Vascular endothelial growth factor-C expression in bladder transitional cell cancer and its relationship to lymph node metastasis

OBJECTIVE: To elucidate the role of vascular endothelial growth factor-C (VEGF-C) in bladder transitional cell carcinoma (TCC), examining VEGF-C expression in bladder TCC tissue and the association of VEGF-C with clinicopathological features, as the expression of VEGF-C in several carcinomas is significantly associated with angiogenesis, lymphangiogenesis and regional lymph node metastasis, but there are few reports of VEGF-C expression in bladder TCC. PATIENTS AND METHODS: The study included 45 patients with bladder TCC; VEGF-C expression was assessed by immunohistochemistry and the association between VEGF-C expression and angiogenesis, as evaluated by microvessel density (MVD), was examined. RESULTS: There was VEGF-C expression in the cytoplasm of tumour cells, but very little in the normal transitional epithelium. VEGF-C expression was significantly associated with tumour size, pathological T stage, pathological grade, lymphatic-venous involvement and pelvic lymph node metastasis (all P < 0.05). Multivariate analysis showed that VEGF-C expression was an exclusive independent factor influencing pelvic lymph node metastasis. Moreover, the patients with high VEGF-C expression had a markedly poorer prognosis than those with no or low VEGF-C expression (P = 0.014). A multivariate analysis based on the Cox proportional hazard model showed that lymph node metastasis was only an independent prognostic factor in the multivariate analysis using the Cox regression model (P = 0.010). CONCLUSION: The present study provides evidence supporting the involvement of VEGF-C expression in the promotion of lymph node metastasis in bladder TCC. Examination of VEGF-C expression in biopsy specimens might be beneficial in predicting pelvic lymph node metastasis.     

转录因子Spl在膀胱癌中的作用及其和VEGF的相关性研究

目的探讨核转录因子Spl在膀胱移行细胞癌（BTCC）组织中的表达及临床意义,分析其与血管内皮生长因子（VEGF）的相关性。方法用免疫组织化学PV-6000法检测Spl和VEGF在63例BTCC、21例膀胱乳头状瘤和13例正常黏膜中的表达。结果 Spl和VEGF在BTCC组织中的阳性表达率为68.3%（43/63）和73.0%（46/63）,明显高于其在乳头状瘤和膀胱黏膜的阳性表达（P〈0.05）。Sp1阳性表达与BTCC的病理分级、临床分期密切相关,且和VEGF的表达呈正相关,和肿瘤复发相关。结论 Spl在膀胱癌发生和进展中起重要作用,检测其和VEGF的表达对评估BTCC预后有较高价值。     

血小板源性内皮细胞生长因子与膀胱移行细胞癌的相关性研究

目的　探讨血小板源性内皮细胞生长因子 (PD ECGF)与膀胱移行细胞癌 (BTCC)的相关性。　方法　采用免疫组化方法对BTCC组织中PD ECGF、血管内皮生长因子 (VEGF)表达及微血管密度 (MVD)进行观察 ,结合 5 2例患者 5年随访结果分析。　结果　 5 2例患者中有完整随访资料者 5 0例 ,术后 5年无瘤生存率 4 2 .9% (2 1/ 4 9) ,总生存率 78.0 % (39/ 5 0 )。PD ECGF在G1肿瘤中阳性表达率 17.6 % (3/ 17) ,G2 5 9.3% (16 / 2 7) ,G3 87.5 % (7/ 8) ,P <0 .0 1。PD ECGF阳性组无瘤生存期 (31.87± 2 3.75 )个月 ,阴性组 (4 2 .19± 2 3.84 )个月 ,P <0 .0 5 ;总生存期阳性组 (4 8.87± 19.88)个月 ,阴性组 (5 7.19± 8.97)个月 ,P <0 .0 5。MVD极高组总生存期 (4 3.5 0± 2 2 .74 )个月 ,远低于高、中、低 3组的平均 (5 6 .4 6± 10 .98)个月 ,P <0 .0 5。随肿瘤MVD增高 ,VEGF阳性表达率显著增高 ,PD ECGF表达无明显增高。　结论　PD ECGF及MVD与BTCC恶性程度有显著相关性。     

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.     

