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1 ; 21 Urological Oncology MUSCULARIS PROPRIA AND UPSTAGING OF ct1 BLADDER CANCER BADALATO ET AL. BJUI Does the presence of muscularis propria on transurethral resection of bladder tumour specimens affect the rate of upstaging in ct1 bladder cancer? Gina Badalato, Trushar Patel, Gregory Hruby and James McKiernan Department of Urology, Columbia University, College of Physicians and Surgeons, New York, NY, USA Accepted for publication 14 September 21 Study Type Therapy (case series) Level of Evidence 4 OBJECTIVE What s known on the subject? and What does the study add? It is already known and accepted that the presence of mucularis propria (MP) on bladder biopsy is incremental to the clinical staging process for this disease entity. This study establishes that the lack of MP also portends a higher risk of pathologic upstaging at the time of radical cystectomy. To determine how the presence of MP on T1 biopsy specimens affects the outcome of patients undergoing RC as compared to when no MP is identified in the TURBT specimen. PATIENTS AND METHODS Patients were retrospectively identified from the Columbia University Urologic Oncology Database. From January 1986 to October 29, 114 patients diagnosed with ct1nm bladder cancer who underwent RC within 4 months of their last biopsy were identified. Patients were stratified based on the presence of MP on T1 biopsy, and upstaging was defined as any tumor T2 or greater, N+, or M+ at the time of radical cystectomy. The rate of upstaging was assessed using univariate and multivariate regression models; Kaplan meier curves were also extrapolated for each cohort to compare disease specific and overall survival patterns. RESULTS Of the 114 patients evaluated in this study, 24 (2.2%) did not have MP on their T1 biopsy before RC. The rate of upstaging (>=pt2) stratified by the presence of MP on biopsy was 5% and 78%, respectively (p=.17). On univariate analysis, lack of MP on biopsy was associated with an increased risk of upstaging (HR 3.52, p=.21, CI ), however did not reach significance as an independent predictor (HR 2.9, p=.56, CI ). At a mean follow-up of 33.5 months, there was no difference in disease specific (p=.41) and overall survival (p=.68) between groups. CONCLUSIONS The lack of MP on TURBT for high grade ct1nm bladder cancer portends a high likelihood of upstaging at RC, although this risk did not translate into a detectable increased risk of disease specific mortality. KEYWORDS bladder cancer, muscularis propria, clinical T1, upstaging, radical cystectomy, transurethral resection of bladder tumor (TURBT) INTRODUCTION High-grade ct1nm urothelial carcinoma represents a challenging management situation because the natural history of the disease is variable. A substantial percentage of these patients will eventually progress to muscle-invasive disease, but clinical understaging of T1 disease can delay definitive therapy which can affect survival [1]. Pathological upstaging during radical cystectomy (RC) in patients with high-grade ct1nm disease is not uncommon, with reported rates of 27 3% [2]. Current AUA guidelines recommend restaging transurethral resection regardless of whether the muscularis propria (MP) is identified on initial transurethral resection of bladder tumour (TURBT) [3]. Accordingly, our aim was to determine how the presence of MP on T1 TURBT specimens affects the rate of upstaging at RC, compared with when MP is not detected in the specimen. PATIENTS AND METHODS Patients were retrospectively identified from the Institutional Review Board-approved Columbia Urologic Oncology Database. The tumours were staged according to the 6 th edition of the TNM system of the American Joint Cancer Committee/ Union Internationale Contre le Cancer Staging Manual [4]. From January 1986 to October 29 a total of 576 patients diagnosed with T1 T4, N N1, M bladder cancer who underwent RC within , doi:1.1111/j x x

