Subsequent Bladder Tumor Research Articles

Diagnostic value of a comprehensive, urothelial carcinoma-specific next-generation sequencing panel in urine cytology and bladder tumor specimens.

Urine cytology can reliably diagnose high-grade urothelial carcinoma (HGUC) but not low-grade urothelial carcinoma (LGUC), and a more sensitive test is needed. Previously, a pilot study highlighted the possible diagnostic utility of next-generation sequencing (NGS) in identifying both LGUC and HGUC in urine cytology specimens. Twenty-eight urine ThinPrep cytology specimens and preceding or subsequent bladder tumor biopsy/resection specimens obtained within 3 months were included in the study (LGUC, n = 15; HGUC, n = 13). A customized, bladder-specific NGS panel was performed; it covered 69 frequently mutated or altered genes in urothelial carcinoma (UC) that were reported by The Cancer Genome Atlas and the Catalogue of Somatic Mutations in Cancer. The sequencing results were compared between the urine cytology specimens and the corresponding bladder tumor biopsies/resections. TP53 was the most frequently identified mutation in HGUC cases (11 of 13 [85%]). PIK3CA and KDM6A were the most frequently identified mutations in LGUC: they occurred in 7 of 15 cases (47%) and in 6 of 15 cases (40%), respectively. Additional frequent mutations identified in the panel included ARID1A (n = 5), EP300 (n = 4), LRP1B (n = 3), ERBB2 (n = 2), STAG2 (n = 2), FGFR3 (n = 3), MLL (n = 2), MLL3 (n = 2), CREBBP1 (n = 1), RB1 (n = 1), and FAT4 (n = 1). Overall, the concordance between the cytology and surgical specimens was 75%. The sensitivity and specificity for identifying mutations in urine cytology specimens were 84% and 100%, respectively. A bladder-specific NGS panel increases the sensitivity and specificity of urine cytology's diagnostic utility in both low- and high-grade tumors and may serve as a noninvasive surveillance method in the follow-up of patients with UC harboring known mutations.

Prognostic Significance of Preoperative Serum Lactate Dehydrogenase in Upper Urinary Tract Urothelial Carcinoma

BackgroundUpper urinary tract urothelial carcinoma (UUTUC) is one of the uncommon malignancies lacking of prognostic indicators. Lactate dehydrogenase (LDH) has been demonstrated to correlate with clinical outcomes in human cancers. In this study, we aimed to evaluate the prognostic implication of the preoperative LDH in UUTUC. Patients and MethodsA cohort of 100 UUTUC samples along with the preoperative LDH value was recruited from January 1990 to June 2011. The cutoff value was set at 245 u/L for the upper value of normal limitation. Univariate and multivariate analyses were conducted to determine the association of LDH with overall survival (OS) and disease-free survival (DFS). ResultsKaplan-Meier analysis revealed that high level of LDH (> 245 u/L) was significantly associated with poor OS (P < .001) and DFS (P = .002). Multivariate Cox proportional analysis indicated LDH, controlled by vascular invasion, pathological stage, lymph node status, subsequent bladder tumor, tumor grade, tumor necrosis, architecture, and multifocality, was as an independent predictor of OS (hazard ratio, 3.181; 95% confidence interval, 1.223-8.276; P = .018) and DFS (hazard ratio, 3.041; 95% confidence interval, 1.247-7.417; P = .015). Stratified showed that elevated serum LDH was correlated with the worse OS in patients without lymph node metastasis (P = .002) and those at advanced pathological stage (P < .001). ConclusionThe preoperative LDH was an independent prognostic factor for patients with UUTUC and could be used as a risk factor to predict the tumor aggressiveness.

Tumor necrosis predicts poor clinical outcomes in patients with node-negative upper urinary tract urothelial carcinoma.

Tumor necrosis has been indicated as a factor for the poor clinical outcome in human cancers. We aim to disclose the association between tumor necrosis and overall survival and recurrence-free survival in node-negative upper urinary tract urothelial carcinoma patients treated with radical nephroureterectomy. A retrospective cohort of 100 patients with upper urinary tract urothelial carcinoma from January 1990 to June 2011 was enrolled in this study. Univariate analysis with Log-rank test and multivariate analysis with Cox proportional hazards regression models were conducted to determine the correlations of tumor necrosis with overall survival and recurrence-free survival. Tumor necrosis was presented in 48 patients with upper urinary tract urothelial carcinoma and was significantly associated with the advanced pathological stage (P < 0.001), high tumor grade (P < 0.001), subsequent bladder tumor (P = 0.018), vascular invasion (P < 0.001) and lymph node metastasis (P = 0.026). Multivariate analysis revealed tumor necrosis as an independent unfavorable predictor of overall survival in node-negative upper urinary tract urothelial carcinoma patients by multivariate analysis (hazard ratio = 9.23, 95% confidence interval = 1.05-80.89, P = 0.045). Tumor necrosis was an independent factor of adverse clinical outcomes in node-negative upper urinary tract urothelial carcinoma patients who received radical nephroureterectomy. Evaluation of tumor necrosis might be of clinical significance to determine whether patients with node-negative upper urinary tract urothelial carcinoma should be given further therapy after radical nephroureterectomy.

