Abstract
Background
Upgrading following prostate biopsy is very common in clinical practice. This study investigated whether the use of 5-alpha reductase inhibitors (ARI) and alpha blockers affect known clinical predictors of Gleason score upgrading or not.
Materials and Methods
A retrospective study on 998 patients treated with robotic assisted laparoscopic prostatectomy for clinically localized biopsy Gleason score 6 prostate cancer were studied. The logarithm of prostate specific antigen concentration, prostate size and tumor volume were compared on the basis of the medication history of 5-ARIs and alpha blockers in the cohort of biopsy Gleason 6 patients with benign prostatic hyperplasia history, and patients whose prostate sizes fall in the top quartile. We compared known clinical and pathologic characteristics associated with upgrading in regression models with and without the addition of medications.
Results
Alpha blockers, but not 5-ARI were associated with a bigger prostate. Upgrading was associated with older age (OR 1.03, 95% CI 1.01-1.06), higher BMI (OR 1.00 CI 1.01-1.08), higher log prostate specific antigen (OR 7.32, CI 3.546-15.52), smaller prostate size (OR 0.97, CI 0.96-0.98), fewer biopsy cores (OR 0.96 CI 0.92-0.99), more positive cores (OR 1.20, CI 1.08-1.34), and higher percentage of tumor at biopsy (OR 1.02, CI 1.01-1.03). Neither of the two medication classes were a significant predictor of upgrading. Medications made minimal changes in the multivariate predictive models.
Conclusion
Although, alpha blockers were associate with bigger prostate size, the modulating effects of alpha blockers and 5-ARIs on common predictors of Gleason score upgrading was not significant.
Key Words: Prostate cancer, Gleason, Upgrading, Alpha blocker, 5-alpha reductase inhibitor
Introduction
Prostate cancer is the most common non-cutaneous cancer and third lethal cancer in men [1]. Over the past years, there has been a push toward active surveillance in treatment of localized low risk prostate cancer [2]. Biopsy samples, prostate specific antigen (PSA) level and clinical findings are used to select eligible patients for active surveillance protocols [2]. Gleason scoring is the universally accepted grading system for prostate cancer and a major criteria used in risk classification systems including D'Amico and National Comprehensive Cancer Network. The Gleason scoring system has undergone several modifications over the last few years [3, 4]. The recent changes in Gleason scoring restricts criteria of pathologic patterns for Gleason score 3 versus Gleason score 4 [5]. Prognostic values of Gleason scores are shown in previous studies. It has been shown that Gleason 7 prostate cancer represents two distinct groups of patients. Gleason 3 + 4 behaves differently than Gleason 4 + 3 [6].
Risk classification systems rely on biopsy Gleason score to determine prostate cancer risk. However, changes in biopsy Gleason scoring are seen in 30-60% of prostatectomy specimens [7, 8, 9, 10]. Several predictive factors of Gleason upgrading in prostatectomy samples are identified [7, 9, 11, 12], though none have helped to reduce the rate of Gleason score discrepancy between biopsy and pathologic samples.
One of the debatable areas in this field is the role of medications in formation or prevention of prostate cancer. Alpha blockers and 5-alpha reductase inhibitors (5-ARI) are common medications used in symptomatic control of benign prostatic hyperplasia (BPH) [13], which is the most common disease in aging men. In the Finnish Prostate Cancer Screening Trial [14], finasteride was associated with lower incidence of prostate cancer in men with serum PSA level more than 4 ng/ml. However, there was no clear relationship between taking finasteride and overall risk of prostate cancer formation. Although the risk of low risk prostate cancer was decreased in the group of patients taking finasteride [14, 15], more patients were diagnosed with high grade prostate cancer (Gleason 8-10). The present study was designed to assess the effect of 5-ARIs and alpha blockers on commonly accepted predictors of upgrading in a sample of Gleason 6 patients undergoing robotic assisted laparoscopic prostatectomy.
