Upper Urinary Tract Urothelial Carcinoma Patients Research Articles

Aristolochic acid‐induced upper tract urothelial carcinoma in Taiwan: Clinical characteristics and outcomes

Aristolochic acid (AA), a component of all Aristolochia-based herbal medicines, is a potent nephrotoxin and human carcinogen associated with upper urinary tract urothelial carcinoma (UUC). To investigate the clinical and pathological characteristics of AA-induced UUC, this study included 152 UUC patients, 93 of whom had been exposed to AA based on the presence of aristolactam-DNA adducts in the renal cortex. Gene sequencing was used to identify tumors with A:T-to-T:A transversions in TP53, a mutational signature associated with AA. Cases with both aristolactam-DNA adducts and A:T-to-T:A transversions in TP53 were defined as AA-UUC, whereas patients lacking both of these biomarkers were classified as non-AA-UUC. Cases with either biomarker were classified as possible-AA-UUC. Forty (26%), 60 (40%), and 52 (34%) patients were classified as AA-UUC, possible-AA-UUC and non-AA-UUC, respectively. AA-UUC patients were younger (median ages: 64, 68, 68 years, respectively; p=0.189), predominately female (65%, 42%, 35%, respectively; p=0.011), had more end-stage renal disease (28%, 10%, 12%, respectively; p=0.055), and were infrequent smokers (5%, 22%, 33%, respectively; p=0.07) compared to possible-AA-UUC and non-AA-UUC patients. All 14 patients who developed contralateral UUC had aristolactam-DNA adducts; ten of these also had signature mutations. The contralateral UUC-free survival period was shorter in AA-UUC compared to possible- or non-AA-UUC (p=0.019 and 0.002, respectively), whereas no differences among groups were observed for bladder cancer recurrence. In conclusion, AA-UUC patients tend to be younger and female, and have more advanced renal disease. Notably, AA exposure was associated with an increased risk for developing synchronous bilateral and metachronous contralateral UUC.

DNA copy number aberrations associated with lymphovascular invasion in upper urinary tract urothelial carcinoma

Recent studies have reported that lymphovascular invasion (LVI) is a predictor of patient prognosis in upper urinary tract urothelial carcinoma (UUTUC). DNA copy number aberrations (DCNAs) identified by array-based comparative genomic hybridization (aCGH) had not previously been examined in UUTUC. We therefore examined DCNAs in UUTUC and compared them with DCNAs in LVI. We applied aCGH technology using DNA chips spotted with 4,030 BAC clones to 32 UUTUC patients. Frequent copy number gains were detected on chromosomal regions 8p23.1 and 20q13.12, whereas frequent copy number losses were detected on chromosomal regions 13q21.1, 17p13.1, 6q16.3, and 17p11.2. DCNAs occurred more frequently in tumors with LVI than in those without it (P = 0.0002), and this parameter was more closely associated with LVI than with the tumor grade or pT stage. Disease-specific survival rate was higher in tumors without LVI than in those with it (P = 0.0120); however, tumor grade and stage were not significant prognostic factors of patient outcome. These data support our hypothesis that tumors with LVI have more genetic alterations in terms of total numbers of DCNAs than those without, and provide proof that aggressive adjuvant therapy should be considered for UUTUC patients with LVI.

Ureteral tumours showing a worse prognosis than renal pelvis tumours may be attributed to ureteral tumours more likely to have hydronephrosis and less likely to have haematuria

To demonstrate the relationships among tumour location, hydronephrosis, and tumour stage in patients with Upper Urinary Tract Urothelial Carcinoma (UUT-UC). Moreover, we want to determine whether primary tumour location is an independent predictor of prognosis in those patients. Retrospective analysis of 251 UUT-UC patients from our centre treated with radical nephroureterectomy between 2000 and 2010. Patients who had previous radical cystectomy, preoperative chemotherapy, previous contralateral UUT-UC, multifocal tumours, or metastatic disease at presentation were excluded. Overall, 217 patients were then available for evaluation. The relationships among tumour location, hydronephrosis, and tumour stage were analysed. Tumour location was categorized as renal pelvis or ureter. Progression-free survival (PFS) and cancer-specific survival (CSS) probabilities were estimated using Kaplan-Meier and Cox regression analyses. Tumour location was renal pelvis in 146 cases (67%), ureter in 71 cases (33%). Median follow-up was 52months. Compared with renal pelvic tumours, ureteral tumours were more likely to have hydronephrosis and to be associated with advanced stages (p<0.001), but less likely to have haematuria. The 5-year CSS estimate was 79.3% for renal pelvic tumours and 64.7% for ureteral tumours (p=0.03). The 5-year PFS probability was 68.7% for renal pelvic tumours and 54.2% for ureteral tumours (p=0.02). On univariable and multivariable analysis, tumour location was an independent prognostic factor for CSS (p<0.05). Ureteral tumours were associated with a worse prognosis than renal pelvis tumours. The possible hypothesis may be due partially to that ureteral tumours are more likely to have hydronephrosis and less likely to have haematuria.