2 MUSCULARIS PROPRIA AND UPSTAGING OF ct1 BLADDER CANCER TABLE 1 Clinical and pathological characteristics among patients with and without MP in initial TURBT specimen, with associated P values Patient characteristics With MP, N = 91 Without MP, N = 23 P Clinical Mean age Male, n (%) 72 (79) 16 (7).329 Race, n.26 White African-American 7 3 Hispanic 11 Other 12 2 Smoker, n (%) 17 (19) 5 (22).74 Mean no. of biopsies Time to RC, months Adjuvant chemotherapy, n (%) 14 (15) 3 (13).778 Intravesical chemotherapy, n (%) 2 (22) 8 (35).112 Pathological Positive margin, n (%) 6 (7) 4 (17).12 CIS, n (%) 91 (1) 23 (1).778 Lymphovascular invasion, n (%) 7 (8) 4 (17).159 High-grade disease, n (%)* 76/84 (9) 2/21 (95).486 Nodal status, n (%).336 pn 68 (75) 19 (83) pnx 8 (9) () pn1 15 (16) 4 (17) *Patients were excluded within this category if the presence of high-grade disease was unknown. Analysis Odds ratio P CI Univariate Age Sex Smoker High-grade disease Time to RC No. of biopsies Absence of MP Multivariate Age Sex Absence of MP TABLE 2 Univariate and multivariate analysis of predictors of pathological upstaging at RC SAS version 9.1, with P <.5 considered significant. RESULTS A total of 114 patients were identified who underwent RC for high-grade ct1 disease. Of these 114 patients, 24 (2.2%) did not have MP on their T1 biopsy before RC. Compared with those with MP present on their biopsy, there was no significant difference with respect to age, gender, race, smoking history, intravesical chemotherapy exposure or adjuvant chemotherapy use (Table 1). At RC, a total of 64 (56%) patients were upstaged from their previous biopsy. The rate of upstaging was 5% if MP was detected on TURBT, and 78% if no MP was detected on TURBT (P =.17). Upstaging to pt3 disease was found in 28.6% (26/91) of patients with MP on TURBT and 65.2% (15/23) of patients without MP on biopsy, respectively (P =.5). The lack of MP on biopsy was not associated with margin status, lymphovascular invasion, carcinoma in situ (CIS), high-grade disease or TNM at time of RC (Table 2). On univariate analysis, lack of MP on biopsy was associated with an increased risk of upstaging (hazard ratio [HR] 3.52, P =.21; CI ). Age (HR 1.5, P =.19; CI ) and gender (HR.39, P =.52; CI.1 1.) were also significant predictors for upstaging on univariate analysis, although the number of biopsies at RC and time to cystectomy were not significant (Table 2). In a stepwise multivariate regression model controlling for age and gender, however, the presence or absence of MP did not correlate with upstaging risk (HR 2.9, P =.56; CI ). In fact, only patient age (HR 1.4, P =.37; CI ) remained a significant predictor of upstaging on multivariate analysis. weeks of their last TURBT were identified. Patients were excluded from the study if there was evidence of muscle invasion ( T1c disease), or if they received neoadjuvant chemotherapy. Of the patients with T1 lesions established by biopsy, those who had advanced disease, as defined by an abnormal examination under anaesthesia or evidence of hydronephrosis on CT, were excluded. Upstaging was defined as any tumour T2, N+, or M+ at the time of RC. Patients were in turn stratified based on the presence of MP on T1 biopsy specimen, and the rate of upstaging was assessed. Both univariate and multivariate analysis were performed, the latter a multivariate regression model, to control for possible confounders identified by the univariate model. Kaplan Meier curves were extrapolated to evaluate disease-specific and overall survival for each cohort, and the cohorts were in turn compared using the logrank test. Statistical analysis was done using At a mean follow-up of 33.5 months, there was no difference with respect to diseasespecific (P =.41) or overall survival (P =.68) between patients within each cohort (Figs 1, 2). DISCUSSION The role of RC for high-grade non-muscleinvasive urothelial carcinoma remains debatable. The risks inherent to overtreatment of high-grade T1 disease must be balanced

3 BADALATO ET AL. against the potential benefits of efficaciously administered local therapy. Certain tumour characteristics are predictive of tumour recurrence and progression [5]. The present study is the first of its kind to characterizes the importance of the presence of MP on precystectomy transurethral resection for highgrade T1 bladder cancer. The lack of MP on TURBT for T1 disease was associated with an increased likelihood of pathological upstaging in this series, although this risk did not seem to translate into an increased risk of diseasespecific mortality. Complete transurethral resection of nonmuscle-invasive bladder cancer is necessary to prevent further