Deletions of chromosomes 9 and 8p in histologically normal urothelium of patients with bladder cancer

OBJECTIVES: Multifocality and frequent recurrence of urothelial carcinoma of the urinary bladder indicate a disease of the entire "urothelial field", but little is known about chromosomal alterations in histologically normal urothelium. Histopathologically normal urothelium from patients with and without concurrent urothelial carcinoma was analyzed for loss of heterozygosity (LOH) on chromosomes 8p, 9 and 17p, regions that are known to play an important role in urothelial carcinogenesis. MATERIALS AND METHODS: Histologically inconspicuous urothelial mucosa samples (n = 160) from cystectomy specimens of patients with urothelial carcinoma (n = 15, max. diagnosis: CIS, pT1-4; all tumors grade 3) were studied. Control samples (n = 50) were obtained from patients with benign prostatic hyperplasia (n = 30) and from cystectomies performed for invasive non-urothelial carcinoma (n = 20). Tissue samples were laser-microdissected and DNA was isolated using standard protocols. LOH analyses were performed using 16 polymorphic markers on chromosomes 8p, 9p/q and 17p. RESULTS: All investigated samples were informative for at least one microsatellite marker on each chromosome/chromosomal arm. Deletions were found on chromosome 9 and/or 8p in 15/160 (9.4%) of normal urothelial samples from urothelial cancer patients. These alterations were only found in 5/15 patients with urothelial carcinoma. There were no deletions on chromosome 17p. The marker D9S1113 on chromosome 9q33-34 was most frequently affected (11/15 samples, 73%). No chromosomal deletions were found in any of the 50 urothelial control samples. CONCLUSION: Specific genetic alterations frequently associated with bladder cancer are detectable in histologically normal urothelium of patients with bladder cancer, supporting the field effect hypothesis in urothelial carcinogenesis. However, intramucosal spread of tumor cells that escape light microscopic detection remains a possibility, since normal urothelium and concurrent carcinomas showed matching deletions. Chromosomal deletions in normal bladder mucosa are not a common finding and argue against a frequent genomic alteration of the entire urothelial field in bladder carcinogenesis.     

Clinical studies on renal pelvic and ureteral tumors

Clinical studies were performed on 35 patients with renal pelvic and/or ureteral cancer treated at Kitano Hospital between 1988 and 1997. They consisted of 17 renal pelvic cancers, 17 ureteral cancers and 1 renal pelvic and ureteral cancer. Twenty-nine patients were males and six were females, and their age ranged from 41 to 82 years old (average: 62.2). Histologically, 34 were transitional cell carcinoma and 1 was adenocarcinoma. Pathological stage of the tumor was pTa in 34.3%, pT1 in 14.3%, pT2 in 11.4%, pT3 in 37.1%, and pT4 in 2.9%, and grade of the tumor G1 in 11.8%, G2 in 58.8% and G3 in 29.4%. Eighteen patients (51%) had or developed bladder cancer, which preceded the diagnosis of cancer of upper urinary tract in 2 cases, coexisted in 4 cases and developed subsequently in 12 cases. The overall cause-specific survival rate was 91.3% at 1 year, 83.8% at 3 years and 79.4% at 5 years. Tumor stage, grade, lymph node metastasis and vascular invasion had impact on survival.     

Grade progression and regression in recurrent urothelial cancer

PURPOSE: Recurrent urothelial cancers are reported to have characteristics similar to those of the primary tumor, with 10% to 25% of low grade tumors recurring as high grade disease. We determined how often grade progression and regression occur and whether abnormalities in p53 protein expression in original tumors are preserved in recurrences. MATERIALS AND METHODS: Two groups of patients treated for recurrent stages Ta/T1 urothelial bladder cancers with at least 1 tumor-free examination between the index and recurrent tumors were reviewed. Group 1 included 115 patients in whom the first available tumor was compared with the last recurrence and group 2 included 42 in whom the initial tumor was compared with the first recurrence. Immunohistochemical analysis of p53 expression was performed on a subset of 34 tumor pairs. RESULTS: In group 1, 33 grade 3 tumors (45%) recurred as grade 1 or 2 tumors, while 9 of 82 grades 1 and 2 tumors (11%) recurred as grade 3 tumors. Five of 7 group 2 grade 3 tumors (71%) recurred as grade 1 or 2 disease, while 1 of 35 grades 1 and 2 tumors (3%) recurred as grade 3 disease. In the 34 pairs studied immunohistochemically 6 of 14 grade 3 tumors recurred at lower grades. Nuclear p53 over expression occurred in 21 index tumors (12 of 14 grade 3, 8 of 17 grade 2 and 1 of 3 grade 1) and in 9 recurrences (6 of 10 grade 3, 2 of 17 grade 2 and 1 of 7 grade 1). Only 7 of 21 p53 positive and 2 of 12 p53 negative index tumors were p53 positive on recurrence. CONCLUSIONS: While progression from low to high grade occurred in less than 15% of patients, grade regression was observed in almost 50%. The loss of p53 positivity in regressing tumors indicates that these recurrences are molecularly distinct from the corresponding initial tumor.     

