Ureteroscopic and percutaneous management of upper tract urothelial carcinoma (UTUC): systematic review

What's known on the subject? and What does the study add? Endoscopic management of upper tract urothelial carcinoma (UTUC) using either ureteroscopy and laser ablation, or percutaneous resection, is a management option for treating selected low‐grade tumours with favourable characteristics. However, the evidence base for such practice is relatively weak, as the reported experience is mainly limited to small case series (level of evidence 4), or non‐randomised comparative studies that are unmatched for tumour stage (level of evidence 3b), with variability of follow‐up duration and reported outcome measures. The present systematic review comprehensively reviews the outcomes of all studies of endoscopic management of UTUC, including the role of topical adjuvant therapy. It establishes for the first time a structured reference for endoscopic management of UTUC, and is a foundation for further clinical studies.

OBJECTIVE

• ? To systematically review the oncological outcomes of upper tract urothelial carcinoma (UTUC) treated with ureteroscopic and percutaneous management.
• ? The standard treatment of UTUC is radical nephroureterectomy (RNU). However, over the last two decades several institutions have treated UTUC endoscopically, either via ureteroscopic ablation or percutaneous nephroscopic resection of tumour (PNRT), for both imperative and elective indications.

METHODS

• ? For evidence acquisition the Pubmed database was searched for English language publications in December 2011 using the following terms: upper tract (UT) transitional cell carcinoma (TCC), upper tract TCC, UTTCC, upper tract urothelial cell carcinoma, upper tract urothelial carcinoma, UTUC, endoscopic management, ureteroscopic management, laser ablation, percutaneous management, PNRT, conservative management, ureteroscopic biopsy, biopsy, BCG, mitomycin C, topical therapy.

RESULTS

• ? There are no randomised trials comparing endoscopic management with RNU. Most published studies were retrospective case series (and database reviews), or unmatched comparative studies.
• ? There was strong selection bias for favourable tumour characteristics in many endoscopically treated groups.
• ? There was variation in medical comorbidity and indication for treatment across different study groups.
• ? The biopsy verification of underlying UTUC pathology was inconsistent.
• ? The follow‐up in most studies was limited, typically to a mean 3 years.

CONCLUSIONS

• ? There is a high rate of UT recurrence with endoscopically managed UTUC, and a grade‐related risk of tumour progression and disease‐specific mortality.
• ? Overall, renal preservation may be high with ≈20% of patients proceeding eventually to RNU. For highly selected Grade 1 (or low‐grade) disease managed in experienced centres, 5‐year disease‐specific survival (DSS) may be equivalent to RNU, although the small study groups and short follow‐ups preclude comments on less favourable Grade 1 (or low‐grade) tumour characteristics, or DSS, in the longer‐term.
• ? For Grade 3 (or high‐grade) disease, DSS outcomes are poor and endoscopic management should only be considered for compelling imperative indications in the context of the patient's overall life expectancy and competing comorbidity.

     

International validation of the prognostic value of subclassification for AJCC stage pT3 upper tract urothelial carcinoma of the renal pelvis

Study Type – Prognosis (inception cohort) Level of Evidence 2a What's known on the subject? and What does the study add? Tumour stage is a powerful predictor of clinical outcomes and the most important factor driving clinical decision‐making after radical nephroureterectomy (RNU) in upper tract urothelial carcinoma (UTUC). It has been suggested that renal pelvic pT3 subclassification into microscopic infiltration of the renal parenchyma (pT3a) versus macroscopic infiltration or invasion of peripelvic adipose tissue (pT3b) has strong prognostic value. This is an external validation study of the prognostic value of pT3 subclassification of renal pelvic UTUC in a large international cohort of patients treated with RNU. pT3b UTUC is associated with features of aggressive tumour biology, disease recurrence and cancer‐specific mortality. However, pT3 subclassification is not an independent predictor of clinical outcomes.

OBJECTIVE

• ? To externally validate the prognostic value of subclassification of pT3 renal pelvic upper tract urothelial carcinoma (UTUC) in a large international cohort of patients treated with radical nephroureterectomy (RNU).

PATIENTS AND METHODS

• ? The RNU specimens with pT3 UTUC of the renal pelvis from 284 patients at 11 centres located in Asia, North America and Europe were retrospectively evaluated. All specimens were reviewed by genitourinary pathologists at each institution. Tumours were categorized as pT3a (microscopic infiltration of the renal parenchyma) or pT3b (macroscopic infiltration of the renal parenchyma and/or infiltration of peripelvic adipose tissue).

RESULTS

• ? Overall, 148 (52%) tumours were classified as pT3a and 136 (48%) as pT3b. Patients with pT3b disease were more likely to have high‐grade tumours and sessile tumour architecture (all P≤ 0.02). Patients with pT3b tumours were at increased risk of disease recurrence (5‐year estimates: 55% versus 42%, P= 0.012) and cancer‐specific mortality (CSM) (5‐year estimates: 48% versus 40%, P= 0.04). Lymph node status, tumour architecture and tumour grade were independently associated with disease recurrence, whereas lymph node status, tumour architecture and lymphovascular invasion were independently associated with CSM. Subclassification of pT3 tumours was not associated with recurrence or CSM in multivariable analyses.

CONCLUSION

• ? Patients with pT3b UTUC were more likely to have tumours with aggressive pathological features and were at higher risk of disease recurrence and CSM after RNU compared with patients with pT3a disease. However, the pT3 subclassification did not remain an independent predictor of disease recurrence or CSM after controlling for tumour grade, lymph node status, tumour architecture and lymphovascular invasion.