local recurrences and progression. In the majority of cases, therapeutic decisions for bladder tumours are based on the results of an initial transurethral resection of a primary tumour or follow-up resection of a recurrent lesion. Yet understaging of the disease is common [6] and residual disease is present in up to 78% of cases upon re-resection. In fact, Herr [7] characterized a retrospective cohort involving 15 consecutive cases from all geographic regions in the USA undergoing repeat TURBT between January and October Of 96 cases with non-muscle-invasive (Ta, Tis, T1) bladder tumours, 72 (75%) had a residual non-invasive tumour and 28 (29%) were upstaged to invasive tumour [7]. Similarly, Bianco et al. [8]endorsed a contemporary, retrospective institutional review of patients with high-grade T1 tumours who underwent RC between 1999 and 2. Within this cohort, although clinical stage proved to be accurate in 44 (66%) of the cases, 27% were upstaged by RC. These data confirm that pathological understaging may occur in a substantial number of patients with nonmuscle-invasive bladder cancer, highlighting the need to characterize further the clinical and pathological factors involved in initial TURBT that predict the risk of such staging inaccuracy. Because depth of invasion is an important prognostic factor in staging bladder carcinoma, the presence of MP on TURBT specimen has been used as an index of diagnostic adequacy and completeness of the endoscopic operation. However, factors such as the absolute depth of involvement and the degree of involvement of the lamina propria may also be used as methods of risk stratifying T1 disease. In fact, Cheng et al. [9] proposed a classification system for bladder cancer based on depth of invasion measured with an ocular micrometer. The authors validated this mechanism of risk stratification within a published report involving 83 consecutive patients with T1 bladder carcinoma diagnosed on TURBT, as depth of invasion measured in μm proved to be an independent predictor of 5-year progressionfree survival. Similarly, Orsola et al. [1] established that the level of muscularis mucosa invasion for T1 bladder cancer, with and without BCG treatment, offered a mechanism for sub-stratifying patients according to progression-free survival. The progression rate for deep lamina propriainvasive tumours (T1b and T1c) was 34% (16/47), in comparison with 8% (3/38) for T1a (P =.16), with progression-free intervals significantly different in patients with (T1b, T1c) or without (T1a) deep lamina propria involvement (P =.3), regardless of BCG treatment. The identification of predictors for pathological upstaging are particularly important because pathological staging might be equivocal in cases of advanced disease. Previous investigations have established that prostatic urethral involvement [11], the presence of multiple tumours and/or CIS [12], absence of muscle in the biopsy specimen, and suspicious radiological findings (extravesical extension or hydronephrosis) [13] predict upstaging, and a trend towards upstaging was identified in patients with a period of 3 months between TURBT and RC [14]. In consideration of variables independent of MP that have an impact on upstaging, and in order to incorporate factors independent of biopsy contributing to clinical staging, patients were excluded from the study if they had evidence of an abnormal examination under anaesthesia or radiographical evidence of hydronephrosis on CT. Certainly, the pathological findings on TURBT must be considered with pelvic exam and radiographic findings in determining patients clinical stage. The purpose of the present study was not to establish a thorough TURBT as a proxy for these other components of clinical evaluation; rather, it was to identify factors that define TURBT adequacy when used in tandem with these other methods of staging. Among the predictors of upstaging, this investigation highlighted the importance of MP on TURBT specimen. This variable had FIG. 1. Disease-specific survival in patients with preoperative clinical T1 disease, with and without MP in initial TURBT specimen. At a mean follow-up of 33.5 months, there was no difference with respect to disease-specific survival (P =.41). At time zero, the number at risk in each cohort was 89 and 