Expression of matrix metalloproteinases 7 and 2 in human renal cell carcinoma

Matrix metalloproteinases (MMPs) are associated with invasion and metastasis of several malignant tumors in human. Especially so MMP-7, as it is mainly produced by the cancer cell itself. However, the expression of MMP-7 in renal cell carcinoma (RCC) has not been investigated. We examined expressions of MMP-7 and MMP-2 in RCC, and compared them with the clinicopathological characteristics in RCC. Tumor samples from 20 patients with RCC, who had surgery performed at Osaka City University Medical School Hospital, were immunohistochemically stained. Expression of MMP-2 was significantly stronger in advanced stage and in high grade tumors than in low stage and low grade tumors. MMP-7 was also expressed in RCCs, with its expression especially and significantly stronger in high grade than in low grade tumors (p=0.004). However, there was no significant difference of MMP-7 expression between advanced and low stages (p=0.1859). This increased expression of MMP-7 in high grade RCC might be associated with tumor invasion and metastasis.     

Cyclooxygenase-2 Expression in Urinary Bladder Transitional Cell Carcinoma and its Association with Clinicopathological Characteristics

Background: Transitional cell carcinoma (TCC) is the most predominant type of urinary bladder tumor. Ascyclooxygenase (COX)-2 is recently introduced as an attractive target molecule in bladder TCC, we evaluated theimmunohistochemical expression of this marker and its association with several clinicopathological characteristics.Materials and Methods: This cross-sectional study was performed in the Pathology department of Sina Hospitalin Tehran, Iran during 2006-2011. Ninety-two paraffin embedded blocks were selected from patients withurinary bladder TCC who underwent cystectomy or transurethral resection (TUR). Then, we assessed COX-2expression by immunohistochemical staining using antibody against COX-2. Staining in more than 5% of tumorcells was considered as positive expression. Results: COX-2 was expressed in 50 % of our patients. This markerwas markedly expressed in high grade bladder TCC (62.1%) versus other grades and there was statisticallya significant difference in COX-2 expression between various grades (p=0.008). In addition, patients’ age,lymphatic and perineurial invasion were associated with the expression of COX-2 (p=0.001, 0.015 and 0.039,respectively). However, other parameters such as stage, tumor size, venous invasion and lymph node metastasisdid not show any significant relationship with this marker (all, p>0.05). Conclusions: COX-2 was expressed inurinary bladder TCC especially in high grade forms, advocating its probable role in the differentiation of thistumor. Accordingly, COX-2 could be a valuable biological target molecule in the evaluation and treatment ofpatients with bladder TCC.     

The prognostic value of angiogenesis and metastasis-related genes for progression of transitional cell carcinoma of the renal pelvis and ureter.

PURPOSE: We reported previously that angiogenesis evaluated by intratumor microvessel density (MVD), expression of such angiogenic factors as vascular endothelial cell growth factor (VEGF) and basic fibroblast growth factor (bFGF), and the matrix metalloproteinase-9:E-cadherin ratio (M:E ratio) could identify patients with advanced transitional cell carcinoma (TCC) of the bladder for whom chemotherapy and cystectomy will be unsuccessful. In the present study, we evaluated the significance of the M:E ratio as a predictor for prognosis for patients with TCC in the upper urinary tract (TCC-UUT). EXPERIMENTAL DESIGN: We evaluated MVD by immunohistochemistry and the expression of angiogenic and metastasis-related factors by in situ hybridization in 55 nephroureterectomy specimens from patients who received no neoadjuvant therapy. The expression of angiogenesis, angiogenic and metastasis-related factors, and clinicopathological characteristics were evaluated for their correlation with metastasis, recurrence, and disease prognosis. RESULTS: We found that tumor grade and pathological stage were important predictors for metastasis and survival in these patients. The expression level of matrix metalloproteinase type 9 (MMP-9) and type 2 (MMP-2) and the M:E ratio correlated with MVD. Increased MVD, elevated expression levels of MMP-9 and MMP-2, and a higher M:E ratio were associated with poor prognosis. Moreover, lower expression levels of E-cadherin were associated with fewer recurrences in the urinary bladder. Multivariate analysis indicated that the M:E ratio and E-cadherin expression were independent prognostic factors for disease progression and intravesical recurrence, respectively. CONCLUSION: We suggest that the M:E ratio and E-cadherin expression may be targets for novel therapeutic strategies.     