     

Long‐term endoscopic management of upper tract urothelial carcinoma: 20‐year single‐centre experience

Study Type – Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Endoscopic management of small, low‐grade, non‐invasive upper tract urothelial cell carcinoma (UTUC) is a management option for selected groups of patients. However, the long‐term survival outcomes of endoscopically‐managed UTUC are uncertain because only four institutions have reported outcomes of more than 40 patients beyond 50 months of follow‐up. Moreover, there is significant variance in the degree of underlying UTUC pathology verification in some of these reports, which precludes an analysis of disease‐specific survival outcomes. The present study represents one of the largest endoscopically managed series of patients with UTUC, with a long‐term follow‐up. The degree of verification of underlying UTUC pathology is one of the highest, which allows a grade‐stratified analysis of different outcomes, including upper‐tract recurrence‐free survival, intravesical recurrence‐free survival, renal unit survival and disease‐specific survival. These outcomes provide further evidence suggesting that endoscopic management of highly selected, low‐grade UTUC can provide effective oncological control, as well as renal preservation, in experienced centres.

OBJECTIVE

• ? To report the long‐term outcomes of patients with upper tract urothelial cell carcinoma (UTUC) who were treated endoscopically (either via ureteroscopic ablation or percutaneous resection) at a single institution over a 20‐year period.

PATIENTS AND METHODS

• ? Departmental operation records were reviewed to identify patients who underwent endoscopic management of UTUC as their primary treatment.
• ? Outcomes were obtained via retrospective analysis of notes, electronic records and registry data.
• ? Survival outcomes, including overall survival (OS), UTUC‐specific survival (disease‐specific survival; DSS), upper‐tract recurrence‐free survival, intravesical recurrence‐free survival, renal unit survival and progression‐free survival, were estimated using Kaplan–Meier methods and grade‐stratified differences were analyzed using the log‐rank test.

RESULTS

• ? Between January 1991 and April 2011, 73 patients underwent endoscopic management of UTUC with a median age at diagnosis of 67.7 years.
• ? All patients underwent ureteroscopy and biopsy‐confirmation of pathology was obtained in 81% (n= 59) of the patients. In total, 14% (n= 10) of the patients underwent percutaneous resection.
• ? Median (range; mean) follow‐up was 54 (1–223; 62.8) months.
• ? Upper tract recurrence occurred in 68% (n= 50). Eventually, 19% (n= 14) of the patients proceeded to nephroureterectomy.
• ? The estimated OS and DSS were 69.7% and 88.9%, respectively, at 5 years, and 40.3% and 77.4%, respectively, at 10 years. The estimated mean and median OS times were 119 months and 107 months, respectively. The estimated mean DSS time was 190 months.

CONCLUSIONS

• ? The present study represents one of the largest reported series of endoscopically‐managed UTUC, with high pathological verification and long‐term follow‐up.
• ? Upper‐tract recurrence is common, which mandates regular ureteroscopic surveillance.
• ? However, in selected patients, this approach has a favourable DSS, with a relatively low nephroureterectomy rate, and therefore provides oncological control and renal preservation in patients more likely to die eventually from other causes.

     

Comparison of oncological outcomes after segmental ureterectomy or radical nephroureterectomy in urothelial carcinomas of the upper urinary tract: results from a large French multicentre study

Study Type – Therapy (multi‐centre retrospective cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Upper urinary tract urothelial carcinomas (UUT‐UCs) are rare tumours. Because of the aggressive pattern of UC, radical nephroureterectomy (RNU) with bladder cuff removal remains the ‘gold‐standard’ treatment. However, conservative strategies, such as segmental ureterectomy (SU) or endourological management, have also been developed in patients with imperative indications. Some teams are now advocating the use of conservative management more commonly in cases of elective indications of UUT‐UCs. Due to the paucity of cases of UUT‐UC, only limited data are available on the oncological outcomes afforded by conservative management. We retrospectively investigated the oncological outcomes after SU and RNU in a large multi‐institutional database. Overall, 52 patients were treated with SU and 416 with RNU. There was no statistical difference between the RNU and SU groups for the 5‐year probability of cancer‐specific survival, recurrence‐free survival and metastasis‐free survival. The type of surgery was not a significant prognostic factor in univariate analysis. The results were the same in a subgroup analysis of only unifocal tumours of the distal ureter with a diameter of <2 cm and of low stage (≤T2). Our results suggest that oncological outcomes after conservative treatment with SU are comparable to RNU for the management of UUT‐UC in select cases.

OBJECTIVE

• ? To compare recurrence‐free survival (RFS), metastasis‐free survival (MFS) and cancer‐specific survival (CSS) after segmental ureterectomy (SU) vs radical nephroureterectomy (RNU) for urothelial carcinoma (UC) of the upper urinary tract (UUT‐UC) located in the ureter.

PATIENTS AND METHODS

• ? We performed a multi‐institutional retrospective review of patients with UUT‐UC who had undergone RNU or SU between 1995 and 2010.
• ? Type of surgery, Tumour‐Node‐Metastasis status, tumour grade, lymphovascular invasion and positive surgical margin were tested as prognostic factors for survival.

