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Objectives: To describe the most recent 7 year experience with 137 Indiana pouch patients at a single institution and provide data on complications with this type of urinary diversion during the first postoperative year., Methods: We queried our bladder cancer database to identify all patients who underwent cystectomy with continent catheterizable urinary reservoir between 2012 and 2018. Pre-, intra-, and postoperative data were collected. Complications were stratified into early (within 90 days) and midterm (90-365 days). The primary outcomes were postoperative complications, and overall and cancer-specific mortality., Results: A total of 137 patients underwent open cystectomy with Indiana pouch creation. Of these, 93% were radical cystectomies. On average, the operation took 422 minutes. There were 53 (39%) patients who experienced any type of complication during the first postoperative year (Clavien II-V). Twenty-five patients (18.2%) readmitted in the early postoperative period vs 18 (13.1%) patients midterm. There were 10 (7.3%) patients that required early reoperation and 11 (8%) in the midterm period. The overall mortality rate was 1.5% early and 3.7% midterm, with the majority of the mortality rate attributed to cancer progression (85.7%)., Conclusion: Patients undergoing continent catheterizable reservoir urinary diversion appear to have comparable complication rates to other urinary diversions published in the literature. At high-volume urologic institutions, Indiana Pouch creation is a suitable option for select patients desiring a continent diversion., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: National and international guidelines recommend the use of 1 dose of intravesical chemotherapy immediately following surgery for nonmuscle invasive bladder cancer, which is performed infrequently on a population level. We sought to understand the importance of potential environmental and clinical dimensions involved in the decision to offer this therapy., Materials and Methods: Urologists from the Michigan Urological Surgery Improvement Collaborative (MUSIC) rated 8 distinct clinical vignettes involving patients with nonmuscle invasive bladder cancer. A ratings-based conjoint analysis method was used to evaluate the clinical vignette responses. Each vignette included 4 clinical dimensions and 2 environmental dimensions, with each dimension consisting of 2 possible attributes. The relative importance of each attribute was derived from the regression model and ranked in order., Results: A total of 58 urologists answered the clinical vignettes which represents >75% of MUSIC sites. The median age of urologists was 53, most were male, and median years in practice was 20 years post residency. An environmental attribute, having a recovery room protocol for instilling and disposing of the chemotherapy, ranked as the most influential attribute for giving postoperative chemotherapy (utility=8.6). The clinical attribute yielding the strongest preference for giving chemotherapy was tumor grade (utility=4.9). These preferences varied by different subgroups of urologists, particularly regarding the type of practice a urologist was in., Conclusions: This study demonstrates that urologists have clear preferences for when they offer postoperative immediate chemotherapy. Factors beyond just clinical variables play a role in this decision making process such as the structure of the recovery room.

Objective: To characterize the health-related quality of life reported by patients who received an ileal conduit (IC), Indiana pouch, or neobladder urinary diversion after radical cystectomy., Materials and Methods: The Functional Assessment of Cancer Therapy-Vanderbilt Cystectomy Index survey was administered to patients with bladder cancer undergoing radical cystectomy and urinary diversion from 2015-2018. Surveys were completed prior to radical cystectomy and then longitudinally throughout the postoperative course., Results: A total of 146 patients completed questionnaires over a median of 12.3 months, 83 (56.8%) received an IC, 31 (21.2%) an Indiana pouch, and 32 (21.9%) an orthotopic neobladder. There were no significant differences in health related quality of life among urinary diversion groups considering the Trial Outcome Index scores, general overall FACT-G assessment, or total Functional Assessment of Cancer Therapy-Vanderbilt Cystectomy Index instruments. Patients who received IC were older and had higher Charlson Comorbidity Index scores (p <.005) yet still experienced similar improvements in health related quality of life commensurate with the other diversion cohorts. There was a significant difference in physical well-being favoring neobladder over IC or Indiana Pouch urinary diversions (p <.05)., Conclusions: To our knowledge this is the first and largest quality of life analysis comparing all three methods of urinary diversion in a longitudinal fashion utilizing a standardized, validated, treatment-specific health survey. Proper preoperative counseling is critical to ensure understanding of the benefits of available urinary diversion., (Published by Elsevier Inc.)

Background: The purpose of this study was to evaluate the effect of neoadjuvant chemotherapy (NACT) on squamous variant (SV) bladder cancer by investigating patients presenting with SV histology at the time of transurethral resection (TUR), stratified by their receipt of NACT., Materials and Methods: The records of 71 patients with muscle-invasive bladder cancer and SV in the TUR specimen who underwent cystectomy between 2008 and 2018 were reviewed. Our primary outcome was pathologic response at time of cystectomy. Secondary outcomes included recurrence-free survival and overall survival stratified by receipt of NACT. A subgroup analysis was then conducted on the patients with defined SV% on TUR stratified by % involvement (< 50% SV vs. ≥ 50% SV)., Results: The median age of the NACT and no-NACT groups was 60.2 and 70 years, respectively (P = .003). The complete response rate at cystectomy was 60% versus 13.7% for the NACT and no-NACT groups, respectively (P < .001). The non-organ-confined disease rate at time of radical cystectomy was 35% for the NACT group and 68.6% for the no-NACT group (P = .01). The NACT group had fewer recurrences than the no-NACT group (10% vs 47.1%; P = .003). In the subgroup analysis, the lower rate of non-organ-confined disease persisted for the patients who underwent NACT at the lower SV percentage but failed to remain significant at greater percentage involvement. This was also true for overall survival., Conclusions: The effect of NACT in variant histology bladder cancer is variable. In patients with SV, these results favor the recommendation in favor of NACT administration, particularly when the primary tumor has < 50% involvement by the variant histology., (Published by Elsevier Inc.)

Objectives: Micropapillary urothelial carcinoma of the urinary bladder (MPUC) is a rare variant of urothelial carcinoma which has aggressive clinical characteristics. The objective is to investigate the molecular subtypes of MPUC and the impact to the clinical outcome and determine whether MPUC represents a variant of adenocarcinoma., Materials and Methods: We evaluated surrogate immunohistochemical markers of luminal, basal, and p53-like subtypes and correlated with prognosis and the expression of markers related to bladder adenocarcinoma and glandular differentiation in 56 cases of MPUC (10 cases of transurethral resection and 46 cases of radical cystectomy). Biomarker expression in co-existing conventional urothelial carcinoma was also analyzed. Cox regression analysis was performed to study the impact of molecular subtype on the clinical outcome., Results: Thirty-four cases (61%) met criteria for the luminal subtype. Twenty-two cases (39%) displayed a p53-like subtype. In contrast, 40/56 (71%) cases of coexisting conventional urothelial carcinoma were classified as luminal subtype and 16/56 (29%) cases were designated as p53-like subtype. There was no significant survival difference between luminal subtype and p53-like subtype. CDX2, villin, and cadherin 17 were negative in all cases. MUC1 was strongly and diffusely expressed in the stroma-facing surface of MPUC tumor cells in all the cases., Conclusions: Our findings suggest that MPUC possesses characteristics of luminal and p53-like subtypes, and does not harbor phenotypic features of the basal subtype. There is no significant difference in the prognosis between luminal and p53-like subtype MPUC. MPUC is not a variant of adenocarcinoma and does not represent a form of glandular differentiation, in contrast to other organ sites., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Bladder cancer is the sixth most common cancer in the United States, and it exhibits an alarming 70% recurrence rate. Thus, the development of more efficient antibladder cancer approaches is a high priority. Accordingly, this work provides the basis for a transformative anticancer strategy that takes advantage of the unique characteristics of the bladder. Unlike mucin-shielded normal bladder cells, cancer cells are exposed to the bladder lumen and overexpress EGFR. Therefore, we used an EGF-conjugated anthrax toxin that after targeting EGFR was internalized and triggered apoptosis in exposed bladder cancer cells. This unique agent presented advantages over other EGF-based technologies and other toxin-derivatives. In contrast to known agents, this EGF-toxin conjugate promoted its own uptake via receptor microclustering even in the presence of Her2 and induced cell death with a LC 50 < 1 nM. Furthermore, our data showed that exposures as short as ≈3 min were enough to commit human (T24), mouse (MB49) and canine (primary) bladder cancer cells to apoptosis. Exposure of tumor-free mice and dogs with the agent resulted in no toxicity. In addition, the EGF-toxin was able to eliminate cells from human patient tumor samples. Importantly, the administration of EGF-toxin to dogs with spontaneous bladder cancer, who had failed or were not eligible for other therapies, resulted in ~30% average tumor reduction after one treatment cycle. Because of its in vitro and in vivo high efficiency, fast action (reducing treatment time from hours to minutes) and safety, we propose that this EGF-anthrax toxin conjugate provides the basis for new, transformative approaches against bladder cancer., (© 2019 UICC.)

