Oncology The Presence of High-grade Prostatic Intraepithelial Neoplasia or Atypia on Prostate Biopsy Does Not Adversely Affect Prostatectomy Outcomes for Patients Otherwise Eligible for Active Surveillance Eugene J. Pietzak III, Abdo E. Kabarriti, Phillip Mucksavage, Thomas Bavaria, Keith Van Arsdalen, S. Bruce Malkowicz, Alan J. Wein, and Thomas J. Guzzo OBJECTIVE
METHODS
RESULTS
CONCLUSION
To investigate if the presence of concomitant high-grade prostatic intraepithelial neoplasia (HGPIN) or atypical small acinar proliferation (ASAP) on biopsy increases the risk of occult adverse pathology in patients otherwise suitable for active surveillance (AS). Patients with D’Amico low-risk prostate cancer on 10-core biopsy who underwent radical prostatectomy at our academic center were evaluated for eligibility for AS by either Epstein criteria or Memorial Sloan Kettering Cancer Center (MSKCC) criteria. Prostatectomy specimens of patients eligible for AS were compared to determine if the presence of clinical HGPIN or ASAP affected the primary outcomes of pathologic upstaging and Gleason score upgrading. Of 553 patients with low-risk prostate cancer, 400 patients (72.3%) met the MSKCC criteria, whereas only 170 patients (30.7%) met the Epstein criteria. HGPIN was present in approximately 32%, and ASAP in approximately 12%, of each AS cohort. On univariate and multivariate analyses, HGPIN and ASAP had no impact on the rate of upgrading and upstaging in either Epstein or MSKCC AS-eligible patients. Furthermore, the presence of HGPIN and ASAP had no impact on the 5-year biochemical recurrence-free survival. The presence of HGPIN or ASAP does not increase the risk of upgrading, upstaging, or adverse pathology at the time of prostatectomy for patients who meet the AS criteria. If otherwise suitable, HGPIN and ASAP should not impact the decision to choose AS. However, analysis of prospective AS trials is required to determine if HGPIN or ASAP impacts tumor progression once on AS. UROLOGY 84: 1442e1447, 2014. 2014 Elsevier Inc.
I
n recent years, the diagnosis and treatment of prostate cancer (PCa) has been under increased scrutiny. Multiple criteria have been developed to help determine suitable candidates for active surveillance (AS) in an effort to better balance the risk of PCa morbidity and mortality with the adverse effects associated with treatment.1 There are still no universally accepted optimal AS criteria. Although most criteria focus on the grade and volume of PCa found on biopsy,
Financial Disclosure: The authors declare that they have no relevant financial interests. Funding Support: This research was supported in part by the Linda and Joel Appel Prostate Cancer Research Fund. From the Division of Urology, Department of Surgery, Hospital of University of Pennsylvania, Philadelphia, PA Address correspondence to: Eugene J. Pietzak III, M.D., Division of Urology, Department of Surgery, Hospital of University of Pennsylvania Philadelphia, PA 19104. E-mail: [email protected] Submitted: March 13, 2014, accepted (with revisions): April 29, 2014
1442
ª 2014 Elsevier Inc. All Rights Reserved
no AS criteria address other histologic findings, such as high-grade prostatic intraepithelial neoplasia (HGPIN) and atypical small acinar proliferation (ASAP).2 Although subject to debate, HGPIN is thought by some to be a precursor lesion of PCa due to similar genetic alterations. Although the association between unifocal HGPIN and PCa is less robust than initially believed, multifocal HGPIN does appear to increase the risk of detecting PCa on repeat biopsy compared with benign biopsies.3,4 Furthermore, ASAP is diagnosed when a high suspicion for PCa exists but the definitive diagnosis of carcinoma cannot be established. Repeating prostate biopsies with additional samples taken in the area of the ASAP can identify PCa in >50% of patients.3 Given the association between both HGPIN and ASAP with PCa, an obvious question is whether these histologic findings on biopsy should be factored into the http://dx.doi.org/10.1016/j.urology.2014.04.066 0090-4295/14
decision making process of AS vs definitive treatment. To the best of our knowledge, this question remains unanswered. To this aim, we looked at the impact of clinical HGPIN and clinical ASAP on prostatectomy outcomes for patients who are eligible for 2 commonly used AS criteria but elected for surgical treatment. We hypothesized that HGPIN would not be associated with an increased risk of Gleason score upgrading and pathologic upstaging for AS-eligible patients, but ASAP would be associated with these worse outcomes.
continuous variables; therefore, the Wilcoxon rank sum test was used for comparisons. Categorical variables were analyzed using the chi-square test and the Fisher exact test when appropriate. The log-rank test was used to detect differences in BCR survival. Statistical significance was declared if P .05. Multiple logistic regression analyses were performed for the primary outcomes in both Epstein and MSKCC cohorts using predictor variables with P values .2 on univariate analysis and for variables thought to have a priori interactions (age, PSA, ASAP, and HGPIN).
RESULTS METHODS We identified patients with D’Amico low-risk PCa (Gleason score [GS] 6, prostate-specific antigen [PSA] level 10 ng/mL, and clinical stage T1c-T2a) found on 10-core biopsy and treated with retropubic radical prostatectomy (RP) from 1998 to 2008 at a single academic center.5 We then evaluated this cohort for eligibility by 2 AS criteria based on their biopsy characteristics. Patients who met either AS criteria were then analyzed for the presence or absence of clinical HGPIN, as well as the presence or absence of clinical ASAP. Epstein criteria and Memorial Sloan Kettering Cancer Center (MSKCC) criteria were the 2 AS criteria selected for this study. Patients were considered to meet Epstein criteria if they had clinical stage T1c, GS 6, 50% carcinoma involvement of any core, 2 positive core, and PSA density 0.15 ng/mL.6 Patients were considered to have met MSKCC criteria if they had clinical stage T1c-T2a, PSA level 10 ng/mL, GS 6, 3 positive core, and 50% involvement of any core.7 Patients who were diagnosed with PCa on biopsies of 0.2 ng/mL using chemiluminescent enzyme immunometric assay. The processing and pathologic analysis of RP specimens at our institution has been previously described.9 A dedicated genitourinary (GU) pathologist reviewed all biopsies and RP specimens, including the rereview of biopsies performed outside our institution. The GU pathologist determined the presence or absence of HGPIN, ASAP, and carcinoma in the specimens.
