p53 and ki67 expression as prognostic factors for cancer-related survival in stage T1 transitional cell bladder carcinoma

OBJECTIVE: To determine prognostic factors for survival in bladder transitional cell carcinoma (TCC), and the prognostic value of p53 and ki67. MATERIAL AND METHODS: A study was made of patients with stage T1 primary bladder TCC (n = 175). The immunohistochemical study was carried out using DO7 and MIB-1 monoclonal antibodies, for p53 and ki67, respectively. Kaplan-Meier methodology was used for the survival analysis, and the log-rank test was applied in order to determine accumulated probability rates of survival. Moreover, Cox's multivariate regression analysis was also used to establish the variables associated with survival. Receiver operating characteristic (ROC) curves were also drawn, with the aim of determining the prognostic capacity of p53 and ki67. RESULTS: The average follow-up period was 7.3 years. Cancer-related survival rates at 5 and 10 years were 89.51 and 80.68%, respectively. The increase in p53 and ki67 expressions paralleled the histological grade, both markers showing significant inter-group differences (P = 0.0000). The variables which modified cancer-related survival significantly in the univariate analysis were the following: tumour multifocality, solid microscopic morphology, large cell nucleus and a high expression of p53 and ki67. Independent cancer-related survival variables were: age, tumour size of >3 cm, a solid microscopic growth pattern and expression of p53. CONCLUSIONS: The expression of p53, increase in age, tumour size of >3 cm and microscopic growth pattern are independent predictors for cancer-related survival. A positive correlation was observed, indicating that, the higher the expression of p53, the greater the probability of death.     

The predictive value of muscularis mucosae invasion and p53 over expression on progression of stage T1 bladder carcinoma

PURPOSE: We determine the significance of muscularis mucosae invasion and nuclear p53 over expression on the progression of stage T1 transitional cell bladder cancer. MATERIALS AND METHODS: The pathological findings in 149 cases of T1 tumors diagnosed between 1973 and 1996 were reviewed. Diagnosis was stage T1 in 94 tumors in which the muscular layer was clearly identifiable and disease-free. Mean followup was 64.9 months (range 5 to 288). T1 bladder cancers were subclassified into 2 groups, with (T1b) or without (T1a) muscularis mucosae invasion. The p53 nuclear antibody immunoreactivity was determined with antibody D07 and a cutoff point at 15%. RESULTS: T1 subclassification was possible in all 94 patients. Of all tumors 37.2% expressed p53 nuclear over expression. Univariate statistical analysis showed that p53 expression (p <0.05) and tumor invasion depth (p <0.001) significantly correlated with progression. However, on multivariate analysis only invasion depth (p <0.0001) and associated carcinoma in situ (p <0.03) remained independently significant as predictors of progression. CONCLUSIONS: In our study the depth of tumor invasion was a significant independent predictor of progression in patients with T1 bladder cancer. This result suggests that the depth of invasion in stage T1 should be included in the histopathological report.     

Intravesical Bacillus Calmette-Guerin treatment improves patient survival in T1G3 bladder tumours

OBJECTIVE: To study the clinical and pathological factors that affect recurrence, progression and survival in pT1G3 bladder tumours treated conservatively. MATERIAL AND METHODS: From January 1979 to December 1996, 80 patients were conservatively treated for pT1G3 bladder tumours. All patients were studied for potential prognostic factors such as: age, sex, previous tumour recurrence, tumour size, multiple tumours, carcinoma in situ, and intravesical instillations. A longitudinal, retrospective, observational and analytical study was conducted to evaluate four different types of events: recurrence, progression, overall survival, and disease-specific survival. The chi(2) (Fischer exact test) and student t tests were used to assess the prognostic value of the qualitative and quantitative variables. Estimations of the survival distributions were calculated according to the Kaplan-Meier method and compared with the Log rank test. Multivariate analysis of the data was performed with Cox proportional hazard models. RESULTS: Among the 80 patients, 67 (84%) were men and 13 (16%) were women, with median age of 65.5 years. The median tumour size was 20 mm, most had single tumour (58.8%) and carcinoma in situ was found in six patients (7.5%). Thirty patients were treated with transurethral resection (TUR) of the bladder tumour and 50 patients were treated with TUR followed by BCG. The two groups of patients were comparable and followed up during a median time of 61 and 65 months, respectively (p=0.454). Kaplan-Meier estimators and Log rank tests demonstrated that patients with TUR alone recurred (p<0.0001), progressed (p<0.040) and died (overall survival: p<0.009; disease-specific p<0.040) earlier than patients who received intravesical instillations of BCG. The results were confirmed with Cox models and odds-ratios are presented. CONCLUSION: In this study, BCG adjuvant immunotherapy was the only factor affecting recurrence, progression and survival. Conservative treatment using TUR followed by BCG may improve disease-specific survival.     

