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Prognostic Implications of Prostatic Urethral Involvement in Non-Muscle

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Prognostic Implications of Prostatic Urethral Involvement in Non-Muscle World Journal of Urology (2019) 37:2683–2689 https://doi.org/10.1007/s00345-019-02673-2 ORIGINAL ARTICLE Prognostic implications of prostatic urethral involvement in non‑muscle‑invasive bladder cancer Aaron Brant1,3 · Marcus Daniels1 · Meera R. Chappidi1 · Gregory A. Joice1 · Nikolai A. Sopko1 · Andres Matoso2 · Trinity J. Bivalacqua1 · Max Kates1 Received: 23 November 2018 / Accepted: 5 February 2019 / Published online: 8 March 2019 © Springer-Verlag GmbH Germany, part of Springer Nature 2019 Abstract Purpose Non-muscle-invasive bladder cancer involving the prostatic urethra is associated with pathologic upstaging and shorter survival. We investigated the survival impact of prostatic urethral involvement in non-muscle-invasive patients who are not upstaged at cystectomy. Methods From 2000 to 2016, 177 male patients underwent cystectomy for high-risk non-muscle-invasive bladder cancer and remained pT1, pTis, or pTa, and N0 on fnal pathology; 63 (35.6%) patients had prostatic urethral involvement and 114 (64.4%) did not. Prostatic involvement was non-invasive (Ta or Tis) in 56 (88.9%) patients and superfcially invasive (T1) in 7 (11.1%) patients. No patient had stromal invasion. Log-rank and Cox regression analyses were used to evaluate survival. Results Compared to patients without prostatic urethral involvement, patients with involvement were more likely to have received intravesical therapy (84.6% vs. 64.4%, p < 0.01), have multifocal tumor (90.8% vs. 51.7%, p < 0.01), and have posi- tive urethral margins (7.7% vs. 0%, p < 0.01) and ureteral margins (18.5% vs. 5.1%, p < 0.01). Log-rank comparison showed inferior recurrence-free, cancer-specifc, and overall survival in patients with prostatic involvement (p = 0.01, p = 0.03, p < 0.01). Patients with prostatic urethral involvement were more likely to experience recurrence in the urinary tract (p < 0.01). On Cox regression, prostatic urethral involvement was an independent predictor of overall mortality (HR = 2.08, p < 0.01). Conclusions Prostatic urethral involvement is associated with inferior survival in patients who undergo cystectomy for non- muscle-invasive bladder cancer and remain pT1, pTis, or pTa on fnal pathology. Prostatic urethral involvement is thus an adverse pathologic feature independent of its association with upstaging. Keywords Bladder cancer · Non-muscle-invasive · Prostatic urethra · Radical cystectomy Introduction with non-muscle-invasive bladder cancer (NMIBC), which is typically treated with transurethral resection of the bladder Bladder cancer is the fourth most common type of cancer in tumor and intravesical therapy. Many patients also go on to men, with 60,490 estimated male cases in 2017 and 12,240 receive radical cystectomy when they are deemed high-risk estimated deaths [1]. Survival is more favorable in patients or Bacillus Calmette–Guerin (BCG) unresponsive [2]. Prostatic urethral involvement (PUI) is a particularly con- cerning feature of NMIBC because the prostatic urethra is * Aaron Brant hypothesized to be a sanctuary site where malignant cells [email protected] have less exposure to intravesical therapy [3–4]. Further- 1 James Buchanan Brady Urological Institute, Johns Hopkins more, tumor in the prostatic urethra is difcult to accurately Medical Institutions, 600 North Wolfe Street, Baltimore, stage because it can creep into the prostatic stroma while MD 21287, USA remaining undetected until the entire prostate is examined 2 Department of Pathology, Johns Hopkins Medical after radical cystoprostatectomy (RCP) [5–7]. This pro- Institutions, Baltimore, MD, USA gression from < T2 to T4 disease can in part explain the 3 Present Address: James Buchanan Brady Foundation inferior survival observed in NMIBC patients with PUI Department of Urology, Weill Cornell Medical College, on transurethral biopsy [5, 6]. However, it is not known if 525 East 68th Street, Starr Pavilion, 9th Floor, New York, PUI afects survival in NMIBC patients who remain < T2 NY 10065, USA Vol.:(0123456789)1 3 2684 World Journal of Urology (2019) 37:2683–2689 on their cystectomy pathology. We hypothesized that PUI histologic evaluation of RCP specimen. TUR specimens is indicative of poor survival in these patients. To test this were reviewed for clinical staging but not used for deter- hypothesis, we compared recurrence-free, cancer-specifc, mination of PUI, as only 76 (42.9%) patients underwent and overall survival in high-risk NMIBC patients with and prostatic biopsy during TUR. Among the patients who without PUI on cystectomy pathology to determine if PUI underwent prostatic biopsy, sensitivity and specificity is predictive of shorter survival independent of its associa- analyses were conducted to determine the accuracy of tion with pathologic upstaging and tumor progression at prostatic biopsy. Patients with PUI on TURBT specimen cystectomy. routinely underwent transurethral resection of prostate (TURP) prior to administration