Statistical Analysis Statistical analysis was performed using Stata 12.0 (College Station, TX). Continuous variables were reported as median values with interquartile rankings (IQR). The Shapiro-Wilk test was used to determine nonparametric distribution for UROLOGY 84 (6), 2014
Included in the entire study cohort were 553 consecutive patients with D’Amico low-risk PCa diagnosed on 10core biopsy. The median time from biopsy to RP was 3.3 months (IQR, 2.7, 4.2) for the entire cohort. Of the 553 patients in the study cohort, 168 (30.4%) had clinical HGPIN, whereas only 76 (13.7%) had clinical ASAP. Of the entire 553 patient cohort, 400 (72.3%) were eligible for MSKCC AS protocol, whereas only 170 (30.7%) were eligible by Epstein AS criteria. Of the 170 patients meeting Epstein criteria, 56 (32.9%) had clinical HGPIN and 20 (11.7%) had clinical ASAP. Of the 400 patients meeting MSKCC criteria, 124 (31.1%) had clinical HGPIN and 47 (11.8%) had clinical ASAP. Comparison Number 1: Presence vs Absence of HGPIN in Epstein ASeeligible Patients Comparing the clinical characteristics for Epstein ASeeligible patients, no clinical variable that was analyzed was statistically different as seen in Supplementary Table 1. Furthermore, no statistical difference was found on comparing RP specimens with regards to upgrading, upstaging, or adverse features (Table 1). Additionally, the presence of clinical HGPIN had no impact with regard to the risk of biochemical failure in Epstein-eligible patients (P ¼ .96). Five-year BCR-free survival (BCRFS) was 100% for both groups. Multivariate logistic regression modeling for Epsteineligible patients is listed in Table 2. Only serum PSA level was a significant predictor of upgrading, and only the total number of biopsy cores taken was inversely related to the risk of upstaging. Clinical HGPIN was not a predictor of either upgrading or upstaging within the Epstein ASeeligible cohort. Comparison Number 2: Presence vs Absence of HGPIN in MSKCC ASeeligible Patients The results of the univariate analysis for clinical features between patients meeting MSKCC criteria with clinical HGPIN and those without HGPIN can be seen in Supplementary Table 1. Those diagnosed with HGPIN were more likely to have more biopsy cores taken (13.5 [IQR, 11-16] vs 12 [IQR, 11-14]; P ¼ .001) and to have 2 cores involved with carcinoma (108 of 124 [89.3%] vs 218 of 275 [80%]; P ¼ .02). MSKCC eligible patients with HGPIN were also more likely to have concomitant ASAP than MSKCC-eligible patients 1443
Table 1. Pathologic outcomes for active surveillance patients with and without high-grade prostatic intraepithelial neoplasia Epstein Criteria With Clinical HGPIN, n (%) Pathologic Gleason score 6 3þ4 4þ3 8 Estimated tumor volume, % 2 2-10 10-25 25 Extracapsular extension Seminal vesicle invasion Lymph node involvement Positive surgical margins Pathologic tumor stage T2a T2b T3 T4 Pathologic upstaging at the time of prostatectomy Gleason score upgrading at the time of prostatectomy
Epstein Criteria Without Clinical HPGIN, n (%)
P Value
MSKCC Criteria With Clinical HGPIN, n (%)
MSKCC Criteria Without Clinical HPGIN, n (%)
.37 45 (80.4) 9 (16.1) 2 (3.6) 0
95 13 2 1
(85.6) (11.7) (1.8) (0.9)
26 19 5 4 3
55 43 8 3 12 2 1 7
(50.5) (39.5) (7.3) (2.8) (10.5) (1.8) (0.9) (6.2)
70 16 10 2 12
(71.4) (16.3) (10.2) (2) (10.5)
16 (14.4)
.42 96 (77.5) 23 (18.5) 5 (4) 0
213 46 6 6
(78.6) (17) (2.2) (2.2)
51 42 20 8 12 1
(42.1) (34.7) (16.5) (6.6) (9.7) (0.8) 0 11 (8.9)
102 109 38 16 36 5 3 30
(38.5) (41.2) (14.3) (6) (13.1) (1.8) (1.1) (10.9)
.33
73 22 11 2 13
153 40 32 4 36
(55.6) (14.5) (11.6) (1.5) (13.1)
.37
.39
28 (22.6)
58 (21.1)
.79
.53 (48.2) (35.2) (9.3) (7.4) (5.3) 0 0 2 (3.6)
29 12 2 1 3
(65.9) (27.3) (4.6) (2.3) (5.3)
11 (19.6)
P Value
.26 .6 .48 .47 .37
.46
(58.9) (1.8) (8.9) (1.6) (10.5)
.33 .61 .24 .06 .87
HGPIN, high-grade prostatic intraepithelial neoplasia; MSKCC, Memorial Sloan Kettering Cancer Center.
Table 2. Multiple variable analyses for Epstein active surveillanceeeligible patients Risk of Upgrading in Epstein ASeeligible Cohort Independent Variables Age PSA ASAP HGPIN Total cores sampled
Odds Ratio (95% CI) 1.0 1.6 1.3 1.4 0.9
(0.9-1.1) (1.2-2.1) (0.38-4.7) (0.54-3.5) (0.77-1.0)
P Value .8 .001 .66 .5 .08
Risk of Upstaging in Epstein ASeeligible Cohort Odds Ratio (95% CI) 1.0 0.92 3.3 0.46 0.76
(0.92-1.11) (0.64-1.32) (0.69-15.5) (0.11-1.9) (0.58-0.99)
P Value .9 .64 .14 .28 .04
AS, active surveillance; ASAP, atypical small acinar proliferation; CI, confidence interval; PSA, prostate-specific antigen; other abbreviation as in Table 1.
