- Email: [email protected]
Validation of New AJCC Exclusion Criteria for Subepithelial Prostatic Stromal Invasion from pT4a Bladder Urothelial Carcinoma
Validation of New AJCC Exclusion Criteria for Subepithelial Prostatic Stromal Invasion from pT4a Bladder Urothelial Carcinoma Amit R. Patel, Joshua A. Cohn, Ahmed Abd El Latif, Ranko Miocinovic, Gary D. Steinberg,* Gladell P. Paner and Donna E. Hansel† From the Section of Urology (ARP, JAC, GDS, GPP) and Department of Pathology (GPP), University of Chicago, Chicago, Illinois, and Glickman Urological and Kidney Institute (AAEL, RM), and Department of Pathology and Laboratory Medicine (DEH), Cleveland Clinic, Cleveland, Ohio
Purpose: In 2010 the AJCC (American Joint Committee on Cancer) excluded urothelial carcinoma with subepithelial prostatic stromal invasion from the pT4a bladder cancer staging class, which is otherwise defined by direct prostatic invasion transmurally from the bladder. We determined if the new guidelines were reflective of differences in survival between subepithelial prostatic stromal invasion and transmural pT4a disease. Materials and Methods: A retrospective, multi-institutional cohort of cystectomy cases with subepithelial prostatic stromal invasion from the University of Chicago and Cleveland Clinic were compared to a cohort with transmural pT4a disease. All pathological specimens were rereviewed at the respective institutions. Patients were excluded from the final cohort if variant bladder cancer histology, pT3 bladder disease or extraprostatic extension of urothelial carcinoma were identified. The primary end points were cancer specific and overall survival. Results: Our study sample consisted of 48 patients with subepithelial prostatic stromal invasion and 49 patients with transmural pT4a disease. Median followup was 12.8 months (IQR 4.9 to 31.4). Patients with subepithelial prostatic stromal invasion had lower rates of lymph node involvement than those with transmural pT4a disease (14.6% vs 61.2%, p ⬍0.001) and lower rates of positive surgical margins (18.7% vs 61.2%, p ⬍0.001). Rates of perioperative chemotherapy were similar in both groups. When comparing subepithelial prostatic stromal invasion and transmural pT4a groups, overall survival was 64.0 vs 9.8 months and median cancer specific survival was not achieved vs 16.5 months, respectively (p ⬍0.001). Conclusions: Subepithelial prostatic stromal invasion from urothelial carcinoma has more favorable outcomes compared to transmural pT4a disease. Our results support the exclusion of subepithelial prostatic stromal invasion from the pT4a bladder urothelial carcinoma staging class.
Abbreviations and Acronyms BCG ⫽ bacillus Calmette-Guérin CSS ⫽ cancer specific survival LN ⫽ lymph node OS ⫽ overall survival SM ⫽ surgical margins SSI ⫽ subepithelial prostatic stromal invasion UC ⫽ urothelial carcinoma Accepted for publication July 17, 2012. Study received institutional review board approval. * Financial interest and/or other relationship with Endo, Abbott Molecular and Predictive Biosciences. † Correspondence: Department of Pathology and Laboratory Medicine, Cleveland Clinic, 9500 Euclid Ave., Cleveland, Ohio 44195 (telephone: 216-444-5893; e-mail: [email protected]).
Key Words: carcinoma, transitional cell; prostate; neoplasm invasiveness; urinary bladder neoplasms; cystectomy IN 2012 there will be an estimated 73,510 new cases and 14,880 deaths from bladder cancer in the United States.1 The estimated lifetime probability of bladder cancer developing in Caucasians in the United States and Western Europe is estimated at 1 in
25 for men and 1 in 80 for women.2 The incidence is increasing in industrialized and in developing nations, with 386,000 incident cases worldwide in 2008.3 Tumor grade, stage and lymph node status are important prognostic
0022-5347/13/1891-0053/0 THE JOURNAL OF UROLOGY® © 2013 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
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factors, and have implications in patient counseling and management, including decisions regarding perioperative chemotherapy. Locally advanced disease portends a poorer prognosis, with estimated 5-year survival rates of 77% for pT2 LN negative disease vs 44% for pT4a, LN negative disease.4 Advanced T stage is generally associated with LN involvement. Pathological T4a disease was associated with a LN positive rate of 42% compared to only 18% for pT2 disease. These data illustrate the tendency of poor prognostic factors to be grouped and underscore the prognostic differences between locally advanced and organ confined invasive disease.4 Prostatic stromal invasion is not uncommon and has typically been associated with poor prognosis.5–7 Urothelial carcinoma of the prostate has an incidence of 12% to 48%, of which approximately 7.6% to 25% have prostatic stromal invasion.5–7 Risk factors for prostatic invasion include multifocal UC, carcinoma in situ and tumor location at the trigone or bladder neck.8 Many cases are associated with concurrent or previous tumors in the bladder and history of intravesical BCG therapy. The 3 described patterns of prostatic stromal invasion from urothelial carcinoma are extravesical, transmural and subepithelial stromal invasion (fig. 1).9 Historically, invasion of the prostatic stroma, whether through transmural invasion or subepithelial invasion via the prostatic urethra, had been classified as a subset of pT4a disease. In 2010 the AJCC reclassified primary staging for bladder cancer to exclude SSI from the pT4a staging status, reserving the pT4a classification for those tumors extending into the prostate by way of transmural invasion through the bladder wall.10
Figure 1. Prostatic invasion from UC via transmural and extravesical route (A), and subepithelial invasion (B).