RESULTS

• ? In all, 52 patients were treated with SU and 416 with RNU. The median (range) follow‐up was 26 (10–48) months.
• ? The 5‐year probability of CSS, RFS and MFS for SU and RNU were 87.9% and 86.3%, respectively (P= 0.99); 37% and 47.9%, respectively (P= 0.48); 81.9% and 85.4%, respectively (P= 0.51).
• ? In univariable analysis, type of surgery (SU vs RNU) failed to affect CSS, RFS and MFS (P= 0.94, 0.42 and 0.53, respectively).
• ? In multivariable analyses, pT stage and pN stage achieved independent predictor status for CSS (P= 0.005 and 0.007, respectively); the positive surgical margin and pT stage were independent prognostic factors of RFS and MFS (P= 0.001, 0.04, 0.009 and 0.001, respectively).
• ? The main limitation of the study is its retrospective design, which is due to the rarity of the disease.

CONCLUSIONS

• ? Short‐term oncological outcomes after conservative treatment with SU are comparable to RNU for the management of UUT‐UC in select cases and should be considered an option.
• ? In every other case, RNU still represents the ‘gold standard’ for the treatment of UUT‐UC.

     

Secondary bladder cancer after upper tract urothelial carcinoma in the US population

Study Type – Prognosis (cohort) Level of Evidence 2a What's known on the subject? and What does the study add? It is known that a certain percentage of patients treated for upper tract urothelial carcinoma (UTUC) will go on to develop a secondary bladder cancer; however, the risk factors for developing a secondary bladder tumour have not been studied in a population‐based setting. Given the large changes in how UTUC has been diagnosed and managed in recent years, this study aimed to evaluate the natural history of UTUC in the US population over a 30‐year period, with a particular emphasis on the development of secondary bladder cancer.

OBJECTIVE

• ? To assess the natural history of upper tract urothelial carcinoma (UTUC) and the development of lower tract secondary cancer.

PATIENTS AND METHODS

• ? Patients diagnosed with UTUC between 1975 and 2005 were identified within nine Surveillance, Epidemiology and End Results registries.
• ? Baseline characteristics of patients with and without secondary bladder cancer were compared.
• ? A multivariate logistic regression model was fitted to test if the year of diagnosis predicted the likelihood of developing a secondary bladder cancer.

RESULTS

• ? Of the 5212 patients with UTUC, 242 (4.6%) had a secondary bladder cancer (range: 1.7–8.2%).
• ? There was a mean interval of 26.5 (95% CI: 22.2–30.8) months between cancer diagnoses.
• ? Compared with those without secondary tumours, patients with secondary bladder malignancy were more likely to present with larger tumours (4.2 vs 3.1 cm, P < 0.001) and with tumours located in the ureter (P < 0.001).
• ? Year of diagnosis was not a predictor of the likelihood of having a secondary bladder malignancy in a multivariate analysis controlling for demographic and tumour characteristics (odds ratio: 0.99; 95% CI: 0.95–1.03)

CONCLUSIONS

• ? Patients with larger urothelial tumours located in the ureter were those most likely to develop a secondary lower tract tumour.
• ? No longitudinal changes in the rate of secondary bladder cancer were noted among patients with UTUC over the 30‐year study period.

     

Upstaging of urothelial cancer at the time of radical cystectomy: factors associated with upstaging and its effect on outcome

Study Type – Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? The reported discordance between staging on transurethral bladder resection and on radical cystectomy pathology in the literature ranges from 20 to 80%.Correct staging in bladder cancer has direct implications for its management. The upstaging from organ‐confined (OC) to non‐organ‐confined (nOC) disease has been reported in 40% of cases. Lymphovascular invasion (LVI) is a factor known to be associated with poor clinical outcome. Pathological upstaging was observed in our cohort in 40% of cases and most cases (80%) were upstaged from OC to nOC disease. During the study period the frequency of upstaging observed increased. We found LVI (hazard ratio [HR]= 5.07, 95% CI = 3.0–8.3, P < 0.001) and any histological variant variant (HR = 2.77, 95% CI = 1.6–4.8, P < 0.001) to be strong independent predictors of upstaging. Patients with clinical T2 bladder cancer found with upstaging at the time of radical cystectomy had a poorer outcome than patients with no upstaging. Identification of patients at high risk of upstaging at radical cystectomy is key to improving their management and outcome.

OBJECTIVES

• ? To analyse the details of bladder cancer (BC) staging in a large combined radical cystectomy (RC) database from two academic centres.
• ? To study rate and time trends, as well as risk factors for upstaging, especially clinical factors associated with staging errors after RC.

PATIENTS AND METHODS

• ? Characteristics of patients undergoing RC at University Health Network, Toronto, Canada (1992–2010) and University of Turku, Turku, Finland (1986–2005) were analysed.

RESULTS

• ? Among 602 patients undergoing RC, 306 (51%) had a discordance in clinical and pathological stages. Upstaging occurred in 240 (40%) patients and 192 (32%) patients were upstaged from organ‐confined (OC) to non‐organ‐confined (nOC) disease.
• ? During the study period, upstaging became more common in both centres.
• ? In multivariate analyses, T2 disease at initial presentation (P= 0.001, odds ratio [OR]= 2.62, 95% confidence interval [CI]: 1.44–4.77), high grade disease (P= 0.01, OR = 2.85, 95% CI: 1.21–6.7), lymphovascular invasion (LVI) (P < 0.001, OR = 5.17, 95% CI: 3.48–7.68), female gender (P= 0.038, OR = 0.6, 95% CI: 0.38–0.97, and histological variants (P < 0.001, OR = 2.77, 95% CI: 1.6–4.8) were associated with a risk of upstaging from OC to nOC disease.
• ? Upstaged patients had worse survival rates than patients with correct staging. This was especially significant among patients with carcinoma invading bladder muscle before undergoing RC (16% vs 46% 10‐year disease‐specific mortality, P < 0.001).

