Age at diagnosis as a powerful predictor for disease recurrence after radical nephrectomy in Japanese patients with pT1 renal cell carcinoma

Objectives: To review clinical outcomes and to identify clinicopathological variables as predictors of disease recurrence in a cohort of Japanese patients undergoing radical nephrectomy for renal cell carcinoma (RCC). Methods: The present study included a total of 710 consecutive Japanese patients who underwent radical nephrectomy and were diagnosed as having localized pT1 RCC. The significance of several clinicopathological factors in predicting postoperative disease recurrence was assessed by univariable and multivariable analyses. Results: Median age was 66 years (range 32–90 years). Open and laparoscopic radical nephrectomies were carried out for 436 (61.4%) and 274 (38.6%) patients, respectively. Tumor size was 4 cm or less in 461 (64.9%) patients and greater than 4 cm and 249 (35.1%) patients. During the observation period (median 36 months; range 3–111 months), postoperative disease recurrence developed in 37 patients (5.2%), of whom 10 (1.4%) died of disease progression. The 1‐, 3‐ and 5‐year recurrence‐free survival rates were 98.3%, 95.0% and 92.7%, respectively. Age at diagnosis and tumor size were found to be significantly associated with recurrence‐free survival at both univariable and multivariable analysis. Furthermore, there were significant differences in the recurrence‐free survival with respect to both independent predictors. Conclusions: Age at diagnosis in addition to tumor size appears to be independently related to disease recurrence in Japanese patients with pT1 RCC. Thus, an intensive follow up for older patients seems to be advisable.     

Radical cystectomy for patients with pT4 urothelial carcinoma in a large population‐based study

Study Type – Therapy (cohort) Level of Evidence 2b What’s known on the subject? and What does the study add? Given the natural history of pT4 urothelial carcinoma of the urinary bladder, and the substantially poorer survival of pT4 patients relative to pT3, it may be argued that radical cystectomy is not justified in these patients. Relying on a large population‐based retrospective analysis, the current study identified two main categories of patients with pT4 urothelial carcinoma of the urinary bladder. The first comprised of patients with pT4b disease, whose disease phenotype was clearly more aggressive than their pT3 counterparts. The second group consisted of patients with pT4a disease, whose disease phenotype was very similar to patients with pT3. These findings indicate that patients with pT4b disease should be provided with the maximal amount of therapeutic interventions, such as administration of early adjuvant chemotherapy and perhaps early adjuvant radiotherapy.

OBJECTIVE

• ? To examine cancer‐specific mortality (CSM) in patients with pT4N_0–3M₀ urothelial carcinoma of the urinary bladder (UCUB) and to compare it to patients with pT3N_0–3M₀, in a population‐based cohort treated with radical cystectomy (RC).

PATIENTS AND METHODS

• ? RCs were performed in 5625 pT3‐T4bN_0–3M₀ patients with UCUB within 17 Surveillance, Epidemiology and End Results (SEER) registries between 1988 and 2006.
• ? Univariable and multivariable models tested the effect of pT4a vs pT4b vs pT3 stages on CSM.
• ? Covariates consisted of age, gender, race, lymph node status and SEER registries.
• ? All analyses were repeated in 3635 pN₀ patients.

RESULTS

• ? Of 5625 patients, 2043 (36.3%) had pT4aN_0–3, 248 (4.4%) had pT4bN_0–3 and 3334 had pT3N_0–3 (59.3%) UCUB.
• ? The 5‐year CSM was 57.6% vs 81.7% vs 53.9% for, respectively, pT4aN_0–3 vs pT4bN_0–3 vs pT3N_0–3 patients (all log‐rank P= 0.008).
• ? In multivariable analyses the rate of CSM was 2.3‐fold higher in pT4b vs pT3 (P < 0.001), 1.1‐fold higher in pT4a vs pT3 (P= 0.002) and 2.0‐fold higher in pT4a vs pT4b patients.
• ? After restriction to pN₀ stage, pT4b patients had a 2.3‐fold higher rate of CSM than pT3 patients (P < 0.001) and pT4b patients had a 2.1‐fold higher rate of CSM than pT4a patients (P < 0.001).
• ? The CSM rate was the same for pT4a and pT3 patients (P= 0.1).