Alteration in urinary matrix metalloproteinase-9 to tissue inhibitor of metalloproteinase-1 ratio predicts recurrence in nonmuscle-invasive bladder cancer.

PURPOSE: The purpose is to assess the prognostic significance of matrix metalloproteinase (MMP)-9 in patients with bladder cancer using a combination of ELISA (to measure MMP-9 in voided urine) and immunohistochemistry (to study MMP-9 in bladder tumors). The relationship between MMP-9 and its principal inhibitor, tissue inhibitor of metalloproteinase (TIMP)-1 (in voided urine samples) was also studied. EXPERIMENTAL DESIGN: A total of 134 patients with bladder tumors (7 cis, 76 T(a), 27 T(1), 24 T(2)-T(4); 40 G1, 43 G2, and 44 G3), 33 patients with benign urological conditions, and 36 healthy volunteers was studied. Samples from 106 patients with bladder cancer and 12 controls were stained for MMP-9. Clinical follow-up data were available on 116 patients (median: 25 months; range: 4-36 months). RESULTS: MMP-9 was present in all urine samples analyzed. There were no differences between patients with cancer and patients with benign disorders. However, patients had significantly higher urinary MMP-9 than normal volunteers (P = 0.0167). Urinary MMP-9 was associated with bladder tumors of advanced stage (P = 0.0065) and large size (P < 0.0001) but not with grade (P = 0.14), multiplicity (P = 0.31), recurrence (P = 0.55), progression (P = 0.83), or survival (P = 0.55). Low MMP-9:TIMP-1 ratios in patients with nonmuscle-invasive tumors were associated with higher recurrence rates (P = 0.0035). Sixty percent (64 of 106) of bladder tumor specimens expressed MMP-9 compared with none of 12 normal urothelial biopsies (P < 0.0001). MMP-9 staining was associated with tumor size (P = 0.014), disease progression (P = 0.005), and poor disease-specific survival (P = 0.022) but was unrelated to tumor stage (P = 0.46), grade (P = 0.26), multiplicity (P = 0.85), or recurrence rate (P = 0.62). CONCLUSIONS: High urinary MMP-9 levels are associated with large bladder tumors. A low urinary MMP-9:TIMP-1 ratio may indicate a higher risk of intraluminal nonmuscle-invasive tumor recurrence and may assist in planning follow-up surveillance protocols.     

Microsatellite instability in transitional cell carcinoma of the urinary tract and its relationship to clinicopathological variables and smoking

To determine whether microsatellite instability is involved in the development of transitional cell carcinoma (TCC) of the urinary tract, a microsatellite instability assay was carried out using PCR with 9 microsatellite loci. Thirty-eight TCC samples (30 patients with bladder cancer, 5 with renal pelvic tumors and 3 with ureteral tumors) and 1 lymph node with metastasis were examined. Microsatellite instability was found in 8 of 38 tumors examined, and 3 showed alterations in more than 2 microsatellite loci. All 8 tumors were beyond grade 2 and stage pT2 advanced tumors. Stages pT1-2 and pT3-4 patients differed significantly. Microsatellite instability was greater in smokers than non-smokers, but the differences were not significant. Microsatellite instability in TCC of the urinary tract is rare in superficial tumors but more common in invasive tumors. Microsatellite alterations would thus appear to occur, and possibly be importantly involved, in the tumorigenesis of urinary tract TCC. © 1996 Wiley-Liss, Inc.     

Promoter hypermethylation is associated with tumor location, stage, and subsequent progression in transitional cell carcinoma.

PURPOSE: Transitional cell carcinoma (TCC) is a pan-urothelial disease characterized by multiplicity. Although little is known about the molecular events in upper-tract TCC, similar carcinogenic mechanisms are thought to occur throughout the urinary tract. However, we have previously shown that distinct patterns of microsatellite instability occur in upper and lower urinary tract TCC, suggesting biologic differences between these tumors. Here we investigate the extent of promoter hypermethylation in TCC throughout the urinary tract. PATIENTS AND METHODS: Tissue was obtained from 280 patients (median follow-up, 56 months) whose tumors comprised 116 bladder and 164 upper-tract tumors (UTT). Analysis for hypermethylation at 11 CpG islands, using methylation-sensitive polymerase chain reaction and bisulfite sequencing, was performed for each sample and compared with the tumor's clinicopathologic details, microsatellite instability status, and subsequent behavior. RESULTS: Promoter methylation was present in 86% of TCC and occurred both more frequently and more extensively in UTT (94%) than in bladder tumors (76%; P < .0001). Methylation was associated with advanced tumor stage (P = .0001) and higher tumor progression (P = .03) and mortality rates (P = .04), when compared with tumors without methylation. Multivariate analysis revealed that methylation at the RASSF1A and DAPK loci, in addition to tumor stage and grade, were associated with disease progression (P < .04). CONCLUSION: Despite morphologic similarities, there are genetic and epigenetic differences between TCC in the upper and lower urinary tracts. Methylation occurs commonly in urinary tract tumors, may affect carcinogenic mechanisms, and is a prognostic marker and a potential therapeutic target.     

