Multiple Repeat Prostate Biopsies and the Detection of Clinically Insignificant Cancer in Men With Large Prostates

Oncology Multiple Repeat Prostate Biopsies and the Detection of Clinically Insignificant Cancer in Men With Large Prostates Eugene J. Pietzak, Matthew J. Resnick, Philip Mucksavage, Keith Van Arsdalen, Alan J. Wein, S. Bruce Malkowicz, and Thomas J. Guzzo OBJECTIVE METHODS

RESULTS

CONCLUSION

To determine the impact of repeating prostate biopsies on the risk of detecting clinically insignificant prostate cancer (PCa) in larger prostate glands. We performed a retrospective cohort study using patients enrolled in our institutional PCa registry from 1991 to 2008 to assess the association of prostate volume and clinically insignificant PCa in men undergoing multiple prostate biopsies. Patients were stratified by prostate volume into 2 cohorts (<50 cm3 or
50 cm3). Additionally, patients were stratified by prostate biopsy on which PCa was identified (1 biopsy or
3 biopsies). Within the subgroup of patients with prostate volume
50 cm3 requiring
3 biopsies before cancer diagnosis, 72.6% (45/62) had pathologic Gleason scores 6 and 81.6% (49/60) had an estimated tumor volume of 10% at the time of radical prostatectomy. This was significantly different from patients with prostate volume <50 cm3 diagnosed on their first biopsy, in which only 48.5% (656/1349) were found to have Gleason scores 6 and 54.2% (705/1300) had estimated tumor volume 10% (P <.01). There was no significant difference in the rate of Gleason score upgrading at time of prostatectomy between any of the subgroups. PCas detected in men with prostatic enlargement requiring multiple biopsies are more likely to be low-grade, low-volume tumors at final pathology than men without prostate enlargement. Men with larger prostates who have already had prior negative biopsies should be counseled regarding the increased risk of detecting clinically insignificant PCa with additional biopsies. UROLOGY 84: 380e385, 2014.
2014 Elsevier Inc.

S

ince the inception of prostate-specific antigen (PSA) screening, there has been a welldocumented increased incidence of prostate cancer (PCa) with a concomitant downward stage migration.1,2 These tumors tend to manifest with lower grade and volume and have been shown to be associated with less risk of adverse pathologic features at the time of radical prostatectomy (RP).1,2 Controversy exists over the clinical significance of many cancers detected by PSA screening.3-6 This has led to a legitimate concern

Financial Disclosure: The authors declare that they have no relevant financial interests. Funding Support: This research was supported by the Joel and Linda Appel Prostate Cancer Research Fund. Dr. Resnick was supported by the Veterans Affairs National Quality Scholars Program with use of facilities at Veterans Health Administration Tennessee Valley Healthcare System and additionally by the T.J. Martell Foundation. From the Division of Urology, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA; and the Department of Urologic Surgery, Vanderbilt University Medical Center, and the Tennessee Valley VA Health Care System, Nashville, TN Reprint requests: Eugene J. Pietzak, M.D., Division of Urology, Department of Surgery , Hospital of the University of Pennsylvania, Perelman Center for Advanced Medicine, 3400 Civic Center Boulevard, 3rd Floor, West Pavilion , Philadelphia, PA 19104. E-mail: [email protected] Submitted: August 21, 2013, accepted (with revisions): April 15, 2014

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regarding the potential for overdiagnosis and subsequent overtreatment of a tumor that is unlikely to result in cancer-specific mortality.5,6 Recent attention has shifted to the dilemma of how to optimally diagnose and treat biologically aggressive PCa early in its course, when it is still curable, while sparing those with clinically insignificant PCa from the morbidity of unnecessary treatment.3,4 To this end, attempts have been made to optimize PCa detection.7-9 Despite these efforts, there are few data to guide management of the patient with a persistently elevated PSA despite a previous negative biopsy. The concern for some is that PCa may have been “missed” by the biopsy needle and these patients may still be harboring an aggressive tumor.7,10,11 Whether PCa identified with additional biopsies has true clinical significance or leads to overdiagnosis of clinically insignificant tumors remains controversial, particularly in men with prostatic enlargement.12,13 The purpose of this study was to elaborate the interaction of prostate volume on PCa detected on first PNBx (prostate needle biopsy) compared with cancer detected after multiple repeat needle biopsies. Our hypothesis is 0090-4295/14/$36.00 http://dx.doi.org/10.1016/j.urology.2014.04.029

that men with prostatic enlargement may confound the documented relationship between number of prostate biopsies and risk of indolent PCa. Specifically, we believe that the presence of prostatic enlargement will increase the risk of detecting indolent disease in men undergoing multiple biopsies.

