Combination of CK20 and Ki-67 Immunostaining Analysis Predicts Recurrence,Progression, and Cancer-Specific Survival in pT1 Urothelial Bladder Cancer

Background

The prognostic value of CK20, Ki-67, and p53 has been investigated for non–muscle-invasive urothelial bladder cancers but not for the distinct and clinically challenging subset of pT1 bladder cancers.

Objective

To evaluate the prognostic value of CK20, Ki-67, and p53 within the largest series of pT1 urothelial bladder cancers.

Design, setting, and participants

Data from 309 patients with pT1 urothelial bladder cancer from one single urologic centre were collected.

Intervention

Adjuvant instillation of bacillus Calmette-Guérin was performed in each patient. A second resection was performed after 4–8 wk. A total of 76 patients underwent cystectomy.

Outcome measurements and statistical analysis

We conducted histomorphologic analysis; immunohistochemistry for CK20, Ki-67, and p53; and univariate and multivariate Cox regression models including recurrence-free survival (RFS), progression-free survival (PFS), and cancer-specific survival (CSS).

Results and limitations

At a median follow-up of 49 mo, we found recurrence and progression and disease-specific mortality rates of 22.7%, 20.1%, and 15.9%, respectively. CK20 expression was significantly correlated with RFS in multivariate analysis (hazard ratio [HR]: 5.89; 95% confidence interval [CI], 1.44–24.15; p = 0.014). In multivariate analysis, Ki-67 was the only marker significantly correlated with PFS (HR: 2.80; 95% CI, 1.45–5.43, p = 0.002). Ki-67 (HR: 3.83; 95% CI, 1.59–9.26; p = 0.003), and CK20 (HR: 8.44; 95% CI,1.16–61.34; p = 0.035) were significantly correlated with CSS in multivariate analysis. The combination of CK20 and Ki-67 showed significantly worse RFS (p = 0.026), PFS (p = 0.003), and CSS (p < 0.001) in tumours with a high proliferation index and abnormal CK20 expression. A retrospective study design was the major limitation of this study.

Conclusions

Our present analysis of the largest series of patients with pT1 urothelial bladder cancer published to date found Ki-67 and CK20 to be potential prognostic markers improving the risk stratification of pT1 bladder tumours. They are reliable indicators of biologic aggressiveness and may contribute to decision making on therapeutic strategy for pT1 bladder carcinomas.     

Ki-67 Expression is a Prognostic Marker of Prostate Cancer Recurrence after Radical Prostatectomy

Purpose

We assessed the cellular proliferation of clinically localized prostate cancer by immunohistochemistry using the monoclonal antibody MIB to Ki-67 antigen in an attempt to identify associations between proliferative indexes and disease progression following radical prostatectomy.

Materials and Methods

Ki-67 proliferative antigen was evaluated using MIB 1 monoclonal antibody in archival paraffin embedded radical prostatectomy specimens from 180 patients followed for 1 to 9 years (mean 4.4). The percentage of tumor nuclei expressing Ki-67 antigen was measured and assigned an MIB 1 score (none or rare-negative, 1+-low score and 2 to 4+-high score) and analyzed for prostate specific antigen, stage, age, race, grade and serological recurrence postoperatively.

Results

There was a significant association between MIB 1 score and nuclear grade (p less than 0.001), Gleason score (p less than 0.001) and pathological stage (p = 0.01). Patients with a high MIB 1 score had earlier progression and a lower 5-year recurrence-free survival rate (44 percent) than those with negative MIB 1 scores (71 percent, p less than 0.001). In multivariate Cox regression analysis with backward elimination, pathological stage (p less than 0.01), pretreatment prostate specific antigen (p = 0.04) and MIB 1 score (p = 0.05) were statistically significant predictors of disease-free survival, and patients with a high MIB 1 score were 3.1 times as likely to have recurrence as those with a negative score. Controlling for stage, patients with organ confined disease and a high MIB 1 score had a lower 5-year disease-free survival rate (68 percent) than those with a low MIB 1 score (95 percent, p greater than 0.01).

Conclusions

Proliferative activity as measured by the Ki-67 proliferative antigen, MIB 1, appears to be a prognostic marker of recurrent prostate cancer after radical prostatectomy.     

