Expression of survivin does not predict survival in patients with transitional cell carcinoma of the upper urinary tract

The members of the IAP (inhibitors of apoptosis) family, which includes survivin, have recently emerged as modulators of an evolutionarily conserved step in apoptosis. Survivin is present during embryonic and fetal development, but it is downregulated in normal adult tissues. However, it becomes re-expressed in a variety of cancers. We investigated the prognostic importance of the expression of survivin in transitional cell carcinoma of the upper urinary tract (TCC-UUT). In 126 cases of TCC-UUT, we examined its expression (using immunohistochemistry), and also its relationship with the expressions of bcl-2 oncoprotein, p53 oncoprotein, and proliferating cell nuclear antigen (PCNA) immunoreactivity, clinicopathologic parameters, and clinical outcome. A positive expression of survivin was recognized in 12.7% of samples, a granular pattern being apparent within the cytoplasm of tumor cells. Survivin expression did not correlate with clinicopathologic findings, bcl-2 oncoprotein expression, p53 oncoprotein expression, PCNA index, or prognosis. In the normal urothelium, its expression was not detected. In conclusion, the expression of survivin does not predict prognosis in TCC-UUT.     

Expression of p27(Kip1) protein in transitional cell carcinoma of the upper urinary tract.

The expression of p27(Kip1), a negative regulator of the cell cycle, has been reported to correlate with the biological behavior and prognosis of several tumors. However, its prognostic importance in transitional cell carcinoma of the upper urinary tract (TCC-UUT) has not previously been investigated. We investigated p27(Kip1) protein expression using immunohistochemistry in 132 cases of TCC-UUT and also its relation to proliferating cell nuclear antigen (PCNA) immunoreactivity, p53 oncoprotein immunoreactivity, clinicopathologic parameters, and clinical outcome. A positive expression of p27(Kip1) protein was recognized in 94.7% of the samples and was apparent within tumor nuclei. In the normal urothelium, its expression was identified in all cell layers. A positive expression of p53 oncoprotein was recognized in 27.2% of the patients. The PCNA index was 7.4 to 93.1% (mean, 66.4%). Examination of the relationships between the expression of p27(Kip1) protein and clinicopathologic findings, PCNA index, and the expression of p53 oncoprotein revealed that the expression of p27(Kip1) protein decreased significantly with stage and grade. In a univariate analysis of disease-free and overall survival rates, no correlation was found between the expression of p27(Kip1) protein and prognosis. The expression of p27(Kip1) protein appears to be of little or no value in informing the prognosis in TCC-UUT.     

Expression of bcl-2 oncoprotein in transitional cell carcinoma of the upper urinary tract

 We investigated the immunoreactivity for bcl-2 oncoprotein in 154 cases of transitional cell carcinoma of the upper urinary tract (TCC-UUT) and its relation with the immunoreactivity for p53 oncoprotein and proliferating cell nuclear antigen (PCNA) immunoreactivity. Immunohistochemically, bcl-2 oncoprotein was recognized as positive in 29.2% of the samples. The immunoreactivity for bcl-2 oncoprotein was significantly (P < 0.05) correlated only with stage, though there was a borderline correlation (P = 0.050) with PCNA immunoreactivity. Furthermore, in invasive TCC the immunoreactivity for bcl-2 oncoprotein was associated with PCNA immunoreactivity (P < 0.041). The 5-year disease-free and overall survival rates were 55.7% and 71.5%, respectively. A univariate analysis of survival revealed that stage, grade, pattern of growth, immunoreactivity for p53 oncoprotein, and PCNA immunoreactivity each had a significant effect on disease-free and overall survival rates, whereas the immunoreactivity for bcl-2 oncoprotein had no significant effect on either rate. In the final models of the multivariate analysis, stage was found to be the only prognostic factor for disease-free survival and for overall survival. Detection of immunoreactivity for bcl-2 oncoprotein appears to be of no real value in deciding the prognosis of TCC-UUT. Received: 3 July 1997 / Accepted: 29 October 1997     

