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Potential Benefit of Transrectal Saturation Prostate Biopsy as an Initial Biopsy Strategy: Decreased Likelihood of Finding Significant Cancer on Future Biopsy
Ambulatory and Office Urology Potential Benefit of Transrectal Saturation Prostate Biopsy as an Initial Biopsy Strategy: Decreased Likelihood of Finding Significant Cancer on Future Biopsy Yong-Hong Li, Ahmed Elshafei, Jianbo Li, Asmaa Hatem, Craig D. Zippe, Khaled Fareed, and J. Stephen Jones OBJECTIVE
MATERIALS AND METHODS
RESULTS
CONCLUSION
To identify the ability of transrectal saturation prostate biopsy (SPBx) as the initial diagnostic approach to reduce the likelihood of finding previously unrecognized prostate cancer (PCa) during repeat prostate biopsy. We reviewed PCa detection in 561 men who underwent first repeat SPBx after initial negative biopsy between March 2002 and April 2012. We divided the patients on the basis of the number of cores retrieved on initial biopsy (group 1, initial negative SPBx [n ¼ 81] and group 2, initial negative extended prostate biopsy [n ¼ 480]). The yield of repeat SPBx was compared between the 2 groups. Insignificant PCa and low-risk PCa were defined according to Epstein criteria and D’Amico risk criteria, respectively. PCa detection on first repeat SPBx was 43.1% lower in group 1 (19.8% vs 34.8%; P ¼ .008). Moreover, lower rate of significant PCa (31.3% vs 74.3%; P <.001) and intermediate- and/or high-risk PCa (25.0% vs 50.9%; P ¼ .048) in group 1. Multivariate analysis confirmed that initial negative SPBx decreased PCa detection on first repeat SPBx (odds ratio ¼ 0.41, 95% confidence interval 0.22-0.78). Men whose initial biopsy was per transrectal saturation technique were less likely to have cancer identified during repeat biopsy. Furthermore, PCa diagnosed after negative initial SPBx was much more likely to be clinically insignificant. These findings suggest that SPBx may be less likely to miss clinically significant cancer during initial prostate biopsy. If confirmed in other studies, this suggests that initial biopsy by saturation technique may eliminate the need for most men to undergo repeat biopsy. UROLOGY 83: 714e718, 2014. 2014 Elsevier Inc.
T
ransrectal ultrasound-guided extended prostate biopsy (EPBx; 10-14 cores) is considered the gold standard initial prostate biopsy (PBx) strategy.1 Multiple studies have demonstrated that EPBx significantly improves prostate cancer (PCa) detection compared with the original sextant protocol, without significantly increasing morbidity or the detection of clinically insignificant PCa.2,3 Although extended, laterally directed templates improve PCa detection, the false negative rate continues to occur in up to one third of cases.4 Yong-Hong Li and Ahmed Elshafei contributed equally. Financial Disclosure: The authors declare that they have no relevant financial interests. From the Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH; the Department of Urology, Cancer Center, Sun Yat-Sen University, Guangzhou, People’s Republic of China; the Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH; and the Department of Urology, Cleveland VA/Case Medical Center, Cleveland, OH Reprint requests: J. Stephen Jones, M.D., F.A.C.S., M.B.A., Glickman Urological and Kidney Institute, Cleveland Clinic, 9500 Euclid Avenue, Q10-1, OH 44195. E-mail: [email protected] Submitted: October 1, 2013, accepted (with revisions): December 16, 2013
714
ª 2014 Elsevier Inc. All Rights Reserved
Intuitively, directing biopsy cores to areas of the gland not sampled by most extended techniques should increase PCa detection. The use of transrectal saturation prostate biopsy (SPBx; 20 cores) as an initial biopsy strategy remains controversial. We and other investigators have shown improved PCa detection with SPBx compared with EPBx as an initial biopsy strategy.5,6 In contrast, other reports did not find benefit of SPBx in the initial biopsy setting.2,7,8 Indeed our initial pilot article did not find benefit, and only on complete analysis of a much larger database did we find that it did increase cancer detection by 25.6%.5 However, SPBx has shown great promise as a repeat biopsy strategy on the basis of a significantly higher PCa detection; our own series found 31.3% higher cancer detection for repeat transrectal SPBx.9 Counter intuitively, complications and pain scores for SPBx have not been higher than reported with EPBx protocols.2,4,9 By increasing the accuracy of cancer detection during initial biopsy, we have the potential to substantially 0090-4295/14/$36.00 http://dx.doi.org/10.1016/j.urology.2013.12.029
decrease the proportion of men who will have subsequent indication for repeat biopsy. Several studies have shown that repeat biopsy detects more PCa in men who had a previous negative initial sextant biopsy than extended biopsy protocol.10,11 We previously reported from our early experience that first repeat SPBx detected PCa in 14 of 59 men (24%) who had an initial negative SPBx,12 which was the same rate in our practice as patients who underwent repeat biopsy after extended biopsy. An editorial comment accompanying that article appropriately suggested verification with larger numbers of patients and direct comparison of cancer detection after initial EPBx vs SPBx.12 Importantly, the comparison group at that time involved patients who had undergone repeat biopsy primarily using extended, not saturation technique. We now report repeat SPBx results in a larger group of men with previous initial negative SPBx compared with men with previous initial negative EPBx in the same period to determine whether initial SPBx decrease PCa detection during follow-up.
Figure 1. The 24-core biopsy scheme. The number of cores on each parasagittal section was decreased from 2 to 1 and yielded 20-core biopsy scheme. (Color version available online.)
