Radical Cystectomy Specimens Research Articles

Assessment of transurethral resection of the bladder specimens with pT1 high-grade urothelial carcinoma for the predictor features of muscularis propria invasion on radical cystectomy specimens

Assessment of transurethral resection of the bladder specimens with pT1 high-grade urothelial carcinoma for the predictor features of muscularis propria invasion on radical cystectomy specimens

The pathologist's role in the detection of rare variants of bladder cancer and analysis of the impact on incidence and type detection.

Histology is one of the most important factors determining the prognosis of bladder cancers and rare variants are generally associated with decreased disease specific survival compared to pure transitional cell carcinomas. We believe that rare bladder cancer variants are likely underdiagnosed in the absence of a dedicated uro-pathologist in many centers. The objective of this study is to evaluate the contribution of a dedicated uro-pathologist on the identification of rare bladder cancer variants. We retrospectively analyzed the clinical and histological records of all patients which underwent a radical cystectomy and lymph node dissection between January 2000 and September 2015. The sample was divided in two groups: Group A, consists of patients who underwent radical cystectomy in the absence of a dedicated uro-pathologist at our institution, whereas the Group B consists of patients who underwent surgery when a dedicated uro-pathology service was available. We then evaluated the impact of a dedicated uro-pathologist on rare variants detection. One hundred thirty-seven out of 551 (24.9%) of patients who underwent RC had at least one rare variant. In Group A 38/238 (16%) of patients showed a rare variant, while 99/313 (31.6%; P<0.001) in group B. Furthermore, the diagnosis of sarcomatoid variant was statistically significantly less common in group A (P=0.0026). The concordance between final radical cystectomy histology and previous transurethral resection of bladder tumor (TURBT) histology was poor in both groups (overall 50.4%). The presence of a dedicated urological anatomical pathologist is of paramount importance and significantly increases the detection rate of non-transitional cell carcinoma bladder cancer types, but it does not increase the concordance rate between histological diagnoses in TURBT and radical cystectomy specimens.

Pièce opératoire ypT0N0 après séquence chimiothérapie néo-adjuvante – cystectomie pour TVIM : épidémiologie et impact pronostique. Une mise au point du CCAFU Vessie

Neoadjuvant chemotherapy (NAC) is recommended for localized muscle-invasive bladder cancer when patients are fit for cisplatin-based chemotherapy. A pathological complete response can be observed, corresponding to ypT0N0 stage on the radical cystectomy specimen. This review discusses the incidence, prognosis and potential therapeutic impact of complete response on pathological specimen in NAC treated patients. A comprehensive review of the literature was conducted using Medline database, with no time frame. The articles were selected using the following keywords association: "Bladder cancer" (Mesh) AND "Neoadjuvant chemotherapy" (Mesh) AND "pT0" (Mesh). After NAC, ypT0N0 rates vary from 9 to 46% among the series, reported rates that are higher compared to those of pT0 without NAC administration. The incidence depends on the chemotherapy regimen (maximal local effect with cisplatin-based chemotherapy) and the pathological type of the disease (presence of variant histologies). Molecular analyses of bladder cancer could probably help in the near future to identify and predict NAC responders. Pathological complete response is associated with a favorable prognosis in terms of recurrence-free and overall survival. Nevertheless, disease recurrences are still observed in 10-15% of cases, which underlies the importance of local treatment and close follow-up even in these patients. ypT0N0 rate is approximately 25% after NAC, that is 4.3 higher than after bladder resection alone. The prognosis is better than that with residual tumor on specimen and is comparable to that of pT0 without NAC administration.

Neoadjuvant chemotherapy with gemcitabine and cisplatin for muscle-invasive bladder cancer: multicenter retrospective study.

