Intravesical bacillus Calmette-Guerin therapy for stage T1 grade 3 transitional cell carcinoma of the bladder: recurrence,progression and survival in a study of 57 patients

PURPOSE: Stage T1 grade 3 transitional cell carcinoma of the bladder is associated with a high risk of tumor recurrence and progression. We report our experience with stage T1 grade 3 bladder tumors treated with bacillus Calmette-Guerin (BCG) therapy in the last 10 years. MATERIALS AND METHODS: We analyzed the outcome in 57 consecutive patients treated with intravesical BCG for stage T1 grade 3 bladder cancer between 1991 and 2001. After initial transurethral resection all patients received a 6-week course of BCG therapy consisting of 1 instillation weekly. All patients underwent systematic biopsies at the end of the first BCG course. 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. Patients with residual tumor received a second course of 6 weekly instillations. Time to tumor recurrence and progression, and the rate of patient survival were retrospectively analyzed. RESULTS: Median followup was 53 months (range 9 to 110). Minimum followup was 2 years in 36 cases (63.2%) and 5 years in 28 (49.1%). After the first BCG course 50 patients (87.7%) had no residual disease, while 7 (12.3%) had residual tumor. The recurrence and progression rates were 42.1% and 22.8%, respectively. The rate of delayed cystectomy was 14%. The rate of disease specific survival was 87.7%. CONCLUSIONS: Our study confirms that BCG therapy is effective conservative treatment for patients with stage T1 grade 3 bladder tumors.     

The management of stage T1 grade 3 transitional cell carcinoma of the bladder

The number of Mini‐Reviews per issue is being increased to three for the foreseeable future. As mentioned before, I believe they add to the reader‐friendliness of the journal, and are enjoyable and informative. This month, the controversial topics of T1 G3 bladder cancer, surgery for penile fractures and managing patients on warfarin are dealt with. I hope that readers will feel free to write to me if they have strong feelings about these or any other subjects in the Journal.     

Over expression of metallothionein predicts resistance of transitional cell carcinoma of bladder to intravesical mitomycin therapy

PURPOSE: Metallothionein, a low molecular weight intracellular protein, binds mitomycin with high affinity protecting the tumor DNA. We prospectively studied the relationship of metallothionein expression in bladder transitional cell carcinoma and resistance to intravesical mitomycin. MATERIALS AND METHODS: A series of 45 consecutive patients with superficial transitional cell carcinoma treated with intravesical mitomycin were studied. Resected tumor tissues were stained with metallothionein monoclonal antibody E9. Two pathologists scored staining intensity and distribution. All patients were followed with regular flexible cystoscopy. RESULTS: Median patient age was 73 years (range 44 to 89). Tumor grade was 1 to 3 in 6, 33 and 6 cases, respectively. In 20 patients (44.44%) tumor recurred after mitomycin therapy. Median cytoplasmic staining scores for recurrent and nonrecurrent tumors were 5 (range 0 to 61) and 0 (0 to 14), respectively. Median nuclear staining scores for recurrent and nonrecurrent tumors were 3 (range 0 to 56) and 0 (0 to 11), respectively. Median followup of patients without recurrence was 18 months (range 12 to 36). Nuclear and cytoplasmic staining scores were significantly higher in recurrent than in nonrecurrent tumors. There was no significant relationship of metallothionein expression with tumor grade. CONCLUSIONS: Over expression of metallothionein predicts the resistance of bladder transitional cell carcinoma to intravesical mitomycin therapy.     

The ablative effect of quarter dose bacillus Calmette-Guerin on a papillary marker lesion of the bladder

PURPOSE: Low dose bacillus Calmette-Guerin (BCG) for stage TaT1 transitional cell carcinoma of the bladder has been given in various studies with the aim of decreasing side effects while maintaining the same efficacy as full dose bacillus Calmette-Guerin. However, its application in clinical practice remains controversial. We examined the ablative activity and incidence of side effects of intravesical quarter dose BCG given for a papillary marker lesion of the bladder. MATERIALS AND METHODS: Included in our study were 44 patients with primary or recurrent, multiple but no more than 10 lesions of stage pTaT1, grades 1 to 2 transitional cell carcinoma of the bladder. Intravesical treatment begun 14 days after the complete transurethral resection of all visible tumors except 1 marker lesion no larger than 1 cm. consisted of instillations of 30 mg. Connaught strain BCG diluted in 50 ml. saline once weekly for 6 consecutive weeks. Two weeks after the last instillation any residual tumor was completely resected. In cases of complete disappearance of the marker lesion deep biopsy of the tumor area was done. Urine cytology was also performed. RESULTS: There was a complete response in 27 of the 44 patients (61%), no response in 12 (27%) and progression to carcinoma in situ in 1 (2%), while the response was not evaluable in 4. Local side effects included dysuria in 54% of cases and macroscopic hematuria in 39%. Neither BCG induced infection nor BCG sepsis was observed. CONCLUSIONS: Quarter dose BCG has a clear ablative effect on superficial bladder cancer with a 61% response rate. Phase III trials are now required to compare its efficacy and toxicity to those of full dose BCG.     