MATERIALS AND METHODS Procedure As part of an ongoing institutional review boardeapproved PBx prospective database, 561 consecutive men underwent first repeat SPBx by 4 experienced urologists. We chose to include only those whose repeat biopsy was via transrectal saturation biopsy based on the desire to assure the highest likelihood that we would have accurate assessment of whether initial biopsy had missed cancer. Furthermore, we did not include subsequent “serial” (third or greater overall) biopsies to have meaningful comparison. Men were divided into groups on the basis of the number of cores retrieved on initial biopsy, including 81 men after initial negative SPBx (group 1) and 480 men after initial negative EPBx (group 2). The indications to perform repeat biopsy included abnormal prostate-specific antigen (PSA) and/or abnormal digital rectal examination and/or suspicious pathologic findings identified during the initial biopsy. Initially, suspicious pathologic findings were classified as atypical small acinar proliferation (ASAP) high-grade prostatic intraepithelial neoplasia (HGPIN) or HGPIN only. We recommended first repeat SPBx <6 months after initial ASAP and 2-3 years after initial HGPIN per the delayed interval biopsy protocol of New York University.13 Timing was otherwise determined by physician determination of clinical risk, but was typically at the 1 year point. Office-based transrectal ultrasound-guided PBx was performed under local anesthesia. We performed 24 cores SPBx in the beginning as first repeat PBx strategy. The location and number of cores biopsied on each side were apex (3), lateral mid (3), parasagittal mid (2), lateral base (2), and parasagittal base (2) as shown in Figure 1. Anterior tissue was always included in the cores from apex, and transition zone was always sampled in the parasagittal cores. On the basis of our publications identifying no unique cancer detection in parasagittal cores from these sectors, we omitted 4 medial cores. This yielded of a 20-core scheme focused on the lateral and apical gland.14 The uropathology team reviewed all cores. HGPIN was divided into unifocal (HGPIN present in 1 biopsy core) and UROLOGY 83 (4), 2014
multifocal (HGPIN present in 2 or more biopsy cores). Insignificant PCa was defined according to the Epstein criteria: PSA density 0.15 ng/mL per gram, Gleason score 6, fewer than 3 positive cores, and <50% cancer involvement in any core.15 Because the criteria were developed on the basis of sextant biopsy, we also used the D’Amico risk criteria to evaluate our results for low-risk PCa.16
Statistical Analysis Data were presented as mean with standard deviations and medians with interquartile range, counts or frequencies with percentages or proportions. Univariate, between-group comparisons were done using Wilcoxon rank sum test for nonnormally distributed continuous variables, the Student t test for normally distributed continuous variables, and the c2 test for categorical variables. Multivariable logistic regression was used to assess the effect of the initial biopsy protocols (initial SPBx vs initial EPBx) on PCa detection and to identify potential factors that influence PCa detection. Odds ratios (OR) were estimated with 95% confidence interval (CI). For continuous variables, the OR estimation was based on between the 25th and 75th percentiles. Results of multivariable analysis were also presented in a plot for easy visualization. All analyses were performed using the statistical software package R version 2.15 (R Development Core Team, www. r-project.org) and with its base package and regression modeling strategies package. All statistics were considered significant at the level of a ¼ 0.05.
RESULTS Demographic, clinical, and pathologic data are summarized in Table 1. There was no significant difference regarding age, race, family history, digital rectal examination, PSA, free PSA, prostate volume, or time interval between initial and repeat biopsy. A greater percentage of men with initial biopsy multifocal HGPIN 715
Table 1. Patient characteristics (n ¼ 561) Variable
Group 1: Initial Negative SPBx n ¼ 81
Age, y (mean/SD) Race, no. (%) White Black Other Family history of PCa, no. (%) Abnormal DRE, no. (%) Time interval between initial and first repeat PBx, mo (IQR) Initial PBx pathologic features, no (%) HGPIN only Unifocal HGPIN Multifocal HGPIN ASAP HGPIN No ASAP and no HGPIN PSA level, ng/mL (IQR) Free-to-total PSA, % (mean/SD) Total prostate volume, mL (IQR) Initial PBx cores (IQR) First repeat PBx cores (IQR)
Group 2: Initial Negative EPBx n ¼ 480
P Value
64.6 (7.4)
63.5 (7.4)
.329
66 7 8 11 6 22.0
(81.5) (8.6) (9.9) (13.6) (7.4) (11.7-38.6)
406 44 30 94 36 19.6
(84.6) (9.2) (6.2) (19.6) (7.5) (7.6-39.7)
.588 .879 .336 .260 .977 .249
31 15 16 12 38 6.3 18.7 52.5 24 20
(38.3) (18.5) (19.8) (14.8) (46.9) (4.1-8.8) (8.3) (35.8-74.5) (20-24) (20-20)
126 72 54 94 260 6.4 17.0 46.5 12 20
(26.3) (15.0) (11.3) (19.6) (54.2) (4.7-9.0) (7.1) (33.0-62.0) (10-12) (20-20)
.036 .418 .032 .389 .213 .336 .248 .081 <.001 .371
ASAP, atypical small acinar proliferation; DRE, digital rectal examination; EPBx, extended prostate biopsy; HGPIN, high-grade prostatic intraepithelial neoplasia; IQR, interquartile range; PBx, prostate biopsy; PCa, prostate cancer; PSA, prostate-specific antigen; SPBx, saturation prostate biopsy; SD, standard deviation. Data in bold are statistically significant (P <.05).
Table 2. Characteristics of PCa diagnosed by first repeat saturation biopsy after initial negative SPBx or EPBx (n ¼ 183) Variable
Group 1: Initial Negative SPBx n ¼ 16
Positive cores, no. (IQR) Max cancer involvement core % (IQR) High-grade PCa, no. (%) Significant PCa, no. (%) Intermediate- and/or high-risk PCa, n (%)
1 10 2 5 4
(1-2) (5-16) (12.5) (31.3) (25.0)
Group 2: Initial Negative EPBx n ¼ 167 2 15 60 124 85
(1-4) (6-33) (35.9) (74.3) (50.9)
P value .032 .345 .059 <.001 .048
Abbreviations as in Table 1. Data in bold are statistically significant (P <.05).