CONCLUSIONS

• ? Our findings indicate that patients with pT4a UCUB have similar CSM as those with pT3 UCUB.
• ? Consequently, RC should be given equal consideration in patients with pT3 and pT4a UCUB.

     

趋化因子受体7蛋白与膀胱尿路上皮癌淋巴结转移的相关性

目的观察趋化因子受体7蛋白(CCR7)在膀胱尿路上皮的表达量,分析CCR7蛋白表达与膀胱尿路上皮癌相关临床参数的相关性。方法对28例膀胱尿路上皮癌患者的标本和5例正常膀胱组织标本,采用免疫组化法检测组织中的CCR7蛋白含量,分析CCR7含量与膀胱尿路上皮癌淋巴结转移发生率、CCR7与肿瘤的分期、分级等临床参数之间的关系。结果膀胱尿路上皮癌组织CCR7阳性率为85.71%,显著高于正常膀胱组织(20.00%);在膀胱尿路上皮癌组织中,淋巴结转移组的CCR7阳性率为90.91%,淋巴结未转移组为41.18%,两组差异有显著性意义(P0.05)。高分期膀胱尿路上皮癌(T3~T4)中CCR7的阳性率也显著高于低分期(T1~T2)(93.75%vs.75.00%),高分级膀胱尿路上皮癌(G3)中的阳性率也显著高于低分级(G1~G2)(93.34%vs.38.46%)。CCR7蛋白表达与肿瘤分期、病理分级以及淋巴结是否转移均有相关性,CCR7蛋白表达是淋巴结转移的独立影响因子(P=0.017,OR=3.152)。结论膀胱尿路上皮癌中CCR7蛋白与淋巴结转移成正相关,是淋巴结转移的独立影响因素。     

膀胱尿路上皮癌中DNMT1的表达及其临床意义

目的研究DNA甲基转移酶1（DNMT1）在膀胱尿路上皮癌（BUC）中的表达,探讨DNMT1与膀胱癌生物学行为之间的关系。方法采用RT—PCR法和Western-blot技术,检测60例膀胱尿路上皮癌及12例正常膀胱黏膜组织中DNMT1的表达;并结合临床资料进行分析。结果①膀胱癌组织中DNMT1蛋白和mRNA的表达水平分别为0．628±0．245和0．774±0．083,显著高于正常膀胱黏膜组织的0．126±0．028和0．175±0．101（P=0．000）;②DNMT1在膀胱癌中的表达水平与肿瘤的临床分期、分化程度、有无淋巴结转移等生物学行为显著相关。结论DNMT1在膀胱尿路上皮癌中过度表达,在膀胱癌的发生发展中起重要作用。     

Pathological stage review is indicated in primary pT1 bladder cancer

Study Type – Diagnosis (case series)
Level of Evidence 4

OBJECTIVE

To evaluate the effect of a pathology review on the clinical outcome of patients with primary pT1 bladder cancer (BC), as the clinical course of such patients is variable.

PATIENTS AND METHODS

The slides of 164 primary (first diagnosis) pT1 bladder tumours from two university hospitals were reviewed by one pathologist for stage and grade (World Health Organization 1973 and 2004). Patients were initially managed conservatively with bacille Calmette‐Guérin (BCG). Uni‐ and multivariate analyses compared the predictive value of age, gender, hospital, carcinoma in situ (CIS), tumour‐size, reviewed grade and reviewed stage.

RESULTS

With a mean follow‐up of 6.4 years, there was disease progression in 48 (29%) patients and 26 (16%) died from BC. Associated CIS was found in 55 (34%) patients. After reviewing the slides, 24 (15%) tumours were downstaged to pTa, 134 (82%) remained pT1 and six (4%) were upstaged to ≥pT2. The grade review resulted in 74 G2, 90 G3, 37 low‐grade and 127 high‐grade lesions for the two systems used. In multivariate analyses, reviewed stage (both P < 0.001) and CIS (P = 0.017 and 0.023) had independent significance for progression and disease‐specific survival, respectively.

CONCLUSION

A stage review is indicated in pT1 BC, as almost 20% of pT1 tumours were up‐ or downstaged, and the reviewed stage predicted the patient’s prognosis. Hence, pathology review identified patients with different prognoses who might benefit from other treatment strategies than BCG. We confirmed that CIS is an unfavourable sign in pT1 bladder cancer.     