The predictive value of p53, p27(kip1), and alpha-catenin for progression in superficial bladder carcinoma

Objective

The aim of the study was to confirm the predictive value of cell cycle regulatory proteins, p53 and p27^kip1, and the cell adhesion complex protein α-catenin, for progression in patients with superficial bladder carcinoma.

Methods

Forty-one patients with progression after primary superficial bladder carcinoma were individually matched to patients with nonprogressive superficial bladder carcinoma. Matching was done for sex, age, tumor stage and grade, concomitant carcinoma in situ (CIS), and duration of follow-up. Immunohistochemical analysis of p53, p27^kip1, and α-catenin was performed on each primary bladder tumor. Analysis for the p53 mutation was done on 41 bladder tumor samples. Conditional logistic regression analysis was used to establish the prognostic value of immunohistochemical p53, p27^kip1, and α-catenin status.

Results

The independent odds ratios for progression were 0.3 (95% confidence interval [CI], 0.1–1.2) for high-risk p27^kip1, 3.4 (95%CI, 0.8–15.2) for high-risk p53, and 2.5 (95%CI, 0.6–10.3) for high-risk α-catenin. Combinations of different markers had no synergistic effects. Two p53 mutations were found in 21 DNA samples analyzed from nonprogressive tumors (9.5%); 8 of 20 samples (40%) from progressive tumors showed a p53 mutation. The probability of high-risk p53 immunostaining was 5-fold increased in case of mutations in p53. The estimated positive predictive value of high-risk p53 or high-risk α-catenin was about 23%.

Conclusions

We confirm that high-risk p53, p53 mutation, and α-catenin immunohistochemistry do have an additional prognostic value in primary bladder carcinoma. However, the clinical value of the investigated parameters remains limited.     

T1G3 transitional cell carcinoma of the bladder: recurrence, progression and survival

OBJECTIVES: To report our experience with T1G3 bladder tumours over the last 10 years. PATIENTS AND METHODS: We analysed the outcome of 74 consecutive patients treated for a T1G3 bladder cancer between 1991 and 2001. Fifty-seven patients (77%) were treated with transurethral resection (TUR) plus six weekly instillations of bacillus Calmette-Guérin (BCG) therapy. Ten patients (13.5%) with contraindications to BCG or with a small T1a tumour were treated with TUR plus mitomycin-C, and seven (9.5%) were treated with TUR alone because of their age. Patients treated with BCG had systematic biopsies taken at the end of the first course. Patients with residual tumour received a second course of six weekly instillations. Patients with negative biopsies received maintenance BCG therapy consisting of intravesical instillations each week for 3 weeks given 3, 6, 12, 18, 24, 30 and 36 months after the first course. RESULTS: The median follow-up was 53 months. The overall recurrence rate was 46% and the overall progression rate 19%. The rate of delayed cystectomy was 8% and that of disease-specific survival 91%. In patients who received BCG therapy, the recurrence and progression rates were 42% and 23%, respectively. In this group the rate of disease-specific survival was 88%. CONCLUSION: This study confirms that maintenance BCG therapy is an effective treatment for T1G3 bladder tumours, with an acceptable rate of bladder preservation.     

Reduced thrombospondin-1 at presentation predicts disease progression in superficial bladder cancer

OBJECTIVES: Superficial bladder cancer (SBC) presents a difficult clinical dilemma at diagnosis as only a small subgroup of patients will subsequently develop invasive disease. Study of cancer biology has found that angiogenesis is central to growth and spread. This study examines the relationship between the angiogenic inhibitory factor Thrombospondin-1 (TSP-1) at initial presentation and subsequent progression of SBC. METHODS: Using immunohistochemistry, 220 cases of SBC were examined for pattern and extent of expression of TSP-1 at initial presentation. RESULTS: TSP-1 was detected in perivascular tissue, at the epithelial-stromal junction, in the stroma and in tumour cells and reduced perivascular TSP-1 staining at presentation was an independent predictive factor for the subsequent development of muscle invasive or metastatic disease. CONCLUSION: This adds further weight to the theory that TSP-1 plays a major part in the biology of bladder cancer possibly through the control of angiogenesis.     

p53, p21/WAF1, pRb的表达与T1G3膀胱癌预后的关系

目的　探讨p5 3,p2 1/WAF1和pRb的异常表达在T1G3 膀胱癌预后判断中的价值。　方法　对 4 7例T1G3 膀胱癌患者进行术后随访 ,采用p5 3,p2 1/WAF1和pRb单克隆抗体对手术标本行免疫组化染色。将肿瘤进展情况与染色结果和与预后相关的临床指标进行分析。　结果　 39例手术保留膀胱的患者总进展率为 5 9% ,其中 9例发生远处转移。 8例行膀胱全切术的患者 1例于术后 2年发现肺转移。肿瘤细胞核p5 3,p2 1/WAF1和pRb蛋白的异常表达率分别为 6 6 .7%、5 1.4 %和 71.8%。多因素分析显示 ,p5 3、pRb同时异常表达 (P <0 .0 5 )和p5 3、p2 1/WAF1、pRb三者同时异常表达(P <0 .0 1)与肿瘤进展显著相关。　结论　p5 3,p2 1/WAF1和pRb的表达与T1G3 膀胱癌患者的预后密切相关     

