Proximal hypospadias repair with bladder mucosal graft: Our 10 years experience.

INTRODUCTION AND OBJECTIVE: A great variety of different surgical techniques has been described for proximal hypospadias repair and an ideal tissue has not been determined yet. We present our 10 years of surgical experience using a bladder mucosal graft for urethroplasty. STUDY DESIGN: Bladder mucosal graft urethroplasty was performed between 2005 and 2015 in 50 patients with severe proximal hypospadias. The mean age of patients was 45.1 months (range 24-164 months). Hypospadias were perineal in 18 patients, scrotal in 22, and penoscrotal in 10. In all cases a chordee correction was performed and median time between the first and the second stages was 12 months (mean 17 months, range 4-68 months). Both foley catheter and a suprapubic cystostomy were positioned and maintained for 2-4 weeks. Follow-up was performed at 1-3 and 6-12 months after surgery, and afterwards annually with clinical examination and flowmetry test. RESULTS: Mean follow-up was 5.3 years (median 5, range 1-10 years). Mean graft length was 57.4 mm (median 55 mm, range 35-85 mm). Among all the only early complication registered was a postoperative infection in one patient (2%) at the site of anastomosis. The long-term complications observed were urethrocutaneous fistula in nine patients (18%), urethral stricture in 15 patients (30%), meatal stricture in four patients (8%), and prolapse of meatus in seven patients (14%). The mean time of complication occurrence was 15 months (median 15.5 months, range 1-96 months). The functional and cosmetic appearance after surgery was satisfactory in 42/50 patients (84%) during the follow-up period. DISCUSSION: There is still an open debate regarding the optimal surgical approach for management of severe proximal hypospadias. Compared with other approaches, our technique showed acceptable results even though encumbered by slightly higher complication rates. CONCLUSION: Our results show that bladder mucosal graft for primary severe proximal hypospadias in selected patients is a possible alternative to other commonly used techniques, with the aim of restoring recovery of the normal continuity of the distal urinary tract see figure below.

Antimicrobial prophylaxis for transrectal ultrasound-guided prostate biopsy: fosfomycin trometamol, an attractive alternative.

OBJECTIVE: To compare fosfomycin trometamol (FT) and ciprofloxacin (CIP) for antibiotic prophylaxis in transrectal prostate biopsy (TR-PB). PATIENTS AND METHODS: Data for 1109 patients (mean age 66.7 ± 8.45) who underwent TR-PB between March to September 2015 in seven Italian urological institutions were retrospectively reviewed, of which 632 received FT (Group 1) and 477 received CIP (Group 2) for prophylaxis. We reviewed all urine culture results obtained after the procedure, all adverse drug reactions (ADRs) related to the drug and all febrile and/or symptomatic urinary tract infections (UTIs) occurring within 1 month after TR-PB. The rate of symptomatic UTIs and the rate of ADRs were considered the main outcome measures. RESULTS: In the total study population, 72/1109 (6.5 %) patients experienced symptomatic UTIs and among these 11 (0.9 % of total) had urosepsis. Out of 72, 53 (73.6 %) symptomatic UTIs were caused by fluoroquinolone-resistant strains. Out of 632, 10 (1.6 %) patients in Group 1 and 62/477 (12.9 %) patients in Group 2 had symptomatic UTIs (p < 0.001); in particular, 2/632 (0.3 %) patients in Group 1 and 9/477 (1.8 %) patients in Group 2 had urosepsis (p < 0.001). No differences were reported in terms of adverse events (0.6 vs 0.4 %; p = 0.70). A Charlson comorbidity index ≤1 and type of antimicrobial prophylaxis (FT) were found to be associated with a lower probability of symptomatic UTIs in the multivariate model. CONCLUSIONS: Antibiotic prophylaxis with FT for TR-PB had a lower rate of adverse events and a lower rate of symptomatic UTIs as compared with CIP. Fosfomycin trometamol appears as an attractive alternative prophylactic regimen in prostate biopsies.

Zoledronic acid impairs stromal reactivity by inhibiting M2-macrophages polarization and prostate cancer-associated fibroblasts.