MATERIAL AND METHODS Patients were selected from our prospectively maintained institutional database of 2411 consecutive men who underwent radical retropubic prostatectomy (RP) at our institution from 1991 to 2008. Preoperative baseline clinical characteristics and biopsy features were recorded, including total number of previous prostate biopsies. Prostate volume was determined by transrectal ultrasound (TRUS) or magnetic resonance imaging (MRI), using standard techniques. We included an MRI-based volume calculation when TRUS volume was not available, as it has been demonstrated to have a high correlation to that of a TRUS-calculated prostate volume at our institution.14 Pathologic characteristics of RP specimens were also recorded and analyzed. Prostatectomy specimens were processed and estimated tumor volume calculations were recorded according to our institution’s previously published and validated protocol.15 Patients without a recorded prostate volume, either by TRUS or MRI, were excluded (n ¼ 266). Patients were also excluded if the number of PNBx performed before cancer detection could not be determined (n ¼ 106). We also excluded men who were diagnosed with PCa on their second PNBx (n ¼ 281). After applying these exclusion criteria, our cohort comprised 1758 men. The indication for initial prostate biopsy was either an elevated PSA or abnormal digital rectal examination. Subsequent biopsies were performed at the discretion of the treating urologist. Indications for subsequent biopsy included a rising PSA, a change in rectal examination, or previous abnormal finding on biopsy (high-grade prostatic intraepithelial neoplasia or atypia). Prostatectomy specimens were analyzed according to our institution’s standardized protocol. After the fresh RP specimens were weighed and measured, the capsule was inked to maintain orientation. The specimen was then sectioned from apex to base, perpendicular to the urethra in 6- to 8-mm intervals. The sections were then inspected for tumor involvement and subsequently fixated in neutral buffered formalin. After fixation, the apex was cut perpendicular to the margin and the remainder of the gland was sectioned into 3- to 4-mm blocks and embedded. Orientation of the specimen was maintained throughout the process. Tumor volume was estimated by multiplying the percentage of nonmargin, nonseminal vesicle slides by the estimated average percentage of cross-sectional area containing tumor, stratified in an asymmetric categorical classification system.15 We defined clinically insignificant PCa as an estimated tumor volume <10%, Gleason score 6, with no extracapsular extension, negative lymph nodes, no seminal vesicle invasion, and negative surgical margins on final RP specimen.16 This definition is consistent with the literature on clinically insignificant cancer being low-volume, low-grade disease without any pathologically aggressive features.17,18 These are the patients who are lowest risk of PCa mortality and the least likely to need treatment.17,18 In this study, patients were categorized based on the number of PNBx they underwent before PCa detection. Patients were dichotomized into 2 groups, one in which PCa was diagnosed on the first biopsy, and the other in which PCa was diagnosed UROLOGY 84 (2), 2014

after
biopsies. Each group was then substratified by prostate volume (
50 or <50 cm3). The cut-off of 50 cm3 was selected based on previously published studies, which have reported the impact of prostate volume on PCa detection rates.10,12 Baseline clinical parameters and pathologic characteristics were compared between subgroups using STATA version 11.0 (STATA Inc., College Station, TX). Statistical analysis included chi-square test for categorical variables and for continuous variables 2-sample t test was used. Multivariable regression modeling was also performed. Statistical significance was declared if P .05.