环氧化酶-2 在膀胱癌组织及尿脱落细胞中的表达和意义

 目的 探讨COX-2在膀胱癌组织中的表达，了解尿脱落细胞COX-2表达在膀胱癌早期诊断中的价值。方法 应用免疫组化技术检测48例膀胱移行细胞癌组织、免疫细胞化学技术检测40例膀胱移行细胞癌患者和30例非肿瘤患者尿脱落细胞COX-2的表达。结果 膀胱移行细胞癌组织COX-2阳性表达率为72．9％，对照组正常膀胱黏膜无表达。COX-2的表达与膀胱癌临床分期显著相关(P<0．05)，不同病理分级膀胱癌的表达差别无显著性意义。非肿瘤患者尿脱落细胞无COx-2表达，膀胱癌尿脱落细胞COX-2免疫细胞化学检测阳性率为67．5％，明显高于常规尿细胞学的37．5％(P<0．05)，尤其对于G1级和Ta～T1期的低级、早期肿瘤，尿脱落细胞COX-2免疫细胞化学检测与常规尿细胞学检查相比，具有显著性意义(P<0．05)。结论 COX-2在膀胱移行细胞癌的发生发展中起重要作用，与肿瘤的浸润、转移相关。尿脱落细胞COX-2表达检测特异性高，可作为早期诊断膀胱癌的一种标志物。     

Assessing CD 10 Expression Level and Its Prognostic Impact in Egyptian Patients with Urothelial Carcinoma

Background and aim: CD10 is expressed in urothelial carcinoma cells and cancer associated fibroblasts (CAF). In the current study, CD10 immunohistochemical staining (IHC) and CD10 mRNA expression in urothelial carcinoma of bladder (UCB) were assessed, and its  relationship with tumor progression and prognosis was investigated. Patients and Methods: In this study, 106 formalin fixed paraffin-embedded (FFPE) tissue of UCB, obtained through radical cystectomy specimen, and 10 matched normal tissue samples were included.CD10 expression was evaluated by immunohistochemistry and real time PCR techniques. Results: CD10 expression in tumor cells and associated stromal fibroblasts was significantly associated with high tumor grade and advanced stage. Significant correlation was found between CD10 tumor expression and lymphovascular invasion (LVI) (P<0.001) as well as perineural invasion (PNI). CD10 expression in stromal fibroblasts was significantly associated with squamous differentiation of tumor cells, lymph node metastasis (LNM), and tumor necrosis. Positive CD10 expression in both tumor cells and associated stromal fibroblasts was associated with shorter OS . CD10 mRNA was overexpressed in tumors in comparison with the matched normal tissues. CD10 mRNA was significantly higher in invasive tumor, advanced stage tumor, and high grade tumor. There was significant correlation between CD10 mRNA tumor expression and LVI, PNI, and tumor recurrence. Conclusion: Increased expression of CD10 in the tumor and CAF was strongly correlated with tumor progression, invasion, metastasis, shorter OS, and RFS in urothelial carcinoma patients. CD10 mRNA showed significantly higher expression in tumor tissue than in matched normal tissue. CD10 mRNA was associated with depth of invasion, TNM stage, tumor grade, vascular tumor invasion, and tumor recurrence.     

Epithelial MMP-2 expression correlates with worse prognosis in pancreatic cancer

OBJECTIVE: Matrix metalloproteinases (MMPs) degrade extracellular matrix and are involved in tumor invasion and metastasis in various cancers. In pancreatic cancer, MMP-2 expression is upregulated and correlates with tumor recurrence. The aim of this study was to evaluate the prognostic significance of MMP-2 in pancreatic ductal adenocarcinoma. METHODS: MMP-2 expression was assessed by immunohistochemistry in 127 patients operated on at Helsinki University Hospital from 1974 to 1998, with expression interpreted separately in epithelial and stromal samples. RESULTS: Epithelial MMP-2 expression was strong in 5%, moderate in 20%, weak in 25% and negative in 50% of the tumors, with high epithelial MMP-2 expression significantly associated in univariate survival analysis with advanced stage, poor grade and poor survival. Stromal MMP-2 expression was strong in 0%, moderate in 14%, weak in 70% and negative in 16% of the cases, and did not significantly correlate with patient survival. CONCLUSION: Epithelial MMP-2 correlates with advanced tumor stage and grade, but is not an independent predictor of survival.     

