EAU Guidelines on Non–Muscle-invasive Urothelial Carcinoma of the Bladder: Update 2013

Context

The first European Association of Urology (EAU) guidelines on bladder cancer were published in 2002 [1]. Since then, the guidelines have been continuously updated.

Objective

To present the 2013 EAU guidelines on non–muscle-invasive bladder cancer (NMIBC).

Evidence acquisition

Literature published between 2010 and 2012 on the diagnosis and treatment of NMIBC was systematically reviewed. Previous guidelines were updated, and the levels of evidence and grades of recommendation were assigned.

Evidence synthesis

Tumours staged as Ta, T1, or carcinoma in situ (CIS) are grouped as NMIBC. Diagnosis depends on cystoscopy and histologic evaluation of the tissue obtained by transurethral resection (TUR) in papillary tumours or by multiple bladder biopsies in CIS. In papillary lesions, a complete TUR is essential for the patient's prognosis. Where the initial resection is incomplete, where there is no muscle in the specimen, or where a high-grade or T1 tumour is detected, a second TUR should be performed within 2–6 wk. The risks of both recurrence and progression may be estimated for individual patients using the EORTC scoring system and risk tables. The stratification of patients into low-, intermediate-, and high-risk groups is pivotal to recommending adjuvant treatment. For patients with a low-risk tumour, one immediate instillation of chemotherapy is recommended. Patients with an intermediate-risk tumour should receive one immediate instillation of chemotherapy followed by 1 yr of full-dose bacillus Calmette-Guérin (BCG) intravesical immunotherapy or by further instillations of chemotherapy for a maximum of 1 yr. In patients with high-risk tumours, full-dose intravesical BCG for 1–3 yr is indicated. In patients at highest risk of tumour progression, immediate radical cystectomy should be considered. Cystectomy is recommended in BCG-refractory tumours. The long version of the guidelines is available from the EAU Web site: http://www.uroweb.org/guidelines/.

Conclusions

These abridged EAU guidelines present updated information on the diagnosis and treatment of NMIBC for incorporation into clinical practice.

Patient summary

The EAU Panel on Non-muscle Invasive Bladder Cancer released an updated version of their guidelines. Current clinical studies support patient selection into different risk groups; low, intermediate and high risk. These risk groups indicate the likelihood of the development of a new (recurrent) cancer after initial treatment (endoscopic resection) or progression to more aggressive (muscle-invasive) bladder cancer and are most important for the decision to provide chemo- or immunotherapy (bladder installations). Surgical removal of the bladder (radical cystectomy) should only be considered in patients who have failed chemo- or immunotherapy, or who are in the highest risk group for progression.     

Oncologic Outcomes of Post–Kidney Transplantation Superficial Urothelial Carcinoma

Purpose

To analyze the oncologic effect of post–kidney transplantation (KT) immunosuppressive status for end-stage renal disease (ESRD) patients with superficial urothelial carcinoma.

ICUD-EAU International Consultation on Bladder Cancer 2012: Non–Muscle-Invasive Urothelial Carcinoma of the Bladder

Context

Our aim was to present a summary of the Second International Consultation on Bladder Cancer recommendations on the diagnosis and treatment options for non–muscle-invasive urothelial cancer of the bladder (NMIBC) using an evidence-based approach.

Objective

To critically review the recent data on the management of NMIBC to arrive at a general consensus.

Evidence acquisition

A detailed Medline analysis was performed for original articles addressing the treatment of NMIBC with regard to diagnosis, surgery, intravesical chemotherapy, and follow-up. Proceedings from the last 5 yr of major conferences were also searched.

Evidence synthesis

The major findings are presented in an evidence-based fashion. We analyzed large retrospective and prospective studies.

Conclusions

Urothelial cancer of the bladder staged Ta, T1, and carcinoma in situ (CIS), also indicated as NMIBC, poses greatly varying but uniformly demanding challenges to urologic care. On the one hand, the high recurrence rate and low progression rate with Ta low-grade demand risk-adapted treatment and surveillance to provide thorough care while minimizing treatment-related burden. On the other hand, the propensity of Ta high-grade, T1, and CIS to progress demands intense care and timely consideration of radical cystectomy.     

