Matthias May

Prognostic accuracy of individual uropathologists in noninvasive urinary bladder carcinoma: a multicentre study comparing the 1973 and 2004 World Health Organisation classifications.

BACKGROUND Grading of noninvasive papillary urinary bladder carcinoma (PUC) is routinely performed in clinical oncologic practice; however, reports regarding diagnostic and prognostic accuracy are contradictory. OBJECTIVE To compare the 1973 and 2004 World Health Organisation (WHO) classifications in terms of interobserver variability and prognostic implications. DESIGN, SETTING, AND PARTICIPANTS Two hundred PUC were retrospectively reviewed by four independent expert genitourinary pathologists blinded with respect to patient identity and clinical outcome. Tumour grading was assigned according to the 1973 and 2004 WHO classifications. Surveying a mean postsurgical follow-up of 71.8 mo (range: 18-163 mo), clinical outcome in terms of recurrence-free and progression-free survival was recorded for all patients. INTERVENTION All of the patients underwent transurethral resection of the bladder. MEASUREMENTS The generalised κ (kappa statistic) for interobserver variability was calculated, and Kaplan-Meier analysis as well as univariate regression analysis were performed to evaluate prognostic implications in terms of recurrence and progression rates. RESULTS AND LIMITATIONS During the follow-up, a total of 84 (42%) patients experienced recurrence, whereas another 18 (9%) patients featured disease progression. Owing to the rare presence of papillary urothelial neoplasms of low malignant potential (PUNLMP) in our cohort (0-3.5%), the 2004 WHO classification approached a two-tier system (low and high grade), which showed less interobserver variability than the 1973 classification (κ: 0.30-0.52 vs 0-0.37, respectively). In comparing the power of both classifications to separate indolent from aggressive PUC, striking pathologist-dependent differences became apparent. CONCLUSIONS Both WHO classifications for grading of PUC suffer from substantial interobserver variability, with the 2004 WHO classification showing less interobserver variability. Stark differences in the prognostic power of the individual grading approaches were also found. These significant differences in the individual interpretation of the WHO grading schemes for noninvasive PUC highlight the necessity of better-defined criteria for conventional tumour grading; otherwise, the subdivision into prognostically different groups by conventional histomorphology might remain of limited value.

Prediction of 90-day Mortality After Radical Cystectomy for Bladder Cancer in a Prospective European Multicenter Cohort

BACKGROUND Despite recent improvements, radical cystectomy (RC) is still associated with adverse rates for 90-d mortality. OBJECTIVE To validate the performance of the Isbarn nomogram incorporating age and postoperative tumor characteristics for predicting 90-d RC mortality in a multicenter series and to generate a new nomogram based strictly on preoperative parameters. DESIGN, SETTING, AND PARTICIPANTS Data of 679 bladder cancer (BCa) patients treated with RC at 18 institutions in 2011 were prospectively collected, from which 597 patients were eligible for final analysis. INTERVENTION RC for BCa. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS An established prediction tool, the Isbarn nomogram, was applied to our cohort. For the purpose of external validation, model discrimination was measured using the receiver operating characteristics-derived area under the curve. Calibration plots examined the relationship between predicted and observed probabilities. Univariable and multivariable logistic regression models were fitted to assess the impact of preoperative characteristics on 90-d mortality. RESULTS AND LIMITATIONS The 30-, 60-, and 90-d mortality rates in the development cohort (n=597) were 2.7%, 6.7%, and 9.0%, respectively. The Isbarn nomogram predicted individual 90-d mortality with an accuracy of 68.6%. Our preoperative multivariable model identified age (odds ratio [OR]:1.052), American Society of Anesthesiologists score (OR: 2.274), hospital volume (OR: 0.982), clinically lymphatic metastases (OR: 4.111), and clinically distant metastases (OR: 7.788) (all p<0.05) as independent predictors of 90-d mortality (predictive accuracy: 78.8%). Our conclusions are limited by the lack of an external validation of the preoperative model. CONCLUSIONS The Isbarn nomogram was validated with moderate discrimination. Our newly developed model consisting of preoperative characteristics might outperform existing models. Our model might be particularly suitable for preoperative patient counseling. PATIENT SUMMARY The current report validated an established nomogram predicting 90-d mortality in patients with bladder cancer after radical cystectomy (RC). We developed a new prediction tool consisting of strictly preoperative parameters, thus allowing clinicians an optimal consultation for RC candidates.