Clonality of bladder tumors following radical nephroureterectomy: Against the field defect hypothesis.

301 Background: Urothelial carcinoma is characterized by multifocal and metachronous tumors. To explain this phenomenon, two hypotheses have been proposed: the ‘field defect’ hypothesis - urothelial cells are primed to undergo transformation by exposure to carcinogens, and the clonal, or ‘single progenitor cell,’ hypothesis - tumors arise from intraluminal seeding of transformed cells. Methods: To examine their clonal relationships, we compared the genomic profiles of primary upper tract urothelial carcinoma (UTUC) tumors and metachronous bladder tumors (intravesical recurrences) in patients treated with radical nephroureterectomy (RNU) and subsequent transurethral resection. Specimens were analyzed using a next-generation, targeted sequencing assay designed to identify point mutations, indels, and copy number alterations in 341 cancer-associated genes. Results: We analyzed 16 primary UTUC tumors and 41 intravesical recurrences in patients treated with RNU. The median number of intravesical recurrences per patient was 2 (range 1-7) and the interval from RNU to intravesical recurrence ranged from 3.5 months to 129 months. With an average sequencing coverage of 516x, we found strong evidence delineating the clonal relationship between primary UTUC tumors and subsequent bladder tumors. The majority of somatic mutations present in the primary UTUC tumors (median=7, range 4-39) were detected in all subsequent bladder tumors (128/146, 88%). In an illustrative case, one patient followed with periodic cystoscopy/cytology who had been NED for 5.5 years then developed 7 bladder tumors over the next 44 months, each with the identical mutation profile (8 mutations) as the primary tumor. Conclusions: We demonstrate that bladder tumors following RNU represent true intravesical recurrences, with almost all tumors sharing the same somatic mutation profile as the primary UTUC tumor. This has important implications for surgical techniques to minimize the risk of intraluminal seeding, the delivery of intravesical therapy following RNU, and the development of strategies employing systemic chemotherapy or targeted agents.

Impact of Smoking Status on Bladder Tumor Recurrence After Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma

Although smoking status has a significant association with clinical features in patients with bladder cancer, there are few reports of the impact of smoking on the clinical outcome of upper tract urothelial cancer. We investigated the possible influence of smoking status on bladder tumor recurrence after radical nephroureterectomy. We identified a study population of 245 consecutive patients treated surgically for upper tract urothelial cancer at our 3 institutions between 1994 and 2010. We analyzed associations between subsequent bladder tumor recurrence and patient clinicopathological parameters, including smoking status. The 3-year bladder tumor recurrence-free survival rate was 32.6% in current smokers, 37.6% in former smokers and 61.7% in nonsmokers. Multivariate analysis revealed that male gender (HR 1.90, 95% CI 1.15-3.16, p = 0.013) and smoking status (former vs none HR 1.77, 95% CI 1.07-2.93, p = 0.027 and current vs none HR 1.58, 95% CI 1.03-2.42, p = 0.035) were independent risk factors for subsequent bladder tumor recurrence. Also, of patients with a positive smoking history those with 50 pack-years or greater showed a significantly higher incidence of bladder tumor recurrence after radical nephroureterectomy (HR 2.00, p = 0.003). Positive smoking history and male gender were independent risk factors for bladder tumor recurrence after radical nephroureterectomy. A larger number of cigarettes smoked may increase the incidence of bladder tumor recurrence in patients with upper tract urothelial cancer.

