Men with High Prostate Specific Antigen Have Higher Risk of Gleason Upgrading after Prostatectomy: A Systematic Review and Meta-analysis Xiaochuan Wang, Yu Zhang, Zhengguo Ji, Peiqian Yang, Ye Tian* Purpose: To examine the correlation between prostate specific antigen (PSA) and the risk of Gleason sum upgrad- ing (GSU) from biopsy Gleason sum (bGS) to prostatectomy Gleason sum (pGS). Materials and Methods: Five electronic databases (Web of Science, Ovid Medline, Ovid Embase, SCOPUS and the Cochrane Library) were searched from inception until March 2020. Studies were included if they focused on the relationship between PSA and GSU analyzed in multivariable analysis. Preferred Reporting Items for System- atic Reviews and Meta-Analyses (PRISMA) guidelines were utilized. Quality of included studies was appraised utilizing the Newcastle-Ottawa Quality Assessment Scale (NOS) for case-control studies. The publication bias was evaluated by funnel plot and Egger’s test. Results: Our search yielded 19 studies with high quality including 42193 patients. GSU was found in 28.2% of patients. Higher PSA level was associated with a significant increased risk of GSU (pooled OR = 1.14, 95% CI: 1.10–1.18; P < .05; I2 = 92%). For the definition of upgrading from bGS ≤ 6 to pGS ≥ 7, the odds of upgrading with higher PSA level as opposed to lower PSA level was 1.12 (95% CI: 1.11–1.14; P < .05; I2 = 13%), while the odds of upgrading with other definitions were 1.11 (95% CI: 1.05–1.18; P < .05; I2 = 89%). Conclusion: Patients with high level of serum PSA are at high risk of undergoing pathologic upgrading at prosta- tectomy. Combined with other risk factors, PSA prompts risk reclassification and improve confidence of urologists in management decisions for optimal therapy. Nevertheless, further robust studies are necessitated to confirm these results. Keywords: gleason score; meta-analysis; needle biopsy; prostate cancer; prostate specific antigen; systematic review INTRODUCTION Prostate cancer (PCa) is the second most common cancer in males in the world(1). Gleason score (GS) is a critical prognostic factor for risk stratification and disease management of PCa. Even if Gleason grading system has been modified over time(2), the accuracy of biopsy Gleason sum (bGS) for predicting prostatecto- my Gleason sum (pGS) was reported to be barely satis- factory. A systematic review of 14839 patients reported that concordance rate between bGS and pGS was 63%, while overall upgrading from bGS to pGS was found in 30%(3). Active surveillance (AS) is recommended for patients with GS 6 or 3+4 and not appropriate for ones with GS 4+3 or greater(4). Patients with GS 8 or greater reap the benefit of undergoing RP followed by lymph node dissection and/ or other ancillary therapy against unfa- vorable outcomes(5). In these scenarios, unpredictable Gleason sum upgrading (GSU) bring urologists into a dilemma that how to assess the true risk for patients with PCa and select optimal treatment modalities for them. It has been demonstrated in large-scale studies Department of Urology, Capital Medical University affiliated Beijing Friendship Hospital, No. 95, Yongan Road, Xicheng District 100050, Beijing, People’s Republic of China. *Correspondence: Department of Urology, Capital Medical University affiliated Beijing Friendship Hospital, No. 95, Yongan Road, Xicheng District, Beijing, People’s Republic of China Tel: +8618611509977. Email: tianye166@126.com. Received April 2020 & Accepted October 2020 that patients with GSU were significantly associated with biochemical recurrence and other unfavourable surgical outcomes(6-8). Prostate specific antigen (PSA) is another critical factor not only for early detection of