We investigated the validity of the new AJCC guidelines using patient cohorts from the Cleveland Clinic and University of Chicago. We determined whether the changes in the AJCC guidelines were reflective of more favorable pathological parameters, such as margin and LN status, and cancer specific and overall survival for patients with SSI compared to transmural pT4a disease.
METHODS With the approval of the institutional review boards at University of Chicago and Cleveland Clinic, the patient cohorts were extracted from institutional databases. The University of Chicago study sample contained all patients who underwent radical cystectomy for UC between December 1994 and October 2011, and were diagnosed with pT4a disease (extravesical/transmural and SSI). The Cleveland Clinic provided a cohort of patients from March 2004 to March 2010 who were diagnosed with pT4a disease based on the finding of SSI rather than transmural invasion. All pathology was reviewed by GPP and DEH at the respective institutions. We included in study only cases considered to be urothelial carcinoma, and excluded those that had nonurothelial morphology such as pure adenocarcinoma, squamous cell carcinoma and small cell carcinoma. We also excluded cases that demonstrated a predominant variant morphology of urothelial carcinoma such as micropapillary or nested urothelial carcinoma. In addition, patients were excluded upon review if they had SSI and additionally had pT3 disease in the bladder or extraprostatic extension of subepithelial UC. The rationale for eliminating pT3 bladder disease was derived from previously published studies that demonstrated survival outcomes to be more strongly dependent on bladder staging alone than SSI.11 Following review of pathology, the pT4a study sample was divided into 2 cohorts of transmural pT4a and SSI. Demographic factors collected included age, ASA (American Society of Anesthesiologists) score and smoking history. Clinical data included history of intravesical BCG, history of radiation therapy and history of perioperative chemotherapy. Pathological data included tumor histology, T stage, LN status and margin status (urethral, ureteral or soft tissue margin). Time of last followup and time to death were obtained by review of the medical records and the Social Security Death Index. Primary end points were overall and cancer specific survival. The likelihood of LN positive disease and margin status was analyzed as an estimate of the extent of disease at surgery. Statistical analysis was performed with MedCalc® version 11.5.1.0 and the chi-square test was used to compare categorical values. Medians were compared via the MannWhitney U test. Kaplan-Meier curves were generated to compare OS and CSS between the 2 groups using the log rank test. Multivariate Cox proportional hazards models were developed using Stata® 11 to estimate the effect of each covariate (age, group, total LN, positive LN and SM) on survival. Additional analysis was performed to evaluate factors (primary bladder stage, SM and LN status) influencing survival in the SSI group.
SUBEPITHELIAL PROSTATIC STROMAL INVASION VERSUS TRANSMURAL BLADDER DISEASE
55
Demographic, clinical and pathology summary statistics
Median pt age (IQR) No. ASA (%): 0–2 Greater than 2 No. ever smoker (%): Yes No No. any pos margin (%): Yes No No. pos LNs (%): Yes No Median LN count (IQR) No. periop chemotherapy (%): Yes No No. bladder pathology (%): T0 Ta Tis T1 T2
Overall
SSI
Transmural/Extravesical T4a
p Value
71.0 (63.7–77.0)
71.0 (63.5–76.5)
71.0 (63.7–78.2)
0.64*
64 33
(66) (34)
27 21
(56) (44)
37 12
(76) (24)
0.18†
81 16
(84) (16)
39 9
(81) (19)
42 7
(86) (14)
0.75†
39 58
(40) (60)
9 39
(19) (81)
30 19
(61) (39)
⬍0.001†
30 (61) 19 (39) 16.0 (12.2–19.8)
⬍0.001† 0.049†
37 (38) 60 (62) 18.0 (11–25.2)
7 41 20.5
47 50
22 26
(46) (54)
6 1 13 5 23
(13) (2) (27) (10) (48)
(48) (52)
(15) (85) (16–25)
25 24
(51) (49)
0.76†
* Mann-Whitney U test. † Chi-square test.
