression as a predictor of survival in patients with a first diagnosis of T1 transitional cell carcinoma (TCC) of the bladder, as several reports implicate p53 as an important prognostic marker for progression and survival, but all previous studies were retrospective, giving conflicting and irreproducible results, rendering inappropriate any attempt at integrating p53 into clinical decision-making. PATIENTS AND METHODS: Patients with a first diagnosis of T1 TCC of the bladder were enrolled; p53 overexpression was assessed by immunohistochemistry (IHC) using both monoclonal antibody 1801 and DO7. The pathological stage and IHC score were assigned by one pathologist, and the markers were scored categorically. RESULTS: Of the 89 patients who were evaluable, 53 had p53-positive tumours. The median follow-up for the survivors was 52 months. Eighty-two patients had high-grade tumours, using the World Health Organisation/International Society of Urological Pathology 1998 grading system. Fifty-eight patients had unifocal tumours and 34 had associated carcinoma in situ. The 3 year and 5 year overall survival rates were 81% (95% Cl: 73%, 90%) and 68% (95% Cl: 56%, 80%) respectively. The 3 year and 5 year disease specific survival rates were 87% (95% Cl: 79%, 94%) and 79% (95% Cl: 70%, 89%) respectively. There was no difference in disease-specific survival between patients with and without p53 over expression (p=0.56) [corrected] CONCLUSIONS: p53 tissue typing by IHC in a prospective cohort of patients with T1 bladder cancer was not clinically useful as a prognostic marker in a contemporary series of T1 tumours.     

p53 and bcl-2 overexpression as associated risk factors in patients 40 years old or less with transitional cell carcinoma of the bladder.

OBJECTIVES: Transitional cell carcinoma (TCC) of the bladder in younger patients has historically a favourable prognosis. bcl-2 and p53 genes are implicated in cell cycle regulation with roles on programmed cell death. Presence of nuclear accumulation of p53 and cytoplasmic accumulation of bcl-2 were proposed to confer a growth advantage to tumour cells. In this study, we investigated the roles of p53 and bcl-2 as prognostic factors in TCC of bladder in patients younger than 40 years. Patients and METHODS: From 1986 to 1998, 25 patients younger than 40 years were treated for TCC of bladder in our hospital. Of the tumour specimens, 24 were adequate for evaluating p53 and bcl-2 oncoproteins (group I). As a control (group II), we randomly selected 30 patients older than 50 years treated for bladder cancer in this period. Two oncoproteins were detected by immunohistochemical analysis in paired tumour tissue specimens in both groups. Retrospectively obtained clinical follow-up data were available, with a mean follow-up of 44 and 25.5 months in groups I and II, respectively. Relations between tumour recurrences and progression with positivity of bcl-2 and p53 were investigated. RESULTS: Expression of bcl-2 was observed in 13 (54.1%) and 11 (36.7%) and nuclear p53 accumulation in 9 (37.5%) and 17 (56.7%) of groups I and II, respectively. In the presence of p53 expression, tumours showed significantly more progression in group I (55 vs. 6.7%) and group II (41.1 vs. 0%). Recurrence rates were not significantly different in tumours with and without nuclear p53 overexpression in both groups. Also, recurrence and progression rates were not significantly different in tumours with and without cytoplasmic bcl-2 overexpression in both groups. Grade (G) and stage appeared as important prognostic factors in both groups since 60% of GIII tumours showed progression in group I, but none of GI and GII tumours. Similarly, 75% of T3 tumours progressed, while these rates were 25 and 25% for T1-T2 tumours in group I. In group II, 31.2, 25 and 0% of GIII, GII and GI tumours progressed, while 50, 41.6 and 0% of T3, T2 and T1 tumours progressed, respectively. CONCLUSIONS: Nuclear p53 expression in TCC appears to be associated with a poorer prognosis in both younger and older patients. Although cytoplasmic bcl-2 overexpression is found in the majority of tumours in the younger group, it is not associated with tumour progression and recurrence.     