PCa but also for risk clas- sification. PSA has appeared in view of urologists with its predictive performance on GSU. In recent years, robust multivariable models with nomograms consist- ing of PSA were built for predicting GSU(9). However, previous literatures were mostly based on single-center studies with limited population and PSA was marginal- ly significant in a few studies. In this systematic review and meta-analysis, we aimed to investigate the corre- lation between PSA and the risk of GSU in the current literature. MATERIALS AND METHODS Our study was performed according to the Preferred Re- porting Items for Systematic Reviews and Meta-analy- sis (PRISMA) guidelines(10). Methods of this analysis and inclusion criteria were specified in advance and documented in a protocol as a reference for our inves- tigators. Urology Journal/Vol 18 No. 5/ September-October 2021/ pp. 477-484. [DOI: 10.22037/uj.v16i7.6127] REVIEW PSA’s impact on Gleason upgrading-Wang et al. Endourology and Stones diseases 130 Vol 18 No 4 July-August 2021 396 Table 1. Summary data for included studies with definitions of upgrading from bGS ≤ 6 to pGS ≥ 7 for this review. Study Characteristic a Patient Characteristic Author (Year ) Study Study Size, No. Selection Criteria of Variables Adjusted in Age, yr PSA, cT No. Cores Region N Upgrading, AS for Eligible Patients Multiple Regression ng/mL Obtained, (Interval) N (%) Who Turned to PV, mL N Immediate Prostatectomy Epstein 2012 (18) USA 5071 1841(36.3) NA age; PW; Mean 57.6, Mean 5.4, NA T1-3 ≥ 10 (2002-2010) GPC Range Range 34.0-79.0 0.2-97.2 Fu 2012 USA 1632 723(44.3) D’Amico criteria b age; race; Median Median 5, NA T1c-2a NR (1993-2009) PW; cT; 61.0, Range TPC; cancer Range 0.2-9.9 laterality; pT; 34.0-79.0 ECE; SVI; PSM Gofrit 2007 (24) USA 448 91(20.3) NA age; PV; Mean 59.1, Mean 6.0 Mean 52.7 T1c-2 8-12 (2003-2006) PSAD; cT; SD 6.5 GPC; PPC; cancer laterality Gokce 2016 (29) Turkey 210 69(32.9) PSA < 10 ng/mL; Neutrophil- Mean 59.2, Mean 5.4, NR T1c-2a NR (2005-2015) GS ≤ 6; ≤ T2a; ≤ 2 to- SD 8.1 SD 1.1 positive cores; ≤ 50% lymphocyte cancer involvement ratio Jalloh 2015 (21) USA 4231 1123(26.5) D’Amico criteria b age; race; Mean 59.9 NA NA T1-2 Mean 9.15 (1990-2012) No. cores obtained; GPC; prostatectomy approach; year of diagnosis Lee 2015 (22) Korea 339 102(30.1) D’Amico criteria b age; BMI; Mean 65.4, Mean 5.4, Mean 38.0, T1c-2a Mean 12.4, (2007-2012) PV; cT; No. SD 6.8 SD 2.0 SD 14.3 SD 0.8 cores obtained; GPC; PPC; TPC; core length Lyon 2016 (13) USA 1256 647(51.5) NA age; race; NR NR NR T1-4 ≥ 6 (1999-2015) BMI; PW; cT; No. cores obtained; GPC; PPC; TPC; year of surgery; statin use; Charlson comorbidity index; IBP; biopsy pathology reviewed Pietzak 2014 (33) USA 400 86(21.5) MSK criteria c age; cT; NR NR NR T1c-2a ≥ 10 (1998-2008) No. cores obtained; No. positive cores; ASAP; HGPIN; biopsy history Porcaro 2017 (14) Italy 170 111(65.3) D’Amico criteria b PV; PPC Mean 73.8, Median 5.7, Median T1c-2a ≥ 12 (2013-2014) SD 6.0, Range 40.0, Median 0.8-9.9, Range 64.0, Mean 5.9, 15.0-120.0, Range SD 1.9 Mean 41.3, 46.0-75.0 SD 15.8 Quintana 2016 (20) USA 375 76(20.3) NA age; race; NA NA NA T1-2 12-33 (2003-2013) PV; cT; No. cores obtained; No. positive Santok 2017 (15) Korea 359 145(40.4) NA cores; age; Mean Mean 39.2, T1-4 12 (2005-2010) race; PSAD; 6.8, SD 20.9, PV; cT; IQR IQR PPC 5.0–10.0 10.5-164.0 Mean 63.0, SD 7.5 Sooriakumaran USA 750 297(39.6) PSA ≤ 10 ng/mL; age; PV; Mean 59.0, Mean 4.6, Mean 54.0, T1-2a NR 2012 (16) (2005-2010) GS ≤ 6; ≤ T2a; ≤ cT; No. SD 6.9 SD 1.9 SD 23.2 2 positive cores; ≤ cores. 