RESULTS The final study sample was comprised of 48 patients with SSI and 49 patients with transmural pT4a disease (see table). Median followup was 12.8 months (IQR 4.9 to 31.4). Mean age of the cohort was 69.9 years (95% CI 67.8 –71.9) with no difference between the groups. There were 22 (23%) patients with a history of intravesical therapy. Patients with SSI had lower rates of LN involvement than men with transmural pT4a disease (14.6% vs 61.2%, p ⬍0.001), as well as lower rates of positive SM (18.7% vs 61.2%, p ⬍0.001). Overall median LN counts were higher in the SSI group (20.5, 95% CI 16.0 –25.0) than in the transmural pT4a group (16.0, 95% CI 12.2–19.8). Rates of perioperative chemotherapy were similar in both groups. Median CSS was not achieved for the SSI group vs 16.5 months for the transmural pT4a group (p ⬍0.001, fig. 2). Median OS for the SSI group was 64 months vs 9.8 months for the transmural pT4a group (p ⬍0.001, fig. 3). After multivariate analysis the transmural pT4a group was the only covariate associated with worse CSS and OS (HR 0.38, 95% CI 0.17– 0.86 and HR 0.41, 95% CI 0.22– 0.80, respectively, p ⫽ 0.008). Additional analysis of factors affecting survival in the SSI group demonstrated that bladder stage, when stratified by pT2 vs less than pT2 (including pT0, pTa, pTis and pT1), did not affect CSS (HR 1.04, 95% CI 0.36 –2.96, p ⫽ 0.95, fig. 4, A). CSS was similar for patients based on LN status (HR 1.13,
95% CI 0.24 –5.6, p ⫽ 0.87) and surgical margins (HR 0.88, 95% CI 0.25–3.1, p ⫽ 0.87, fig. 4, B and C).
DISCUSSION With a multi-institutional cohort of patients we demonstrated that the mechanism of prostatic stromal invasion by UC, either subepithelial invasion vs transmural/extravesical invasion, significantly influences survival. Patients with transmural invasion of the prostate had higher rates of LN positive disease and positive surgical margins at cystectomy. These factors were not independent predictors of survival after multivariate modeling, which may be
Figure 2. Kaplan-Meier curves for CSS between pT4a and SSI (HR 0.28, 95% CI 0.14 – 0.55, p ⬍0.001).
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SUBEPITHELIAL PROSTATIC STROMAL INVASION VERSUS TRANSMURAL BLADDER DISEASE
(61%) had transmural or extravesical prostatic invasion, with a 5-year survival of 40% vs 7%, respectively. However, this study was limited by the low
Figure 3. Kaplan-Meier curves for OS between pT4a and SSI (HR 0.33, 95% CI 0.19 – 0.57, p ⬍0.0001).
due to aggressive tumor biology in transmural and extravesical stromal invasion. In contrast, patients with SSI have organ confined disease, and theoretically should have lower positive margin rates and LN positive disease. This is supported by our results as LN positive disease was found in 17% of patients with SSI vs 61% of patients with true locally advanced disease (pT4a). Previous reports from large, single institution studies have demonstrated similar rates of LN positive disease for bladder pT2 (organ confined disease) compared to pT4a (locally advanced disease).4,12 Our findings support SSI as an entity different from pT4a disease biologically and pathologically. Secondary invasion of UC that originates within the prostatic urethra into the surrounding stroma is not uncommon, and has an estimated frequency of occurrence in 12% to 48% of patients with bladder cancer.8,9 Risk factors for prostatic UC include noninvasive or invasive carcinoma in the region of the trigone and bladder neck, or a history of high risk noninvasive bladder cancer with repeat transurethral resection and BCG therapy.6,7,13 In one of the largest series of its kind, Herr and Donat followed 186 patients for a minimum of 15 years with high risk noninvasive bladder cancer who received BCG therapy and underwent repeat transurethral resections.7 Overall, 39% of patients had relapse of UC that involved the prostate during followup, which did not appear to impact CSS at a 15-year minimum followup. However, when the authors stratified the mechanism of prostatic stromal invasion in 27 patients, they found that the 15-year survival rate for SSI was significantly higher when compared with transmural/extravesical stromal invasion (75% vs 9%, p ⬍0.001). Pagano et al also demonstrated a difference in survival based on the invasion pathways of the prostate in patients with UC.14 In their study of 72 patients with pT4 disease, 8 (11%) had SSI and 44
Figure 4. CSS for patients with SSI stratified by bladder pT2 stage and less than pT2 stage (p ⫽ 0.95) (A), LN involvement (p ⫽ 0.87) (B) and SM (p ⫽ 0.85) (C).