Significance of the time period between diagnosis of muscle invasion and radical cystectomy with regard to the prognosis of transitional cell carcinoma of the urothelium in the bladder

Objective: Standard treatment of muscle-infiltrated transitional cell carcinoma (TCC) of the urothelium consists of radical cystectomy. In some cases there is a delay between the initial diagnosis and a definitive treatment being administered. The objective of this study was to determine the effect of the time window between evidence of muscle invasion and radical cystectomy on the pathological stage and progression-free survival. Material and Methods: Between February 1992 and August 2002, 239 radical cystectomies were carried out as a result of TCC of the bladder. In a total of 189 patients (79%), cystectomy was carried out due to muscle-infiltrated TCC with no evidence of distant metastases (≥T2, M0). The time between the diagnosis of muscle invasion and cystectomy was determined for all of these patients, who were then divided into two groups on the basis of a 3-month cut-off period. Univariate and multivariate analyses were used to determine the effect of the time period on clinical factors and progression-free survival. Results: The average age of the patients was 63 (range 35–80) years. A median follow-up of 40 months showed a progression-free survival rate of 49% after 5 years. The average time between the diagnosis of muscle invasion and cystectomy was 1.8 (0.3–12.1) months. For a time window of >3 months, 30/42 patients (72%) showed signs of extravesical tumor growth and/or tumor-positive lymph nodes, compared to 89/147 patients (60%) (p = 0.198) for a time window of ≤3 months. In terms of the distribution of tumor stages according to the time groups, there were significantly more pT4 stage tumors in patients with delayed cystectomy (p = 0.009). Patients with a time interval of ≤3 months between diagnosis of muscle invasion and cystectomy had a significantly better progression-free survival rate (55%) than those with a longer time window (34%) (p = 0.04). In contrast to lymph node status, clinical stage, pathological tumor stage and differentiation level, the prognostic relevance of the time window fell just short of the significance level in Coxs multivariate regression analysis (p = 0.057). Lymph node status (p < 0.001) and pathological tumor stage (p = 0.05) were the only independent prognostic parameters which could be used to predict progression-free survival. Conclusion: Patients with a time window of >3 months between diagnosis of muscle invasion and radical cystectomy were associated with an advanced pathological stage and a poorer progression-free survival. These results underline the need for early cystectomy within the 3-month period between diagnosis of muscle invasion and cystectomy.

Lymph Node Density Affects Cancer-Specific Survival in Patients with Lymph Node–Positive Urothelial Bladder Cancer Following Radical Cystectomy

BACKGROUND The prognosis for patients with lymph node (LN)-positive bladder cancer (BCa) is likely affected by the extent of lymphadenectomy in radical cystectomy (RC) cases. Specifically, the prognostic significance of the LN density (ratio of positive LNs to the total number removed) has been demonstrated. OBJECTIVE To evaluate the prognostic signature of lymphadenectomy variables, including the LN density, for a large, multicentre cohort of RC patients with LN-positive BCa. DESIGN, SETTING, AND PARTICIPANTS The clinical and histopathologic data from 477 patients with LN-positive urothelial BCa (pN1-2) were analysed. The median follow-up period for all living patients was 28 mo. MEASUREMENTS Multivariable Cox regression analysis was used to test the effect of various pelvic lymph node dissection (PLND) variables on cancer-specific survival (CSS) based on colinearity in various models. RESULTS AND LIMITATIONS The median number of LNs removed was 12 (range: 1-66), and the median number of positive LNs was 2 (range: 1-25). Two hundred ninety (60.8%) of the patients presented with stage pN2 disease. The median and mean LN density was 17.6% and 29% (range: 2.3-100), respectively, where 268 (56.2%) and 209 (43.8%) patients exhibited am LN density of ≤20% and >20%, respectively. In separate multivariable Cox regression models adjusted for age, sex, pTN stage, grade, associated Tis, and adjuvant chemotherapy, the interval-scaled LN density (hazard ratio [HR]: 1.01; p=0.002) and the LN density, ordinal-scaled by 20% (HR: 1.65; p<0.001) exhibit independent effects on CSS. In addition, an independent contribution appears from the pT but not the pN stage. Limitations include surgeon selection bias when determining the extent of lymphadenectomy. CONCLUSIONS Our results support the prognostic relevance of LN density in patients with LN-positive BCa, where a threshold value of 20% stratifies the population into two prognostically distinct groups. Before LN density is integrated into the clinical decision-making process, these results should be validated by prospective studies with defined LN templates and standardised histopathologic methods.

Survival rates after radical cystectomy according to tumor stage of bladder carcinoma at first presentation.