The aim of this study was to evaluate the efficacy of neoadjuvant gemcitabine and cisplatin (GC) therapy for muscle-invasive bladder cancer (MIBC). We retrospectively evaluated patients who underwent neoadjuvant GC therapy followed by radical cystectomy from April 2009 through December 2015 in the Sapporo Medical University Urologic Consortium. The efficacy of neoadjuvant chemotherapy (NAC) was assessed based on the pathological T0 (pT0) rate in radical cystectomy specimens, and the recurrence-free survival, cause-specific survival and overall survival (OS) rates. To compare the oncological benefit of NC with GC to that of the methotrexate, vinblastine, adriamycin and cisplatin (MVAC) regimen, we also utilized historical clinical data of patients who were treated with MVAC as NAC followed by radical cystectomy in our institute from 1986 through 2010. Fifty-eight patients receiving neoadjuvant GC therapy and 74 receiving neoadjuvant MVAC were included. The pT0 achieving rates were comparable between the two groups (20.7% vs. 18.9%, P = 0.83). Neoadjuvant GC was associated with a better 2-year OS rate than neoadjuvant MVAC for clinical T2 disease (95.2% vs. 70.8%, P = 0.036). In contrast, in patients with clinical T3 or more advanced disease, neoadjuvant MVAC provided more pT0 (20.0% vs. 5.6%, P = 0.07) and better 2-year OS than neoadjuvant GC (71.1% vs. 55.0%, P = 0.142), although the difference did not reach statistical significance. Neoadjuvant GC had no inferiority in oncological outcomes to MVAC for MIBC.

Prognostic Value of Testing PD-L1 Expression After Radical Cystectomy in High-risk Patients.

The use of cisplatin-based adjuvant chemotherapy (AC) after radical cystectomy (RC) is a highly controversial issue and has been infrequently used owing to the high rates of postoperative complications, cisplatin ineligibility, and lack of randomized trials. Checkpoint inhibitors such as nivolumab, pembrolizumab, or atezolizumab are currently being tested in phase III studies in the adjuvant setting owing to their more favorable safety profile compared with chemotherapy. The aim of the present study was to investigate whether compartmentalization of programmed cell death ligand 1 (PD-L1) expression in different locations of RC specimens influences recurrence-free survival (RFS) after RC. PD-L1 expression was quantified on tumor cells and immune cells by immunohistochemistry in 83 "high-risk" patients (stage≥ pT3a and/or pN+ disease) who had undergone RC without cisplatin-based AC. PD-L1 (≥ 1%) was expressed on tumor cells in 33 patients (39.8%) and immune cells in 51 patients (61.4%), respectively. PD-L1 positivity on tumor cells was not associated with RFS (P= .455). In contrast, PD-L1+ expression on immune cells was significantly associated with shorter RFS compared with PD-L1- expression (P= .015). We have confirmed the high heterogeneity of PD-L1 cell type-dependent expression, with the resulting divergent outcomes. Ultimately, no clear statement about PD-L1 expression as a prognostic biomarker for further AC after RC could be made, although PD-L1 expression on immune cells seemed to have the greatest effect in predicting the outcome.

Mechanistic target of rapamycin (MTOR) protein expression in the tumor and its microenvironment correlates with more aggressive pathology at cystectomy

BackgroundThe mechanistic target of rapamycin (mTOR) has been implicated in driving tumor biology in multiple malignancies, including urothelial carcinoma (UC). We investigate how mTOR and phosphorylated mTOR (pmTOR) protein expression correlate with chemoresponsiveness in the tumor and its microenvironment at final pathologic staging after neoadjuvant chemotherapy (NAC). MethodsA single-institution retrospective analysis was performed on 62 patients with cT2–4Nany UC undergoing NAC followed by radical cystectomy. Diagnostic (transurethral resection specimens, TURBT) and postchemotherapy radical cystectomy specimens were evaluated for mTOR and pmTOR protein expression using immunohistochemistry of the tumor, peritumoral stroma, and normal surrounding stroma. Protein expression levels were compared between clinical and pathologic stage. Whole transcriptome analysis was performed to evaluate mRNA expression relative to mTOR pathway activation. ResultsBaseline levels of mTOR and pmTOR within TURBT specimens were not associated with clinical stage and response to chemotherapy overall. Nonresponders with advanced pathologic stage at cystectomy (ypT2–4/ypTanyN+) had significantly elevated mTOR tumor staining (P = 0.006) and a sustained mTOR and pmTOR staining in the peritumoral and surrounding normal stroma (NS). Several genes relevant to mTOR activity were found to be up-regulated in the tumors of nonresponders. Remarkably, complete responders at cystectomy (ypT0) had significant decreases in both mTOR and pmTOR protein expression in the peritumoral and normal stroma (P = 0.01–0.03). ConclusionsOur results suggest that mTOR pathway activity is increased in tumor and sustained in its microenvironment in patients with adverse pathologic findings at cystectomy. These findings suggest the relevance of targeting this pathway in bladder cancer.