without HGPIN (21 of 124 [17%] vs 26 of 275 [9.5%]; P ¼ .03). Although these differences were seen for clinical characteristics, no difference was seen in any of the pathologic outcomes for MSKCC-eligible patients with or without HGPIN, including no difference on upgrading and upstaging (Table 1). Furthermore, HGPIN also had no impact on BCRFS in patients meeting MSKCC AS criteria (P ¼ .7). The 5-year BCRFS was 98.6% for those with HGPIN and 100% for those without HGPIN. Multiple logistic regression analyses for upgrading and upstaging within the MSKCC-eligible cohort are listed in Table 3. Increased serum PSA level was associated with a greater risk of both upgrading and upstaging. Although increasing age was associated with less risk of upstaging, it was not an independent predictor of upgrading. Similar to Epstein-eligible patients, HGPIN was not predictive of upgrading or upstaging on multiple variable analyses in the MSKCC ASeeligible cohort. 1444
Comparison Number 3: Presence vs Absence of ASAP in Epstein ASeeligible Patients Clinical characteristics for Epstein eligible patients with and without ASAP are described in Supplementary Table 2. Pathologic outcomes are shown in Table 4. ASAP had no impact on upgrading or upstaging on univariate analysis. Additionally, ASAP had no impact on BCRFS in Epstein ASeeligible patients (P ¼ .29). The 5-year BCRFS was 100% for both those with and without clinical ASAP. Just as for HGPIN, multivariate logistic regression analyses failed to demonstrate ASAP as predictors of upgrading or upstaging for Epstein ASeeligible patients (Table 2). Comparison Number 4: Presence vs Absence of ASAP in MSKCC ASeeligible Patients Clinical variables for MSKCC-eligible patients with and without ASAP are shown in Supplementary Table 2. The UROLOGY 84 (6), 2014
Table 3. Multiple variable analyses for the Memorial Sloan Kettering Cancer Center active surveillanceeeligible patients Risk of Upgrading in MSKCC ASeeligible Cohort Independent Variables
P Value
Odds Ratio (95% CI)
Age PSA ASAP HGPIN Previous biopsy Clinical stage Total cores sampled 2 Positive cores
0.99 1.18 1.42 1.29 1.12 1.17 0.92 0.59
Risk of Upstaging in MSKCC ASeeligible Cohort
(0.95-1.03) (1.04-1.34) (0.68-2.97) (0.74-2.24) (0.90-1.39) (0.64-2.13) (0.84-1.00) (0.32-1.11)
Odds Ratio (95% CI)
.60 .01 .35 .90 .32 .60 .06 .1
0.94 1.20 1.11 0.77 1.03 0.94 0.94 0.93
(0.89-0.98) (1.02-1.42) (0.42-2.89) (0.37-1.60) (0.74-1.41) (0.43-2.04) (0.84-1.05) (0.42-2.06)
P Value .007 .03 .84 .48 .88 .88 .26 .86
Abbreviations as in Tables 1 and 2.
Table 4. Pathologic outcomes for active surveillance patients with and without atypical small acinar proliferation Epstein Criteria With Clinical ASAP, n (%) Pathologic Gleason score 6 3þ4 4þ3 8 Estimated tumor volume, % 2 2-10 10-25 25 Extracapsular extension Seminal vesicle invasion Lymph node involvement Positive surgical margins Pathologic tumor stage T2a T2b T3 T4 Pathologic upstaging at the time of prostatectomy Gleason score upgrading at the time of prostatectomy
Epstein Criteria Without Clinical ASAP, n (%)
P Value
MSKCC Criteria With Clinical ASAP, n (%)
MSKCC Criteria Without Clinical ASAP, n (%)
.54 14 (73.7) 4 (21) 1 (5.3) 0
126 18 3 1
(85.1) (12.2) (2) (0.7)
(31.6) (47.4) (15.8) (5.3) (15) 0 0 2 (10)
75 53 10 6 12 2 1 7
(52.1) (36.8) (6.9) (4.2) (8) (1.3) (0.7) (4.7)
8 6 2 1 3
91 22 10 2 12
(72.8) (17.6) (8) (1.6) (9.6)
22 (14.9)
.69 34 (73.9) 11 (23.9) 1 (2.2) 0
276 58 10 6
(78.9) (16.6) (3) (1.7)
15 17 10 4 6 1 1 4
(32.6) (37) (21.7) (8.7) (12.8) (2.1) (2.1) (8.5)
139 134 48 20 42 5 2 37
(40.8) (39.3) (14.1) (5.9) (11.9) (1.4) (0.5) (10.5)
.39
22 13 5 1 6
(53.7) (31.7) (12.2) (2.4) (12.8)
205 49 38 5 43
(69) (16.5) (10.8) (1.4) (12.2)
.38
12 (25.5)
.31 6 9 63 1 3
(47) (35.3) (11.8) (5.9) (17.7)
5 (26.3)
.3 .74 .69 .72 .15
P Value
.54
74 (21)
.86 .62 .24 .79 .09
.98 .45
Abbreviations as in Tables 1 and 2.
only statistical difference was that clinical HGPIN was more common in patients with ASAP than those without ASAP (21 of 47 [44.7%] vs 103 of 353 [29.3%]; P ¼ .03). Pathologic information is listed in Table 4. Yet again, there was no difference between any pathologic variables including the primary outcomes of upgrading and upstaging. Again, ASAP resulted in no statistical difference for BCRFS within the MSKCC-eligible cohort (P ¼ .67). The 5-year BCRFS for those with ASAP was 100% compared with that of 99.4% for those without ASAP. The multivariate logistic regression analysis for risk of upgrading and upstaging in MSKCC ASeeligible patients is listed in Table 3. Neither the presence of clinical HGPIN nor clinical ASAP, was a predictor of either upgrading or upstaging.