was found in group 1 (men with initial negative SPBx) compared with group 2 (men with initial negative EPBx) (19.8% vs 11.3%; P ¼ .032). There was no significant difference according to men with ASAP HGPIN. Overall PCa detection was lower in group 1 (19.8% vs 34.8%; P ¼ .008). Table 2 lists characteristics of PCa diagnosed by first repeat saturation biopsy. Group 1 had less positive cores (P ¼ .032). PCa was categorized as low grade (Gleason score 6) and high grade (Gleason score 7). Although not statistically significant, there was a trend toward lower rate of high grade cancer in group 1 (12.5% vs 35.9%; P ¼ .059). Moreover, group 1 had a lower rate of clinically significant PCa according to Epstein criteria (31.3% vs 74.3%; P <.001), and lower rate of D’Amico intermediate- and/or high-risk PCa (25.0% vs 50.9%; P ¼ .048). Supplementary Table 1 lists PCa detection of first repeat SPBx in men with no ASAP and no HGPIN, HGPIN only and ASAP HGPIN findings on initial PBx. PCa detection was lower in group 1 when men detected no ASAP and no HGPIN in the initial PBx (7.9% vs 27.3%; P ¼ .010). Only 6.2% of patients who 716
underwent repeat biopsy after initial negative SPBx were found to have a clinically significant cancer. If their initial saturation biopsy had no HGPIN and no ASAP findings, then there was only a 2.6% chance that repeats saturation biopsy would identify significant cancer (Supplementary Table 2). Figure 2 shows backward logistic regression multivariate analysis results. The OR for detecting PCa was 0.41 (95% CI 0.22-0.78) in men after initial negative SPBx compared with men after initial negative EPBx.
COMMENT The first repeat biopsy has the highest likelihood of PCa detection during serial repeat biopsy.17,18 Thus, we chose it as the best measure available for false negativity during initial biopsy. We limited our study to patients whose second biopsy was performed by saturation technique to minimize the chance that the second biopsy would have false negative results. It has been shown that PCa detection should be very low after 2 negative biopsies (with at least 1 SPBx).19,20 UROLOGY 83 (4), 2014
Any cancer Variable Initial negative SPBx Age Black race Family history Abnormal DRE PSA Total prostate volume Time interval No ASAP & no HGPIN on initial PBx
OR (95% CI) 0.41 (0.22−0.78) 1.26 (0.93−1.7) 1.5 (0.73−3.06) 1.83 (1.13−2.98) 1.35 (0.64−2.87) 1.34 (1.05−1.7) 0.54 (0.39−0.75) 1.05 (0.77−1.44) 0.4 (0.25−0.62) 0
0.5
1
1.5
2
2.5
3
3.5
Odds Ratio
Figure 2. Backward logistic regression multivariate analysis of different factors associated with prostate cancer detection rate of first repeat biopsy after initial negative SPBx or EPBx. ASAP, atypical small acinar proliferation; CI, confidence interval; DRE, digital rectal examination; EPBx, extended prostate biopsy; HGPIN, high-grade prostatic intraepithelial neoplasia; OR, odds ratio; PBx, prostate biopsy; PSA, prostate-specific antigen; SPBx, saturation prostate biopsy.
It has been shown that the PCa detection on repeat biopsies varies as a function of PBx technique on initial PBx. Eskicorapci et al10 reported that 14-core repeat biopsy detected PCa in 36.1% and 18.7% of the men who had a previous sextant biopsy and 10-core biopsy protocol, respectively (P ¼ .005). In the Stanford series, a trend that higher PCa detection was found by repeat PBx in men with previous initial negative sextant biopsy than with priori initial negative EPBx (39% vs 28%; P ¼ .16).11 Thus, it is intuitive to consider the possibility that even higher numbers of cores will provide additional diagnostic accuracy and will be less likely to have a false negative outcome leading to the need for repeat biopsy because of the presence of cancer that was missed during initial biopsy. We previously reported that first repeat SPBx detected PCa in 14 of 59 men (24%) who had an initial negative SPBx.12 We subsequently reported a much higher PCa detection by first repeat SPBx of 32.7% in men who underwent SPBx after previous initial sextant or extended negative PBx.9 Intuitively, initial SPBx should decrease PCa detection on repeat biopsies. Initial small studies appeared not to support this logic, but outcomes were only compared indirectly and only with patients undergoing primarily repeat EPBx.12 In the present study, PCa detection was 43.1% lower in men with previous initial negative SPBx than men with previous initial negative EPBx (19.8% vs 34.8%; P ¼ .008), suggesting a false negative rate 75.8% higher for EPBx compared with SPBx. Furthermore, fewer positive cores (P ¼ .032), lower significant PCa (31.3% vs 74.3%; P <.001), lower D’Amico intermediate- and/or high-risk PCa (25.0% vs 50.9%; P ¼ .048) and a trend of less high-grade PCa (12.5% vs 35.9%; P ¼ .059) was noted in men with initial SPBx. Thus, PCa detected in men with negative initial SPBx tended to be lower grade and less likely to be clinically significant PCa; more patients with PCa are identified by initial SPBx so that specific number of patients do not need a second biopsy, suggesting that initial SPBx may decrease the need for UROLOGY 83 (4), 2014
repeat biopsy and significant PCa detection during follow-up. Importantly, the likelihood of missing clinically significant cancer becomes so low that a high threshold to repeat biopsy appears justified in patients whose initial biopsy was by transrectal saturation technique, especially if there is no HGPIN or ASAP. Initial pathologic findings of HGPIN and/or ASAP are an important indication for repeat PBx. Men with no HGPIN and no ASAP in the initial SPBx had much lower PCa detection compared with men with no HGPIN and no ASAP findings in the initial EPBx (7.9% vs 27.3%; P ¼ .001). However, when HGPIN and/or ASAP was found in the previous initial PBx, there were no significant difference regarding PCa detection on the repeat SPBx (P ¼ .089 and P ¼ 1.000, respectively). This suggests that if initial SPBx proves to be negative for PCa and with no HGPIN or ASAP findings, it is reasonable to consider further biopsies only for men with very high risk of unrecognized PCa, such as those with rapidly rising PSA, or positive PCA3 or very low %free PSA during follow-up. This may decrease the need for repeat biopsy by use of initial SPBx. In contrast, if HGPIN and/or ASAP was detected in the initial SPBx, repeat PBx should be considered as the same similar to men with previous initial EPBx. Several studies have reported multifocal HGPIN associated with a significantly higher risk of PCa on repeat PBx. In contrast, focal HGPIN apparently does not increase cancer detection.21,22 In the present study, we also found that PCa detection was higher in men with multifocal HGPIN compared with normal biopsy (42.9% vs 24.8%; P ¼ .003). In contrast, there was no significant difference according to PCa detection in men with unifocal HGPIN compared with no HGPIN or ASAP findings (29.9% vs 24.8%; P ¼ .344). The main limitation of the study is retrospective nature, although this is managed by the prospective nature of our database. However, there was no significant difference in demographic or clinical characteristics between 717