GPX2 promotes development of bladder cancer with squamous cell differentiation through the control of apoptosis.

Herein, we elucidated the molecular mechanisms and therapeutic potential of glutathione peroxidase 2 (GPX2) in bladder cancer. GPX2 expression gradually increased during progression from normal to papillary or nodular hyperplasia (PNHP) and urothelial carcinoma (UC) in a rat N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced bladder carcinogenesis model. GPX2 overexpression was more marked in UC with squamous differentiation (SqD) than in pure UC. Clinical intraepithelial lesions of papillary UC and invasive UC with SqD also had strong GPX2 expression in human radical cystectomy specimens. In addition, prognostic analysis using transurethral specimens revealed that low expression level of GPX2 predicted poor prognosis in patients with pure UC. Further, UC cell lines, BC31 and RT4, cultured in vitro also overexpressed GPX2. Knock-down of GPX2 induced significant inhibition of intracellular reactive oxygen species (ROS) production, in addition to significant growth inhibition and increased apoptosis with activation of caspase 3 or 7 in both BC31 and RT4 cells. Interestingly, tumor growth of BC31 cells subcutaneously transplanted in nude mice was significantly caused the induction of apoptosis, as well as inhibition of angiogenesis and SqD by GPX2 down-regulation. Our findings demonstrated that GPX2 plays an important role in bladder carcinogenesis through the regulation of apoptosis against intracellular ROS, and may be considered as a novel biomarker or therapeutic target in bladder cancer.

573 - Prognostic value of concomitant carcinoma in situ in radical cystectomy specimens on patients with bladder cancer: A meta-analysis of 24,136 patients

573 - Prognostic value of concomitant carcinoma in situ in radical cystectomy specimens on patients with bladder cancer: A meta-analysis of 24,136 patients

Predictive role of neutrophil-to-lymphocyte ratio on upstaging of organ-confined invasive urothelial bladder cancer to non-organ-confined disease.

The aim of this study is to examine the usefulness of preoperative neutrophile-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and lymphocyte-to-monocyte ratios to predict pathological upstaging of invasive bladder cancer who underwent radical cystectomy. A total of 126 patients who underwent radical cystectomy at our clinic between January 2006 and March 2015 were retrospectively analysed. One hundred and twelve patients with organ-confined invasive bladder tumors (T2) detected at histopathological examination of transuretral resection material were included in the study. Upstaging was seen at histopathological examination of radical cystectomy specimens of 42 patients. We compared preoperative neutrophile-to-lymphocyte ratio, platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio between upstaged and not-upstaged groups. There were no statistically significant correlation between age, time to radical cystectomy, gender, lymphocyte-to-monocyte ratio, platelet-to-lymphocyte ratio ratios and carcinoma in situ in upstaged and non-upstaged groups. Statistical analyses showed that preoperative neutrophile-to-lymphocyte ratio was higher in upstaged patients (p=0.009). In multivariate analysis preoperative neutrophile-to-lymphocyte ratio and positive surgical margin were significantly higher in upstaged group. In organ-confined muscle invasive bladder cancer neutrophile-to-lymphocyte ratio seems to be an acceptable parameter to predict locally advanced disease.

Prognostic impact of percentage of squamous differentiation in patients with nonbilharzial squamous cell carcinoma and transitional cell carcinoma treated with radical cystectomy.

