Extended versus limited lymph node dissection in radical cystectomy: impact on recurrence pattern and survival.

OBJECTIVES: To compare recurrence patterns and survival of patients with carcinoma of the urinary bladder undergoing radical cystectomy and extended or limited lymph node dissection. METHODS: From a consecutive series of 469 patients undergoing radical cystectomy, two different historical cohorts were constructed; one with 265 patients intentionally undergoing extended lymph node dissection and one with 204 patients undergoing limited lymph node dissection. RESULTS: Early lymph node recurrences were more frequently located outside the pelvic region in patients from the extended lymph node dissection cohort, whereas the overall risk of recurrence was not reduced by carrying out an extended lymph node dissection compared with the limited lymph node dissection cohort (8% vs 6%, P = 0.5). However, positive node patients had a significantly better prognosis after extended lymph node dissection (5-year disease-specific survival 29% vs 8%, P = 0.002). Improved survival was also found in negative node patients with non-organ confined tumors undergoing extended lymph node dissection compared with limited lymph node dissection (5-year disease-specific survival 76% vs 62%, P = 0.008). A total of 16 positive node patients (6%) in the extended lymph node dissection cohort were identified as possible stage migrators with metastasis exclusively in lymph nodes outside the limited template. A total of 5% of patients undergoing extended lymph node dissection had an evident survival benefit of an extended lymph node dissection compared with a limited lymph node dissection. CONCLUSIONS: Extended lymph node dissection provides more accurate nodal staging than a limited lymph node dissection. However, recurrence patterns are not significantly altered by extending the limits of lymph node dissection, suggesting a survival benefit only in a minority of patients. Improved survival is more likely in patients with locally advanced disease.

Long-term risk of progression of carcinoma in situ of the bladder and impact of bacille Calmette-Guérin immunotherapy on the outcome.

OBJECTIVE: This study aimed to determine the long-term risk of cancer progression of carcinoma in situ (CIS) of the urinary bladder, and whether intravesical bacille Calmette-Guérin (BCG) immunotherapy can reduce the risk of progression of CIS. MATERIAL AND METHODS: From a prospectively enrolled cohort of bladder cancer patients treated at Århus University Hospital Skejby, Denmark, between 1994 and 2008, all 163 cases with CIS in the bladder, and a history free of invasive bladder cancer (stage T1-4) at least 1 year prior to inclusion were included in the study. RESULTS: Median follow-up was 51 (0-253) months for progression. Initial treatment consisted of transurethral resection (TUR) alone (109 patients) or TUR plus BCG (54 patients). Twenty-eight patients underwent delayed treatment with BCG. Twenty-one patients in the TUR-alone group (19%) and 42 BCG-treated patients (51%) were free of disease at the end of follow-up (p < 0.001). Progression occurred in 18 BCG-treated patients (22%) versus 31 patients (41%) treated by TUR alone. The 10-year progression-free survival was 62% overall, 50% without BCG and 71% after BCG treatment (p = 0.04). BCG reduced the risk of progression by 46% (hazard ratio 0.54, 95% confidence interval 0.3-0.97). Thirteen patients (9%) experienced progression in the prostate and nine (6%) showed extravesical progression (upper urinary tract or metastases). This was independent of BCG treatment. CONCLUSION: CIS in the absence of invasive (T1) disease carried a 10-year risk of progression of 29?48%. Although BCG was effective against CIS, this effect was limited to the bladder. BCG provided a marginal, but significant reduction in the overall long-term risk of progression.

Incidence of occult lymph-node metastasis missed by standard pathological examination in patients with bladder cancer undergoing radical cystectomy.