524 LOSS OF NUCLEAR PROTHYMOSIN-αEXPRESSION INCREASES TUMOR RECURRENCE IN BLADDER CANCER WHICH IS ASSOCIATED WITH LOSS OF PTEN EXPRESSION

You have accessJournal of UrologyBladder Cancer: Basic Research1 Apr 2011524 LOSS OF NUCLEAR PROTHYMOSIN-αEXPRESSION INCREASES TUMOR RECURRENCE IN BLADDER CANCER WHICH IS ASSOCIATED WITH LOSS OF PTEN EXPRESSION Yuh-Shyan Tsai, Tzong-Shin Tzai, Yeong-Chin Jou, Hsin-Tzu Tsai, Chao-Liang Wu, and Ai-Li Shiau Yuh-Shyan TsaiYuh-Shyan Tsai Tainan, Taiwan More articles by this author , Tzong-Shin TzaiTzong-Shin Tzai Tainan, Taiwan More articles by this author , Yeong-Chin JouYeong-Chin Jou Chia-Yi, Taiwan More articles by this author , Hsin-Tzu TsaiHsin-Tzu Tsai Tainan, Taiwan More articles by this author , Chao-Liang WuChao-Liang Wu Tainan, Taiwan More articles by this author , and Ai-Li ShiauAi-Li Shiau Tainan, Taiwan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.1220AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Prothymosin-α(PTMA) is a nuclear protein that is usually transported into the nucleus and involves many biologic functions. We previously reported aberrant PTMA expression occurs in urothelial carcinoma of the urinary bladder and loss of nuclear entry of PTMA protein, resulting in cytoplasmic accumulation, is significantly associated with subsequent bladder tumor recurrence in urothelial carcinoma of upper urinary tract. The aim of this study is to investigate whether loss of nuclear PTMA expression affects tumors recurrence in human bladder cancer and explore its mechanism. METHODS Paraffin-embedded tissues were collected from 151 bladder cancer patients, treating with endoscopic resection with or without intravesical therapy as indicated. Immunohistochemical PTMA staining was performed and analyzed whether PTMA expression correlates with clinicopathologic characteristics and patient survival or not. Three stable transfectants of human J82 bladder cancer cells expressing either ectopic nuclear, cytoplasmic PTMA expression or vector only were developed for subsequent in vitrocell proliferation, migration assays and in vivotumorigenesis assays and mice survival in SCID mice. Further, cDNA differential array was performed and the involved molecular pathways were postulated and validated with quantitative RT-PCR assay from the frozen specimens of human bladder tumor. RESULTS Loss of nuclear PTMA expression, significantly associated with non-papillary morphology (p=0.04), grade (p=0.01), and staging (p=0.01), was an independent prognostic indicator for short recurrence-free survival (p=0.009). Although that there were no differences in cell proliferation or migration assays, Mice with ectopic cytoplasmic PTMA-expressing J82 transfectants exhibited significantly more rapid tumor growth and shorter survival than those with nuclear PTMA-expressing ones. The result from cDNA array assay of three J82 transfectants showed PIK3-Akt pathway was one of the postulated molecular pathways. As compared with vector only transfactants, nuclear PTMA-expressing transfectants regained PTEN, but cytoplasmic ones did not, both of them were demonstrated from the qRT-PCR and western blotting assays. Similarly, nuclear PTMA-expressing bladder tumor specimens had significantly higher PTEN mRNA levels than others, as shown from qRT-PCR assay. CONCLUSIONS In this study we demonstrated that loss of nuclear PTMA expression increased tumor recurrence in bladder cancer which was associated with loss of PTEN expression. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e213 Peer Review Report Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Yuh-Shyan Tsai Tainan, Taiwan More articles by this author Tzong-Shin Tzai Tainan, Taiwan More articles by this author Yeong-Chin Jou Chia-Yi, Taiwan More articles by this author Hsin-Tzu Tsai Tainan, Taiwan More articles by this author Chao-Liang Wu Tainan, Taiwan More articles by this author Ai-Li Shiau Tainan, Taiwan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Bladder cancer after managing upper urinary tract transitional cell carcinoma: risk factors and survival

