Michael C. Gong

Inadequacy of Biopsy for Diagnosis of Upper Tract Urothelial Carcinoma: Implications for Conservative Management

OBJECTIVE To report changes in grade and stage between initial diagnostic and repeat biopsies or resection for urothelial carcinoma (UTUC) and investigate the consequences for endoscopic management. Ureteroscopic management of upper tract UTUC is an alternative to nephroureterectomy, which is less invasive and preserves renal function. However, concerns about potential understaging, inaccurate grading, incomplete resection, lack of effective tertiary chemoprevention, and need for ureteroscopic surveillance limits it appeal. METHODS Clinicopathological records of patients with UTUC treated at our institution were reviewed. Fifty-six patients with a histologic diagnosis of UTUC and 2 or more consecutive biopsies or biopsy followed by surgical resection were included, resulting in 65 biopsy specimens. RESULTS The median interval between diagnostic biopsy and subsequent biopsy or resection was 6 weeks (range, 1 week to 60 months). Change in grade from the diagnostic biopsy occurred in 24 of 65 biopsies (37%), including 9 in which diagnosis changed from low to high grade. Change in the stage from the diagnostic biopsy occurred in 25 of 65 biopsies (38%). Overall, 24 (43%) patients were reclassified from low-grade, noninvasive disease to high-grade and/or invasive disease. CONCLUSION A change in grade and/or stage from the diagnostic biopsy occurred in more than one third of patients with UTUC managed conservatively. Because of the short median time interval between biopsies, this finding likely represents variability in tumor sampling on biopsy. Because of the concerns of undergrading and understaging, appropriate patient selection and vigilant endoscopic surveillance are mandatory for UTUC managed endoscopically.

Lack of Pathologic Down-Staging With Neoadjuvant Chemotherapy for Muscle-invasive Urothelial Carcinoma of the Bladder

The postcystectomy survival benefit associated with the combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) neoadjuvant chemotherapy (NC) for muscle‐invasive bladder cancer has been most evident in patients who achieve a pathologic complete response. The outcome of NC and open radical cystectomy (RC) was evaluated in a contemporary cohort of patients in a tertiary referral setting.

Neoadjuvant Systemic Therapy or Early Cystectomy? Single-center Analysis of Outcomes After Therapy for Patients With Clinically Localized Micropapillary Urothelial Carcinoma of the Bladder

OBJECTIVES To analyze the treatment outcomes of patients with micropapillary bladder cancer (MPBC). MPBC is a rare variant of urothelial carcinoma with aggressive clinical behavior. Radical cystectomy is considered the standard approach for treatment of patients with localized disease; however, the role of perioperative systemic therapy has been poorly defined. MATERIAL AND METHODS A retrospective review identified 38 consecutive patients who had been treated at our institution for MPBC from 2000 to 2010. The patient data were analyzed for the pre- and postoperative clinicopathologic features, treatment course, and cancer-specific survival. RESULTS The median follow-up of surviving patients after cystectomy was 17 months (range 2-75). At the initial transurethral biopsy, 28 patients (74%) had clinical Stage T2N0 or less. In this group, 26 (93%) of 28 were upstaged to nonorgan-confined and/or lymph node-positive disease. Overall, 32 patients (86%) had evidence of lymph node metastasis on the final pathologic examination. All patients with cTis-T1 who had undergone initial bladder-sparing therapy with bacille Calmette-Guérin had pathologically advanced disease at cystectomy. All 15 patients who had received perioperative cisplatin-based chemotherapy died of metastatic disease. The 5-year overall survival rate was 40% (95% confidence interval 16-64). CONCLUSIONS MPBC is an aggressive disease with a high likelihood of regional lymph node metastasis at the initial presentation. Although radical cystectomy plays a critical role in treatment, systemic neoadjuvant chemotherapy might be a more appropriate strategy than immediate cystectomy. Because of the poor response to current chemotherapy agents, the development of new and effective drugs for this subset of patients could be needed.

How Do Commonly Performed Lymphadenectomy Templates Influence Bladder Cancer Nodal Stage

PURPOSE Determining pathological nodal stage in patients with bladder cancer is important for prognosis. We determined how the extent of lymphadenectomy and the lymph node count influence accurate nodal staging. MATERIALS AND METHODS The study included 120 patients who underwent at least extended lymphadenectomy at radical cystectomy. Different anatomical templates for lymphadenectomy were evaluated for nodal staging accuracy. The cumulative percent was plotted to determine a lymph node count that confidently identified node positive cases. RESULTS The mean +/- SD total lymph node count in the study population was 36.9 +/- 14.8 at extended lymphadenectomy. Of the patients 36 (30%) had lymph node metastasis, including 14 (39%) with metastasis involving the common iliac and/or presacral lymph nodes. Limited, standard and extended lymphadenectomy accurately identified 75%, 88.9% and 100% of node positive cases, respectively. Removing 23 and 27 lymph nodes provided 80% and 90% confidence, respectively, that a case was accurately staged as pN0. No patient had lymph node metastasis above the aortic bifurcation without nodal metastasis below the aortic bifurcation and none had a change in pN stage by extending lymphadenectomy above the aortic bifurcation. CONCLUSIONS To accurately identify node positive and negative cases, and correctly assign pN stage in node positive cases it is necessary to perform extended lymphadenectomy. Identifying at least 23 to 27 lymph nodes on final pathological evaluation provides a high level of confidence that a case is correctly staged as node positive or negative.

