David D'Andrea

Characteristics and clinical significance of histological variants of bladder cancer.

In the past 10 years evidence for the clinical relevance of variant histology in urinary bladder cancer has been increasing. This increase has resulted in new classifications of urothelial cancers by the WHO in 2016, highlighting the importance of an accurate morphological description of pathological specimens for the therapeutic management of patients with bladder cancer. The rising awareness of the importance of an accurate pathological report manifests itself in the increasing prevalence of reporting of variant histology in daily practice. Histological variants can generally be divided into urothelial and nonurothelial. Urothelial variants often have similar features that also have specific morphological phenotypes, whereas nonurothelial variants have independent features. Overall, histological variants follow a more aggressive clinical course than conventional urothelial carcinoma, but conclusive data on their effect on survival are currently lacking. The clinical relevance of variant histology can manifest at three different levels: diagnostic, as identification is challenging and misinterpretation is not uncommon; prognostic, for patient risk stratification and outcome estimation; and therapeutic, as particular variants could be responsive to specific treatment strategies. An accurate morphological description of histological variants is necessary for patient consultation and therapy planning. Moreover, the association of variant histology with specific mutation patterns promises to be helpful in discovering targeted therapeutic approaches based on specific molecular pathways.

Prognostic Role of Neutrophil-to-Lymphocyte Ratio in Primary Non–muscle-invasive Bladder Cancer

Micro‐Abstract The neutrophil‐to‐lymphocyte ratio is associated with poor outcomes in patients with muscle‐invasive bladder cancer. We found that the neutrophil‐to‐lymphocyte ratio is independently associated with disease recurrence and progression in patients with non–muscle‐invasive bladder cancer. Introduction: The purpose of this study was to assess the role of pretreatment neutrophil‐to‐lymphocyte ratio (NLR) as a predictor of clinical outcomes in patients treated with transurethral resection (TURB) for primary non–muscle‐invasive bladder cancer (NMIBC). Patients and Methods: Data from 918 patients treated with TURB for primary NMIBC were retrospectively collected. NLR was evaluated as binary variable with the cut‐point of 3 based on the visual best correlation of the receiver operating curve analyses focusing on disease recurrence. The median follow‐up was 62 months. Cox regression analyses were used to evaluate associations with recurrence (RFS) and progression‐free survival (PFS). Subgroup analyses were done according to risk groups and receipt of intravesical bacillus Calmette‐Guérin therapy. Results: Overall, 293 patients had a NLR ≥ 3. High NLR was associated with pathologic T stage and smoking status. The 5‐year RFS and PFS for NLR < 3 and NLR ≥ 3 were, respectively, 55.5% versus 45.9% (P = .01) and 94.9% versus 89.9% (P = .004). On multivariable analyses, NLR ≥ 3 remained significantly associated with RFS and PFS. The addition of NLR increased the discrimination of a multivariable model by 0.6% and 2.3% for RFS and PFS, respectively. Moreover, NLR showed a trend in the association with outcomes in patients treated with intravesical bacillus Calmette‐Guérin therapy. Conclusions: Integration of NLR in a prediction model could be helpful in predicting RFS and PFS in patients with primary NMIBC and identifying those who are likely to fail therapy and may benefit from an early radical cystectomy. Limitations are associated to the retrospective design.

Lymphocyte-to-monocyte ratio and neutrophil-to-lymphocyte ratio as biomarkers for predicting lymph node metastasis and survival in patients treated with radical cystectomy.

To evaluate the role of lymphocyte‐to‐monocyte ratio (LMR) and neutrophil‐to‐lymphocyte ratio (NLR) as pre‐operative markers for predicting extravesical disease and survival outcomes in patients undergoing radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB).