HER2用于评估非肌层浸润性膀胱癌复发及进展的研究

目的探讨HER2表达用于评估非肌层浸润性膀胱癌(NMIBC)复发及进展的意义。方法采用免疫组化染色的方法,检测301例NMIBC患者肿瘤HER2的表达情况,并且对所有患者肿瘤复发及进展情况进行随访。结果肿瘤数目(单发、数目1;[HR]:1.91,P=0.001)〗、肿瘤大小(3cm、≥3cm;[HR]:2.20,P0.0001)、肿瘤分期(T_a、T_1;[HR]:2.08,P=0.001)、肿瘤分级(G_1、G_2、G_3;[HR]:1.71,P=0.041)与膀胱癌复发相关;而肿瘤大小(3 cm、≥3 cm;[HR]:2.50,P=0.015)、肿瘤分期(T_a、T_1;[HR]:3.68,P=0.007)、肿瘤分级(G_1、G_2、G_3;[HR]:2.72,P=0.018)、是否伴发原位癌([HR]:3.33,P=0.008)、HER2(阴性、阳性;[HR]:2.36,P=0.030)均可影响膀胱癌进展。HER2表达阴性的患者与HER2表达阳性患者相比,膀胱癌进展至肌层浸润性的风险明显降低。结论 HER2表达可作为预测NMIBC进展的指标,HER2阳性患者疾病进展风险更大。     

HYAL-1 Hyaluronidase: A Potential Prognostic Indicator for Progression to Muscle Invasion and Recurrence in Bladder Cancer

Background

For bladder cancer (BCa) patients undergoing bladder-sparing treatments, molecular markers may aid in accurately predicting progression to muscle invasion and recurrence. Hyaluronic acid (HA) is a glycosaminoglycan that promotes tumor metastasis. Hyaluronoglucosaminidase 1 (HYAL-1)–type hyaluronidase (HAase) promotes tumor growth, invasion, and angiogenesis. Urinary HA and HAase levels are diagnostic markers for BCa.

Objective

We evaluated whether HA and HYAL-1 can predict progression to muscle invasion and recurrence among patients with non–muscle-invasive BCa.

Design, setting, and participants

: Based on tissue availability, tissue microarrays were prepared from a cohort of 178 BCa specimens (144 non–muscle invasive, 34 muscle invasive). Follow-up information was available on 111 patients with non–muscle-invasive BCa (mean follow-up: 69.5 mo); 58 patients recurred and 25 progressed to muscle invasion (mean time to progress: 22.3 mo).

Measurements

HA and HYAL-1 expression was evaluated by immunohistochemistry and graded for intensity and area of staining. Association of HA and HYAL-1 staining with BCa recurrence and muscle invasion was evaluated by univariate and multivariate models.

Results and limitations

HA and HYAL-1 expression correlated with tumor grade, stage, and multifocality (p < 0.05). In non–muscle-invasive BCa specimens, HYAL-1 staining was higher (234.3 ± 52.2; 200.6 ± 61.4) if patients experienced progression to muscle invasion or recurrence when compared with no progression or recurrence (164.1 ± 48.2; 172.1 ± 57; p < 0.001). HA staining correlated with muscle invasion (p < 0.001). In univariate analysis, age (p = 0.014), multifocality (p = 0.023), and HYAL-1 staining (p < 0.001) correlated with muscle invasion, whereas only HYAL-1 correlated with recurrence (p = 0.013). In multivariate analysis, HYAL-1 significantly associated with muscle invasion (p < 0.001; 76.8% accuracy) and recurrence (p = 0.01; 67.8% accuracy).

Conclusions

HYAL-1 is a potential prognostic marker for predicting progression to muscle invasion and recurrence.     

动脉化疗栓塞对膀胱癌组织中Ki-67和PCNA表达的影响

目的：探讨术前动脉化疗栓塞对膀胱癌组织Ki-67和增殖细胞核抗原（PCNA）表达的影响及其临床意义。方法：对30例膀胱癌患者化疗栓塞前后的肿瘤组织,应用免疫组织化学法测定Ki-67和PCNA的表达,并分析Ki-67和PCNA与膀胱癌病理分级和临床分期的关系。结果：对30例膀胱癌患者化疗栓塞前后的肿瘤组织,应用免疫组织化学法测定Ki-67和PCNA的表达,并分析Ki-67和PCNA与膀胱癌病理分级和临床分期的关系。结论：化疗栓塞前后Ki67中高度阳性表达率为70％、26.67％,PCNA为73.33％、20％,差异均有非常显著性意义（P〈0.01）,经随访24.6个月,复发率为16.67％。Ki-67和PCNA阳性表达及下降幅度与膀朊癌的病理分级、临床分期和患者术后复发率关系密切,两者阳性表达及表达强度呈正相关（P〈0.001）。结论：术前化疗栓塞能降低膀胱癌组织Ki-67和PCNA的表达,调节膀胱癌的分化程度,使肿瘤降级降期,减少术后转移,降低复发率,提高生存率。Ki-67和PCNA的表达可作为膀胱癌预后估计的指标。     