Aims: To describe a large tertiary care academic centre's experience with patients who achieve a complete pathological response (ie, ypT0N0) following neoadjuvant chemotherapy (NAC) and radical cystectomy (RC) with emphasis on morphological features present in the RC and clinical outcome., Methods: 41 patients with ypT0N0 disease following transurethral resection of bladder tumour (TURBT), NAC and RC with available clinical follow-up information were analysed. Slides from all RCs were reviewed to confirm pathological stage and assess for morphological parameters (eg, foreign body giant cell reaction, dystrophic calcification, scar and fat necrosis)., Results: With median follow-up of 32.8 months, the recurrence-free survival at 1 and 5 years was 97.4% and 93.5%, while the overall survival at 3 and 5 years was 94.2% and 88.6%, respectively. No patients died of urothelial carcinoma. Stage assigned at TURBT was 1 pTa (2%), 1 pT1 (2%), 38 pT2 (93%) and 1 pT3a (2%). 17 TURBTs demonstrated variant histology, with the majority of these being squamous (65%). The most common morphological features present at RC were scar (100%), foreign body giant cell reaction (80%), chronic inflammation within lamina propria (68%) and dystrophic calcifications (39%). Other morphological features were less common or absent., Conclusion: ypT0N0 disease at RC portends an excellent prognosis, regardless of stage or variant histology in the TURBT; scar, foreign body giant cell reaction, chronic inflammation and dystrophic calcifications are often present., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Environmental factors that play a role in the urothelial carcinogenesis have been well characterized. Current research is continuously exploring potential heritable forms of bladder cancer. Lynch syndrome is a well-known inheritable disease that increases the risk for a variety of cancers, including urothelial carcinomas. Screening of patients with known Lynch syndrome is important to evaluate for development of new primary tumors. Further study may provide more information on what level of follow-up each patient needs. Recent data suggest that mismatch repair mutations confer a greater risk for urothelial cancer. Additional large patient series as well as advancement of molecular testing may provide triage for Lynch syndrome patients in regards to the frequency and type of screening best suited for individual patient.

Background: Carcinoma in situ (CIS) is a poor prognostic finding in urothelial carcinoma. However, its significance in muscle-invasive urothelial carcinoma (MIUC) treated with neoadjuvant chemotherapy (NAC) is uncertain. We assessed the effect of CIS found in pretreatment transurethral resection of bladder tumor (TURBT) biopsies on the pathologic and clinical outcomes., Materials and Methods: Subjects with MIUC treated with NAC before cystectomy were identified. The pathologic complete response (pCR) rates stratified by TURBT CIS status were compared. The secondary analyses included tumor response, progression-free survival (PFS), overall survival (OS), and an exploratory post hoc analysis of patients with pathologic CIS only (pTisN0) at cystectomy., Results: A total of 137 patients with MIUC were identified. TURBT CIS was noted in 30.7% of the patients. The absence of TURBT CIS was associated with a significantly increased pCR rate (23.2% vs. 9.5%; odds ratio, 4.08; 95% confidence interval, 1.19-13.98; P = .025). Stage pTisN0 disease was observed in 19.0% of the TURBT CIS patients. TURBT CIS status did not significantly affect the PFS or OS outcomes. Post hoc analysis of the pTisN0 patients revealed prolonged median PFS (104.5 vs. 139.9 months; P = .055) and OS (104.5 vs. 152.3 months; P = .091) outcomes similar to those for the pCR patients., Conclusion: The absence of CIS on pretreatment TURBT in patients with MIUC undergoing NAC was associated with increased pCR rates, with no observed differences in PFS or OS. Isolated CIS at cystectomy was frequently observed, with lengthy PFS and OS durations similar to those for pCR patients. Further studies aimed at understanding the biology and clinical effect of CIS in MIUC are warranted., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: To evaluate the long-term (>5 years) health-related quality of life (HRQOL) outcomes following radical cystectomy, comparing Indiana pouch (IP), neobladder (NB), and ileal conduit (IC)., Materials and Methods: The departmental radical cystectomy database was queried to identify patients who underwent radical cystectomy and urinary diversion for bladder cancer between 1991 and 2009 and had not died. Three hundred patients were identified and sent the validated Bladder Cancer Index instrument., Results: A total of 128 (43%) patients completed the survey. When adjusted for gender, age at surgery, surgeon, and time since surgery, IC and IP patients had significantly better urinary function than NB patients (P = .0013). Sexual bother was less in NB than IP (P = .0387). Among men ≥65 years of age, IC patients had significantly better urinary function (P = .0376) than NB patients (91.6 vs 49.4, respectively). Among men <65 years of age, IC and IP patients (76.0 and 82.8, respectively) had significantly better urinary function than NB patients (50.7) (P = .0199). Among women greater than 65 years, bowel bother was significantly better (P = .0095) for IC patients than IP patients (44.8 vs 69.5, respectively)., Conclusion: Urinary diversion type after radical cystectomy affects HRQOL differently in long-term survivors. Age and gender at surgery influenced HRQOL based on diversion procedure. Urinary function but not urinary bother was significantly better in IC and IP compared to NB diversions. Prospective longitudinal studies using validated HRQOL tools will further help guide preoperative diversion choice decisions between patient and surgeon., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: To assess the clinical and pharmacodynamic activity of dovitinib in a treatment-resistant, molecularly enriched non-muscle-invasive urothelial carcinoma of the bladder (NMIUC) population. Experimental Design: A multi-site pilot phase II trial was conducted. Key eligibility criteria included the following: Bacillus Calmette-Guerin (BCG)-unresponsive NMIUC ( > 2 prior intravesical regimens) with increased phosphorylated FGFR3 (pFGFR3) expression by centrally analyzed immunohistochemistry (IHC+) or FGFR3 mutations (Mut+) assessed in a CLIA-licensed laboratory. Patients received oral dovitinib 500 mg daily (5 days on/2 days off). The primary endpoint was 6-month TURBT-confirmed complete response (CR) rate. Results: Between 11/2013 and 10/2014, 13 patients enrolled (10 IHC+ Mut-, 3 IHC+ Mut+). Accrual ended prematurely due to cessation of dovitinib clinical development. Demographics included the following: median age 70 years; 85% male; carcinoma in situ (CIS; 3 patients), Ta/T1 (8 patients), and Ta/T1 + CIS (2 patients); median prior regimens 3. Toxicity was frequent with all patients experiencing at least one grade 3-4 event. Six-month CR rate was 8% (0% in IHC+ Mut-; 33% in IHC+ Mut+). The primary endpoint was not met. Pharmacodynamically active (94-5,812 nmol/L) dovitinib concentrations in urothelial tissue were observed in all evaluable patients. Reductions in pFGFR3 IHC staining were observed post-dovitinib treatment. Conclusions: Dovitinib consistently achieved biologically active concentrations within the urothelium and demonstrated pharmacodynamic pFGFR3 inhibition. These results support systemic administration as a viable approach to clinical trials in patients with NMIUC. Long-term dovitinib administration was not feasible due to frequent toxicity. Absent clinical activity suggests that patient selection by pFGFR3 IHC alone does not enrich for response to FGFR3 kinase inhibitors in urothelial carcinoma. Clin Cancer Res; 23(12); 3003-11. ©2016 AACR ., (©2016 American Association for Cancer Research.)