CONCLUSIONS

• ? Upstaging is a common problem and unfortunately no improvements have been observed during the last two decades.
• ? LVI and the presence of histological variants are strong predictors of upstaging at the time of RC.
• ? Pathologists should be encouraged to report LVI and any histological variant at the time of TURBT.

     

Impact of pathological tumour characteristics in patients with sarcomatoid renal cell carcinoma

Study Type – Prognosis (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Sarcomatoid renal cell carcinoma can occur in the setting of all histological subtypes of kidney cancer. These tumours are very aggressive and many patients present with disseminated disease. Long‐term survival is poor and the durable responses to systemic therapy are infrequent. Our large cohort analyses the influence of pathological tumour characteristics in determining prognosis for patients with sarcomatoid renal cell carcinoma undergoing surgical resection. This series helps define the prognostic influence of histological subtype, type of sarcomatoid morphology, the percentage necrosis and sarcomatoid features, and the presence of microvascular invasion.

OBJECTIVES

• ? To examine the influence of pathological tumour characteristics on survival to aid prognostication and clinical trial design.
• ? Patients with sarcomatoid renal cell carcinoma (sRCC) are known to have poor prognosis and response to systemic therapy.

PATIENTS AND METHODS

• ? A single‐centre database was reviewed to identify all patients with sRCC.
• ? Clinical variables and pathological information, including histology, necrosis, percentage of sarcomatoid features (PSF) and microvascular invasion (MVI), were recorded and correlated to outcome.

RESULTS

• ? Analyses of 104 patients with sRCC found that the median (range) size of tumours was 9.5 cm (2.5–30), 65% of patients had areas of clear cell histology, and 69.2% had metastatic disease at presentation.
• ? The PSF did not influence tumour size, stage, necrosis, MVI, nodes or metastasis.
• ? A total of 85 patients (81.7%) died during the follow‐up period with a median (95% confidence interval [CI]) survival of 5.9 months (4.7–8.9).
• ? In the overall cohort, Eastern Cooperative Group performance status (ECOGPS), tumour size and metastatic disease were independent predictors of poor survival. MVI, PSF and percentage necrosis were strongly associated with outcome but were not independent predictors of outcome.
• ? A multivariate risk model was established that incorporated six covariates (tumour size, MVI, ECOGPS, PSF, necrosis, and metastatic disease) to produce a predictive tool.

CONCLUSIONS

• ? Both patients with localized and metastatic sRCC have very poor survival outcomes.
• ? Pathological features MVI, PSF and necrosis are important predictors of survival and could be used in a prognostic model while grade and histology do not influence prognosis.
• ? A prognostic model, if validated, could aid in patient counselling and/or clinical trial design.

     

The use of estramustine phosphate in the modern management of advanced prostate cancer

What’s known on the subject? and What does the study add? Estramustine phosphate has anti‐tumour properties and it improves patient outcomes if combined with other chemotherapy agents such as doeetaxel. The efficacy of estramustine phosphate in selected patients and its safety profile, provided used with any low‐molecular‐weight heparin support its use as a second‐line treatment in hormone‐resistant prostate cancer.

OBJECTIVES

• ? Estramustine phosphate is a nitrogen mustard derivative of estradiol‐17β‐phosphate and has anti‐tumour properties.
• ? Interest in estramustine has been renewed because of the results of clinical studies showing improved patient outcomes if estramustine is combined with other chemotherapy agents such as docetaxel.

PATIENTS AND METHODS

• ? Relevant clinical studies using chemotherapy combinations including estramustine are discussed.
• ? Efficacy and safety outcomes are summarized.

RESULTS

• ? Combination therapy with estramustine and docetaxel can increase PSA response rates, improve quality of life and increase median patient survival compared with chemotherapy regimens that do not include estramustine.
• ? Although the overall tolerability of estramustine is favourable, its use can be associated with an increased risk of thromboembolic events.

CONCLUSIONS

• ? The identification of suitable patient groups and the effective management of the risk of thromboembolism with the adjunct of low‐molecular‐weight heparins support the use of estramustine as an effective second‐line treatment strategy in hormone‐resistant prostate cancer.
• ? These promising findings warrant further investigation in a randomized clinical trial.

     

Erectile dysfunction is predictive of all-cause mortality in patients with prostate cancer treated with permanent interstitial brachytherapy

Study Type – Prognosis (individual cohort) Level of Evidence 2b What’s known on the subject? and What does the study add? Cardiovascular disease is a leading cause of death in prostate cancer patients. Pretreatment ED is a surrogate for vascular pathology. Aggressive treatment of medical co‐morbidity in prostate cancer patients may positively impact overall survival.

OBJECTIVE

• ? To evaluate the relationship between pre‐treatment erectile function and all‐cause mortality in patients with prostate cancer treated with brachytherapy.

PATIENTS AND METHODS

• ? In all, 1279 consecutive patients with clinically localized prostate cancer and pre‐implant erectile function assessed by the International Index of Erectile Function‐6 (IIEF‐6) underwent brachytherapy.
• ? Potency was defined as an IIEF‐6 score of ≥13 without pharmacological or mechanical support.
• ? Patients were stratified into IIEF‐6‐score cohorts (≤12, 13–23 and 24–30).
• ? The median follow‐up was 5.0 years.