COMMENT There has been a growing interest in AS for the management of low-risk PCa due to concern about overtreatment UROLOGY 84 (6), 2014
of indolent tumors and an increasing acknowledgment of treatment-related morbidity.2,10,11 Although AS participation has increased in recent years, utilization of AS remains low compared with the number of patients who are eligible.12 A top priority for all stakeholders involved in the diagnosis and treatment of PCa should be to better define the patient population most appropriate for AS. An additional priority should be identifying barriers to enrollment in AS. For certain patients, distress and anxiety from living with “untreated” cancer may be a potential barrier.13 Given the association between HGPIN and ASAP with PCa, a critically important question is whether these findings should factor into decision making about AS. Even if a biopsy suggests a low-risk PCa, the addition of a possible premalignant lesion might push an anxiety-prone patient toward active treatment. The objective of our present study was to help guide the management of low-risk PCa patients considering AS who also have concomitant HGPIN or ASAP. 1445
Our results confirm that HGPIN and ASAP should not preclude initial enrollment into AS programs. We found no statistical difference in our primary outcomes of GS upgrading and pathologic upstaging at the time of prostatectomy in AS candidates with either HGPIN or ASAP. We also found no difference in other adverse pathologic features. Furthermore, the rate of BCR did not differ for patients with HGPIN or ASAP, albeit with a median follow-up for the entire cohort of only 4.9 years. The findings from our study should provide further reassurance to patients experiencing anxiety and distress over their newly diagnosed low-risk cancer that initial management with AS is a reasonable option, even in the presence of HGPIN or ASAP. For this study, we selected Epstein criteria and MSKCC criteria for AS enrollment, as these criteria are commonly used in the reported literature, and although Epstein criteria is considered to have a fairly strict inclusion criteria, the MSKCC criteria is relatively more inclusive.1 Our aim was to allow our results to be more generalizable to a wide array of patients considering AS by including a spectrum of patients. The difference in these 2 criteria is demonstrated in our study with only 30.7% (170 of 553) of patients with D’Amico low-risk PCa meeting Epstein criteria, compared with the 72.3% (400 of 553) of patients meeting MSKCC criteria. In fact, the group at Johns Hopkins have acknowledged that Epstein criteria may be too strict, which may exclude many potential candidates for AS. They have recently published a preliminary analysis using more inclusive criteria.14 Based on their early analysis, the criteria of PSA density 0.15 ng/mL and a Gleason score of 6 were important in selecting appropriate AS candidates, but the criteria of clinical stage T1c were not. They concluded that patients with higher clinical stage can safely be included in AS if other AS criteria are met.14 For our study, we used the original strict version of Epstein criteria to select for patients with the lowest risk disease. On the other hand, MSKCC criteria for AS require an immediate confirmatory biopsy before enrollment into AS.7 The MSKCC group found that 35% (185 of 531) of patients originally eligible for AS by their criteria on initial biopsy were found to be ineligible on subsequent confirmatory biopsy.7 Because our study cohort were patients who elected for treatment with prostatectomy after PCa was detected, no confirmatory biopsies were obtained for our cohort. The absence of confirmatory biopsy allows for a more liberal inclusion of patients in our study so the entire spectrum of AS eligibility can be analyzed. However, our study is not without limitations; this was an observational study; therefore, we were unable to control for biopsy indications and to standardize biopsy technique. Although, an experienced GU pathologist reviewed all biopsies and prostatectomy specimens, bias may be introduced by interobserver variability. An additional limitation is our inability to adjust for the amount of HGPIN or ASAP on biopsy, as multifocal HGPIN and multifocal ASAP have a greater association 1446
with PCa.3 Similarly, HGPIN with adjacent ASAP on biopsy also has an increased risk of PCa, but the small number of patients with these concomitant findings limited this analysis. It is also important to recognize that this study used the surrogate endpoints of pathologic GS and pathologic stage to determine appropriateness for AS enrollment. Because all patients in this study were treated with RP and the natural history of HGPIN and ASAP is unclear, the impact that these histologic findings have on tumor progression while a patient is on AS is unknown. The findings of this retrospective observational study will need to be confirmed by the ongoing prospective trials looking at outcomes of AS.
CONCLUSION The presence of clinical HGPIN and clinical ASAP did not increase the risk of Gleason score upgrading or pathologic upstaging at the time of RP for patients who meet AS criteria. Our data suggest that simply the existence of HGPIN and ASAP should not impact the decision to enroll into AS, thus removing a potential barrier to AS. However, analysis of the prospective AS trials will be needed to determine if HGPIN and ASAP impact tumor progression when on AS. References 1. Iremashvili V, Pelaez L, Manoharan M, et al. Pathologic prostate cancer characteristics in patients eligible for active surveillance: a head-to-head comparison of contemporary protocols. Eur Urol. 2012;62:462-468. 2. Buethe DD, Pow-Sang J. Enrollment criteria controversies for active surveillance and triggers for conversion to treatment in prostate cancer. J Natl Compr Canc Netw. 2012;10:1101-1110. 3. Epstein JI, Herawi M. Prostate needle biopsies containing prostatic intraepithelial neoplasia or atypical foci suspicious for carcinoma: implications for patient care. J Urol. 2006;175:820-834. 4. Merrimen JL, Jones G, Walker D, et al. Multifocal high grade prostatic intraepithelial neoplasia is a significant risk factor for prostatic adenocarcinoma. J Urol. 2009;182:485-490; discussion 490. 5. D’Amico AV, Whittington R, Malkowicz SB, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA. 1998;280:969-974. 6. Tosoian JJ, Trock BJ, Landis P, et al. Active surveillance program for prostate cancer: an update of the Johns Hopkins experience. J Clin Oncol. 2011;29:2185-2190. 7. Adamy A, Yee DS, Matsushita K, et al. Role of prostate specific antigen and immediate confirmatory biopsy in predicting progression during active surveillance for low risk prostate cancer. J Urol. 2011;185:477-482. 8. Divrik RT, Eroglu A, Sahin A, et al. Increasing the number of biopsies increases the concordance of Gleason scores of needle biopsies and prostatectomy specimens. Urol Oncol. 2007;25: 376-382. 9. Guzzo TJ, Vira MA, Neway W, et al. Minimal tumor volume may provide additional prognostic information in good performance patients after radical prostatectomy. Urology. 2007;69:1147-1151. 10. Resnick MJ, Koyama T, Fan KH, et al. Long-term functional outcomes after treatment for localized prostate cancer. N Engl J Med. 2013;368:436-445.
UROLOGY 84 (6), 2014
11. Epstein JI, Chan DW, Sokoll LJ, et al. Nonpalpable stage T1c prostate cancer: prediction of insignificant disease using free/total prostate specific antigen levels and needle biopsy findings. J Urol. 1998;160:2407-2411. 12. Barocas DA, Cowan JE, Smith JA Jr, et al. What percentage of patients with newly diagnosed carcinoma of the prostate are candidates for surveillance? An analysis of the CaPSURE database. J Urol. 2008;180:1330-1334; discussion 1334-1335. 13. Kazer MW, Psutka SP, Latini DM, et al. Psychosocial aspects of active surveillance. Curr Opin Urol. 2013;23:273-277.