50% cancer involvement obtained; No positive cores; GPC; HGPIN Tosoian 2013 USA 7486 1620(21.6) D’Amico criteria b age; race; Mean 57.3, Mean 5.2, NR T1c-2a Mean \ (1975-2013) BMI; No. SD 6.4 SD 2.2 12.2, SD 3.6 cores obtained; GPC; risk stratification; year of surgery Abbreviations: AS, active surveillance cT, clinical T-stage; pT, pathologic T-stage; PSA, prostate specific antigen; PSAD, PSA density; PV, prostate volume; PW, prostate weight; BMI, body mass index; bGS, biopsy Gleason sum; pGS, prostatectomy Gleason sum; GSU, Gleason sum upgrading; PPC, percentage of positive cores; GPC, greatest percentage of cancer in any core; TPC, total percentage of cancer in all cores; ASAP, atypical small acinar proliferation; HGPIN, high-grade prostatic intraepithelial neoplasia; ECE, extra-capsular extension; SVI, seminal vesical invasion; PSM, positive surgical margin; NR, not reported; NA, not available; SD, standard deviation; IQR, interquartile range. a all studies were case-control designs; b PSA ≤ 10 ng/mL; GS ≤ 6; ≤ T2a; c PSA ≤ 10 ng/mL; GS ≤ 6; ≤ T2a; ≤ 3 positive cores; ≤ 50% cancer involvement Review 478 Vol 18 No 5 September-October 2021 479 Search strategy A comprehensive search for eligible records was con- ducted using the following databases from inception until March 10th, 2020: Web of Science, Ovid Medline, Ovid Embase, SCOPUS and the Cochrane Library. Be- sides, we managed to find relevant records from elec- tronic website of grey literatures including Grey Litera- ture Report, Open Grey and GreyNet International. No restriction of language was included in the search. The search used search terms included MeSH and Emtree terms combined with free-words. The major terms con- sist of ‘Prostatic Neoplasms’, ‘Multivariate Analysis’, ‘Neoplasm Grading’, ‘Odds Ratio’ and ‘Upgrad*’. The full Ovid Medline search strategy was shown in Sup- plementary Figure 1. Additional records were identified through reviewing reference lists of relevant articles. Eligibility criteria and study selection Eligible studies had to meet the following inclusion cri- teria: (1) original studies with experimental design; (2) peer-reviewed studies; (3) studies with a sample size more than 50 patients. Exclusion criteria included as follows: (1) case reports, reviews, meta-analyses, and commentaries; (2) studies not in the field of Gleason upgrading of prostate cancer; (3) full-text was not avail- able; (4) studies in which PSA was not included in mul- tivariable analysis (MVA); (5) studies in which adjust- ed odds ratios (AORs), confidence intervals (CIs) or p value were not available for pooled analysis. Records retrieved from electronic databases and reference lists were deduplicated and the remaining were screened via title and abstract for eligibility of full-text review. If studies reported the overlapping results (same author or institution), we selected the one with the latest year of publication. The final included articles were evaluated in both qualitative synthesis and quantitative synthesis (meta-analysis). See Figure 1 for the PRISMA flow diagram detailing the study criteria and the selection process. This whole selection process was conducted by two investigators (XW, YZ) independently and dis- agreement was resolved by consensus and approved by a third investigator (ZJ). Data extraction, data synthesis, and quality evaluation Included studies were categorized into subgroups by definition of upgrading. Subgroup A consisted of stud- ies with the upgrading definition (from bGS ≤ 6 to pGS ≥ 7). Patients in studies of subgroup A might be eligi- ble for active surveillance but finally turned to imme- diate prostatectomy. Subgroup B consisted of studies with other definitions of Gleason upgrading. Data from included studies were independently extracted by two investigators (XW, YZ) and any discrepancies