RESULTS

• ? The 8‐year overall survival (OS) of the study population was 85.1%.
• ? The 8‐year OS for IIEF‐6scores ≤12, 13–23 and 24–30 were 78.0%, 92.8% and 91.4%, respectively (P < 0.001).
• ? Cardiovascular events accounted for a significant portion of deaths in each IIEF‐6 group.
• ? When combined with other risk factors for cardiovascular disease, an IIEF‐6 score of ≤12 had an additive effect on all‐cause mortality (IIEF‐6 score of ≤12 and less than two comorbidities vs two or more comorbidities were 18.2% and 32.1%).

CONCLUSIONS

• ? A pre‐implant IIEF‐6score of ≤12 was associated with a higher incidence of all‐cause mortality.
• ? Pre‐treatment erectile dysfunction is a surrogate for underlying vascular pathology, probably explaining the lower OS in this subset of patients.
• ? Aggressive treatment of medical co‐morbidity is warranted to impactOS.

     

Human papillomavirus prevalence, distribution and correlation to histopathological parameters in a large Swedish cohort of men with penile carcinoma

Study Type – Aetiology (case series) Level of Evidence 4

OBJECTIVE

• ? To analyse the overall and type‐specific human papillomavirus (HPV) prevalence and distribution in penile carcinoma and determine the correlation to histopathological parameters.

PATIENTS AND METHODS

• ? In this retrospective study, we analysed HPV status in 241 patients with penile carcinoma, treated at Örebro University Hospital, Örebro, Sweden, between 1984 and 2008. Age and date at diagnosis was recorded.
• ? The tumour specimens were categorized according to the UICC 2002 TNM classification. A subset of patients was operatively staged with regard to lymph node status.
• ? A commercially available Real Time PCR was used to detect 13 different types of HPV (6,11,16,18,31,33,35,45,51,52,56,58 and 59).

RESULTS

• ? We excluded 25 patients due to low DNA quality. Of the remaining 216, 179 (82.9%) tumour specimens were HPV infected. The majority of cases positive for HPV (70.4%) were infected by a single‐type. The most frequent type was HPV 16 followed by HPV 18.
• ? No significant association between HPV status and pathological tumour stage, grade or lymph node status was found.

CONCLUSION

• ? The HPV prevalence found is higher than in most other studies, further strengthening HPV as an etiological agent in penile carcinoma. Furthermore, the high prevalence of HPV 16 and 18 raises the question of what potential impact current HPV vaccines that target these specific HPV types might have on penile carcinoma. No significant association between HPV status and histopathological parameters was found in the present study. Additional investigations are needed to draw final conclusions on the prognostic value of HPV status in penile carcinoma.

     

Prognostic significance of lymphovascular invasion in radical prostatectomy specimens

Study Type – Prognosis (systematic review) Level of Evidence 1a What's known on the subject? and What does the study add? Prognostic factors such as serum PSA, tumor T stage, and Gleason grading are commonly used to predict disease progression and mortality in prostate cancer and to guide treatment decision‐making. These markers are combined to define risk strata that are commonly accepted in practice. Despite the assignment of patients to a specific risk stratum (e.g. intermediate‐risk disease), however, within‐stratum survival duration varies considerably, suggesting that many other factors, including lymphovascular invasion (LVI) may influence prognosis. LVI is currently a recognized prognostic factor in the management of some cancers (e.g. in early‐stage breast cancer) and prostate cancer is known to spread via lymphatic channels. Furthermore, the reporting of microscopic lymphovascular invasion is now considered part of the standard pathologic report of prostatectomy specimens. Nevertheless, scientific studies in this area have produced conflicting conclusions regarding the utility of LVI as a prognostic indicator in prostate cancer. This paper provides a comprehensive review and synthesis of the recent literature. Although a number of studies examining the role of LVI as an independent prognostic factor for biochemical recurrence in prostate cancer have been reported, the characteristics, quality and results of these studies vary considerably. The value of using LVI as a prognostic factor in prostate cancer remains unclear. This study provides a systematically‐performed synthesis of the results of recent research including lymphovascular invasion (LVI) in the multivariate analyses of potential prostate cancer prognostic factors. Not only do we report on the results of these studies, we assess the heterogeneity of the study populations, disease characteristics, and quality of the studies. Ultimately, we determined that meta‐analysis of the existing data is not possible, and thus, there is no ‘best estimate’ of the strength of association between LVI status and disease recurrence after prostatectomy. Most studies, but not all, reveal a weak or statistically insignificant association between LVI status and recurrence. We therefore conclude with a recommendation to clinicians that they should not overweight the importance of LVI status on clinical prognostication. The use of LVI status as a strong predictor of clinical outcomes is not recommended.

OBJECTIVES

• ? To synthesize the results of studies including lymphovascular invasion (LVI) in the multivariate analyses of potential prostate cancer prognostic factors.
• ? To determine the role of LVI as an independent prognostic factor for biochemical recurrence in prostate cancer.

PATIENTS AND METHODS

• ? We performed a comprehensive systematic literature review of studies examining the association between LVI in prostatectomy specimens and prostate cancer recurrence.
• ? Ovid MEDLINE, Embase, Web of Knowledge, Cochrane Database of Systematic Reviews, Database of Abstracts of Review of Effects (DARE) and Google Scholar were searched from January 2000 to February 2009.
• ? The primary outcome of interest was biochemical recurrence measured by serum prostate specific antigen (PSA).

RESULTS

• ? One thousand two hundred and forty‐eight papers met our search criteria. Of these, 19 articles meeting our selection criteria reported results of a multivariate analysis to evaluate LVI as an independent prognostic factor of biochemical recurrence.
• ? Eleven (58%) of these studies concluded that LVI was an independent prognostic factor.
• ? Significant heterogeneity in the study population, disease characteristics and quality of the studies prevented meta‐analysis of the results.
• ? In the nine studies in which the magnitude of independent association of LVI with recurrence was reported, it ranged from an odds ratio or relative risk of 1.37 to 4.39.