Introduction: The aim of this study was to establish to what extent the survival rates of muscle-invasive bladder carcinoma are influenced by the tumor stage at initial presentation. Patients and Methods: This study examined the clinical course of 230 patients who underwent radical cystectomy for bladder carcinoma from 1992 to 2002. The patients were divided into three groups according to the histological results of the initial and final transurethral tumor resection (TURB). In group 1 (n = 41) radical cystectomy was carried out for a superficial bladder carcinoma which had a high likelihood of progressing. Group 2 (n = 57) consisted of patients who displayed a superficial tumor stage when they first presented and developed progressive muscle-invasive bladder carcinoma under conservative treatment. Group 3 (n = 132) was made up of patients who were already at the muscle-invasive tumor stage in the course of primary TURB. The histopathological characteristics of all transurethral tumor resections and radical cystectomy were recorded. Progression-free survival and overall survival in the three groups were then compared. Results: The average patient age when cystectomy was carried out was 63.9 (35–80) years and the average follow-up period was 38 months. An average of 2.3 (1–16) transurethral tumor resections were carried out before radical cystectomy (median = 1). Progression-free survival and overall survival of all 230 patients was 54 and 50%, respectively, after 5 years. The best result was a 74% progression-free 5-year survival rate with organ-confined lymph node-negative tumors (n = 106) which was statistically significant (p = 0.0004) compared to the progression-free 5-year survival rate of 50% for non-organ-confined, lymph node-negative tumors (n = 64). Lymph node-positive patients achieved a progression-free survival rate of 21% after 5 years regardless of the tumor infiltration. Patients in group 1 achieved a progression-free 5-year survival rate of 77% and an overall survival rate of 63% after 5 years. In group 2 patients achieved a progression-free survival rate of 51% after 5 years and an overall survival rate of 50%. In the case of primary muscle invasion (group 3), progression-free survival and overall survival were 49 and 46%, respectively, after 5 years. There was no significant difference between groups 2 and 3 with regard to their progression-free or overall survival rates (p > 0.35). However, both groups displayed a significantly poorer progression-free and overall survival rate compared with group 1 (p < 0.01). Conclusion: Our results show that superficial bladder carcinoma with tumor progress to muscle invasion does not have a better prognosis after radical cystectomy than initial muscle-invasive bladder carcinoma. Survival rates in this group can only be improved by singling out patients on the basis of risk factors at an earlier stage and carrying out a cystectomy.

Predictive capacity of four comorbidity indices estimating perioperative mortality after radical cystectomy for urothelial carcinoma of the bladder

Study Type – Prognosis (case series)

Features associated with recurrence beyond 5 years after nephrectomy and nephron-sparing surgery for renal cell carcinoma: Development and internal validation of a risk model (PRELANE score) to predict late recurrence based on a large multicenter database (CORONA/SATURN Project)

BACKGROUND Approximately 10-20% of recurrences in patients treated with nephrectomy for renal cell carcinoma (RCC) develop beyond 5 yr after surgery (late recurrence). OBJECTIVE To determine features associated with late recurrence. DESIGN, SETTING, AND PARTICIPANTS A total of 5009 patients from a multicenter database comprising 13 107 RCC patients treated surgically had a minimum recurrence-free survival of 60 mo (median follow-up [FU]: 105 mo [range: 78-135]); at last FU, 4699 were disease free (median FU: 103 mo [range: 78-134]), and 310 patients (6.2%) experienced disease recurrence (median FU: 120 mo [range: 93-149]). INTERVENTIONS Patients underwent radical nephrectomy or nephron-sparing surgery. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Multivariable regression analyses identified features associated with late recurrence. Cox regression analyses evaluated the association of features with cancer-specific mortality (CSM). RESULTS AND LIMITATIONS Lymphovascular invasion (LVI) (odds ratio [OR]: 3.07; p<0.001), Fuhrman grade 3-4 (OR: 1.60; p=0.001), and pT stage >pT1 (OR: 2.28; p<0.001) were significantly associated with late recurrence. Based on accordant regression coefficients, these parameters were weighted with point values (LVI: 2 points; Fuhrman grade 3-4: 1 point, pT stage >1: 2 points), and a risk score was developed for the prediction of late recurrences. The calculated values (0 points: late recurrence risk 3.1%; 1-3 points: 8.4%; 4-5 points: 22.1%) resulted in a good-, intermediate- and poor-prognosis group (area under the curve value for the model: 70%; 95% confidence interval, 67-73). Multivariable Cox regression analysis showed LVI (HR: 2.75; p<0.001), pT stage (HR: 1.24; p<0.001), Fuhrman grade (HR: 2.40; p<0.001), age (HR: 1.01; p<0.001), and gender (HR: 0.71; p=0.027) to influence CSM significantly. Limitations are based on the multicenter and retrospective study design. CONCLUSIONS LVI, Fuhrman grade 3/4, and a tumor stage >pT1 are independent predictors of late recurrence after at least 5 yr from surgery in patients with RCC. We developed a risk score that allows for prognostic stratification and individualized aftercare of patients with regard to counseling, follow-up scheduling, and clinical trial design.