Prognostic Significance of Thymidine Phosphorylase in Superficial Bladder Carcinoma

Objective: We investigated the expression of thymidine phosphorylase (TP) in bladder carcinomas and assessed its prognostic significance in superficial bladder cancer samples. Patients and methods: We studied 142 primary bladder cancer samples immunohistochemically for nuclear thymidine phosphorylase (TPN), cytoplasmic (TPC) and stromal (TPSTR) expression. We correlated them with standard clinicopathological features (grade, stage, concurrent in situ, multiplicity, primary or recurrent status), as well with recurrence and progression. We examined also the relationship between TP and tumor microvessel density. Results: The level of all types of TP correlated well with stage, while grade correlated well only with TPSTR and the presence of carcinoma in situ only with TPN. Patients with low levels of TPN had a longer tumor free interval, during a 38.6 months mean follow up time. Regarding the association between TP count and microvessel density we found the strongest association with TPSTR (p=0.003), a borderline statistical significance with TPC (p=0.049) and no relationship with TPN (p=0.072). Conclusions: We suggest that the assessment of TPN might be useful for predicting recurrence in superficial bladder cancer. We propose also that TP may stimulate angiogenesis.     

Clinicopathological Evaluation of Repeated Courses of Intravesical Bacillus Calmette-Guerin Instillation for Preventing Recurrence of Initially Resistant Superficial Bladder Cancer

Purpose

The efficacy of repeated courses of intravesical bacillus Calmette-Guerin (BCG) for superficial bladder cancer was assessed with particular attention to initially resistant cases.

Materials and Methods

A total of 75 patients with stages Ta to T1b superficial transitional cell bladder carcinoma received 6 weekly instillations of 80 mg. Tokyo strain BCG in 40 ml. saline followed by 6 instillations at monthly intervals. If tumors recurred, another course of treatment was given with surgery.

Results

Of 17 patients (22.7 percent) with recurrent tumor at followup periods of up to 84 months 12 received an additional course of BCG instillations according to the same protocol after transurethral resection of bladder tumors, and 10 (83.3 percent) showed no further recurrence with or without additional surgery and BCG therapy after a median followup of 42.9 months. Thus, the overall success rate with this approach was 90.7 percent (68 of 75 patients). Comparison of patients with and without recurrence revealed a significant difference in number of tumors before therapy (p less than 0.05), and a pronounced tendency (p = 0.00507) for recurrence after prior systemic chemotherapy or intravesical instillation.

Conclusions

The results suggest that up to 3 courses of repeated intravesical instillation of BCG are effective even for cases that initially did not respond, and that best results may be achieved if no other prior chemotherapy has been attempted.     

Early Disease Progression after Intravesical Bacillus Calmette-Guérin (BCG) Therapy for Superficial Bladder Cancer

Background : Disease progression after Bacillus Calmette-Guérin (BCG) instillation therapy for bladder cancer is not rare. The purpose of this study was to evaluate the outcome of patients treated with BCG for superficial bladder cancer, focusing on the patients who developed invasive disease during follow-up. The possible mechanism and risk factors for early progression after BCG therapy are discussed. Methods : A total of 25 patients with superficial bladder cancer (pTa, pT1, and/or pTis) were treated with intravesical BCG instillation (80 mg in 80 mL saline) once a week for eight weeks. Four of the 25 patients received maintenance therapy with BCG (once a month for 3 to 10 months). Patients were followed every three months and underwent cystoscopy, biopsy, and urinary cytology at these intervals. Disease progression was defined as invasion to muscle or prostate, or development of metastatic disease. Clinicopathological features of the patients, especially those with progression, were analyzed. Results : Progression was observed in six of the 25 patients (including four of 19 patients with carcinoma in situ and two of five patients treated prophylactically with BCG). The average time to progression was 8.7 months. Four patients died of cancer despite intensive treatment. Two patients are alive: one without evidence of disease after cystectomy and the other with metastatic disease. Conclusions : Proper patient selection, careful follow-up, and immediate aggressive therapy in case of progression were considered to be important factors to obtain satisfactory results with BCG therapy for bladder cancer.     

Recurrence and Progression of Disease in Non–Muscle-Invasive Bladder Cancer: From Epidemiology to Treatment Strategy

Context

This review focuses on the prediction of recurrence and progression in non–muscle invasive bladder cancer (NMIBC) and the treatments advocated for this disease.