PD-1 topographically defines distinct T cell subpopulations in urothelial cell carcinoma of the bladder and predicts patient survival

IntroductionThe pre-existing tumor-infiltrating T cell landscape in urothelial cell carcinoma of the bladder (UCB) may obtain prognostic significance and guide treatment decisions, particularly regarding immunotherapy. However, the current studies typically lead to inconsistent conclusions due to the extreme heterogeneity of T cells in cancer. Herein, we investigated the heterogeneity, distribution and clinical significance of tumor-infiltrating T cells based on PD-1 expression, their spatial organization, and the balance between subsets in a series of UCB patients.MethodsFlow cytometry for PD-1, CD4, and CD8 was performed in 6 UBC patients and 5 healthy donors. A series of 155 UBC patients with tissue slides were stained for triple color immunofluorescence. Stromal and intratumoral regions of the cancer tissue were respectively evaluated. Features derived from triple staining were analyzed for their correlations with clinical characteristics and patient prognosis.ResultsFlow cytometric analysis showed PD-1⁺ T cells were more frequently accumulated at the tumor site than in blood (p < 0.001). The proportion of PD-1⁺ T cells within CD4⁺ and/or CD8⁺ T cells is higher in the intratumoral region, as compared with the stroma by immunofluorescence evaluation (all p < 0.001, n = 155). Moreover, a high proportion of PD-1⁺ T cells within T cells in the intratumoral region, but not in the stroma, was predictive of a poorer overall survival (p = 0.0075) and recurrence-free survival (p = 0.0062), and was positively associated with aggressive clinical features (all p < 0.05). However, a low CD4/CD8 ratio among the PD-1⁺ T cells in the tumor stroma, but not in the intratumoral region, was significantly associated with shorter overall survival (p = 0.0164) and recurrence-free survival (p = 0.0016), which emerged as an independent predictor in multivariate analysis for UCB patients.ConclusionsTaken together, our results emphasize that PD-1 expression in T cell subsets, based on their topographic micro-localizations, provides valuable prognostic information for UCB patients.     

Loss of carcinoembryonic antigen-related cell adhesion molecule 1 expression predicts metachronous pulmonary metastasis and poor survival in patients with hepatoblastoma

Purpose

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a member of the carcinoembryonic antigen family of immunoglobulin-like adhesion molecules. The aim of this study was to test the hypothesis that loss of CEACAM1 expression in hepatoblastoma cells may promote hematogeneous metastasis and function as an adverse prognostic factor.

Methods

Immunohistochemical expression of CEACAM1 in surgically resected specimens from 19 patients with hepatoblastoma was examined retrospectively. The CEACAM1 expression in the epithelial area of the tumor was classified into 2 categories as follows: diffuse expression, characterized by positive staining throughout the tumor specimen, or loss of expression, in which there were distinct areas of negative staining within the tumor specimen.

Results

Of the 19 patients, 12 were classified as having tumors with diffuse expression, and 7 had loss-of-expression tumors. Survival after treatment was significantly worse in patients with tumors with loss of CEACAM1 expression (cumulative 5-year survival rate, 29%) than in patients with diffuse CEACAM1 expression (cumulative 5-year survival rate, 92%; P = .0062). Loss of CEACAM1 expression was a significant risk factor for metachronous pulmonary metastases (P = .0105).

Conclusions

Loss of CEACAM1 expression may reflect a high metastatic potential and thus indicate a poor prognosis for patients with hepatoblastoma.     

Caveolin 1 protein expression in renal cell carcinoma predicts survival

Background

Caveolae play a significant role in disease phenotypes such as cancer, diabetes, bladder dysfunction, and muscular dystrophy. The aim of this study was to elucidate the caveolin-1 ( CAV1) protein expression in renal cell cancer (RCC) and to determine its potential prognostic relevance.

Methods

289 clear cell RCC tissue specimens were collected from patients undergoing surgery for renal tumors. Both cytoplasmic and membranous CAV1 expression were determined by immunohistochemistry and correlated with clinical variables. Survival analysis was carried out for 169 evaluable patients with a median follow up of 80.5 months (interquartile range (IQR), 24.5 - 131.7 months).