Zoledronic acid (ZA) is a biphosphonate used for osteoporosis treatment and also proved to be effective to reduce the pain induced by bone metastases when used as adjuvant therapy in solid cancers. However, it has been recently proposed that ZA could have direct anti-tumour effects, although the molecular mechanism is unknown. We herein unravel a novel anti-tumour activity of ZA in prostate cancer (PCa), by targeting the pro-tumorigenic properties of both stromal and immune cells. Particularly, we demonstrate that ZA impairs PCa-induced M2-macrophages polarization, reducing their pro-invasive effect on tumour cells and their pro-angiogenic features. Crucially, ZA administration reverts cancer associated fibroblasts (CAFs) activation by targeting the mevalonate pathway and RhoA geranyl-geranylation, thereby impairing smooth muscle actin-α fibers organization, a prerequisite of fibroblast activation. Moreover, ZA prevents the M2 macrophages-mediated activation of normal fibroblast, highlighting the broad efficacy of this drug on tumour microenvironment. These results are confirmed in a metastatic xenograft PCa mouse model in which ZA-induced stromal normalization impairs cancer-stromal cells crosstalk, resulting in a significant reduction of primary tumour growth and metastases. Overall these findings reinforce the efficacy of ZA as a potential therapeutic approach to reduce cancer aggressiveness, by abrogating the supportive role of tumour microenvironment.

Management of sexual dysfunction due to central nervous system disorders: a systematic review.

OBJECTIVE: To systematically review the management of sexual dysfunction due to central nervous system (CNS) disorders. PATIENTS AND METHODS: The review was done according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Studies were identified independently by two reviewers using electronic searches of MEDLINE and OVID (from January 2004 to August 2014) and hand searches of reference lists and review articles. RESULTS: In patients with CNS disorders, neuro-urological assessment is recommended for both genders before starting any treatment for sexual dysfunction. For men, blood sexual hormones evaluation is the main investigation performed before phosphodiesterase type 5 inhibitors (PDE5Is) treatment, whereas there is no consensus on routine laboratory tests for women. PDE5Is are the first-line medical treatment for men, with the most robust data derived from patients with spinal cord injury assessed by validated questionnaires, mainly the International Index of Erectile Function-15. There is no effective medical treatment for sexual dysfunction in women. Sacral neuromodulation for lower urinary tract dysfunction may improve sexual dysfunction in both genders. CONCLUSIONS: Although sexual dysfunction is a major burden for patients with CNS disorders, high-evidence level studies are rare and only available for PDE5Is treating erectile dysfunction. Well-designed prospective studies are urgently needed for both genders.

Current indications and results of orthotopic ileal neobladder for bladder cancer.

During the past three decades, the reconstructive aspects of urologic surgery emerged and became a major component of our surgical specialty, and the most relevant developments have been observed in the field of urinary diversions. Health-related quality of life and self esteem have been improved following orthotopic bladder substitutions, which are actually the preferred method for continent urinary diversion. Patients with neobladders have enhanced cosmesis and the potential for normal voiding function with no abdominal stoma. Patient's selection for orthotopic neobladder formation is mandatory as most of the surgical complications or consequences associated with a neobladder are correlated not only with surgical technique or management after surgery, but also with wrong patient's selection. The principles of intestinal detubularization and reconfiguration to obtain spherical reservoir are the basis of continent urinary diversions and ileum seems to be preferable over any other segment. Nowadays, ileal neobladder is a widely adopted solution after cystectomy with a neobladder rate of 9-19% for population-based data with an increase to 39.1-74% for high-volume centers. However, controversies still exist in this urological field about the best candidates for neobladder construction, the best type of neobladder to offer, whether or not an antireflux uretero intestinal anastomosis should be used, the future of minimally invasive approaches, that is, robotic assisted cystectomy plus extracorporeal or intracorporeal neobladder, and last but very important, the functional results and the level of symptoms-induced distress and quality of life in the long term in patients with bladder cancer receiving an orthotopic bladder substitution. All these issues are discussed on the basis of the most recent published data.

The impact of prior TURP on radical prostatectomy surgical margins: a multicenter analysis.