Significance of chromosome 9 alterations as an initial step in urothelial carcinogenesis

One of the most important features of urothelial cancers of the bladder and upper urinary tract is metachronous and/or synchronous multifocal occurrence with high frequency. Since such multifocal recurrent tumors are derived from a common transformed cell, the chronological tracing of genetic alterations in such multifocal tumors may reveal the precise timing and role of genetic alterations in urothelial carcinogenesis. In this study, we tested the presence of microsatellite alterations in synchronous and/or metachronous multifocal urothelial cancers to examine the chronological genetic alterations for the presence of hierarchy of genetic alterations in urothelial cancer development. Genetic alterations at 20 microsatellite loci on 8 chromosomal arms (2q, 4p, 4q, 8p, 9p, 9q, 11p, and 17p) were tested. Judging from the patterns of allelic deletion and microsatellite shifts, multifocal tumors in at least 21 (81%) of the 26 evaluable patients were considered to be derived from a single progenitor cell. In patients with multifocal tumors of an identical clonal origin, discordant microsatellite alterations were observed at significantly lower frequencies on chromosome 9 compared with those on the other chromosomes tested. The heterotopic spread and genetic divergence may occur long before the clinical manifestation of multiplicity from a single transformed cell. The data strengthens the previous view that heterotopic spread of transformed progenitor cells and genetic divergence occur after chromosome 9 alterations in most of urothelial cancers.     

CORRELATION OF p53 PROTEIN EXPRESSION IN HUMAN UROTHELIAL TRANSITIONAL CELL CANCERS WITH MALIGNANT POTENTIAL AND PATIENT SURVIVAL

The p53 gene product has been detected frequently in various human malignancies. We have studied the expression of p53 protein in urothelial transitional cell cancers (TCCs) and examined its correlation with pathologic grade, stage(pT) and patient survival. Specimens from 69 surgically-resected TCCs (38 cases of urinary bladder cancer, 17 cases of ureteral cancer and 14 cases of renal pelvic cancer) were examined by immunohistochemical staining, using two anti-p53 monoclonal antibodies, PAb1801 and PAb240, and a polyclonal antibody, CM-1. Twenty-six TCCs (37.6%) were positively stained by at least one of the three antibodies. Statistical analysis showed a significant correlation between p53 expression and high pathologic grade (p less than 0.05, p less than 0.001) or progressive pathologic stage (p less than 0.01). In addition, in 51 of the patients who were available for follow-up (23 cases of urinary bladder cancer, 13 cases of ureteral cancer, and 15 cases of renal pelvic cancer), the correlation between p53 protein expression and prognosis was examined. The survival of patients exhibiting positive p53 protein expression was significantly worse than those with p53-negative tumors (p less than 0.05). These results suggest that an immunohistochemical test for p53 protein may be a useful method of evaluating the malignant potential of TCCs. Additionally, expression of p53 protein in TCCs is an indicator of a poor prognosis which should be considered in drawing up treatment strategies.     

Tumor Location Based Segmentation in Upper-Tract Urothelial Carcinoma Impacts on the Urothelial Recurrence-Free Survival: A Multi-Institutional Database Study

