Updated pathology reporting standards for bladder cancer: biopsies, transurethral resections and radical cystectomies.

AIM: Optimal management of bladder cancer requires an accurate, standardised and timely pathological diagnosis, and close communication between surgeons and pathologists. Here, we provide an update on pathology reporting standards of transurethral resections of the bladder and cystectomies. METHODS: We reviewed recent literature, focusing on developments between 2013 and 2021. RESULTS: Published reporting standards developed by pathology organizations have improved diagnosis and treatment. Tumor sub-staging and subtyping has gained increased attention. Lymph nodes continue to be an area of debate, and their staging has seen minor modifications. Several tasks, particularly regarding specimen preparation ("grossing"), are not yet standardized and offer opportunity for improvement. Molecular classification is rapidly evolving, but currently has only limited impact on management. CONCLUSION: Pathological reporting of bladder cancer is continuously evolving and remains challenging in some areas. This review provides an overview of recent major developments, with a particular focus on published reporting standards.

Cardiovascular Disease in Testicular Cancer Survivors: Identification of Risk Factors and Impact on Quality of Life.

PURPOSE: Testicular cancer (TC) treatment is clearly associated with cardiovascular morbidity and mortality. To enable development of preventive strategies for cardiovascular disease (CVD), we assessed cardiometabolic risk factors and quality of life (QoL) in TC survivors. METHODS: Incidence of coronary artery disease, myocardial infarction, and heart failure after TC treatment was assessed in a multicenter cohort comprising 4,748 patients treated at the age of 12-50 years between 1976 and 2007. Patients who had developed CVD and a random sample from the cohort (subcohort) received a questionnaire on cardiometabolic risk factors and QoL. A subgroup of responders in the subcohort additionally underwent clinical evaluation of cardiovascular risk factors. RESULTS: After a median follow-up of 16 years, 272 patients had developed CVD. Compared with orchidectomy only, cisplatin combination chemotherapy was associated with an increased CVD risk (hazard ratio [HR], 1.9; 95% CI, 1.1 to 3.1). Patients who were obese or a smoker at diagnosis (HR, 4.6; 95% CI, 2.0 to 10.0 and HR, 1.7; 95% CI, 1.1 to 2.4, respectively), developed Raynaud's phenomenon (HR, 1.9; 95% CI, 1.1 to 3.6) or dyslipidemia (HR, 2.8; 95% CI, 1.6 to 4.7) or had a positive family history for CVD (HR, 2.9; 95% CI, 1.7 to 4.9) had higher CVD risk. More TC survivors with CVD reported inferior QoL on physical domains than survivors who did not develop CVD. Of 304 TC survivors who underwent clinical evaluation for cardiovascular risk factors (median age at assessment: 51 years), 86% had dyslipidemia, 50% had hypertension, and 35% had metabolic syndrome, irrespective of treatment. CONCLUSION: Cardiovascular events in TC survivors impair QoL. Many TC survivors have undetected cardiovascular risk factors. We advocate early lifestyle adjustments and lifelong follow-up with low-threshold treatment of cardiovascular risk factors, especially in obese and smoking patients treated with platinum-based chemotherapy.

Clinical epidemiology of nonurothelial bladder cancer: analysis of the Netherlands Cancer Registry.

PURPOSE: Nonurothelial malignancies represent a small fraction of bladder malignancies and are less extensively studied, resulting in sparse empirical data on these tumors. We sought insight into tumor characteristics and survival. MATERIALS AND METHODS: Data were obtained from the nationwide Netherlands Cancer Registry on patient and tumor characteristics, and followup in all patients with primary invasive (T1 or greater) bladder tumors in The Netherlands between 1995 and 2006. Data were analyzed using frequency tables. Relative survival analysis was done. RESULTS: We identified 28,807 patients with invasive bladder cancer, of whom 7.7% presented with nonurothelial carcinoma. Mean patient age range at diagnosis of adenocarcinoma and soft tissue tumors was 66.4 years, and 78.3 years at diagnosis of nonspecified tumors. Most histological subtypes were more common in males except squamous cell carcinoma and lymphoma. Muscle invasion was seen in 52.2% of urothelial carcinoma cases vs 87.5%, 71.9% and 89.0% of squamous cell carcinoma, adenocarcinoma and neuroendocrine tumor cases, respectively. For urothelial carcinoma, squamous cell carcinoma and adenocarcinoma women presented at more advanced stage. In the neuroendocrine group this stage difference was the opposite. Survival analysis showed a 5-year relative survival rate of 32.2%, 22.9%, 31.8% and 21.1% for T2 or greater urothelial carcinoma, squamous cell carcinoma, adenocarcinoma and neuroendocrine tumors, respectively. CONCLUSIONS: Patients with nonurothelial carcinoma present at more advanced stage and overall have worse survival. Relative survival of muscle invasive adenocarcinoma equals survival of muscle invasive urothelial carcinoma. For stage II and III disease these cases do even better. Muscle invasive squamous cell carcinoma and neuroendocrine tumors show worse survival regardless of stage.