Abstract 4564: Dysregulated p15 in urothelial carcinoma of the upper urinary tract

Abstract OBJECTIVE: To investigate tumorigenic characteristics of upper urinary tract urothelial carcinoma (UTUC) by evaluating genomic alterations and protein expression of p15, located in 9p21, in primary tumors and in the morphologically normal pelvis of UTUC patients. METHODS: 10 pairs of tumor and pelvis tissues were submitted for comparative genomic hybridization (CGH) to examine chromosome abberations. Western blotting assays were performed to compare the fold change of p15 expression between another 16 pairs of tumor and normal tissues. Immunohistochemistry was conducted to determine the presence of p15-positive tumor cells and staining intensity in 53 tumor tissues, including 26 superficial and 27 invasive tumors. The Student's t-test and Chi-square test were applied to explore the correlation between the p15 expression and clinicopathologic parameters of UTUC patients. RESULTS AND CONCLUSIONS: CGH revealed incomplete 9p21 in 70% of UTUC tumors, including 3 low-grade and 7 high-grade cases. Results of Western blotting assays showed high frequencies (75%) of p15 downregulation (fold change &amp;gt; 1.5) in UTUC tissues compared to their normal pelvis control. Immunohistochemistry results indicated that superficial tumors had lower p15 expression than invasive tumors (p=0.002). In patients with tumor metastases, local recurrence or distal recurrence, the p15 expression level was significantly increased in UTUC tissues (p=0.038, 0.01 and 0.017, respectively). Taken together, our data suggest that the decreased expression of p15 may be an important step in early neoplastic transformation of the urothelium of upper urinary tract and, during tumor progression, p15 may be up-regulated by other molecules, such as SP-1. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4564. doi:1538-7445.AM2012-4564

634 GENOME-WIDE ANALYSIS OF COPY NUMBER ALTERATIONS IN RENAL-PELVIC AND URETERAL CANCERS

including urothelial cancers. We aimed to evaluate the prognostic impact of CRP for upper urinary tract urothelial carcinoma (UUT-UC) in a large multicenter cohort. METHODS: Among 1032 UUT-UC patients of the Tokyo Metropolitan Database of Urologic Disease (TMDU), 637 patients without distant metastasis treated by nephroureterectomy, whose preoperative CRP levels were available, were enrolled in this study. The cut-off point of CRP was set at 5 mg/l. The Cox proportional hazard model was used to assess prognostic impacts on survival. The predictive accuracy of the multivariate model was calculated with the concordance index (c-index). RESULTS: During the follow-up period, a median of 36 months (range: 1–238 months), 136 patients (22%) developed disease recurrence and 112 patients (18%) died of disease. The 5-year recurrencefree (RFS) and cancer-specific survival (CSS) rates of the total number of patients were 73.5% and 75.9%, respectively. In 107 patients (17%), preoperative CRP levels were elevated to 5 mg/l. The 5-year RFS and CSS rates of patients with preoperative CRP elevation (62.1% and 63.8%, respectively), were significantly worse than those of patients without CRP elevation (75.7% and 78.2%, respectively) (p 0.01). Multivariate analysis revealed that CRP was an independent predictor for CSS in both a continuous (hazard ratio [HR]: 1.01: p 0.01) and categorized fashion (HR: 1.6; p 0.03) as well as in pathological stage 3 or 4, histological grade 3, with lymph node involvement, and with lymphovascular invasion. Similarly, logarithmic CRP was an independent predictor for RFS (HR: 1.52; p 0.01). Adding CRP as both a continuous and categorized variable to the multivariable model, the predictive accuracy to CSS was improved by 5.5% or 2.0%, respectively, from 74.5%. CONCLUSIONS: The current results indicate that CRP is an informative predictor of survival for UUT-UC patients in a large database cohort. Its routine use may allow better risk stratification and risk-adjusted follow up.

Prognostic Factors for Upper Urinary Tract Urothelial Carcinoma after Nephroureterectomy

Introduction: The purpose of this study was to evaluate prognostic factors for patients with upper urinary tract urothelial carcinoma (UUT-UC) after nephroureterectomy and to seek a better way of finding more favorable clinical results for these patients. Patients and Methods: We retrospectively reviewed the medical records of 121 UUT-UC patients who underwent a nephroureterectomy at our institution, and analyzed the prognostic significance of various clinicopathological parameters for progression-free and disease-specific survival rates by using univariate and multivariate analysis. Results: A Cox proportional hazards model showed that extravesical tumor recurrence after surgery was an independent prognostic factor for disease-specific survival (p < 0.0001). An additional model showed that lymphovascular invasion (LVI) was one of the independent predictors of lower extravesical-recurrence-free survival rates (p = 0.0004). Our final finding was that pathological tumor stage and positive surgical margin were significantly associated with the presence of LVI (p < 0.0001 and p = 0.0029, respectively). Conclusions: We conclude that there is a high possibility of LVI in patients with large tumors. Our findings should be helpful in terms of determining whether or not to perform neoadjuvant chemotherapy for patients with large tumors, given the fact that we frequently find a severe reduction in renal function after nephroureterectomy.

