The Accuracy of Sequential Urethral Frozen Section and its Impact on Urethral Recurrence After Radical Cystectomy.

OBJECTIVE: To assess the accuracy of frozen section analysis (FSA) for detecting and eliminating malignant urethral margins during radical cystectomy (RC) for bladder cancer (BC) and its impact on urethral recurrence. METHODS: Urethral margins were initially examined by FSA in 217 patients at RC. When positive, additional resections were performed. Subsequently, all specimens were re-examined on formalin-fixed, paraffin-embedded sections (FFPE). Malignancy was defined as either the presence of carcinoma in situ, high-grade or invasive tumor cells at the urethral margin. Kaplan-Meier analysis was used to assess the impact of the final urethral margin status on urethral recurrence. Multinomial logistic regression addressed independent risk factors for a positive final urethral margin. RESULTS: At initial examination, urethral margins were positive on FSA and FFPE in 21 (9.7%) and 17 (7.8) patients, respectively. The corresponding sensitivity, specificity, positive and negative predictive values were 88.2%, 97.0%, 71.4% and 99.0% (overall accuracy: 96.3%). After initial FSA, 23 patients (including 2 with equivocal histological findings) received re-resections (median: 1, total range: 1-3). Persistent positive margins were detected on FSA in 10 (43.5%) while none of these margins were positive on FFPE (overall accuracy: 52.2%). A positive urethral FSA at initial assessment was the only independent risk for a positive final urethral margin. The 3-year urethral recurrence-free survival was 99.1% for patients with negative margins on initial assessment (I), 100% for those with negative final margins after re-resection (II) and 83.3% for patients with positive final margins (III; P= .013 for I/II vs. III). CONCLUSIONS: The accuracy of FSA for detecting malignant urethral margins is high on initial examination but drops considerably in case of re-resection while most positive margins at initial FSA are converted to negative final ones on FFPE. Conversion of a positive to a negative margin was associated with a lower risk of urethral recurrence.

The Predictive and Prognostic Value of Precystectomy Serum Gamma-Glutamyltransferase Levels in Patients With Invasive Bladder Cancer.

INTRODUCTION: The aim of the study was to elucidate the predictive and prognostic value of serum gamma-glutamyltransferase (GGT) in patients with invasive bladder cancer (BC). PATIENTS AND METHODS: Preoperative serum GGT concentrations were assessed in 324 patients treated with RC for cM0 BC between 2002 and 2013. Laboratory values were obtained 1 to 3 days prior to RC. Uni- and multivariable analyses were carried out to evaluate clinicopathologic risk factors for survival. The median follow-up was 36 months (IQR: 10-55). RESULTS: Elevated preoperative GGT levels were diagnosed in 77 patients (23.8%). Elevated GGT was significantly associated with higher ECOG PS and tumor stage (both P = .001), lymph-node tumor involvement (P < .001), positive surgical margins (P = .018), lymphovascular invasion (P = .024), muscle-invasive disease at primary diagnosis (P = .033), increased tumor size (P = .035), hydronephrosis at RC (P = .049) and increased preoperative CRP, GPT and GOT levels (both P < .001). Patients with elevated GGT had decreased 3-year overall (49.2% vs. 69.6%; P = .005) and cancer-specific survival (71.1% vs. 80.9%; P = .042) compared with patients with normal levels. On multivariable analysis, advanced tumor stage (P = .032), lymph node positive disease (P = .030), positive soft tissue surgical margins (P = .014), hydronephrosis at RC (both P = .010), higher ECOG performance status and elevated GGT (P = .043) levels were independent predictors of all-cause mortality. CONCLUSION: Elevated preoperative serum GGT levels are associated with increased risk of locally advanced BC and mortality after RC. These data suggest that GGT levels may be useful for improved prognostication in invasive BC.

Prognostic significance of previous tonsillectomy after radical cystectomy for bladder cancer.