Analysis of the clinicopathological characteristics of patients with upper urinary tract transitional cell carcinoma

OBJECTIVE: To describe the clinicopathological characteristics of patients with upper urinary tract transitional cell carcinomas who are treated surgically and to analyze the occurrence of bladder tumors as well as the development of metastases outside the urinary tract. MATERIALS AND METHODS: The study comprised a retrospective analysis of 25 patients treated between February 1994 and August 2006. The variables analyzed were: patient age, gender, and clinical presentation; diagnostic methods; pathologic characteristics at the primary site of the tumor (pelvis or ureter); tumor stage and grade; and presence of carcinoma in situ, microvascular invasion and squamous differentiation. The Kaplan-Meier method and the Log-Rank test were used for statistical analysis of bladder recurrence-free survival. RESULTS: Eighty-four percent of patients were male, and macroscopic hematuria was the most common clinical presentation. The majority of cases (56%) were infiltrative (T2-T3) and high-grade (76%) tumors. Synchronous or metachronous bladder tumors were found in 72% of cases. Five (20%) patients had a history of bladder tumor before the diagnosis of upper urinary tract transitional cell carcinomas. The mean follow-up period was 36 months (range: 1.5 to 156). During the follow-up period, eleven (44%) patients developed bladder tumors. After five years, the probability of being free of bladder tumor recurrence was 40%. No pathological variable was predictive for bladder tumor recurrence. Four patients presented disease recurrence outside the urinary tract. CONCLUSIONS: The presence of metachronous bladder tumors is more often observed after the diagnosis of upper urinary tract transitional cell carcinomas. All of these patients should undergo rigorous follow-up during the postoperative period. Only patients with infiltrative and high-grade tumors developed metastases outside the urinary tract.     

Prognostic factors influencing survival after nephroureterectomy for transitional cell carcinoma of the upper urinary tract

We analyzed the prognostic factors influencing survival after surgeries for upper urinary tract urothelial carcinoma (UUT-UC) with longer follow-up periods than in previous studies. Between January 2000 and December 2004, 386 patients underwent nephroureterectomy for UUT-UC. The data for the 221 patients with UUT-UC were retrospectively reviewed. Nine variables were evaluated for association with the survival outcomes of disease-specific survival. The prognostic significance was tested univariately with the log-rank test. The simultaneous effects of multiple prognostic factors were estimated by multiple regression analysis using the Cox proportional hazards model. The median follow-up was 38.4 months. The 5-year over all survival was 62.3%. Significant prognostic factors for disease-specific survival rate on univariate analysis were pathological stage (p＜0.0001), tumor grade (p＝0.0324), and venous invasion (p＜0.0001). Multivariate analysis revealed that only venous invasion was significant for disease-specific survival rate (p＝0.0205). Venous invasion was the only independent prognostic factor in pathologically localized UUT-UC.     

Expression of LAT1 predicts risk of progression of transitional cell carcinoma of the upper urinary tract

L-type amino acid transporter 1 (LAT1), a neutral amino acid transporter, requires covalent association with the heavy chain of 4F2 cell surface antigen (4F2hc) for its functional form. We investigated the importance of LAT1 and 4F2hc expressions to progression in upper urinary tract cancer. We examined their expressions and their relationships to clinicopathologic parameters and clinical outcome in 124 cases. Positive expressions of LAT1 (protein and messenger ribonucleic acid) and 4F2hc (protein) were recognized in 79.8, 89.5, and 87.9% of tumor samples, respectively. In tumor cells, LAT1 protein was detected either as nodular granules within the cytoplasm or diffusely within the cytoplasm and/or on plasma membrane. In the normal urothelium, its expression was detected as nodular granules within the cytoplasm. A correlation with stage was shown for LAT1 protein expression and for a cooperative expression of LAT1 protein with 4F2hc protein (active form of LAT1 protein). Further, in all tumors, a cooperative expression of LAT1 protein and 4F2hc protein was significantly correlated with both overall and disease-free survival rates in the univariate analysis but not in the multivariate analysis. In conclusion, the detection of the active form of LAT1 protein would appear to be of value in informing the risk of progression in transitional cell carcinoma of the upper urinary tract.     