22, respectively; three patients did not have >1-month follow-up and were censored. % Disease- Specific Survival Number at risk Biopsy w/mp Biopsy w/out MP P =.419 (log-rank test) Follow-Up, months Biopsy w/mp 3 2 Biopsy w/out MP FIG. 2. Overall survival in patients with high-grade T1 disease on preoperative biopsy, with and without MP in initial TURBT specimen. There was no significant difference in overall survival (P =.68) between the two cohorts P =.6815 (log-rank test) Time, months Biopsy with MP Biopsy without MP previously been identified as an indicator of staging accuracy by Dutta et al. [13] in a retrospective review involving high-risk nonmuscle-invasive urothelial carcinoma treated with RC. The lack of MP in TURBT specimens, even in cases of extensive disease, had been a theoretical consideration for pathological understaging in studies antedating the aforementioned report [9]. Yet within a series of 78 patients who underwent RC for nonmuscle-invasive urothelial carcinoma, the Dutta et al. investigation clearly defined the lack of MP in TURBT specimen as a risk factor of understaging. Cancer was clinically understaged with stages pt2 disease in 31 patients (4%) according to final pathology results. Understaging was most pronounced in 1 patients (67%) with suspicious

4 MUSCULARIS PROPRIA AND UPSTAGING OF ct1 BLADDER CANCER radiography, and in the 18 (64%) with absent MP in the biopsy specimen (P <.1). Upstaging was in turn associated with a statistically worse disease-specific and recurrence-free survival. From these results, the authors concluded that the selection of high-risk non-muscle-invasive transitional cell carcinoma cases for continued bladdersparing treatment should include uninvolved muscle on TURBT, in conjunction with absent radiographical suspicion for invasion [13]. The findings of Dutta et al. highlight the limitations of current staging techniques, which are known to commonly understage bladder cancer, even in known muscleinvasive disease. Limitations to the present study must nevertheless be considered, and may account for the variable significance of MP on TURBT evident in contemporary metanalysis. First, patients were not stratified based on the number of antecedent TURBT procedures before their last TURBT leading to cystectomy. Tumour pathophysiology among patients with T1 disease certainly differs between patients with no previous TURBT or who are naïve to intravesical chemotherapy as compared with those who sustained multiple complete TURBTs and subsequently received BCG or chemotherapy [15]. Moreover, the treatment delay in time to RC for those patients who underwent multiple rounds of intravesical therapy is known to be an independent predictor of worse overall survival, especially among patients who originally presented with lower stage lesions [16]. Furthermore, although there was no statistical difference between the cohorts with respect to receipt of intravesical therapy overall, the number of cycles and nature/type of previous intravesical treatments represent variables for consideration in future univariate and multivariate models involving these datasets. An additional consideration is the observation that the rate of upstaging of 56%, while comparable to some contemporary reports [14,17], is higher than previously published rates for high-grade T1 disease, which are 27 4% [11,13,18,19]. This discrepancy may be attributable to the fact that many patients had multiple courses of intravesical therapy and some patients may have received their pre-cystectomy resection at an outside institution, thus precluding true standardization of the biopsy scheme. Lastly, because the absence of MP did not translate into an upstaging risk by a narrow margin on multivariate analysis, future studies powered with a larger cohort might be informative in better capturing both upstaging and survival trends. Forthcoming studies might also be designed to validate the variables of age and/ or gender as predictors of upstaging. Despite the limitations of this study, and given the fact that pathological understaging by TURBT has been reported in a substantial number of patients with bladder cancer, this investigation establishes a framework with which to assess TURBT quality and, in turn, to stratify patients for optimal management. In conclusion, a significant