were re- solved by consensus and approved by a third investiga- tor (ZJ). Procedures of extraction were performed using Table 2. Summary data for included studies with other definitions of Gleason sum upgrading for this review. Study Characteristic a Patient Characteristic Author (Year ) Study Study No. Definition of Variables Age, yr PSA, PV, mL GS cT No. Cores Region Size, N Upgrading, Upgrading Adjusted in ng/mL Obtained, N (Interval) N (%) Multiple Regression Bullock 2019 (27) UK 17598 4489(25.5) Any GSU age; cT; Mean 63.2, Median 7.9, NR > 7: 14% T1-4 NR (2011-2016) bGG; year Median 64.0, Range of surgery; Range 0-181.0, geographical 35.0-92.0 Mean 10.1 region Freedland 2007 (32) USA 1113 299(26.9) Any GSU BMI; bGS; Mean 60.6, Median 6.4, NR > 3+4: 13% T1-3 Median 10, (1996-2007) No. cores SD 6.5 Mean 8.3, Range 6-40 obtained; No. SD 7.4 positive cores; year of surgery Kassouf 2007 (19) Canada 247 80(32.4) Any GSU age; PV; Median Median Median > 7: 10% T1c-3 10-11 (1997-2004) cT; bGS 61.0, 5.5, 37.0, Range Range Range 56.0-65.0 4.3-8.7 28.5-48.0 Martin 2017 (30) USA 136 19(14.0) From bGS ≤ 7 to age; cT; Median Median NR ≤ 7 T1c-2 ≥ 10 (2005-2008) pGS ≥ 8 bGS; GPC; 60.5, 5.8, PPC IQR IQR 56.1-64.3 4.7-8.1 Porcaro(2) 2017 (23) Italy 135 12(8.9) From bGS = total Median Median Median ≤ 3+4 T1c-2b ≥ 12 (2014-2015) 6/3+4 to pGS ≥ 8 testosterone; 65.0, 6.4, 40.0, PSAD Range Range Range 51.0-75.0 1.2–17.9 14.0-105.0 Xu 2017 China 237 62(26.2) Any GSU age; BMI; Mean 67.8, Mean 19.2, NA > 7: 19% T1-3 10 (2011-2015) cT; bGS; Median Median DRE; 67.0, 13.4, Range Range 47.0-86.0 1.0-293. Abbreviations: cT, clinical T-stage; PSA, prostate specific antigen; PSAD, PSA density; PV, prostate volume; BMI, body mass index; GS, Gleason sum; bGS, biopsy Gleason sum; pGS, prostatectomy Gleason sum; GSU, Gleason sum upgrading; bGG, biopsy grade group; PPC, percentage of positive cores; GPC, greatest percentage of cancer in any core; DRE, digital rectal examination; NR, not reported; NA, not available; SD, standard deviation; IQR, interquartile range. a all studies were case-control designs PSA’s impact on Gleason upgrading-Wang et al. a standardized form (Table 1 and Table 2). Two investigators (ZJ and QP) independently evalu- ated each included study utilizing the Newcastle-Otta- wa Quality Assessment Scale (NOS) for case-control studies. Discrepancies in score assignment were later resolved by consensus. Statistical analysis The conversion to means of variables was roughly calculated using medians combined with range or in- Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) flow diagram. Figure 2. Newcastle-Ottawa Quality Assessment Scale (NOS) of 19 included studies. PSA’s impact on Gleason upgrading-Wang et al. Review 480 Vol 18 No 5 September-October 2021 481 terquartile range (IQR) according to Luo’s methods (11). The meta-analysis was conducted by computing log-transformed AORs (logAORs) and their standard errors (SEs). Fixed effect model was used for analysis of subgroup A and random effect models were used for analysis of subgroup B and total group in order to assess the predictive performance of PSA on GSU. Further subgroup analysis was carried out utilizing subgroup A and B. Forest plot was performed to provide the pooled results in total and subgroups. The forest plot also pro- vided the overall effect measure (Z) and heterogeneity among studies. Heterogeneity was appraised using I2 statistic, which represented whether the variation was attributed to heterogeneity or chance. The publication bias was evaluated by visually inspecting the asym- metry of funnel plot and subsequently quantifying the asymmetry by Egger’s test. Tests were 2 sided and P = .05 was the threshold