Introduction: To examine whether previous tonsillectomy (TE) impacts on survival after radical cystectomy (RC) for bladder cancer (BC).Patients and Methods: A total of 320 patients were staged cM0 and underwent RC for BC between 2002 and 2013. We retrospectively investigated whether patients had undergone TE prior to RC. Chi-square/Fisher-Exact test was carried out to compare clinicopathological features between the TE- and non-TE-group. Kaplan-Meier analysis with log-rank test was used to estimate recurrence-free survival (RFS) and multivariable Cox-regression analysis of risk factors of recurrence. The median follow-up was 31 months (interquartile range: 9-54).Results: A history of TE was present in 18 of the 320 patients (5.6%). All TEs were performed for benign conditions. TE prior to RC was associated with a history of appendectomy (p = 0.045), lower age at RC (p = 0.029), tumor unifocality (p < 0.001), advanced histopathological tumor stage (p = 0.015), non-pure urothelial carcinoma (p = 0.025), lymphovascular invasion (p = 0.035) and receipt of palliative chemotherapy (p = 0.004). The 3-year RFS was 39.2% for patients with previous TE and 62.4% for those without (p = 0.008). In multivariable analysis, adjusted for all significant parameters of univariable analysis, lymph-node tumor involvement (p = 0.017), positive surgical margins (p = 0.047), tumor grade (p = 0.032), advanced tumor stage (≥pT3a; p = 0.049) and a history of TE (p = 0.021) remained independent prognosticators of recurrence.Conclusion: In this series, previous TE was an independent predictor of recurrence after RC for BC. Further studies are needed to assess whether TE induces immunological alterations that might exert adverse effects on cancer progression of patients with invasive BC.

Prognostic impact of tumor-associated immune cell infiltrates at radical cystectomy for bladder cancer.

OBJECTIVES: To assess whether the presence and location of tumor-associated immune cell infiltrates (TAIC) on histological slides obtained from cystectomy specimens impacts on oncological outcomes of patients with bladder cancer (BC). MATERIAL AND METHODS: A total of 320 consecutive patients staged with cM0 bladder cancer underwent radical cystectomy (RC) between 2004 and 2013. The presence of TAIC (either located peritumorally [PIC] and/or intratumorally [IIC]) on histological slides was retrospectively assessed and correlated with outcomes. Kaplan-Meier analyses were used to estimate the impact of TAIC on recurrence-free (RFS), cancer-specific (CSS), and overall survival (OS). Multivariable Cox-regression analysis was carried out to evaluate risk factors of recurrence. The median follow-up was 37 months (IQR: 10-55). RESULTS: Of the 320 patients, 42 (13.1%) exhibited IIC, 141 (44.1%) PIC and 137 (42.8%) no TAIC in the cystectomy specimens. Absence of TAIC was associated with higher ECOG performance status (P = 0.042), histologically advanced tumor stage (≥pT3a; P < 0.001), lymph node tumor involvement (pN+; P = 0.022), positive soft tissue surgical margins (P = 0.006), lymphovascular invasion (P < 0.001), and elevated serum C-reactive protein levels (P < 0.001). The rate of never smokers was significantly higher in the IIC-group (64.3%) compared to the PIC-group (39.7%, P = 0.007) and those without TAIC (35.8%, P = 0.001). The 3-year RFS/CSS/OS was 73.9%/88.5%/76.7% for patients with IIC, 69.4%/85.2%/70.1% for PIC and 47.6%/68.5%/56.1% for patients without TAIC (P < 0.001/<0.001/0.001 for TAIC vs. no TAIC). In multivariable analysis, adjusted for all significant parameters of univariable analysis, histologically advanced tumor stage (P = 0.003), node-positive disease (P = 0.002), and the absence of TAIC (P = 0.035) were independent prognosticators for recurrence. CONCLUSIONS: In this analysis, the presence and location of TAIC in cystectomy specimens was a strong prognosticator for RFS after RC. This finding suggests that the capability of immune cells to migrate into the tumor at the time of RC is prognostically important in invasive bladder cancer.