血管生成素-2在膀胱移行细胞癌中的表达及意义

目的　初步探讨血管生成素 2 (Ang 2 )在膀胱移行细胞癌组织中的表达及其与临床分期、病理分级的关系。方法　应用免疫组织化学S P法检测 4 3例初治膀胱癌及 2 8例正常膀胱组织中的Ang 2表达水平 ,并与临床资料对照进行统计分析。 结果　正常膀胱组织中未见Ang 2阳性染色 ;4 3例膀胱移行细胞癌中Ang 2阳性染色者 2 1例 ,Ang 2在许多膀胱癌细胞和癌组织中微血管内皮上呈强阳性染色 ,且染色率随膀胱癌病理分级、临床分期的上升而升高 (P <0 .0 5 )。结论　①Ang 2促进肿瘤新生血管形成 ,参与膀胱癌的发生和发展。②Ang 2的表达与膀胱移行细胞癌的临床分期、病理分级正相关。     

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.     

胃癌组织中血管内皮生长因子C的表达与淋巴结微转移的关系

目的：检测胃癌患者血管内皮因子C（VEGF-C）蛋白及mRNA在胃癌组织中的表达情况,探讨其与胃癌淋巴结微转移的关系。方法应用免疫组织化学法及RT-PCR法检测80例胃癌组织、癌旁组织及正常组织中的VEGF-C蛋白及mRNA表达情况;免疫组化法检测淋巴结微转移情况,比较有无淋巴结微转移的VEGF-C蛋白和mRNA的表达差异,明确存在的关联性。结果VEGF-C蛋白及mRNA两者在胃癌组织中明显高于癌旁组织和正常组织（P＜0.05）。结论胃癌组织中的VEGF-C蛋白及mRNA与胃癌淋巴结微转移相关,基因检测优于蛋白,可作为评价胃癌患者是否存在淋巴结微转移的优选指标。     

Extensive cutaneous metastasis of transitional cell carcinoma of the bladder

Cutaneous metastasis of bladder carcinoma is extremely rare. Iatrogenic implantations have been the main cause in the majority of cases of transitional cell carcinoma with cutaneous metastasis. Otherwise, primary cutaneous metastasis is accepted as the late manifestation of systemic spread. The present paper describes a case of relatively early and extensive skin metastasis of transitional cell carcinoma in a 78-year-old man. The patient had a histopathological diagnosis of poorly differentiated (grade III) muscle invasive transitional cell carcinoma with a staging of T2NOMO 6 months prior to presenting. He presented to our outpatient clinic with a 3-month history of skin lesions as multiple, rubbery subcutaneous nodules. Radiological reinvestigation revealed no other metastatic site (including bone and lung), except for a metastatic nodule in the liver. The present paper reports an interesting and rare case of extensive skin metastasis of transitional cell carcinoma as the primary complaint.     

浸润性膀胱癌组织中肿瘤血管形成与淋巴结转移间的关系

目的 通过对浸润性膀胱移行细胞癌(TCCB,T2～T4 NXMO)组织中血管形成的定量研究,探讨微血管密度(Microvessel Density,MVD)与淋巴结转移之间的关系。方法 应用免疫组织化学SP法对23例淋巴结阴性及15例淋巴结阳性浸润性膀胱移行细胞癌组织中的血管进行染色,用微血管密度(MVD)表示血管形成的程度。结果 有淋巴结转移的病例TCCB肿瘤组织中MVD明显高于无转移组(p<0.01)。结论 肿瘤血管形成在TCCB的生长转移过程中起到重要作用,在浸润性ICCB中MVD可推测淋巴结转移状况。     

The impact factors on prognosis of patients with pT3 upper urinary tract transitional cell carcinoma

PURPOSE: Stage 3 upper urinary tract transitional cell carcinoma is a heterogeneous disease including different tumor locations (pelvis vs ureter) and invasion patterns (renal parenchyma, peripelvic fat and periureteral fat). Unfortunately the outcomes of patients with pT3 disease with different invasion pattern are largely unknown. This study presents the clinical outcome of patients with pT3 disease with upper urinary tract transitional cell carcinoma. MATERIALS AND METHODS: We retrospectively reviewed the medical records of all patients with pT3 disease with upper urinary tract transitional cell carcinoma. Four patient groups were classified according to tumor location and tumor invasion pattern. Prognostic factors including age, gender, tumor grade, tumor size, tumor number, tumor location and microscopic finding of vascular invasion were analyzed with respect to disease recurrence and survival. RESULTS: A total of 72 patients were included in this study. The most common complaint and tumor relapse pattern were painless gross hematuria and distant metastasis, respectively. Patients with pT3 disease with superficial parenchymal invasion had better disease-free and recurrence-free survival than the other 3 groups. Initial tumor location (p = 0.02) and vascular invasion (p = 0.02) were independent factors for disease-free survival, and vascular invasion (p = 0.001) was the only predictive factor for recurrence-free survival. CONCLUSIONS: The present study demonstrated that patients with pT3 disease with superficial parenchymal invasion should be considered to have lower stage disease, and that vascular involvement is the only independent prognostic factor for patients with pT3 disease for disease-free and recurrence-free survival. Systemic adjuvant therapy should be recommended for patients with pT3 disease with vascular involvement.     