OBJECTIVE: To analyze positive surgical margins (PSM) after radical prostatectomy (RP) in the overall population and in patients previously treated with transurethral resection of the prostate (TURP). MATERIALS AND METHODS: 2,408 patients treated with RP for clinically localized prostate cancer (PCa) were consecutively enrolled in 135 departments. We correlated PSM rates and all preoperative, surgical and pathological features. We stratified the site of PSM as unique or multifocal. Moreover, we analyzed differences between 75 patients who had undergone previous TURP and the remaining 2,333 patients. RESULTS: In the entire study population, we identified 702 patients with PSM (29%). Using univariate analysis, we reported a significant correlation between overall PSM and prostate-specific antigen (PSA), stage cT, biopsy Gleason score, number of biopsy cores, number of positive cores, percentage of positive cores and nerve-sparing approach. PSM proved to be strongly dependent on pT in particular in patients with pT2 PCa. When we compared the data from 75 patients previously treated with TURP and those from 2,333 without previous prostatic surgery, a statistically significant difference in margin localization was found. Moreover, we analyzed the 75 patients mentioned above, stratified in incidental PCa diagnosed at TURP or PCa detected with prostate biopsy for PSA rising during the post-TURP follow-up: no statistical differences were found between the 2 groups regarding margin status, even if PSM were more frequent in incidental PCa with no significance deriving from the stratification for PSM location at the apex or base. CONCLUSION: Men treated with TURP before RP presented an overall incidence of PSM similar to those without previous TURP, but with a higher risk of PSM at the bladder neck and a lower risk of PSM at the prostatic apex.

Quality of life in women undergoing urinary diversion for bladder cancer: results of a multicenter study among long-term disease-free survivors.

PURPOSE: Women undergoing radical cystectomy (RC) and urinary diversion for bladder cancer experience substantial limitations in health-related quality of life (HRQOL). However, the level of discomfort caused by different urinary diversion has been never evaluated in long term survivors. The aim of this multicenter study is to evaluate differences in HRQOL among recurrence-free women undergoing cutaneous ureterostomy (CUS), Bricker's ileal conduit (BK-IC) and Orthotopic neobladder VIP (ONB-VIP) in disease-free females treated with radical cystectomy (RC), with long-term follow up (mean 60.1 months; range 36-122 months). MATERIALS AND METHODS: All consecutively treated female patients from two urological institutions who underwent RC and urinary diversion from January 2000 to December 2008, with no evidence of tumor recurrence at a minimum follow up of 36 months, were included. Patients received the European Organisation for Research and Treatment of Cancer (EORTC) generic (QLQ-C30) and bladder cancer-specific instruments (QLQ-BLM30) and the Functional Assessment of Cancer Therapy for Bladder Cancer (FACT-BL). Clinical data and questionnaire results were analyzed in order to evaluate the HRQOL differences among diversion groups. RESULTS: We identified 37 females (median age: 68, range 45-82 years), including 12 status-post CUS, 16 who underwent BK-IC, and 9 who underwent ONB-VIP. Most were healthy (24/37 with no comorbidities, 4/37 Charlson 1-2, 9/37 Charlson 3 or greater - we didn't considered bladder cancer in Charlson evaluation because bladder cancer was the main inclusion criteria). Women undergoing CUS endorsed worse FACT-BL scores compared with BK-IC and ONB-VIP patients, worse HRQOL regarding physical and emotional well-being (p=0.008 and p=0.02, respectively), and a trend toward worse EORTC QLQ-C30 scores for appetite loss and fatigue (p=0.05 for both). CONCLUSIONS: In our study long-term disease-free females treated with CUS endorsed worse HRQOL compared with women who underwent BK-IC or ONB-VIP, mostly due to worse physical and emotional perception of their body image.

External validation of the updated nomogram predicting lymph node invasion in patients with prostate cancer undergoing extended pelvic lymph node dissection.