Materials and Methods
After institutional review board approval, a database of single surgeon patients undergoing robotic assisted laparoscopic prostatectomy was investigated for patients with biopsy Gleason 6. The database was searched for clinical, pathologic and medication data on the patient profiles. The database contains de-identified information regarding medical conditions, core biopsy data, surgical report, pathologic data of prostatectomy specimens and follow up data. In this study, clinical information, past medical history, core biopsy and pathologic data were used. Patient records were searched for diagnosis of BPH, history of taking any kind of alpha blockers or 5-ARIs. Past medical history in the database was derived from the office files, primary care physician reports and surgical medical clearance data. The medication history was obtained via questionnaire at the time of obtaining consent from patients to take part in the database and was checked with the record on the hospital chart prior to data entry to the database. The clinical and biopsy core data were recorded during the office visits of the patients, all documents were stored electronically for further review if necessary. Biopsy results were reported by the genitourinary department of our institution. However, if a patient provided biopsy results from a different institution, the report was checked to include number of cores, Gleason score and percentage of tumor tissue in each single core. If any data was missing, the biopsy samples were reviewed at our institution. No patient was excluded based on biopsy result from other institutions. All pathologic data after surgery are reported by the genitourinary pathology department. The specimens were weighted and mounted in standard fashion and sectioned in quadrants. The margin of the specimen was considered focally or extensively involved using a 3 mm cut-off value for extension of tumor tissue to the margins of the specimen. Volume of cancer was estimated based on the percentage of slides containing tumor (the positive-block ratio). Data was imported into SPSS v 22 (IBM Inc., Armonk, N.Y.) for analysis. Student t-test and Chi-square were used for parametric and categorical variables accordingly. PSA values were transformed into logarithmic scale for analysis purposes.
The presence of Gleason pattern 4 or 5 in radical prostatectomy specimen was considered as upgrading. Minor upgrading was defined as presence of small amount of Gleason pattern 4 in the pathologic specimens (final Gleason 3 + 4). Major upgrading was defined as presence of Gleason pattern 4 or 5 as the most common histologic features in pathologic specimen (final Gleason 4 + 3 or higher). Univariate and multivariate logistic regressions were performed to study the effect of alpha blockers and 5-ARIs as predictors of Gleason score upgrading. Logistic regressions were performed with R statistical software 3.3.1 [16] with the use of “Rcmdr” [17] graphical package. A set of commonly recognized predictors of upgrading were selected according to the literature [7] and univariate logistic regression results. Statin usage was added to the analysis due to its effect on PSA level [18]. Alpha blockers and 5-ARIs were then added to the multivariate analysis and the change was observed. A subgroup analyses were performed on patients diagnosed with BPH and patients with prostate weight ≥ 60 g (representing the top quartile of weight in our sample). All tests performed were two-sided and significance was defined as p < 0.05.
Results
The database contained data of 3,094 patients, of which 998 met the inclusion criteria (biopsy Gleason 6) for this study. General characteristics of the patients in the study are shown in table 1. The mean age of the patients was 58.7 years (range 38-78 years). Most patients were white (81.3%) with an overall body mass index (BMI) of 27.5 ± 3.9. The mean PSA level was 5.2 ± 2.9 ng/ml (log scale 0.66 ± 0.21). In the study population (n = 998), 125 (12.5%) patients were taking alpha blockers while 28 (2.8%) patients used 5-ARIs (table 1). A diagnosis of BPH was observed in 157 patients. Patients with clinical T2 disease had lower PSA level (p < 0.001), fewer biopsy cores (p = 0.02), more positive biopsy cores (p < 0.001), and higher percentage of cores involved with the tumor (p < 0.001). Although the patients in clinical T1 and T2 group had similar mean age, clinical T2 patients were less commonly associated with family history of prostate cancer (p = 0.02). Interestingly, clinical T2 patients were more commonly upgraded as observed in the prostatectomy specimens (p < 0.01) (table 1). There was no difference in medication history, prostate weight, and total tumor volume.
Table 1.