Prognostic value of keratin subtyping in transitional cell carcinoma of the upper urinary tract

To investigate the prognostic value of keratin subtyping in invasive transitional cell carcinomas (TCCs), we performed a systematic study applying 15 different monoclonal keratin antibodies on 53 upper urinary tract TCCs using a tissue microarray technique. Immunoreactivity was correlated with pT stages and tumour grades using the Fishers exact test. Impact on disease-free survival was analysed using the Kaplan-Meier method and compared by the log-rank test. Immunoreactivity for keratins 5/6, 6, 7, 8, 13, 14, 17, 18, 19, 20, low molecular weight (LMW) keratins (8, 18) and high molecular weight (HMW) keratins (1, 5, 10, 14) was detected in varying quantities. Regarding semi-quantitative assessment, a prognostic impact was found for keratins 5/6, 7, 8, 13, 17, 20 and HMW keratins, with reduced expression or loss of immunoreactivity being significantly associated with disease progression. With respect to analysis of staining patterns, the retention of a basally accentuated labelling for keratin 5/6 and HMW keratin as well as a superficially accentuated labelling for keratin 20 was significantly associated with a favourable outcome. In conclusion, this investigation is the first to demonstrate a possible prognostic value for keratin subtyping in invasive (upper urinary tract) TCCs with respect to metastasis-free survival. Further studies, however, are needed to substantiate our results.     

Scanning electron microscopy of the upper urinary tract in transitional cell carcinoma of the renal pelvis.

Three nephrectomy specimens with transitional cell carcinoma (TCC) of the renal pelvis were thoroughly examined by both light and scanning electron microscopy. The tumours as well as the urothelium of the upper urinary tract were studied. In all three cases, extensive areas of the urothelium, even in places remote from the tumours, were found by scanning electron microscopy (SEM) to be covered by pleomorphic microvilli. This suggests that there is a widespread failure of differentiation of the urothelium to a much greater extent than can be appreciated by conventional light microscopy.     

Cytogenetic investigation of transitional cell carcinomas of the upper urinary tract.

Cytogenetic investigation was attempted on 44 tumors from 44 patients with transitional cell carcinoma (TCC) of the upper urinary tract (pelvis and ureter), and karyotypes were obtained in 27 tumors. Numerical changes prevailed, but are not specific for this type of tumor (trisomy 7, -Y, or both). In the light of previously reported data on TCC, the finding of a del(9q) as the only anomaly in one of the cases may be meaningful. Patients showing -Y and/or trisomy 7 had a poor prognosis.     

Immunohistochemical evaluation of p53 oncoprotein in transitional cell carcinoma of the upper urinary tract

The p53 gene, which is located on human chromosome 17, encodes for a nuclear phosphoprotein and is thought to regulate cell growth and proliferation. Although the immunoreactivity for p53 oncoprotein in transitional cell carcinoma (TCC) of the urinary bladder has been shown to correlate with clinicopathologic findings and prognoses, there have been no such reports on TCC of the upper urinary tract (TCC-UUT). The present study investigated the prognostic value of p53 oncoprotein in TCC-UUT. Formalin-fixed, paraffin-embedded tumor tissues from 149 TCC-UUT patients were analyzed using immunohistochemical staining. Immunohistochemically, p53 oncoprotein was recognized as positive in 26.8% of the samples. The immunoreactivity for p53 oncoprotein was significantly (P < .05) correlated with both stage, grade, and pattern of growth. The 5-year disease-free and overall survival rates were 58.4% and 69.7%, respectively. A univariate analysis of survival showed that stage, grade, pattern of growth, and the immunoreactivity for p53 oncoprotein have a significant effect on disease-free and overall survival rates. In the final models of multivariate analysis, only stage for disease-free survival, and stage and the immunoreactivity for p53 oncoprotein for overall survival were found to be progressive or prognostic factors. Detection of immunoreactivity for p53 oncoprotein appears to be of real value in deciding the prognosis of TCC-UUT.     