SUBEPITHELIAL PROSTATIC STROMAL INVASION VERSUS TRANSMURAL BLADDER DISEASE
number of patients with SSI. Esrig et al conducted a study in 143 patients with UC involving the prostate.11 The 5-year recurrence-free survival and OS in 58 (41%) patients with SSI was 48% and 36%, respectively, compared to 19 (13%) patients with transmural invasion who had recurrence-free survival and OS of 25% and 21%. However, almost half of the patients in the SSI cohort also had pT3 disease, which limits stratification of the subgroups and may have negatively influenced the outcome of the SSI group. Based on their findings, the authors of these studies recommended a change in the staging classification of prostatic stromal invasion based on the mechanism of invasion. However, based on prior reports that claimed that stromal invasion was an ominous prognostic factor, there remains nonconsensus among pathologists and urologists.15,16 For example, numerous studies have demonstrated no difference in survival when comparing SSI to transmural pT4a disease, although study size and inclusion of pT3 bladder disease limit some of the conclusions from these studies. Njinou Ngninkeu et al found similar 5-year overall and recurrence-free survival for patients with SSI and transmural prostate invasion (29% and 35%, vs 22% and 28%, respectively) in a small series of patients.17 Barocas et al conducted a pathological review of 59 patients with prostatic stromal invasion, and found no difference in survival between SSI and transmural prostatic invasion (3-year overall survival 17% vs 7%, p ⫽ 0.619).18 Ayyathurai et al examined 47 patients with prostatic invasion of UC.19 Although SSI was not directly compared to transmural invasion, 5-year OS for SSI was 26% vs 6% for transmural stromal invasion (no p value reported). Shen et al demonstrated a 5-year survival probability of 32% for prostatic stromal invasion in 27 patients, but SSI and transmural invasion were not differentiated.20 Given that numerous previous studies have suggested that bladder stage influences survival to a greater extent than prostatic stromal invasion alone, the results for survival in patients with SSI would be negatively affected when including pT3 patients in the cohort.7,11,14 Despite the limitations of study design and smaller cohorts, these studies support the controversy over the AJCC reclassification of SSI.
57
Although the AJCC excluded SSI from the pT4a staging status, there are no guidelines as to how subepithelial prostatic invasion should be staged.10 The staging of secondary prostatic UC could potentially follow the staging guidelines of primary prostatic UC, ie SSI would be classified as pT2 disease.10 Furthermore, prostatic involvement in a patient with concurrent bladder cancer could be reported as a secondary stage in the final pathology report. Examining true staging assignment and differences in tumor biology should be the goals of future multiinstitutional efforts. Recent studies have attempted to evaluate outcomes based on the amount of extramural prostatic stromal invasion. Oliva et al found no difference in median OS when comparing focal vs extensive extramural prostatic invasion in 35 patients (17.4 vs 16.3 months).21 These findings support the theory that tumor biology of transmural/extramural prostatic invasion, whether focal or extensive, may be more aggressive than SSI. Limitations of our study include its retrospective nature and accompanying treatment biases, as well as a relatively small cohort of patients. However, the updated AJCC classification requires validation, and this retrospective effort will be followed with prospective studies of subepithelial prostatic stromal invasion of UC. Other limitations may include the elimination of bladder pT3 disease from the SSI cohort. This was planned a priori to keep the study sample pure and to properly study the newly reclassified SSI vs pT4a disease. In addition, 6 (13%) patients in our SSI cohort had bladder pT0 disease but had viable urothelial carcinoma in the prostatic stroma. We included these cases in the study as they were once considered pT4a disease, but based on our results may have different tumor biology and outcomes. Stratification based on bladder stage for outcomes and proper staging classification of SSI will be the goals of future efforts.
CONCLUSIONS In a retrospective, multi-institutional cohort we demonstrated that SSI from bladder UC has more favorable pathological and clinical outcomes compared to transmural pT4a disease at cystectomy. Our results support the exclusion of SSI from pT4a staging classification for bladder cancer.
REFERENCES 1. Siegel R, Naishadham D and Jemal A: Cancer statistics, 2012. CA Cancer J Clin 2012; 62: 10.
2. Howlader N, Noone AM, Krapcho M et al: SEER Cancer Statistics Review, 1975–2009 (Vintage 2009 Populations), National Cancer Institute. Bethesda, MD,
http://seer.cancer.gov/csr/1975_2009_pops09/, based on November 2011 SEER data submission, posted to the SEER web site, April 2012.
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3. Ferlay J, Shin HR, Bray F et al: Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010; 127: 2893.
10. Edge SB, Byrd DR, Compton CC et al: AJCC Cancer Staging Manual, 7th ed. New York: Springer 2010.
4. Stein JP, Lieskovsky G, Cote R et al: Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. J Clin Oncol 2001; 19: 666.
11. Esrig D, Freeman JA, Elmajian DA et al: Transitional cell carcinoma involving the prostate with a proposed staging classification for stromal invasion. J Urol 1996; 156: 1071.
5. Palou J, Baniel J, Klotz L et al: Urothelial carcinoma of the prostate. Urology 2007; 69: 50.
12. Tarin TV, Power NE, Ehdaie B et al: Lymph nodepositive bladder cancer treated with radical cystectomy and lymphadenectomy: effect of the level of node positivity. Eur Urol 2012; 61: 1025.
6. Wood DP Jr, Montie JE, Pontes JE et al: Transitional cell carcinoma of the prostate in cystoprostatectomy specimens removed for bladder cancer. J Urol 1989; 141: 346. 7. Herr HW and Donat SM: Prostatic tumor relapse in patients with superficial bladder tumors: 15year outcome. J Urol 1999; 161: 1854.