Results

A high CAV1 expression in the tumor cell cytoplasm was significantly associated with male sex (p = 0.04), a positive nodal status (p = 0.04), and poor tumor differentiation (p = 0.04). In contrast, a higher than average (i.e. > median) CAV1 expression in tumor cell membranes was only linked to male sex (p = 0.03). Kaplan-Meier analysis disclosed significant differences in 5-year overall (51.4 vs. 75.2%, p = 0.001) and tumor specific survival (55.3 vs. 80.1%, p = 0.001) for patients with higher and lower than average cytoplasmic CAV1 expression levels, respectively. Applying multivariable Cox regression analysis a high CAV1 protein expression level in the tumor cell cytoplasm could be identified as an independent poor prognostic marker of both overall (p = 0.02) and tumor specific survival (p = 0.03) in clear cell RCC patients.

Conclusion

Over expression of caveolin-1 in the tumour cell cytoplasm predicts a poor prognosis of patients with clear cell RCC. CAV1 is likely to be a useful prognostic marker and may play an important role in tumour progression. Therefore, our data encourage further investigations to enlighten the role of CAV1 and its function as diagnostic and prognostic marker in serum and/or urine of RCC patients.

     

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     

尼古丁对膀胱癌p53基因表达的相关研究

目的：探讨尼古丁与癌基因表达和膀胱癌生物学行为的关系。方法：对40只大鼠以10％BBN为致癌剂膀胱灌注诱发膀胱癌,其中30只分25、15、5mg／kg剂量以咽管灌胃方式给予尼古丁,10只作为对照,应用免疫组化方法对膀胱癌模型中p53蛋白进行检测。结果：不同剂量的尼古丁干预下的p53蛋白表达的阳性率分别为60％、30％、20％。p53蛋白表达阳性率与给药剂量、给药时间呈正相关。结论：尼古丁对癌基因的异常表达及协同作用,在膀胱癌的发生发展中起一定作用。     

Management of T1G3 tumours of the bladder

T1G3 tumours are the most aggressive superficial tumours of the bladder, with a high risk of recurrence and progression. Complete endoscopic resection of the tumour is the first diagnostic and therapeutic step in T1G3 management. A second resection should be done at 1 month to avoid residual tumour and misdiagnosis of a muscle infiltrative cancer. As a result of treatment by instillations of Calmette and Guérin bacillus following endoscopic resection, a 5-year survival rate of 80% has been reported, with 50 to 60% of bladder preservation. BCG is the only conservative treatment that has proven effectiveness on both tumour recurrence and progression. Long term protocols seem to give the best results. Endovesical chemotherapy is not commonly used as its impact on progression has not been demonstrated. Radical cystectomy can be chosen as first line treatment in patients with particularly aggressive tumours. Long term and close surveillance should be achieved in every patient.     

p53 and retinoblastoma pathways in bladder cancer

A majority of the aggressive, invasive bladder carcinomas have alterations in the p53 and retinoblastoma genes and pathways. Examination of the alterations in the molecules in these pathways that regulate the cell cycle and their effects on the prognosis of bladder cancer are areas of active research. While defects in the p53-Mdm2-p14 axis have been implicated in urothelial cancer, perturbations in the cyclin-dependent kinases and their inhibitors have also been extensively studied in this context. Genetic alterations of the retinoblastoma gene and aberrant post-translational modifications of its protein have also been incriminated in invasive bladder cancer. This article reviews the individual prognostic roles of alterations in these molecules in the context of bladder cancer. Additionally, we review findings from recent studies that are attempting to analyze these markers in combination in an effort to construct molecular panels that can serve as more robust outcome predictors. More importantly, alterations in these molecules are now becoming enticing targets for novel therapeutics. We also review some of these agents that can restore the tumor cells’ altered homeostatic mechanisms, thereby having potential in transitional cell carcinoma therapy. Future management of bladder cancer will employ validated marker panels for outcome prediction, and novel genetic and pharmacologic agents that will be able to target molecular alterations in individual tumors based on their respective profiles. A.P. Mitra and M. Birkhahn contributed equally to this paper.     

Survivin在胆管癌表达与预后的关系

目的 探讨胆管癌患者中Survivin的表达在提示预后中的作用.方法 48例手术切除的胆管癌标本,应用免疫组织化学技术(SP法)检测Survivin基因在48例胆管癌中的表达.Survivin的表达分别描述为阴性或弱阳性和强阳性.结果 Survivin在胞质和细胞核表达例数分别为26例和22例患者.细胞质中强阳性表达为12例,而细胞核强阳性表达的则有8例.细胞核强阳性表达的患者平均存活期为10个月,明显低于弱阳性表达的患者(19个月,P＜0.05).Cox比例风险率模型的多因素分析方法 证实存在2个独立的预后因素:Survivin细胞核表达(P＜0.05)和远处转移(P＜0.05).结论 胆管癌中Survivin的细胞核表达可提示较差的预后.