proportion of patients with high-grade ct1nm bladder cancer will be upstaged at the time of RC. The lack of MP on TURBT for T1 bladder cancer is predictive of a high likelihood of this risk. These findings corroborate current AUA guidelines for the clinical staging of bladder cancer and establish a means of assessing the diagnostic quality of TURBT. CONFLICT OF INTEREST None declared. Source of Funding: Columbia University Medical Center. REFERENCES 1 Freeeman JA, Esrig D, Stein JP et al. Radical cystectomy for high risk patients with superficial bladder cancer in the era of orthotopic urinary reconstruction. Cancer 1995; 76: Amling CL, Thrasher JB, Frazier HA, Dodge RK, Robertson JE, Paulson DF. Radical cystectomy for stages Ta, Tis and T1 transitional cell carcinoma of the bladder. J Urol 1994; 151: Dalbagni G, Herr H, Reuter VE. Impact of second transurethral resection on the staging of T1 bladder cancer. Urology 22; 6: Greene FL, Page D, Morrow M et al. eds. AJCC Cancer Staging Manual, 6th edn. New York: Springer, 22 5 Heney NM, Ahmed S, Flanagan MJ et al. Superficial bladder cancer: progression and recurrence. J Urol 1983; 13: Ficarra V, Dalpiaz O, Alrabi N, Novara G, Galdano A, Artibani W. Correlation between clinical and pathological staging in a series of radical cystectomies for bladder carcinoma. BJU Int 25; 95: Herr HW. The value of a second transurethral resection in evaluating patients with bladder tumors. J Urol 1999; 162: Bianco FJ, Justa D, Grignon DJ, Sakr WA, Pontes JE, Wood DP Jr. Management of clinical T1 bladder transitional cell carcinoma by radical cystectomy. Urol Oncol 24; 22: Cheng L, Neumann RM, Weaver AL, Spotts BE, Bostwick DG. Predicting cancer progression in patients with stage T1 bladder carcinoma. J Clin Oncol 1999; 17: Orsola A, Trias I, Raventos CX et al. Initial high-grade T1 urothelial cell carcinoma: feasibility and prognostic significance of lamina propria invasion microstaging (T1a/b/c) in BCG-treated and BCG-non-treated patients. Eur Urol 25; 48: Huguet J, Crego M, Sabate S, Salvador J, Palou J, Villavicencio H. Cystectomy in patients with high risk superficial bladder tumors who fail intravesical BCG therapy: pre-cystectomy prostate involvement as a prognostic factor. Eur Urol 25; 48: Masood S, Sriprasad S, Palmer JH, Mufti GR. T1G3 bladder cancer: indications for early cystectomy. Int Urol Nephrol 24; 36: Dutta SC, Smith JA, Shappell SB, Coffey CS, Chang SS, Cookson MS. Clinical under staging of high risk nonmuscle invasive urothelial carcinoma treated with radical cystectomy. J Urol 21; 166: Gupta A, Lotan Y, Bastian PJ et al. Outcomes of patients with clinical T1 grade 3 urothelial cell bladder carcinoma treated with radical cystectomy. Urology 28; 71: Guzzo TJ, Magheli A, Bivalacqua TJ et al. Pathological upstaging during radical cystectomy is associated with worse recurrence-free survival in patients with bacillus Calmette-Guerin-refractory bladder cancer. Urology 29; 74: Kulkarni GS, Urbach DR, Austin PC, Fleshner NE, Laupacis A. Longer wait times increase overall mortality in patients with bladder cancer. J Urol 29; 182: Fritsche HM, Burger M, Svatek RS et al. Characteristics and outcomes of patients with clinical T1 grade 3 urothelial

5 BADALATO ET AL. carcinoma treated with radical cystectomy: results from an international cohort. Eur Urol 21; 57: Hautmann RE, Volkmer BG, Gust K. Quantification of the survival benefit of early versus deferred cystectomy in high-risk non-muscle invasive bladder cancer (T1 G3). World J Urol 29; 27: Stein JP, Lieskovsky G, Cote R et al. Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,54 patients. J Clin Oncol 21; 19: Correspondence: Gina Badalato, Department of Urology, Columbia University, College of Physicians and Surgeons, 161 Fort Washington Avenue Herbert Irving Pavillion 11th Foor, New York, NY, 132 USA. gmb217@columbia.edu Abbreviations: RC, radical cystectomy; MP, muscularis propria; TURBT, transurethral resection of bladder tumour; CIS, carcinoma in situ; HR, hazard ratio

Influence of stage discrepancy on outcome in. in patients treated with radical cystectomy.

Tumori, 96: 699-703, 2010 Influence of stage discrepancy on outcome in patients treated with radical cystectomy Ja Hyeon Ku 1, Kyung Chul Moon 2, Cheol Kwak 1, and Hyeon Hoe Kim 1 1 Department of Urology,