13. Hardeman SW, Perry A and Soloway MS: Transitional cell carcinoma of the prostate following intravesical therapy for transitional cell carcinoma of the bladder. J Urol 1988; 140: 289.
8. Lerner SP and Shen S: Pathologic assessment and clinical significance of prostatic involvement by transitional cell carcinoma and prostate cancer. Urol Oncol 2008; 26: 481.
14. Pagano F, Bassi P, Ferrante GL et al: Is stage pT4a (D1) reliable in assessing transitional cell carcinoma involvement of the prostate in patients with a concurrent bladder cancer? A necessary distinction for contiguous or noncontiguous involvement. J Urol 1996; 155: 244.
9. Donat SM, Genega EM, Herr HW et al: Mechanisms of prostatic stromal invasion in patients with bladder cancer: clinical significance. J Urol 2001; 165: 1117.
15. Cheville JC, Dundore PA, Bostwick DG et al: Transitional cell carcinoma of the prostate: clinicopathologic study of 50 cases. Cancer 1998; 82: 703.
16. Schellhammer PF, Bean MA and Whitmore WF Jr: Prostatic involvement by transitional cell carcinoma: pathogenesis, patterns and prognosis. J Urol 1977; 118: 399. 17. Njinou Ngninkeu B, Lorge F, Moulin P et al: Transitional cell carcinoma involving the prostate: a clinicopathological retrospective study of 76 cases. J Urol 2003; 169: 149. 18. Barocas DA, Patel SG, Chang SS et al: Outcomes of patients undergoing radical cystoprostatectomy for bladder cancer with prostatic involvement on final pathology. BJU Int 2009; 104: 1091. 19. Ayyathurai R, Gomez P, Luongo T et al: Prostatic involvement by urothelial carcinoma of the bladder: clinicopathological features and outcome after radical cystectomy. BJU Int 2007; 100: 1021. 20. Shen SS, Lerner SP, Muezzinoglu B et al: Prostatic involvement by transitional cell carcinoma in patients with bladder cancer and its prognostic significance. Hum Pathol 2006; 37: 726. 21. Oliva IV, Smith SL, Chen Z et al: Urothelial carcinoma of the bladder with transmural and direct prostatic stromal invasion: does extent of stromal invasion significantly impact patient outcome? Hum Pathol 2011; 42: 51.
Purpose: In 2010 the AJCC (American Joint Committee on Cancer) excluded urothelial carcinoma with subepithelial prostatic stromal invasion from the pT4a bladder cancer staging class, which is otherwise defined by direct prostatic invasion transmurally from the bladder. We determined if the new guidelines were reflective of differences in survival between subepithelial prostatic stromal invasion and transmural pT4a disease. Materials and Methods: A retrospective, multi-institutional cohort of cystectomy cases with subepithelial prostatic stromal invasion from the University of Chicago and Cleveland Clinic were compared to a cohort with transmural pT4a disease. All pathological specimens were rereviewed at the respective institutions. Patients were excluded from the final cohort if variant bladder cancer histology, pT3 bladder disease or extraprostatic extension of urothelial carcinoma were identified. The primary end points were cancer specific and overall survival. Results: Our study sample consisted of 48 patients with subepithelial prostatic stromal invasion and 49 patients with transmural pT4a disease. Median followup was 12.8 months (IQR 4.9 to 31.4). Patients with subepithelial prostatic stromal invasion had lower rates of lymph node involvement than those with transmural pT4a disease (14.6% vs 61.2%, p ⬍0.001) and lower rates of positive surgical margins (18.7% vs 61.2%, p ⬍0.001). Rates of perioperative chemotherapy were similar in both groups. When comparing subepithelial prostatic stromal invasion and transmural pT4a groups, overall survival was 64.0 vs 9.8 months and median cancer specific survival was not achieved vs 16.5 months, respectively (p ⬍0.001). Conclusions: Subepithelial prostatic stromal invasion from urothelial carcinoma has more favorable outcomes compared to transmural pT4a disease. Our results support the exclusion of subepithelial prostatic stromal invasion from the pT4a bladder urothelial carcinoma staging class.
Abbreviations and Acronyms BCG ⫽ bacillus Calmette-Guérin CSS ⫽ cancer specific survival LN ⫽ lymph node OS ⫽ overall survival SM ⫽ surgical margins SSI ⫽ subepithelial prostatic stromal invasion UC ⫽ urothelial carcinoma Accepted for publication July 17, 2012. Study received institutional review board approval. * Financial interest and/or other relationship with Endo, Abbott Molecular and Predictive Biosciences. † Correspondence: Department of Pathology and Laboratory Medicine, Cleveland Clinic, 9500 Euclid Ave., Cleveland, Ohio 44195 (telephone: 216-444-5893; e-mail: [email protected]).