Aggregate Lymph Node Metastasis Diameter and Survival After Radical Cystectomy for Invasive Bladder Cancer

OBJECTIVES The current tumor-node-metastasis (TNM)-staging system for urothelial carcinoma of the bladder (UCB) is based on the number and size of the largest positive lymph node (LN). The aggregate LN metastasis diameter (ALNMD) may better reflect the burden of metastatic disease and improve the ability to predict recurrence-free (RFS) and overall survival (OS). METHODS Clinical characteristics and follow-up information of 134 patients with LN-positive UCB treated by radical cystectomy was modeled using Cox proportional hazards regression analysis to predict OS. Pathologic specimens were retrospectively reviewed by a single genitourinary pathologist unaware of treatment outcome to determine the greatest dimension of metastasis in all affected LN. The median follow-up of survivors was 23 months. RESULTS The median OS was 17 months; median LN density, 17%; and median number of LN removed, 14. ALNMD was a significant predictor of RFS and OS after adjusting for pathologic T stage, lymphovascular invasion, LN density, comorbidity, and extranodal extension (adjusted HR 1.1; P = .02), even when restricting the analysis to patients in whom 10 or more LN have been removed. The predictive accuracy of a model for OS that contained ALNMD was superior to the one without this parameter and the TNM-staging system (c-index 0.71 vs 0.67 vs 0.62). CONCLUSIONS ALNMD is a significant predictor of RFS and OS after adjusting for standard prognostic parameters among patients with LN-positive UCB and may be a useful parameter to include in future predictive nomograms and TNM-staging systems.

Presacral and Retroperitoneal Lymph Node Involvement in Urothelial Bladder Cancer: Results of a Prospective Mapping Study

PURPOSE We evaluated the incidence of positive lymph nodes in the presacral and retroperitoneal regions in patients who underwent radical cystectomy and extended pelvic lymph node dissection for urothelial bladder cancer. MATERIALS AND METHODS As part of a prospective mapping study, 143 patients underwent radical cystectomy and extended pelvic lymph node dissection for urothelial bladder cancer between 2006 and 2010. Lymph nodes from 6 separate regions were labeled, including bilateral pelvic and common iliac, presacral and retroperitoneal. We evaluated pathological features, treatment outcomes and cancer specific survival in patients with or without lymph node positive disease in the presacral and retroperitoneal regions. RESULTS A median of 37 lymph nodes (IQR 27-49) were removed. Overall 52 (36%) patients had positive lymph nodes, of whom 24 (46%) had metastatic disease in the presacral or retroperitoneal region. Four patients (3%) had an isolated solitary positive lymph node in these 2 templates. Two-year overall survival in patients without vs with presacral/retroperitoneal lymph node positive disease was 44% (95% CI 24-64) vs 25% (95% CI 5-45) (p = 0.11). In contrast, 2-year cancer specific survival in the 2 groups was 55% (95% CI 33-77) and 29% (95% CI 7-51), respectively (p = 0.02). CONCLUSIONS A substantial proportion of patients have lymph node positive disease in the presacral and retroperitoneal regions, including some with isolated and/or solitary lymph node involvement. While the limited positive lymph node burden in these templates suggests a potential therapeutic role for extending the anatomical boundaries of lymph node dissection, patient survival was poor. Extended lymph node dissection provides important staging information but to our knowledge the therapeutic benefit has yet to be definitively proved.

Prostate-sparing cystectomy: has Pandora’s box been opened?

En bloc removal of the prostate has traditionally been an integral component of radical cystectomy for men with bladder cancer owing to a high incidence of occult prostatic malignancy. However, the risk of functional morbidity following this procedure is considerable and can delay patient acceptance of cystectomy, which can adversely affect the long-term prognosis. Recently, some investigators have advocated prostate-sparing cystectomy (PSCx) to improve postoperative continence and potency rates, and this may also improve timely patient acceptance of cystectomy. Several of these PSCx series describe excellent functional results postoperatively and PSCx may also facilitate a laparoscopic approach, offering further dividends. However, valid concerns regarding the oncologic efficacy of this procedure still predominate and protocols for patient selection, technique and postoperative surveillance are not well defined. The concept of PSCx is arguably one of the most controversial topics in the field of bladder cancer today.