Introduction and ObjectivesThe predictive impact of primary tumor location for patients with upper-tract urothelial carcinoma (UTUC) in the presence of concomitant urothelial bladder cancer, along with urothelial recurrence after the curative treatment is still contentious. We evaluated the association between precise tumor location and concomitant presence of urothelial bladder cancer and urothelial recurrence-free survival in patients with UTUC treated by radical nephroureterectomy with a bladder cuff.MethodsA total of 1,349 patients with localized UTUC (Ta-4N0M0) from a retrospective multi-institutional cohort were studied. We queried four UTUC databases. This retrospective clinical series was of patients with localized UTUC managed by nephroureter-ectomy with a bladder cuff, for whom data were from the Nishinihon Uro-Oncology Collaborative Group registries. Patients with a history of chemotherapy or radiotherapy were excluded from the study. Associations between the location of the tumor and subsequent outcome following nephroureterectomy were assessed using COX multivariate analysis. The location of the tumor was verified by pathological samples. Urothelial recurrence was defined as tumor relapse in any local urothelium, and coded apart from distant metastasis. The median follow-up was 34 months.ResultsA total of 887 patients had an evaluation of the tumor location in which 475 patients had pelvic tumors (53.6%), 96 had ureteral tumors in the U1 segment (10.8%), 87 in the U2 segment (9.8%), and 176 in the U3 segment (19.8%). There were 52 patients who had multifocal tumors (5.9%) as follows: 8 (0.9%) in the pelvis and ureter, 11 (1.2%) in U1 + U2, 1 (0.1%) in U1 + U3, 27 (3.0 %) in U2 + U3, and 6 (0.7%) in U1 + U2 + U3. In all, 145 (16.3%) had concomitant bladder tumors. Logistic regression analysis of gender, age, hydronephrosis, cytology, performance status, grade, lymphovascular invasion, pT, pN, and tumor focality showed that tumor location was associated with the presence of concomitant bladder cancer (p = 0.004, HR = 1.265). When the tumor location was stratified into 8 segments, including multifocal tumors, only the U3 segment remained as a predictor for the presence of concomitant bladder cancer (p = 0.002, HR = 2.872). Kaplan-Meier analysis for unifocal disease showed that lower ureter tumors (a combination of U2 and U3) had a worse prognosis for urothelial recurrence than pelvic tumors or upper ureteral tumors (U1) (p < 0.001 for lower ureteral tumors versus pelvic tumors, p = 0.322 for upper ureteral tumor versus pelvic tumor by log rank). Multivariate analysis showed that lower ureter remained as a prognostic factor for urothelial recurrence after adjusting for gender, age, hydronephrosis, urine cytology, lymphovascular invasion, pT, and pN (p < 0.001, HR = 1.469), and a similar tendency was found when the analysis was run for patients without concomitant bladder tumors (p = 0.003, HR = 1.446). Patients with lower ureteral tumors had a higher prevalence of deaths (HR = 2.227) compared to patients with upper ureter tumors.ConclusionsThis multi-institutional study showed that the primary tumor locations were independently associated with the presence of concomitant bladder tumors and subsequent urothelial recurrence.Key Words: Upper-tract urothelial carcinoma, Prognosis, Tumor location     

The clinical usefulness of urinary basic fetoprotein (BFP) in patients with urological malignancies]

Basic fetoprotein (BFP) was measured by enzyme immunoassay in the urine of healthy adults and patients with benign or malignant urological diseases. Urinary BFP level in 34 healthy donors was very low (2.75 +/- 2.27 ng/ml). Since the BFP-positive rate is under 5% in healthy donors and, considering diagnostic efficiency for urological malignancies, a urinary BFP-concentration of 15 ng/ml was used as the cut off value. Urinary BFP was positive in 17.0% of 106 patients with benign urological diseases, in 51.9% of 52 patients with bladder cancer, in 75.0% of 8 patients with renal pelvic or ureteral cancer, in 25.0% of 20 patients with prostate cancer, and in 19.0% of 21 patients with renal cell carcinoma. In 60 patients with urothelial carcinomas, urinary BFP was higher in invasive diseases (greater than pT1) than in superficial diseases (p less than 0.05). The BFP level in urine also increased with a higher histological grade. The positive rate of urinary BFP was 78.9% in patients with invasive diseases and 66.7% in patients with grade 3 diseases. In 44 patients with urothelial carcinomas who underwent urinary cytological examination the positive rate was improved from 38.6% (17/44) to 81.4% (37/44) when measurement of urinary BFP was added. BFP in urine was found to be useful as a tumor marker for urothelial carcinomas. In addition, it was demonstrated that combined examination of urinary cytology with urinary BFP was more efficient for diagnosis of urothelial carcinomas.     