RESULTS Of the 1758 patients included in this analysis, 1430 (81.3%) had prostate volume <50 cm3 and 328 patients (18.7%) had prostate volume
50 cm3. The baseline clinical characteristics of this cohort are reported in Table 1. The proportion of patients with prostatic enlargement (>50 cm3) increased with the number of PNBx required for detection of PCa. Specifically, 16.5% of patients diagnosed on first PNBx had prostatic enlargement compared with 41.3% of those who requiring
3 PNBx before diagnosis (P .001). With respect to clinical Gleason score, patients with prostatic enlargement were more likely to have low-grade disease (Gleason score 6) both in men diagnosed on first biopsy (74.4% vs 66.4%; P ¼ .012) and those requiring
3 PNBx (98.4% vs 76.1%; P .001). The pathologic characteristics of the study population are presented in Table 2. There was an increased likelihood of having Gleason score 6 PCa in the RP specimens of patients with prostatic enlargement when compared with patients without prostatic enlargement, for those patients diagnosed with PCa on their first PNBx (60.7% vs 48.5%; P .001). This effect was greater for patients who underwent multiple PNBx, with 72.6% of patients with prostatic enlargement having pathologic Gleason scores of 6, compared with 52.3% for smaller prostates (P ¼ .01). This is demonstrated in Figure 1. Interestingly, the incremental within-group risk of low-grade disease with serial prostate biopsies was far more pronounced in patients with prostatic enlargement (3.8% vs 11.9%). Similarly, as shown in Figure 1, a significantly higher proportion of men with prostatic enlargement had estimated tumor volumes <2% on first PNBx and multiple PNBx (P ¼ .001). Again, within-group comparisons revealed the incremental risk of low-volume disease with serial biopsy to be 26.7% and 8.2% in the prostatic enlargement and no enlargement subgroups, respectively. With regard to adverse pathologic features on RP specimens, extraprostatic extension (P .001), nodal involvement (P ¼ .68), and seminal vesicle involvement (P ¼ .05) was less often seen in patients with prostatic enlargement when compared with those without prostatic enlargement. Although prostate volume had no statistically significant impact on these adverse features in the multiple PNBx group, lower rates of adverse features were seen in the multiple biopsies groups when compared with those diagnosed on first PNBx. The rate of Gleason 381

Table 1. Clinical characteristics Diagnosed on First Biopsy, n ¼ 1608 Characteristics n Age Race, n (%) White Black Other BMI Baseline PSA PSAD (PSA/prostate volume) Number of cores taken Clinical Gleason score Low risk 6 High risk
7 Associated PIN, n (%) Associated atypia, n (%) Clinical stage, n (%) T1 T2 T3

Diagnosed on
3 Biopsies, n ¼ 150

<50 cm3


50 cm3

P Value

<50 cm3


50 cm3

P Value

1342 58.7

266 61.8

<.001

88 60.8

62 62.5

.07

72 (82) 7 (8) 9 (10) 27 10.19 0.321 14.4

49 (79) 7 (11) 6 (10) 27 10.9 0.17 14.6

67 21 35 11

61 1 18 7

.24 1040 (77) 173 (13) 136 (10) 27.5 7.84 0.295 9.4 898 451 237 127

(66.4) (33.4) (17.7) (9.5)

675 (52.3) 582 (46.9) 10 (0.8)

218 (81) 35 (13) 17 (6) 27.8 9 0.137 9.8 201 69 53 26

.27

.28 .08 <.0001 .23 .01

(74.4) (25.6) (19.7) (9.7)

.43 .92 .003

147 (57.2) 100 (38.9) 10 (3.9)

(76.1) (23.9) (40.7) (12.8)

56 (67.5) 43 (69.3) 0 (0)

(98.4) (1.6) (29.0) (11.3)

.96 .67 .004 .86 <.001 .14 .78 .866

43 (69.3) 19 (30.7) 0 (0)

BMI, body mass index; PIN, prostatic intraepithelial neoplasia; PSA, prostate-specific antigen; PSAD, prostate-specific antigen density.

Table 2. Pathologic characteristics Diagnosed on
3 Biopsies

Diagnosed on First Biopsy Characteristics Pathologic Gleason score Low risk 6 High risk
7 Estimated tumor volume <2% 2%-10% 11%-25% 25%-50% >50% Extraprostatic extension Lymph node involvement Seminal vesicle invasion Pathologic stage pT2 pT3 pT4 Upgraded after RP

<50 cm , n (%) 3


50 cm , n (%) 3

P Value

<50 cm , n (%)


50 cm3, n (%)

46 (52.3) 42 (47.7)

45 (72.6) 17 (27.4)

21 37 15 11 3 23 2 0

35 14 6 2 3 9 0 1

(58.3) (23.3) (10.0) (3.3) (5.0) (14.5) (0) (1.6)