Clinical study of transitional cell carcinoma of the prostate associated with bladder transitional cell carcinoma

BACKGROUND: Transitional cell carcinoma of the prostate in patients with bladder cancer appears to influence the prognosis and affects the decision about therapeutic modality. Therefore, it is important to characterize transitional cell carcinoma associated with bladder cancer. METHODS: From April 1980 to December 1998, 81 male patients underwent total cystoprostatectomies for transitional cell carcinoma of the bladder. The 81 cystoprostatectomy specimens were examined to clarify the characteristics of prostatic involvement by transitional cell carcinoma. The extent, origin, mode of spread and risk factor of prostatic involvement as well as the prognosis were investigated. In 13 of 15 patients with prostatic involvement the prostate was examined by sequential step sections. RESULTS: Prostatic involvement was observed in 15 of 81 patients (18.5%). Prostatic urethral involvement, invasion to prostatic duct/acinus, prostatic stromal invasion and extraprostatic extension and/or seminal vesicle involvement were recognized in 12 (80%), 14 (93.3%), six (40%), and five (33.3%) of the 15 patients, respectively. Twelve of the 15 patients (80%) with prostatic involvement had papillary or non-papillary tumors (i.e. carcinoma in situ) both in the prostatic urethra and prostatic duct. In 10 of these 12 patients (88.3%), there was contiguity between prostatic urethral and ductal tumors. Seven of the 23 patients (30.4%) with carcinoma in situ of the bladder showed prostatic involvement, which increased to 50% in the presence of carcinoma in situ of the trigone or bladder neck. CONCLUSIONS: Eighty per cent of the patients with prostatic involvement showed papillary or non-papillary tumors both in the prostatic urethra and prostatic duct. There was a high level of contiguity between both tumors. Patients with carcinoma in situ of the trigone or bladder neck revealed significantly higher incidence of prostatic involvement.     

Clinical outcomes following radical cystectomy for primary nontransitional cell carcinoma of the bladder compared to transitional cell carcinoma of the bladder

PURPOSE: The effect of bladder cancer histological subtypes other than transitional cell carcinoma (nonTCC) on clinical outcomes remains uncertain. We conducted a multi-institutional retrospective study of patients with bladder cancer treated with radical cystectomy to assess the impact of nonTCC histology on bladder cancer specific outcomes. MATERIALS AND METHODS: A total of 955 consecutive patients underwent radical cystectomy with bilateral pelvic lymphadenectomy for bladder cancer at 3 academic institutions. TCC was present in the radical cystectomy specimen in 888 patients (93%). NonTCC histology was present in 67 patients (7%), including squamous cell carcinoma in 26, adenocarcinoma in 13, small cell carcinoma in 10 and other nonTCC subtypes (ie spindle cell carcinoma, carcinosarcoma and undifferentiated carcinoma) in 18. For patients alive at last followup median followup was 39 and 23 months for patients with TCC and nonTCC histologies, respectively. Bladder cancer specific progression and survival were assessed using Kaplan-Meier and multivariate Cox proportional hazards analyses. RESULTS: Bladder cancer specific progression and mortality did not differ significantly between patients with SCC and TCC histologies. Patients with nonTCC and nonSCC bladder cancer were at significantly increased risk for progression and death compared to patients with TCC or SCC (p <0.001). This association remained statistically significant in patients with organ confined disease (stage pT2 or lower) and patients with nonorgan confined disease (stage pT3 or higher) (p <0.001). In a multivariate analysis nonTCC and nonSCC histology was associated with an increased risk of bladder cancer progression and death (OR 2.272 and 2.585, respectively, p <0.001), even after adjusting for final pathological stage, lymph node status, lymphovascular invasion and neoadjuvant or adjuvant treatments. CONCLUSIONS: NonTCC and nonSCC histological subtype is an independent predictor of bladder cancer progression and mortality in patients undergoing radical cystectomy for bladder cancer. Patients with bladder TCC and SCC share similar stage specific clinical outcomes.     