OBJECTIVE: The aim was to conduct an exploratory study of the ability of standard pathological examination (SPE) of lymph nodes (LNs) to detect metastasis in LN specimens from patients with bladder cancer undergoing radical cystectomy (RC). MATERIAL AND METHODS: From a cystectomy database, 10 LN-negative patients with invasive bladder cancer were randomly selected based on their Tstage (two T1, four T2 and four T3). LN specimens were step sectioned and stained by immunohistochemistry to identify occult metastases missed by the SPE. RESULTS: In total, 173 LNs negative by SPE were investigated. Metastasis was identified in one LN in one patient with non-organ-confined disease. No other positive LNs were found. Thus, SPE had a negative predictive value of 99.4% per LN (95% confidence interval CI96.8?99.99%) in this small series. CONCLUSIONS: Occult nodal metastasis can be overlooked by SPE in a minority of patients undergoing RC because of bladder cancer. This is presumably more likely in patients with non-organ-confined tumours because of a higher risk of LN metastasis in this patient category. Therefore, the importance of a thorough LN dissection in presumably LN-negative patients is emphasized. However, the number of patients in the present study is too low for conclusions to be drawn regarding the true frequency of occult LN metastases.

Prognostic value of lymph-node dissection in patients undergoing radical cystectomy following previous oncological treatment for bladder cancer.

OBJECTIVE: To investigate the prognostic value of lymph-node dissection (LND) in patients undergoing radical cystectomy (RC) following previous oncological treatment. MATERIAL AND METHODS: Perioperative findings and recurrence patterns of 46 patients undergoing RC for bladder cancer were evaluated. Twenty-six patients underwent salvage cystectomy because of local bladder cancer recurrence following intended curative external beam radiotherapy; 20 patients underwent preoperative chemotherapy because of non-regional lymph-node metastases (10 patients), clinically fixed primary tumour (cT4b) (eight patients) or pulmonary metastases (two patients). RESULTS: Difficulties with LND because of fibrous tissue were accounted in the majority of previously irradiated patients. No metastatic lymph nodes were found within the irradiation field at the time of surgery or during follow-up. Two- and 5-year disease-specific survival (DSS) was 47% and 31%, respectively. In patients undergoing preoperative chemotherapy because of lymph-node metastasis, three patients (30%) had vital tumour cells within the removed lymph-nodes. Two- and 5-year DSS was 67% and 50%, respectively. Despite preoperative chemotherapy, all patients with cT4b tumours and previously diagnosed pulmonary metastases died because of recurrent disease within 2 years. CONCLUSIONS: LND in the previously irradiated pelvis may be difficult and remains controversial. Because of a high risk of vital tumours cells within the removed lymph nodes despite chemotherapy, extended LND should be performed in patients with non-regional lymph-node metastasis following preoperative chemotherapy. In patients with fixed tumours and minimal response to chemotherapy and in patients with visceral metastases, RC should be attempted for palliative reasons only.

Size and volume of metastatic and non-metastatic lymph nodes in pelvis and lower abdomen in patients with carcinoma of the bladder undergoing radical cystectomy.

OBJECTIVE: This study aimed to evaluate the usability of size and volume of lymph nodes (LNs) in the pelvis and lower abdomen to predict metastatic disease in patients with carcinoma of the urinary bladder. MATERIAL AND METHODS: LNs retrieved from 177 patients undergoing radical cystectomy and extended LN dissection were prospectively registered with number, location, presence of metastatic disease, longitudinal length, transverse diameter and a calculated LN volume. RESULTS: A mean of 21.2 LNs was removed from each patient. Thirty-eight patients (21.5%) had positive LNs. The total LN volume per patient was independent of the number of LNs removed, whereas mean volume per LN was inversely proportional to the number of LNs removed in node-negative patients, suggesting a physiological variation in the number of pelvic LNs. Positive LNs were generally larger than negative LNs. This difference was more pronounced using the transverse diameter than using longitudinal length. Calculated higher volume of an LN was also associated with an increased risk of metastases. However, no optimal cut-off values predicting metastatic disease based on LN size were found owing to low sensitivity and low predictive value at the tested cut-off values. The size difference comparing positive and negative LNs was therefore not clinically applicable as an overall preoperative risk estimation of metastatic disease. CONCLUSIONS: A fixed volume of lymphatic tissue rather than a fixed number of LNs seems to be present in node-negative patients. Size of LNs remains a poor predictor of metastatic disease in bladder cancer.