Grading the invasive component of urothelial carcinoma of the bladder and its relationship with progression-free survival

Although grading is valuable prognostically in pTa and pT1 papillary urothelial carcinoma, it is unclear whether it provides any prognostic information when applied to the invasive component in muscle-invasive carcinoma. The authors analyzed 93 cases of muscle-invasive urothelial carcinoma of the bladder treated with radical cystectomy for which follow-up information was available. Each case was graded using the Malmstr?m grading system for urothelial carcinoma, applied to the invasive component. Pathologic stage, lymph node status, and histologic invasion pattern were also recorded and correlated with progression-free survival. Thirty-four cases (37%) were pT2, 40 (43%) were pT3, and 19 (20%) were pT4. Of the 77 patients who had a lymph node dissection at the time of cystectomy, 34 (44%) had metastatic carcinoma to one or more lymph nodes. The median survival for pT2, pT3, and pT4 stages was 85, 24, and 29 months, respectively (p = 0.0001). Lymph node-negative and lymph node-positive patients had a median survival of 63 and 23 months, respectively (p = 0.0001). Fifteen patients (16%) were graded as 2b and 78 patients (84%) were graded as 3. Median survival of patients graded as 2b was 34 months compared with 31 months for patients graded as 3 (p value not significant). Three invasive patterns were recognized: nodular (n = 13, 14%), trabecular (n = 39, 42%), and infiltrative (n = 41, 44%). The presence of any infiltrative pattern in the tumor was associated with a median survival of 29 months, compared with 85 months in tumors without an infiltrative pattern (p = 0.06). Pathologic T stage and lymph node status remain the most powerful predictors of progression in muscle-invasive urothelial carcinoma. In this group of patients histologic grade, as defined by the Malmstr?m system and as applied to the invasive component, provided no additional prognostic information. An infiltrative growth pattern may be associated with a more dismal prognosis.     

Percutaneous management of renal pelvic urothelial tumors: long-term followup

PURPOSE: We present the long-term outcome of percutaneous resection of renal urothelial tumor. MATERIALS AND METHODS: A total of 24 patients underwent primary percutaneous resection of renal urothelial tumor. Patients with low stage pT0-1 disease were treated primarily with percutaneous surgery. All pelvicaliceal tumors were taken for biopsy and treated with percutaneous resection. Patients with multi-segmental pelvicaliceal system involvement, stage greater than pT1, high grade histology or additional ureteral tumors were considered for nephroureterectomy. Topical chemotherapy (mitomycin C or epirubicin) was administered via nephrostomy tube or intravesical instillation after Double-J stent (Medical Engineering Corp., New York, New York) insertion. Surveillance included upper tract cytology, nephroscopy or fiberoptic ureterorenoscopy. Long-term followup was correlated with histopathology. RESULTS: Of the 24 cases 2 had squamous cell carcinoma, 5 had grade III transitional cell carcinoma, 15 had grade I to II transitional cell carcinoma and 2 had no tumor. Control was established with initial percutaneous resection in 18 (75%) cases and second look nephroscopy in 4. Early recurrences were detected by excretory urography (IVP) in 3 cases, small pelvic recurrences by IVP in 2, fiberoptic ureterorenoscopy in 2 and bladder tumors by flexible cystoscopy in 3 after 1 year. A total of 10 nephroscopies were performed in 5 cases, 24 flexible uretereorenoscopies in 9 and IVP in 6. Three synchronous, grade I bladder tumors were managed conventionally. All patients with high grade disease died of malignancy except one (with no further treatment) and 6 of the 15 patients with low grade noninvasive transitional cell carcinoma underwent nephroureterectomy during followup either due to progression of disease, concomitant tumor or complications. Two patients with solitary kidneys died of renal failure unrelated to malignancy. High grade tumors or tumors greater than T1 were treated with nephroureterectomy early during management. There was no perioperative mortality and 9 (60%) of the low grade cases the kidneys were preserved at a mean followup +/- SD of 64 +/- 15 months. All excised tracks from patients who underwent nephroureterectomy and the renal fossae were free of tumor on histopathological examination. CONCLUSIONS: Percutaneous resection of transitional cell tumor should be considered primarily in patients with early stage disease excluding tumors crossing caliceal infundibula, ureteropelvic junction tumor, tumor extending over multiple calices and synchronous ureteral tumors. The long-term outcome of low grade tumors is good and they should be managed by either form of minimally invasive surgery. Nephron sparing is possible in a large percentage of low grade disease but high grade tumors should be treated with nephroureterectomy.     