the groups except for a greater percentage of men with initial biopsy detected multifocal HGPIN in group 1 (Table 1). Multivariate analysis further supports that men with initial negative SPBx had lower PCa detection in the following first repeat SPBx compared with men with initial negative EPBx (OR ¼ 0.41, 95% CI 0.22-0.78). Second, the definition of clinically insignificant PCa was based on the preoperative Epstein criteria, as most patients did not undergo radical prostatectomy, which would be a better measure. As we know, the preoperative Epstein criteria misclassify about one third of patients who would have unfavorable pathologic features in radical prostatectomy specimen.23 Third, the variability existed between groups according to urologists who performed PBx. Four urologists performed both initial and repeat SPBx, but other urologists other than the 4 urologists performed EPBx only. However, there was no significant difference between the 4 urologists and the other urologists according to cancer detection in the initial EPBx. It is possible that our findings would be different if the repeat biopsy was performed by extended technique, but knowing that it is less likely to identify cancer based on multiple reports make this a less meaningful comparison.9 Finally, it is possible that some men would have developed new PCa instead of our hypothesis that this cancer was simply missed by initial biopsy. The fact that PCa typically develops over decades instead of years makes this unlikely, but our data cannot answer that question.24
CONCLUSION Transrectal saturation biopsy decreases the likelihood that significant cancer will be missed during initial diagnostic PBx and may decrease the need for repeat biopsy. However, repeat PBx should be considered for men with HGPIN and/or ASAP identified on initial SPBx and for men suspected of having unrecognized cancer based on other clinical or laboratory factors. These findings suggest that SPBx may be appropriate as an initial biopsy strategy. References 1. Bjurlin MA, Carter HB, Schellhammer P, et al. Optimization of initial prostate biopsy in clinical practice: sampling, labeling and specimen processing. J Urol. 2013;189:2039-2046. 2. Scattoni V, Zlotta A, Montironi R, et al. Extended and saturation prostatic biopsy in the diagnosis and characterisation of prostate cancer: a critical analysis of the literature. Eur Urol. 2007;52:13091322. 3. Siu W, Dunn RL, Shah RB, et al. Use of extended pattern technique for initial prostate biopsy. J Urol. 2005;174:505-509. 4. Ukimura O, Coleman JA, de la Taille A, et al. Contemporary role of systematic prostate biopsies: indications, techniques, and implications for patient care. Eur Urol. 2013;63:214-230. 5. Li YH, Elshafei A, Li J, et al. Transrectal saturation technique may improve cancer detection as an initial prostate biopsy strategy in men with prostate-specific antigen <10 ng/ml [e-pub ahead of print]. Eur Urol. doi: 10.1016/j.eururo.2013.05.047, accessed June 17, 2013.
718
6. Jiang X, Zhu S, Feng G, et al. Is an initial saturation prostate biopsy scheme better than an extended scheme for detection of prostate cancer? A systematic review and meta-analysis. Eur Urol. 2013;63: 1031-1039. 7. Jones JS, Patel A, Schoenfield L, et al. Saturation technique does not improve cancer detection as an initial prostate biopsy strategy. J Urol. 2006;175:485-488. 8. Irani J, Blanchet P, Salomon L, et al. Is an extended 20-core prostate biopsy protocol more efficient than the standard 12-core? A randomized multicenter trial. J Urol. 2013;190:77-83. 9. Zaytoun OM, Moussa AS, Gao T, et al. Office based transrectal saturation biopsy improves prostate cancer detection compared to extended biopsy in the repeat biopsy population. J Urol. 2011;186: 850-854. 10. Eskicorapci SY, Guliyev F, Islamoglu E, et al. The effect of prior biopsy scheme on prostate cancer detection for repeat biopsy population: results of the 14-core prostate biopsy technique. Int Urol Nephrol. 2007;39:189-195. 11. Hong YM, Lai FC, Chon CH, et al. Impact of prior biopsy scheme on pathologic features of cancers detected on repeat biopsies. Urol Oncol. 2004;22:7-10. 12. Lane BR, Zippe CD, Abouassaly R, et al. Saturation technique does not decrease cancer detection during followup after initial prostate biopsy. J Urol. 2008;179:1746-1750. 13. Lefkowitz GK, Taneja SS, Brown J, et al. Followup interval prostate biopsy 3 years after diagnosis of high grade prostatic intraepithelial neoplasia is associated with high likelihood of prostate cancer, independent of change in prostate specific antigen levels. J Urol. 2002; 168:1415-1418. 14. Patel AR, Jones JS, Rabets J, et al. Parasagittal biopsies add minimal information in repeat saturation prostate biopsy. Urology. 2004;63: 87-89. 15. Bastian PJ, Mangold LA, Epstein JI, et al. Characteristics of insignificant clinical T1c prostate tumors. A contemporary analysis. Cancer. 2004;101:2001-2005. 16. D’Amico AV, Whittington R, Malkowicz SB. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA. 1998;280:969-974. 17. Djavan B, Margreiter M. Biopsy standards for detection of prostate cancer. World J Urol. 2007;25:11-17. 18. Djavan B, Zlotta A, Remzi M, et al. Optimal predictors of prostate cancer on repeat prostate biopsy: a prospective study of 1,051 men. J Urol. 2000;163:1144-1148. 19. Tan N, Lane BR, Li J, et al. Prostate cancers diagnosed at repeat biopsy are smaller and less likely to be high grade. J Urol. 2008;180: 1325-1329. 20. Zaytoun OM, Stephenson AJ, Fareed K, et al. When serial prostate biopsy is recommended: most cancers detected are clinically insignificant. BJU Int. 2012;110:987-992. 21. 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. 22. Lee MC, Moussa AS, Yu C, et al. Multifocal high grade prostatic intraepithelial neoplasia is a risk factor for subsequent prostate cancer. J Urol. 2010;184:1958-1962. 23. Ploussard G, Epstein JI, Montironi R, et al. The contemporary concept of significant versus insignificant prostate cancer. Eur Urol. 2011;60:291-303. 24. Sakr WA, Haas GP, Cassin BF, et al. The frequency of carcinoma and intraepithelial neoplasia of the prostate in young male patients. J Urol. 1993;150:379-385.