Chromosomal imbalance in the progression of high-risk non-muscle invasive bladder cancer.

BACKGROUND: Non-muscle invasive bladder neoplasms with invasion of the lamina propria (stage T1) or high grade of dysplasia are at "high risk" of progression to life-threatening cancer. However, the individual course is difficult to predict. Chromosomal instability (CI) is associated with high tumor stage and grade, and possibly with the risk of progression. METHODS: To investigate the relationship between CI and subsequent disease progression, we performed a case-control-study of 125 patients with "high-risk" non-muscle invasive bladder neoplasms, 67 with later disease progression, and 58 with no progression. Selection criteria were conservative (non-radical) resections and full prospective clinical follow-up (> 5 years). We investigated primary lesions in 59, and recurrent lesions in 66 cases.We used Affymetrix GeneChip Mapping 10 K and 50 K SNP microarrays to evaluate genome wide chromosomal imbalance (loss-of-heterozygosity and DNA copy number changes) in 48 representative tumors. DNA copy number changes of 15 key instability regions were further investigated using QPCR in 101 tumors (including 25 tumors also analysed on 50 K SNP microarrays). RESULTS: Chromosomal instability did not predict any higher risk of subsequent progression. Stage T1 and high-grade tumors had generally more unstable genomes than tumors of lower stage and grade (mostly non-primary tumors following a "high-risk" tumor). However, about 25% of the "high-risk" tumors had very few alterations. This was independent of subsequent progression. Recurrent lesions represent underlying field disease. A separate analysis of these lesions did neither reflect any difference in the risk of progression. Of specific chromosomal alterations, a possible association between loss of chromosome 8p11 and the risk of progression was found. However, the predictive value was limited by the heterogeneity of the changes. CONCLUSION: Chromosomal instability (CI) was associated with "high risk" tumors (stage T1 or high-grade), but did not predict subsequent progression. Recurrences after "high-risk" tumors had fewer chromosomal alterations, but there was no association with the risk of progression in this group either. Thus, the prediction of progression of "high risk" non-muscle invasive bladder tumors using chromosomal changes is difficult. Loss of chromosome 8p11 may play a role in the progression process. About 25% of the "high risk" tumors were chromosomal stable.

Sentinel lymph-node biopsy in patients with squamous cell carcinoma of the penis.

OBJECTIVES: To evaluate a single-centre experience with sentinel lymph-node biopsy (SLNB) as a staging procedure in patients with squamous cell carcinoma (SCC) of the penis. PATIENTS AND METHODS: The study included 60 patients with SCC of the penis, who had SLNB in all groins where no palpable nodes were found, and in groins with palpable nodes with negative fine-needle aspiration cytology. Lymphoscintigraphy and intraoperative lymph node detection was done using (99m)Tc-nanocolloid and no use of blue dye. RESULTS: In all, there were 97 SLNB procedures in 52 patients; 20 (20.6%) of the SLNB were positive for nodal metastases. Two negative SLNB proved to be false-negative during the observation period. The false negative-rate was 9%, the sensitivity 91% and the negative predictive value 97.5%. Minor early complications occurred after 4% of the SLNB procedures. No major or late complications were recorded. CONCLUSIONS: SLNB is minimally invasive and can be used as a safe and reliable staging procedure in patients with SCC of the penis. Thus standard lymph-node dissection can be avoided in most patients.

Estimation of the true number of lymph nodes in lymphadenectomy specimens from radical cystectomy.

OBJECTIVE: To evaluate the sensitivity of conventional pathological examination of lymphadenectomy specimens regarding identification of lymph nodes. MATERIAL AND METHODS: Fifteen cystectomy specimens with separate package lymphadenectomy specimens from patients with invasive carcinoma of the bladder were subjected to conventional pathological examination followed by paraffin embedding and sectioning of all remaining fatty tissue. Identification of additional lymph nodes missed by the initial investigation was registered. RESULTS: In six of the 15 specimens, additional nodes were identified by sectioning of the fatty tissue. Sensitivity per lymph node of the conventional method was 95% (292 of 308 nodes). One patient with multiple metastatic lymph nodes had one additional positive node. No other additional positive nodes were identified in the specimens. Thus no stage migration was seen. CONCLUSIONS: Only a minority of lymph nodes are missed by conventional pathological examination of lymphadenectomy specimens from radical cystectomy. The method is therefore sufficient from a staging perspective.