A comparison of cytology and fluorescence in situ hybridization for the detection of urothelial carcinoma

PURPOSE: We determine the relative sensitivities of cytology and fluorescence in situ hybridization (FISH) for the detection of urothelial carcinoma. MATERIALS AND METHODS: A mixture of fluorescent labeled probes to the centromeres of chromosomes 3, 7 and 17, and band 9p21 (P16/CDKN2A gene) was used to assess urinary cells for chromosomal abnormalities indicative of malignancy. A total of 280 urine specimens from 265 patients, including 150 with a history of urothelial carcinoma and 115 without a history of urothelial carcinoma, were analyzed. FISH analysis was performed without prior knowledge of clinical findings, that is biopsy, cystoscopy and cytology results. A positive result was defined as 5 or more urinary cells with gains of 2 or more chromosomes. RESULTS: A total of 75 biopsies showed urothelial carcinoma at FISH analysis among the 265 patients. The sensitivity of urine cytology for pTa (36 cases), pTis (18) and pT1-pT4 (15) tumors was 47%, 78% and 60%, respectively, for an overall sensitivity of 58%. The sensitivity of FISH for pTa (37 cases), pTis (17) and pT1-pT4 (19) tumors was 65%, 100% and 95%, respectively, for an overall sensitivity of 81%. FISH was significantly more sensitive than cytology for pTis (p = 0.046), pT1-pT4 (p = 0.025), grade 3 (p = 0.003) and all tumors (p = 0.001). The specificity of cytology and FISH among patients without cystoscopic evidence of urothelial carcinoma and no history of urothelial carcinoma was 98% and 96%, respectively (p = 0.564). CONCLUSIONS: The sensitivity of FISH for the detection of urothelial carcinoma is superior to that of cytology, and the specificity of FISH and cytology for urothelial carcinoma are not significantly different. Further prospective studies are required but FISH has the potential to improve significantly the management of urothelial carcinoma.     

p53 tumor suppressor gene mutation and prognosis in 105 cases of bladder cancer--the relationship between mutation of the p53 gene with clinicopathological features and smoking]

PURPOSE: Alterations of the p53 tumor suppressor gene are the most common genetic change detected in human cancers. The incidence of p53 gene mutation in bladder tumor patients were studied and were compared with clinicopathological findings, smoking history and prognosis. MATERIALS AND METHODS: Polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) was used for analysis from exon 4 to 9 of p53 gene in 105 cases of primary bladder tumors. RESULT: p53 matations were detected in 38 or 105 patients (36.2%). Kaplan-Meier Survival curves fo groups wit or without p53 gene mutation show a statistically significant difference (p = 0.0098). The mutation of p53 gene in stages pT 1 pT 1. pT 2, pT 3, pT 4 was found in 2 of 12 (16.7%), 8 of 32 (25.0%), 10 of 25 (40.0%), 12 of 20 (60.0%), 6 of 16 (37.5%) and in grades I, II, III, was noted in 1 of 17 (5.9%), 16 of 49 (32.7%), 21 of 39 (53.8%) cases, respectively. Significant differences were found for groups with grade I and grade II-III (p = 0.0045) cancers and in cases of superficial (stage pTa-1) and muscle-invasive (pT 2-4) tumors (p = 0.0148). However, mutation of p53 was not related to either age or sex in 105 patients. Recurrence rates in stage pTa-1 superficial tumor group with or without p53 mutation showed a statistically significant difference (p = 0.0419). No statistically significant difference was noted between p53 mutation and habitual smoking as well as durations of smoking. CONCLUSIONS: p53 mutations occur more commonly in higher grades and later stages of bladder tumors. Our results suggest that the prognostic factor is linked to not only histological findings but also to the presence of p53 mutation. The mutations of the p53 gene may be involved in the late events of tumorigenesis and might be used as good molecular markers for prognosis in bladder tumor.     