Pure but Not Mixed Histologic Variants Are Associated With Poor Survival at Radical Cystectomy in Bladder Cancer Patients

Purpose To evaluate the impact of pure and mixed histologic variant versus pure urothelial carcinoma in nonmetastatic bladder cancer (BCa) patients treated with radical cystectomy (RC). Patients and Methods We evaluated data from 1067 patients treated with RC and pelvic lymph node dissection between 1990 and 2013 at a single institution tertiary‐care referral center. All specimens were evaluated by dedicated uropathologists. Univariable and multivariable Cox regression analyses tested the impact of the presence of pure and mixed histologic variants versus pure urothelial on recurrence, cancer‐specific mortality, and overall mortality after accounting for all available confounders. Results In total, 201 (19%) and 137 (13%) patients were found with mixed and pure variants at RC, respectively. Mixed preponderant variants were sarcomatoid, lymphoepitelial, squamous, and glandular; small‐cell and micropapillary variants were found mostly as pure variants. With a median follow‐up of 6.5 years, patients who harbored pure variant were found by multivariable analyses to have lower survival outcomes compared to pure urothelial carcinoma (all P < .01). Conversely, no differences were found between mixed variant versus pure urothelial by multivariable Cox regression analyses predicting recurrence, cancer‐specific mortality, and overall mortality (all P > .1). Conclusion The presence of histologic variants at RC is a common finding, accounting for approximately 30% of specimens. In this setting, the presence of a pure variant but not the presence of mixed variant with urothelial carcinoma is related to a detrimental effect on survival outcomes after RC. Micro‐Abstract The importance of a correct histologic variant classification in the decision making of bladder cancer patients have been recently highlighted by the new World Health Organization classification of the urothelial tract. Histologic variants at the time of radical cystectomy is a common finding, accounting for almost 30% of specimens, yet only pure histologic variants but not mixed histologic variants are associated with worse survival compared to pure urothelial cancer. Physicians should consider this parameter when counseling surgical patients.

Impact of Intra- and Postoperative Blood Transfusion on the Incidence, Timing, and Pattern of Disease Recurrence After Radical Cystectomy

Background The administration of blood transfusion (BT) has been associated with a decrease in survival expectancies in patients treated with radical cystectomy (RC), as a consequence of the immunosuppressive effect mediated by BT. We sought therefore to evaluate if the usage of BT may influence the risk and pattern location of distant recurrences after RC, which may be influenced by this effect. Methods Data from 2 independent cohorts of consecutive patients with bladder cancer treated with RC were analyzed. Distant recurrence included all recurrence locations outside of the true pelvis, such as lung, liver, bone, extra pelvic lymph nodes, peritoneal, or brain recurrences. Cox regression analyses evaluating the risk of developing distant recurrence after RC were built. Results In the testing cohort, composed of 1081 patients, 41.2% received a perioperative BT. Within a median follow‐up of 52 months (interquartile range, 44‐61 months), 277 (25.6%) patients experienced a distant recurrence. In the validation cohort, composed of 433 patients, 42.3% received perioperative BT within a median follow‐up of 83 months, and 127 (28.3%) patients experienced distant recurrence. On multivariable analyses predicting distant recurrences, BT was not associated with the risk of distant recurrence stratified by location and time (within first year or later after RC; all P ≥ .2) in both cohorts. Conclusions BT administration was not associated with a different pattern, timing, or rate of distant recurrences in patients when compared with those who did not receive BT. New data are needed to investigate the mechanisms behind the association between BT and survival in RC patients. Micro‐Abstract Blood transfusion (BT) has been found to be related to worse survival outcomes in patients treated with many major urologic and nonurologic surgeries. The immunosuppressive effect of BT was advocated to explain this effect. We evaluated here the pattern and incidence of recurrence after radical cystectomy (RC), stratifying according to BT. We found that no difference in pattern and incidence in recurrence after RC was evident for patients with BT when compared with those who did not receive BT. New high quality data are required to explain the association between BT and survival in RC patients described in previous literature.