Terminal patients with urinary diversion: are there specific treatment or nursing care problems in the primary healthcare sector?

OBJECTIVE: To investigate the treatment and nursing care problems related to the type of urinary diversion in terminal patients experienced by the primary healthcare sector. METHODS: A questionnaire about treatment and nursing care problems related to urinary diversion was sent to general practitioners (GPs) and district nurse units (DNUs) that had been in contact with 1 of 71 patients who died following cystectomy in a 5-year period. The patients had 1 of 3 types of urinary diversion: ileal conduit (IC), Indiana pouch (IP), or Hautmann orthotopic neobladder (NB). RESULTS: Both GPs and DNUs reported significant difference in problems associated with the 3 types of urinary diversion favoring the IC (P = .049 and .025, respectively). However, clinical decisions about urinary diversion types are often based on incontinent versus continent diversions. When divided into continent versus incontinent diversions, the analysis revealed no differences in the number of problems (P = .31 and .052, respectively). Comparing IC and NB alone made the difference even less significant (P = .82 and .23, respectively). CONCLUSIONS: It seems that there are no major disadvantages with one type of urinary diversion when compared to the other as perceived by primary healthcare providers. Relevant and thorough information should be provided to GPs and DNUs in order to minimize problems with all forms of urinary diversion.

SOX4 expression in bladder carcinoma: clinical aspects and in vitro functional characterization.

The human transcription factor SOX4 was 5-fold up-regulated in bladder tumors compared with normal tissue based on whole-genome expression profiling of 166 clinical bladder tumor samples and 27 normal urothelium samples. Using a SOX4-specific antibody, we found that the cancer cells expressed the SOX4 protein and, thus, did an evaluation of SOX4 protein expression in 2,360 bladder tumors using a tissue microarray with clinical annotation. We found a correlation (P < 0.05) between strong SOX4 expression and increased patient survival. When overexpressed in the bladder cell line HU609, SOX4 strongly impaired cell viability and promoted apoptosis. To characterize downstream target genes and SOX4-induced pathways, we used a time-course global expression study of the overexpressed SOX4. Analysis of the microarray data showed 130 novel SOX4-related genes, some involved in signal transduction (MAP2K5), angiogenesis (NRP2), and cell cycle arrest (PIK3R3) and others with unknown functions (CGI-62). Among the genes regulated by SOX4, 25 contained at least one SOX4-binding motif in the promoter sequence, suggesting a direct binding of SOX4. The gene set identified in vitro was analyzed in the clinical bladder material and a small subset of the genes showed a high correlation to SOX4 expression. The present data suggest a role of SOX4 in the bladder cancer disease.

Role of activating fibroblast growth factor receptor 3 mutations in the development of bladder tumors.

PURPOSE: Bladder tumors develop through different molecular pathways. Recent reports suggest activating mutations of the fibroblast growth factor receptor 3 (FGFR3) gene as marker for the "papillary" pathway with good prognosis, in contrast to the more malignant "carcinoma in situ" (CIS) pathway. The aim of this clinical follow-up study was to investigate the role of FGFR3 mutations in bladder cancer development in a longitudinal study. EXPERIMENTAL DESIGN: We selected 85 patients with superficial bladder tumors, stratified into early (stage T(a)/grade 1-2, n = 35) and more advanced (either stage T(1) or grade 3, n = 50) developmental stages. The patients were followed prospectively, and metachronous tumors were included. We did screening for FGFR3 and TP53 mutations by direct bidirectional sequencing and for genome-wide molecular changes with microarray technology. RESULTS: A total of 43 of 85 cases (51%) showed activating mutations of FGFR3. The mutations were associated with papillary tumors of early developmental stage. However, after stratifying for developmental stage, FGFR3-mutated tumors showed the same malignant potential as wild-type tumors. Tumors with concomitant CIS were generally FGFR3 wild type. They were characterized by different patterns of chromosomal changes and gene expression signatures compared with FGFR3-mutated tumors, indicating different molecular pathways. CONCLUSIONS: FGFR3 mutations seem to have a central role in the early development of papillary bladder tumors. These tumors follow a common molecular pathway, which is different from tumors with concomitant CIS. FGFR3 mutations do not seem to play a role in bladder cancer progression.