Recurrence and progression of stage T1, grade 3 transitional cell carcinoma of the bladder following intravesical immunotherapy with bacillus Calmette-Guerin

PURPOSE: We prospectively examined the incidence of recurrence and progression in patients with stage pT1, grade 3 carcinoma of the bladder following complete transurethral resection of the bladder tumor and adjuvant immunotherapy with bacillus Calmette-Guerin (BCG). MATERIALS AND METHODS: Between July 1987 and March 1999, 123 patients presenting to our clinic with superficial urothelial carcinoma (stage pT1, grades 1 to 3) received adjuvant intravesical immunotherapy with BCG after histologically confirmed complete transurethral tumor resection. Disease was stage pT1, grade 3 in 44 patients (36%). Median followup was 28 months (mean 43, range 5 to 141). RESULTS: Of the patients 36 (82%) with bladder preservation remained tumor-free during followup after 1 or 2 cycles of BCG. Superficial tumor recurred in 5 patients (11%) and muscle invasive progression was noted in 7 (16%). Radical cystectomy was performed in 4 cases (9%). Of the patients 5 (11%) died of cancer. Tumor-free survival for all patients was 89% (39 of 44). CONCLUSIONS: Adjuvant immunotherapy with BCG after complete transurethral resection of bladder tumor represents a highly effective primary treatment of stage pT1, grade 3 carcinoma of the bladder. Immediate radical cystectomy does not appear necessary.     

Initial tumor stage and grade as a predictive factor for recurrence in patients with stage T1 grade 3 bladder cancer

PURPOSE: We evaluated whether the risk of progression and the recurrence rate were different in patients with primary and nonprimary stage T1 grade 3 transitional cell carcinoma of the bladder. MATERIALS AND METHODS: Between 1983 and 1997, 75 patients were treated for stage T1 grade 3 transitional cell carcinoma of the bladder. Of these patients 68 (primary and nonprimary tumor in 58 and 14, respectively) without carcinoma in situ who had not undergone complete cystectomy immediately after diagnosis were included in the study. No maintenance regimen was used. Median followup was 100 months (range 9 to 217). RESULTS: The incidence of multiple tumors in patients with nonprimary tumors was significantly higher than in patients with primary disease (p = 0.035). However, the recurrence-free survival rate in patients with primary T1 GIII bladder tumor was significantly lower than that of patients with nonprimary T1 GIII bladder tumor (p = 0.0016). Multivariate analysis using Cox's proportional hazard regression model revealed that only initial tumor status had statistically significant effects on tumor recurrence (p = 0.007) and no other factors had a significant influence on recurrence-free survival. Progression-free and cancer specific survival rates were also significantly different between the 2 groups (p = 0.036 and 0.0307, respectively). CONCLUSIONS: Our study indicates that patients with primary stage T1 grade 3 bladder cancers have higher recurrence and progression potential than those with nonprimary disease despite the higher incidence of multiple tumors in patients with nonprimary tumors.     

膀胱移行细胞癌DNA测定的临床意义

应用图像分析技术对３７例膀胱移行癌细胞核ＤＮＡ含量进行测定，３５例得到随访，结果发现，膀胱移行细胞癌ＤＮＡ含量和异倍体出现率随种瘤恶性程度的增加而明显升高，肿瘤的复发和病人存活时间与肿瘤异倍体出率亦明显相关。结果表明，ＤＮＡ含量测定对膀胱瘤的诊断及预后是一个可靠指标。     

Cost-effectiveness of a modified care protocol substituting bladder tumor markers for cystoscopy for the followup of patients with transitional cell carcinoma of the bladder: a decision analytical approach.