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. 2013.12.029. UROLOGY 83 (4), 2014
MATERIALS AND METHODS
RESULTS
CONCLUSION
To identify the ability of transrectal saturation prostate biopsy (SPBx) as the initial diagnostic approach to reduce the likelihood of finding previously unrecognized prostate cancer (PCa) during repeat prostate biopsy. We reviewed PCa detection in 561 men who underwent first repeat SPBx after initial negative biopsy between March 2002 and April 2012. We divided the patients on the basis of the number of cores retrieved on initial biopsy (group 1, initial negative SPBx [n ¼ 81] and group 2, initial negative extended prostate biopsy [n ¼ 480]). The yield of repeat SPBx was compared between the 2 groups. Insignificant PCa and low-risk PCa were defined according to Epstein criteria and D’Amico risk criteria, respectively. PCa detection on first repeat SPBx was 43.1% lower in group 1 (19.8% vs 34.8%; P ¼ .008). Moreover, lower rate of significant PCa (31.3% vs 74.3%; P <.001) and intermediate- and/or high-risk PCa (25.0% vs 50.9%; P ¼ .048) in group 1. Multivariate analysis confirmed that initial negative SPBx decreased PCa detection on first repeat SPBx (odds ratio ¼ 0.41, 95% confidence interval 0.22-0.78). Men whose initial biopsy was per transrectal saturation technique were less likely to have cancer identified during repeat biopsy. Furthermore, PCa diagnosed after negative initial SPBx was much more likely to be clinically insignificant. These findings suggest that SPBx may be less likely to miss clinically significant cancer during initial prostate biopsy. If confirmed in other studies, this suggests that initial biopsy by saturation technique may eliminate the need for most men to undergo repeat biopsy. UROLOGY 83: 714e718, 2014. 2014 Elsevier Inc.
T
ransrectal ultrasound-guided extended prostate biopsy (EPBx; 10-14 cores) is considered the gold standard initial prostate biopsy (PBx) strategy.1 Multiple studies have demonstrated that EPBx significantly improves prostate cancer (PCa) detection compared with the original sextant protocol, without significantly increasing morbidity or the detection of clinically insignificant PCa.2,3 Although extended, laterally directed templates improve PCa detection, the false negative rate continues to occur in up to one third of cases.4 Yong-Hong Li and Ahmed Elshafei contributed equally. Financial Disclosure: The authors declare that they have no relevant financial interests. From the Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH; the Department of Urology, Cancer Center, Sun Yat-Sen University, Guangzhou, People’s Republic of China; the Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH; and the Department of Urology, Cleveland VA/Case Medical Center, Cleveland, OH Reprint requests: J. Stephen Jones, M.D., F.A.C.S., M.B.A., Glickman Urological and Kidney Institute, Cleveland Clinic, 9500 Euclid Avenue, Q10-1, OH 44195. E-mail: [email protected] Submitted: October 1, 2013, accepted (with revisions): December 16, 2013
714
ª 2014 Elsevier Inc. All Rights Reserved
Intuitively, directing biopsy cores to areas of the gland not sampled by most extended techniques should increase PCa detection. The use of transrectal saturation prostate biopsy (SPBx; 20 cores) as an initial biopsy strategy remains controversial. We and other investigators have shown improved PCa detection with SPBx compared with EPBx as an initial biopsy strategy.5,6 In contrast, other reports did not find benefit of SPBx in the initial biopsy setting.2,7,8 Indeed our initial pilot article did not find benefit, and only on complete analysis of a much larger database did we find that it did increase cancer detection by 25.6%.5 However, SPBx has shown great promise as a repeat biopsy strategy on the basis of a significantly higher PCa detection; our own series found 31.3% higher cancer detection for repeat transrectal SPBx.9 Counter intuitively, complications and pain scores for SPBx have not been higher than reported with EPBx protocols.2,4,9 By increasing the accuracy of cancer detection during initial biopsy, we have the potential to substantially 0090-4295/14/$36.00 http://dx.doi.org/10.1016/j.urology.2013.12.029
decrease the proportion of men who will have subsequent indication for repeat biopsy. Several studies have shown that repeat biopsy detects more PCa in men who had a previous negative initial sextant biopsy than extended biopsy protocol.10,11 We previously reported from our early experience that first repeat SPBx detected PCa in 14 of 59 men (24%) who had an initial negative SPBx,12 which was the same rate in our practice as patients who underwent repeat biopsy after extended biopsy. An editorial comment accompanying that article appropriately suggested verification with larger numbers of patients and direct comparison of cancer detection after initial EPBx vs SPBx.12 Importantly, the comparison group at that time involved patients who had undergone repeat biopsy primarily using extended, not saturation technique. We now report repeat SPBx results in a larger group of men with previous initial negative SPBx compared with men with previous initial negative EPBx in the same period to determine whether initial SPBx decrease PCa detection during follow-up.
Figure 1. The 24-core biopsy scheme. The number of cores on each parasagittal section was decreased from 2 to 1 and yielded 20-core biopsy scheme. (Color version available online.)