of intravesical therapy. BCG was used in 123 (96.1%) of the 128 patients who Methods received at least one course of intravesical treatment. After cystectomy, patients were followed at 3–6 month Between January 2000 and August 2016, 950 consecutive intervals for 3 years and then annually thereafter. Post-cys- men underwent RCP at our institution. From this group, tectomy recurrence and mortality data were collected from we identifed 316 men with cTa, cTis, or cT1 high-grade these follow-up screening visits as well as from our institu- urothelial carcinoma of the bladder on transurethral resec- tional cancer registry and the national death index. Recur- tion, of whom 196 were found to be pTa, pTis, or pT1 and rence was defned as a biopsy-confrmed urothelial carci- N0 on pathologic evaluation of RCP specimen. Of these 196 noma lesion found anytime after cystectomy. This included men, fve were excluded from the study for having under- recurrence in the urinary tract, lymph nodes, and distant went prior prostatectomy, four were excluded for having metastasis. received neoadjuvant chemotherapy, four were excluded for Comparisons of baseline characteristics between PUI and having upper tract disease requiring concurrent nephroure- non-PUI patients were made using Wilcoxon–Mann–Whit- terectomy, four were excluded for having variant histology, ney test for continuous variables and Chi-squared test for and two were excluded for having lymphovascular invasion. categorical variables. Time from diagnosis to cystectomy This resulted in a cohort of 177 patients with non-muscle- was analyzed as a categorical variable with stratifica- invasive urothelial carcinoma, of whom 63 (35.6%) had PUI tion at 2 years, based on prior research showing increased on RCP specimen and 114 (64.4%) did not. Indication for risk of mortality at >2 years after initial BCG therapy cystectomy was BCG failure in 123 (69.5%) patients, high- [8]. Kaplan–Meier curves with log-rank test were created grade T1 disease in 35 (19.8%) patients, and large volume or to compare recurrence-free, cancer-specifc, and overall multifocal tumor unresectable by TURBT in the remaining survival between PUI and non-PUI patients. Multivariate 19 (10.7%) patients. logistic and Cox regression were used to identify independ- Clinicopathologic variables were collected from the Insti- ent predictors of prostatic urethral involvement and overall tutional Review Board-approved Cancers of the Urinary mortality. The multivariate regression models were created Tract Database, which combines patient medical records, using the stepwise selection process, with a p value < 0.10 patient-completed surveys, the Johns Hopkins Cancer Reg- required for entry into the model. Statistical signifcance istry, and the National Death Index. Collected variables was defned as a two-tailed α of 0.05. All analyses were included age at cystectomy, race, Charlson comorbidity performed using SAS Studio 3.6 (Cary, NC). index, intravesical therapy, type of urinary diversion, pres- ence of PUI, carcinoma in situ (CIS), multifocal tumor, and positive surgical margin on RCP specimen, American Joint Committee on Cancer TNM staging prior to RCP (clinical Results stage) and at time of RCP (pathologic stage), cause of death, days from diagnosis to cystectomy, and days from cystec- In a cohort of 177 patients who underwent cystectomy for tomy to cancer recurrence, death, or censoring. high-risk NMIBC and remained pTa, pTis, or pT1 and N0 The presence of PUI was determined by review of at cystectomy, there were 63 PUI patients and 114 non-PUI pathology from RCP specimen. On RCP specimen, PUI patients. On fnal pathology, PUI was non-invasive (Ta or was categorized as either non-invasive (Ta or Tis) or Tis) in 56 (88.9%) patients and superfcially invasive (T1) superficially invasive (T1). Patients with invasion into the in 7 (11.1%) patients. Non-invasive PUI consisted of CIS in prostatic stroma were excluded from the cohort. Clinical 49 of 56 (86.0%) patients and high-grade Ta in 7 (14.0%) stage was determined by histologic evaluation of tran- patients. Of the 63 patients with PUI, 6 (9.5%) patients surethral resection (TUR) specimens, physical exami- had tumor isolated in the prostatic urethra and 57 (90.5%) nation, and imaging via computerized tomography or patients had additional tumor in the bladder. Prostatic ure- magnetic resonance. Pathologic stage was determined by thral biopsy slides were available for review for 76 patients 1 3 World Journal of Urology (2019) 37:2683–2689 2685 Table 1 Sensitivity and specifcity of transurethral biopsy prior to positive urinary tract margin (OR = 4.01, p = 0.01), and cystectomy multifocal tumor (OR = 7.56, p < 0.01) as independent pre- Radical cystectomy dictors of prostatic urethral involvement (Table 3). In mul- tivariate Cox regression, age (HR = 1.03, p = 0.02), posi- PUI No PUI Total tive urinary tract margin (HR = 2.01, p = 0.03), and PUI Biopsy (HR = 2.02, p = 0.01) were independent predictors of overall PUI 26 7 33 mortality, while CIS was predictive of decreased mortality No PUI 12 31 43 risk (HR = 0.40, p < 0.01) (Table 4).
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