Demographic and clinical characteristics of the population in the study based on clinical stage.
| Variable | Overall (n = 998) | Clinical Stage |
p | |
|---|---|---|---|---|
| T1 (n = 892) | T2 (n = 106) | |||
| Age mean (range) | 58.7 (38-78) | 58.6 (30-78) | 58.9 (38-74) | 0.70 |
| Race* | 0.29 | |||
| White | 811 (81.3%) | 717 (80.4%) | 94 (88.7%) | |
| Black | 107 (10.7%) | 100 (11.2%) | 7 (6.6%) | |
| Other | 63 (6.3%) | 58 (5.8%) | 5 (4.7%) | |
| Log PSA ng/mL (mean ± SD) | 0.66 ± 0.21 | 0.67 ± 0.20 | 0.58 ± 0.28 | < 0.001 |
| BMI (mean ± SD) | 27.5 ± 3.9 | 27.5 ± 3.9 | 27.3 ± 3.1 | 0.58 |
| Family history of prostate cancer | 0.02 | |||
| Yes | 324 (32.5%) | 301 (33.8%) | 23 (21.7%) | |
| No | 674 (67.5%) | 586 (66.2%) | 83 (78.3%) | |
| Number of biopsy cores | 0.02 | |||
| ≤ 12 | 747 (74.8%) | 658 (73.8%) | 89 (84.0%) | |
| > 12 | 251 (25.2%) | 234 (26.2%) | 17 (16.0%) | |
| Positive biopsy cores | < 0.001 | |||
| < 3 | 618 (61.9%) | 569 (63.8%) | 49 (46.2%) | |
| ≥ 3 | 380 (38.1%) | 323 (36.2%) | 57 (53.8%) | |
| Highest % single cores (mean ± SD) | 23.5 ± 22.5 | 22.3 ± 21.8 | 33.1 ± 26.1 | < 0.001 |
| Pathologic Gleason | < 0.01 | |||
| 6 | 892 (89.4%) | 320 (35.9%) | 31 (29.2%) | |
| ≥ 7 | 106 (10.6%) | 572 (64.1%) | 75 (70.8%) | |
| Tumor volume % (mean ± SD) | 30.8 ± 20.4 | 30.7 ± 20.3 | 31.7 ± 21.0 | 0.61 |
| Prostate weight (mean ± SD) | 52.2 ± 18.7 | 52.5 ± 18.7 | 50.0 ± 18.5 | 0.19 |
| Pathologic s–tage | 0.10 | |||
| pT2 | 908 (91.0%) | 817 (91.6%) | 91 (85.8%) | |
| pT3 | 90 (9.0%) | 75 (8.4%) | 15 (14.2%) | |
| History of BPH | 0.70 | |||
| Yes | 157 (15.7%) | 139 (15.6%) | 18 (17.0%) | |
| No | 841 (84.3%) | 753 (84.4%) | 88 (83.0%) | |
| History of TURP | 0.44 | |||
| Yes | 5 (0.5%) | 5 (0.6%) | 0 | |
| No | 993 (99.5%) | 887 (99.4%) | 106 (100%) | |
| Statins | 0.48 | |||
| Yes | 328 (32.9%) | 290 (32.5%) | 38 (35.8%) | |
| No | 670 (67.1%) | 602 (67.5%) | 68 (64.2%) | |
| Alpha blocker | 0.39 | |||
| Yes | 125 (12.5%) | 109 (12.2%) | 16 (15.1%) | |
| No | 873 (87.5%) | 783 (87.8%) | 90 (84.9%) | |
| 5-Alpha reductase inhibitor | 0.98 | |||
| Yes | 28 (2.8%) | 25 (2.8%) | 3 (2.8%) | |
| No | 970 (97.2%) | 867 (97.2%) | 103 (97.2%) | |
Race for 17 patients was not available.
BPH = Benign prostatic hyperplasia; TURP = transurethral resection, prostate.
Upgrading was observed in 64.8% of patients. Minor upgrade (Gleason 3 + 3 to Gleason 3 + 4) was observed in 59.8% of patients and a major upgrade (Gleason 3 + 3 to Gleason 4 + 3) was observed in 5.0% of patients. Table 2 compares patients according to final pathologic Gleason score. Although, the patients with pathologic Gleason 6 had lower mean age (58.2 years) than patients with Gleason ≥ 7 (58.9 years), the difference was not statistically significant (p = 0.09). PSA level, number of positive biopsy cores, highest percentage of tumor in biopsy cores and total tumor volume were higher in pathologic Gleason score ≥ 7 (all p < 0.001). However, patients with Gleason ≥ 7 had lower prostate weight 49.9 ± 16.6 g vs. 56.5 ± 21.4 g, p < 0.001. There was no difference in use of alpha blockers, 5-ARIs or statins (table 2).
Table 2.