输尿管部分切除术治疗尿路上皮癌复发的影响因素

目的：探讨输尿管部分切除术治疗尿路上皮癌术后复发的危险因素。方法：回顾性分析52例因输尿管尿路上皮癌行输尿管部分切除术患者的临床资料,采用KaplairMeier法、Log-rank检验及Cox模型对临床资料进行统计分析,并对肿瘤是否复发进行随访。结果：尿找瘤细胞阳性（P=0.036）及病理高级别（P=0.011）是肿瘤复发的危险因素。对浸润型肿瘤（pT2、pT3）及并发脉管瘤栓者,术后行局部放疗不能降低复发风险（P=0.660）。对具有复发危险因素者,术后行膀胱灌注能降低复发风险（P=0.037）。对于肿瘤位于输尿管远端需行输尿管膀胱再植者,术中打开膀胱与未打开膀胱相比,术后复发率差异无统计学意义（P=0.565）。结论：临床应提高对术前尿找瘤细胞检查的重视程度,因为它既是明确上尿路肿瘤诊断的常用方法,也是判断预后的重要依据。对具有病理高级别及尿找瘤细胞阳性等复发危险因素者,术后应行膀胱灌注治疗。     

Prognostic relevance of DNA ploidy and proliferative activity in urothelial carcinoma of the renal pelvis and ureter. A study on a follow-up period of 6 years

In 55 patients with urothelial carcinoma of the renal pelvis or ureter, the ploidy, the DNA heterogeneity and the counts of cell cycle phases in the tumor were examined by means of single-cell DNA cytophotometry in order to find more prognostic factors than those already known (stage and grade). Follow-up periods ranged from 1 to 6 years. At the time of first diagnosis, 42 (76%) of the patients had tumors of the renal pelvis, 13 (24%) of them had ureteral tumors. 23 (42%) patients were in stage pT 1 N 0, 15 (27%) in stage pT 2 N 0, 12 (22%) in stage pT 3 N 0, and 5 (9%) were in stage pT 3 N+. The histological malignancy grade most frequently seen in the patients examined--i.e. in 51% of cases--was malignancy grade II. 25% of the patients had grade III tumors whereas only 24% had grade I tumors. With malignancy grade I, DNA cytophotometry showed DNA frequency peaks to be in the diploid range while tumors with malignancy grade II showed heterogenous DNA patterns. 71% of the patients with malignancy grade III showed aneuploid DNA values; 29% of them had polyploid DNA values. For malignancy grades II and III, the proliferation rate of the tumor cells was statistically significantly higher than for malignancy grade I. The determination of tumor heterogeneity and tumor cell proliferation by means of DNA cytophotometry gives valuable clues regarding prognosis.     

Genetic aberrations of NAT2 and chromosome 8: their association with progression in transitional cell carcinoma of the urinary bladder

INTRODUCTION/OBJECTIVE: N-acetyltransferase 2 (NAT2), mapped to 8p22, is a polymorphic enzyme which metabolizes aromatic amines. Loss of heterozygosity of 8p22 is associated with an increased risk of bladder cancer. This study evaluated NAT2 and chromosome 8 in sequential tumours from bladder cancer patients to determine if NAT2 alterations increase the risk of progression. MATERIALS AND METHODS: Thirty-seven sequential carcinomas from 19 patients were assessed using fluorescence in situ hybridization. RESULTS: Five carcinomas showed loss of NAT2; 4 of these were from pTa/pT1 tumours. Polysomy 8 was observed in 4 of 14 (29%) primary carcinomas (pTa/pT1), in 4 of 12 (33%) pTa/pT1 recurrences, and in 90% (9/10) of the detrusor muscle invasive tumours (pT2+). 6 of 8 (75%) locally invasive tumours with polysomy 8 were from patients who subsequently developed disease progression (pT2+). In total, 13.5% (5/37) of the carcinomas were abnormal for NAT2, and 46% (17/37) were abnormal for chromosome 8 copy number. Polysomy 8 was associated with high grade (p = 0.01) and stage (p = 0.03) and disease progression (p = 0.03). CONCLUSION: Whilst there does not appear to be an association between loss of NAT2 and risk of progression in transitional cell carcinoma, the high rate of polysomy of chromosome 8 implies that other genes on this chromosome significantly influence disease progression.     