NDRG-1及MMP-7在肾细胞癌中的表达及意义

目的研究N-myc 下游调节基因(NDRG-1)和基质金属蛋白酶7（MMP-7）在肾细胞癌组织中的表达,探讨其与肾细胞癌临床病理因素和预后的关系及意义。方法应用免疫组织化学SP法检测78例肾细胞癌组织及相对应的癌旁肾脏组织中NDRG-1、MMP-7表达情况。结果 NDRG-1在正常肾组织和肾细胞癌组织中的表达率分别为100%和52.6%,差异有统计学意义（P<0.05）。NDRG-1表达与肿瘤大小、肾静脉癌栓、肾门淋巴结转移、肾盂浸润、病理组织学分级、临床分期有显著性差异,呈负相关（P<0.05）。MMP-7在肾细胞癌组织中表达率为55.1%,在癌旁肾脏组织中几乎不表达。MMP-7表达与肾细胞癌包膜浸润、淋巴结转移差异有统计学意义(P< 0.05),并与病理组织学分级、临床分期呈正相关(P< 0.05)。NDRG-1表达阴性和MMP-7表达阳性病例术后生存时间分别显著短于NDRG-1阳性和MMP-7阴性病例（P=0.001）。肾细胞癌组织中NDRG-1和 MMP-7表达无相关性（r_s=-0.198,P=0.082）。结论NDRG-1表达降低和MMP-7升高与肾细胞癌的浸润、转移及生存时间密切相关,NDRG-1和MMP-7可作为早期预测肾细胞癌转移和判断恶性度及预后有意义的指标。     

上皮细胞钙粘蛋白(E-cadherin) 在膀胱移行细胞癌中的表达及其意义

 目的　观察上皮细胞钙粘蛋白(E-cad)表达与膀胱移行细 胞癌(TCC)分级、分期等生物学行为的关系。方法　采用恒冷切片免疫组 织化学SP法,对28例TCC和10例正常膀胱粘膜新鲜冰冻标本进行E-cad表达的检测。结果　对照组10例正常膀胱粘膜E-cad均正常表达,实验组28例TCC,仅50%(14/ 28)正常表达,二组差异显著(P<0.01)。TCC不同分级、分期间E-cad表达有显著性差 异(P<0.05),G3比G1+G2表达低,浸润性TCC比浅表性TCC表达低。初发与复发、 单发与 多发TCC之间比较,E-cad表达均未见显著性差异(P>0.05)。本组未见E-cad表达完全 缺失的TCC。结论　正常膀胱粘膜组织E-cad保留表达,TCCE-cad表达降 低,E-cad表达与TCC分级、分期呈负相关;E-cad表达与TCC的数目,与肿瘤的初发或复发 无关。     

Prognostic Significance of Matrix Metalloproteinase-7 (MMP-7) Expression at the Invasive Front in Gastric Carcinoma

To evaluate the clinicopathological significance of matrix metalloproteinase-7 (MMP-7) expression in gastric carcinoma, we investigated immunohistochemically MMP-7 expression in 214 gastric carcinomas, and examined its relations with the clinicopathologic parameters including patient prognosis. MMP-7 expressed predominantly in cancer cells, and MMP-7-positive tumor cells were preferentially found in deeply invading nests, especially at the invasive front. The mean MMP-7 labeling index (LI) at the invasive front was significantly higher in tumors invading or penetrating the muscularis propria and in stages II-IV than within the submucosal layer and in stage I, respectively ( P <0.001). Statistical analysis revealed that MMP-7 LI at the invasive front was related to lymph node metastasis, vascular invasion, and lymphatic permeation, when all 214 cases were examined as one group ( P <0.05 for all), and the cases with high MMP-7 expression at the invasive front showed significantly more unfavorable prognosis as compared with that of low MMP-7 expression tumors ( P <0.01). Multivariate analysis revealed that TNM stage and MMP-7 expression status at the invasive front were independent prognostic factors ( P =0.0017, relative risk (RR)=3.12; P =0.0019, RR=2.67, respectively). Our findings indicated that expression of MMP-7 at the invasive front is closely associated with local invasiveness, and might be a reliable prognostic marker for patients with gastric carcinoma.     