PURPOSE: Decision analysis models were established to determine the cost-effectiveness of a plan alternating a bladder tumor marker with cystoscopy and cytology at 3-months intervals or modified care versus followup cystoscopy and cytology every 3 months or standard care. MATERIALS AND METHODS: We performed a comprehensive literature review for bladder tumor markers using 1966 to current MEDLINE data and other search engines. Statistical performance data on tumor markers were calculated by hierarchical Bayes meta-analysis with 95% confidence intervals used for the model. Other basic assumptions included cost data on tumor markers, cytology, cystoscopy, transurethral bladder resection and cystectomy as well as recurrence and progression rates from the literature. Decision trees were built with computer software using a 12 and a 24-month model with linear recurrence and progression rate assumptions. RESULTS: Overall specificity for common tumor markers was 73% to 90% and sensitivity was 49% to 77%. As expected, sensitivity increased for higher disease grades and stages. The modified care protocol was more cost-effective than standard care for the 1 and 2-year followups. On 1-year 1-way sensitivity analysis for cost only tumor marker cost, recurrence and progression rates achieved a threshold at which the modified care protocol was as or more expensive as standard care. Modified care was more cost-effective at a tumor marker cost of less than $264. On 2-way sensitivity analysis there was no significant impact of parameters at a wide range of tumor marker costs, recurrence and progression rates. CONCLUSIONS: Using a modified followup protocol in transitional cell carcinoma cases with an initial tumor occurrence using a urine based tumor marker alternating with cystoscopy and/or cytology is cost-effective for a wide range of marker sensitivities, specificities and costs, cystoscopy and/or cytology cost, a 20% to 80% yearly recurrence and a 2% to 40% yearly progression rate. This protocol should be evaluated in a prospective randomized trial to determine whether the financial and emotional benefits outweigh any potential drawbacks.     

MMP2及MMP9在膀胱移行细胞癌尿液中的表达及与侵袭转移关系的研究

目的探讨MMP2及MMP9在膀胱移行细胞癌患者尿液中的表达,并研究它们与膀胱移行细胞癌侵袭转移之间的关系。方法采用酶联免疫吸附法(ELISA)定量检测尿液中MMP2及MMP9的含量,并分析其表达水平与膀胱移行细胞癌临床分期和病理分级之间的关系。结果MMP2在膀胱移行细胞癌患者尿液中的含量明显高于非癌症患者,二者差异有统计学意义(P<0.01);MMP9在膀胱移行细胞癌患者尿液中的含量也明显高于非癌症患者(P<0.01)。MMP9在膀胱移行细胞癌患者尿液中的含量与肿瘤临床分期呈显著正相关(r=0.51361,P<0.01);与肿瘤病理分级也呈显著正相关(r=0.47378,P<0.01)。MMP2在膀胱移行细胞癌者尿液中的含量与肿瘤临床分期呈正相关(r=0.32271,P<0.01);而与肿瘤病理分级不相关(r=0.29818,P>0.05)。MMP2和MMP9在膀胱移行细胞癌患者尿液中的含量呈显著正相关(r=0.55674,P<0.01)。结论膀胱移行细胞癌患者尿液中增高的MMP2及MMP9与肿瘤细胞侵袭能力密切相关。进一步研究对指导临床治疗、判断预后有重要意义。     

Cyclooxygenase-2 is highly expressed in carcinoma in situ and T1 transitional cell carcinoma of the bladder

PURPOSE: We describe cyclooxygenase-2 (COX-2) expression patterns in patients with carcinoma in situ and/or stage T1 transitional cell carcinoma. We determined whether expression is associated with clinical outcome in these patients. MATERIALS AND METHODS: Immunostaining for COX-2 was performed on paraffin embedded bladder biopsy specimens from 2 independent groups of patients without muscle invasive carcinoma, including 39 with carcinoma in situ and 34 with stage T1 tumors. Immunoreactivity was scored as the percent of carcinoma in situ cells with cytoplasmic staining for COX-2 in the carcinoma in situ group and as the percent of stage T1 cells expressing COX-2 in the stage T1 transitional cell carcinoma group. We evaluated other molecular alterations, including E-cadherin, p21 and p53, because evidence suggests a biological association of COX-2 with alterations in these molecular markers. RESULTS: In the carcinoma in situ group 5 patients (13%) had no immunoreactivity, while 2 (5%), 5 (13%) and 27 (69%) had 10%, 20% and 30% or greater carcinoma in situ cells positive for COX-2, respectively. In the transitional cell carcinoma group 1 (3%), 4 (12%) and 29 (85%) patients had 10%, 20% and 30% or greater positive cells, respectively. COX-2 expression was not associated with any clinical or pathological parameters, or with molecular markers regardless of the cutoff used. It was also not associated with clinical outcomes in the stage T1 transitional cell carcinoma group. In the carcinoma in situ group COX-2 expression was significantly associated with disease recurrence using cutoffs of 0% and greater than 10% positive cells, and with disease progression using a greater than 20% cutoff. However, it was not associated with bladder cancer related survival. CONCLUSIONS: COX-2 is expressed in a high percent of patients with carcinoma in situ and stage T1 transitional cell carcinoma, supporting the rationale for chemoprevention studies with selective COX-2. We could not substantiate a role for COX-2 immunohistochemistry for the staging and prognosis of carcinoma in situ and/or stage T1 transitional cell carcinoma.     