MATERIALS AND METHODS Procedure As part of an ongoing institutional review boardeapproved PBx prospective database, 561 consecutive men underwent first repeat SPBx by 4 experienced urologists. We chose to include only those whose repeat biopsy was via transrectal saturation biopsy based on the desire to assure the highest likelihood that we would have accurate assessment of whether initial biopsy had missed cancer. Furthermore, we did not include subsequent “serial” (third or greater overall) biopsies to have meaningful comparison. Men were divided into groups on the basis of the number of cores retrieved on initial biopsy, including 81 men after initial negative SPBx (group 1) and 480 men after initial negative EPBx (group 2). The indications to perform repeat biopsy included abnormal prostate-specific antigen (PSA) and/or abnormal digital rectal examination and/or suspicious pathologic findings identified during the initial biopsy. Initially, suspicious pathologic findings were classified as atypical small acinar proliferation (ASAP) high-grade prostatic intraepithelial neoplasia (HGPIN) or HGPIN only. We recommended first repeat SPBx <6 months after initial ASAP and 2-3 years after initial HGPIN per the delayed interval biopsy protocol of New York University.13 Timing was otherwise determined by physician determination of clinical risk, but was typically at the 1 year point. Office-based transrectal ultrasound-guided PBx was performed under local anesthesia. We performed 24 cores SPBx in the beginning as first repeat PBx strategy. The location and number of cores biopsied on each side were apex (3), lateral mid (3), parasagittal mid (2), lateral base (2), and parasagittal base (2) as shown in Figure 1. Anterior tissue was always included in the cores from apex, and transition zone was always sampled in the parasagittal cores. On the basis of our publications identifying no unique cancer detection in parasagittal cores from these sectors, we omitted 4 medial cores. This yielded of a 20-core scheme focused on the lateral and apical gland.14 The uropathology team reviewed all cores. HGPIN was divided into unifocal (HGPIN present in 1 biopsy core) and UROLOGY 83 (4), 2014
multifocal (HGPIN present in 2 or more biopsy cores). Insignificant PCa was defined according to the Epstein criteria: PSA density 0.15 ng/mL per gram, Gleason score 6, fewer than 3 positive cores, and <50% cancer involvement in any core.15 Because the criteria were developed on the basis of sextant biopsy, we also used the D’Amico risk criteria to evaluate our results for low-risk PCa.16
Statistical Analysis Data were presented as mean with standard deviations and medians with interquartile range, counts or frequencies with percentages or proportions. Univariate, between-group comparisons were done using Wilcoxon rank sum test for nonnormally distributed continuous variables, the Student t test for normally distributed continuous variables, and the c2 test for categorical variables. Multivariable logistic regression was used to assess the effect of the initial biopsy protocols (initial SPBx vs initial EPBx) on PCa detection and to identify potential factors that influence PCa detection. Odds ratios (OR) were estimated with 95% confidence interval (CI). For continuous variables, the OR estimation was based on between the 25th and 75th percentiles. Results of multivariable analysis were also presented in a plot for easy visualization. All analyses were performed using the statistical software package R version 2.15 (R Development Core Team, www. r-project.org) and with its base package and regression modeling strategies package. All statistics were considered significant at the level of a ¼ 0.05.
RESULTS Demographic, clinical, and pathologic data are summarized in Table 1. There was no significant difference regarding age, race, family history, digital rectal examination, PSA, free PSA, prostate volume, or time interval between initial and repeat biopsy. A greater percentage of men with initial biopsy multifocal HGPIN 715
Table 1. Patient characteristics (n ¼ 561) Variable
Group 1: Initial Negative SPBx n ¼ 81
Age, y (mean/SD) Race, no. (%) White Black Other Family history of PCa, no. (%) Abnormal DRE, no. (%) Time interval between initial and first repeat PBx, mo (IQR) Initial PBx pathologic features, no (%) HGPIN only Unifocal HGPIN Multifocal HGPIN ASAP HGPIN No ASAP and no HGPIN PSA level, ng/mL (IQR) Free-to-total PSA, % (mean/SD) Total prostate volume, mL (IQR) Initial PBx cores (IQR) First repeat PBx cores (IQR)
Group 2: Initial Negative EPBx n ¼ 480
P Value
64.6 (7.4)
63.5 (7.4)
.329
66 7 8 11 6 22.0
(81.5) (8.6) (9.9) (13.6) (7.4) (11.7-38.6)
406 44 30 94 36 19.6
(84.6) (9.2) (6.2) (19.6) (7.5) (7.6-39.7)
.588 .879 .336 .260 .977 .249
31 15 16 12 38 6.3 18.7 52.5 24 20
(38.3) (18.5) (19.8) (14.8) (46.9) (4.1-8.8) (8.3) (35.8-74.5) (20-24) (20-20)
126 72 54 94 260 6.4 17.0 46.5 12 20
(26.3) (15.0) (11.3) (19.6) (54.2) (4.7-9.0) (7.1) (33.0-62.0) (10-12) (20-20)
.036 .418 .032 .389 .213 .336 .248 .081 <.001 .371
ASAP, atypical small acinar proliferation; DRE, digital rectal examination; EPBx, extended prostate biopsy; HGPIN, high-grade prostatic intraepithelial neoplasia; IQR, interquartile range; PBx, prostate biopsy; PCa, prostate cancer; PSA, prostate-specific antigen; SPBx, saturation prostate biopsy; SD, standard deviation. Data in bold are statistically significant (P <.05).
Table 2. Characteristics of PCa diagnosed by first repeat saturation biopsy after initial negative SPBx or EPBx (n ¼ 183) Variable
Group 1: Initial Negative SPBx n ¼ 16
Positive cores, no. (IQR) Max cancer involvement core % (IQR) High-grade PCa, no. (%) Significant PCa, no. (%) Intermediate- and/or high-risk PCa, n (%)
1 10 2 5 4
(1-2) (5-16) (12.5) (31.3) (25.0)
Group 2: Initial Negative EPBx n ¼ 167 2 15 60 124 85
(1-4) (6-33) (35.9) (74.3) (50.9)
P value .032 .345 .059 <.001 .048
Abbreviations as in Table 1. Data in bold are statistically significant (P <.05).
was found in group 1 (men with initial negative SPBx) compared with group 2 (men with initial negative EPBx) (19.8% vs 11.3%; P ¼ .032). There was no significant difference according to men with ASAP HGPIN. Overall PCa detection was lower in group 1 (19.8% vs 34.8%; P ¼ .008). Table 2 lists characteristics of PCa diagnosed by first repeat saturation biopsy. Group 1 had less positive cores (P ¼ .032). PCa was categorized as low grade (Gleason score 6) and high grade (Gleason score 7). Although not statistically significant, there was a trend toward lower rate of high grade cancer in group 1 (12.5% vs 35.9%; P ¼ .059). Moreover, group 1 had a lower rate of clinically significant PCa according to Epstein criteria (31.3% vs 74.3%; P <.001), and lower rate of D’Amico intermediate- and/or high-risk PCa (25.0% vs 50.9%; P ¼ .048). Supplementary Table 1 lists PCa detection of first repeat SPBx in men with no ASAP and no HGPIN, HGPIN only and ASAP HGPIN findings on initial PBx. PCa detection was lower in group 1 when men detected no ASAP and no HGPIN in the initial PBx (7.9% vs 27.3%; P ¼ .010). Only 6.2% of patients who 716
underwent repeat biopsy after initial negative SPBx were found to have a clinically significant cancer. If their initial saturation biopsy had no HGPIN and no ASAP findings, then there was only a 2.6% chance that repeats saturation biopsy would identify significant cancer (Supplementary Table 2). Figure 2 shows backward logistic regression multivariate analysis results. The OR for detecting PCa was 0.41 (95% CI 0.22-0.78) in men after initial negative SPBx compared with men after initial negative EPBx.