In this review, we discuss the types of liquid biopsies currently available, and their recent and potential clinical applications, especially as they relate to the detection of molecular biomarkers of bladder cancer. The advances in research using high-throughput next-generation genomic techniques have identified a number of promising molecular biomarkers of bladder urothelial carcinoma. Liquid biopsy has recently received enormous attention as a potential tool for real-time monitoring of disease status in cancer patients, and genomic profiles are reported to closely match those of corresponding tumors. It is noninvasive and easily repeated, and allows monitoring during treatment and detection of different genomic alterations that are potentially accessible to targeted therapy or are associated with treatment resistance in bladder cancer patients. Moreover, liquid biopsy is a tool that allows rapid access to biomarker assessment in patients for whom solid biopsies are not available. Liquid biopsy will be widely applied to daily clinical practice and serve as an important tool for the screening, surveillance, prediction of outcomes, and selection of effective targeted therapies in bladder carcinoma.

Aim: We compared the efficacy of methotrexate/vinblastine/doxorubicin/cisplatin (MVAC) versus gemcitabine/cisplatin in urothelial cancer and neoadjuvant chemotherapy (NACT) efficacy in variant histology (VH)., Materials & Methods: Radical cystectomy patients were retrospectively compared with those who received NACT. Factors associated with survival, pathologic complete response (pCR) and downstaging (pDS) were evaluated in multivariable models., Results: 9% of radical cystectomy patients (84/919) received NACT, with improved survival, pCR and pDS on both regimens. MVAC lead to higher pDS without an increase in pCR. On multivariable analysis, there was a nonsignificant increase in pDS with MVAC. NACT conferred similar responses in squamous and glandular differentiation VH., Conclusion: NACT was associated with improved survival, pCR and pDS. Furthermore, responses to NACT were not dependent on presence of VH.

The discovery that the role human papillomavirus (HPV) plays in the induction of human cancer represents an important achievement in oncologic research. It has taken on even greater importance since the development of vaccines, which promise the hope of preventing these cancers from ever occurring. Because of these important implications, many have attempted to determine a possible role for the virus in cancers of the urinary bladder-an organ in close anatomic proximity to the primary sites of HPV-induced neoplasia and one which already has an established oncogenic infectious agent in Schistosoma haematobium. Here we review the current literature exploring this possible role in the most common subtype of cancer of the urinary bladder, urothelial carcinoma, and two much more rare histologic subtypes that have well established roles for HPV-induced neoplasia in other anatomic sites-squamous cell carcinoma and adenocarcinoma.

Objectives: Preclinical urothelial carcinoma models suggest activity of dasatinib, an oral SRC-family kinase (SFK) inhibitor. We sought to determine the feasibility and biologic activity of neoadjuvant dasatinib (Neo-D) in patients with muscle-invasive urothelial carcinoma of the bladder (miUCB) preceding radical cystectomy (RC)., Materials and Methods: A prospective multisite phase II trial was conducted. Key eligibility criteria included: resectable miUCB (T2-T4a, N0, M0), and Eastern Cooperative Oncology Group performance status 0 to 1. Patients received oral Neo-D 100mg once daily for 28±7 days followed by RC 8 to 24 hours after the last dose. The primary end point was feasibility, defined as≥60% of patients with miUCB completing therapy without treatment-related dose-limiting toxicity (DLT). Pre- and posttreatment tumor immunohistochemistry of phosphorylated SFK (pSFK), Ki-67, and cleaved caspase (Cas)-3 results were analyzed by paired t test., Results: The study completed full accrual with enrollment of 25 patients of whom 23 were evaluable for feasibility. The study achieved its primary end point with 15 patients (65%) completing therapy without treatment-related DLTs. DLTs included: fatigue (n = 2), pulmonary embolism, abdominal pain, supraventricular tachycardia, enteric fistula, hematuria, and dyspnea (n = 1 each). At RC, 5 patients (23%) had

Introduction: This study seeks to evaluate the incidence and associated risk factors of Clostridium difficile infection (CDI) in patients undergoing radical cystectomy (RC) for bladder cancer., Methods: We retrospectively reviewed a single institution׳s bladder cancer database including all patients who underwent RC between 2010 and 2013. CDI was diagnosed by detection of Clostridium difficile toxin B gene using polymerase chain reaction-based stool assay in patients with clinically significant diarrhea within 90 days of the index operation. A multivariable logistic regression model was used to identify demographics and perioperative factors associated with developing CDI., Results: Of the 552 patients who underwent RC, postoperative CDI occurred in 49 patients (8.8%) with a median time to diagnosis after RC of 7 days (interquartile range: 5-19). Of the 122 readmissions for postoperative complications, 10% (n = 12) were related to CDI; 2 patients died of sepsis directly related to severe CDI. On multivariate logistic regression, the use of chronic antacid therapy (odds ratio = 1.9, 95% CI: 1.02-3.68, P = 0.04) and antibiotic exposure greater than 7 days (odds ratio = 2.2, 95% CI: 1.11-4.44, P = 0.02) were independently associated with developing CDI. The use of preoperative antibiotics for positive findings on urine culture within 30 days before surgery was not statistically significantly associated with development of CDI (P = 0.06)., Conclusions: The development of CDI occurs in 8.8% of patients undergoing RC. Our study demonstrates that use of chronic antacid therapy and long duration of antimicrobial exposure are associated with development of CDI. Efforts focusing on minimizing antibiotic exposure in patients undergoing RC are needed, and perioperative antimicrobial prophylaxis guidelines should be followed., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objectives: To assess the effect of non-squamous differentiation (non-SQD) variant histology on survival in muscle-invasive bladder urothelial cancer (UC)., Patients and Methods: A cohort of 411 radical cystectomy (RC) cases performed with curative intent for muscle-invasive primary UC was identified between 2008 and June 2013. Survival analysis was evaluated using Kaplan-Meier methodology comparing non-variant (NV) + SQD histology to non-SQD variant histology (non-SQD variants). Multivariable cox proportional hazards regression assessed all-cause and disease-specific mortality., Results: Of the 411 RC cases, 77 (19%) had non-SQD variant histology. The median overall survival (OS) for non-SQD variant histology was 28 months, whereas the NV+SQD group had not reached the median OS at 74 months (log-rank test P < 0.001). After adjusting for sex, age, pathological stage, and any systemic chemotherapy, patients with non-SQD variant histology at RC had a 1.57-times increased adjusted risk of all-cause mortality (P = 0.027) and 1.69-times increased risk of disease-specific mortality (P = 0.030) compared with NV+SQD patients., Conclusions: While SQD behaves similarly to NV, non-SQD variant histology portends worse OS and disease-specific survival regardless of neoadjuvant or adjuvant chemotherapy and pathological stage. Non-SQD variants of UC could perhaps be considered a distinct clinical entity in UC with goals for developing new treatment algorithms through novel clinical trials., (© 2014 The Authors BJU International © 2014 BJU International Published by John Wiley & Sons Ltd.)

Objectives: The effect that the presence of urothelial variant (UV) histologies has on the behavior of urothelial carcinoma remains poorly defined. The goal of this study is to examine the relationship between different histologic variants and the presence and histology of lymph node metastases., Materials and Methods: Our institutional bladder cancer database was examined for all patients demonstrating UV at cystectomy performed between 2001 and 2012. Patients with primary bladder sarcoma, primary bladder adenocarcinoma, and squamous cell carcinoma were excluded. The cystectomy and nodal pathology reports were reviewed in node-positive cases with the goal of determining the relative percentages of UVs in the bladder and lymph nodes., Results: Overall, 292 patients demonstrated UV at cystectomy. After excluding patients with primary adenocarcinoma, sarcoma, and squamous variants, 141 patients remained, of which 65 demonstrated node-positive disease. Of these node-positive patients, 57 had slides available for review. Node positivity was most common in the micropapillary (MP), clear cell urothelial carcinoma (CC), and plasmacytoid (PC) variants. Remaining variants demonstrated node-positive rates ranging from 11.1% to 37.5%. When nodes were positive, the variants found in the nodal metastases most commonly were MP, CC, glandular, nested, and lymphoepitheliomalike. Median lymph node density was highest in PC (33%) and CC (35%) variants, although these differences were not statistically significant. Variant histology predominated the nodal metastases regardless of predominance in bladder for the MP (84%) and CC (100%) variants. The PC variant exhibited the high incidence of positive surgical margins., Conclusion: Lymph node metastases were most common in the MP, CC, and PC variants. Variant histology was present and predominated nodal histology in most MP and CC cases. These results suggest that the variant histology itself may be driving lymphatic spread in MP and CC cases. Conversely, the PC variant may be a marker for locally advanced and aggressive disease rather than specifically influencing lymphatic spread., (Published by Elsevier Inc.)