Stage-Specific Impact of Tumor Location on Oncologic Outcomes in Patients With Upper and Lower Tract Urothelial Carcinoma Following Radical Surgery

BACKGROUND: Dissimilarities in management and outcomes exist between upper tract urothelial carcinoma (UTUC) and urothelial carcinoma of the bladder (UCB). OBJECTIVE: The aim of this study was to analyze the stage-specific impact of upper or lower urinary tract tumor location on oncologic outcomes. DESIGN, SETTING, AND PARTICIPANTS: Data were collected from 4335 patients with UCB treated with radical cystectomy (RC) and bilateral pelvic lymphadenectomy (PLND), 877 patients with ureteral UTUC, and 1615 with pelvicalyceal UTUC treated with radical nephroureterectomy (RNU). No patient received preoperative chemotherapy or radiation therapy. INTERVENTIONS: Patients were treated with RC and bilateral PLND or RNU. MEASUREMENTS: Outcomes were assessed according to primary tumor location. RESULTS AND LIMITATIONS: Compared to UTUC patients, UCB patients had more advanced tumor stage and higher grade, and they were more likely to harbor lymphovascular invasion (LVI) and lymph node metastasis (p<0.001). In non-muscle-invasive tumor stages, UCB patients were more likely to experience disease recurrence and mortality compared to renal pelvicalyceal tumor patients (p<0.002) but not ureteral tumors (p>0.05). In pT2 and pT3 tumors, there was no difference in outcomes between the three tumor locations. In pT4 tumors, patients with ureteral and pelvicalyceal tumors were more likely to experience disease recurrence and mortality compared to UCB patients (p<0.004). These stage-specific findings were unchanged after adjustment for the effects of age, gender, tumor grade, LVI, lymph node status, and adjuvant chemotherapy. This study is limited by its retrospective and multicenter nature. CONCLUSIONS: Stage-specific differences in outcomes exist between UCB and UTUC. The differentially worse outcomes by stage between UCB and UTUC patients underline the differences between both cancer entities and the need for individualized stage-specific management for each patient.     

Squamous cell carcinoma of the renal pelvis and ureter: incidence, symptoms, treatment and outcome

PURPOSE: Squamous cell carcinomas of the renal pelvis and ureter are rare. We report a large series of patients and compare it to patients with urothelial carcinoma. MATERIALS AND METHODS: The initial material was comprised of 808 patients with renal pelvis or ureteral cancer. A review of the histopathological material and clinical records was performed. RESULTS: Only 2 (4%) of 65 patients with squamous cell carcinoma had stage pTa/pT1/pT2 tumors compared to 460 (62%) of 743 patients with urothelial carcinoma. Median survival was much shorter for surgically treated patients with squamous cell carcinoma compared to those with urothelial carcinoma (7 vs 50 months). However, there was no significant difference in the disease specific 5-year survival rate between patients with squamous cell carcinoma and urothelial carcinoma in the same disease stage. Vascular invasion, microscopic solid tumor pattern and large tumor size had negative prognostic significance in multivariate analyses. Histopathological tumor type (squamous cell carcinoma or urothelial carcinoma) had no prognostic significance. CONCLUSIONS: The prognosis for squamous cell carcinoma is poor, but stage for stage the prognosis is not different between patients with urothelial carcinoma and squamous cell carcinoma of the renal pelvis and ureter. It can be presumed that high stage squamous cell carcinoma and urothelial carcinoma become symptomatic first at a time when the tumors already are large, deeply invasive and most often incurable. New treatment modalities are urgently needed to improve the poor prognosis in patients with advanced stage squamous cell carcinoma and urothelial carcinoma of the upper urinary tract.     

CD10 expression in urothelial bladder carcinomas: a pilot study

OBJECTIVES: The aims of this study were to investigate the expression of CD10 in normal bladder tissue and urothelial bladder carcinomas and to clarify its association with histopathological variables. MATERIALS AND METHODS: A total of 79 urothelial bladder carcinomas were selected from routine archival material. All cases were reevaluated histopathologically and graded according to the World Health Organization (WHO) 1973, WHO/ISUP 1998, and WHO 1999 systems. The TNM system was used for their pathological staging. CD10 immunohistochemical staining was performed in selected slides. RESULTS: Tumoral cases consisted of 74 men (93.7%) and 5 women (6.3%). According to the pathological stage, 25 (31.6%), 33 (41.8%), and 21 (26.6%) cases had pTa, pT1, and pT2-3 carcinomas, respectively. 34 of 79 (43%) urothelial carcinomas and only 1 of 11 (9.1%) nontumoral cases showed positive CD10 immunostaining. It was a cytoplasmic diffuse or granular immunostaining pattern both in nontumoral and tumoral urothelia. There was no statistically significant difference between tumoral and nontumoral cases with respect to CD10 reactivity (p = 0.051), but there was a trend toward significance. In urothelial tumors, there was a significant inverse correlation between pathological stages and CD10 immunoreactivity (p = 0.036, r = -0,237). There was also a statistically significant difference between pTa and pT2-3 urothelial tumors in relation to the CD10 expression (p = 0.034). No association was detected between CD10 expression and grades according to all systems used (p > 0.05). CONCLUSIONS: According to our findings, the CD10 expression in noninvasive carcinomas showed a higher level than that in invasive carcinomas, and it is inversely correlated with the pathological stage. CD10 may play an important role in the progression of urothelial bladder carcinomas, and downregulation probably facilitates invasion, especially muscle invasion.     