CONCLUSIONS

• ? The existing literature is conflicting and of insufficient homogeneity to definitively establish LVI as an important independent prognostic factor of biochemical recurrence in prostate cancer prostatectomy specimens.
• ? Additional adequately powered studies are required to determine the clinical value of reports of LVI involvement.
• ? In the meantime, the use of LVI status as an independent prognostic factor for clinical prognostication and medical decision making is not recommended.

     

Evans blue as a selective dye marker for white-light diagnosis of non-muscle-invasive bladder cancer: an in vitro study

What's known on the subject? and What does the study add? We found that Evans blue preferentially accumulate in spheroids prepared from urothelial cell carcinoma (UCC) cells as compared to spheroids composed of normal human urothelial (NHU) cells. The present findings could be important for future developments in clinical diagnostics for early bladder cancer detection staging and grading involving white light cystocopy.

OBJECTIVE

• ? To develop a diagnostic method relying on the preferential accumulation of a dye in non‐muscle‐invasive bladder cancer (NMIBC) that is visible in conjunction with white‐light cystoscopy (WLC).

MATERIALS AND METHODS

• ? We investigated in detail the permeation of Evans blue in urothelial cell carcinoma (UCC) spheroids prepared from T24, J82 and RT‐112 human cell lines and spheroids composed of normal human urothelial (NHU) cells.
• ? To gain more insight into the differential accumulation, all spheroids were investigated ultrastructurally using transmission electron microscopy (TEM).

RESULTS

• ? We found that, after exposure to Evans blue for 2 h, UCC spheroids accumulated dramatically more dye than spheroids composed of NHU cells.
• ? Using TEM it was found that the malignant spheroids contain similar ultrastructural characteristics, i.e. a wide intercellular space and a decreased number of desmosome‐like cell attachments, to those from clinical samples of non‐papillary carcinoma in situ of the bladder.

CONCLUSION

• ? We believe the present findings could be important for future developments in clinical diagnostics for early bladder cancer detection, staging and grading involving WLC.

     

Impact of age on clinicopathological outcomes and recurrence-free survival after the surgical management of nonseminomatous germ cell tumour

Study Type – Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? The effect of advancing age on the clinicopathological outcomes of men with germ cell testicular cancers remains uncertain. Through the review and comparison of the present large cohort of men with testis cancer, we report on our experience in men aged ≥50 years. Our results showed similar clinical and pathological characteristics, and survival outcomes that compare favourably with those of men aged <50 years.

OBJECTIVE

• ? To determine the impact of age on clinicopathological findings and disease recurrence in men with nonseminomatous germ cell tumour (NSGCT) undergoing retroperitoneal lymph node dissection (RPLND).

PATIENTS AND METHODS

• ? We identified 1246 patients with NSGCT who underwent either primary or post‐chemotherapy‐RPLND (PC‐RPLND) between 1989 and 2006 from our prospective testis cancer database.
• ? Perioperative characteristics were compared among men aged < or ≥50 years.
• ? Multivariable models were used to evaluate the association of age with disease‐free survival, controlling for established clinical and pathological features.

RESULTS

• ? Of 514 men undergoing primary and 732 men undergoing PC‐RPLND, 12 (2.3%) and 23 (3.1%) were aged ≥50 years, respectively.
• ? There were no significant differences between men aged < or ≥50 years for perioperative clinicopathological characteristics, with the exception of pre‐RPLND CT nodal size.
• ? The pathological distributions at primary RPLND were similar in men aged < or ≥50 years. After PC‐RPLND, there were no differences in RPLND histology, number of lymph nodes resected, estimated blood loss, hospital stay, or perioperative complication rate.
• ? Age at surgery was not a significant predictor of disease recurrence when subjected to a multivariable analysis.

CONCLUSIONS

• ? Our data suggests that age at RPLND does not predict for disease recurrence and men aged ≥50 years had similar pre‐ and postoperative characteristics to those aged <50 years.
• ? We conclude that RPLND can be safely performed in men aged ≥50 years and these patients should be offered optimal treatment regimens for NSGCT as directed according to established guidelines.

     

Significant impact of age at diagnosis on the prognosis of Japanese patients with pT1 renal cell carcinoma following surgical resection

Study Type – Prognosis (individual cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Several parameters significantly associated with the prognosis of patients with small venal cell carcinoma (RCC) have been reported; however, the outcomes described in such studies are not totally consistent, and the majority of these studies were based on the data from Western populations. Age of diagnosis is a significant predictor of disease recurrence as well as overall survivals in Japanese patients with pT1 RCC following surgical resection; therefore, intensive follow‐up of older patients is necessary even for those with pT1 RCC.

OBJECTIVE

• ? To retrospectively review oncological outcomes following surgical resection in Japanese patients with pT1 renal cell carcinoma (RCC).

PATIENTS AND METHODS

• ? The present study included a total of 832 consecutive Japanese patients who underwent either radical or partial nephrectomy and were subsequently diagnosed as having localized pT1 RCC.
• ? The significance of several clinicopathological factors in their postoperative outcomes was analysed.