To identify independent risk factors for the development of bladder cancer after surgical management of upper urinary tract transitional cell carcinoma (UUT-TCC). Between January 1999 and December 2008, 154 patients were treated surgically for UUT-TCC at the Clinic of Urology, Clinical Center of Serbia. Patients with a previous history of bladder cancer and patients with concomitant bladder cancer were excluded from the study. In all, 92 patients were then available for evaluation. The median follow-up after surgery was 39.5 months. Univariate and multivariate analyses using the logistic regression model were performed. The intravesical disease-free rate and survival were calculated using the Kaplan-Meier method, and the log-rank test was used to determine statistical differences. In this study, 21.7% patients treated for UUT-TCC developed subsequent bladder tumors. Tumor multifocality was the only independent predictor associated with the development of subsequent bladder cancer (P = 0.028, RR = 3.52). Intravesical recurrence-free survival rates for these 92 patients at 1, 3, 5, and 7 years were 85.8, 80, 79.3, and 78.3%, respectively. Patients with tumors extending to multiple sites were significantly more likely to present subsequent intravesical recurrence (P = 0.006). The development of bladder cancer had no significant effect on the survival of patients who underwent surgical treatment of UUT-TCC, compared to patients without bladder cancer development (P = 0.660). Neither did the type of surgery mode affect patient survival (P = 0.245). This study is limited by biases associated with its retrospective design. The multiplicity of the UUT-TCC is an independent risk factor for the occurrence of bladder cancer.

Primary Urothelial Carcinoma of the Upper Urinary Tract in Dialysis Patients with 5-year Follow-up

In this study, we assessed the clinical and pathological characteristics of urothelial cancers of the upper urinary tract (UUT) in patient under dialysis and evaluated the efficacy and complications of surgical management of the disease. A total of 70 dialysis patients with primary urothelial carcinoma (UC) of the UUT were identified with 5-year follow-up after surgery (61-122 months). Potential factors were analysed to determine the risk factors of subsequent tumours and unfavourable prognostic factors of overall survival. Incidence of urothelial tumours and overall survival of 7503 dialysis patients were also evaluated. The incidence of primary UC of the UUT in dialysis patients in Taiwan was 0.93%. The 2-year and 5-year overall survival rates of dialysis patients with primary UC of the UUT were 74.3% and 42.9%, respectively. Subsequent bladder tumours and contralateral UUT tumours developed in 52.6% and 37.9% patients, respectively. No significant risk factor could be identified to predict subsequent tumours in dialysis patients. Pathological stage (P = 0.021) and grade (P < 0.001) were the unfavourable prognostic factors in the log-rank test. No significant difference was observed in perioperative mortality and overall survival between patients receiving one-stage nephroureterectomy and those receiving two-stage bilateral nephroureterectomy; however, the cystectomy procedure increased perioperative mortality according to the chi(2) test (P = 0.042). Closely monitoring the residual urinary tracts after nephroureterectomy in dialysis patients with primary UC of the UUT should be performed. There is no statistical difference for overall survival between one-stage and two-stage bilateral nephroureterectomy.

A Rare Case of Hematuria from Colonic Adenocarcinoma Spreading to the Bladder via the Stented Ureter

Background The direct extension of advanced tumors from adjacent organs to the bladder is not uncommon. Secondary bladder involvement through hematogenous and/or lymphatic metastases and implant of cells by tumors involving higher urinary tract via the ureter are rare. Therefore, the histological resemblance between primary bladder adenocarcinoma and colorectal adenocarcinoma can be a dilemma for pathologists. Methods A 67-year-old female underwent total right hemicolectomy for ascending colon adenocarcinoma. After a 20-month follow-up the lesion was removed (which was histopathologically similar to the previous colon cancer) and the patient underwent ureteral stenting because of a mass in the right internal iliac nodes with homolateral hydronephrosis. Subsequently intermittent gross hematuria urged on performing cystoscopy detecting a non-papillary mass situated above the right ureteral orifice, previously revealed on ultrasonography and CT scan. Results A TURBT was performed. Histopathologically the mass, partially covered by intact urothelium, consisted of tubular and pseudoglandular structures intermixed with solid foci of mucin-producing signet-ring-cells-type adenocarcinoma, very similar to the original colon cancer. The tumor base was healthy. Immunohistochemically stains for cytokeratin 7 (CK7) and cytokeratin 20 (CK20) presented multifocal positivity, suggesting the colorectal origin of the neoplasm. Conclusions In order to optimize the therapeutic options, it is important to distinguish the primary disease of the bladder from other causes of hematuria, and achieve a correct differentiation between primary enteric-type adenocarcinoma of the bladder and secondary colorectal adenocarcinoma involving the bladder, these entities being morphologically indistinguishable. Therefore, in patients with history of colonic adenocarcinoma, the presence of a subsequent bladder tumor should be considered as an eventuality of a secondary disease.