Frequent administration of angiogenesis inhibitor TNP-470 (AGM-1470) at an optimal biological dose inhibits tumor growth and metastasis of metastatic human transitional cell carcinoma in the urinary bladder.

PURPOSE: The angiogenic inhibitor TNP-470 (AGM-1470, O-chloracetyl-carbamoyl fumagillol) has been reported to inhibit the growth of human transitional cell carcinoma (TCC) in the urinary bladder. However, it is still unknown whether TNP-470 inhibits metastasis of TCC. Here, we identify an efficient protocol using TNP-470, and optimize its antitumor and antimetastatic effects on human TCC in the urinary bladder. EXPERIMENTAL DESIGN: In vitro, the human metastatic TCC cell line 253J B-V and human umbilical vascular endothelial cells were treated with TNP-470, and examined for cell growth and protein production of angiogenic factors. To study in vivo effects of TNP-470, 253J B-V cells were implanted orthotopically into athymic nude mice. TNP-470 was administered in several dosing and scheduling regimens, and its effects on tumor growth, metastasis, intratumor neovascularization, and mRNA expression of angiogenic factors were determined in both nonestablished and established tumors. RESULTS: In vitro treatment with TNP-470 inhibited cell growth and production of basic fibroblast growth factor protein in 253J B-V and human umbilical vascular endothelial cells in a dose-dependent manner. In vivo daily administration of TNP-470 significantly inhibited tumor growth (P < 0.001), metastasis (P < 0.05), intratumor neovascularization (P < 0.005), and mRNA expression of basic fibroblast growth factor and MMP-9 (P < 0.005), in both nonestablished and established tumors. Increasing the daily dose did not increase the effect on tumor growth, metastasis, and angiogenesis; however, the drug-induced toxicity did increase in a dose-dependent manner. CONCLUSIONS: Frequent administration of TNP-470 at an optimal biological dose provided maximal antitumor and antimetastatic effects of human TCC of the urinary bladder. It may function by down-regulating angiogenic factors.     

人膀胱移行细胞癌内的16／18型人乳头状瘤病毒感染

目的 探讨人膀胱移行细胞癌与高危型人乳头瘤病毒感染的关系。方法 采用聚合酶链式反应（ＰＣＲ法）检测１１２例膀胱移行细胞组织（包括７５例石蜡包埋组织和３７例手术切除组织）和７例正常膀胱粘膜组织的ＨＰＶ－１６／１８感染率及ＨＰＶ－１６／１８感染与膀胱移行细胞癌病理分极及临床分期的关系。同时检测了２４例膀胱癌病人尿液沉淀中ＨＰＶ阳性率。结果 膀胱移行细胞癌的ＨＰＶ－１６／１８的总感染率为６２．５０％（７     

髓母细胞瘤的CT诊断(附50例分析)

 目前CT在诊断髓母细胞瘤方面虽有经验，但也经常遇到一些非典型CT表现的特殊病例误诊为其他颅内肿瘤。为进一步提高髓母细胞瘤的CT诊断水平，对经CT检查，并经手术病理证实的50例髓母细胞瘤总结如下。     

Prognostic significance of matrix metalloproteinase-7 (MMP-7) expression at the invasive front in gastric carcinoma.

To evaluate the clinicopathological significance of matrix metalloproteinase-7 (MMP-7) expression in gastric carcinoma, we investigated immunohistochemically MMP-7 expression in 214 gastric carcinomas, and examined its relations with the clinicopathologic parameters including patient prognosis. MMP-7 expressed predominantly in cancer cells, and MMP-7-positive tumor cells were preferentially found in deeply invading nests, especially at the invasive front. The mean MMP-7 labeling index (LI) at the invasive front was significantly higher in tumors invading or penetrating the muscularis propria and in stages II - IV than within the submucosal layer and in stage I, respectively (P < 0.001). Statistical analysis revealed that MMP-7 LI at the invasive front was related to lymph node metastasis, vascular invasion, and lymphatic permeation, when all 214 cases were examined as one group (P < 0.05 for all), and the cases with high MMP-7 expression at the invasive front showed significantly more unfavorable prognosis as compared with that of low MMP-7 expression tumors (P < 0.01). Multivariate analysis revealed that TNM stage and MMP-7 expression status at the invasive front were independent prognostic factors (P = 0.0017, relative risk (RR) = 3.12; P = 0.0019, RR = 2.67, respectively). Our findings indicated that expression of MMP-7 at the invasive front is closely associated with local invasiveness, and might be a reliable prognostic marker for patients with gastric carcinoma.     