Evaluation of p21WAF1/CIP1 and cyclin D1 expression in the progression of superficial bladder cancer

Immunoreactivity of p21^WAF1/CIP1 and cyclin D₁ proteins was assessed in a cohort of 207 patients with superficial (pTa-pT₁) bladder cancer followed up for a mean of 4.9 years. The results of the immunostainings were compared with T category, WHO grade, tumor cell proliferation rate (MIB-1 score), the expressions of p53 and bcl-2 as well as survival. Sixty-eight percent and 75% of the tumors were p21^WAF1/CIP1 positive (≥5% of cells positive) and cyclin D₁ positive (≥10% of cells positive), respectively. The p21^WAF1/CIP1 expression was related to cyclin D₁ immunolabelling (P < 0.001) but not to the other variables studied. The expression of cyclin D₁ was inversely associated with T category (P=0.001), WHO grade (P=0.006), MIB-1 score (P=0.014), p53 expression (P=0.001), and bcl-2 (P=0.011) immunoreactivity. In univariate analysis, T category (P=0.0001), WHO grade (P < 0.0001), MIB-1 score (P < 0.0001), bcl-2 (P=0.0092), p53 (P=0.0016) and p21^WAF1/CIP1 (P=0.009) expressions were significant prognostic factors with regard to tumor progression, whereas cyclin D₁ was without any prognostic significance (P=0.1). Out of 123 p21 positive tumors 21 progressed, whereas only 2 out of 58 p21 negative tumors progressed. In multivariate analysis, the MIB-1 score was the only independent predictor of cancer-specific survival (P=0.03), whereas tumor grade (P=0.002) and cyclin D₁ expression (P=0.04) were independent predictors of tumor recurrence. Only the WHO grade (P=0.04) retained its prognostic value indicating the risk of progression. We suggest that in superficial bladder cancer p21^WAF1/CIP1 and cyclin D₁ immunohistochemistry provide no additional prognostic information compared with already established prognostic factors for predicting the risk of progressive disease. Received: 13 September 1999 / 22 March 2000     

Prognostic implications of aberrations in p16/pRb pathway in urothelial bladder carcinomas: a multivariate analysis including p53 expression and proliferation markers

OBJECTIVE: To assess the prognostic value of the expression of two negative regulators of the cell cycle, namely CDKN2/INK4a gene product (p16) and retinoblastoma gene product (pRb), in urinary bladder cancer in relation to clinicopathological parameters, proliferative fraction and p53 protein accumulation. METHODS: Paraffin sections from 139 patients with urothelial carcinomas were stained immunohistochemically with antibodies to p16 (F12), pRb (PMG3-245), p53 (DO1), PCNA (PC10) and Ki-67 (MIB-1). RESULTS: Diminished p16 and pRb expression occurred in 29 and 74% of cases, respectively, being associated with advanced stage but not with histological grade, papillary status or proliferation rate. In most cases (53%) with some fault in the p16/pRb pathway, only one gene was affected. A double-negative p16/pRb phenotype was comparatively uncommon (25%) and was usually seen in T3-T4 tumours. In survival analysis (either univariate or multivariate) aberrant p16 expression was an adverse prognostic parameter only in T3-T4 tumours. In contrast, the abnormal p16/pRb and p53/p16 phenotypes were linked to a diminished overall and disease-free survival (univariate analysis); p53/p16 abnormal expression was also found to be an independent predictor of reduced survival in muscle-invasive tumours, while proliferation markers were the only parameters with independent significance in superficial (Ta-T1) tumours. CONCLUSION: Our results suggest that lack of p16 immunoexpression, when combined with p53 accumulation, plays an important role in determining the clinical outcome in muscle-invasive urothelial carcinomas.     

T1G3 bladder cancer – Indications for early cystectomy

Objectives: To review our experience with early radical cystectomy in patients with T1G3 Transitional Cell Carcinoma of bladder (TCC). Patients and methods: Thirty patients, who underwent early radical cystectomy over a 10-year period for clinical stage T1G3 TCC bladder, were studied. Of these 21 (70%) had radical cystectomy without treatment with intravesical chemo/immunotherapy. The number of tumours, presence or absence of Carcinoma In-Situ (CIS) and the pathological stage of the cystectomy specimen were recorded in each patient. Disease specific survival was determined in the subgroups using Kaplan-Meier estimates. Results: Seventeen patients underwent radical surgery for a single tumour without concomitant CIS (Group A). The other 13 had multiple tumours with or without concomitant CIS or a single tumour with CIS (Group B). The disease was upstaged after cystectomy in 1 (6%) patient in Group A compared to 7 (55%) in Group B, (p = 0.009). Nine (53%) had pT0 disease in Group A compared to 0% in Group B, (p = 0.0017). The 5-year cancer specific survival rates were 92% in Group A and 82% in Group B. Conclusions: In patients with multiple T1G3 tumours with or without associated CIS, or in those with single T1G3 tumour with associated CIS the incidence of the disease being already muscle invasive at the time of clinical diagnosis is 55%. Early radical cystectomy should be advocated in this group. Conversely, for a single T1G3 tumour without associated CIS, conservative bladder preserving strategy with immuno-chemotherapy and close surveillance is justified. This revised version was published online in August 2006 with corrections to the Cover Date.