Solitary abdominal wall metastasis from a urothelial carcinoma of the urinary bladder

Few cases of abdominal wall metastasis from a urothelial carcinoma were reported in the literature, and those were mostly attributed to iatrogenic implantation after laparoscopic surgery or a percutaneous nephrostomy. An 85-year-old man presented with an infraumbilical mass 6 months after transurethral resection of a bladder tumor (TURBt) for a T4 urinary bladder urothelial carcinoma. Abdominal sonography disclosed a 1.6 cm × 1.5 cm subcutaneous hypoechoic lesion. Wide excision of the mass was performed, and skin flaps were used for skin coverage. A combination of the patient's clinical history, tumor morphology, and immunostaining results were compatible with the pathologic characteristic of his previous bladder urothelial carcinoma. We present this rare case of solitary abdominal wall mass metastasis from a urothelial carcinoma of the urinary bladder.     

Low expression of TMEM67 is a critical predictor of poor prognosis in human urothelial carcinoma of the bladder

Objectives

The aim of the study was to evaluate the expression of TMEM67 in urothelial carcinoma of the bladder (UCB) tissues and to determine the potential relevance between the expression of TMEM67 and prognosis of UCB.

Cyclooxygenase-2 promotes angiogenesis in pTa/T1 urothelial bladder carcinoma but does not predict recurrence

OBJECTIVE: To investigate the effect of cyclooxygenase-2 (COX-2) on microvessel density (MVD) and on the clinical prognosis in patients with non-muscle invasive urothelial carcinoma of the bladder, as COX-2 expression is significantly greater in epithelial tumours and there is increasing evidence that COX-2 might contribute to tumour neovascularization. PATIENTS AND METHODS: We assessed tumour samples from 110 patients undergoing transurethral resection for primary pTa/pT1 bladder carcinoma (pTa, 84; pT1, 26; grade 1, 22; grade 2, 81; grade 3, seven). Paraffin sections were assessed immunohistochemically using antibodies against COX-2, CD34 (endothelial cells) and CD105 (proliferating vessels). COX-2 expression was quantified by the number of stained cells (negative, +, ++) and the MVD calculated as vessels per field. RESULTS: Of the 110 tumours, 45 (41%) had no immunostaining for COX-2, 40 had faint staining with at least isolated positive cells (+) and 25 stained ++. COX-2 positive tumours had significantly greater vascularization for proliferating vessels. In COX-2 negative tumours the MVD was 22.1, identified by CD34 immunostaining, and 3.4 for proliferating vessels (CD105), whereas COX-2 positive tumours had a MVD of 18.3 (CD34), and of 5.8, respectively (CD105). Complete follow-up data were available in 91 patients; after a mean follow-up of 25 months, 18 (20%) had tumour recurrences. There was no significant difference in the recurrence rates or disease-free survival between COX-2-positive (19%, 25.6 months) or -negative patients (21%, 25.2 months). CONCLUSION: These results confirm the involvement of COX-2 in angiogenesis in bladder cancer, as COX-2 promoted blood vessel proliferation in the tumour zone, and indicate the usefulness of COX-2-inhibiting drugs in preventing and treating superficial bladder cancer.     

膀胱尿路上皮癌MRP-1/CD9和cyclinD1的表达与肿瘤生物学行为的关系

目的:探讨MRP-1/CD9和cyclinD1的表达与膀胱尿路上皮癌生物学行为的关系。方法:应用免疫组化法检测80例膀胱尿路上皮癌组织和12例正常对照组膀胱组织MRP-1/CD9和cyclinD1的表达情况。结果:MRP-1/CD9阳性表达率膀胱癌组为51.25%,对照组为91.11%(P<0.05);Ta～T1肿瘤阳性表达率为71.42%,T2～T4为35.56%;G1肿瘤阳性表达率为78.57%,G2为43.48%,G3为31.03%,随着肿瘤浸润性和分级上升,阳性表达率逐渐下降(P<0.01,P<0.05);MRP-1/CD9阳性表达率肿瘤初发和复发者之间差异无统计学意义(P>0.05);肿瘤单发者高于多发者(P<0.05)。膀胱尿路上皮癌cyclinD1阳性表达率为53.75%,对照组为0(P<0.01);Ta～T1肿瘤阳性表达率为78.57%,T2～T4为17.65%;G1肿瘤阳性表达率为85.71%,G2为56.52%,G3为20.69%,随着肿瘤浸润性和分级升高,cyclinD1阳性表达率逐渐降低(P<0.05,P<0.05)。cyclinD1阳性表达率肿瘤初发和复发者、多发者和单发者之间差异无统计学意义(P>0.05,P>0.05)。结论:MRP-1/CD9表达与膀胱尿路上皮癌的浸润性和分级相关,其表达缺失可能是判断该肿瘤预后的一个指标;cy-clinD1较能准确地评估膀胱尿路上皮癌的生物学行为,二者对于判断膀胱癌的预后有重要的临床意义     