44 8 1 21

(83) (15) (2) (33.9)

3

<.001 656 (48.5) 693 (51.4)

164 (60.7) 106 (39.3)

207 498 368 191 36 39 33 94

(15.9) (38.3) (28.3) (14.7) (2.8) (29.6) (2.5) (7.0)

81 108 42 15 10 45 6 11

(31.6) (42.2) (16.4) (5.9) (3.9) (16.7) (2.3) (4.1)

811 271 89 459

(69.3) (23.1) (7.6) (34.0)

175 32 10 82

(80.6) (14.7) (4.6) (30.4)

<.001

<.001 .85 .08 <.001

.25

P Value .012 .001

(24.1) (42.5) (17.2) (12.64) (3.45) (26.1) (2.4) (0)

52 (72.2) 20 (27.8) 0 30 (34.1)

.064 .23 .23 .25

.98

RP, radical prostatectomy.

scoring upgrading at RP was similar across all groups and was not impacted by prostate volume. On subsequent multivariable regression analysis (Table 3), increasing prostate volume was associated with an increased risk of clinically insignificant cancer at prostatectomy on both first prostate biopsy and in the multiple prostate biopsy group, odds ratio, 1.01 (95% confidence interval, 1.01-1.02) for every 1 cm3 increase in prostate volume. Increasing the number of biopsy cores taken was also associated with clinically insignificant PCa on multivariable regression analysis on first prostate biopsy.

COMMENT We have previously reported our experience with serial PNBx16 and have demonstrated that although the risk of 382

detecting clinically insignificant PCa was higher with multiple biopsies, a substantial proportion of patients still had adverse features on prostatectomy specimens despite prior negative biopsies. Of particular concern was the incremental increased risk of upgrading at final pathologic review with serial biopsies. One hypothesis for this finding was an increase in sampling error on biopsy due to the larger prostate volumes found in the multiple biopsy group. Volume-grade bias is thought to occur in those patients with larger prostates whose abundant benign prostatic tissue can cause a decrease in the sampling density at the time of PNBx, which reduces the ability of biopsies to detect high grade PCa.19,20 This has raised concerns that larger glands may give more false negatives on PNBx, which result in “missed cancer”.10 This remains controversial and has been a source of debate, particularly UROLOGY 84 (2), 2014

Figure 1. Pathologic Gleason score and pathologic estimated tumor volume <2%. eTV, estimated tumor volume; pGS, pathologic Gleason score; PNBx, prostate needle biopsy. (Color version available online.) Table 3. Multivariable analysis for risk of clinically insignificant cancer at prostatectomy Risk of Clinically Insignificant Prostate Cancer on First Prostate Biopsy Variable

Odds Ratio (95% CI)

Age African-American race (ref ¼ White American) BMI PSA Number of cores taken Clinical Gleason score Prostate volume (per 1 cm3 increase)

0.98 1.07 1.02 0.98 1.03 0.99 1.01

(0.96-1.00) (0.93-1.2) (0.99-1.06) (0.96-1.01) (1.01-1.07) (0.86-1.13) (1.01-1.02)

P Value .06 .33 .12 .14 .008 .86 .001

Risk of Clinically Insignificant Prostate Cancer on Multiple Prostate Biopsy Odds Ratio (95% CI) 0.98 1.37 1.01 0.98 1.04 0.82 1.01

(0.95-1.03) (1.04-1.8) (0.95-1.03) (0.95-1.2) (0.99-1.01) (0.62-1.08) (1.01-1.02)

P Value .58 .025 .57 .31 .09 .16 .04

CI, confidence interval; other abbreviations as in Table 1.