Ureteroscopic biopsy of upper tract urothelial carcinoma: improved diagnostic accuracy and histopathological considerations using a multi-biopsy approach

PURPOSE: We assessed the diagnostic accuracy of a ureteroscopic multi-biopsy approach to upper tract urothelial carcinoma compared with subsequently resected surgical specimens. MATERIALS AND METHODS: From 1990 to 1998, 45 upper tract lesions were ureteroscopically evaluated and biopsied with 3Fr cup forceps and/or an 11.5Fr resectoscope before nephroureterectomy or ureterectomy. A definitive diagnosis of urothelial carcinoma was made by biopsy in 40 lesions (89%). Each tumor was histopathologically graded but only staged if the lamina propria were uninvolved (Ta), and if the lamina propria were invaded by tumor (T1+). RESULTS: Of the 40 urothelial tumors 16 (40%) were in the renal pelvis, and 8 (20%) in the proximal and 16 (40%) in the distal ureter. Of the lesions 95% were papillary and 65% were grade 2. Ureteroscopic biopsy grade matched surgical pathological grade in 31 of the 40 cases (78%), and was less than surgical pathological grade in the remainder. Lamina propria was detected in 27 of the 40 biopsies, including 21 of the 34 cup (62%) and all 6 resection loop (100%) biopsies. Ureteroscopic biopsy staging in 27 cases revealed Ta and T1+ disease in 22 and 5, respectively. In the 5 cases in which ureteroscopic biopsy stage was T1+ surgical pathological stage was also pT1+ (range pT1 to pT3). Tumors were pathologically up staged to pT1+ (range pT1 to pT3) in 10 of the 22 cases (45%) in which ureteroscopic biopsy stage was Ta. Tumor location did not affect diagnostic accuracy. CONCLUSIONS: This multi-biopsy ureteroscopic approach provided the tissue diagnosis of urothelial carcinoma in 89% of cases and predicted exact histopathological grade in 78%. Although it is not accurate as a staging modality, multi-biopsy ureteroscopy may assess lamina propria invasion in two-thirds of cases.     

Molecular biological testing for diagnosis and treatment of urothelial cancer]

Detection of urinary telomerase activity is superior to the conventional urine cytological examination in terms of sensitivity for diagnosis of low grade urothelial cancers. Several causative factors including pyuria and hematuria which might have affected falsely positive and negative rates of urinary telomerase activity were investigated but their influence seemed negligible. As for progression from superficial to invasive urothelial cancers, destruction of the basement membrane underlying tumor is considered as an important event in the initial step of invasion. Our immunohistochemical analyses revealed that expression of type IV collagen in the basement membrane was reduced or disappeared in more than half of grade 2 to 3, pTa urothelial cancers. Overexpression of p53 tumor suppressor and/or mdm2 oncoprotein was strongly correlated with this basement membrane destruction. Urothelial cancers harboring p53 aberration may be resistant to cisplatin-based chemotherapy because of impairment of apoptosis induction. The relationship between chemosensitivity and p53 status in urothelial cancers was investigated, and a favorable response to neoadjuvant chemotherapy was found in tumors without p53 aberration.     

Simultaneous bilateral renal pelvic tumors: a case report]

A case of simultaneous bilateral renal pelvic tumors is reported. A 64-year-old man with the chief complaint of gross hematuria and left flank pain was admitted. Clinical investigations revealed a tumor in the right pelvis and ureter, and another tumor in the left renal pelvis. The right ureteral tumor had invaded the bladder. Right nephroureterectomy, total cystectomy, left partial pyelectomy and ureterocutaneostomy were performed. By pathological examination, right renal pelvic and ureteral tumors were non-papillary transitional cell carcinoma, grade 3, pT4, and the left renal pelvic tumor was papillary transitional cell carcinoma, grade 2, pT1. To our knowledge, this is the 16th case of simultaneous bilateral urothelial tumors of the upper urinary tract in Japan.