Small cell carcinoma is an aggressive malignancy often associated with dismal prognosis due to the presence of advanced disease. Small cell malignancies, initially described in the lung (small cell carcinoma of the lung), can occur in extrapulmonary sites, such as prostate (small cell carcinoma of the prostate) and bladder (small cell carcinoma of the bladder), with similar clinicopathologic outcomes. There has been a paradigm shift in the management of small cell carcinoma of the lung from initial surgical treatment to use of chemotherapy followed by local therapies. Such treatment modalities have been applied to small cell carcinoma of the prostate and the bladder, with promise in improving patient survival. Use of platinum-based combination chemotherapy followed by surgical resection and/or radiation offers the most benefit. Further investigation at the molecular level may offer targeted therapies earlier in the course of the disease.

Objectives: To evaluate pathologic and survival outcomes among patients with variant histology (VH) urothelial carcinoma of the bladder., Methods: A retrospective review of an institutional database was performed to identify all patients who underwent radical cystectomy with curative intent for urothelial carcinoma between 2008 and June 2013. VH was assigned by genitourinary pathologists. Descriptive statistics comparing clinicopathologic outcomes were performed using the Pearson chi-square test and analysis of variance. Survival was evaluated using the Kaplan-Meier methodology and the Cox proportional hazards regression., Results: In total, 624 patients were identified. Overall, 26% (n = 162) had VH, with the most common being squamous differentiation (n = 68), micropapillary variant (MPV, n = 28), plasmacytoid variant (PCV, n = 25), and sarcomatoid variant (n = 15); 64% of MPV and 72% of PCV had positive lymph nodes. Compared with 8% of patients with a non VH, 44% of those with VH were categorized as pT4 (P<0.001). MPV and PCV were independently associated with twice the risk of all-cause mortality compared with nonvariant, when adjusting for demographics, American Society of Anesthesiologists class, transurethral resection of bladder tumor stage, cystectomy stage, positive lymph nodes, and reception of chemotherapy (odds ratio = 2.20, 95% CI: 1.28-3.78; P = 0.004; odds ratio = 2.42, 95% CI: 1.33-4.42; P = 0.004, respectively). There was no difference in risk of mortality associated with squamous differentiation or sarcomatoid variant (P>0.05 each)., Conclusions: MPV and PCV are associated with increased risk of mortality. Improved recognition of VH will enable larger cohorts of study and better prognostic understanding of the significance of specific VH involvement., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Aim: To evaluate a three-tiered prognostic stratification using one, two to five and >five positive lymph nodes (LNs) and this nodal staging system performs across different pelvic LN dissection (PLND) templates and adjuvant chemotherapy status., Methods: We evaluated 244 patients with positive LN urothelial cancer who underwent radical cystectomy and PLND between 2000 and 2011. Survival analyses utilizing the Kaplan-Meier method and log rank test were performed. Median follow-up was 55.3 months (range: 0.4-141). Multivariable Cox proportional hazards models were built to evaluate the prognostic stratification., Results: Extended PLND template was performed on 152 (62.3%) patients and standard on 92 (37.7%). The median number of LNs resected was 14 in the standard group vs 22 in the extended group (p < 0.01) and positive LNs was 2 vs 3 (p = 0.09), respectively. Stratification in patients with: one positive LN, two to five positive LNs or >five positive LNs lead to 5-year recurrence-free survival of: 48.6, 34.5 and 15.9% for each group, while the 5-year overall survival was: 43.0, 22.1 and 11.3%, respectively. Stratification in the three groups was also verified irrespective of PLND template and adjuvant chemotherapy. Two multivariable models confirmed the findings when controlling for demographic features and known pathologic risk factors., Conclusion: Three-tiered nodal classification system using the number of metastatic LNs (one, two to five and >five) stratifies patients with lymphatic disease into distinct prognostic groups.

Purpose: Literature surrounding Indiana pouch (IP) urinary diversion suggests a higher incidence of complications and longer operative time compared with ileal conduit (IC) and neobladder (NB). We sought to assess short-term complications of IP diversions compared with other diversions at our institution., Materials and Methods: Using institutional National Surgical Quality Improvement Program data, we identified radical cystectomy cases performed for bladder cancer at Indiana University from January 2011 until June 2013. During this time period, the National Surgical Quality Improvement Program randomly evaluated approximately 70% of radical cystectomies performed for urothelial carcinoma at our institution. Multivariable logistic regression was performed to identify factors associated with Clavien grade III-V complications., Results: A total of 233 cases were identified, 139 IC, 39 IP, and 55 NB. Mean (standard deviation) operative times for IC, IP, and NB were 257 (84), 383 (78), and 327 (88) minutes, respectively (P<0.001). Half of the patients required blood transfusion during the hospitalization. The overall rate of complications was significantly lower among NB (P = 0.009). Overall, 12% of patients developed a Clavien grade III-V complication, with no difference observed between groups (P = 0.884). After controlling for preoperative confounders, IP patients were not at increased odds of developing a Clavien III-V complication compared with IC (odds ratio = 1.38, P = 0.599)., Conclusions: At a high-volume center, the incidence of serious complications was similar between diversion types. IP patients were more likely to experience minor complications. Patients should be counseled regarding rates of short-term complications and blood transfusion., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Urothelial neoplasms in children and young adult patients are rare and hypothesized to have a lower rate of recurrence and progression than those of older adults. Because of their rarity, data regarding molecular abnormalities in these tumors are limited. We studied molecular characteristics of urothelial neoplasms from patients under age 30 years using UroVysion fluorescence in situ hybridization (chromosomes 3, 7, 17, and 9p21) and DNA mutational analysis for the FGFR3 and TP53 genes. Seventeen tumors were identified in patients 6-26 years of age, including low-grade papillary urothelial carcinoma (n=10), high-grade papillary urothelial carcinoma (n=5), urothelial papilloma (n=1), and papillary urothelial neoplasm of low malignant potential (n=1). No tumor demonstrated mutation of FGFR3 or TP53. Chromosomal abnormalities were detected only in patients aged ≥19 years: two low-grade urothelial carcinomas had loss of 9p21 as a sole chromosomal abnormality and three high-grade urothelial carcinomas had other or multiple chromosomal abnormalities. Under age 19 years, no tumor showed molecular abnormalities with either method (five low-grade papillary urothelial carcinomas and one each of high-grade papillary urothelial carcinoma, papillary urothelial neoplasm of low malignant potential, and urothelial papilloma). Our results support the idea that mutations of the FGFR3 and TP53 genes are rare or absent in urothelial neoplasms of young patients. In contrast, chromosomal abnormalities detected by UroVysion fluorescence in situ hybridization are sometimes present in patients above 19-20 years of age. This finding supports the recently proposed hypothesis that an age of 19-20 years separates distinct molecular pathways of urothelial carcinogenesis.