Bladder cancer after nephroureterectomy in patients with urothelial carcinoma of the upper urinary tract

Objectives To determine the independent risk factors of bladder recurrence in patients with upper urinary tract (UUT) urothelial carcinoma (UC). Materials and methods A total of 181 patients with UUT-UC were enrolled in this study. Their median age was 63 years (range 36–90), and median follow-up after total nephroureterectomy was 37.5 months (range 1.0–174.0). The end-point of this study was defined as the initial intravesical recurrence of UC. Results Of the 181 patients, 64 (35.4%) developed subsequent bladder tumors at a median interval of 6.3 months (range 1.7–50.1) after initial treatment. By univariate analysis, a previous bladder tumor history ( P = 0.046) and tumor necrosis ( P < 0.001) were found to have a significant prognostic impact on bladder tumor-free survival in patients with superficial UUT-UC, whereas surgical margin status ( P = 0.045) and the use of adjuvant chemotherapy ( P = 0.003) were found to be prognostic factors for bladder tumor-free survival in those with invasive UUT-UC. However, by multivariate analysis, only tumor necrosis ( P = 0.012, relative risk = 6.512) was found to have a significant impact on intravesical recurrence in patients with superficial UUT-UC. However, surgical margin status ( P = 0.007, relative risk = 5.846) and the use of adjuvant chemotherapy ( P = 0.001, relative risk = 0.223) were retained as independent predictors of bladder tumor survival in those with invasive UUT-UC. Conclusions Our findings may be useful in patients with UUT-UC who may require more stringent follow-up by cystoscopy to detect bladder tumors.

The Prognostic Predictors of Primary Ureteral Transitional Cell Carcinoma After Radical Nephroureterectomy

We studied the long-term prognosis, and evaluated the predictors of disease specific and recurrence-free survival in a large cohort of patients who had undergone radical nephroureterectomy for primary transitional cell carcinoma of the ureter. From January 1990 to December 2006, 145 patients with primary ureteral transitional cell carcinoma treated with nephroureterectomy and bladder cuff removal at our institution were included in the study. The medical records of these patients were reviewed retrospectively. The clinical and histopathological data were analyzed to evaluate the prognostic predictive factors. Univariate and multivariate statistical analyses were performed. The 5-year disease specific survival rates of stage pTa/Tis/T1, pT2, pT3 and pT4 were 94.6%, 81.8%, 47.4% and 0%, respectively. The 5-year recurrence-free survival rates according to tumor grade were 68.4% for low grade and 35.7% for high grade disease. Of the 145 patients subsequent bladder tumors developed in 38 (26.2%), local recurrence developed in 11 (7.6%) and metachronous contralateral upper urinary tract tumor developed in 3 (2.1%). Most patients had subsequent tumor recurrence within the first year after radical surgery. On univariate and multivariate analyses tumor stage, tumor grade, severity of chronic renal disease, synchronous bladder tumor and hematuria were the significant prognostic variables predicting disease specific and recurrence-free survival. Advanced tumor and chronic renal disease stages were significantly associated with a worse prognosis in patients with primary ureteral transitional cell carcinoma who had undergone radical nephroureterectomy. With regard to tumor recurrence, advanced tumor stage, high tumor grade and synchronous bladder tumor were independent risk factors.

The Role of Lymphovascular Invasion in Predicting the Prognosis of Clinically Localized Upper Tract Urothelial Carcinoma (pT1-3cN0M0)

We assessed the impact of lymphovascular invasion on the prognosis of patients treated for clinically localized (pT1-3N0M0) upper tract urothelial carcinoma. From January 1998 to December 2004, 106 patients treated surgically for clinically localized upper tract urothelial carcinoma (pT1-3cN0M0) were recruited for analysis retrospectively. We assessed the impact of multiple prognostic factors including age, sex, smoking, tumor multiplicity, pathological stage, grading, squamous differentiation, subsequent bladder tumor recurrence, tumor site and lymphovascular invasion on the recurrence-free survival rate. We clarified the role of lymphovascular invasion in predicting cancer specific survival in these patients. Mean patient age was 67.2 +/- 11.1 years and median followup was 47.5 months (range 40 to 115). Lymphovascular invasion was present in 32 of 106 (30.2%) patients. The 5-year recurrence-free survival rate in patients with and without lymphovascular invasion was 65.3% and 91.9%, respectively (p <0.001). On multivariate analysis lymphovascular invasion status, pT3 and ureteral involvement were significant predictors of patient recurrence-free survival. The positivity of lymphovascular invasion was also significantly associated with the risk of higher stage disease (OR 7.49). Patients with lymphovascular invasion had a higher risk of greater pathological stage disease. Lymphovascular invasion and high stage disease with ureteral involvement led to a greater risk of disease recurrence and, in turn, recurrence caused a higher mortality rate. This finding could help identify patients at greater risk for disease recurrence who would benefit from close followup and early adjuvant therapy.