Objective

To review the current status of epidemiology, recurrence, and progression of NMIBC and the state-of-the art treatment for this disease.

Evidence acquisition

A literature search in English was performed using PubMed and the guidelines of the European Association of Urology and the American Urological Association. Relevant papers on epidemiology, recurrence, progression, and management of NMIBC were selected. Special attention was given to fluorescent cystoscopy, the new World Health Organisation 2004 classification system for grade, and the role of substaging of T1 NMIBC.

Evidence synthesis

In NMIBC, approximately 70% of patients present as pTa, 20% as pT1, and 10% with carcinoma in situ (CIS) lesions. Bladder cancer (BCa) is the fifth most frequent type of cancer in western society and the most expensive cancer per patient. Recurrence (in ≤80% of patients) is the main problem for pTa NMIBC patients, whereas progression (in ≤45% of patients) is the main threat in pT1 and CIS NMIBC. In a recent European Organisation for Research and Treatment of Cancer analysis, multiplicity, tumour size, and prior recurrence rate are the most important variables for recurrence. Tumour grade, stage, and CIS are the most important variables for progression. Treatment ranges from transurethral resection (TUR) followed by a single chemotherapy instillation in low-risk NMIBC to, sometimes, re-TUR and adjuvant intravesical therapy in intermediate- and high-risk patients to early cystectomy for treatment-refractory high-risk NMIBC.

Conclusions

NMIBC is a heterogeneous disease with varying therapies, follow-up strategies, and oncologic outcomes for an individual patient.     

Predicting Recurrence and Progression of Noninvasive Papillary Bladder Cancer at Initial Presentation Based on Quantitative Gene Expression Profiles

Background

Currently, tumor grade is the best predictor of outcome at first presentation of noninvasive papillary (Ta) bladder cancer. However, reliable predictors of Ta tumor recurrence and progression for individual patients, which could optimize treatment and follow-up schedules based on specific tumor biology, are yet to be identified.

Objective

To identify genes predictive for recurrence and progression in Ta bladder cancer at first presentation using a quantitative, pathway-specific approach.

Design, setting, and participants

Retrospective study of patients with Ta G2/3 bladder tumors at initial presentation with three distinct clinical outcomes: absence of recurrence (n = 16), recurrence without progression (n = 16), and progression to carcinoma in situ or invasive disease (n = 16).

Measurements

Expressions of 24 genes that feature in relevant pathways that are deregulated in bladder cancer were quantified by real-time polymerase chain reaction on tumor biopsies from the patients at initial presentation.

Results and limitations

CCND3 (p = 0.003) and HRAS (p = 0.01) were predictive for recurrence by univariate analysis. In a multivariable model based on CCND3 expression, sensitivity and specificity for recurrence were 97% and 63%, respectively. HRAS (p < 0.001), E2F1 (p = 0.017), BIRC5/Survivin (p = 0.038), and VEGFR2 (p = 0.047) were predictive for progression by univariate analysis. Multivariable analysis based on HRAS, VEGFR2, and VEGF identified progression with 81% sensitivity and 94% specificity. Since this is a small retrospective study using medium-throughput profiling, larger confirmatory studies are needed.

Conclusions

Gene expression profiling across relevant cancer pathways appears to be a promising approach for Ta bladder tumor outcome prediction at initial diagnosis. These results could help differentiate between patients who need aggressive versus expectant management.     

PCNA and Ki-67 as Prognostic Markers in Human Parathyroid Carcinomas

Background: It is widely accepted that histological diagnosis of parathyroid tumors is established with great difficulty. Carcinomas cannot be reliably separated from adenomas by histology alone. In this study, immunohistochemical staining for proliferating cell nuclear antigen (PCNA) and Ki-67 was determined in 10 cases of parathyroid carcinomas, labeling indices (LIs) were calculated, and the results were correlated with the clinical outcomes.Methods: Ten cases of formalin-fixed, paraffin-embedded tissue with surgically resected parathyroid carcinoma were used. Immunohistochemical staining for PCNA and Ki-67 was performed and the LIs were calculated. We also examined whether LI could become a useful marker for parathyroid carcinomas.Results: Although nine patients with minimally invasive growth without recurrence of the tumor showed a low LI for both markers, one patient with a widely invasive neoplasm, and who died, had a high LI.Conclusions: These results suggested that the LI of PCNA and Ki-67, in addition to the histological appearance, may be markers of the biological behavior of parathyroid carcinomas. However, this study was on a small scale, so it may be valuable to repeat these studies in a larger group of patients with better defined histological criteria.     