INTRODUCTION: The aim of our study was to determine the validity of the updated nomogram [Briganti et al.: Eur Urol 2012;61:480-487] as a prediction tool for pelvic lymph node invasion (LNI) in the current era by using a large multicentric population of men who underwent extended pelvic lymph node dissection (ePLND) at the time of radical prostatectomy (RP) at tertiary referral centers. PATIENTS AND METHODS: Between 2000 and 2011, 896 consecutive patients underwent RP and ePLND at two tertiary referral centers for clinically localized prostate cancer (PCa). Uni- and multivariable logistic regression models predicting the presence of LNI at ePLND were built in. Covariates consisted of preoperative PSA, clinical stage, primary and secondary biopsy Gleason grade with or without percentage of positive cores. Patients' data were entered into a logistic model formula derived from the original publication of Briganti. The nomogram was assessed by comparing its predicted probability of LNI with the actual presence of LNI. The area under the curve was used to quantify its predictive accuracy. RESULTS: Mean preoperative PSA, clinical and pathological stage, primary and secondary biopsy and pathological Gleason grade, such as mean number of total cores, positive cores and percentage of positive cores differed significantly between LNI-positive and LNI-negative patients (all p < 0.001 except for number of total cores, p = 0.019). The mean number of lymph nodes removed was 14.8, and LNI was found in 101 patients (11.8%). In the univariate analysis the percentage of positive cores was the most accurate predictor of LNI (72%), followed by PSA (69%), primary biopsy Gleason grade (64%), clinical stage (60%), and secondary biopsy Gleason grade (59%). The predictions of the nomogram were virtually perfect when the predicted probability was ≤20%. We tested the performance characteristics of various Briganti nomogram-derived cut-offs (1-14%) for discriminating between patients with and without LNI. In our population, 41.6% of patients were classified below the 5% cut-off proposed in the original Briganti et al. report. In the multivariate analysis these variables remained statistically significant predictors for the presence of lymph node metastases. The predictive accuracy of the full model reached 79%. CONCLUSIONS: The updated nomogram predicting LNI in patients with PCa undergoing ePLND has been externally validated, demonstrating excellent accuracy and calibration characteristics and a general applicability for predicting the presence of LNI.

Reciprocal metabolic reprogramming through lactate shuttle coordinately influences tumor-stroma interplay.

Cancer-associated fibroblasts (CAF) engage in tumor progression by promoting the ability of cancer cells to undergo epithelial-mesenchymal transition (EMT), and also by enhancing stem cells traits and metastatic dissemination. Here we show that the reciprocal interplay between CAFs and prostate cancer cells goes beyond the engagement of EMT to include mutual metabolic reprogramming. Gene expression analysis of CAFs cultured ex vivo or human prostate fibroblasts obtained from benign prostate hyperplasia revealed that CAFs undergo Warburg metabolism and mitochondrial oxidative stress. This metabolic reprogramming toward a Warburg phenotype occurred as a result of contact with prostate cancer cells. Intercellular contact activated the stromal fibroblasts, triggering increased expression of glucose transporter GLUT1, lactate production, and extrusion of lactate by de novo expressed monocarboxylate transporter-4 (MCT4). Conversely, prostate cancer cells, upon contact with CAFs, were reprogrammed toward aerobic metabolism, with a decrease in GLUT1 expression and an increase in lactate upload via the lactate transporter MCT1. Metabolic reprogramming of both stromal and cancer cells was under strict control of the hypoxia-inducible factor 1 (HIF1), which drove redox- and SIRT3-dependent stabilization of HIF1 in normoxic conditions. Prostate cancer cells gradually became independent of glucose consumption, while developing a dependence on lactate upload to drive anabolic pathways and thereby cell growth. In agreement, pharmacologic inhibition of MCT1-mediated lactate upload dramatically affected prostate cancer cell survival and tumor outgrowth. Hence, cancer cells allocate Warburg metabolism to their corrupted CAFs, exploiting their byproducts to grow in a low glucose environment, symbiotically adapting with stromal cells to glucose availability.

The prognostic role of preoperative chromogranin A expression in prostate cancer after radical prostatectomy.

PURPOSES: The aim was to analyze the prognostic role of preoperative chromogranin A CgA) as a marker of poor prognosis and recurrence after radical prostatectomy (RP) and to find a correlation with the other well known prognostic variables. MATERIALS AND METHODS: This study comprises 306 patients with prostate cancer prospectively recruited who underwent RP from between 2000 and 2005. A blood sample for the determination of serum preoperative CgA value was obtained in all cases. Spearman correlation test was used to compare CgA to other variables, Kruskal-Wallis test to analyze CgA differences among > or = 3 groups (PSA, GS, Stage), Mann-Whitney test for 2 grouping variables. Survival analysis was estimated by Kaplan-Meier method, log-rank test to estimate differences among the analyzed variables. RESULTS: Median CgA level was 68 ng/ml. Correlation between age and CgA levels was positive and statistically significant (p < 0.001). Patient were divided in 2 groups based on median age.The difference was statistically significant (p = 0.002). Comparison of CgA among patients grouped according to other variables and patient stratified on normal (123 ng/ml) and cut-off value (68 ng/ml) of CgA did not achieve significant risk stratification. CONCLUSION: Studies on a possible prognostic role of CgA have provided conflicting results. In our series we found a significant positive correlation between CgA and age, but no significant statistical correlation with other available variables analyzed.

