Potential and limitations of diffusion-weighted magnetic resonance imaging in kidney, prostate, and bladder cancer including pelvic lymph node staging: a critical analysis of the literature

Diagnosis, staging, and treatment monitoring are still suboptimal for most genitourinary tumours. Diffusion-weighted magnetic resonance imaging (DW-MRI) has already shown promise as a noninvasive imaging modality in the early detection of microstructural and functional changes in several pathologies of various organs.

Preexisting BCG-specific T cells improve intravesical immunotherapy for bladder cancer

Therapeutic intravesical instillation of bacillus Calmette-Guérin (BCG) is effective at triggering inflammation and eliciting successful tumor immunity in patients with non-muscle invasive bladder cancer, with 50 to 70% clinical response. Therapeutic success relies on repeated instillations of live BCG administered as adjuvant therapy shortly after tumor resection; however, the precise mechanisms remain unclear. Using an experimental model, we demonstrate that after a single instillation, BCG could disseminate to bladder draining lymph nodes and prime interferon-γ-producing T cells. Nonetheless, repeated instillations with live BCG were necessary for a robust T cell infiltration into the bladder. Parenteral exposure to BCG before instillation overcame this requirement; after the first intravesical instillation, BCG triggered a more robust acute inflammatory process and accelerated T cell entry into the bladder, as compared to the standard protocol. Moreover, parenteral exposure to BCG before intravesical treatment of an orthotopic tumor markedly improved response to therapy. Indeed, patients with sustained preexisting immunity to BCG showed a significant improvement in recurrence-free survival. Together, these data suggest that monitoring patients' response to purified protein derivative, and, in their absence, boosting BCG responses by parenteral exposure before intravesical treatment initiation, may be a safe and effective means of improving intravesical BCG-induced clinical responses.

Is bilateral extended pelvic lymphadenectomy necessary for strictly unilateral invasive bladder cancer?

We determined the necessary extent of pelvic lymph node dissection in patients with strictly unilateral bladder cancer.

[Lymphadenectomy for bladder cancer: current status and controversies]

Pelvic lymph node dissection is an integral part of the radical cystectomy procedure for patients with muscle-invasive bladder cancer. The optimal extent of the lymphadenectomy (LND) and mainly the proximal template boundary remain controversial issues. In view of the existing mapping studies and retrospective analyses, extended LND up to the mid-upper third of the common iliac vessels appears to provide further prognostic and therapeutic benefit and therefore should be defined as standard LND. This applies for all procedures irrespective of the choice of surgical approach (open surgery, minimally invasive approach). In this context total lymph node count is not a quality criterion because nodal yield is overly influenced by the individual patient's anatomy, surgical technique, template applied and pathological work-up. Consecutively, considerable inter-institutional differences result, which render any comparison impossible. Lymph node density is thought to be a superior prognostic factor, but it is similarly influenced by the above-mentioned factors. Concerning molecular techniques to improve the sensitivity of postoperative nodal staging further research is necessary. The two ongoing prospective randomized trials will potentially help to further define the optimal LND template.

ICUD-EAU International Consultation on Bladder Cancer 2012: urinary diversion

A summary of the 2nd International Consultation on Bladder Cancer recommendations on the reconstructive options after radical cystectomy (RC), their outcomes, and their complications.

Role and extent of lymphadenectomy during radical cystectomy for invasive bladder cancer

There is substantial variability in the extent of the node dissection performed during radical cystectomy for bladder cancer. Here, we review the diagnostic assessment of lymph node metastasis and the prognostic and therapeutic benefit for pelvic node dissection for bladder cancer. A review of the applicable urologic literature regarding the topics of lymphadenectomy for bladder cancer was conducted. Nodal metastasis above a limited or standard template is not uncommon, with up to 16% of all nodal metastasis detected proximal to the aortic bifurcation. However, skip metastasis is extremely rare. Proteins associated purely with epithelial tissue such as cytokeratin (CK)-19, CK-20, and uroplakin II have been observed in reportedly negative nodal specimens, which indicates that routine microscopic analysis of nodal tissue may miss small foci of metastatic cancer. In addition to the surgical technique, the total number of lymph nodes removed is influenced by patient anatomy and pathologic processing and therefore may be unsuitable as a procedural quality statement. Consecutively, meticulous removal of tissue within a defined and uniformly applied template may be more relevant than absolute nodal count. Observational cohort series indicate an improved oncologic outcome for patients undergoing extensive nodal dissection. The results of two randomized controlled trials addressing the extent of nodal dissection for bladder cancer are forthcoming.