Demographic and clinical characteristics of the population in the study based on clinical stage.
| Variable | Biopsy Gleason 6 (n = 998) | Pathologic Gleason |
p | |
|---|---|---|---|---|
| 6 (n = 351) | ≥7 (n = 647) | |||
| Age mean (range) | 58.7 (38-78) | 58.2 (38-78) | 58.9 (38-78) | 0.09 |
| Race* | 0.05 | |||
| White | 811 (81.3%) | 282 (80.3%) | 529 (81.8%) | |
| Black | 107 (10.7%) | 31 (8.8%) | 76 (11.7%) | |
| Other | 63 (6.3%) | 38 (10.9%) | 42 (6.5%) | |
| Log PSA ng/mL (mean ± SD) | 0.66 ± 0.21 | 0.62 ± 0.24 | 0.68 ± 0.19 | < 0.001 |
| BMI (mean ± SD) | 27.5 ± 3.9 | 27.3 ± 4.0 | 27.6 ± 3.8 | 0.27 |
| Family history of prostate cancer | 0.98 | |||
| Yes | 324 (32.5%) | 115 (32.8%) | 209 (32.4%) | |
| No | 674 (67.5%) | 236 (67.2%) | 438 (67.6%) | |
| Number of biopsy cores | 0.13 | |||
| ≤ 12 | 747 (74.8%) | 253 (72.1%) | 494 (76.4%) | |
| > 12 | 251 (25.2%) | 98 (27.9%) | 153 (23.6%) | |
| Positive biopsy cores | < 0.001 | |||
| < 3 | 618 (61.9%) | 269 (76.6%) | 349 (53.9%) | |
| ≥ 3 | 380 (38.1%) | 82 (23.4%) | 298 (46.1%) | |
| Highest % single cores (mean ± SD) | 23.5 ± 22.5 | 15.3 ± 15.9 | 27.9 ± 24.2 | < 0.001 |
| Clinical Stage | 0.17 | |||
| T1c | 892 (89.4%) | 320 (91.2%) | 572 (88.4%) | |
| T2a | 106 (10.6%) | 31 (8.8%) | 75 (11.6%) | |
| Tumor volume % (mean ± SD) | 30.8 ± 20.4 | 18.3 ± 15.3 | 37.5 ± 19.6 | < 0.001 |
| Prostate weight (mean ± SD) | 52.2 ± 18.7 | 56.5 ± 21.4 | 49.9 ± 16.6 | < 0.001 |
| Pathologic stage | < 0.001 | |||
| pT2 | 908 (91.0%) | 348 (99.1%) | 560 (86.6%) | |
| pT3 | 90 (9.0%) | 3 (0.9%) | 87 (13.4%) | |
| History of BPH | 0.21 | |||
| Yes | 157 (15.7%) | 62 (17.7%) | 95 (14.7%) | |
| No | 841 (84.3%) | 289 (82.3%) | 552 (85.3%) | |
| History of TURP | 0.82 | |||
| Yes | 5 (0.5%) | 2 (0.6%) | 3 (0.5%) | |
| No | 993 (99.5%) | 349 (99.4%) | 644 (99.5%) | |
| Statins | 0.51 | |||
| Yes | 328 (32.9%) | 231 (65.8%) | 439 (65.8%) | |
| No | 670 (67.1%) | 120 (34.2%) | 208 (32.1%) | |
| Alpha blocker | 0.15 | |||
| Yes | 125 (12.5%) | 51 (14.5%) | 74 (11.4%) | |
| No | 873 (87.5%) | 300 (85.5%) | 573 (88.6%) | |
| 5-Alpha reductase inhibitor | 0.95 | |||
| Yes | 28 (2.8%) | 10 (2.8%) | 18 (2.8%) | |
| No | 970 (97.2%) | 341 (97.2%) | 629 (97.2%) | |
Race for 17 patients was not available.
BPH = Benign prostatic hyperplasia; TURP = transurethral resection, prostate.
Table 3 shows the effect of alpha blockers and 5-ARIs on prostate weight, tumor volume and PSA level. Statins (not shown in the table) were associated with lower PSA level. There was no difference in frequency of statin use in the population taking alpha blockers or 5-ARIs. Overall, patients taking 5-ARIs had similar PSA level (p = 0.07), prostate weight (p = 0.20) or tumor volume (p = 0.51) to patients not taking 5-ARIs (table 3). Taking alpha blockers was associated with higher prostate weight (p < 0.001) (table 3).