The role of free to total PSA ratio in prediction of extracapsular tumor extension and biochemical recurrence after radical prostatectomy in patients with PSA between 4 and 10 ng/ml.

OBJECTIVES: The prognostic value of free to total PSA ratio (F/T PSA) in patients eligible for radical prostatectomy (RP) is controversial. The aim of the present study was to evaluate correlation of F/T PSA with tumor extracapsular extension (ECE) and biochemical recurrence (BR) at long-term follow-up. PATIENT AND METHODS: Clinical and pathological data were prospectively gathered from 200 patients treated with RP for clinically localized prostate cancer (PCa) and PSA between 4 and 10 ng/mL. Correlations of preoperative variables including F/T PSA with ECE and BR were evaluated with uni- and multivariate analysis. Adjunctive analyses evaluated the association of PSA F/T with other pathological results. The relationship between preoperative F/T PSA and BR was also assessed with Kaplan­Meier survival analysis. RESULTS: Lower F/T PSA was significantly correlated with ECE (p = 0.0063), higher GS (p = 0.0054), and seminal vesicles involvement (p = 0.0047). The F/T PSA value of 14% provided the greatest discrimination in predicting ECE. At multivariate analysis, F/T PSA did not achieve the statistical significance for predicting ECE independently. At a mean (median, range) follow-up of 52 (48, 14­116) months, preoperative F/T PSA resulted significantly correlated with BR (p = 0.001). At the Kaplan­Meier survival analysis, the 5-year BR free survival rate resulted 89.3 and 68.9% in the group with F/T PSA >14 and ≤14 ng/mL, respectively (log rank p = 0.0022). At Cox proportional hazard model, only ECE resulted an independent predictor of BR (R = 2.646, p = 0.037). CONCLUSION: In patients with clinically localized PCa and PSA 4­10 ng/ml, lower F/T PSA was significantly associated with ECE, other adverse pathologic features, and with BR at the long-term follow-up, but only ECE resulted an independent predictor of BR in our series.

Simple enucleation versus radical nephrectomy in the treatment of pT1a and pT1b renal cell carcinoma.

BACKGROUND: Simple tumor enucleation (TE) showed excellent oncologic results in large retrospective series. No study has compared oncologic outcomes after TE and radical nephrectomy (RN) for the treatment of pT1 renal cell carcinoma (RCC). The aim of the present study is to compare the oncologic outcomes after TE and RN in pT1 RCCs. METHODS: We retrospectively analyzed 475 patients who underwent TE or RN for pT1 RCC, N0, M0, between 1995 and 2007. TE was performed in 332 patients and RN in 143. Local recurrence, progression-free survival (PFS), and cancer-specific survival (CSS) were the main outcomes of this study. The Kaplan-Meier method was used to calculate survival functions, and differences were assessed with the log rank statistic. Univariate and multivariate Cox regression models were also used. RESULTS: The 5- and 10-year PFS estimates were 91.3 and 88.7% after RN and 95.3 and 92.8% after TE (P = NS), respectively. The 5- and 10-year CSS estimates were 92.1 and 89.4% after RN and 94.4% (5- and 10-year CSS) after TE (P = NS), respectively. No statistically significant differences between RN and TE were found after adjusting CSS probabilities according to age at surgery, grade, stage, or clear cell subtype. Surgical treatment was not a predictor of PFS or CSS by both univariate and multivariate analyses. The potential limitation of this study is that the data originate from a retrospective review. CONCLUSIONS: TE can achieve oncologic results similar to those of RN for the treatment of pT1 RCCs, provided tumors are carefully selected on the basis of their safe and complete removal.

Prognostic role of perineural invasion in 239 consecutive patients with pathologically organ-confined prostate cancer.