Screening for prostate cancer in Dutch hereditary prostate cancer families.

It is common belief that in families with hereditary prostate cancer (HPC), unaffected men should be screened periodically with PSA, but little is known about the effects of such screening. We studied test and tumor characteristics in unaffected 50-75-year-old screenees from HPC families. In the Netherlands, 153 verified HPC families are registered; 132 unaffected men in these families were not under surveillance for prostate cancer and gave informed consent for PSA testing by their GP and referral to a urologist in the case of a PSA level >or= 3.0 ng/ml. Results were compared to published data from the Rotterdam and Göteborg sections of the European Randomized Study of Screening for Prostate Cancer (ERSPC). A PSA >or= 3.0 ng/ml was found in 20 men: referral rate, 15.1% (ERSPC Rotterdam: 20.1%; ERSPC Göteborg: 12.0%). Only 3 cases of prostate cancer were diagnosed in these men: detection rate in the first screening round 2.3% (ERSPC Rotterdam: 5.3%; ERSPC Göteborg: 2.3%). Frequent opportunistic PSA testing made it impossible to estimate the detection rates in subsequent screening rounds. In the first and subsequent PSA screening rounds, 11 cases of cancer were detected. All but 1 had favorable tumor characteristics (cT1c/pT2; Gleason < 7). These results raise the question as to whether men from all HPC families should be considered at high-risk. We suggest that the same PSA testing guidelines should apply to HPC families and the general population. A more aggressive screening policy in HPC families does not seem to be justified.

Components of the plasminogen activator system and their complexes in renal cell and bladder cancer: comparison between normal and matched cancerous tissues.

OBJECTIVE: To analyse and compare the concentration of plasminogen activator (PA), urokinase-type PA (uPA), tissue-type PA (tPA), PA inhibitor (PAI)-1 and PAI-2, and the complexes uPA-PAI-1 and tPA-PAI-1 and calculated uPA and tPA uncomplexed with PAI-1 ('free') in urothelial cell carcinoma and matched benign urothelium, and in renal cell carcinoma (RCC) and matched benign renal tissue. PATIENTS AND METHODS: Tissue samples were obtained during cystectomy (33 patients) and nephrectomy (55), and specific enzyme-linked immunosorbent assays were used to assess the PA components in extracts of these tissues. RESULTS: Tissue levels of uPA-PAI-1 and tPA-PAI-1, but also PAI-1 itself, were greater in tumorous bladder and kidney tissue than in matched normal tissue (by 1.5-7.8 times). Free tPA was clearly lower in tumour tissue (by 0-0.12-fold). In bladder cancer, but not in RCC, levels of uPA (15.8-fold) and free uPA (16.4-fold) were greater in tumour tissue. Free uPA levels were less in RCC (0.41-fold). For both normal bladder and kidney tissue, there was no clear correlation between uPA-PAI-1 complex and either component. However, the formation of tPA-PAI-1 complexes in normal bladder and kidney tissue was primarily determined by PAI-1. Interestingly, in tumour tissues there was a strong, significant correlation between complex levels and both components. CONCLUSION: RCC and bladder cancer show distinct profiles of components of the PA system. This study provides a basis for further studies into both the (patho)physiological role of the PA system in these tumours, and into a possible relation with tumour progression and prognosis, and as target for therapy.

Risk of Solid Cancer After Treatment of Testicular Germ Cell Cancer in the Platinum Era.