Should Bladder Cuff Excision Remain the Standard of Care at Nephroureterectomy in Patients with Urothelial Carcinoma of the Renal Pelvis? A Population-based Study

Background

A large, multi-institutional, tertiary care center study suggested no benefit from bladder cuff excision (BCE) at nephroureterectomy in patients with upper tract urothelial carcinoma (UC).

Objective

We tested and quantified the prognostic impact of BCE at nephroureterectomy on cancer-specific mortality (CSM) in a large population-based cohort of patients with UC of the renal pelvis.

Design, setting, and participants

A cohort of 4210 patients with UC of the renal pelvis were treated with nephroureterectomy with (NUC) or without (NU) a BCE between 1988 and 2006 within 17 Surveillance, Epidemiology, and End Results registries.

Measurements

Cumulative incidence plots and competing risks regression models compared CSM after either NUC or NU. Covariates consisted of pathologic T and N stages, grade, age, year of surgery, gender, and race.

Results and limitations

Respectively, 2492 (59.2%) and 1718 (40.8%) patients underwent a nephroureterectomy with or without BCE. In univariable and multivariable analyses, BCE omission increased CSM rates in patients with pT3N0/x, pT4N0/x, and pT(any)N1-3 UC of the renal pelvis. For example, in patients with pT3N0/x disease, holding all other variables constant, BCE omission increased CSM in a 1.25-fold fashion (p = 0.04). Similarly, in patients with pT4N0/x disease, BCE omission resulted in a 1.45-fold increase (p = 0.02). The main limitation of our study is the lack of data on disease recurrence.

Conclusions

Nephroureterectomy with BCE remains the standard of care in the treatment of UC of the renal pelvis and should invariably be performed in patients with locally advanced disease. Conversely, patients with pT1 and pT2 disease could be considered for NU without compromising CSM. However, recurrence data are needed to fully confirm the validity of this option.     

Confocal Laser Endomicroscopy of Bladder and Upper Tract Urothelial Carcinoma: A New Era of Optical Diagnosis?

To critically review recent literature on lower urinary tract symptoms (LUTS) in patients with Parkinson’s Disease.A literature search was conducted using the keywords LUTS, urinary symptoms, non-motor, and Parkinson’s disease (PD) via the PubMed/Medline search engine. In the literature, we critically examined lower urinary symptoms in Parkinson’s patients by analyzing prevalence, pathogenesis, urinary manifestations, pharmacologic trials and interventions, and prior review articles. The data collected ranged from 1986 to the present with an emphasis placed on recent publications.The literature regards LUTS in PD as a major comorbidity, especially with respect to a patient’s quality of life. Parkinson’s patients experience both storage and voiding difficulties. Storage symptoms, specifically overactive bladder, are markedly worse in patients with PD than in the general population. Surgical management of prostatic obstruction in PD can improve urinary symptoms. Multiple management options exist to alleviate storage LUTS in patients with PD, ranging from behavioral modification to surgery, and vary in efficacy.Lower urinary tract dysfunction in PD may be debilitating. Quality of life can be improved with a multi-pronged diagnosis-specific approach to treatment that takes into consideration a patient’s ability to comply with treatment. A stepwise algorithm is presented and may be utilized by clinicians in managing LUTS in Parkinson’s patients.     

Prognostic Value of Perinodal Lymphovascular Invasion Following Radical Cystectomy for Lymph Node–positive Urothelial Carcinoma

Background

Metastasis of urothelial carcinoma of the bladder (UCB) into regional lymph nodes (LNs) is a key prognosticator for cancer-specific survival (CSS) after radical cystectomy (RC). Perinodal lymphovascular invasion (pnLVI) has not yet been defined.

Objective

To assess the prognostic value of histopathologic prognostic factors, especially pnLVI, on survival.

Design, setting, and participants

A total of 598 patients were included in a prospective multicentre study after RC for UCB without distant metastasis and neoadjuvant and/or adjuvant chemotherapy. En bloc resection and histopathologic evaluation of regional LNs were performed based on a prospective protocol. The final study group comprised 158 patients with positive LNs (26.4%).

Intervention

Histopathologic analysis was performed based on prospectively defined morphologic criteria of LN metastases.