regarding the relatively higher incidence of high-grade PCa noted in those taking finasteride vs placebo (37% vs 22.2%) in the Prostate Cancer Prevention Trial.21 However, retrospective reanalyses of the Prostate Cancer Prevention Trial raises questions as to if this is a true effect.19,22 A similar concern with a volume-grade bias is theoretical increased likelihood of under-grading in men with prostatic enlargement. Our study, however, failed to reveal a significant difference between any groups in regard to upgrading at the time of RP. Prostate volume did not impact the rate of upgrading, as one might have suspected giving the concern of volume-grade bias. In fact, we found increasing prostate volume to be associated with an increased risk of clinically insignificant PCa on both first biopsy and multiple prostate biopsies. Interestingly, the total number of cores in our cohort did not differ between prostate volumes
50 cm3 and <50 cm3, but increasing the number of biopsy cores taken was associated with clinically insignificant PCa on first prostate biopsy on multivariable analysis. Unfortunately, biopsy parameters, such as pattern and number of cores, could not be controlled for in our study but certainly could impact the rate of Gleason upgrading at final pathology. In our present study, the estimated tumor volume at the time of RP was significantly lower in the multiple PNBx group. This finding is consistent with previous UROLOGY 84 (2), 2014

reports documenting the direct relationship between prostate volume and the risk of small-volume disease.12 In those patients in the
3 PNBx group, 58.2% of largevolume prostates had an estimated tumor volume of <2%, compared with the 24.1% of patients with prostates <50 cm3 with estimated tumor volumes of <2%. Another possible explanation for the increased diagnostic frequency of low-risk PCa in men with prostatic enlargement is that, in the setting of PSA screening, larger glands may result in a lead-time bias in PCa detection from the PSA elevation above threshold level. This is because of the greater amounts of benign adenomatous tissue known to produce PSA.5,12 It is controversial as to whether these tumors were detected earlier in their course or they represent “incidentally” found indolent PCa that would never have any significance clinically.5,6,12 Lead-time bias may explain the inverse relationship between prostate size and risk of high-grade PCa at the time of RP.23 In the present study, lead-time bias may certainly have contributed to the greater incidence of low-volume low-grade disease in prostates
50 cm3. One way to potentially account for some of the effect of PSA produced by benign adenomatous tissue is to consider PSA density (PSAD). Kundu et al24 found that PSAD can help predict tumor aggressiveness at final pathology. However, it is not clear how many patients in 383

their study cohort had prior negative biopsies.24 Furthermore, several active surveillance criteria use a low PSAD within their selection criteria.25 Certainly within our patient cohorts, there were significant differences between the PSAD in small prostates and those with larger glands, which may aid in patient discussion. Further support for the indolent course of PCa diagnosed on repeat PNBx can be seen in the subgroup analysis of the 3056 men in the European Randomized Study of Screening in Prostate Cancer with a negative sextant PNBx during baseline screening who were later diagnosed with PCa.26 Within the 11-year follow-up period, just 49 (17.1%) had progressive disease and only 7 (0.03%), 4 of whom had refused repeat PNBx, died of PCa.26 These rates were less than the population as a whole (0.35% PCa deaths) and were similar to the rates seen in those without an indication for initial PNBx (0.02% PCa deaths).26 The authors concluded that in a PSA screening population, little harm is done “missing” PCa at initial PNBx in an 11-year period.26 Although, the impact of prostate volume was not addressed in this subgroup analysis, increased detection of PCa would be expected if a standard PNBx template was used in place of the sextant biopsies in European Randomized Study of Screening in Prostate Cancer.26 There are several limitations of this study. It is a retrospective analysis of a surgical cohort, without standardization of PNBx technique, or indication for PNBx. PCa detection rates vary by PNBx technique used, and patients undergoing repeat biopsy for different indications will differ in the natural history of their disease. Although, dedicated genitourinary pathologists at our institution reviewed all pathologic samples, many biopsies were not performed at our institution because of the large referral basis. Also, an important limitation is that we could not account for patients taking 5-alpha reductase inhibitors, given the concern over their effect on PCa detection and grading.19 It is important to mention that there is no universally accepted definition of clinically insignificant PCa, as it remains poorly defined.27 In our study, PCa was considered clinically insignificant if it was low grade, low volume, and without adverse pathologic features on RP specimen. It is clear that not every PCa in every patient needs to be treated; however, there is much disagreement over what is an accurate predictor of clinical insignificance.27 The investigating impetus must be on finding improved biomarkers with better predictive ability of tumor aggressiveness.

CONCLUSION Prostate volume and number of prior prostate biopsies are both directly related to the risk of diagnosis of low-grade, low-volume PCa. Men with larger prostates who have undergone multiple negative biopsies should be counseled on the risk of detecting clinically insignificant PCa with additional biopsies.

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