The prognostic impact of hexaminolevulinate-based bladder tumor resection in patients with primary non-muscle invasive bladder cancer treated with radical cystectomy.

PURPOSE: To investigate whether hexaminolevulinate-based (HAL) bladder tumor resection (TURBT) impacts on outcomes of patients with primary non-muscle-invasive bladder cancer (NMIBC) who were eventually treated with radical cystectomy (RC). METHODS: A total of 131 consecutive patients exhibiting NMIBC at primary diagnosis were retrospectively investigated whether they had undergone any HAL-guided TURBT prior to RC. Uni- and multivariable analyses were used to evaluate the impact of HAL-TURBT on cancer-specific (CSS) and overall survival (OS). The median follow-up was 38 months (IQR 13-56). RESULTS: Of the 131 patients, 69 (52.7%) were managed with HAL- and 62 (47.3%) with white light (WL)-TURBT only prior to RC. HAL-TURBT was associated with a higher number of TURBTs prior to RC (p = 0.002) and administration of intravesical chemotherapy (p = 0.043). A trend towards a higher rate of tumor-associated immune cell infiltrates in RC specimens (p = 0.07) and a lower utilization rate of post-operative systemic chemotherapy (p = 0.10) was noted for patients who were treated with HAL-TURBT. The 5-year CSS/OS was 90.9%/74.5% for the HAL-group and 73.8%/55.8% for the WL-group (p = 0.042/0.038). In multivariable analysis, lymph node tumor involvement (p = 0.007), positive surgical margins (p = 0.001) and performance of WL-TURBT only (p = 0.040) were independent predictors for cancer-specific death. CONCLUSIONS: The present data suggest that the resection of NMIBC under HAL exerts a beneficial impact on outcomes of patients who will need to undergo RC during their course of disease. This finding may be due to improved risk stratification as the resection under HAL may allow more patients to be treated timely and adequately.

Fluorescence-guided bladder tumour resection: impact on survival after radical cystectomy.

PURPOSE: To investigate whether photodynamic diagnosis (PDD)-guided bladder tumour resection (TUR-BT) is of prognostic value in patients undergoing subsequent radical cystectomy (RC) for bladder cancer (BC). METHODS: In 224 consecutive patients who underwent RC and bilateral pelvic lymphadenectomy for BC between 2002 and 2010 (median follow-up 29 months [IQR 8-59]), we retrospectively investigated whether patients had previously undergone PDD-guided (hexaminolevulinate [HAL] vs. 5-aminolevulinate [ALA]) versus white light (WL)-TUR-BT. Kaplan-Meier analysis was used to estimate recurrence-free survival (RFS), cancer-specific survival (CSS) and overall survival (OS) using log-rank and Cox regression model for uni- and multivariable analysis. RESULTS: Of the 224 patients, 66 (29.5 %) underwent HAL-, 23 (10.3 %) ALA- and 135 (60.2 %) WL-TUR-BT before RC. The 3-year RFS/CSS/OS was 77.8/83.9/74.0 % for HAL-, 53.6/74.5/60.9 % for ALA- and 52.4/59.7/56.5 % for WL-TUR-BT (p = 0.002/0.023/0.037 for HAL vs. WL/ALA). PDD-TUR-BT was associated with a higher number of TUR-BTs before RC (p < 0.001) and re-resections (p = 0.015), a longer time between the first TUR-BT and RC (p = 0.044) and a lower rate of post-operative systemic chemotherapy (p = 0.001). In multivariable analysis, performance of HAL-TUR-BT, pathologic tumour and nodal stage as well as soft tissue surgical margin status were independent predictors for RFS, CSS and OS. CONCLUSIONS: This series indicates for the first time that HAL-guided TUR-BT is an independent predictor for improved survival after RC.