UROLOGY 84 (6), 2014
14. Reese AC, Landis P, Han M, et al. Expanded criteria to identify men eligible for active surveillance of low risk prostate cancer at Johns Hopkins: a preliminary analysis. J Urol. 2013;190:2033-2038.
APPENDIX SUPPLEMENTARY DATA
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.urology. 2014.04.066.
1447
METHODS
RESULTS
CONCLUSION
To investigate if the presence of concomitant high-grade prostatic intraepithelial neoplasia (HGPIN) or atypical small acinar proliferation (ASAP) on biopsy increases the risk of occult adverse pathology in patients otherwise suitable for active surveillance (AS). Patients with D’Amico low-risk prostate cancer on 10-core biopsy who underwent radical prostatectomy at our academic center were evaluated for eligibility for AS by either Epstein criteria or Memorial Sloan Kettering Cancer Center (MSKCC) criteria. Prostatectomy specimens of patients eligible for AS were compared to determine if the presence of clinical HGPIN or ASAP affected the primary outcomes of pathologic upstaging and Gleason score upgrading. Of 553 patients with low-risk prostate cancer, 400 patients (72.3%) met the MSKCC criteria, whereas only 170 patients (30.7%) met the Epstein criteria. HGPIN was present in approximately 32%, and ASAP in approximately 12%, of each AS cohort. On univariate and multivariate analyses, HGPIN and ASAP had no impact on the rate of upgrading and upstaging in either Epstein or MSKCC AS-eligible patients. Furthermore, the presence of HGPIN and ASAP had no impact on the 5-year biochemical recurrence-free survival. The presence of HGPIN or ASAP does not increase the risk of upgrading, upstaging, or adverse pathology at the time of prostatectomy for patients who meet the AS criteria. If otherwise suitable, HGPIN and ASAP should not impact the decision to choose AS. However, analysis of prospective AS trials is required to determine if HGPIN or ASAP impacts tumor progression once on AS. UROLOGY 84: 1442e1447, 2014. 2014 Elsevier Inc.
I
n recent years, the diagnosis and treatment of prostate cancer (PCa) has been under increased scrutiny. Multiple criteria have been developed to help determine suitable candidates for active surveillance (AS) in an effort to better balance the risk of PCa morbidity and mortality with the adverse effects associated with treatment.1 There are still no universally accepted optimal AS criteria. Although most criteria focus on the grade and volume of PCa found on biopsy,
Financial Disclosure: The authors declare that they have no relevant financial interests. Funding Support: This research was supported in part by the Linda and Joel Appel Prostate Cancer Research Fund. From the Division of Urology, Department of Surgery, Hospital of University of Pennsylvania, Philadelphia, PA Address correspondence to: Eugene J. Pietzak III, M.D., Division of Urology, Department of Surgery, Hospital of University of Pennsylvania Philadelphia, PA 19104. E-mail: [email protected] Submitted: March 13, 2014, accepted (with revisions): April 29, 2014
1442
ª 2014 Elsevier Inc. All Rights Reserved
no AS criteria address other histologic findings, such as high-grade prostatic intraepithelial neoplasia (HGPIN) and atypical small acinar proliferation (ASAP).2 Although subject to debate, HGPIN is thought by some to be a precursor lesion of PCa due to similar genetic alterations. Although the association between unifocal HGPIN and PCa is less robust than initially believed, multifocal HGPIN does appear to increase the risk of detecting PCa on repeat biopsy compared with benign biopsies.3,4 Furthermore, ASAP is diagnosed when a high suspicion for PCa exists but the definitive diagnosis of carcinoma cannot be established. Repeating prostate biopsies with additional samples taken in the area of the ASAP can identify PCa in >50% of patients.3 Given the association between both HGPIN and ASAP with PCa, an obvious question is whether these histologic findings on biopsy should be factored into the http://dx.doi.org/10.1016/j.urology.2014.04.066 0090-4295/14
decision making process of AS vs definitive treatment. To the best of our knowledge, this question remains unanswered. To this aim, we looked at the impact of clinical HGPIN and clinical ASAP on prostatectomy outcomes for patients who are eligible for 2 commonly used AS criteria but elected for surgical treatment. We hypothesized that HGPIN would not be associated with an increased risk of Gleason score upgrading and pathologic upstaging for AS-eligible patients, but ASAP would be associated with these worse outcomes.
continuous variables; therefore, the Wilcoxon rank sum test was used for comparisons. Categorical variables were analyzed using the chi-square test and the Fisher exact test when appropriate. The log-rank test was used to detect differences in BCR survival. Statistical significance was declared if P .05. Multiple logistic regression analyses were performed for the primary outcomes in both Epstein and MSKCC cohorts using predictor variables with P values .2 on univariate analysis and for variables thought to have a priori interactions (age, PSA, ASAP, and HGPIN).
RESULTS METHODS We identified patients with D’Amico low-risk PCa (Gleason score [GS] 6, prostate-specific antigen [PSA] level 10 ng/mL, and clinical stage T1c-T2a) found on 10-core biopsy and treated with retropubic radical prostatectomy (RP) from 1998 to 2008 at a single academic center.5 We then evaluated this cohort for eligibility by 2 AS criteria based on their biopsy characteristics. Patients who met either AS criteria were then analyzed for the presence or absence of clinical HGPIN, as well as the presence or absence of clinical ASAP. Epstein criteria and Memorial Sloan Kettering Cancer Center (MSKCC) criteria were the 2 AS criteria selected for this study. Patients were considered to meet Epstein criteria if they had clinical stage T1c, GS 6, 50% carcinoma involvement of any core, 2 positive core, and PSA density 0.15 ng/mL.6 Patients were considered to have met MSKCC criteria if they had clinical stage T1c-T2a, PSA level 10 ng/mL, GS 6, 3 positive core, and 50% involvement of any core.7 Patients who were diagnosed with PCa on biopsies of 0.2 ng/mL using chemiluminescent enzyme immunometric assay. The processing and pathologic analysis of RP specimens at our institution has been previously described.9 A dedicated genitourinary (GU) pathologist reviewed all biopsies and RP specimens, including the rereview of biopsies performed outside our institution. The GU pathologist determined the presence or absence of HGPIN, ASAP, and carcinoma in the specimens.