Profiling of matrix metalloproteinases and tissue inhibitors of metalloproteinases proteins in bladder urothelial carcinoma

We investigated the matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinase (TIMPs) proteins in transitional cell carcinoma (TCC) cell lines and surgical specimens of the bladder neoplasm. The expression level was correlated to the degree of cellular differentiation and invasiveness of bladder cancer. Panels of six TCC cell lines with different degrees of differentiation were tested with monoclonal antibodies (mAbs) to MMP-1, MMP-2, MMP-3, MMP-9a, MMP-9b, TIMP-1 and TIMP-2 by immunocytochemistry. Gelatin zymography was also conducted on the cell lines for MMP-2 and -9. In addition, immunohistochemistry with the mAbs to MMP and TIM molecules was performed on 30 TCC specimens. We found that TCC cell lines were stained positively for MMP-1 (6/6), weakly for MMP-9a (2/6), MMP9b (5/6) and TIMP-1 (3/6), and negatively for MMP-2 (3/6) and MMP-3 (3/6). Zymographic analysis of the cell lines showed a high level of MMP2 in the MGH-U4 cell line. In bladder cancer surgical specimens, all specimens were positive for MMP1 (30/30), 19 were positive for MMP-2 (63.3%), 21 positive for MMP-9a (70%) and 15 positive for MMP-9b (50%). The expression of MMP-2 was found to be positively correlated with higher-grade tumors (p=0.036) and the expression of MMP-9a and -9b was found to be positively correlated with tumor stage (p=0.012 and 0.023, respectively). However, the expression of MMP-1, MMP-3, TIMP-1 and TIMP-2 was not correlated with either tumor staging or grading. In conclusion, the expression of MMP-2 and -9 was correlated with high-grade or high-stage bladder tumors, respectively. However, this correlation was not observed with TCC cell lines in which high- and low-grade tumors are included. Immunohistochemical results on tumor lesions may have more clinical relevance, since in a given tumor microenvironment the interaction among tumor cells in situ and tumor-associated cells, such as neutrophils, macrophages, lymphocytes and endothelial cells, as well as environmental factors (hypoxia and pH), cytokines and growth factors released by these cells may be required for TCC to express selective MMPs and TIMPs. The selective expression of these molecules then regulates tumor progression.     

Tumor grade and stage as prognostic variables in upper tract urothelial tumors

Clinical and pathologic data of 54 patients with clinically localized transitional cell tumors of the upper urinary tract were reviewed to determine the significance of tumor grade and stage on patient survival. There were 43 tumors of the renal pelvis (one bilateral) and 11 tumors of the ureter. The primary tumor was staged by the new TNM classification into low stage (Ta: limited to mucosa; T1: lamina propria invasion) and high stage (T2: muscularis invasion; T3; invasion beyond the muscularis). Tumors were low stage (Ta/T1) in 28 cases (51.8%) and advanced (T2/T3) in 26 cases (48.2%). Twenty-five of 54 (46.3%) of the patients had low grade (Grades 1 and 2) and 29 of 54 (53.7%) had high grade (Grades 3 and 4) tumors. Median survival for all patients from date of diagnosis was 31 months, with a 5-year survival rate of 45.8%. Grade (low/high) matched stage (low/high) in 45 of 54 patients (83%). Median survival for patients with low grade tumors was 66.8 months compared to 14.1 months in patients with high grade tumors. Median survival for low stage tumors was 91.1 months and for high stage tumors was 12.9 months. These differences in survival related to both tumor stage (P = 0.001) and grade (P = 0.004) were statistically significant by log-rank test. Fourteen of the 54 patients (25.9%) developed local recurrence and 29 (53.7%) developed distant metastases. The lung was the most common site of metastasis. Eighteen patients (33.3%) had or developed transitional cell carcinoma of the bladder, which preceded the diagnosis of transitional cell carcinoma of the upper tract in seven cases and developed subsequently in 11 cases. Primary tumor stage by the new TNM classification is a better predictor of prognosis than tumor grade, although both variables are strongly predictive of patient course and survival. The advantages of the new TNM classification are discussed.