Analysis of T1c Prostate Cancers Treated at Very Low Prostate-Specific Antigen Levels

BACKGROUND The Prostate Cancer Prevention Trial (PCPT) has challenged the validity of recommended prostate-specific antigen (PSA) thresholds for prostate biopsy (> 2.5 ng/ml) given the 17% prostate cancer (pCA) detection rate at PSA of 1.1-2.0. The outcome of patients treated at PSA < or = 2.5 is poorly defined, and advantages associated with such an early diagnosis are uncertain. OBJECTIVE Compare the outcome of patients with T1c pCA with pretreatment PSA < or = 2.5 and 2.6-4.0. DESIGN, SETTING, AND PARTICIPANTS Since 1998, 351 patients with clinical stage T1c and PSA < or = 4.0 have been treated at our institution; 84 (24%) of those patients had PSA < or = 2.5. Clinical information was obtained from a prospective database. Treatment was radical prostatectomy (RP), brachytherapy, and external-beam radiotherapy (EBRT) in 261 (74%), 67 (19%), and 23 (7%) patients, respectively. INTERVENTION Definitive therapy for clinically localized pCA. MEASUREMENTS Progression-free probability and pathologic end points. RESULTS AND LIMITATIONS No significant differences between the groups were observed in terms of biopsy (18% vs 22%) or specimen Gleason score 7-8 (44% vs 56%), non-organ-confined cancer (11% vs 13%), indolent cancer (34% vs 24%), or 5-yr progression-free probability (89% vs 93%; p>0.1 for all). More biologically unimportant cancers (defined as pathologically organ-confined and Gleason < or = 6) were identified among patients with PSA < or = 2.5 (55% vs 41%, p=0.050), and indolent cancers were three times more frequent than non-organ-confined cancers among these patients (p=0.003). CONCLUSIONS The pathologic features and outcome of patients treated at low PSA levels are favorable and similar for patients with PSA < or = 2.5 versus 2.6-4.0. However, > 50% of the former have potentially biologically unimportant cancer. We failed to identify a therapeutic benefit to the diagnosis of cancers below accepted PSA thresholds for biopsy.

Utility of percent free prostate-specific antigen in repeat prostate biopsy.

OBJECTIVES To assess the utility of the percent free prostate-specific antigen (%fPSA) for the prediction of prostate cancer in men undergoing repeat biopsy. METHODS A retrospective review was performed of 1037 patients in an institutional review board-approved repeat prostate biopsy database. A total of 617 patients who underwent 683 biopsies had all their data available for analysis. The patients were categorized as having undergone 1 repeat biopsy or >1 repeat biopsy. RESULTS The overall cancer detection rate was 27% and 22% in men who underwent 1 and >1 repeat biopsy, respectively. The area under the receiver operating characteristic curve for the %fPSA was 0.65 for men who underwent 1 repeat biopsy. Multivariate analysis demonstrated that a positive family history, decreasing %fPSA, and presence of high-grade intraepithelial neoplasia and/or atypical small acinar proliferation predicted for cancer. The univariate odds ratio for every 5% decrease in the %fPSA was 1.5 (95% confidence interval 1.2-1.7). The performance of %fPSA was further improved in men who underwent >1 repeat biopsy, with an area under the curve of 0.72. In men who underwent >1 repeat biopsy, multivariate analysis showed that a decreasing %fPSA, >20 cores removed, and high-grade intraepithelial neoplasia predicted for cancer. The univariate odds ratio for every 5% decrease in the %fPSA was 1.8 (95% confidence interval 1.4-2.3). A %fPSA cutoff of 10% achieved 90% and 91% specificity in the 1 repeat biopsy and >1 repeat biopsy groups, respectively. CONCLUSIONS %fPSA is useful in predicting for prostate cancer in the repeat biopsy population, particularly for those who have undergone multiple repeat biopsies. A persistently low %fPSA should prompt additional investigation in these men.

Evaluation of prognostic factors in upper tract urothelial carcinoma (UTUC).

372 Background: UTUC is relatively rare (5-10% of UC). Limited data on prognostic factors is available. Methods: A retrospective study of UTUC patients (pts) who had surgery (1995-2014) at Cleveland Clinic (n = 454) was conducted. Univariable (UVA) and multivariable (MVA) analysis (proportional hazards) with a stepwise selection algorithm (p = .10 and .05, as criteria for entry and retention in the model) was used to identify independent predictors of recurrence-free survival (RFS) and overall survival (OS). Results: 192 pts with invasive high grade UTUC were identified; median age at resection was 72; 69% men. 72% of pts had laparoscopic and 17% open nephrouretectomy, 23% had +ve margins (including bladder/ureter cuff), 22% had multifocal tumor. Median tumor size 3.5 cm (0.2-12); 70% had tumors < 5 cm; 65% pT3, 8% pT4 stage; among pts with lymph node (LN) dissection, 25% had +ve LN. All but 3 pts (2 sarcomatoid, 1 small cell) had primarily UC; 28% mixed UC histology; 40% CIS, 54% confirmed lymphovascular...