Statistical Analysis Statistical analysis was performed using Stata 12.0 (College Station, TX). Continuous variables were reported as median values with interquartile rankings (IQR). The Shapiro-Wilk test was used to determine nonparametric distribution for UROLOGY 84 (6), 2014
Included in the entire study cohort were 553 consecutive patients with D’Amico low-risk PCa diagnosed on 10core biopsy. The median time from biopsy to RP was 3.3 months (IQR, 2.7, 4.2) for the entire cohort. Of the 553 patients in the study cohort, 168 (30.4%) had clinical HGPIN, whereas only 76 (13.7%) had clinical ASAP. Of the entire 553 patient cohort, 400 (72.3%) were eligible for MSKCC AS protocol, whereas only 170 (30.7%) were eligible by Epstein AS criteria. Of the 170 patients meeting Epstein criteria, 56 (32.9%) had clinical HGPIN and 20 (11.7%) had clinical ASAP. Of the 400 patients meeting MSKCC criteria, 124 (31.1%) had clinical HGPIN and 47 (11.8%) had clinical ASAP. Comparison Number 1: Presence vs Absence of HGPIN in Epstein ASeeligible Patients Comparing the clinical characteristics for Epstein ASeeligible patients, no clinical variable that was analyzed was statistically different as seen in Supplementary Table 1. Furthermore, no statistical difference was found on comparing RP specimens with regards to upgrading, upstaging, or adverse features (Table 1). Additionally, the presence of clinical HGPIN had no impact with regard to the risk of biochemical failure in Epstein-eligible patients (P ¼ .96). Five-year BCR-free survival (BCRFS) was 100% for both groups. Multivariate logistic regression modeling for Epsteineligible patients is listed in Table 2. Only serum PSA level was a significant predictor of upgrading, and only the total number of biopsy cores taken was inversely related to the risk of upstaging. Clinical HGPIN was not a predictor of either upgrading or upstaging within the Epstein ASeeligible cohort. Comparison Number 2: Presence vs Absence of HGPIN in MSKCC ASeeligible Patients The results of the univariate analysis for clinical features between patients meeting MSKCC criteria with clinical HGPIN and those without HGPIN can be seen in Supplementary Table 1. Those diagnosed with HGPIN were more likely to have more biopsy cores taken (13.5 [IQR, 11-16] vs 12 [IQR, 11-14]; P ¼ .001) and to have 2 cores involved with carcinoma (108 of 124 [89.3%] vs 218 of 275 [80%]; P ¼ .02). MSKCC eligible patients with HGPIN were also more likely to have concomitant ASAP than MSKCC-eligible patients 1443
Table 1. Pathologic outcomes for active surveillance patients with and without high-grade prostatic intraepithelial neoplasia Epstein Criteria With Clinical HGPIN, n (%) Pathologic Gleason score 6 3þ4 4þ3 8 Estimated tumor volume, % 2 2-10 10-25 25 Extracapsular extension Seminal vesicle invasion Lymph node involvement Positive surgical margins Pathologic tumor stage T2a T2b T3 T4 Pathologic upstaging at the time of prostatectomy Gleason score upgrading at the time of prostatectomy
Epstein Criteria Without Clinical HPGIN, n (%)
P Value
MSKCC Criteria With Clinical HGPIN, n (%)
MSKCC Criteria Without Clinical HPGIN, n (%)
.37 45 (80.4) 9 (16.1) 2 (3.6) 0
95 13 2 1
(85.6) (11.7) (1.8) (0.9)
26 19 5 4 3
55 43 8 3 12 2 1 7
(50.5) (39.5) (7.3) (2.8) (10.5) (1.8) (0.9) (6.2)
70 16 10 2 12
(71.4) (16.3) (10.2) (2) (10.5)
16 (14.4)
.42 96 (77.5) 23 (18.5) 5 (4) 0
213 46 6 6
(78.6) (17) (2.2) (2.2)
51 42 20 8 12 1
(42.1) (34.7) (16.5) (6.6) (9.7) (0.8) 0 11 (8.9)
102 109 38 16 36 5 3 30
(38.5) (41.2) (14.3) (6) (13.1) (1.8) (1.1) (10.9)
.33
73 22 11 2 13
153 40 32 4 36
(55.6) (14.5) (11.6) (1.5) (13.1)
.37
.39
28 (22.6)
58 (21.1)
.79
.53 (48.2) (35.2) (9.3) (7.4) (5.3) 0 0 2 (3.6)
29 12 2 1 3
(65.9) (27.3) (4.6) (2.3) (5.3)
11 (19.6)
P Value
.26 .6 .48 .47 .37
.46
(58.9) (1.8) (8.9) (1.6) (10.5)
.33 .61 .24 .06 .87
HGPIN, high-grade prostatic intraepithelial neoplasia; MSKCC, Memorial Sloan Kettering Cancer Center.
Table 2. Multiple variable analyses for Epstein active surveillanceeeligible patients Risk of Upgrading in Epstein ASeeligible Cohort Independent Variables Age PSA ASAP HGPIN Total cores sampled
Odds Ratio (95% CI) 1.0 1.6 1.3 1.4 0.9
(0.9-1.1) (1.2-2.1) (0.38-4.7) (0.54-3.5) (0.77-1.0)
P Value .8 .001 .66 .5 .08
Risk of Upstaging in Epstein ASeeligible Cohort Odds Ratio (95% CI) 1.0 0.92 3.3 0.46 0.76
(0.92-1.11) (0.64-1.32) (0.69-15.5) (0.11-1.9) (0.58-0.99)
P Value .9 .64 .14 .28 .04
AS, active surveillance; ASAP, atypical small acinar proliferation; CI, confidence interval; PSA, prostate-specific antigen; other abbreviation as in Table 1.