Purpose Testicular cancer (TC) treatment increases risk of subsequent malignant neoplasms (SMNs). It is unknown whether changes in TC treatment over time have affected SMN risk. Methods Solid SMN risk was evaluated in a multicenter cohort comprising 5,848 1-year survivors treated for TC before age 50 years between 1976 and 2007. SMN incidence was compared with cancer incidence in the general population. Treatment-specific risks were assessed using multivariable regression in a case-cohort design. Results After a median follow-up of 14.1 years, 350 solid SMNs were observed, translating into a 1.8-fold (95% CI, 1.6-2.0) increased risk compared with general population rates. Solid SMN risk was increased in patients with seminoma and those with nonseminoma (standardized incidence ratio, 1.52 and 2.21, respectively). Patients with nonseminoma experienced increased risk of SMNs of the thyroid, lung, stomach, pancreas, colon, and bladder and of melanoma and soft tissue sarcoma, whereas those with seminoma experienced increased risk of SMNs of the small intestine, pancreas, and urinary bladder. The 25-year cumulative incidence of solid SMNs was 10.3% (95% CI, 9.0% to 11.6%). In multivariable analysis, platinum-based chemotherapy was associated with increased risk of a solid SMN (hazard ratio [HR], 2.40; 95% CI, 1.58 to 3.62), colorectal SMN (HR, 3.85; 95% CI, 1.67 to 8.92), and noncolorectal GI SMN (HR, 5.00; 95% CI, 2.28 to 10.95). Receipt of platinum 400 to 499 and ≥ 500 mg/m2 increased solid SMN risk compared with surgery only (HR, 2.43; 95% CI, 1.40 to 4.23 and HR, 2.42; 95% CI, 1.50 to 3.90, respectively), whereas risk was not significantly increased with lower doses (HR, 1.75; 95% CI, 0.90 to 3.43). The HR of a GI SMN increased by 53% (95% CI, 26% to 80%) per 100 mg/m2 of platinum-containing chemotherapy. The HR of an infradiaphragmatic SMN increased by 8% per Gray of radiation dose administered (95% CI, 6% to 9%; P < .001). Conclusion Radiotherapy and platinum-containing chemotherapy are associated with increased solid SMN risk, specifically with GI SMNs.

Radiofrequency-induced thermo-chemotherapy effect (RITE) for non muscle invasive bladder cancer treatment: current role and perspectives.

OBJECTIVE: An updated review of intravesical radiofrequency (RF)-induced thermo-chemotherapy effect (RITE) for NMIBC with regard to efficacy, adverse events (AEs) and perspectives. EVIDENCE ACQUISITION: An extensive and sensitive search for RF-induced chemo-hyperthermia in Medline, Embase, Cochrane and ClinicalTrials.gov databases was performed. A table of published clinical trials up to 2016 was constructed. No meta-analysis could be performed on the basis of new papers. EVIDENCE SYNTHESIS: Recurrence was seen 59% less after RITE than after mitomycin C (MMC) alone in adjuvant clinical setting with an overall bladder preservation rate after RITE of 85%. The efficacy was proved to be comparable to that of Bacillus Calmette-Guèrin (BCG), based on a single comparative multicentric study. Due to short follow-up, no conclusions can be drawn about time to recurrence and progression. The AE rate in RITE was higher, although not statistically significant, than MMC alone and similar to that of BCG, albeit different in the type of AE. In almost all studies, no severe AEs are reported. CONCLUSIONS: RITE appears as a promising treatment option for NMIBC, particularly for high-risk patients with recurrent tumors, for those unsuitable for radical cystectomy and when Bacillus Calmette-Guèrin treatment is contraindicated. Further high-level evidence is needed for both reliable and reproducible data on efficacy and adverse events.

Gene expression test for the non-invasive diagnosis of bladder cancer: A prospective, blinded, international and multicenter validation study.