Objectives: In 2010, a new TNM staging system was published by American Joint Committee on Cancer, changing the nodal classification to include the presence of common iliac lymph node (LN) involvement as N3 category. The objective of this study was to define the capability of the current TNM nodal classification to separate patients with different prognostic stages and to evaluate the effect of LN disease burden., Methods and Materials: A total of 93 patients with metastatic LNs after radical cystectomy and extended LN dissection for urothelial carcinoma of the bladder between 1999 and 2012 were included. The median follow-up was 21.5 months. The correlation between N3 and indicators of LN disease burden was analyzed using the Spearman correlation coefficient. Recurrence-free survival (RFS) and overall survival (OS) analysis was performed using the Kaplan-Meier and Cox proportional hazards methods., Results: The presence of N3 disease was associated with higher number of metastatic LNs (7 vs. 2, P<0.01); however, this was highly variable and correlation coefficients between common iliac metastatic LNs and other lymphatic disease burden indicators demonstrated weak association (0.39-0.63). Patients with N1 lesions were found to have a distinct RFS and OS (P<0.01 and P = 0.01, respectively). A trend toward worse RFS (P = 0.07) and OS (P = 0.08) was observed in patients with N3 lesions. However, no difference in RFS or OS was found between patients with N2 and N3 lesions (P = 0.83 and 0.50, respectively)., Conclusions: The N3 category in the current TNM classification defines a group of patients with high but heterogeneous disease burden. This may be the explanation for its lack of prognostic stratification when compared with N2 category bladder cancer., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objectives: To determine temporal and regional trends in utilization of robotic-assisted radical cystectomy (RARC) in the United States and to explore factors associated with utilization of robotic assistance., Materials and Methods: Using 2009 to 2011 data from the Nationwide Inpatient Sample, we identified radical cystectomy cases that were performed using either open or robotic assistance and applied Nationwide Inpatient Sample discharge weights to determine national incidence. Univariable and multivariable logistic regressions were performed to assess regional trends and characteristics associated with having RARC. Descriptive analysis was performed using the chi-square test, the Student t test, and the Mann-Whitney U test., Results: Of the 29,719 radical cystectomy patients, 3,733 were RARC (12.6%). Although there was no change in the proportion of RARC performed annually (P = 0.702). Length of stay was 1 day longer for open cystectomy than RARC (P<0.001). On multivariate regression, patients whose primary payer was Medicaid were less likely than private insurance patients to undergo RARC (odds ratio = 0.60, P = 0.074). Additionally, patients in the south were at 50% reduced odds of undergoing RARC (odds ratio = 0.49, P = 0.044). Median hospital costs were $5,000 greater for RARC (P<0.001)., Conclusions: Regional variation in utilization should be monitored to ensure equal access to new technology and to assess potential overuse of new technology. Although RARC is associated with higher median hospital costs, further studies to assess its benefits are warranted., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objectives: Plasmacytoid variant (PCV) urothelial cancer (UC) of the bladder is rare, with poor clinical outcomes. We sought to identify factors that may better inform expectations of tumor behavior and improve management options in patients with PCV UC., Materials and Methods: A retrospective analysis of the Indiana University Bladder Cancer Database between January 2008 and June 2013 was performed comparing 30 patients with PCV UC at cystectomy to 278 patients with nonvariant (NV) UC at cystectomy who underwent surgery for muscle-invasive disease. Multivariable logistic regression was used to assess precystectomy variables associated with non-organ-confined disease at cystectomy and Cox regression analysis to assess variables associated with mortality., Results: Patients with PCV UC who were diagnosed with a higher stage at cystectomy (73% pT3-4 vs. 40%, P = 0.001) were more likely to have lymph node involvement (70% vs. 25%, P<0.001), and positive surgical margins were found in 40% of patients with PCV UC vs. 10% of patients with NV UC (P<0.001). Median overall survival and disease-specific survival were 19 and 22 months for PCV, respectively. Median overall survival and disease-specific survival had not been reached for NV at 68 months (P<0.001). Presence of PCV UC on transurethral resection of bladder tumor was associated with non-organ-confined disease (odds ratio = 4.02; 95% CI: 1.06-15.22; P = 0.040), and PCV at cystectomy was associated with increased adjusted risk of mortality (hazard ratio = 2.1; 95% CI: 1.2-3.8; P = 0.016)., Conclusions: PCV is an aggressive UC variant, predicting non-organ-confined disease and poor survival. Differentiating between non-muscle- and muscle-invasive disease in patients with PCV UC seems less important than the aggressive nature of this disease. Instead, any evidence of PCV on transurethral resection of bladder tumor may warrant aggressive therapy., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: To examine differences in disease progression and nature of tumor invasion that may lead to more accurate expectations of tumor behavior and improved management options for plasmacytoid variant (PCV) histology urothelial bladder cancer patients., Methods: Using the Indiana University Bladder Cancer Database, we conducted a retrospective analysis of patients undergoing radical cystectomy from 2008 to June 2013 to identify patients with PCV, micropapillary variant (MPV), or nonvariant (NV) histology and either positive ureteral margins (+UM), paravesical surgical margins (+PSM), or lymph node (+LN) involvement. Pearson's chi-squared test and analysis of variance were used for descriptive analysis., Results: Of 510 patients who met inclusion criteria, 30 had +UM on final pathology. The incidence of +UM in NV patients was 17 of 457 (3.7%), in MPV 5 of 28 (17.9%), and in PCV 8 of 25 (32.0%) (P <.001). Carcinoma in situ on the luminal margin was noted for all cases, except in 5 of the 8 PCV patients with +UM, in whom retrograde longitudinal invasion along the subserosal and adventitia was noted. +PSM and +LN were significantly higher for both PCV (28.0%, 72.0%) and MPV (10.7%, 64.3%) than NV (2.6%, 18.6%, P <.001, each)., Conclusion: PCV exhibits a unique pattern of spread along the ureter. This proposes a new mode of invasion along the fascial sheath. The incidence of +PSM and +LN liken PCV to the known aggressive MPV, and in conjunction with the increased incidence of +UM, may lead to a paradigm shift, with surgeons and pathologists being more vigilant with surgical margins., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Primary adenocarcinoma of the urinary bladder is rare. The molecular and cellular events leading to its pathogenesis are not well delineated. The goal of this study was to investigate p53 and p16 expression, as well as HPV status, in a relatively large series of primary bladder adenocarcinomas., Materials and Methods: Thirty six cases of urinary bladder adenocarcinoma were chosen from participating institutions. The diagnosis and available clinical history were reviewed in each case. Immunostains for p53, p16 and HPV and high-risk and low-risk HPV-ISH were performed on all tumors., Results: Patients had an average age of 61 years with a male predominance (1.5 ∶ 1 male ∶ female ratio). The average tumor size in cystectomy specimens was 4.3 cm. Of the cases managed by transurethral resection, 40% were pT2 at the time of diagnosis. In cystectomy specimens, 77% were either pT3 or pT4. Strong nuclear p16 expression was seen in 67% of all cases and p53 expression was present in 58% of the cases. Expression of both markers was seen in 33% of cases. Expression of p16 or p53 alone was present in 12 (33%) and 9 (25%) cases, respectively. Neither marker was expressed in only 3 (8%) of the tumors. No significant correlation between clinical variables and any of the markers we studied was identified. No HPV infection was detected in any case., Conclusions: Expression of p53 and/or p16 is very common in urinary bladder adenocarcinoma. These findings implicate a high likelihood that alterations in these cell cycle proteins contribute to the pathogenesis of these tumors. Despite frequent immunohistochemical labeling for p16, no evidence of HPV infection was found.

The identification of mutations in epidermal growth factor receptor (EGFR) and translocations involving anaplastic lymphoma kinase (ALK) in lung adenocarcinoma has drastically changed understanding of the disease and led to the development of targeted therapies. Adenocarcinoma of the urinary bladder is rare and poorly understood at the molecular level. We undertook this study to determine whether EGFR mutations, increases in EGFR copy number, or ALK translocations are present in these tumors. Twenty-eight cases of primary bladder adenocarcinoma were analyzed. For EGFR mutational analysis, PCR-amplified products were analyzed on the Q24 Pyrosequencer with Qiagen EGFR Pyro Kits. All cases were analyzed via fluorescence in situ hybridization (FISH) using Vysis ALK Break Apart FISH Probes for detection of ALK chromosomal translocation and Vysis Dual Color Probes to assess for increased gene copy number of EGFR. None of the 28 cases examined showed mutational events in EGFR or ALK rearrangements. EGFR polysomy was seen in 10 out of 28 (36%) cases. No correlation with EGFR polysomy was seen in the tumors with respect to age, histologic subtypes, pathologic stage, or lymph node metastasis. In summary, EGFR mutations and ALK rearrangements do not appear to be involved in the development of primary adenocarcinoma of the urinary bladder. A subgroup of cases (36%), however, demonstrated increased gene copy number of EGFR by FISH.