RESULTS

• ? The median (range) age of the 832 patients was 66 (31–90) years. Radical and partial nephrectomies were performed for 710 patients (85.3%) and 122 patients (14.7%), respectively. Distribution of pathological stage was pT1a in 582 patients (70.0%) and pT1b in 250 patients (30.0%).
• ? During the observation period (median 44 months, range 3–114 months), postoperative disease recurrence developed in 38 patients (4.6%) and death occurred in 34 (4.1%). The 5‐year recurrence‐free and overall survival rates were 93.6% and 94.1%, respectively.
• ? Of several factors examined, only age at diagnosis was identified as an independent predictor of both postoperative disease recurrence and overall survival in these patients. Furthermore, there were significant differences in the recurrence‐free and overall survivals among patient groups stratified by age at diagnosis.

CONCLUSION

• ? These findings suggest that age at diagnosis is a significant predictor of disease recurrence as well as overall survival in patients with pT1 RCC following surgical resection; therefore, intensive follow‐up of older patients is necessary even for those with pT1 RCC.

     

Radical nephrectomy with vena caval thrombectomy: a contemporary experience

Study Type – Therapy (case series)
Level of Evidence 4 What’s known on the subject? and What does the study add? Renal tumours with caval thrombus are relatively rare. Surgical management is the standard of care for lesions of this nature. Small series have been published by other groups, but our understanding of the optimal management continues to evolve. We present the Memorial Sloan‐Kettering Cancer Center series, with a discussion of techniques and complications. Of interest, we include several patients with high‐level caval thrombi which were managed without bypass, supporting previous publications by the group from University of Miami.

OBJECTIVE

• ? To report on the contemporary Memorial Sloan‐Kettering Cancer Center experience with radical nephrectomy and vena caval thrombectomy.

PATIENTS AND METHODS

• ? Patients who underwent radical nephrectomy and vena caval thrombectomy without the use of bypass techniques were retrospectively identified.
• ? Data were collected on intraoperative and pathological findings as well as postoperative complications and oncological outcomes.

RESULTS

• ? In all, 78 patients underwent radical nephrectomy with off‐bypass resection of vena caval thrombus between 1989 and 2009.
• ? The median (interquartile range, IQR) operation duration was 293 (226–370) min, and median (IQR) blood loss was 1300 (750–2500) mL. In all, 10 patients (13%) were confirmed to have intra‐ or supra‐hepatic tumour thrombus (level 3/4), eight of whom required supra‐hepatic control of the inferior vena cava (IVC).
• ? Major (grade 3–5) postoperative complications occurred in 14 (18%), with five postoperative deaths. Disease recurred in 27/62 patients who were considered completely resected at surgery and had adequate follow‐up.
• ? The overall 5‐year survival (95% confidence interval) probability was 48% (35–60%).

CONCLUSIONS

• ? Radical nephrectomy with vena caval thrombectomy is associated with acceptable postoperative morbidity and mortality, and long‐term survival is possible in some patients.
• ? Many level 3/4 thrombi could be safely approached without the use of bypass techniques.

     

RADICAL CYSTECTOMY FOR BCG FAILURE: HAS THE TIMING IMPROVED IN RECENT YEARS?

Study Type – Therapy (case series) Level of Evidence 4 What’s known on the subject? and What does the study add? High‐grade Ta‐T1‐carcinoma in situ bladder cancer is a heterogeneous group; long‐term studies have shown that intravesical BCG therapy can be inadequate in a substantial percentage. Despite concerns about delay in performing RC for patients failing one or more courses of BCG, in our study we have not observed a trend towards a lower pathological stage for patients undergoing RC after BCG.

OBJECTIVE

• ? To analyse if there is a trend in recent years towards performing radical cystectomy (RC) before muscle invasion or extravesical spread after failure of bacille Calmette–Guérin (BCG) for high grade Ta/T1 bladder cancer. Although BCG is indicated for prophylaxis after endoscopic tumour resection there is still a risk of progression.

PATIENTS AND METHODS

• ? A retrospective analysis of our RC database (1992–2008) was performed to identify patients who underwent RC after receiving BCG.
• ? Relevant clinical and pathological data for the patients with clinical stage Ta, T1 and/or Tis at initial transurethral resection of bladder tumour were analysed.
• ? Pathological stage and survival for patients undergoing RC from 2003 to 2007 (group 2) were compared with those for patients operated between 1992 and 2002 (group 1).

RESULTS

• ? A total of 152 patients were included (75 in group 2 and 77 in group 1). Both groups were similar in T‐stage before BCG initiation, number of BCG cycles received and time interval to RC.
• ? There was no change in the proportion of patients undergoing RC with ≥pT2 bladder cancer in recent years (P= 0.5).
• ? Fifty‐two percent of group 2 and 43% of group 1 had ≥pT2 BC. The 5‐year survival was similar.

CONCLUSIONS

• ? Despite concerns about delay in performing RC for patients failing one or more courses of BCG we have not observed a trend towards a lower pathological stage for patients undergoing RC after BCG.
• ? A high proportion of patients have muscle‐invasive bladder cancer; more than 10% have lymph node metastasis.

     

Genome gender diversity in affected sib-pairs with familial vesico-ureteric reflux identified by single nucleotide polymorphism linkage analysis

Study Type – Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Despite a lack of randomised controlled trials, most men with locally advanced prostate cancer are recommended to undergo external beam radiotherapy (EBRT), often combined with long‐term androgen‐deprivation therapy (ADT). Many of these men are not offered radical prostatectomy (RP) by their treating urologist. Additionally, it is know that EBRT with long‐term ADT does provide good cancer control (88% at 10 years). We have previously published intermediate‐term follow‐up of a large series of men treatment with RP for cT3 prostate cancer. We report long‐term follow‐up of a large series of men treated with RP as primary treatment for cT3 prostate cancer. Our study shows that with long‐term follow‐up RP provides excellent oncological outcomes even at 20 years. While most men do require a multimodal treatment approach, many men can be managed successfully with RP alone.