KAI-1在肾细胞癌中的表达及意义

目的 研究KAI-1在不同分期、分级、预后和年龄组肾细胞癌中的表达，分析其表达的意义。方法 随访1991～2000年入院治疗并留取病理标本的肾癌病例预后。根据临床分期、细胞分级、年龄、T1-3aN0M0病例是否术后转移分别将肾癌病例分组，应用免疫组织化学方法检测肾癌标本KAI-1表达，卡方检验分析KAI-1表达的差异。结果 30～70岁每十年龄段KAI-1阴性表达率为34．4％～47．8％，比较低表达率χ^2值为0．54～1．19，P均〉0．05，过表达率χ^2值为0．84～1．84，P均〉0．05。肾癌TNMⅠ～Ⅳ期KAI-1阴性表达率为34．2％、25．2％、54．4％和80．0％，Ⅰ、Ⅲ、Ⅳ期间过表达比较P〈0．05。Fuhrman分级Ⅰ～Ⅲ级KAI-1阴性表达率为33．0％、47．8％、81．4％，Ⅱ和Ⅲ、Ⅰ和Ⅲ级比较χ^2值分别为9．11、27．24，P均〈0．01。T1-3aN0M0术后转移组24例和未转移组194例KAI-1阴性表达率为79．2％、9．8％；两组低表达率比较χ^2值=64.49，P〈0．01；过表达χ^2值=0．02，P〉0．05。结论 转移抑制基因KAI-1在肾癌中的表达与年龄因素无关。KAI-1低表达或表达缺失率在Ⅲ期、Ⅳ期和FuhrmanⅢ级肾癌中最高。KAI-1基因缺失可能参与了T1-3aN0M0肾癌术后转移的发生，检测KAI-1表达具有临床预后指导价值。     

TLR-4介导的免疫逃逸信号转导系统在膀胱尿路上皮癌中的表达及意义

目的：探讨TLR-4介导的免疫逃逸信号转导系统在膀胱尿路上皮癌免疫逃逸 膀胱癌生物学行为的关系。方法：采用免疫组化染色法检测60例膀胱尿路上皮癌和10例正 4、B7-HI、PD-1、Fas及FasL的表达。结果：TLR-4在正常膀胱组织中均有表达,而在膀胱尿路上皮癌中表达有所降低;B7-H1、PD-1、Fas、FasL在正常膀胱组织中无表达或表达极低,而在膀胱尿路上皮癌中的表达均明显增高,并且其表达与肿瘤的病理分级和临床分期密切相关,同时B7-H1表达与复发亦密切相关。结论：TLR-4介导的免疫逃逸信号转导系统可能与膀胱尿路上皮癌的免疫逃逸密切相关,在膀胱尿路上皮癌的发生发展中可能存在着TLR-4介导的免疫逃逸信号转导系统的活化和相关免疫抑制分子表达的上调。     

Overexpression of Eg5 predicts unfavorable prognosis in non‐muscle invasive bladder urothelial carcinoma