Outcome measurements and statistical analysis

Multivariable Cox proportional hazard regression models determined prognostic impact of clinical and histopathologic variables (age, gender, tumour stage, surgical margin status, pN, diameter of LN metastasis, LN density [LND], extranodal extension [ENE], pnLVI) on CSS. The median follow-up was 20 mo (interquartile range: 11–38).

Results and limitations

Thirty-one percent of patients were staged pN1, and 69% were staged pN2/3. ENE and pnLVI was present in 52% and 39%, respectively. CSS rates after 1 yr, 3 yr, and 5 yr were 77%, 44%, and 27%, respectively. Five-year CSS rates in patients with and without pnLVI were 16% and 34% (p < 0.001), respectively. PN stage, maximum diameter of LN metastasis, LND, and ENE had no independent influence on CSS. In the multivariable Cox model, the only parameters that were significant for CSS were pnLVI (hazard ratio: 2.47; p = 0.003) and pT stage. However, pnLVI demonstrated only a minimal gain in predictive accuracy (0.1%; p = 0.856), and the incremental accuracy of prediction is of uncertain clinical value.

Conclusions

We present the first explorative study on the prognostic impact of pnLVI. In contrast to other parameters that show the extent of LN metastasis, pnLVI is an independent prognosticator for CSS.     

Association Between the Number of Dissected Lymph Nodes During Pelvic Lymphadenectomy and Cancer-Specific Survival in Patients with Lymph Node–Negative Urothelial Carcinoma of the Bladder Undergoing Radical Cystectomy

Background

A larger number of dissected lymph nodes (LN) during pelvic lymphadenectomy in patients with muscle-invasive transitional-cell carcinoma of the bladder treated by radical cystectomy (RC) is crucial for exact tumor staging and is associated with a positive oncological outcome.

Methods

Clinical and pathological records of 1291 patients undergoing RC due to LN-negative transitional-cell carcinoma of the bladder were summarized and evaluated in a multi-institutional database. The number of removed LNs and the presence or absence of lymphovascular invasion were assessed. On the basis of multivariate Cox regression analyses, a threshold number of removed LNs was defined that exerted an independent influence on cancer-specific survival (CSS).

Results

In multivariate Cox regression models for different numbers of removed LNs, a statistically significant enhancement of CSS could be demonstrated for a LN count of 16. Furthermore, the integration of the dichotomized LN count of 16 resulted in a statistically significantly enhanced predictive ability of the model for CSS. Patients with <16 and ≥16 removed LNs showed CSS rates after 5 years of 72% and 83%, respectively (P = 0.01). In addition, age, sex, pT stage, and lymphovascular invasion had independent influences on CSS in every Cox regression model.

Conclusions

In patients undergoing RC, removal of a higher LN count is associated with an improved oncological outcome. The information resulting from an assessment of lymphovascular invasion and an extended lymphadenectomy is critical for stratification of risk groups and identification of patients who might benefit from adjuvant treatment.

     

Low-Grade Salivary Duct Carcinoma or Low-Grade Intraductal Carcinoma? Review of the Literature

Low-grade salivary duct carcinoma (LG-SDC) is a rare neoplasm characterized by predominant intraductal growth, luminal ductal phenotype, bland microscopic features, and favorable clinical behavior with an appearance reminiscent of florid to atypical ductal hyperplasia to low grade intraductal breast carcinoma. LG-SDC is composed of multiple cysts, cribriform architecture with “Roman Bridges”, “pseudocribriform” proliferations with floppy fenestrations or irregular slits, micropapillae with epithelial tufts, fibrovascular cores, and solid areas. Most of the tumor cells are small to medium sized with pale eosinophilic cytoplasm, and round to oval nuclei, which may contain finely dispersed or dark condensed chromatin. Foci of intermediate to high grade atypia, and invasive carcinoma or micro-invasion have been reported in up to 23 % of cases. The neoplastic cells have a ductal phenotype with coexpression of keratins and S100 protein and are surrounded by a layer of myoepithelial cells in non-invasive cases. The main differential diagnosis of LG-SDC includes cystadenoma, cystadenocarcinoma, sclerosing polycystic adenosis, salivary duct carcinoma in situ/high-grade intraductal carcinoma, and papillary-cystic variant of acinic cell carcinoma. There is no published data supporting the continuous classification of LG-SDC as a variant of cystadenocarcinoma. Given that most LG-SDC are non-invasive neoplasms; the terms “cribriform cystadenocarcinoma” and LG-SDC should be replaced by “low-grade intraductal carcinoma” (LG-IDC) of salivary gland or “low-grade intraductal carcinoma with areas of invasive carcinoma” in those cases with evidence of invasive carcinoma.     