Key Words: carcinoma, transitional cell; prostate; neoplasm invasiveness; urinary bladder neoplasms; cystectomy IN 2012 there will be an estimated 73,510 new cases and 14,880 deaths from bladder cancer in the United States.1 The estimated lifetime probability of bladder cancer developing in Caucasians in the United States and Western Europe is estimated at 1 in
25 for men and 1 in 80 for women.2 The incidence is increasing in industrialized and in developing nations, with 386,000 incident cases worldwide in 2008.3 Tumor grade, stage and lymph node status are important prognostic
0022-5347/13/1891-0053/0 THE JOURNAL OF UROLOGY® © 2013 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
http://dx.doi.org/10.1016/j.juro.2012.09.006 Vol. 189, 53-58, January 2013 RESEARCH, INC. Printed in U.S.A.
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SUBEPITHELIAL PROSTATIC STROMAL INVASION VERSUS TRANSMURAL BLADDER DISEASE
factors, and have implications in patient counseling and management, including decisions regarding perioperative chemotherapy. Locally advanced disease portends a poorer prognosis, with estimated 5-year survival rates of 77% for pT2 LN negative disease vs 44% for pT4a, LN negative disease.4 Advanced T stage is generally associated with LN involvement. Pathological T4a disease was associated with a LN positive rate of 42% compared to only 18% for pT2 disease. These data illustrate the tendency of poor prognostic factors to be grouped and underscore the prognostic differences between locally advanced and organ confined invasive disease.4 Prostatic stromal invasion is not uncommon and has typically been associated with poor prognosis.5–7 Urothelial carcinoma of the prostate has an incidence of 12% to 48%, of which approximately 7.6% to 25% have prostatic stromal invasion.5–7 Risk factors for prostatic invasion include multifocal UC, carcinoma in situ and tumor location at the trigone or bladder neck.8 Many cases are associated with concurrent or previous tumors in the bladder and history of intravesical BCG therapy. The 3 described patterns of prostatic stromal invasion from urothelial carcinoma are extravesical, transmural and subepithelial stromal invasion (fig. 1).9 Historically, invasion of the prostatic stroma, whether through transmural invasion or subepithelial invasion via the prostatic urethra, had been classified as a subset of pT4a disease. In 2010 the AJCC reclassified primary staging for bladder cancer to exclude SSI from the pT4a staging status, reserving the pT4a classification for those tumors extending into the prostate by way of transmural invasion through the bladder wall.10
Figure 1. Prostatic invasion from UC via transmural and extravesical route (A), and subepithelial invasion (B).
We investigated the validity of the new AJCC guidelines using patient cohorts from the Cleveland Clinic and University of Chicago. We determined whether the changes in the AJCC guidelines were reflective of more favorable pathological parameters, such as margin and LN status, and cancer specific and overall survival for patients with SSI compared to transmural pT4a disease.
METHODS With the approval of the institutional review boards at University of Chicago and Cleveland Clinic, the patient cohorts were extracted from institutional databases. The University of Chicago study sample contained all patients who underwent radical cystectomy for UC between December 1994 and October 2011, and were diagnosed with pT4a disease (extravesical/transmural and SSI). The Cleveland Clinic provided a cohort of patients from March 2004 to March 2010 who were diagnosed with pT4a disease based on the finding of SSI rather than transmural invasion. All pathology was reviewed by GPP and DEH at the respective institutions. We included in study only cases considered to be urothelial carcinoma, and excluded those that had nonurothelial morphology such as pure adenocarcinoma, squamous cell carcinoma and small cell carcinoma. We also excluded cases that demonstrated a predominant variant morphology of urothelial carcinoma such as micropapillary or nested urothelial carcinoma. In addition, patients were excluded upon review if they had SSI and additionally had pT3 disease in the bladder or extraprostatic extension of subepithelial UC. The rationale for eliminating pT3 bladder disease was derived from previously published studies that demonstrated survival outcomes to be more strongly dependent on bladder staging alone than SSI.11 Following review of pathology, the pT4a study sample was divided into 2 cohorts of transmural pT4a and SSI. Demographic factors collected included age, ASA (American Society of Anesthesiologists) score and smoking history. Clinical data included history of intravesical BCG, history of radiation therapy and history of perioperative chemotherapy. Pathological data included tumor histology, T stage, LN status and margin status (urethral, ureteral or soft tissue margin). Time of last followup and time to death were obtained by review of the medical records and the Social Security Death Index. Primary end points were overall and cancer specific survival. The likelihood of LN positive disease and margin status was analyzed as an estimate of the extent of disease at surgery. Statistical analysis was performed with MedCalc® version 11.5.1.0 and the chi-square test was used to compare categorical values. Medians were compared via the MannWhitney U test. Kaplan-Meier curves were generated to compare OS and CSS between the 2 groups using the log rank test. Multivariate Cox proportional hazards models were developed using Stata® 11 to estimate the effect of each covariate (age, group, total LN, positive LN and SM) on survival. Additional analysis was performed to evaluate factors (primary bladder stage, SM and LN status) influencing survival in the SSI group.