498 Background: Squamous differentiation has been reported to occur in 10-22 % of transitional cell carcinoma. The prognostic impact of squamous differentiation is controversial. In addition, it remains unclear whether the percentage of squamous differentiation impact outcome of patients with nonbilharzial squamous cell carcinoma and transitional cell carcinoma treated with radical cystectomy Methods: We performed a retrospective study of patients with non-bilharzial squamous variants or squamous bladder carcinoma treated in two French institutions. The percentage of squamous differentiation was determined by an expert GU pathologist on radical cystectomy specimens. Progression-free survival (PFS) and cancer-specific survival (CSS) were analyzed according to the percent of squamous differentiation. Survivals were estimated using the Kaplan-Meier method and compared using multivariate Cox proportional hazard regression analysis. Results: Forty patients were identified including 28 and 12 patients which tumors were classified as transitional cell carcinomas cases with squamous cell differentiation and pure non-bilharzial squamous bladder carcinoma, respectively. Patients with tumors harboring more than 50% of squamous differentiation had a PFS of 6.3 months as compared to 60.2 months for those with squamous differentiation present in less than 50% (p = 0.014). In multivariate analysis, the percentage of squamous differentiation was the only independent prognostic factor for PFS (HR = 2.63 (IC 95%: 1.22-5.67). First site of recurrence of patients with squamous differentiation ≥50% were more frequently the pelvis (72% versus 17 %; p = 0.049). No difference in CSS were observed between patients with tumors &lt; 50% or ≥50% squamous differentiation (16.3 months versus 62 months) (p = 0.2). Conclusions: Extensive squamous differentiation in bladder cancer is associated with poor PFS and pelvic progression, suggesting that those patients might benefit from adjuvant pelvic radiotherapy. Larger studies are needed to validate these findings.

Correlation of MTOR protein expression in the tumor and its microenvironment with more aggressive pathology at cystectomy.

438 Background: The mechanistic target of rapamycin (mTOR) has been implicated in driving tumor biology in multiple malignancies, including urothelial carcinoma (UC). We investigate how mTOR and phosphorylated mTOR (pmTOR) protein expression in both the tumor, and the tumor microenvironment, correlate with final pathologic stage at cystectomy after neoadjuvant chemotherapy (NAC). Methods: A single-institution retrospective analysis was performed on 62 patients with cT2-4Nany UC undergoing NAC followed by radical cystectomy. Diagnostic (transurethral resection specimens, TURBT) and post-NAC radical cystectomy specimens were evaluated for mTOR and pmTOR protein expression using immunohistochemistry of the tumor, peritumoral stroma, and normal surrounding tissue. Protein expression levels were compared between TURBT and cystectomy samples. Whole transcriptome analysis was performed to evaluate mRNA expression relative to mTOR pathway activation. Results: Baseline levels of mTOR and pmTOR within TURBT specimens were not associated with clinical stage or response to NAC overall. Non-responder patients, defined as pT2-T4/pTanyN+, had significantly elevated mTOR tumor staining (p = 0.006) and sustained mTOR and pmTOR staining in the peritumoral and surrounding normal stroma of cystectomy specimens compared with baseline TURBT samples (NS). In contrast, complete responders (pT0), had significant decreases in tumoral mTOR and pmTOR protein expression at cystectomy (p = 0.01-0.03). Several genes relevant to mTOR activity were found to be overexpressed in post-NAC cystectomy samples (compared with TURBT) of non-responder patients (THBS1, FN1, FOS, CNN1, COL1A2). Conclusions: Our results suggest that mTOR pathway activity is increased in the tumor and sustained the tumor microenvironment of patients with adverse pathologic findings at cystectomy after NAC. These findings suggest the relevance of targeting the mTOR pathway in bladder cancer.

Apparent plasticity in the biological response to neoadjuvant chemotherapy in muscle-invasive bladder cancer.

433 Background: After cisplatin-based neoadjuvant chemotherapy (NAC) almost two thirds of patients have residual muscle-invasive bladder cancer (MIBC) present at radical cystectomy (RC). The alterations induced by NAC in these cisplatin-resistant tumors remain largely unstudied. Here, we aim to investigate the characteristics of cisplatin-resistant tumors. Methods: RC samples were available for gene expression analysis from 133 patients with residual invasive disease after cisplatin-based NAC, of whom 116 had matched pre-NAC samples. In addition, the tumor bed (scar tissue) of 21 post-NAC RC specimens with no residual tumor was profiled. Unsupervised consensus clustering (CC) was performed and the CC were investigated for their biological and clinical characteristics. H&amp;E and immunohistochemistry (KRT5/6, GATA3, KI67 and CD8) were used to confirm tissue sampling and gene expression analysis. Results: Unsupervised consensus clustering yielded four distinct consensus clusters (CC). Consistent basal-(CC1) and luminal-like (CC2) phenotype similar to pre-NAC subtyping was observed in 42% of cases. One third of cases became immune-infiltrated (CC3) in the post-NAC setting but lacked basal and luminal markers. These tumors expressed a strong T-cell signature, chemokine signaling and checkpoint molecules. Conversely, CC4 was associated with healing/scarring. This ‘scar-like’ character of CC4 was consistent with the scar samples. Despite being pathological non-responders, the relative risk of death for CC4 was 2.8 and 3 times less than CC2-Luminal (p = 0.038) and CC3-Infiltrated (p = 0.018), respectively. Luminal-like pre-NAC samples were more likely to adopt a scar-like character (CC4) in the post-NAC setting, while the basal-like tumors were more likely to develop luminal features (CC2). Conclusions: This study expands our knowledge of cisplatin-resistant MIBC by suggesting molecular subtypes to understand the biology of these tumors. Clinical trials are necessary to test the impact of these molecular subtypes with respect to selection of adjuvant and salvage treatments. Post-NAC immune infiltration could have implications for subsequent immunotherapy.