The presence of lymphatic metastasis is associated with markedly worse prognosis in patients with bladder cancer, although surgical resection and chemotherapy can still provide long-term survival for selected patients. The prognostic stratification of patients with positive lymph nodes has been broadly discussed in the current literature and a more extensive pelvic lymph node dissection and thorough pathologic assessment has been advocated. It is clear that stratification using the tumor node metastasis staging system is insufficient to adequately discriminate prognosis between patients with different lymph node involvement. Lymph node density and extranodal extension have been extensively investigated and appear to influence the prognosis of these patients. Molecular markers have been developed to improve the diagnosis of micrometastatic disease, and new targeted therapies have shown promising preclinical results and are now being tested in different clinical scenarios.

Urinary bladder squamous cell carcinoma and urothelial carcinoma with squamous differentiation are often high-grade and high-stage tumors that are thought to be associated with a poorer prognosis and response to therapy compared with urothelial carcinoma without divergent differentiation. Therefore, recognition of a squamous component is increasingly important in guiding prognosis and therapy. We investigated the expression of MAC387, desmoglein-3, and TRIM29 in pure squamous cell carcinoma and urothelial carcinoma with squamous differentiation to determine whether they have utility as diagnostic biomarkers for squamous differentiation. Eighty-four cases were retrieved from participating institutions including 51 pure urinary bladder squamous cell carcinomas and 33 urothelial carcinomas with squamous differentiation. MAC387, desmoglein-3, and TRIM29 antibodies demonstrated positive staining in pure squamous cell carcinoma in 51 (100%), 46 (90%), and 48 (93%) cases, respectively. Urothelial carcinoma with squamous differentiation showed reactivity for MAC387, desmoglein-3, and TRIM29 in the squamous component for 32 (97%), 26 (79%), and 32 (97%) cases, respectively. MAC387 demonstrated a sensitivity of 99% and a specificity of 70% for squamous differentiation, whereas desmoglein-3 yielded a sensitivity of 86% and a specificity of 91%. No urothelial component showed greater than 10% labeling for desmoglein-3. TRIM29 labeling showed a sensitivity of 95%, but a poorer specificity of 33%. In summary, MAC387 and desmoglein-3 are reliable diagnostic markers for supporting the morphologic impression of squamous differentiation in urinary bladder carcinoma. Desmoglein-3 shows high specificity, whereas TRIM29 was most likely to demonstrate labeling in areas without light microscopically recognizable squamous differentiation., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Folate receptors (FR) may be of use for targeted delivery of cytotoxic drugs in invasive urothelial carcinoma (iUC), for which improved therapy is needed. FR expression and function in iUC were explored and the antitumor activity and toxicity of a folate-targeted vinblastine conjugate were evaluated in dogs with naturally occurring iUC, an excellent model for human iUC. FR immunohistochemistry was carried out on iUC and normal human and dog bladder tissues together with nuclear scintigraphy in dogs to monitor iUC folate uptake. Dose escalation of a folate-targeted vinblastine compound, EC0905, was conducted in dogs with biopsy-confirmed, FR-positive iUC. FRs were detected by immunohistochemistry (PU17) in most primary iUC and many nodal and lung metastases from dogs, and scintigraphy confirmed folate uptake in both primary and metastatic lesions. The maximum tolerated dose of EC0905 in dogs was 0.25 mg/kg IV weekly, with neutropenia at higher doses. Tumor responses included partial remission (≥ 50% reduction in tumor volume) in five dogs and stable disease (<50% change in tumor volume) in four dogs. Immunoreactivity to PU17 was similar in humans (78% of primary iUC, 80% of nodal metastases). Less immunoreactivity to mab343 (22% of cases) occurred. FR-β was noted in 21% of human iUC cases. Our findings suggest folate-targeted therapy holds considerable promise for treating iUC, where FR-β may be important in addition to FR-α.

Diagnosis of human bladder cancer in untreated tissue sections is achieved by using imaging data from desorption electrospray ionization mass spectrometry (DESI-MS) combined with multivariate statistical analysis. We use the distinctive DESI-MS glycerophospholipid (GP) mass spectral profiles to visually characterize and formally classify twenty pairs (40 tissue samples) of human cancerous and adjacent normal bladder tissue samples. The individual ion images derived from the acquired profiles correlate with standard histological hematoxylin and eosin (H&E)-stained serial sections. The profiles allow us to classify the disease status of the tissue samples with high accuracy as judged by reference histological data. To achieve this, the data from the twenty pairs were divided into a training set and a validation set. Spectra from the tumor and normal regions of each of the tissue sections in the training set were used for orthogonal projection to latent structures (O-PLS) treated partial least-square discriminate analysis (PLS-DA). This predictive model was then validated by using the validation set and showed a 5% error rate for classification and a misclassification rate of 12%. It was also used to create synthetic images of the tissue sections showing pixel-by-pixel disease classification of the tissue and these data agreed well with the independent classification that uses histological data by a certified pathologist. This represents the first application of multivariate statistical methods for classification by ambient ionization although these methods have been applied previously to other MS imaging methods. The results are encouraging in terms of the development of a method that could be utilized in a clinical setting through visualization and diagnosis of intact tissue., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

It is now widely believed that there are two major pathways for urothelial carcinogenesis. One pathway usually involves mutation of FGF receptor 3 and gives rise to low-grade papillary tumors that frequently recur but seldom invade. By contrast, high-grade urothelial malignancies, including high-grade papillary urothelial carcinoma and urothelial carcinoma in situ (CIS) usually exhibit deletions or mutations of TP53. Urothelial CIS is the most likely precursor of high-grade invasive bladder cancer. It is a 'flat lesion' that may be relatively inconspicuous at cystoscopy, or even endoscopically undetectable. The clinical hazards associated with this elusive and biologically dangerous neoplasm have been increasingly well documented since the original studies by Melicow in 1952. Primary or secondary urothelial dysplasia is even more challenging to detect and diagnose than CIS. It is theorized that dysplasia may antedate the onset of CIS, but support for the putative progression of dysplasia to CIS is found in fewer than 20% of cases. Since many benign urothelial changes may resemble CIS at cystoscopy, in biopsies and even with molecular profiling, care must be exercised when making a diagnosis of CIS. For patients whose screening tests are worrisome for the presence of premalignant urothelial disease, newer bladder imaging modalities, including Raman spectral imaging and optical coherence tomography, may enable improved biopsy site selection. In this article, we discuss the above-noted topics, as well as other related issues, such as the possible role of papillary urothelial hyperplasia as a preneoplastic lesion and the roles of cancer stem cells and field cancerization in urothelial carcinogenesis.

Tumor recurrence is a major clinical concern for patients with urothelial carcinoma of the urinary bladder. Traditional morphological analysis is of limited utility for identifying cases in which recurrence will occur. However, molecular and genetic analyses offer new perspectives on the prediction of bladder tumor recurrence. Recent studies have suggested that urothelial carcinogenesis occurs as a 'field effect' that can involve any number of sites in the bladder mucosa. Accumulating evidence supports the notion that resident urothelial stem cells in the affected field are transformed into cancer stem cells by acquiring genetic alterations that lead to tumor formation through clonal expansion. Both initial and recurrent tumors are derived from cancer stem cells in the affected field via two distinct molecular pathways. These provide a genetic framework for understanding urothelial carcinogenesis, tumor recurrence and progression: the FGFR3-associated pathway and the TP53-associated pathway. These two pathways are characterized by different genomic, epigenetic and gene-expression alterations. Their outcomes correlate with the markedly different clinical and pathologic features of both relatively indolent low-grade cancers and the aggressive high-grade cancers. As such, these molecular findings are potentially useful for counseling patients and for assessing risk of recurrence or biological aggressiveness of the patient's tumor. The molecular changes may additionally prove useful for developing preventive and therapeutic strategies for urothelial bladder cancer. A unifying model of urothelial carcinogenesis, tumor recurrence and progression is proposed in this review.