OBJECTIVE: This study aimed to validate, in a prospective, blinded, international and multicenter cohort, our previously reported four non-invasive tests for bladder cancer (BC) diagnosis based on the gene expression patterns of urine. METHODS: Consecutive voided urine samples from BC patients and controls were prospectively collected in five European centres (n=789). Finally, 525 samples were successfully analysed. Gene expression values were quantified using TaqMan Arrays and previously reported diagnostic algorithms were applied to gene expression data. Results from the most accurate gene signature for BC diagnosis were associated with clinical parameters using analysis of variance test. RESULTS: High diagnostic accuracy for the four gene signatures was found in the independent validation set (area under curve [AUC]=0.903-0.918), with the signature composed of two genes (GS_D2) having the best performance (sensitivity: 81.48%; specificity: 91.26%; AUC: 0.918). The diagnostic accuracy of GS_D2 was not affected by the number of tumours (p=0.58) but was statistically associated with tumour size (p=0.008). Also, GS_D2 diagnostic accuracy increases with increasing BC tumour risk. We found no differences in the performance of the GS_D2 test among the populations and centres in detecting tumours (p=0.7) and controls (p=0.2). CONCLUSIONS: Our GS_D2 test is non-invasive, non-observer dependent and non-labour-intensive, and has demonstrated diagnostic accuracy in an independent, international and multicenter study, equal or superior to the current gold standard (cystoscopy combined with cytology). Additionally, it has higher sensitivity than cytology while maintaining its specificity. Consequently, it meets the requirements for consideration as a molecular test applicable to clinical practice in the management of BC.

Brachytherapy versus cystectomy in solitary bladder cancer: a case control, multicentre, East-Netherlands study.

PURPOSE: Comparing the outcome of surgery and brachytherapy-based radiotherapy in patients with solitary T1G3/T2 bladder tumour in, a retrospective case-control study, because efforts for a randomised clinical trial comparing these modalities have failed. MATERIALS AND METHODS: Cystectomy group. Patients were selected using the pathological registration system (PALGA). 289 cases of TURT followed by cystectomy, indicated by a muscle--invading bladder tumour were performed in three East-Netherlands medical centres between 1991 and 2001. Out of this group 179 patients with clinical T2N0M0 bladder tumour were selected. All the consecutive files were analysed by a urologist and a radiation oncologist and 65 of those patients (mean age 63.7 years) would have been eligible for brachytherapy, based on an initial analysis: cystoscopy estimated tumour size, post-TURT pathological report, completed by CT-scan and/or, MRI-scan. A final pathological report after radical cystectomy was not considered for patients' selection. Brachytherapy group. Patients were selected using a prospective registration study aiming at determination of our treatment results. 89 Patients (mean age 68.4 years) underwent TURT followed by a course of external beam irradiation and interstitial brachytherapy from 1983 till 2005 in the Arnhem Radiotherapy Institute. RESULTS: The median follow-up for the brachytherapy group was 5.7 years (range 0.2-21.4 years), for the cystectomy group was 5.05 years (range: 0.04-16.8 years). No difference in disease-specific survival (DSS) could be detected with a 5- and 10-year DSS of 71% and 66% in the brachytherapy group and 60% and 57% in the cystectomy group, respectively. Five-year overall survival (OS) was 57% in the brachytherapy group and 52% in the cystectomy group, however, the 10-year OS was better in the cystectomy than in the brachytherapy group (42% and 33%, respectively). This is caused by the significant age difference in favour of the cystectomy group. Cystectomy-free survival in the brachytherapy group was 70%. CONCLUSION: Radical cystectomy is the treatment of choice for patients with muscle-invasive bladder carcinoma. However, in a selected patient population a bladder sparing treatment, i.e. a combination of transurethral tumour resection (TURT), external beam irradiation and interstitial brachytherapy, can be applied successfully. This concerns a solitary, T1G3 or T2 bladder tumour, with a diameter<5 cm.

Management of BCG failures in superficial bladder cancer: a review.

OBJECTIVE: Review management of bacillus Calmette-Guérin (BCG) failures in superficial bladder cancer. METHOD: Search of published literature and meeting abstracts. RESULTS: Patients in whom BCG fails are not a uniform group. Failure cannot be predicted but high-risk patients can be identified. In case of failure and progression the outcome is bad. Conservative but investigative alternatives are BCG/interferon-alpha, intravesical hyperthermia/chemotherapy, or photodynamic therapy. Standard treatment in failing patients remains cystoprostatectomy. CONCLUSION: BCG failures need careful and individualized therapy in experienced hands.