Prognostic Role of N-cadherin Expression in Patients With Invasive Bladder Cancer

Background We assessed the role of N‐cadherin as a prognostic biomarker in patients with invasive bladder cancer (BCa) who had undergone radical cystectomy (RC). Patients and Methods The present retrospective single‐center study included 433 BCa patients who had undergone RC and bilateral lymph node dissection. Formalin‐fixed paraffin tissue microarrays were stained with an anti–N‐cadherin monoclonal mouse antibody. N‐cadherin expression was considered positive if any immunoreactivity was detected. Multivariable Cox regression models were created to evaluate the prognostic effect of N‐cadherin on survival. Results N‐cadherin expression was observed in 189 patients (43.7%). It was associated with advanced pathologic stage (P = .001) and lymph node metastasis (P < .001). During a median follow‐up period of 10.6 years, N‐cadherin expression was associated with worse recurrence‐free survival, overall survival, and cancer‐specific survival (P < .001, P = .001, and P < .001, respectively). On multivariable analysis adjusted for the effects of standard clinicopathologic features, N‐cadherin expression retained its association with worse recurrence‐free survival (hazard ratio, 1.41; 95% confidence interval, 1.02‐1.92; P = .032) but not cancer‐specific survival (P = .07) and overall survival (P = .3). Conclusion N‐cadherin was expressed in approximately 40% of patients with invasive BCa. Its expression was associated with features of biologically and pathologically adverse disease and worse recurrence‐free survival. N‐cadherin could be a part of a marker panel to help clinical decision‐making and therapy for BCa. Micro‐Abstract We assessed the expression of N‐cadherin (a cell–cell adhesion molecule) in 433 bladder cancer patients who had undergone radical cystectomy and pelvic lymph node dissection. We found that N‐cadherin is expressed in ˜40% of patients, and it was associated with features of aggressive disease and worse recurrence‐free survival.

A systematic review and meta-analysis of lymphovascular invasion in patients treated with radical cystectomy for bladder cancer

PURPOSE Lymphovascular invasion (LVI) is an important step in bladder cancer cell dissemination. We aimed to perform a systematic review and meta-analysis of the literature to assess the prognostic value of LVI in radical cystectomy (RC) specimens. PATIENTS AND METHODS A systematic review and meta-analysis of the last 10 years was performed using the MEDLINE, EMBASE, and the Cochrane libraries in July 2017. The analyses were performed in accordance with the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement. RESULTS We retrieved 65 studies (including 78,107 patients) evaluating the effect of LVI on oncologic outcomes in patients treated with RC. LVI was reported in 35.4% of patients. LVI was associated with disease recurrence (pooled hazard ratio [HR] = 1.57; 95% CI: 1.45-1.70) and cancer-specific mortality (CSM) (pooled HR = 1.59; 95% CI: 1.48-1.73) in all studies regardless of tumor stage and node status (pT1-4 pN0-2). LVI was associated with recurrence and CSM in patients with node-negative bladder cancer (BC). In patients with node-negative BC, LVI rate increased and was associated with worse oncologic outcome. LVI had a lower but still significant association with disease recurrence and CSM in node-positive BC. CONCLUSIONS LVI is a strong prognostic factor of worse prognosis in patients treated with RC for bladder cancer. This association is strongest in node-negative BC, but it is also in node-positive BC. LVI should be part of all pathological reporting and could provide additional information for treatment-decision making regarding adjuvant therapy after RC.

Surgical checklist impact on recurrence-free survival of patients with non-muscle-invasive bladder cancer undergoing transurethral resection of bladder tumour

To evaluate the impact of an eight‐item surgical checklist (SC) on the recurrence‐free survival (RFS) of patients with non‐muscle‐invasive bladder cancer (NMIBC) undergoing transurethral resection of bladder tumour (TURBT).