The prognostic value of cytology and fluorescence in situ hybridization in the follow-up of nonmuscle-invasive bladder cancer after intravesical Bacillus Calmette-Guérin therapy

Molecular markers reliably predicting failure or success of Bacillus Calmette-Guérin (BCG) in the treatment of nonmuscle-invasive urothelial bladder cancer (NMIBC) are lacking. The aim of our study was to evaluate the value of cytology and chromosomal aberrations detected by fluorescence in situ hybridization (FISH) in predicting failure to BCG therapy. Sixty-eight patients with NMIBC were prospectively recruited. Bladder washings collected before and after BCG instillation were analyzed by conventional cytology and by multitarget FISH assay (UroVysion, Abbott/Vysis, Des Plaines, IL) for aberrations of chromosomes 3, 7, 17 and 9p21. Persistent and recurrent bladder cancers were defined as positive events during follow-up. Twenty-six of 68 (38%) NMIBC failed to BCG. Both positive post-BCG cytology and positive post-BCG FISH were significantly associated with failure of BCG (hazard ratio (HR)= 5.1 and HR= 5.6, respectively; p < 0.001 each) when compared to those with negative results. In the subgroup of nondefinitive cytology (all except those with unequivocally positive cytology), FISH was superior to cytology as a marker of relapse (HR= 6.2 and 1.4, respectively). Cytology and FISH in post-BCG bladder washings are highly interrelated and a positive result predicts failure to BCG therapy in patients with NMIBC equally well. FISH is most useful in the diagnostically less certain cytology categories but does not provide additional information in clearly malignant cytology.

Complications following radical cystectomy for bladder cancer in the elderly

CONTEXT: The incidence of bladder cancer increases with advancing age. Considering the increasing life expectancy and the increasing proportion of elderly people in the general population, radical cystectomy will be considered for a growing number of elderly patients who suffer from muscle-invasive or recurrent bladder cancer. OBJECTIVE: This article reviews contemporary complication and mortality rates after radical cystectomy in elderly patients and the relationship between age and short-term outcome after this procedure. EVIDENCE ACQUISITION: A literature review was performed using the PubMed database with combinations of the following keywords cystectomy, elderly, complications, and comorbidity. English-language articles published in the year 2000 or later were reviewed. Papers were included in this review if the authors investigated any relationship between age and complication rates with radical cystectomy for bladder cancer or if they reported complication rates stratified by age groups. EVIDENCE SYNTHESIS: Perioperative morbidity and mortality are increased and continence rates after orthotopic urinary diversion are impaired in elderly patients undergoing radical cystectomy. Complications are frequent in this population, particularly when an extended postoperative period (90 d instead of 30 d) is considered. CONCLUSIONS: Although age alone does not preclude radical cystectomy for muscle-invasive or recurrent bladder cancer or for certain types of urinary diversion, careful surveillance is required, even after the first 30 d after surgery. Excellent perioperative management may contribute to the prevention of morbidity and mortality of radical cystectomy, supplementary to the skills of the surgeon, and is probably a reason for the better perioperative results obtained in high-volume centers.

The impact of lymphadenectomy and lymph node metastasis on the outcomes of radical cystectomy for bladder cancer

CONTEXT: The presence of lymph node metastases and the extent of lymphadenectomy have both been shown to influence the outcome of patients with muscle-invasive bladder cancer. OBJECTIVE: Current standards for detection of lymph node metastases, lymph-node mapping studies, histopathologic techniques, and risk factors in relation to lymph node involvement are discussed. The impact of lymph node metastases and the extent of lymphadenectomy on the outcome of patients treated with radical cystectomy are analyzed. EVIDENCE ACQUISITION: A systematic literature review of bladder cancer and lymph nodes was performed searching the electronic databases Pubmed/Medline, Cochrane, and Embase. Articles were selected based on title, abstract, study format, and content by a consensus of all participating authors. EVIDENCE SYNTHESIS: Lymph node status is highly consequential in bladder cancer patients because the presence of lymph node metastases is predictive of poor outcome. Knowledge of primary landing sites of lymph node metastases is important for optimum therapeutic management. Accurate pathologic work-ups of resected lymph node tissue are mandatory. Molecular markers could potentially guide therapeutic decisions in the future because they may enable the detection of micrometastatic disease. In current series, radical cystectomy with an extended lymphadenectomy seems to provide a clinically meaningful therapeutic benefit compared with a limited approach. However, the anatomic boundaries of lymph node dissection are still under debate. Therefore, large prospective multicenter trials are needed to validate the influence of extended lymph node dissection on disease-specific survival. CONCLUSIONS: An extended pelvic lymph node dissection (encompassing the external iliac vessels, the obturator fossa, the lateral and medial aspects of the internal iliac vessels, and at least the distal half of the common iliac vessels together with its bifurcation) can be curative in patients with metastasis or micrometastasis to a few nodes. Therefore, the procedure may be offered to all patients undergoing radical cystectomy for invasive bladder cancer.