Is Survival from Infiltrating Lobular Carcinoma of the Breast Different from That of Infiltrating Ductal Carcinoma?

Previous studies of patients with breast cancer have compared survival of invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) with contradictory results. This study examines the effect of the diagnosis of IDC or ILC in conjunction with age at diagnosis, pathologic tumor size, pathologic stage, histologic grade, and lymph node status of 307 women with IDC or ILC in 1992 in the Greater Western region of Sydney in Australia. Survival analysis was conducted using the Kaplan-Meier method. Relative risks associated with IDC or ILC and other important prognostic factors and adjusted for each other were computed using Cox proportional hazard regression. The proportion of grade I tumors was significantly higher in ILC (41%) than in IDC (16%). Conversely, the proportion of grade III tumors was only 18% in ILC as against 41% in IDC (p = 0.020). The 10-year survival of women with IDC was 69%, compared to 84% for ILC (p = 0.073). However, the 15 percentile point difference between overall survival of IDC and ILC was markedly reduced after adjustment for nodal status. The difference was eight percentile points for node-negative patients (p = 0.361) and five percentile points for node-positive patients (p = 0.464). Age at diagnosis, tumor size, pathologic stage, and lymph node status were independent prognostic indicators for 10-year survival. There was no prognostic difference between IDC and ILC. The result shows the importance of adjusting for other important clinicopathologic characteristics before comparing the overall survival of IDC and ILC.     

Early Versus Deferred Cystectomy for Initial High-Risk pT1G3 Urothelial Carcinoma of the Bladder: Do Risk Factors Define Feasibility of Bladder-Sparing Approach?

OBJECTIVES: We compared long-term outcome in patients with initial pT1G3 bladder cancer (BC) treated with early versus deferred cystectomy (CX) for recurrent pT1G3 or muscle-invasive BC after an initial bladder-sparing approach. The aim of this study was to compare survival rates and to analyse the influence of the recognised risk factors multifocality, tumour size, and carcinoma in situ (CIS) in initial transurethral resection of the bladder. METHODS: Between 1995 and 2005, a total of 105 patients were diagnosed with initial pT1G3 BC featuring>or=2 risk factors. Forty-five percent had multiple tumours, 73% tumours>3 cm in size, and 46% CIS. All patients were offered early CX. Fifty-one percent of patients opted for early and 49% underwent deferred CX for recurring BC. Risk factors were distributed evenly between the groups. RESULTS: Upstaging in the CX specimen was found in 30% of cases. No risk factor was related to upstaging. The 10-yr cancer-specific survival rate was 78% in early CX and 51% in deferred CX (p<0.01). No risk factor predicted cancer-related death in early CX. In survival analysis, CIS was related to a lower cancer-specific survival rate in deferred CX (p<0.001). CONCLUSIONS: Early as opposed to deferred CX seems to prolong the cancer-specific survival rate in high-risk pT1G3 BC. Patients with CIS should be considered for early CX owing to reduced cancer-specific survival in case of deferred CX.     

Using Hematuria as Detection of Post–kidney Transplantation Upper Urinary Tract Urothelial Carcinoma Is Associated With Delayed Diagnosis of Cancer Occurrence

Objectives

Kidney transplantation (KT) is an important renal replacement therapy for end-stage renal disease (ESRD). The incidence of upper urinary tract urothelial carcinoma (UTUC) is relatively higher in Taiwan. According to our institutional database, early onset of post-KT UTUC is not uncommon. Early detection of post-KT UTUC is an important issue to improve oncologic outcome. Because painless hematuria is a common symptom for UTUC, this study analyzes whether using hematuria as post-KT UTUC screening delayed cancer diagnosis or not.