Scanning electron microscopy of the upper urinary tract in transitional cell carcinoma of the renal pelvis

Three nephrectomy specimens with transitional cell carcinoma (TCC) of the renal pelvis were thoroughly examined by both light and scanning electron microscopy. The tumours as well as the urothelium of the upper urinary tract were studied. In all three cases, extensive areas of the urothelium, even in places remote from the tumours, were found by scanning electron microscopy (SEM) to be covered by pleomorphic microvilli. This suggests that there is a widespread failure of differentiation of the urothelium to a much greater extent than can be appreciated by conventional light microscopy.     

Pathological function of prostaglandin E2 receptors in transitional cell carcinoma of the upper urinary tract

The prostaglandin E2 receptor, EP4 receptor (EP4R), plays an important role in the development of transitional cell carcinoma of the upper urinary tract (TCC-UUT). However, the clinical significance of other EP receptors (EP1R–3R) is not clear. Furthermore, the pathological function of EP receptors in such patients is not understood. In the present study, we examined the expression of EP1R–3R in 101 TCC-UUT tissues by immunohistochemistry. Furthermore, we defined the relationship between cyclooxygenase (COX)-2 and EP receptor expression, proliferation index (PI), microvessel density (MVD), and expression of metalloproteinase-2 (MMP-2), urokinase-type plasminogen activator (uPA), and exon v6 containing CD44 isoform (CD44 v6) by multivariate analysis. The expression of EP1R, EP2R, and EP3R was positive in 20 (19.8%), 26 (25.7%), and 14 (13.9%) tumor samples, respectively. Expression of these receptors was not associated with pathological findings or survival. COX-2 and EP4R were independently associated with MVD and MMP-2, and uPA or PI and MMP-2, respectively. Other EP receptors were not influenced by any factors. Our results suggest that EP1R–3R play a minimal role in cancer progression in patients with TCC-UUT. On the other hand, EP4R regulates tumor progression via cancer cell proliferation and MMP-2, distinct from COX-2.This study was not funded by any commercial organization. It was supported in part by a Grant-in-Aid from the Japanese Society of the Promotion of Science.     

Expression of matrix metalloproteinase-2 (MMP-2) and of membrane-type-1-matrix metalloproteinase (MT1-MMP) in transitional cell carcinoma of the upper urinary tract

Tumor cell invasion and metastasis are biologically dependent on the proteolytic destruction of surrounding matrix components. Matrix metalloproteinase-2 (MMP-2) is able to cleave type IV collagen, and membrane-type-1-matrix metalloproteinase (MT1-MMP) induces activation of proMMP-2. We investigated the expression of MMP-2 and MT1-MMP using in situ hybridization and immunohistochemistry in 102 cases of transitional cell carcinoma of the upper urinary tract (TCC-UUT). A positive expression of each metalloproteinase was recognized in all samples and was apparent within the cytoplasm of tumor epithelial cells and/or stromal cells situated at the interface between tumor and stroma. Our analysis of clinicopathologic findings showed a relationship between MMP-2 and MT1-MMP expression and stage. The correlation between the MMP-2 protein staining score for tumor epithelial cells and overall survival rate reached significance in the univariate analysis. However, only stage was associated with disease-free and overall survivals in the multivariate analysis. In conclusion, the detection of MMP-2 and MT1-MMP would appear to be of limited value in informing the prognosis of TCC-UUT.     