Recurrence of Primary Superficial Bladder Cancer Treated with Prophylactic Intravesical Tokyo 172 Bacillus Calmette-Guerin: A Long-Term Follow-up

Background Long-term results after transurethral resection (TUR) and prophylactic intravesical Tokyo 172 bacillus Calmette-Guerin (BCG) therapy for primary superficial bladder cancer were analyzed by multivariate analysis, and factors affecting the recurrence of bladder tumors after this therapy were examined.
Methods One-hundred and forty-one consecutive patients with primary superficial bladder cancer who consulted the Department of Urology at Wakayama Medical College and affiliated hospitals between May 1985 and May 1990 were studied. Tokyo strain BCG was given intravesically (80 mg in 40mL saline) weekly for 6 weeks.
Results The 5-year cumulative recurrence-free rate by the Kaplan-Meier method was 0.702 in 141 patients with primary superficial bladder cancer. The 5-year recurrence-free function using the proportional hazard model was 0.743. Using the Cox proportional hazard model, variables that significantly contributed to recurrence after intravesical BCG included female sex, tumor size less than 1 cm in diameter, and T1 tumor stage. Patient age, tumor type, multiplicity, tumor grade, and concomitant carcinoma in situ did not contribute to recurrence.
Conclusion Long-term results showed that prophylactic intravesical Tokyo strain BCG after TUR for primary superficial bladder cancer is also effective in preventing the recurrence of bladder cancer, and the biologic behavior of superficial bladder cancer other than stage T1 tumor may be altered after intravesical BCG.     

经尿道膀胱电切术后吡柔比星灌注治疗表浅性膀胱癌临床分析

目的总结膀胱肿瘤电切术（transurethral resection of bladder tumor,TURBt）加吡柔比星（tetrahydnopyrany adriamyrin,THP）灌注治疗表浅性膀胱癌的疗效。方法48例表浅性膀胱癌患者,均行TURBt,术毕用THP40mg＋注射用水40ml行灌注化疗30min,术后每周化疗1次,共8次,然后改为每个月1次,持续1年。结果均顺利完成手术,术中未出现膀胱穿孔、膀胱出血等并发症。48例患者平均随访2.1（0.5~3）年,术后1年内6例在非原来位置复发（12.5%）,再次行TURBt加THP灌注,随访1年无复发。结论TURBt加THP膀胱灌注疗效确切,可降低复发率,是治疗表浅膀胱癌的有效方法。     

Prognostic Significance of Ki-67 Labeling Index in Papillary Thyroid Carcinoma

Background  

Ki-67 is a useful tool for evaluating cell proliferative activity in various tumors. Although the utility of Ki-67 labeling index (LI) to diagnose thyroid neoplasms has been investigated, little is known regarding the relationship between Ki-67 LI and the biological behavior of papillary thyroid carcinoma. In this study, we examined Ki-67 in 371 patients with papillary thyroid carcinoma to elucidate this issue.     

Frequent Recurrence of Superficial Bladder Tumors in the Periorificial Region: Possible Predictor for Delayed Appearance of Invasive Intramural Ureteric Cancer

Two cases of invasive lower ureteric cancer developed following frequent recurrence of superficial bladder tumors in the region of the ureteral orifice. The cancer focus could not be identified in the intramural ureter prior to intravenous urography which revealed hydronephrosis. When bladder tumors repeatedly develop near the ureteric orifice, careful investigations such as ureteral catheterization with a small brush for cytology or ureteroscopy are necessary for the early detection of invasive disease.
bladder neoplasms,
ureteral neoplasms     

Ki-67抗原与乳腺癌的相关性研究

目的探讨Ki-67抗原在乳腺癌组织中的表达,并评价其表达与乳腺癌生物学行为及判断乳腺癌预后的关系。方法检索近年来有关Ki-67与乳腺癌的相关性研究的文献并做综述。结果Ki-67在乳腺癌组织中的表达水平显著高于癌旁组织及正常乳腺组织,且Ki-67表达阳性率与乳腺癌病理分级、临床分期呈正相关,而Ki-67表达与乳腺癌腋窝淋巴结转移的相关性研究结果不尽一致。结论Ki-67抗原是与细胞增殖周期相关的细胞核抗原,其表达随细胞周期的变化而变化,是检测细胞增殖活性较为可靠的标志物,其可能成为判断肿瘤恶性程度及评估预后的重要指标;Ki-67表达水平的检测在乳腺肿瘤的早期诊断、指导新辅助化疗、评估预后等方面有重要意义。