CCND1/CyclinD1 status in metastasizing bladder cancer: a prognosticator and predictor of chemotherapeutic response

The CCND1 gene encodes the protein CyclinD1, which is an important promoter of the cell cycle and a prognostic and predictive factor in different cancers. CCND1 is amplified to a substantial proportion in various tumors, and this may contribute to CyclinD1 overexpression. In bladder cancer, information about the clinical relevance of CCND1/CyclinD1 alterations is limited. In the present study, amplification status of CCND1 and expression of CyclinD1 were evaluated by fluorescence in situ hybridization and immunohistochemistry on tissue microarrays from 152 lymph node-positive urothelial bladder cancers (one sample each from the center and invasion front of the primary tumors, two samples per corresponding lymph node metastasis) treated by cystectomy and lymphadenectomy. CCND1 amplification status and the percentage of immunostained cancer cells were correlated with histopathological tumor characteristics, cancer-specific survival and response to adjuvant chemotherapy. CCND1 amplification in primary tumors was homogeneous in 15% and heterogeneous in 6% (metastases: 22 and 2%). Median nuclear CyclinD1 expression in amplified samples was similar in all tumor compartments (60-70% immunostained tumor nuclei) and significantly higher than in non-amplified samples (5-20% immunostained tumor nuclei; P<0.05). CCND1 status and CyclinD1 expression were not associated with primary tumor stage or lymph node tumor burden. CCND1 amplification in primary tumors (P=0.001) and metastases (P=0.02) and high nuclear CyclinD1 in metastases (P=0.01) predicted early cancer-related death independently. Subgroup analyses showed that chemotherapy was particularly beneficial in patients with high nuclear CyclinD1 expression in the metastases, whereas expression in primary tumors and CCND1 status did not predict chemotherapeutic response. In conclusion, CCND1 amplification status and CyclinD1 expression are independent risk factors in metastasizing bladder cancer. High nuclear CyclinD1 expression in lymph node metastases predicts favorable response to chemotherapy. This information may help to personalize prognostication and administration of adjuvant chemotherapy.

Timing and outcomes for radical cystectomy in nonmuscle invasive bladder cancer

PURPOSE OF REVIEW To provide an overview on the available clinical and pathological factors in high-risk nonmuscle invasive bladder cancer (NMIBC) patients that help to approximate the risk of progression to muscle invasion and identify 'the' patients requiring timely cystectomy. The value of a high-quality transurethral tumor resection is pointed out. Outcomes following radical cystectomy are compared with a primarily bladder preserving strategy. RECENT FINDINGS Carcinoma in situ within the prostatic urethra of NMIBC patients impacts on patient's outcome. Therefore, biopsies taken from the prostatic urethra improve the initial tumor staging accuracy. Lamina propria substaging may provide more detailed prognostic information. Lympho-vascular invasion within the transurethral resection specimen may help to detect patients who benefit from timely cystectomy. Recent findings from patients undergoing radical cystectomy including super-extended lymphadenectomy for clinically NMIBC confirm the substantial rate (25%) of tumor understaging. The fact that almost 10% were found to harbor lymph node metastases underlines the necessity to perform a meticulous lymphadenectomy in NMIBC patients undergoing radical cystectomy. SUMMARY High-quality transurethral bladder tumor resection including underlying muscle fibers is of utmost importance. Nevertheless, tumor understaging remains an issue of concern and warrants the value of a second transurethral resection in high-risk NMIBC patients. There is a persisting lack of rigid therapeutic recommendations in patients with high-risk NMIBC. Instead, treatment strategy is based on individual risk factors. However, irrespective of initial treatment strategy, there is a subgroup of high-risk NMIBC patients with progressive disease, leading almost inevitably to death.