Table 3.
PSA level, prostate size, and tumor volume in general and specific populations in the study by medication history
| Variable | No |
Yes |
p | ||
|---|---|---|---|---|---|
| Mean ± SD | n | Mean ± SD | n | ||
| All patients (n = 998) | |||||
| 5-Alpha reductase inhibitor | 970 | 28 | |||
| Log PSA (ng/ml) | 0.66 ± 0.21 | 0.59 ± 0.25 | 0.07 | ||
| Prostate weight (g) | 52.1 ± 18.2 | 56.6 ± 30.4 | 0.20 | ||
| Tumor volume (%) | 30.9 ± 20.3 | 28.3 ± 21.2 | 0.51 | ||
| Alpha blocker | 873 | 125 | |||
| Log PSA (ng/ml) | 0.66 ± 0.20 | 0.68 ± 0.23 | 0.29 | ||
| Prostate weight (g) | 50.7 ± 16.8 | 63.1 ± 26.1 | < 0.001 | ||
| Tumor volume (%) | 31.7 ± 20.1 | 24.5 ± 21.2 | < 0.001 | ||
| BPH patients (n = 157) | |||||
| 5-Alpha reductase inhibitor | 129 | 28 | |||
| Log PSA (ng/ml) | 0.68 ± 0.23 | 0.59 ± 0.25 | 0.06 | ||
| Prostate weight (g) | 61.0 ± 23.8 | 56.6 ± 30.4 | 0.41 | ||
| Tumor volume (%) | 25.3 ± 20.6 | 28.3 ± 21.2 | 0.48 | ||
| Alpha blocker | 32 | 125 | |||
| Log PSA (ng/ml) | 0.60 ± 0.21 | 0.68 ± 0.23 | 0.11 | ||
| Prostate weight (g) | 49.0 ± 16.7 | 63.1 ± 26.1 | < 0.01 | ||
| Tumor volume (%) | 31.1 ± 17.7 | 24.5 ± 21.2 | 0.10 | ||
| Prostate ≥ 60 g (n = 270) | |||||
| 5-Alpha reductase inhibitor | 263 | 7 | |||
| Log PSA (ng/ml) | 0.73 ± 0.18 | 0.79 ± 0.13 | 0.38 | ||
| Prostate weight (g) | 75.9 ± 16.8 | 97.2 ± 36.9 | < 0.01 | ||
| Tumor volume (%) | 22.1 ± 15.8 | 21.8 ± 22.3 | 0.96 | ||
| Alpha blocker | 213 | 57 | |||
| Log PSA (ng/ml) | 0.73 ± 0.18 | 0.75 ± 0.19 | 0.52 | ||
| Prostate weight (g) | 74.5 ± 14.7 | 83.7 ± 25.3 | < 0.001 | ||
| Tumor volume (%) | 23.0 ± 15.9 | 18.8 ± 16.0 | 0.07 | ||
In the general population of the study, alpha blockers were associated with lower tumor volume in the observed prostatectomy specimens (p < 0.001). Although, analyses in subgroups of patients with history of BPH or patients with prostate weight ≥ 60 g, revealed lower tumor volume in patients taking alpha blockers, this difference could not reach statistical significance, p = 0.10 and p = 0.07, respectively.
Univariate and multivariate logistic regression models were applied to find possible predictors of upgrading at time of biopsy (table 4). In the univariate model, higher logarithm PSA level (Odds Ratio (OR) 3.99 CI 95% 2.14-7.57), more positive cores (OR 1.36 CI 95% 1.25-1.50), higher percentage of tumor at biopsy (1.03 CI 95% 1.02-1.04), smaller prostate size (OR 0.98 CI 95% 0.97-0.98) and fewer cores (OR 0.96 CI 95% 0.93-0.99) were associated with upgrading at pathologic specimen evaluation. No medication usage was associated with upgrading.
Table 4.