TURBT for Treatment of Recurrent High Risk Superficial or Muscle-Invasive Bladder Tumours: Factors Contributing to T0 Radical Cystectomy Specimens

TURBT for Treatment of Recurrent High Risk Superficial or Muscle-Invasive Bladder Tumours: Factors Contributing to T0 Radical Cystectomy Specimens

Accuracy and prognostic value of variant histology and lymphovascular invasion at transurethral resection of bladder.

To evaluate the concordance rate of lymphovascular invasion (LVI) and variant histology (VH) of transurethral resection (TUR) with radical cystectomy (RC) specimens. Furthermore, to evaluate the value of LVI and VH at TUR for predicting non-organ confined (NOC) disease, lymph node metastasis, and survival outcomes. Two hundred and sixty-eight patients who underwent TUR and subsequent RC were reviewed. Logistic regression analyses were performed to evaluate the association of LVI and VH with NOC and lymph node metastasis at RC. Cox regression analyses were used to estimate recurrence-free survival (RFS) and cancer-specific survival (CSS). LVI and VH were detected in 13.8 and 11.2% of TUR specimens, and in 30.2 and 25.4% of RC specimens, respectively. The concordance rate between LVI and VH at TUR and subsequent RC was 69.8 and 83.6%, respectively. They were both associated with adverse pathological features such as lymph node metastasis and advanced stage. TUR LVI and VH were both independently associated with lymph node metastasis and TUR VH was independently associated with NOC. On univariable Cox regression analyses, TUR LVI was associated with RFS and CSS while TUR VH was only associated with RFS. Only TUR LVI was independently associated with RFS. Detection of LVI is missed in a third of TUR specimens while VH seems more accurately identified. TUR LVI and VH are associated with more advanced disease and LVI predicts disease recurrence. Assessment and reporting of LVI and VH on TUR specimen are important for risk stratification and decision-making.

The role of LIM and SH3 protein-1 in bladder cancer metastasis.

The LIM and SH3 protein-1 (LASP-1) is a multi-domain protein that is involved in several malignant cancers. The role of LASP-1 in malignant phenotypes including high invasive properties and unrestricted cell proliferation, remain to be elucidated. The present study reported the association of LASP-1 expression with bladder cancer malignancy and its role in cancer cell invasion and proliferation. The immunohistochemical analysis of the expression status of LASP-1 in radical cystectomy specimens from invasive bladder cancer patients revealed that the LASP-1-positive patients demonstrated a decreased survival rate compared with the LASP-1-negative patients. The expression level of LASP-1 was increased in invasive bladder cancer cell lines compared with the non-invasive bladder cancer cell lines. Invasive cancer cells form invadopodia, the filamentous actin-based membrane protrusions that are essential in cancer cell invasion. Knockdown of LASP-1 reduced the ability to form invadopodia, resulting in decreased invasive capacity of the LASP-1 knockdown cells. In addition, knockdown of LASP-1 reduced cell proliferation. These results suggest that LASP-1 is important in invadopodia formation and cell proliferation of bladder cancer cells, promoting the malignant properties and resulting in poor-prognosis.

PD-L1 expression in bladder cancer and metastasis and its influence on oncologic outcome after cystectomy.