Significant Predictive Factors for Prognosis of Primary Upper Urinary Tract Cancer after Radical Nephroureterectomy in Taiwanese Patients

ObjectivesTo follow up the long-term prognosis of patients who underwent nephroureterectomy for primary upper urinary tract (UUT) cancer and to evaluate the predictive factors of tumour recurrence and survival. MethodsBetween January 1990 and June 2005, 260 patients with primary UUT transitional cell carcinoma (TCC) underwent radical nephroureterectomy at our institution. The medical records of these patients were retrospectively reviewed. The clinical and histopathological data were analyzed to evaluate predictive factors. ResultsThe median follow-up time was 52 mo. In total, 89 patients (34.1%) developed subsequent bladder tumours. Predictive factors of bladder tumour recurrence were being male and having renal insufficiency. Local recurrence developed in 16 patients (6.2%); only the tumour stage was significantly associated with local recurrence. Metachronous contralateral UUT tumour was diagnosed in 12 patients (4.6%), with gender being the only predictive factor. Of the 260 patients, 167 (63.9%) were disease-free and alive at a median follow-up of 56.5 mo, and 45 (17.2%) died of urothelial cancer at a median period of 20 mo. Only the tumour stage was a prognostic factor to predict cancer-specific survival. ConclusionsIn patients with UUT-TCC after radical nephroureterectomy, tumour stage is the only prognostic factor for both local recurrence and cancer-specific survival. Male patients with renal insufficiency should be alerted to the possibility of bladder tumour recurrence. Because female patients were more likely to develop contralateral recurrences, renal ultrasonography, intravenous pyelography, or retrograde pyelography should be performed more frequently for female patients who live in the high-prevalence area.

Pathologic Features of Bladder Tumors After Nephroureterectomy or Segmental Ureterectomy for Upper Urinary Tract Transitional Cell Carcinoma

To determine the pathologic features of bladder tumors after nephroureterectomy or segmental ureterectomy for upper urinary tract transitional cell carcinoma (UUT-TCC). From 1993 to 2003, 82 patients without a history of bladder cancer underwent nephroureterectomy or segmental distal ureterectomy for UUT-TCC. We reviewed the pathologic features of the subsequent bladder tumors, including stage, grade, and progression to cystectomy in these patients at a median follow-up of 44.1 months. A total of 36 (44%) of 82 patients developed bladder tumors after definitive therapy for UUT-TCC at a mean interval of 13.9 months. The mean number of bladder tumors diagnosed per patient in the follow-up interval was 2.1 (range 1 to 6), for a total of 74 bladder tumors. Of the 74 bladder tumors, 71 (96%) were superficial (Stage Ta, Tis, T1), 49 of these superficial tumors (69%) being low grade (grade 1 and 2) and 22 (31%) high grade (grade 3). Three patients had high-grade, muscle-invasive disease, and all progressed to cystectomy during follow-up. A greater than 75% concordance was found in pathologic grade between the UUT lesion and subsequent bladder tumors. The stage of the UUT malignancy, however, did not correlate with subsequent bladder tumor pathologic findings. Bladder tumors developed in 44% of patients after treatment of UUT-TCC. Of these bladder tumors, over 60% were superficial, low-grade lesions, yielding a similar pathologic distribution to that of bladder cancer de novo. The grade, but not the stage, of the UUT tumors correlated with the pathologic findings of subsequent bladder tumor recurrence. Aggressive surveillance with cystoscopy and urinary cytology after surgical management of UUT-TCC is imperative.

Bladder tumour development after urothelial carcinoma of the upper urinary tract is related to primary tumour location