High expression of karyopherin-α2 defines poor prognosis in non-muscle-invasive bladder cancer and in patients with invasive bladder cancer undergoing radical cystectomy.

BACKGROUND: Conventional clinicopathologic risk factors have failed to accurately predict the prognosis of patients with bladder cancer (BC). OBJECTIVE: To evaluate karyopherin-α2 (KPNA2) expression as a progression marker in patients with non-muscle-invasive BC (NMIBC) treated by conservative methods and as a prognostic marker in patients with invasive BC undergoing radical cystectomy (RC). DESIGN, SETTING, AND PARTICIPANTS: Two different tissue microarrays were constructed, one with 234 primary Ta/T1 tumours from patients treated by transurethral resection of the bladder and one with 377 tumours from RC patients. INTERVENTION: KPNA2 expression based on immunohistochemistry. MEASUREMENTS: Risk of progression of Ta/T1 patients to muscle-invasive BC was estimated in clinical follow-up to progression or a minimum of 53 mo. Risk of recurrent disease and death following RC was estimated in clinical follow-up of a minimum of 24 mo in patients alive. RESULTS AND LIMITATIONS: A high KPNA2 expression in Ta/T1 patients was significantly correlated with a higher risk of progression that was independent of conventional risk factors in multivariate analysis. In patients undergoing RC, a high KPNA2 expression was an independent predictor of poor prognosis. A high KPNA2 expression was correlated with a higher risk of visceral metastasis rather than lymphatic spread. CONCLUSIONS: KPNA2 expression is a marker for progression of NMIBC and a prognostic marker in patients undergoing RC.

[Cystectomy in Denmark 2000-2005]. / Cystektomi i Danmark 2000-2005.

INTRODUCTION: The organization and results after cystectomy in Denmark are unknown. MATERIALS AND METHODS: Based upon the Danish National Hospital Register and discharge notes, postoperative hospitalization, readmission within 30 days, re-operations and mortality after cystectomy in Denmark in the period January 1, 2000-December 31, 2005 were assessed. RESULTS: There were 995 cystectomies with a median postoperative hospital stay of 18.9 days (including readmissions) and hospital mortality of 3.7%. The operations were performed in seven departments without difference in outcome between departments. Morbidity was observed in 58%, 16.8% of which were re-operated for wound or urinary diversion complications. CONCLUSION: It is concluded that cystectomy should be performed in only five departments in Denmark, and the results suggest that an intensified multicenter collaboration should be initiated to improve outcome.

[Function of neobladders in women after cystectomy]. / Funktion af neoblaere hos kvinder efter cystektomi.

INTRODUCTION: Since 1999, Rigshospitalet (RH) and Aarhus University Hospital, Skejby (SKS) have been offering women an orthotopic neobladder following cystectomy. The aim of the present study was to describe the function of the neobladders in women by examining continence and voiding function. Cancer stage, cancer recurrence, complications and mortality are also described. MATERIALS AND METHODS: The data was retrospectively collected from patient files. Between 1999 and 2006, a total of 20 female patients at RH and SKS underwent reconstructive surgery with a neobladder. Continence and voiding function were evaluated from existing tests and examinations performed during follow-up. RESULTS: The average follow-up was 3.1 years (range: 0.4-7.4). The average age was 57.1 years (40.1-70.6). Fifteen patients (75%) were continent during the daytime, and three of the patients (15%) were incontinent during the night-time. Five patients (25%) were partly incontinent during the day- and night-time, but in two of the patients the incontinence was related to recurrence. Eight patients (40%) used intermittent catheterization as a supplement to the spontaneous voiding. Ten patients (50%) had early complications. Six patients (30%) had late complications. The most common complication was pyelonephritis. Fifteen patients (75%) were alive at the end of follow-up, and twelve patients (60%) were without recurrence. CONCLUSION: Neobladders in women after cystectomy function adequately. Patients achieve a high degree of continence and acceptable bladder emptying. However, the best functional results were seen in patients without cancer recurrence.