Univariate and multivariate logistic regression with drug–adjusted models of preoperative variables predicting upgrading
| Variable | Univariate |
Multivariate |
Multivariate Drug Adjusted |
||||||
|---|---|---|---|---|---|---|---|---|---|
| OR | 95% CI | p | OR | 95% CI | p | OR | 95% CI | p | |
| Biopsy Gleason 6 (n = 998) | |||||||||
| Age | 1.01 | 0.99–1.01 | 0.09 | 1.03 | 1.01–1.05 | < 0.01 | 1.03 | 1.01–1.06 | < 0.01 |
| BMI | 1.01 | 0.98–1.05 | 0.27 | 1.03 | 1.00–1.07 | 0.04 | 1.04 | 1.00–1.08 | 0.03 |
| Log PSA | 3.99 | 2.14–7.57 | < 0.001 | 7.22 | 3.51–15.22 | < 0.001 | 7.32 | 3.54–15.52 | < 0.001 |
| Prostate size | 0.98 | 0.97–0.98 | < 0.001 | 0.97 | 0.96–0.98 | < 0.001 | 0.97 | 0.96–0.98 | < 0.001 |
| No. total biopsy cores | 0.96 | 0.93–0.99 | 0.04 | 0.96 | 0.92–0.99 | 0.04 | 0.96 | 0.92–0.99 | 0.03 |
| No. positive cores | 1.36 | 1.25–1.50 | < 0.001 | 0.83 | 1.08–1.33 | < 0.001 | 1.20 | 1.08–1.34 | < 0.001 |
| Max. % cancer in any core | 1.03 | 1.02–1.04 | < 0.001 | 1.02 | 1.01–1.03 | < 0.001 | 1.02 | 1.01–1.03 | < 0.001 |
| Clinical stage | 1.35 | 0.87–2.12 | 0.18 | 1.20 | 0.73–2.01 | 0.48 | 1.21 | 0.73–2.03 | 0.45 |
| Statin | 0.91 | 0.69–1.20 | 0.51 | – | – | – | 0.88 | 0.65–1.20 | 0.43 |
| Alpha blocker | 0.75 | 0.51–1.11 | 0.15 | – | – | – | 1.00 | 0.65–1.56 | 0.98 |
| 5-Alpha reductase inhibitor | 0.97 | 0.45–2.21 | 0.95 | – | – | – | 1.61 | 0.68–4.00 | 0.28 |
In multivariate analysis, age and BMI became significantly associated with upgrading while all other variables remained significant. Only clinical stage of the disease was not associated with upgrading in multivariate analysis (table 4). Further investigation with addition of medications to the model made no significant change in the predictors (table 4). Separate models were fitted to patients with clinical stage cT1 and cT2. Alpha blockers were associated with upgrading in multivariate analysis but not in the univariate analysis, only in patients with cT2. In all univariate and multivariate analysis higher log PSA, smaller prostate size and highest percentage of tumor at core biopsy were associated with upgrading.
Discussion
In this study we investigated the modulating effect of alpha blockers and 5-ARIs on Gleason upgrading predictors for a population of patients with localized prostate cancer. Gleason upgrading was observed in 64.8% of patients in the study. Rate of upgrading observed in this study was higher than available literature [7, 8, 9, 10]. It is possible that patients in the study population represent a population with higher risk prostate cancer which were referred for definitive treatment. On the other hand, a study by Quintana et al. [19] showed a discrepancy rate of 22% when Gleason scoring was reviewed at different pathology centers. In this study, we did not review all pathologic blocks from other institutions. The higher rate of upgrading might be contributed to the location of cancer focus in the radical prostatectomy specimen as well. Upgrading observed in prostatectomy specimens most commonly represents a focus of cancerous tissue which is missed in biopsy cores [7]. Tumors located at the anterior prostate or unusual places (bladder neck, apex) are less likely to undergo sampling during routine ultrasound guided biopsy process with 12-cores or more [19]. Data on location of the tumor was not available to compare the upgrading rates between tumors at the anterior lobe, with other segments of the prostate.
Presence of Gleason 4 pattern is shown to impact the oncologic outcome after definitive treatment. Generally, presence of Gleason 4 pattern is regarded as significant prostate cancer and requires definitive treatment. The most common pattern of upgrading in our series of patients was Gleason 3 + 4. The high rate of upgrading in our series of patients depicts the difficulties in active surveillance protocols, which depend on biopsy sampling Gleason score. It might also reflect the potential additional role of a more focused method of biopsy sampling i.e. MRI guided biopsy in active surveillance protocols.