COMMENT The first repeat biopsy has the highest likelihood of PCa detection during serial repeat biopsy.17,18 Thus, we chose it as the best measure available for false negativity during initial biopsy. We limited our study to patients whose second biopsy was performed by saturation technique to minimize the chance that the second biopsy would have false negative results. It has been shown that PCa detection should be very low after 2 negative biopsies (with at least 1 SPBx).19,20 UROLOGY 83 (4), 2014
Any cancer Variable Initial negative SPBx Age Black race Family history Abnormal DRE PSA Total prostate volume Time interval No ASAP & no HGPIN on initial PBx
OR (95% CI) 0.41 (0.22−0.78) 1.26 (0.93−1.7) 1.5 (0.73−3.06) 1.83 (1.13−2.98) 1.35 (0.64−2.87) 1.34 (1.05−1.7) 0.54 (0.39−0.75) 1.05 (0.77−1.44) 0.4 (0.25−0.62) 0
0.5
1
1.5
2
2.5
3
3.5
Odds Ratio
Figure 2. Backward logistic regression multivariate analysis of different factors associated with prostate cancer detection rate of first repeat biopsy after initial negative SPBx or EPBx. ASAP, atypical small acinar proliferation; CI, confidence interval; DRE, digital rectal examination; EPBx, extended prostate biopsy; HGPIN, high-grade prostatic intraepithelial neoplasia; OR, odds ratio; PBx, prostate biopsy; PSA, prostate-specific antigen; SPBx, saturation prostate biopsy.
It has been shown that the PCa detection on repeat biopsies varies as a function of PBx technique on initial PBx. Eskicorapci et al10 reported that 14-core repeat biopsy detected PCa in 36.1% and 18.7% of the men who had a previous sextant biopsy and 10-core biopsy protocol, respectively (P ¼ .005). In the Stanford series, a trend that higher PCa detection was found by repeat PBx in men with previous initial negative sextant biopsy than with priori initial negative EPBx (39% vs 28%; P ¼ .16).11 Thus, it is intuitive to consider the possibility that even higher numbers of cores will provide additional diagnostic accuracy and will be less likely to have a false negative outcome leading to the need for repeat biopsy because of the presence of cancer that was missed during initial biopsy. We previously reported that first repeat SPBx detected PCa in 14 of 59 men (24%) who had an initial negative SPBx.12 We subsequently reported a much higher PCa detection by first repeat SPBx of 32.7% in men who underwent SPBx after previous initial sextant or extended negative PBx.9 Intuitively, initial SPBx should decrease PCa detection on repeat biopsies. Initial small studies appeared not to support this logic, but outcomes were only compared indirectly and only with patients undergoing primarily repeat EPBx.12 In the present study, PCa detection was 43.1% lower in men with previous initial negative SPBx than men with previous initial negative EPBx (19.8% vs 34.8%; P ¼ .008), suggesting a false negative rate 75.8% higher for EPBx compared with SPBx. Furthermore, fewer positive cores (P ¼ .032), lower significant PCa (31.3% vs 74.3%; P <.001), lower D’Amico intermediate- and/or high-risk PCa (25.0% vs 50.9%; P ¼ .048) and a trend of less high-grade PCa (12.5% vs 35.9%; P ¼ .059) was noted in men with initial SPBx. Thus, PCa detected in men with negative initial SPBx tended to be lower grade and less likely to be clinically significant PCa; more patients with PCa are identified by initial SPBx so that specific number of patients do not need a second biopsy, suggesting that initial SPBx may decrease the need for UROLOGY 83 (4), 2014
repeat biopsy and significant PCa detection during follow-up. Importantly, the likelihood of missing clinically significant cancer becomes so low that a high threshold to repeat biopsy appears justified in patients whose initial biopsy was by transrectal saturation technique, especially if there is no HGPIN or ASAP. Initial pathologic findings of HGPIN and/or ASAP are an important indication for repeat PBx. Men with no HGPIN and no ASAP in the initial SPBx had much lower PCa detection compared with men with no HGPIN and no ASAP findings in the initial EPBx (7.9% vs 27.3%; P ¼ .001). However, when HGPIN and/or ASAP was found in the previous initial PBx, there were no significant difference regarding PCa detection on the repeat SPBx (P ¼ .089 and P ¼ 1.000, respectively). This suggests that if initial SPBx proves to be negative for PCa and with no HGPIN or ASAP findings, it is reasonable to consider further biopsies only for men with very high risk of unrecognized PCa, such as those with rapidly rising PSA, or positive PCA3 or very low %free PSA during follow-up. This may decrease the need for repeat biopsy by use of initial SPBx. In contrast, if HGPIN and/or ASAP was detected in the initial SPBx, repeat PBx should be considered as the same similar to men with previous initial EPBx. Several studies have reported multifocal HGPIN associated with a significantly higher risk of PCa on repeat PBx. In contrast, focal HGPIN apparently does not increase cancer detection.21,22 In the present study, we also found that PCa detection was higher in men with multifocal HGPIN compared with normal biopsy (42.9% vs 24.8%; P ¼ .003). In contrast, there was no significant difference according to PCa detection in men with unifocal HGPIN compared with no HGPIN or ASAP findings (29.9% vs 24.8%; P ¼ .344). The main limitation of the study is retrospective nature, although this is managed by the prospective nature of our database. However, there was no significant difference in demographic or clinical characteristics between 717