SUBEPITHELIAL PROSTATIC STROMAL INVASION VERSUS TRANSMURAL BLADDER DISEASE
55
Demographic, clinical and pathology summary statistics
Median pt age (IQR) No. ASA (%): 0–2 Greater than 2 No. ever smoker (%): Yes No No. any pos margin (%): Yes No No. pos LNs (%): Yes No Median LN count (IQR) No. periop chemotherapy (%): Yes No No. bladder pathology (%): T0 Ta Tis T1 T2
Overall
SSI
Transmural/Extravesical T4a
p Value
71.0 (63.7–77.0)
71.0 (63.5–76.5)
71.0 (63.7–78.2)
0.64*
64 33
(66) (34)
27 21
(56) (44)
37 12
(76) (24)
0.18†
81 16
(84) (16)
39 9
(81) (19)
42 7
(86) (14)
0.75†
39 58
(40) (60)
9 39
(19) (81)
30 19
(61) (39)
⬍0.001†
30 (61) 19 (39) 16.0 (12.2–19.8)
⬍0.001† 0.049†
37 (38) 60 (62) 18.0 (11–25.2)
7 41 20.5
47 50
22 26
(46) (54)
6 1 13 5 23
(13) (2) (27) (10) (48)
(48) (52)
(15) (85) (16–25)
25 24
(51) (49)
0.76†
* Mann-Whitney U test. † Chi-square test.
RESULTS The final study sample was comprised of 48 patients with SSI and 49 patients with transmural pT4a disease (see table). Median followup was 12.8 months (IQR 4.9 to 31.4). Mean age of the cohort was 69.9 years (95% CI 67.8 –71.9) with no difference between the groups. There were 22 (23%) patients with a history of intravesical therapy. Patients with SSI had lower rates of LN involvement than men with transmural pT4a disease (14.6% vs 61.2%, p ⬍0.001), as well as lower rates of positive SM (18.7% vs 61.2%, p ⬍0.001). Overall median LN counts were higher in the SSI group (20.5, 95% CI 16.0 –25.0) than in the transmural pT4a group (16.0, 95% CI 12.2–19.8). Rates of perioperative chemotherapy were similar in both groups. Median CSS was not achieved for the SSI group vs 16.5 months for the transmural pT4a group (p ⬍0.001, fig. 2). Median OS for the SSI group was 64 months vs 9.8 months for the transmural pT4a group (p ⬍0.001, fig. 3). After multivariate analysis the transmural pT4a group was the only covariate associated with worse CSS and OS (HR 0.38, 95% CI 0.17– 0.86 and HR 0.41, 95% CI 0.22– 0.80, respectively, p ⫽ 0.008). Additional analysis of factors affecting survival in the SSI group demonstrated that bladder stage, when stratified by pT2 vs less than pT2 (including pT0, pTa, pTis and pT1), did not affect CSS (HR 1.04, 95% CI 0.36 –2.96, p ⫽ 0.95, fig. 4, A). CSS was similar for patients based on LN status (HR 1.13,
95% CI 0.24 –5.6, p ⫽ 0.87) and surgical margins (HR 0.88, 95% CI 0.25–3.1, p ⫽ 0.87, fig. 4, B and C).
DISCUSSION With a multi-institutional cohort of patients we demonstrated that the mechanism of prostatic stromal invasion by UC, either subepithelial invasion vs transmural/extravesical invasion, significantly influences survival. Patients with transmural invasion of the prostate had higher rates of LN positive disease and positive surgical margins at cystectomy. These factors were not independent predictors of survival after multivariate modeling, which may be
Figure 2. Kaplan-Meier curves for CSS between pT4a and SSI (HR 0.28, 95% CI 0.14 – 0.55, p ⬍0.001).
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SUBEPITHELIAL PROSTATIC STROMAL INVASION VERSUS TRANSMURAL BLADDER DISEASE
(61%) had transmural or extravesical prostatic invasion, with a 5-year survival of 40% vs 7%, respectively. However, this study was limited by the low
Figure 3. Kaplan-Meier curves for OS between pT4a and SSI (HR 0.33, 95% CI 0.19 – 0.57, p ⬍0.0001).