To better define the predictors of bladder tumour development in patients operated for upper urinary tract urothelial cancer (UT-UC). Surgical specimens from 191 consecutive patients with no history of bladder cancer and operated for UT-UC were chosen for analysis. Bladder tumour development was assessed in relation to UT-UC location, tumour multiplicity, stage and grade, margin status, mode of operation, age and gender. Overall, 51 of 191 (27%) patients developed subsequent bladder tumours, including 25 of 123 (20%) with pelvic, 19 of 47 (40%) with ureteric and seven of 21 (33%) with multifocal tumours (P = 0.04 for all subgroups; P = 0.01 for pelvic vs ureteric). There was no influence of the other variables. The median (mean, range) time to recurrence was 12 (18, 3-64) months. In a multivariate analysis, ureteric tumour location was an independent predictor (P = 0.02; risk ratio, RR, 2.0, 95% confidence interval, CI, 1.1-3.7). After excluding 68 patients with systemic disease progression, bladder tumour development was noted in 39 of 123 (32%), including 18 of 76 (24%) with pelvic, 16 of 34 (47%) with ureteric and five of 13 with multifocal tumours (P = 0.06 for all subgroups; P = 0.02 for pelvic vs ureteric). In a multivariate analysis, ureteric location (P = 0.03; RR 2.1, 95% CI 1.1-4.2) and high tumour grade (P = 0.04; RR 2.2, 95% CI 1.03-4.7) were independent predictors of subsequent bladder tumour development. The risk of developing a bladder tumour after surgery for UT-UC is significantly related to ureteric tumour location and high tumour grade. Clinical trials to evaluate a possible reduction of bladder cancer risk by intraoperative ureteric ligation and/or peri-operative topical intravesical chemotherapy instillation are justified.

Bilateral Metachronous Ureteral and Renal Pelvic Carcinomas: Incidence, Clinical Presentation, Histopathology, Treatment and Outcome

Metachronous bilateral UUTTs are rare. The authors reported baseline and long-term followup data for all patients diagnosed in Western Sweden during a 28-year period. We performed a clinical and histopathological analysis of all patients in Western Sweden surgically treated for ureteral and renal pelvic tumors from 1971 to 1998. Of 768 patients a contralateral UUTT developed in 24 (3.1%) after a median of 46 months (range 2 to 232). The projected incidence after initial UUTT diagnosis was 2.7%, 5.8% and 6.5% at 5, 10 and 15 years, respectively. Median age of the 24 patients at initial UUTT diagnosis was 67 years and the median age at death was 77 years. Bladder cancer was significantly more common among patients with bilateral UUTT compared to those with unilateral UUTT (83% vs 31%, p <0.0001). Routine followup urography was normal in 9 patients 2 to 11 months before the diagnosis of the contralateral UUTT. Nine patients died of UUTT and 5 patients died of bladder cancer. Bilateral subsequent upper tract tumors are rare, in general diagnosed at an older age and associated with short survival. Many patients die of bladder cancer and it may be possible to improve survival if the bladder cancer is treated early and aggressively. Routine followup urography is not indicated among patients with a tumor-free bladder and a history of UUTT.

Bladder cancer after managing upper urinary tract transitional cell carcinoma: predictive factors and pathology

To evaluate patients with a history of transitional cell carcinoma (TCC) of the upper urinary tract (UUT) to determine the incidence, pathological distribution, and risk factors for developing subsequent bladder tumours. Between 1993 and 2003, 103 patients were treated at our institution for UUT-TCC. We reviewed demographic, clinical, surgical, and pathological data from these patients at a median follow-up of 38.7 months, and used univariate and multivariate analyses with logistic regression modelling to determine prognostic variables for bladder recurrences. In all, 51 (49.5%) patients developed bladder tumours after treatment for UUT-TCC, at a mean interval of 13.2 months. Patient age (P = 0.01), UUT tumour size (P = 0.03), UUT tumour multifocality (P = 0.05), a history of bladder tumours (P = 0.03), and the number of previous bladder tumours (P = 0.05) predicted the development of bladder recurrences on univariate analysis. On multivariate analysis, only a previous history of bladder tumours (odds ratio 2.6, P = 0.05) remained significant. Over 90% of the recurrent bladder tumours were superficial, with two-thirds of these being low to moderate grade. Six patients had muscle-invasive disease, and five had a cystectomy. Bladder tumours occurred in half the patients after treatment for UUT-TCC; > 60% of these subsequent bladder tumours were superficial, low- to moderate-grade lesions. Neither the pathology of the UUT tumours nor the method of treatment for the UUT disease was associated with recurrent bladder tumours. Only a history of bladder cancer predicted the development of subsequent bladder tumours.