A systematic review and meta-analysis of the impact of lymphovascular invasion in bladder cancer transurethral resection specimens

The aim of the present review was to assess the prognostic impact of lymphovascular invasion (LVI) in transurethral resection (TUR) of bladder cancer (BCa) specimens on clinical outcomes. A systematic review and meta‐analysis of the available literature from the past 10 years was performed using MEDLINE, EMBASE and Cochrane library in August 2017. The protocol for this systematic review was registered on PROSPERO (Central Registration Depository: CRD42018084876) and is available in full on the University of York website. Overall, 33 studies (including 6194 patients) evaluating the presence of LVI at TUR were retrieved. LVI was detected in 17.3% of TUR specimens. In 19 studies, including 2941 patients with ≤cT1 stage only, LVI was detected in 15% of specimens. In patients with ≤cT1 stage, LVI at TUR of the bladder tumour (TURBT) was a significant prognostic factor for disease recurrence (pooled hazard ratio [HR] 1.97, 95% CI: 1.47–2.62) and progression (pooled HR 2.95, 95% CI: 2.11–4.13), without heterogeneity (I2 = 0.0%, P = 0.84 and I2 = 0.0%, P = 0.93, respectively). For patients with cT1–2 disease, LVI was significantly associated with upstaging at time of radical cystectomy (pooled odds ratio 2.39, 95% CI: 1.45–3.96), with heterogeneity among studies (I2 = 53.6%, P = 0.044). LVI at TURBT is a robust prognostic factor of disease recurrence and progression in non‐muscle invasive BCa. Furthermore, LVI has a strong impact on upstaging in patients with organ‐confined disease. The assessment of LVI should be standardized, reported, and considered for inclusion in the TNM classification system, helping clinicians in decision‐making and patient counselling.

Oncologic Effect of Cumulative Smoking Exposure in Patients Treated With Salvage Radical Prostatectomy for Radiation-recurrent Prostate Cancer

&NA; Smoking is associated with prostate cancer mortality and disease progression after treatment for clinically nonmetastatic prostate cancer with curative intent. We investigated the effect of smoking on biochemical recurrence and metastasis in a retrospective cohort of 214 radiation‐recurrent prostate cancer patients who underwent salvage radical prostatectomy. High cumulative smoking exposure was associated with the biologic and clinical aggressiveness of prostate cancer and was an independent predictor of biochemical recurrence after adjusting for established clinicopathologic features. These data support the body of evidence that smoking is detrimental beyond the initial diagnosis of prostate cancer, even when the disease is more advanced. Introduction: The purpose of the present study was to investigate the association of smoking with biochemical recurrence (BCR) and metastasis in radiation‐recurrent prostate cancer (PCa) patients undergoing salvage radical prostatectomy (SRP). Patients and Methods: A total of 214 patients treated with SRP for radiation‐recurrent PCa in 5 tertiary referral centers were included from January 2007 to December 2015. Kaplan‐Meier analyses were used to assess the time to BCR and metastasis. Pre‐ and postoperative multivariable Cox proportional hazard regression models were fitted. Results: Overall, 120 (56.1%), 49 (22.9%), and 45 (21%) patients were never, former, and current smokers, respectively. Low‐, medium‐, and high‐cumulative smoking exposure was registered in 59.8%, 16.4%, and 23.8% of cases, respectively. Patients with high cumulative smoking exposure had a significantly greater rate of a pathologic Gleason score of ≥ 8 (P = .01) and extracapsular extension (P = .004). Smoking status, cumulative smoking exposure, intensity, and duration were significantly associated with BCR‐free survival (P < .001 for all). Smoking status, cumulative smoking exposure, and smoking intensity were significantly associated with metastasis‐free survival (P = .03 for all). High cumulative smoking exposure was independently associated with BCR in both pre‐ (hazard ratio, 2.23; P = .001) and postoperative (hazard ratio, 1.64; P = .04) multivariable models adjusted for the effects of established clinicopathologic features. Smoking cessation did not affect either BCR‐ or metastasis‐free survival (P = .56 and P = .40, respectively). Conclusion: High cumulative smoking exposure was associated with the biologic and clinical aggressiveness of PCa in patients treated with SRP for radiation‐recurrent disease. Smoking is a modifiable risk factor that detrimentally affected the outcomes, even in patients with advanced PCa.