Objective: To investigate the relationship between Eg5 expression and prognosis of patients with non‐muscle invasive bladder urothelial carcinoma. Methods: Eg5 expression was examined by immunohistochemistry in non‐muscle invasive urothelial carcinoma specimens (grade: G1, 32 cases; G2, 92 cases; and G3, 39 cases. Stage: pTa, 49 cases and pT1, 114 cases). The correlation between clinicopathological characteristics and Eg5 expression was evaluated. The prognostic significance of Eg5 immunoreactivity was analyzed through survival analysis in 163 non‐muscle invasive cases that were treated with transurethral resection and adjuvant intravesical instillations. Results: The expression of Eg5 was significantly associated with tumor grade (P = 0.006), with a trend towards significant association with stage (P = 0.057). The 163 patients with non‐muscle invasive tumors were regularly followed with the mean of 32.52 (from 6 to 72) months. Univariate analysis showed Eg5 overexpression exhibited a significant unfavorable influence on intravesical recurrence (P = 0.012) while having only a marginal correlation with disease progression (P = 0.070). Subsequent Cox hazard multivariate analysis showed that both grade (P = 0.045) and Eg5 expression (P = 0.029) were independent predictors for early intravesical recurrence. Conclusions: Overexpression of Eg5 correlates with poor differentiation of bladder cancer, and it represents an independent prognostic factor in predicting early intravesical recurrence in non‐muscle invasive bladder carcinoma patients.     

Risk factors for urothelial carcinoma of the prostate in patients undergoing radical cystoprostatectomy for bladder cancer

OBJECTIVE

To examine the risk factors for urothelial carcinoma (UC) involvement of the prostate in patients undergoing radical cystoprostatectomy (RCP) for bladder cancer, as such involvement has both prognostic and therapeutic implications.

PATIENTS AND METHODS

We examined 308 consecutive men from 1998 to 2005 who had RCP for UC of the bladder, with whole‐mount processing of their prostate. Prostatic involvement was categorized by site of origin (the bladder or the prostatic urethra) and, in the case of prostatic urethral origin, by depth of invasion, i.e. dysplasia/carcinoma in situ (CIS), involving the prostatic urethra, prostatic ductal invasion or prostatic stromal invasion. The impact of pathological characteristics was evaluated.

RESULTS

In all, 121 (39.3%) patients had some form of urothelial involvement of the prostate, of whom 59 (48.8%) had dysplasia/CIS of the prostatic urethra, 20 (16.5%) had ductal involvement and 32 (26.4%) had stromal involvement. Multivariate analysis showed that bladder CIS (odds ratio 2.0, 95% confidence interval, 1.2–3.6, P = 0.012) and trigonal involvement of bladder tumours (2.0, 1.1–3.7, P = 0.028) were independent risk factors for urothelial involvement of the prostate.

CONCLUSION

There was prostatic involvement with UC in nearly 40% of patients undergoing RCP. In this study CIS and trigonal involvement were independent predictors of risk, but were not adequate enough to accurately identify most patients who have UC within their prostate; further prospective studies are needed to more accurately predict risk factors and depth of invasion.     

Expression profile of epithelial-mesenchymal transition markers in non–muscle-invasive urothelial carcinoma of the bladder: Correlation with intravesical recurrence following transurethral resection

ObjectivesTo evaluate the expression of molecular markers involved in epithelial-mesenchymal transition (EMT), a key process mediating the progression of malignant tumors, in non–muscle-invasive urothelial carcinoma of the bladder (NMIUCB) to clarify the significance of these markers as predictors of intravesical recurrence in patients treated with transurethral resection (TUR).Materials and methodsExpression levels of 13 EMT markers, including E-cadherin, N-cadherin, β-catenin, γ-catenin, fibronectin, matrix metalloproteinase (MMP)-2, MMP-9, Slug, Snail, TWIST, vimentin, ZEB1, and ZEB2, in TUR specimens obtained from 161 consecutive patients with NMIUCB were measured by immunohistochemical staining.ResultsOf these 13 markers, significant differences in the incidence of intravesical recurrence were noted according to expression levels of E-cadherin, N-cadherin, MMP-2, MMP-9, and TWIST. Univariate analysis also identified expression levels of E-cadherin, N-cadherin, MMP-2, MMP-9 and TWIST, in addition to the tumor size, pathological T category, and concomitant carcinoma in situ, as significant predictors of intravesical recurrence-free survival. Of these significant factors, expression levels of E-cadherin, MMP-9, and TWIST; tumor size; and concomitant carcinoma in situ appeared to be independently associated with intravesical recurrence-free survival on multivariate analysis. Furthermore, there were significant differences in recurrence-free survival according to positive numbers of these 5 independent risk factors (i.e., positive for 0 or 1 factor vs. positive for 2 factors vs. positive for 3 or more factors).ConclusionsConsideration of expression levels of EMT-associated markers in TUR specimens, in addition to conventional prognostic parameters, would contribute to the accurate prediction of intravesical recurrence following TUR for NMIUCB.