MULTIVARIATE ANALYSIS OF CLINICAL PARAMETERS OF SYNCHRONOUS PRIMARY SUPERFICIAL BLADDER CANCER AND UPPER URINARY TRACT TUMOR

We determined the incidence and characteristic of synchronous upper urinary tract tumors (UUTTs) in patients with primary superficial bladder carcinoma and evaluated the characteristics of bladder tumors related to UUTTs. We performed a retrospective study of 1,529 patients with primary superficial bladder carcinoma who underwent initial examination of the upper urinary tract with excretory urography. Data were analyzed by multivariate analysis using logistic regression. Variables evaluated and related to the incidence of UUTT were multiplicity, carcinoma in situ, bladder tumor size, localization of tumor in the bladder, and tumor grade and stage. A total of 28 patients (1.8%) had simultaneous bladder tumor and UUTT. UUTTs showed no preferred location and 17.9% were multiple. Of UUTTs 46% were invasive and almost 87% were grade 2 or 3. The only significant variable related to UUTT was bladder tumor in the trigone (RR 5.8, 95% IC 2.18 to 15.9, p <0.0005). Of 147 tumors located in the trigone 11 (7.5%) were associated with UUTT, corresponding to 41% of the UUTTs first diagnosed. If multiplicity and tumors in the trigone (551 cases) had been considered, 66.7% of tumors would have been diagnosed. Synchronous UUTT and superficial bladder tumor are uncommon but 46% are invasive. Considering the possible examination of the upper urinary tract only in patients with tumor in the trigone or with multiple bladder tumors 41.4% or 69% of UUTTs, respectively, would have been diagnosed. Patients with tumor in the trigone are at almost 6-fold higher risk for a synchronous tumor in the upper urinary tract.

DISTINCT MICROSATELLITE ALTERATIONS IN UPPER URINARY TRACT TUMORS AND SUBSEQUENT BLADDER TUMORS

Although synchronous and/or metachronous tumor development is common in urothelial cancer, genetic and biological differences in upper urinary tract and bladder tumors are unclear. We compared the genetic alteration pattern in multifocal disease in patients with upper urinary tract and subsequent bladder tumors, and those with recurrent bladder tumor. Using 21 microsatellite markers on the 8 chromosomal arms 2q, 4p, 4q, 8p, 9p, 9q, 11p and 17p we analyzed 34 tumors from 15 patients with upper urinary tract and subsequent bladder disease, and 70 tumors from 22 with recurrent bladder disease. Judging from the patterns of genetic alterations multifocal tumors were considered to have derived from an identical progenitor cell in 7 of 13 evaluable patients (54%) with upper urinary tract and subsequent bladder tumors, and 16 of 19 (84%) who were evaluable with recurrent bladder tumor. These data confirm the view that seeding or intraepithelial spread is a major mechanism for the multifocal development of urothelial cancer in general. However, a discordant microsatellite alteration pattern in multifocal tumors was observed in 6 of 7 patients (86%) with upper urinary tract and subsequent bladder lesions but in 2 of 16 (13%) with recurrent bladder cancer (p <0.005). Our results imply that upper urinary tract neoplasms may be genetically more unstable than bladder neoplasms. The implantation of tumor cells from upper urinary tract to bladder may involve additional and diverse genetic alterations. Furthermore, a considerable number of multifocal upper urinary tract and subsequent bladder lesions may arise independently via field cancerization mechanism. Our study indicates that the factors contributing to multifocal development are different in the 2 groups.

Relationship between grade and stage of renal pelvic and/or ureteral tumor and associated bladder tumor

The purpose of this study was to analyze bladder tumor (BT) associated with renal pelvic and/or ureteral tumor (RUT), with emphasis on the relationship between the grade and stage of these tumors. We reviewed 77 cases of RUT operated upon at our hospital during the last 14 years. We herein define stage T1b tumor as invasive since this stage of tumor is considered to have a different biologic behavior and potential compared to stage Ta tumor. Of the 77 patients, 29 had associated BTs: 8 with a concomitant BT, 3 with BT antedating RUT, and 18 with a subsequent BT. In addition, one patient with preceding BT and two with concomitant cases developed BT after the RUT operation, permitting 21 cases to be categorized in the subsequent BT group. Thirty one out of 32 cases of associated BTs had the same or a lower grade of RUT while one-patient who initially had G2 T1b RUT developed G3 T2 BT 5 years after total nephroureterectomy. In the preceding cases, two patients with Ta BTs, had Ta RUTs, and one patient with T1b BT antedated T2 RUT. In the concomitant BTs, all four cases with stage Ta RUT exhibited Ta BT, and another four with invasive RUT presented invasive BT. In the subsequent cases, 18 out of 21 patients developed Ta BT. In the preceding and concomitant cases, associated BT & RUT tend to have the same nature, that is, to be either invasive or non-invasive. In contrast to these cases, 18 out of 21 patients in subsequent cases developed Ta BT. However, since three out of 10 patients with invasive RUT subsequently developed invasive BTs1 careful follow-up for invasive RUT should be mandatory to detect recurrent invasive BTs in their early stage.