Independent predictors of metachronous bladder transitional cell carcinoma (TCC) after nephroureterectomy for TCC of the upper urinary tract

OBJECTIVE

To identify the prognostic factors predictive of metachronous bladder transitional cell carcinoma (TCC) in a multi‐institutional dataset of patients who had undergone nephroureterectomy (NU) for nonmetastatic upper urinary tract (UUT) TCC.

PATIENTS AND METHODS

The clinical and pathological data of 231 patients who had had NU for UUT‐TCC from 1989 to 2005 in three European centres were collected retrospectively, and analysed for clinical and pathological variables.

RESULTS

The median follow‐up was 38 months; during the follow‐up, bladder TCC was detected in 109 patients (47.2%), and was significantly more common in patients who had UUT‐TCC after previous bladder TCC (P < 0.001), in those with ureteric cancer (P = 0.022), and in those with pT2 UUT‐TCC (P = 0.017). On multivariate analysis, a previous history of bladder TCC was the only independent predictor of metachronous bladder TCC (hazard ratio 2.825; P < 0.001). The 5‐year probability of being free from metachronous bladder TCC was 45.5%. A history of bladder TCC (P < 0.001) and UUT tumour site (P = 0.01) were significantly associated with the probability of bladder recurrence‐free survival. On multivariate analyses, a previous history of bladder TCC (hazard ratio 2.226; P < 0.001) and the presence of ureteric TCC (1.562; P = 0.036) were independent predictors of the probabilities of being free from metachronous bladder TCC.

CONCLUSION

In this multi‐institutional study of patients who had had NU for UUT‐TCC, a history of bladder TCC was the only independent predictor of metachronous bladder TCC, while both a history of bladder TCC and the presence of ureteric tumours were predictive of the probabilities of being free from metachronous bladder TCC.     

人膀胱浅表性移行细胞癌基因表达变化的基因芯片研究

目的研究人膀胱浅表性移行上皮细胞癌（TCC）和正常膀胱组织差异表达基因。方法应用基因芯片技术对6例膀胱浅表性TCC癌组织和正常膀胱组织的总RNA进行检测。结果在13939条目的基因中共发现差异表达基因720条。在癌组织中234条表达增加，486条表达降低；678条能在GeneBank中登录。结论膀胱浅表性TCC的发生、发展足多基因异常引起多条传导通路异常致使细胞恶性转化的结果，基因芯片技术可同时定量研究大量基因表达水平，是一种稳定、高效的方法。     

淋巴管内皮生长因子-C在膀胱移行细胞癌中的表达及其临床意义

目的 :探讨具有促进淋巴管内皮细胞增殖和毛细淋巴管增生的淋巴管内皮生长因子 C(VEGF C)在膀胱移行细胞癌 (BTCC)中的表达及其与肿瘤淋巴管浸润、淋巴结转移等临床病理因素的关系。方法 :采用免疫组织化学方法研究 4 5例BTCC中VEGF C的表达水平 ,观察评估VEGF C的阳性表达与淋巴管浸润、淋巴结转移等临床病理资料的相关性。结果 :4 5例中 ,VEGF C阳性 36例 ,VEGF C的阳性表达与肿瘤分级、分期、静脉或淋巴管浸润、淋巴结及前列腺侵犯明显相关 (P <0 .0 5 ) ;多因素分析显示VEGF C的表达是唯一影响盆腔淋巴结转移的独立因素 (P =0 .0 0 3)。结论 :VEGF C与BTCC淋巴管浸润和转移有显著相关性 ,检测BTCC中VEGF C的表达能够预示盆腔淋巴结是否转移。     

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。     

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。     

The lymphatic system and its specific growth factor vascular endothelial growth factor C in kidney tissue and in renal cell carcinoma

OBJECTIVE

To determine the role of vascular endothelial growth factor C (VEGF‐C) and the quantitative extent of the lymphatic system in renal cell carcinoma (RCC) to analyse a possible correlation with the metastatic spread of cancer cells.