Production of beta-human chorionic gonadotropin by prostatic adenocarcinoma and transitional cell carcinoma of the upper urinary tract.

Ectopic production and secretion of hormones by a wide variety of tumours has been known for many years. Recently human chorionic gonadotropin (HCG) production and/or secretion have been noted in 15 cases with prostatic adenocarcinoma (Fukutani et al. 1983; Papapetrou et al. 1980: Broder et al. 1977; Menon & Stefani 1980; McManus et al. 1976) and in two with upper urinary tract transitional cell carcinoma (Fukutani et al. 1983; McManus et al. 1976). In this study we utilised the indirect immunoperoxidate technique to demonstrate beta-HCG production in prostatic adenocarcinoma and upper urinary tract urothelial tumours. Of 100 cases of prostatic adenocarcinoma beta-HCG production was demonstrated in nine cases, eight of which were poorly differentiated, and of 14 urothelial tumours of the upper urinary tract beta-HCG production was present in two high grade transitional cell carcinomas.     

Impact of caveolin-1 expression on the prognosis of transitional cell carcinoma of the upper urinary tract

This study aimed to investigate the relationship of caveolin-1 expression with prognosis in patients with transitional cell carcinoma of the upper urinary tract (TCCUUT). Formalin-fixed, paraffin-embedded tissue sections of TCC-UUT from 98 patients, who had undergone radical nephroureterectomy, were stained immunohistochemically using antibodies against caveolin-1. The expression pattern of caveolin- 1 was compared with the clinicopathological variables. The caveolin-1 expression was significantly correlated with T stage (p<0.001) and grade (p=0.036). The survival rate of patients with caveolin-1 positive tumors was significantly lower than that of patients with caveolin-1 negative tumors (p<0.0001). The univariate analyses identified T stage, grade, and caveolin-1 expression as significant prognostic factors for cancer-specific survival, whereas the multivariate analyses indicated that T stage and caveolin-1 expression were independent prognostic factors. These results show that the increased expression of caveolin-1 is associated with tumor progression and poor prognosis in TCC-UUT, suggesting that caveolin-1 may play an important role in the progression of TCC-UUT.     

Production of beta-human chorionic gonadotropin by prostatic adenocarcinoma and transitional cell carcinoma of the upper urinary tract

Ectopic production and secretion of hormones by a wide variety of tumours has been known for many years. Recently human chorionic gonadotropin (HCG) production and/or secretion have been noted in 15 cases with prostatic adenocarcinoma (Fukutani et al. 1983; Papapetrou et al. 1980: Broder et al. 1977; Menon & Stefani 1980; McManus et al. 1976) and in two with upper urinary tract transitional cell carcinoma (Fukutani et al. 1983; McManus et al. 1976). In this study we utilised the indirect immunoperoxidate technique to demonstrate beta-HCG production in prostatic adenocarcinoma and upper urinary tract urothelial tumours. Of 100 cases of prostatic adenocarcinoma beta-HCG production was demonstrated in nine cases, eight of which were poorly differentiated, and of 14 urothelial tumours of the upper urinary tract beta-HCG production was present in two high grade transitional cell carcinomas.     

Expression of CD15 antigen in urinary bladder transitional cell carcinoma.

The biopsy specimens of 91 patients between the ages of 38 and 94 with transitional cell carcinoma of the bladder were retrospectively reviewed to determine if the expression of CD15 antigen detected by a monoclonal antibody MC2 was correlated with prognosis. Expression was variable, ranging from strong expression of the antigen by only the superficial cells in well differentiated papillary lesions to weak expression by most cells in solid or invasive tumours. In the invasive component there was a correlation between MC2 expression and tumour type, suggesting that the cell surface carbohydrate detected by MC2 may have a role in cell adhesion. There was no correlation between staining and survival. It is concluded that tumour type, grade, and stage remain the best prognostic indicators of urothelial tumours.