OBJECTIVE: The aim of our study was to analyze the role of perineural invasion (PNI) as a predictive parameter of outcome after radical prostatectomy (RRP) in pathologically organ-confined prostate cancer (PCa) and to assess its possible correlation with other well-known prognostic features. PATIENTS AND METHODS: At our institution between January 2000 and December 2007, we prospectively collected data from 251 consecutive patients with pathologically localized PCa after antegrade RRP. In our analysis 239 patients were included. PNI was defined as adenocarcinoma within the perineural space adjacent to a nerve. We evaluated the biochemical progression-free survival rate using the Kaplan-Meier method to establish the correlation between PNI and prognosis, the log-rank test to verify the statistical significance, and χ(2) test to investigate the correlation between PNI and other clinicopathological parameters. RESULTS: We found intraprostatic PNI in 157 patients (65.7%). The PNI rate was 73% (149/204) in pT2b-c vs. 26% (8/35) in pT2a surgical specimens (p < 0.001), and it was 78.5% (73/93) in patients with a Gleason score of 7-10 vs. 57% (84/146) in a Gleason score of 2-6 (p < 0.01). The mean follow-up was 65.4 (median 62, range 24-118) months. Overall, 11/239 (4.6%) patients presented biochemical recurrence after surgery and 7 (63.6%) of these patients showed PNI, but this was not statistically higher than in patients free from progression (150/228, 65.7%). The actuarial biochemical progression-free survival rate for all patients was 96.9 and 93.5% at 60 and 84 months, respectively, and the stratification based on the presence or absence of PNI did not allow us to identify different prognostic groups. CONCLUSIONS: Perineural infiltration frequently takes part in the pathway of extraprostatic extension. In our series, patients with pathological T2 stages and PNI were found to present a higher pT2 stage and Gleason score, even though our early biochemical-free outcome was not significantly higher than in patients without PNI.

Urinary and sexual outcomes in long-term (5+ years) prostate cancer disease free survivors after radical prostatectomy.

BACKGROUND: After long term disease free follow up (FUp) patients reconsider quality of life (QOL) outcomes. Aim of this study is assess QoL in prostate cancer patients who are disease-free at least 5 years after radical prostatectomy (RP). METHODS: 367 patients treated with RP for clinically localized pCa, without biochemical failure (PSA or= 5 years were recruited.Urinary (UF) and Sexual Function (SF), Urinary (UB) and Sexual Bother (SB) were assessed by using UCLA-PCI questionnaire. UF, UB, SF and SB were analyzed according to: treatment timing (age at time of RP, FUp duration, age at time of FUp), tumor characteristics (preoperative PSA, TNM stage, pathological Gleason score), nerve sparing (NS) procedure, and hormonal treatment (HT).We calculated the differences between 93 NS-RP without HT (group A) and 274 non-NS-RP or NS-RP with HT (group B). We evaluated the correlation between function and bother in group A according to follow-up duration. RESULTS: Time since prostatectomy had a negative effect on SF and a positive effect SB (both p < 0.001). Elderly men at follow up experienced worse UF and SF (p = 0.02 and p < 0.001) and better SB (p < 0.001).Higher stage PCa negatively affected UB, SF, and SB (all: p

Prognostic role of histological necrosis for nonmetastatic clear cell renal cell carcinoma: correlation with pathological features and molecular markers.

PURPOSE: We defined the prognostic role of tumor necrosis and its extent in nonmetastatic clear cell renal cell carcinoma. Also, we further investigated its pathogenesis by correlating this tumor feature with other pathological characteristics and molecular markers related to the von Hippel Lindau-hypoxia inducible factor pathway and to tumor proliferation. MATERIALS AND METHODS: A total of 213 patients with nonmetastatic clear cell renal cell carcinoma were evaluated. Mean followup was 66 months. The presence and extent of histological necrosis were correlated with clinicopathological factors, Ki-67 antigen expression calculated by the MIB-1 (Ki-67 antibody) index, pVHL, HIF-1alpha, the tumor infiltrating lymphocyte subset and cancer specific survival. RESULTS: Histological necrosis was present in 63.8% of clear cell renal cell carcinoma cases. Necrosis was significantly associated with grade and the degree of tumor infiltrating lymphocytes, while its extent correlated significantly with grade, the degree of tumor infiltrating lymphocytes and stage. Tumor necrosis was a significant prognostic factor, which was confirmed even when limiting analysis to patients with intracapsular renal cell carcinoma. On multivariate analysis histological necrosis was not an independent predictor of cancer specific survival. The extent of tumor necrosis was not a significant prognostic factor. The presence and extent of histological necrosis was not associated with high Ki-67 expression and it did not correlate with pVHL expression or with nuclear and cytoplasmic HIF-1alpha expression. CONCLUSIONS: Based on our results we cannot support histological necrosis and its extent as prognostic factors for clear cell renal cell carcinoma. Efforts should be made to develop nomograms that use routinely available and objective predictor variables. The precise mechanism that causes tumor necrosis remains unknown but the host immune response might significantly contribute to its development.