OBJECTIVE

• ? To present long‐term survival outcomes after radical prostatectomy (RP) for patients with cT3 prostate cancer, as the optimal treatment for patients with clinical T3 prostate cancer is debated.

PATIENTS AND METHODS

• ? We identified 843 men who underwent RP for cT3 tumours between 1987 and 1997.
• ? Survival was estimated using the Kaplan–Meier method.
• ? Cox proportional hazards regression models were used to evaluate the association of clinicopathological features with outcome

RESULTS

• ? The median (range) postoperative follow‐up was 14.3 (0.1–23.5) years.
• ? Down‐staging to pT2 disease occurred in 26% (223/843) at surgery.
• ? Local recurrence‐free, systemic progression‐free and cancer‐specific survival for men with cT3 prostate cancer after RP was 76%, 72%, and 81%, respectively, at 20 years.
• ? On multivariate analysis, increasing RP Gleason score (hazard ratio [HR] 1.8; P= 0.01), non‐diploid chromatin content (HR 1.8; P= 0.01), positive surgical margins (HR 2.1; P= 0.007), and seminal vesicle invasion (HR 2.1; P= 0.005) were associated with a significant risk of prostate cancer death, while a more recent year of surgery was associated with a decreased risk of cancer‐specific mortality (HR 0.88; P= 0.01)

CONCLUSIONS

• ? RP affords accurate pathological staging and may be associated with durable cancer control for cT3 prostate cancer, with 20 years of follow‐up presented here.
• ? RP as part of a multimodal treatment strategy therefore remains a viable treatment option for patients with cT3 tumours.

     

Early oncological outcomes for bladder urothelial carcinoma patients treated with robotic-assisted radical cystectomy

Study Type – Therapy (case series) Level of Evidence 4

OBJECTIVE

• ? To determine oncological outcomes including early survival rates among unselected bladder urothelial carcinoma (BUC) patients treated with robotic‐assisted radical cystectomy (RRC).

PATIENTS AND METHODS

• ? Clinicopathologic and survival data were prospectively gathered for 85 consecutive BUC patients treated with RRC.
• ? The decision to undergo a robotic rather than open approach was made without regard to tumor volume or surgical candidacy.
• ? Kaplan–Meier survival rates were determined and stratified by tumor stage and LN positivity, and multivariate analysis was performed to identify independent predictors of survival.

RESULTS

• ? Patients were relatively old (25% >80 years; median 73.5 years), with frequent comorbidities (46% with ASA class ≥3). Of these patients 28% had undergone previous pelvic radiation or pelvic surgery, and 20% had received neoadjuvant chemotherapy.
• ? Extended pelvic lymphadenectomy was performed in 98% of patients, with on average 19.1 LN retrieved.
• ? On final pathology, extravesical disease was common (36.5%).
• ? Positive surgicalmargins were detected in five (6%) patients, all of whom had extravesical tumors with perineural and/or lymphovascular invasion, and most of whom were >80 years old.
• ? At a mean postoperative interval of 18 months, 20 (24%) patients had developed recurrent disease, but only three (4%) patients had recurrence locally. Disease‐free, cancer‐specific and overall survival rates at 2 years were 74%, 85% and 79%, respectively. Patients with low‐stage/LN(?) cancers had significantly better survival than extravesical/LN(?) or any‐stage/LN(+) patients, with stage being the most important predictor on multivariate analysis.

CONCLUSION

• ? RRC can achieve adequately high LN yields with a low positive margin rate among unselected BUC patients.
• ? Early survival outcomes are similar to those reported in contemporary open series, with an encouragingly low incidence of local recurrence, however long‐term follow‐up and head‐to‐head comparison with the open approach are still needed.

     

Comparison of the rate, location and size of positive surgical margins after laparoscopic and robot-assisted laparoscopic radical prostatectomy

Study Type – Therapy (case series) Level of Evidence 4

OBJECTIVE

• ? To review and compare the rate, location and size of positive surgical margins (PSMs) after pure laparoscopic radical prostatectomy (LRP) and robot‐assisted laparoscopic radical prostatectomy (RALP).

PATIENTS AND METHODS

• ? The study comprised 200 patients who underwent RALP and 200 patients who underwent LRP up to January 2008.
• ? We compared patient age, body mass index, preoperative prostate‐specific antigen (PSA), preoperative stage and grade, prostate size, pathological stage and grade and neurovascular bundle preservation, as well as PSM rate, size and location.
• ? Continuous and categorical data were compared using Student’s t‐test and Pearson’s chi‐squared test.
• ? Multivariate regression analyses were used to identify preoperative and intraoperative predictors of PSMs.

RESULTS

• ? Although the PSM rate was similar between the two groups (LRP: 12% vs RALP: 13.5%; P= 0.76), location and size were not. PSMs after LRP were mostly at the apex (58.3%; P= 0.038), while most PSMs after RALP were posterolateral ([PL] 48%; P= 0.046).
• ? In addition, the median margin size after RALP was significantly smaller than after LRP (RALP: 2 mm vs LRP: 3.5 mm; P= 0.041).
• ? In univariate and multivariate analyses, tumour‐node‐metastasis (TNM) stage and preoperative PSA were the only independent preoperative predictors of PSMs (P= 0.044 and P= 0.01, respectively).

CONCLUSION

• ? The PSM risk is dependent on TNM stage and preoperative PSA and not the surgical technique, when comparing LRP with RALP.