the groups except for a greater percentage of men with initial biopsy detected multifocal HGPIN in group 1 (Table 1). Multivariate analysis further supports that men with initial negative SPBx had lower PCa detection in the following first repeat SPBx compared with men with initial negative EPBx (OR ¼ 0.41, 95% CI 0.22-0.78). Second, the definition of clinically insignificant PCa was based on the preoperative Epstein criteria, as most patients did not undergo radical prostatectomy, which would be a better measure. As we know, the preoperative Epstein criteria misclassify about one third of patients who would have unfavorable pathologic features in radical prostatectomy specimen.23 Third, the variability existed between groups according to urologists who performed PBx. Four urologists performed both initial and repeat SPBx, but other urologists other than the 4 urologists performed EPBx only. However, there was no significant difference between the 4 urologists and the other urologists according to cancer detection in the initial EPBx. It is possible that our findings would be different if the repeat biopsy was performed by extended technique, but knowing that it is less likely to identify cancer based on multiple reports make this a less meaningful comparison.9 Finally, it is possible that some men would have developed new PCa instead of our hypothesis that this cancer was simply missed by initial biopsy. The fact that PCa typically develops over decades instead of years makes this unlikely, but our data cannot answer that question.24
CONCLUSION Transrectal saturation biopsy decreases the likelihood that significant cancer will be missed during initial diagnostic PBx and may decrease the need for repeat biopsy. However, repeat PBx should be considered for men with HGPIN and/or ASAP identified on initial SPBx and for men suspected of having unrecognized cancer based on other clinical or laboratory factors. These findings suggest that SPBx may be appropriate as an initial biopsy strategy. References 1. Bjurlin MA, Carter HB, Schellhammer P, et al. Optimization of initial prostate biopsy in clinical practice: sampling, labeling and specimen processing. J Urol. 2013;189:2039-2046. 2. Scattoni V, Zlotta A, Montironi R, et al. Extended and saturation prostatic biopsy in the diagnosis and characterisation of prostate cancer: a critical analysis of the literature. Eur Urol. 2007;52:13091322. 3. Siu W, Dunn RL, Shah RB, et al. Use of extended pattern technique for initial prostate biopsy. J Urol. 2005;174:505-509. 4. Ukimura O, Coleman JA, de la Taille A, et al. Contemporary role of systematic prostate biopsies: indications, techniques, and implications for patient care. Eur Urol. 2013;63:214-230. 5. Li YH, Elshafei A, Li J, et al. Transrectal saturation technique may improve cancer detection as an initial prostate biopsy strategy in men with prostate-specific antigen <10 ng/ml [e-pub ahead of print]. Eur Urol. doi: 10.1016/j.eururo.2013.05.047, accessed June 17, 2013.
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6. Jiang X, Zhu S, Feng G, et al. Is an initial saturation prostate biopsy scheme better than an extended scheme for detection of prostate cancer? A systematic review and meta-analysis. Eur Urol. 2013;63: 1031-1039. 7. Jones JS, Patel A, Schoenfield L, et al. Saturation technique does not improve cancer detection as an initial prostate biopsy strategy. J Urol. 2006;175:485-488. 8. Irani J, Blanchet P, Salomon L, et al. Is an extended 20-core prostate biopsy protocol more efficient than the standard 12-core? A randomized multicenter trial. J Urol. 2013;190:77-83. 9. Zaytoun OM, Moussa AS, Gao T, et al. Office based transrectal saturation biopsy improves prostate cancer detection compared to extended biopsy in the repeat biopsy population. J Urol. 2011;186: 850-854. 10. Eskicorapci SY, Guliyev F, Islamoglu E, et al. The effect of prior biopsy scheme on prostate cancer detection for repeat biopsy population: results of the 14-core prostate biopsy technique. Int Urol Nephrol. 2007;39:189-195. 11. Hong YM, Lai FC, Chon CH, et al. Impact of prior biopsy scheme on pathologic features of cancers detected on repeat biopsies. Urol Oncol. 2004;22:7-10. 12. Lane BR, Zippe CD, Abouassaly R, et al. Saturation technique does not decrease cancer detection during followup after initial prostate biopsy. J Urol. 2008;179:1746-1750. 13. Lefkowitz GK, Taneja SS, Brown J, et al. Followup interval prostate biopsy 3 years after diagnosis of high grade prostatic intraepithelial neoplasia is associated with high likelihood of prostate cancer, independent of change in prostate specific antigen levels. J Urol. 2002; 168:1415-1418. 14. Patel AR, Jones JS, Rabets J, et al. Parasagittal biopsies add minimal information in repeat saturation prostate biopsy. Urology. 2004;63: 87-89. 15. Bastian PJ, Mangold LA, Epstein JI, et al. Characteristics of insignificant clinical T1c prostate tumors. A contemporary analysis. Cancer. 2004;101:2001-2005. 16. D’Amico AV, Whittington R, Malkowicz SB. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA. 1998;280:969-974. 17. Djavan B, Margreiter M. Biopsy standards for detection of prostate cancer. World J Urol. 2007;25:11-17. 18. Djavan B, Zlotta A, Remzi M, et al. Optimal predictors of prostate cancer on repeat prostate biopsy: a prospective study of 1,051 men. J Urol. 2000;163:1144-1148. 19. Tan N, Lane BR, Li J, et al. Prostate cancers diagnosed at repeat biopsy are smaller and less likely to be high grade. J Urol. 2008;180: 1325-1329. 20. Zaytoun OM, Stephenson AJ, Fareed K, et al. When serial prostate biopsy is recommended: most cancers detected are clinically insignificant. BJU Int. 2012;110:987-992. 21. 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. 22. Lee MC, Moussa AS, Yu C, et al. Multifocal high grade prostatic intraepithelial neoplasia is a risk factor for subsequent prostate cancer. J Urol. 2010;184:1958-1962. 23. Ploussard G, Epstein JI, Montironi R, et al. The contemporary concept of significant versus insignificant prostate cancer. Eur Urol. 2011;60:291-303. 24. Sakr WA, Haas GP, Cassin BF, et al. The frequency of carcinoma and intraepithelial neoplasia of the prostate in young male patients. J Urol. 1993;150:379-385.
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. 2013.12.029. UROLOGY 83 (4), 2014