Complications and neobladder function of the Hautmann orthotopic ileal neobladder.

OBJECTIVE: To report the complications and function of the Hautmann orthotopic ileal neobladder . PATIENTS AND METHODS: In a 6.5-year period, 67 patients had an ileal neobladder constructed after radical cystectomy as treatment for invasive carcinoma of the bladder. All complications were reported systematically. Neobladder function was assessed by patient interviews, uroflowmetry and cystometric analyses. RESULTS: There were early complications in 41 patients (61%), and late complications in 32 (48%); 23 (34%) had both early and late complications and 17 (25%) had none. Eighteen of the patients (27%) required a re-operation for complications. At the 4-month follow-up, 90% were continent during the day and 65% during the night; at 1 year after surgery 95% were continent during the day and 73% during the night. The functional bladder capacity and maximum cystometric capacity were close to the natural bladder volume (median 450 and 480 mL, respectively). CONCLUSIONS: Despite the high rate of complications in this study, most were considered as minor and could be treated by conservative or minimally invasive methods. The neobladder had an acceptable resemblance to the native bladder in capacity and function. Consequently the ileal neobladder might be preferred as a urinary diversion after radical cystectomy, if no contraindications are present.

Clinical experience with the Mentor Alpha-1 inflatable penile prosthesis: report on 65 patients.

OBJECTIVE: To evaluate the complications and prosthesis survival associated with implantation of the Mentor Alpha-1 inflatable penile prosthesis (IPP) for the treatment of erectile dysfunction (ED). MATERIAL AND METHODS: Between August 1995 and March 2003, 65 patients underwent implantation of a Mentor Alpha-1 IPP at the Urological Departments of Skejby or Aalborg University Hospitals. Patient data were obtained retrospectively from medical files. RESULTS: The follow-up period ranged from 1 to 96 months (median 48.5 months). Twenty-one patients (32%) experienced complications that required revision. The majority of complications consisted of mechanical problems, but infection was also a large contributor to the complication rate. Seven patients (11%) had the prosthesis permanently removed due to infection. Kaplan-Meier estimates of the 5-year prosthesis survival rates with and without successful revisions due to complications were 88% and 63%, respectively. CONCLUSIONS: The Mentor Alpha-1 IPP is an efficient treatment for ED in situations where less invasive therapy has failed. The risk of infection or mechanical failure must not be ignored. Patients should be informed of this risk before agreeing to implantation surgery.

Patient and partner satisfaction with the Mentor Alpha-1 inflatable penile prosthesis.

OBJECTIVE: To evaluate the satisfaction level of patients and partners after implantation of a Mentor Alpha-1 inflatable penile prosthesis (IPP) for the treatment of erectile dysfunction (ED). MATERIAL AND METHODS: A questionnaire was sent to 46 patients who had been operated on for ED with implantation of a Mentor Alpha-1 IPP. The investigation was designed to evaluate patient and partner satisfaction. RESULTS: Eighty-five percent of the questionnaires were returned. Sexual desire had not changed but the quality of sexual activity had significantly improved. Acceptance by the partner was good. Overall satisfaction among both patients and partners was high. In total, 95% of patients said that they would recommend the procedure to other patients in the same situation. CONCLUSIONS: Patient and partner satisfaction with the Mentor Alpha-1 IPP was high, with the exception of the minority of patients who experienced unacceptable complications. Infection and mechanical failure are important risks which patients should be informed of before agreeing to implantation surgery.