Micropapillary variant of transitional cell carcinoma of the bladder

A 77-year-old man visited the Kobe City General Hospital complaining of macroscopic hematuria. A computed tomography scan found a bladder tumor with left iliac and para-aortic lymph node metastasis. Two courses of cisplatin, cyclophosphamide and doxorubicin chemotherapy resulted in a minimal response. Radical cystectomy and a retroperitoneal lymph node dissection with bilateral ureterocutaneostomy reconstruction were then performed. A pathological examination revealed a micropapillary variant of transitional cell carcinoma (Grade 3, pT1pN2M1). The patient died of pelvic recurrence 7 months after the initiation of chemotherapy. Peritonitis carcinomatosa and lung metastases were observed at autopsy.     

Hypermethylation of an E-cadherin (CDH1) promoter region in high grade transitional cell carcinoma of the bladder comprising carcinoma in situ

PURPOSE: We elucidated the role of methylation in the promoter region of the 1 gene in bladder carcinogenesis, particularly in those comprising carcinoma in situ. MATERIALS AND METHODS: A total of 49 cases of transitional cell carcinoma of the bladder obtained from transurethral resection were examined. Methylation status of the 1 promoter region was analyzed by methylation specific polymerase chain reaction from chemically modified DNA after Na-bisulfite treatment. Loss of heterozygosity on 16q was examined by blunt end single strand DNA conformation polymorphism using 4 tetranucleotide repeat microsatellite markers assigned on 16q13 to 22.1. E-cadherin expression was evaluated by immunostaining on formalin fixed, paraffin embedded tissue sections using anti E-cadherin murine monoclonal antibody, HECD1 and standard avidin-biotin immunoperoxidase complex technique. RESULTS: Analysis of the 49 bladder transitional cell carcinoma samples showed 1 promoter methylation in 23 (47%). Methylation of the 1 gene did not correlate with tumor stage (p = 0.2097) but with high grade transitional cell carcinoma (p = 0.0416). 1 promoter methylation was observed at a significantly higher frequency in the carcinoma in situ positive group than in the carcinoma in situ negative group (16 of 18 cases or 89% versus 7 of 31 or 23%, p <0.0001) and it strongly correlated with abnormal E-cadherin expression (p <0.0001). We found 16q loss of heterozygosity in 16 of 47 cases (34%), which correlated with higher histological grade (p = 0.0069) but not with the presence of the carcinoma in situ component (p = 0.1235). CONCLUSIONS: This study showed that 1 gene promoter methylation is strongly associated with bladder transitional cell carcinoma comprising carcinoma in situ.     

小分子肽CSNRDARRC与膀胱移行细胞癌组织特异性结合的研究

目的明确小分子肽CSNRDARRC与膀胱移行细胞癌组织结合的特异性及其结合位点。方法选用膀胱移行细胞癌、肾癌、胃癌及腺性膀胱炎石蜡组织块,分别为107、43、68、16例;进行连续切片、烤片、脱蜡、抗原修复,封闭,再采用免疫荧光技术加FITC-六氨基己酸-CSNRDARRC复合物,荧光显微镜定性分析,单纯加FITC作为阴性对照。采用SPSS13.0软件进行统计分析,P〈0.05为有显著性统计学差异。结果单纯FITC标记的各蜡块组织（阴性对照组）均未见有高亮荧光点,FITC-六氨基己酸-CSNRDARRC复合物标记的膀胱移行细胞癌组织有99例出现高亮荧光点,特异性为92.52%（99/107）,而在肾癌、胃癌及腺性膀胱炎组织分别有6例、5例、2例有荧光亮点,特异性分别为9.52%（5/43）,8.82%（6/68）,12.50%（2/16）,通过DAPI着色确定高亮荧光点主要定位于细胞核。CSNRDARRC与膀胱移行细胞癌组织的结合较其与肾癌、胃癌及腺性膀胱炎组织的结合有显著差异（P〈0.05）,而CSNRDARRC与肾癌、胃癌及腺性膀胱炎组织间结合比较无统计学意义（P〉0.05）。结论小分子肽CSNRDARRC与膀胱移行细胞癌特异性结合率显著高于其他肿瘤组织,但对其他组织仍有标记,且结合位点在细胞核内,这为该肽段对膀胱移行细胞癌临床诊断提供理论基础;为膀胱癌的治疗奠定一定的理论依据。