due to aggressive tumor biology in transmural and extravesical stromal invasion. In contrast, patients with SSI have organ confined disease, and theoretically should have lower positive margin rates and LN positive disease. This is supported by our results as LN positive disease was found in 17% of patients with SSI vs 61% of patients with true locally advanced disease (pT4a). Previous reports from large, single institution studies have demonstrated similar rates of LN positive disease for bladder pT2 (organ confined disease) compared to pT4a (locally advanced disease).4,12 Our findings support SSI as an entity different from pT4a disease biologically and pathologically. Secondary invasion of UC that originates within the prostatic urethra into the surrounding stroma is not uncommon, and has an estimated frequency of occurrence in 12% to 48% of patients with bladder cancer.8,9 Risk factors for prostatic UC include noninvasive or invasive carcinoma in the region of the trigone and bladder neck, or a history of high risk noninvasive bladder cancer with repeat transurethral resection and BCG therapy.6,7,13 In one of the largest series of its kind, Herr and Donat followed 186 patients for a minimum of 15 years with high risk noninvasive bladder cancer who received BCG therapy and underwent repeat transurethral resections.7 Overall, 39% of patients had relapse of UC that involved the prostate during followup, which did not appear to impact CSS at a 15-year minimum followup. However, when the authors stratified the mechanism of prostatic stromal invasion in 27 patients, they found that the 15-year survival rate for SSI was significantly higher when compared with transmural/extravesical stromal invasion (75% vs 9%, p ⬍0.001). Pagano et al also demonstrated a difference in survival based on the invasion pathways of the prostate in patients with UC.14 In their study of 72 patients with pT4 disease, 8 (11%) had SSI and 44
Figure 4. CSS for patients with SSI stratified by bladder pT2 stage and less than pT2 stage (p ⫽ 0.95) (A), LN involvement (p ⫽ 0.87) (B) and SM (p ⫽ 0.85) (C).
SUBEPITHELIAL PROSTATIC STROMAL INVASION VERSUS TRANSMURAL BLADDER DISEASE
number of patients with SSI. Esrig et al conducted a study in 143 patients with UC involving the prostate.11 The 5-year recurrence-free survival and OS in 58 (41%) patients with SSI was 48% and 36%, respectively, compared to 19 (13%) patients with transmural invasion who had recurrence-free survival and OS of 25% and 21%. However, almost half of the patients in the SSI cohort also had pT3 disease, which limits stratification of the subgroups and may have negatively influenced the outcome of the SSI group. Based on their findings, the authors of these studies recommended a change in the staging classification of prostatic stromal invasion based on the mechanism of invasion. However, based on prior reports that claimed that stromal invasion was an ominous prognostic factor, there remains nonconsensus among pathologists and urologists.15,16 For example, numerous studies have demonstrated no difference in survival when comparing SSI to transmural pT4a disease, although study size and inclusion of pT3 bladder disease limit some of the conclusions from these studies. Njinou Ngninkeu et al found similar 5-year overall and recurrence-free survival for patients with SSI and transmural prostate invasion (29% and 35%, vs 22% and 28%, respectively) in a small series of patients.17 Barocas et al conducted a pathological review of 59 patients with prostatic stromal invasion, and found no difference in survival between SSI and transmural prostatic invasion (3-year overall survival 17% vs 7%, p ⫽ 0.619).18 Ayyathurai et al examined 47 patients with prostatic invasion of UC.19 Although SSI was not directly compared to transmural invasion, 5-year OS for SSI was 26% vs 6% for transmural stromal invasion (no p value reported). Shen et al demonstrated a 5-year survival probability of 32% for prostatic stromal invasion in 27 patients, but SSI and transmural invasion were not differentiated.20 Given that numerous previous studies have suggested that bladder stage influences survival to a greater extent than prostatic stromal invasion alone, the results for survival in patients with SSI would be negatively affected when including pT3 patients in the cohort.7,11,14 Despite the limitations of study design and smaller cohorts, these studies support the controversy over the AJCC reclassification of SSI.
57
Although the AJCC excluded SSI from the pT4a staging status, there are no guidelines as to how subepithelial prostatic invasion should be staged.10 The staging of secondary prostatic UC could potentially follow the staging guidelines of primary prostatic UC, ie SSI would be classified as pT2 disease.10 Furthermore, prostatic involvement in a patient with concurrent bladder cancer could be reported as a secondary stage in the final pathology report. Examining true staging assignment and differences in tumor biology should be the goals of future multiinstitutional efforts. Recent studies have attempted to evaluate outcomes based on the amount of extramural prostatic stromal invasion. Oliva et al found no difference in median OS when comparing focal vs extensive extramural prostatic invasion in 35 patients (17.4 vs 16.3 months).21 These findings support the theory that tumor biology of transmural/extramural prostatic invasion, whether focal or extensive, may be more aggressive than SSI. Limitations of our study include its retrospective nature and accompanying treatment biases, as well as a relatively small cohort of patients. However, the updated AJCC classification requires validation, and this retrospective effort will be followed with prospective studies of subepithelial prostatic stromal invasion of UC. Other limitations may include the elimination of bladder pT3 disease from the SSI cohort. This was planned a priori to keep the study sample pure and to properly study the newly reclassified SSI vs pT4a disease. In addition, 6 (13%) patients in our SSI cohort had bladder pT0 disease but had viable urothelial carcinoma in the prostatic stroma. We included these cases in the study as they were once considered pT4a disease, but based on our results may have different tumor biology and outcomes. Stratification based on bladder stage for outcomes and proper staging classification of SSI will be the goals of future efforts.
CONCLUSIONS In a retrospective, multi-institutional cohort we demonstrated that SSI from bladder UC has more favorable pathological and clinical outcomes compared to transmural pT4a disease at cystectomy. Our results support the exclusion of SSI from pT4a staging classification for bladder cancer.
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