Platinum-based chemotherapy is the standard of care in metastatic bladder cancer. With the approval of various checkpoint inhibitors, immunotherapy has revolutionized the traditional treatment modalities. The aim of the study was to evaluate whether PD-L1 expression on tumor cells (TCs) and tumor-infiltrating immune cells (ICs) can be used as biomarker to predict recurrence-free survival (RFS), overall survival (OS) and disease-specific survival (DSS) in bladder cancer patients after radical cystectomy (RC) developing disease recurrence followed by first-line chemotherapy. PD-L1 was measured on formalin-fixed, paraffin-embedded tissue sections of RC specimens in all patients (n=61) and in 27 matched metastatic biopsy samples by immunohistochemistry. PD-L1 expression on TCs was defined by the percentage of PD-L1 positive tumor cells (< 1%= IC0, ≥1% but <5%=IC1, ≥5 %=IC2/3), and was considered negative or positive for ICs. On 27 paired samples, IC1/2/3 score on TCs was homogeneous distributed with 59.3% in primary tumors and metastases, but with a high discordance rate of 44.4% of PD-L1 positivity on ICs. High PD-L1 expression (IC2/3) on TCs was more frequently seen in histologic subtypes of urothelial cancer compared to pure urothelial cancers (46.2% vs. 20.8%; p=0.002). PD-L1 expression on TCs in primary tumors (IC2/3 vs. IC0, median: 3.2 vs. 13.8 months, p=0.019) and metastatic sites (IC2/3 vs. IC0, median: 6.1 vs. 21.8 months, p=0.014) was associated with poor chemo-response, represented by significant shortened DSS. These results suggest that PD-L1 may be a potential target being involved in chemo-resistance mechanisms and poses potential for therapy stratification in the future.

Predictive factors for final pathologic ureteral sections on 700 radical cystectomy specimens: Implications for intraoperative frozen section decision-making

PurposeTo identify preoperative predictive factors for final ureteral section invasion after radical cystectomy (RC) and to validate significant factors on an external independent cohort. Material and methodsWe retrospectively reviewed data of all consecutive RC performed for bladder cancer in 2 high-volume institutions. Clinical, pathological, and follow-up data were collected prospectively and reviewed retrospectively. Pathological evaluation was performed by 2 well-trained uropathologists in each center. Logistic regression analyses were performed to identify predictive factors for final ureteral sections involvement. Significant factors in cohort A were validated in cohort B. Receiver operating curve and area under curve were modeled to evaluate predictive accuracy of the markers. ResultsA total of 441 RC were performed in center A and 307 RC were performed in center B. Mean follow-ups were 36.2 and 38.1 months, respectively. Invasion of the final ureteral section was observed on 5.5% of patients in cohort A and 4.8% of patients in cohort B. In cohort A, multivariable logistic regression identified preoperative hydronephrosis on computed tomography scan (odds ratio [OR] = 4.9, P = 0.004) and presence of Carcinoma in situ (CIS, OR = 3.9, P = 0.01) as the only factors associated with ureteral sections positivity. In cohort B, hydronephrosis and CIS were both associated with ureteral sections positivity in univariable analysis. In multivariable analysis, only hydronephrosis remained significant (OR = 5.9, P = 0.01). Predictive accuracy of hydronephrosis and CIS combined in 1 variable was 0.72. ConclusionHydronephrosis and bladder CIS have good accuracy in predicting ureteral sections positivity after RC. In the presence of those factors, ureteral frozen sections should be performed.

FDG-PET/CT for response evaluation of invasive bladder cancer following neoadjuvant chemotherapy.

We investigated the accuracy of FDG-PET/CT response identification following neoadjuvant or induction chemotherapy (NAIC) for invasive bladder cancer (BC) as to better select patients for radical cystectomy (RC). Between 2010 and 2014, 37 cT1-4N1-3 BC patients received a FDG-PET/CT before and after NAIC followed by RC. Metabolic lymph node (LN) response was evaluated according to EORTC recommendations. Additionally, primary tumor response was evaluated for 23 patients by means of delayed pelvic imaging after forced diuresis. Gold standard was response on pathologic analysis of RC specimens. Response was defined as partial response (pPR, any pathologic downstaging) or complete response (pCR,<ypT1N0). Cancer-specific survival (CSS) was correlated with pCR and metabolic CR. Twenty-four cN+patients achieved LN pCR. FDG-PET/CT identified pCR with 67% sensitivity and 46% specificity. Primary tumor response was evaluable for 17/23 patients, of whom 12 were responders. Tumor downstaging (pPR or pCR) was identified with 83% sensitivity and 80% specificity. Tumor pCR was detected with 70% sensitivity and 71% specificity. pCR of overall disease (primary tumor and LNs, n=17) was detected with 67% sensitivity and 75% specificity. CSS was positively associated with pathologic CR (HR 0.16, p=0.027), but not with metabolic CR (HR 0.560, p=0.612). FDG-PET/CT can accurately distinguish primary tumor downstaging from non-response, which suggests that response monitoring (in cN0 patients) might be used to adjust neoadjuvant treatment. pCR identification is less accurate, especially for LN metastases, which suggests that FDG-PET/CT cannot be used to select patients for RC.