Gender effect on renal outcome in patients with urothelial carcinoma

Taiwan is a highly endemic area for urothelial carcinoma (UC) and chronic kidney disease (CKD). We evaluate the gender effect on the relationship between renal outcome and clinical characteristics of CKD patients with UC. The clinical and pathologic records of 404 patients were retrospectively analyzed. We calculated glomerular filtration rate (GFR) using the Modification of Diet in Renal Disease (MDRD) equation, and staged CKD status according to K/DOQI guideline. The female group had a significantly higher proportion (67.6% vs 29.0%, P<0.001) of upper urinary tract urothelial carcinoma (UUT-UC). Pathologically, the frequency of high T stage UC (32.4% and 19.1%; P=0.003), high-grade UC (89.4% and 75.6%; P=0.001), and larger UC (51.4% and 37.8%; P=0.009) in the female patients were significantly higher, when compared with the male group. Male gender, diabetes, anemia, poor preoperative renal function, UUT-UC, and low-grade tumor were independent risk factors of poor renal outcome by multivariate analysis in these UC patients. Diabetes was a risk factor of poor renal outcome in male UUT-UC patients, but not in the female patients (P=0.009). Female gender had a more aggressive histological urothelial carcinoma pattern than male patients did, but paradoxically had a more favorable renal outcome.

Prognostic significance of preoperative serum CYFRA 21‐1 in patients with upper urinary tract urothelial carcinoma

The prognosis for upper urinary tract urothelial carcinoma is generally poorer than that for bladder cancer, and prognostic predictors with a high specificity for upper urinary tract urothelial carcinoma (UUT-UC) are needed to optimize treatment. In fact, the only preoperative predictor currently available is C-reactive protein. In the present study, we investigated the usefulness of pretreatment serum CYFRA 21-1 as a new prognostic predictor in UUT-UC. A total of 45 UUT-UC patients for whom serum CYFRA 21-1 was measured before treatment were included in this retrospective analysis. Patients were separated into high and low serum CYFRA 21-1 groups based on a cut-off value of 2.7 ng/mL determined from a receiver operating characteristic curve. Kaplan-Meier survival curves were calculated and the overall survival rate was statistically analyzed for the high and low pretreatment serum CYFRA 21-1 groups using the log-rank test. Multivariable analysis was carried out using the Cox proportional hazards analysis. By the median follow-up period of 14.4 months, 20 patients (44.4%) had died. Of the 45 patients, 23 (51.1%) were in the high pretreatment serum CYFRA 21-1 group, and the overall survival rate of this group was significantly lower (P < 0.001). Multivariable analysis identified only distant metastasis (P < 0.001) and pretreatment serum CYFRA 21-1 (P = 0.039) as independent prognostic predictors. Distant metastasis did not significantly differ between the two groups or correlate with pretreatment serum CYFRA 21-1. These findings suggest that pretreatment serum CYFRA 21-1 values could serve as a prognostic predictor of UUT-UC.

Chronic kidney disease as a risk factor for synchronous bladder cancer in patients with upper urinary tract urothelial carcinoma

Objective To evaluate chronic kidney disease (CKD) as a risk factor for synchronous bladder cancer in a cohort of Chinese patients with upper urinary tract urothelial carcinoma (UUTUC). Methods Between 2005 and 2007, 161 patients (61 males and 100 females) underwent surgical management at our institution for pathologically proven UUTUC. The clinical, surgical, and pathological data were reviewed. The glomerular filtration rate(GFR) was calculated using the Modification of Diet in Renal Disease Study equation. And the presence of CKD was determined according to GFR＜60 ml/min. The univariate and multivariate analyses were used to determine prognostic variables for synchronous bladder tumor. Results Of the 161 consecutive cases, the mean age was 67years (range 37 to 87 years). Twenty cases (12.4%) had simultaneous bladder tumor and UUTUC.Ninety-three patients (57.8 % ) had CKD. Fifteen cases (9.3 %) had the history of urothelial carcinoma. Univariate analyses showed that patients with CKD (P=0.008) and the history of urothelial carcinoma (P= 0.001 ) were likely to have synchronous bladder tumor;however, there was no significant impact of other factors on the synchronous intravesical disease, including age, gender, tumor multiplicity, tumor stage, tumor grade, and tumor size. Furthermore, CKD (HR 4. 907, 95% CI 1. 206-19. 959, P=0. 026) and the history of urothelial carcinoma (HR 6. 444, 95% CI 1. 699-24. 445,P=0. 006) were identified as independent predictors for the development of synchronous bladder tumor by multivariate analyses. Conclusions The incidence of synchronous bladder cancer in Chinese patients with UUTUC is not very low. Concurrent CKD and the history of urothelial carcinoma are associated with greater risk of synchronous bladder cancer in UUTUC patients. Key words: Urologic neoplasms; Carcinoma, transitional cell; Urinary bladder neoplasms; Renal insufficiency, chronic; Risk assessment