Aims: Patients who have undergone intestinal augmentation cystoplasty are at risk for developing latent vesicle malignancy. The aim was to evaluate the histological and immunohistochemical characteristics and molecular genetic alterations in these neoplasms., Methods and Results: Four patients developing urothelial neoplasms after augmentation cystoplasty were included in the current study. The mean age of the patients, including two men and two women, was 37 years. The latency from bladder augmentation to developing malignancy ranged from 17 to 21 years (mean 19 years). All patients died of cancer shortly after diagnosis (mean 5 months). In the morphological evaluation, all tumours were high-grade (grade 3) invasive urothelial carcinoma comprising various architectural patterns with brisk mitoses and tumour necrosis. Three harboured glandular differentiation and the remaining one showed squamous differentiation. All cases revealed abnormal decreasing beta-catenin expression. Two tumours showed nuclear expression of CDX2. On UroVysion fluorescence in situ hybridization (FISH) analysis, all tumours displayed characteristic chromosomal abnormalities. Point mutations of both FGFR3 and p53 genes were identified in one case., Conclusions: Urothelial carcinomas developed after augmentation cystoplasty are extremely aggressive and exhibit distinct morphological, immunohistochemical and genetic characteristics. UroVysion FISH analysis may offer a surveillance strategy in patients who undergo augmentation cystoplasty.

Small cell carcinoma of the urinary bladder is a rare and highly aggressive tumor. P53 expression has been shown to be associated with poor prognosis in a variety of tumors. This study was undertaken to investigate p53 expression in a large series of small cell carcinomas of the urinary bladder and to correlate the findings with clinicopathologic parameters and clinical outcome. Pathologic findings were reviewed and were correlated with clinical findings and follow-up information. Immunohistochemical staining for p53 was performed on paraffin-embedded tissue sections using the avidin-biotin-peroxidase method. Results were recorded as positive expression (> or =10% of cells with nuclear staining) or negative expression (<10% of cells with nuclear staining). The series included 40 males and 10 females. All 50 patients except one had advanced disease (T2 or above) at presentation. Pathologic stages were as follows: T1 in 1, T2 in 25, T3 in 21, and T4 in 3 patients. During a median follow-up of 12 months (range: 1 month to 122 months), 38 patients died of cancer. Two-year and 5-year cancer-specific survival rates were 45% and 16%, respectively. P53 overexpression was present in 27 out of 50 (54%) cases (7 with 10-25% staining, 4 with 25-50% staining, 11 with 50-75% staining and 5 with 75-100% staining); conversely, negative staining for p53 was observed in 23 out of 50 (46%) cases (19 with no staining and 4 with <10% staining). No correlation was demonstrated between the level of p53 expression and survival (p =0. 16). The 5-year cancer-specific survival was 16.6% for patients with tumors expressing p53 in greater than or equal to 10% of cells and was 14.7% for patients with tumors expressing p53 in less than 10% of tumor cells. There was no correlation between p53 expression and other clinicopathologic characteristics, including age (p =0.20), gender (p=0.84), history of smoking (p=0.25), pathologic Tstage (p=0.38), clinical stage (p=0.60), lymph node metastasis (p=0.17), and distant metastasis (p=0.88). Our data indicate that p53 is frequently expressed in small cell carcinoma of the urinary bladder. However, no correlation is found between p53 expression and clinicopathologic parameters, including long-term survival.

In most cases, small-cell carcinoma of the urinary bladder is admixed with other histological types of bladder carcinoma. To understand the pathogenetic relationship between the two tumor types, we analyzed histologically distinct tumor cell populations from the same patient for loss of heterozygosity (LOH) and X chromosome inactivation (in female patients). We examined five polymorphic microsatellite markers located on chromosome 3p25-26 (D3S3050), chromosome 9p21 (IFNA and D9S171), chromosome 9q32-33 (D9S177), and chromosome 17p13 (TP53) in 20 patients with small-cell carcinoma of the urinary bladder and concurrent urothelial carcinoma. DNA samples were prepared from formalin-fixed, paraffin-embedded tissue sections using laser-assisted microdissection. A nearly identical pattern of allelic loss was observed in the two tumor types in all cases, with an overall frequency of allelic loss of 90% (18 of 20 cases). Three patients showed different allelic loss patterns in the two tumor types at a single locus; however, the LOH patterns at the remaining loci were identical. Similarly, the same pattern of nonrandom X chromosome inactivation was present in both carcinoma components in the four cases analyzed. Concordant genetic alterations and X chromosome inactivation between small-cell carcinoma and coexisting urothelial carcinoma suggest that both tumor components originate from the same cells in the urothelium.

The prognosis for small cell carcinoma of the urinary bladder is poor, and strategies for improved therapy are needed. Targeted therapy against the c-kit proto-oncogene has been successful in the management of gastrointestinal stromal tumor. We investigated the expression of c-kit in 52 cases of small cell carcinoma of the urinary bladder. Specimens with more than 10% of cells demonstrating strong membrane staining were considered to have positive immunostaining for c-kit. c-kit expression was detected in 21 of 52 specimens from these patients. Among the 21 specimens, seven had less than 10% staining, and were considered to be negative. Nine had 11-50% staining, and five had more than 50% staining. Overall, 14 of 52 (27%) small cell carcinomas of the urinary bladder were positive for c-kit expression. During a median follow-up of 11 months, 60% of the patients died of bladder cancer. No association was found between c-kit expression and survival or other clinicopathologic parameters. Five-year cancer-specific survivals for c-kit-positive and c-kit-negative tumors were 9 and 15%, respectively (P=0.36). A significant proportion (27%) of small cell carcinomas of the urinary bladder expressed c-kit, suggesting that it may prove useful as a therapeutic target in small cell carcinoma of the urinary bladder.

Purpose: Cancer following augmentation cystoplasty is a recognized risk factor. The procedure has only gained popularity in pediatric urology within the last 25 years, limiting the population being studied by statistical power and the lack of long-term followup. The majority of reported cases of post-augmentation malignancy have occurred in adults with multiple risk factors. Currently the most common indication for augmentation cystoplasty in children and adolescents is neuropathic bladder. We review 3 cases of transitional cell carcinoma (TCC) following augmentation cystoplasty in this unique population with no additional risk factors for bladder cancer., Materials and Methods: We reviewed our clinical database of children and adolescents who underwent bladder augmentation since 1978 to evaluate the incidence of cancer. This study represents a captured population within a single institutional practice. There were 483 cases entered into the database, and particular attention was paid to 260 augmentations with at least 10 years of followup. We reviewed medical history, clinical outcomes, cancer risk factors, augmentation type and pathology of the 3 patients who presented with TCC after augmentation cystoplasty., Results: Three patients presented with grade 2 to 3 TCC following bladder augmentation, all of whom underwent exploratory laparotomy and eventually died of metastatic disease. No patient had a history of smoking exposure greater than 10 packs per year or other known risk factors for bladder cancer. Two patients had an ileocecal augmentation and 1 had a cecal augmentation for neuropathic bladder. Patient age at augmentation was 8, 20 and 24 years, and age at diagnosis of TCC was 29, 37 and 44 years, respectively. Mean time from augmentation to TCC was 19 years. Assuming a 10-year lag period before the risk of cancer, in at least 1.2% of bladder augmentation cases in our database cancer has developed., Conclusions: This study supports the hypothesis that bladder augmentation appears to be an independent risk factor for TCC, with a lag time of less than 20 years. We recommend endoscopic surveillance of all patients with a history of bladder augmentation beginning 10 years after initial surgery.