Prognostic significance of lymphatic, vascular and perineural invasion for bladder cancer patients treated by radical cystectomy

In radical cystectomy specimens with bladder cancer, lymphatic and vascular invasion are often reported as 'angiolymphatic' or 'lymphovascular' invasion, terms that combine the findings of tumour within simple endothelial-lined lymphatic spaces and tumour within muscle-lined blood vessels. It is unclear if these patterns of invasion have different prognostic significance. In addition, there are conflicting data regarding the significance of lymphatic, vascular and perineural invasion in patients with bladder cancer. Herein, we studied 1504 patients treated by radical cystectomy for bladder cancer at our institution and followed for a mean of 10.6 years. Cases were re-reviewed by a urological pathologist for lymphatic invasion defined as tumour within a non-muscle-lined endothelial-lined lymphatic space, vascular invasion defined as tumour in a muscle-lined blood vessel, and perineural invasion defined as tumour within the perineural sheath. Associations of clinical and pathological features with bladder cancer death were evaluated using Cox proportional hazards regression models and summarised with hazard ratios and 95% confidence intervals. Survival was estimated by the Kaplan-Meier method. Multivariate analysis showed that lymphatic and vascular invasion but not perineural invasion were significantly associated with cancer specific survival (p<0.0001 and p=0.02, respectively). There was a significant association of lymphatic and vascular invasion but not perineural invasion with involved regional lymph nodes (p<0.0001 and p=0.004, respectively). In patients with metastasis to regional lymph nodes, lymphatic invasion remained significantly associated with outcome (p=0.02). The frequency of lymphatic and vascular invasion varied amongst histological subtypes of bladder cancer. Vascular and lymphatic invasion should be clearly defined and reported for radical cystectomy specimens containing bladder cancer.

Incidence and effect of variant histology on oncological outcomes in patients with bladder cancer treated with radical cystectomy

IntroductionWe sought to describe incidence of histological variants after radical cystectomy (RC) due to bladder cancer (BCa). Moreover, we investigated survival outcomes accounting for this parameter. MethodsWe retrospectively evaluated data from 1,067 patients with BCa treated with RC between 1990 and 2013 at a single tertiary care referral center. All specimen were evaluated by dedicated uropathologists. Univariable and multivariable Cox regression analyses tested the effect of different histopathological variant on recurrence, cancer-specific mortality (CSM), and overall mortality (OM) after accounting for all available confounders. ResultsOf 1,067 patients, 729 (68.3%) harbored pure urothelial BCa while 338 (31.7%) were found to have a variant. Considering uncommon variants, 21 (2.0%) were sarcomatoid, 10 (0.9%) lymphoepitelial, 19 (1.8%) small cell, 109 (10.2%) squamous, 89 (8.3%) micropapillary, 23 (2.2%) glandular, 34 (3.2%) mixed variants, and 33 (3.1%) were found with other types of variants. With a median follow-up of 6.2 years, 343 recurrence, 365 CSM, and 451 OM were recorded, respectively. At multivariable Cox regression analyses, the presence of small cell variant was associated with higher recurrence (hazard ratio [HR] = 3.47, P<0.001), CSM (HR = 3.30, P<0.04), and OM (HR = 2.97, P<0.003) as compared with pure urothelial cancer. Conversely, no survival differences were recorded considering other histological variants (all P> 0.1). ConclusionOur study confirms that histological variant is not an infrequent event at RC specimen. However, in our single-center series, only patients found with small cell variant were associated with a negative effect on survival after RC.