without HGPIN (21 of 124 [17%] vs 26 of 275 [9.5%]; P ¼ .03). Although these differences were seen for clinical characteristics, no difference was seen in any of the pathologic outcomes for MSKCC-eligible patients with or without HGPIN, including no difference on upgrading and upstaging (Table 1). Furthermore, HGPIN also had no impact on BCRFS in patients meeting MSKCC AS criteria (P ¼ .7). The 5-year BCRFS was 98.6% for those with HGPIN and 100% for those without HGPIN. Multiple logistic regression analyses for upgrading and upstaging within the MSKCC-eligible cohort are listed in Table 3. Increased serum PSA level was associated with a greater risk of both upgrading and upstaging. Although increasing age was associated with less risk of upstaging, it was not an independent predictor of upgrading. Similar to Epstein-eligible patients, HGPIN was not predictive of upgrading or upstaging on multiple variable analyses in the MSKCC ASeeligible cohort. 1444
Comparison Number 3: Presence vs Absence of ASAP in Epstein ASeeligible Patients Clinical characteristics for Epstein eligible patients with and without ASAP are described in Supplementary Table 2. Pathologic outcomes are shown in Table 4. ASAP had no impact on upgrading or upstaging on univariate analysis. Additionally, ASAP had no impact on BCRFS in Epstein ASeeligible patients (P ¼ .29). The 5-year BCRFS was 100% for both those with and without clinical ASAP. Just as for HGPIN, multivariate logistic regression analyses failed to demonstrate ASAP as predictors of upgrading or upstaging for Epstein ASeeligible patients (Table 2). Comparison Number 4: Presence vs Absence of ASAP in MSKCC ASeeligible Patients Clinical variables for MSKCC-eligible patients with and without ASAP are shown in Supplementary Table 2. The UROLOGY 84 (6), 2014
Table 3. Multiple variable analyses for the Memorial Sloan Kettering Cancer Center active surveillanceeeligible patients Risk of Upgrading in MSKCC ASeeligible Cohort Independent Variables
P Value
Odds Ratio (95% CI)
Age PSA ASAP HGPIN Previous biopsy Clinical stage Total cores sampled 2 Positive cores
0.99 1.18 1.42 1.29 1.12 1.17 0.92 0.59
Risk of Upstaging in MSKCC ASeeligible Cohort
(0.95-1.03) (1.04-1.34) (0.68-2.97) (0.74-2.24) (0.90-1.39) (0.64-2.13) (0.84-1.00) (0.32-1.11)
Odds Ratio (95% CI)
.60 .01 .35 .90 .32 .60 .06 .1
0.94 1.20 1.11 0.77 1.03 0.94 0.94 0.93
(0.89-0.98) (1.02-1.42) (0.42-2.89) (0.37-1.60) (0.74-1.41) (0.43-2.04) (0.84-1.05) (0.42-2.06)
P Value .007 .03 .84 .48 .88 .88 .26 .86
Abbreviations as in Tables 1 and 2.
Table 4. Pathologic outcomes for active surveillance patients with and without atypical small acinar proliferation Epstein Criteria With Clinical ASAP, n (%) Pathologic Gleason score 6 3þ4 4þ3 8 Estimated tumor volume, % 2 2-10 10-25 25 Extracapsular extension Seminal vesicle invasion Lymph node involvement Positive surgical margins Pathologic tumor stage T2a T2b T3 T4 Pathologic upstaging at the time of prostatectomy Gleason score upgrading at the time of prostatectomy
Epstein Criteria Without Clinical ASAP, n (%)
P Value
MSKCC Criteria With Clinical ASAP, n (%)
MSKCC Criteria Without Clinical ASAP, n (%)
.54 14 (73.7) 4 (21) 1 (5.3) 0
126 18 3 1
(85.1) (12.2) (2) (0.7)
(31.6) (47.4) (15.8) (5.3) (15) 0 0 2 (10)
75 53 10 6 12 2 1 7
(52.1) (36.8) (6.9) (4.2) (8) (1.3) (0.7) (4.7)
8 6 2 1 3
91 22 10 2 12
(72.8) (17.6) (8) (1.6) (9.6)
22 (14.9)
.69 34 (73.9) 11 (23.9) 1 (2.2) 0
276 58 10 6
(78.9) (16.6) (3) (1.7)
15 17 10 4 6 1 1 4
(32.6) (37) (21.7) (8.7) (12.8) (2.1) (2.1) (8.5)
139 134 48 20 42 5 2 37
(40.8) (39.3) (14.1) (5.9) (11.9) (1.4) (0.5) (10.5)
.39
22 13 5 1 6
(53.7) (31.7) (12.2) (2.4) (12.8)
205 49 38 5 43
(69) (16.5) (10.8) (1.4) (12.2)
.38
12 (25.5)
.31 6 9 63 1 3
(47) (35.3) (11.8) (5.9) (17.7)
5 (26.3)
.3 .74 .69 .72 .15
P Value
.54
74 (21)
.86 .62 .24 .79 .09
.98 .45
Abbreviations as in Tables 1 and 2.
only statistical difference was that clinical HGPIN was more common in patients with ASAP than those without ASAP (21 of 47 [44.7%] vs 103 of 353 [29.3%]; P ¼ .03). Pathologic information is listed in Table 4. Yet again, there was no difference between any pathologic variables including the primary outcomes of upgrading and upstaging. Again, ASAP resulted in no statistical difference for BCRFS within the MSKCC-eligible cohort (P ¼ .67). The 5-year BCRFS for those with ASAP was 100% compared with that of 99.4% for those without ASAP. The multivariate logistic regression analysis for risk of upgrading and upstaging in MSKCC ASeeligible patients is listed in Table 3. Neither the presence of clinical HGPIN nor clinical ASAP, was a predictor of either upgrading or upstaging.