Background: Small cell carcinoma of the urinary bladder is an uncommon tumor that has been described in case reports or small series. Herein, the authors report a series of 64 patients with small cell carcinoma of the urinary bladder., Methods: Histologic slides and medical records from 64 patients with small cell carcinoma of the urinary bladder were reviewed for morphologic, demographic, and clinical data. All patients fulfilled the criteria established for small cell carcinoma according to the World Health Organization classification system. The 2002 tumor, lymph node, and metastasis (TNM) system was used for pathologic staging. The correlations of various clinicopathologic characteristics with survival were analyzed., Results: Patients ranged in age from 36 years to 85 years (mean age, 66 years). The male-to-female ratio was 3.3:1.0. Among patients with clinical information available, 65% had a history of cigarette smoking, and 88% presented with hematuria. All but one patient had muscle-invasive disease at presentation. Thirty-eight patients (59%) underwent cystectomy. Sixty-six percent of patients had lymph node metastasis at the time of cystectomy. Twenty patients (32%) had pure small cell carcinoma, and 44 patients (68%) had small cell carcinoma with other histologic types (35 patients had urothelial carcinoma, 4 patients had adenocarcinoma, 2 patients had sarcomatoid urothelial carcinoma, and 3 patients had both adenocarcinoma and urothelial carcinoma). With a mean follow-up of 21 months, 68% of patients died of bladder carcinoma. None of the clinicopathologic parameters studied (age, gender, presenting symptoms, smoking history, the presence of a nonsmall cell carcinoma component, chemotherapy, or radiation therapy) were associated with survival. No significant survival difference was found between patients who did and did not undergo cystectomy (P = 0.65). Patients who had organ-confined disease had marginally better survival compared with patients who had nonorgan-confined disease (P = 0.06). The overall, 1-year, 18-month, 3-year, and 5-year disease-specific survival rates were 56%, 41%, 23%, and 16%, respectively., Conclusions: The prognosis for patients with small cell carcinoma of the urinary bladder remains poor, even though the overall survival for patients with bladder carcinoma has improved significantly over the last decade., (Copyright 2004 American Cancer Society.)

Background: In the 1999 World Health Organization classification system, papillary tumors of the urinary bladder were classified as papilloma, papillary urothelial neoplasm of low malignant potential (PUNLMP), and as Grade 1, Grade 2, and Grade 3 urothelial carcinoma. The biologic potential of PUNLMP of the urinary bladder is controversial. To the authors' knowledge, information regarding the genetic changes of PUNLMP tumors of the bladder is limited., Methods: The authors examined loss of heterogygosity (LOH) at 5 polymorphic microsatellite markers on chromosome 9q32-33 (D9S177), 9p22 (IFNA), 17p13.1 (TP53), 12q14-24 (D12S1051), and 3p25-26 (D3S3050) from 26 patients who were diagnosed with PUNLMP tumors of the urinary bladder. Tumors were microdissected from sections prepared from formalin-fixed, paraffin-processed tissue specimens using laser capture microdissection., Results: LOH was found in 21 of 26 (81%) patients with PUNLMP. The rate of LOH was 41% with D9S177, 32% with IFNA, 29% with TP53, 26% with D12S1051, and 44% with D3S3050. Allelic loss of multiple chromosome loci was often present in patients with PUNLMP tumors., Conclusions: Genetic changes that commonly occur in advanced bladder carcinoma (> or = pT2) are frequently found in PUNLMP of the urinary bladder., (Copyright 2004 American Cancer Society.)

Background: Urothelial carcinoma commonly manifested loss of heterozygosity (LOH) at different regions of chromosomes 17p, 3p, and 9q. Recent studies suggested that bladder stromal cells may be implicated in the growth and progression of urothelial carcinoma. To better understand the genetic alterations in the stromal cells in patients with bladder carcinoma, the authors evaluated the prevalence of allelic loss at three microsatellite polymorphic markers on chromosomes 17p13 (TP53), 3p25-26 (D3S3050), and 9q32-33 (D9S177). In addition, the pattern of X-chromosome inactivation of the stromal cells was evaluated by analyzing the DNA methylation pattern at a polymorphic site on the androgen receptor gene., Methods: The authors studied 18 female patients who underwent either transurethral resection (n = 2) or radical cystectomy (n = 16) for high-grade muscle-invasive urothelial carcinoma of the urinary bladder. Genomic DNA samples from the stromal cells immediately adjacent to the tumor and the tumor itself were prepared from formalin-fixed, paraffin-processed tissues using laser-assisted microdissection and LOH was determined., Results: The stromal cells showed a high frequency of LOH on chromosomes 17p13 (29%), 3p25-26 (61%), and 9q32-33 (47%) with no clear concordance with the adjacent tumor cells. Fourteen specimens (78%) showed LOH in the stroma in at least 1 of 3 markers examined. Nonrandom X-chromosome inactivation was frequent in the stromal cells (50% of informative specimens)., Conclusions: The current study revealed that some of the genetic changes that commonly occur with invasive urothelial carcinoma were frequently found in the adjacent stroma and suggested that the stroma of urothelial carcinoma may play an important role in bladder carcinogenesis., (Copyright 2003 American Cancer Society.)

Background: Human bladder carcinoma is thought to arise from a field change that affects the entire urothelium. Whether independently transformed urothelial cell populations exist in the same patient is uncertain., Methods: We studied the clonality of urinary bladder carcinoma in 18 female patients who underwent cystectomy for urothelial carcinoma. None had multiple tumors. Tumor samples were obtained from different areas of the same tumor. Sixty-seven tumor samples were analyzed. Tumor genomic DNA was microdissected and extracted from formalin-fixed, paraffin-embedded slides. The clonality of urothelial tumors was evaluated on the basis of a polymorphism of the X chromosome-linked human androgen receptor gene (HUMARA) locus. The technique is dependent on digestion of DNA with the methylation-sensitive restriction enzyme HhaI, polymerase chain reaction (PCR) amplification of HUMARA locus, and detection of methylation of this locus. With this method, only the methylated HUMARA allele is selectively amplified by PCR., Results: Eleven of 18 patients were informative. Nonrandom inactivation of the X chromosome was found in 9 of the 11 informative patients (82%). Seven patients showed different patterns of nonrandom X chromosome inactivation for tumor samples obtained from different regions of the same tumor. Two patients showed the same pattern of nonrandom X chromosome inactivation in all samples., Conclusions: Some muscle-invasive urothelial carcinomas may arise from independently transformed progenitor urothelial cells, supporting the "field effect" theory for bladder carcinogenesis., (Copyright 2002 American Cancer Society.)

Purpose: We evaluate the incidence and risk factors of parastomal hernia formation in patients undergoing radical cystectomy and ileal conduit urinary diversion. Materials and Methods: We retrospectively reviewed the Indiana University cystectomy database between 2001 and 2011, and identified 516 patients who underwent radical cystectomy and ileal conduit diversion. Overall 199 patients had a clinical followup of at least 12 months and all underwent postoperative staging computerized tomography to confirm the presence of parastomal hernia. The incidence of parastomal hernia is reported with correlations made to demographic, patient level and perioperative risk factors. Results: A parastomal hernia developed in 58 patients (29%) at a median followup of 27 months (range 12 to 125). Of these patients 26 (45%) underwent surgical repair due to abdominal discomfort (58%), acute strangulation or obstruction of the small bowel (15%), partial small bowel obstructions (15%) and elective repair for other intra-abdominal procedures (12%). Prior exploratory laparotomy (adjusted HR 1.98, 95% CI 1.97–3.36, p = 0.011) and severe obesity (adjusted HR 4.26, 95% CI 1.52–11.93, p = 0.006) were predictive of parastomal herniation. The cumulative risk of parastomal hernia formation at 1 and 2 years after cystectomy was 12.2% and 22.5%, respectively. Conclusions: We demonstrated that parastomal hernia will develop in nearly a third of patients after radical cystectomy with ileal conduit diversion. Prior laparotomy and severe obesity are independent risk factors. Preoperative counseling and preventative measures regarding parastomal hernia formation should be emphasized, particularly in these at risk patients. [ABSTRACT FROM AUTHOR]