PATIENTS AND METHODS

In all, 44 patients with clear cell RCC and 12 with papillary or chromophobe RCC were included in an immunohistochemical study. The lymphatic vessel density (LVD) was assessed in the tumour body, the tumour capsule and the tumour‐free adherent renal tissue. The expression of VEGF‐C was semiquantitatively assessed by the percentage of positive epithelial and cancer cells. Data were analysed for any correlation with the clinicopathological variables.

RESULTS

The clear and papillary cell RCC contained no lymphatic vessels (0.2, sd 0.8). Chromophobe RCC specimens showed scattered obliterated vessels (0.0–7.7). Several lymphatic vessels were found in the normal renal tissue, mainly associated with blood vessels (2.9, sd 1.9). The highest mean (sd ) LVD was in the tumour capsule, of 6.9 (3.4). There was no statistical correlation between the LVD and VEGF‐C. In clear cell RCC the expression of VEGF‐C was correlated with the size of the tumour (P = 0.042).

CONCLUSIONS

RCC does not promote the growth of its own lymphatic vessels. The role of a high LVD in the tumour capsule needs to be determined. The VEGF‐C staining pattern in normal kidney tissue hints at functions other than lymphangiogenesis.     

基质金属蛋白酶-9和血管内皮生长因子在膀胱移行上皮细胞癌中的表达及其临床意义

目的探讨基质金属蛋白酶-9（MMP-9）和血管内皮生长因子（VEGF）在膀胱移行上皮细胞癌（BTCC）中的表达及其临床意义。方法采用免疫组织化学SP法检测46例BTCC和10例正常膀胱黏膜组织中MMP-9和VEGF的表达。结果MMP-9和VEGF的阳性表达率在BTCC组中分别为76．09％和67．39％,均显著高于正常组,两组比较差异有统计学意义（P〈0．01）;BTCC中两种蛋白表达水平在高分化组与中低分化组之间、Tis-T1期与T2-T4期间的差异均有统计学意义（P〈0．05）。MMP-9和VEGF两者表达呈正相关。结论MMP-9和VEGF与膀胱移行上皮细胞癌的恶性程度有关,并可作为研究膀胱肿瘤的生物学行为和判断预后的参考指标。     

Contemporary management of stage T1 transitional cell carcinoma of the bladder

PURPOSE: Transitional cell carcinoma involving the lamina propria (stage T1) is associated with a high recurrence and progression rate with implications for patient survival and quality of life. A better understanding of the natural history of and treatment alternatives for this tumor may improve the outcome in patients with this stage of bladder cancer. MATERIALS AND METHODS: Literature of the last decade was comprehensively reviewed in regard to clinical and pathological diagnosis, adjuvant treatments, prognosis, and the role and timing of cystectomy. The information was gathered from MEDLINE, current urology journals, abstracts from recent urological meetings and personal experience. RESULTS: High grade and the depth of lamina propria invasion are important prognostic factors. Early diagnosis and accurate pathological assessment are essential for determining the most adequate treatment pathway. Initial treatment consists of complete transurethral resection and adjuvant treatment with intravesical instillation of bacillus Calmette-Guerin (BCG). Immediate postoperative instillation of mitomycin C decreases the risk of recurrence possibly related to tumor implantation. Intravesical treatment does not substantially decrease the chance of progression. Lack of a complete response to BCG at 3 to 6 months, high grade, the depth of lamina propria invasion, the association of carcinoma in situ and prostate mucosa or duct involvement represent significant predictors for progression. Cystectomy should be suggested for recurrent stage T1 tumor after BCG, new onset or persistent carcinoma in situ, tumor located at a difficult site for resection, prostatic duct or stromal involvement and muscle invasion. CONCLUSIONS: High grade stage T1 transitional cell carcinoma is a highly malignant tumor. Complete resection followed by immediate mitomycin C instillation and 6 weekly BCG instillations results in an acceptably low recurrence and progression rate. Rigorous long-term surveillance and continuous reconsideration of radical cystectomy in concordance with the evolution of the disease are essential.