External Validation of Postoperative Nomograms for Prediction of All-Cause Mortality, Cancer-Specific Mortality, and Recurrence in Patients With Urothelial Carcinoma of the Bladder

BACKGROUND The Bladder Cancer Research Consortium (BCRC) created nomograms to predict all-cause mortality (ACM), cancer-specific mortality (CSM), and recurrence after radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB). OBJECTIVE To perform a formal validation of the BCRC nomograms in a large multi-institutional patient cohort from Europe. DESIGN, SETTING, AND PARTICIPANTS Records of 2501 patients who underwent RC for UCB at eight European centers were reviewed. Complete information for external validation was available in 2404 patients for the ACM and CSM nomograms and in 2243 patients for the recurrence nomogram. MEASUREMENTS For the purpose of external validation, model discrimination was measured using the receiver operating characteristics derived area under the curve. Calibration plots examined the relationship between predicted and observed probabilities at 2 yr, 5 yr, and 8 yr. Decision curve analyses were applied to assess the net benefit derived from the three models. RESULTS AND LIMITATIONS The discrimination accuracies of the BCRC nomograms for ACM and CSM at 2 yr, 5 yr, and 8 yr after RC were 71.0%, 69.1%, and 68.2%, and 74.9%, 73.1%, and 72.4%, respectively. The accuracy of discrimination for the recurrence nomogram at the same time points was 76.5%, 75.3%, and 74.9%, respectively. Calibration plots revealed slight underestimations from ideal predictions. Decision curve analyses showed an increased net benefit for the use of the BCRC nomograms in this cohort. Limitations include the retrospective study design, potential surgeon bias, and lack of a central pathologic review. CONCLUSIONS The ACM, CSM, and recurrence nomograms showed acceptable predictive accuracies and could thus be adopted into clinical practice in UCB patients treated in Europe.

Analysis of sex differences in cancer-specific survival and perioperative mortality following radical cystectomy: results of a large German multicenter study of nearly 2500 patients with urothelial carcinoma of the bladder.

BACKGROUND Outcome of patients with urothelial carcinoma of the bladder (UCB) varies between sexes. Although overall incidence is higher in men, cancer-specific survival (CSS) has been suggested to be lower in women. Although the former effect is attributed to greater exposure to carcinogens in men, the latter has not been elucidated. OBJECTIVES The aim of the study was to identify sex-specific outcomes based on one of the largest databases of patients with UCB who underwent radical cystectomy (RC). METHODS This retrospective multicenter series comprised 2483 patients in Stage M0 who underwent RC for UCB from 1989 to 2008; 20.4% of patients were women. The impact of sex on CSS in the entire study group and in specific subgroups was analyzed. The median follow-up time was 42 months (interquartile range, 21-79). RESULTS Histopathologic criteria of pathologic tumor (pT), pathologic nodal (pN), grade, lymphovascular invasion (LVI), and associated carcinoma in situ (CIS) of the study did not differ between sexes. The percentage of female patients increased over time. Five-year CSS in female patients was significantly lower than in male patients (60% vs 66%; P = 0.005). In multivariate analysis adjusted to other covariates, tumor stage ≥pT3 (hazard ratio [HR] = 2.44; P < 0.001), positive pN status (HR = 1.91; P < 0.001), LVI (HR = 1.48; P < 0.001), lower count of lymph nodes removed (HR = 0.98; P = 0.002), older age (HR = 1.01; P < 0.001), and female gender (HR = 1.26; P = 0.011) had an independent impact on CSS. Deterioration of CSS in female patients was pronounced when LVI was present (HR = 1.57; P < 0.001) and when RC was performed in the earlier time period (HR = 2.44; P < 0.001). However, women showed significantly lower perioperative mortality (within 90 days after RC) compared with men. CONCLUSIONS After RC for UCB, cancer-specific mortality was higher in female patients; this disadvantage was more pronounced in earlier time periods. In addition, worse outcome of women with verified LVI was shown to be comparable with men. These findings were suggestive of different tumor biology and potentially unequal access to timely RC in earlier time periods because of reduced awareness of UCB in women. Further studies are required to improve UCB outcome in both sexes, notably in female patients.

Prognostic impact of lymphovascular invasion in radical prostatectomy specimens

To estimate the prognostic value of lymphovascular invasion (LVI) in patients with node‐negative prostate cancer treated by radical prostatectomy (RP).