COMMENT There has been a growing interest in AS for the management of low-risk PCa due to concern about overtreatment UROLOGY 84 (6), 2014
of indolent tumors and an increasing acknowledgment of treatment-related morbidity.2,10,11 Although AS participation has increased in recent years, utilization of AS remains low compared with the number of patients who are eligible.12 A top priority for all stakeholders involved in the diagnosis and treatment of PCa should be to better define the patient population most appropriate for AS. An additional priority should be identifying barriers to enrollment in AS. For certain patients, distress and anxiety from living with “untreated” cancer may be a potential barrier.13 Given the association between HGPIN and ASAP with PCa, a critically important question is whether these findings should factor into decision making about AS. Even if a biopsy suggests a low-risk PCa, the addition of a possible premalignant lesion might push an anxiety-prone patient toward active treatment. The objective of our present study was to help guide the management of low-risk PCa patients considering AS who also have concomitant HGPIN or ASAP. 1445
Our results confirm that HGPIN and ASAP should not preclude initial enrollment into AS programs. We found no statistical difference in our primary outcomes of GS upgrading and pathologic upstaging at the time of prostatectomy in AS candidates with either HGPIN or ASAP. We also found no difference in other adverse pathologic features. Furthermore, the rate of BCR did not differ for patients with HGPIN or ASAP, albeit with a median follow-up for the entire cohort of only 4.9 years. The findings from our study should provide further reassurance to patients experiencing anxiety and distress over their newly diagnosed low-risk cancer that initial management with AS is a reasonable option, even in the presence of HGPIN or ASAP. For this study, we selected Epstein criteria and MSKCC criteria for AS enrollment, as these criteria are commonly used in the reported literature, and although Epstein criteria is considered to have a fairly strict inclusion criteria, the MSKCC criteria is relatively more inclusive.1 Our aim was to allow our results to be more generalizable to a wide array of patients considering AS by including a spectrum of patients. The difference in these 2 criteria is demonstrated in our study with only 30.7% (170 of 553) of patients with D’Amico low-risk PCa meeting Epstein criteria, compared with the 72.3% (400 of 553) of patients meeting MSKCC criteria. In fact, the group at Johns Hopkins have acknowledged that Epstein criteria may be too strict, which may exclude many potential candidates for AS. They have recently published a preliminary analysis using more inclusive criteria.14 Based on their early analysis, the criteria of PSA density 0.15 ng/mL and a Gleason score of 6 were important in selecting appropriate AS candidates, but the criteria of clinical stage T1c were not. They concluded that patients with higher clinical stage can safely be included in AS if other AS criteria are met.14 For our study, we used the original strict version of Epstein criteria to select for patients with the lowest risk disease. On the other hand, MSKCC criteria for AS require an immediate confirmatory biopsy before enrollment into AS.7 The MSKCC group found that 35% (185 of 531) of patients originally eligible for AS by their criteria on initial biopsy were found to be ineligible on subsequent confirmatory biopsy.7 Because our study cohort were patients who elected for treatment with prostatectomy after PCa was detected, no confirmatory biopsies were obtained for our cohort. The absence of confirmatory biopsy allows for a more liberal inclusion of patients in our study so the entire spectrum of AS eligibility can be analyzed. However, our study is not without limitations; this was an observational study; therefore, we were unable to control for biopsy indications and to standardize biopsy technique. Although, an experienced GU pathologist reviewed all biopsies and prostatectomy specimens, bias may be introduced by interobserver variability. An additional limitation is our inability to adjust for the amount of HGPIN or ASAP on biopsy, as multifocal HGPIN and multifocal ASAP have a greater association 1446
with PCa.3 Similarly, HGPIN with adjacent ASAP on biopsy also has an increased risk of PCa, but the small number of patients with these concomitant findings limited this analysis. It is also important to recognize that this study used the surrogate endpoints of pathologic GS and pathologic stage to determine appropriateness for AS enrollment. Because all patients in this study were treated with RP and the natural history of HGPIN and ASAP is unclear, the impact that these histologic findings have on tumor progression while a patient is on AS is unknown. The findings of this retrospective observational study will need to be confirmed by the ongoing prospective trials looking at outcomes of AS.
CONCLUSION The presence of clinical HGPIN and clinical ASAP did not increase the risk of Gleason score upgrading or pathologic upstaging at the time of RP for patients who meet AS criteria. Our data suggest that simply the existence of HGPIN and ASAP should not impact the decision to enroll into AS, thus removing a potential barrier to AS. However, analysis of the prospective AS trials will be needed to determine if HGPIN and ASAP impact tumor progression when on AS. References 1. Iremashvili V, Pelaez L, Manoharan M, et al. Pathologic prostate cancer characteristics in patients eligible for active surveillance: a head-to-head comparison of contemporary protocols. Eur Urol. 2012;62:462-468. 2. Buethe DD, Pow-Sang J. Enrollment criteria controversies for active surveillance and triggers for conversion to treatment in prostate cancer. J Natl Compr Canc Netw. 2012;10:1101-1110. 3. Epstein JI, Herawi M. Prostate needle biopsies containing prostatic intraepithelial neoplasia or atypical foci suspicious for carcinoma: implications for patient care. J Urol. 2006;175:820-834. 4. Merrimen JL, Jones G, Walker D, et al. Multifocal high grade prostatic intraepithelial neoplasia is a significant risk factor for prostatic adenocarcinoma. J Urol. 2009;182:485-490; discussion 490. 5. D’Amico AV, Whittington R, Malkowicz SB, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA. 1998;280:969-974. 6. Tosoian JJ, Trock BJ, Landis P, et al. Active surveillance program for prostate cancer: an update of the Johns Hopkins experience. J Clin Oncol. 2011;29:2185-2190. 7. Adamy A, Yee DS, Matsushita K, et al. Role of prostate specific antigen and immediate confirmatory biopsy in predicting progression during active surveillance for low risk prostate cancer. J Urol. 2011;185:477-482. 8. Divrik RT, Eroglu A, Sahin A, et al. Increasing the number of biopsies increases the concordance of Gleason scores of needle biopsies and prostatectomy specimens. Urol Oncol. 2007;25: 376-382. 9. Guzzo TJ, Vira MA, Neway W, et al. Minimal tumor volume may provide additional prognostic information in good performance patients after radical prostatectomy. Urology. 2007;69:1147-1151. 10. Resnick MJ, Koyama T, Fan KH, et al. Long-term functional outcomes after treatment for localized prostate cancer. N Engl J Med. 2013;368:436-445.
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11. Epstein JI, Chan DW, Sokoll LJ, et al. Nonpalpable stage T1c prostate cancer: prediction of insignificant disease using free/total prostate specific antigen levels and needle biopsy findings. J Urol. 1998;160:2407-2411. 12. Barocas DA, Cowan JE, Smith JA Jr, et al. What percentage of patients with newly diagnosed carcinoma of the prostate are candidates for surveillance? An analysis of the CaPSURE database. J Urol. 2008;180:1330-1334; discussion 1334-1335. 13. Kazer MW, Psutka SP, Latini DM, et al. Psychosocial aspects of active surveillance. Curr Opin Urol. 2013;23:273-277.
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14. Reese AC, Landis P, Han M, et al. Expanded criteria to identify men eligible for active surveillance of low risk prostate cancer at Johns Hopkins: a preliminary analysis. J Urol. 2013;190:2033-2038.
APPENDIX SUPPLEMENTARY DATA
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.urology. 2014.04.066.
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