Factors predicting upgrading Gleason score have been studied previously. In our study, age was not a significant predictor in univariate analyses. Most data available show no predictive value for age in terms of upgrading [20, 21]. Although, age became a statistically recognized significant predictor for upgrading in our multivariate analyses, similar to the study by Epstein et al. [7], the association is relatively weak. Similarly, in accordance to previous findings, clinical stage was not predictive of upgrading [11]. PSA level was associated with upgrading. The increase in PSA has been shown to associate with upgrading [7, 11, 20, 22, 23]. In the present study, logarithmic scale of PSA was used in the prediction method. In addition to PSA level, previous data demonstrates a link between free PSA [24] and PSA velocity [22] with upgrading. Smaller prostate size was associated with an increased chance of upgrading. This is supported in the published literature [7, 11, 12, 20, 21]. Considering the PSA level and prostate size relation to upgrading, it is not surprising that PSA density has been reported to predict upgrading. However, PSA density was not assessed in our study. The maximum percentage of tumor in biopsy cores, and number of positive biopsy cores has been shown to predict upgrading during prostatectomy specimen evaluation in multivariate regression models [7, 25]. In this study, higher BMI and few biopsy cores were associated with upgrading at radical prostatectomy as well.
After involving medication history in the multivariate analysis, minimal changes were noticed. In a multivariate model, alpha blockers were associated with upgrading only in patients with cT2 disease. No effect on common predictors was observed. Alpha blockers effect on prostate cancer is controversial. Epidemiologic studies suggest increased risk of colorectal and breast cancer in alpha blocker users while no effect is observed for prostate cancer [26]. Laboratory studies suggest a protective effect for alpha blockers against malignant cell growth and migration [27, 28, 29]. Arguments have been made that the chemopreventive effects of alpha blockers are independent of adrenergic blocker activity and different drugs in the same class represent a different profile on effects on prostate cancer cells [27]. The detailed medication list was not available to investigate whether specific alpha blockers are associated with upgrading. Nevertheless, the association of alpha blocker use and upgrading in cT2 patients was an unpredicted finding, which requires further investigation.
5-ARIs are well known for reducing overall risk of prostate cancer in Prostate Cancer Prevention Trial and Reduction by Dutasteride of Prostate Cancer Events among other previously published literature. A higher portion of patients using 5-ARIs are diagnosed with high grade prostate cancer [14, 15, 30]. However, a recent study by Murtola et al. [26] has not shown any significant increase in prostate cancer mortality in 5-ARI users. In our study, 5-ARIs did not impact any predictors of upgrading in multivariate logistic models. The number of patient taking 5-ARIs was relatively small and the results should be interpreted with caution. In patients with larger prostates, 5-ARIs were associated with the enlarged size of prostate, which reflects the treatment pattern in patients with bothersome lower urinary tract symptoms.
The results of the present study are of importance for active surveillance implication in clinical practice. Many of the patients in this study are potential candidates for active surveillance. The mean age of the population in the study is 58.7 years with a mean PSA of 5.2 ng/ml and biopsy Gleason 6. However, after prostatectomy only 35.2% of the patients were Gleason 6 and 64.8% had at least one component Gleason 4. Although, the higher rates of upgrading in this population may relate to the referral setting of our institution, these findings encourage the use of more biopsy cores with target focused technologies at biopsy sampling.
Conclusion
Gleason score upgrading in prostatectomy specimen was observed in 64.8% of the patients in the study. In multivariate analysis elder age, higher BMI, higher PSA level, smaller prostate size, fewer biopsy cores, more positive cores, and higher percentage of tumor at biopsy samples were predictive of upgrading. However, none of the predictive variables were impacted by alpha blocker or 5-ARI use. Further investigations are necessary to assess the potential measures in reducing upgrading rate for patients willing to undergo active surveillance.
Clinical Practice Points
This study shows a high rate of upgrading in patients with localized prostate cancer who may be candidates for active surveillance.
Patients with a small prostate, multiple positive cores of Gleason 6 and with a high proportion of cancer are more likely to be upgraded in pathologic evaluations. Alpha blockers and 5-alpha reductase inhibitors do not affect the predictive models of upgrading.
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