for statistical significance. Me- Figure 3. Forest plot of prostate specific antigen (PSA) predicting Gleason sum upgrading in total and subgroups. An odds ratio of > 1 indicates relative chance of upgrading for higher level of PSA versus lower level of PSA. Figure 4. Funnel plot of studies focused on Gleason sum upgrading. A: all 19 included studies; B: studies defining upgrading from bGS ≤ 6 to pGS ≥ 7. PSA’s impact on Gleason upgrading-Wang et al. ta-analysis and statistical tests were performed using computer software of RevMan version 5.3 and Stata version 12.0. RESULTS 4878 records were retrieved from electronic databas- es (53 records from electronic websites of grey liter- atures) and 31 were from pertinent references. Total 2375 results were deduplicated and the remaining 2534 records were screened via title and abstract for eligibil- ity of full-text review. 189 articles were selected after screening and 19 of them published between 2007 and 2019 met the criteria for this review. All were studies of case-control series with total sample size of 42193 patients and with a study interval of 41 years (1975- 2016). 7 studies were large series (sample size great- er than 1000) from the USA and the UK. There were 11 articles from the USA, 2 from Korea and another 2 from Italy and the remaining 4 were from the China, UK, Canada and Turkey respectively. 13 series applied the definition of upgrading from bGS ≤ 6 to pGS ≥ 7, while 4 focused on any GSU and 2 consisted of patients upgraded from bGS ≤ 3+4 or 7 to pGS ≥ 8. (Table 1 and Table 2) Of 42193 patients, the GSU was found in 11892 (28.2%) with higher-grade RP specimens. The rate of GSU in subgroup A (25.5%) was lower than that in subgroup B (30.5%). The pooled mean age of 40537 patients was 60.8 years (95%CI: 46.3-75.3) from 17 articles with ex- tractable data. The pooled mean age of 21071 patients in subgroup A was 58.7 years (95%CI: 44.9-72.5), whilst the 19466 patients in subgroup B were older with pooled mean age of 63.1 years (95%CI: 49.1-77.0). Patients in 8 subgroup A studies were eligible for AS criteria but turned to prostatectomy instead. Even if pa- tients in other 5 subgroup A studies were not all eligible for AS criteria, they all had opportunities to undergo surgeries for curative treatment. Patients in subgroup A were likely to have lower PSA level (mean or median 4.6-6.8 ng/mL) than ones in subgroup B (mean or medi- an 5.5-19.2 ng/mL). Most patients (at least 77.7%) had organ confined disease ( ≤ T2) in subgroup B. (Table 1 and Table 2) All included studies had high quality according to NOS scale with attained scores greater than 6. 11 articles were rated as a total score of 7, while other studies were rated 8. (Figure 2) As shown in the forest plot (Figure 3), PSA level was found to be an independent predictor of GSU regardless of definitions of upgrading. Higher PSA level was as- sociated with a significant increased risk of GSU with high heterogeneity observed (pooled AOR = 1.14, 95% CI: 1.10–1.18; P < .05; I2 = 92%). For the definition of upgrading from bGS ≤ 6 to pGS ≥ 7 (subgroup A), the odds of upgrading with higher PSA level as opposed to lower PSA level was 1.12 (95% CI: 1.11–1.14, P < .05; I2 = 13%), while the odds of upgrading in subgroup B was 1.11 (95% CI: 1.05–1.18, P < .05; I2 = 89%). As shown in funnel plots (Figure 4), publication bias was pronounced with apparent asymmetry in the analysis of 19 included studies. Egger’s test also demonstrated that the publication bias existed with PEgger < .05. After 6 studies of subgroup B removed, asymmetry of funnel plot improved significantly with PEgger = .239 which indicated that no evidence of publication bias was ob- served in the 13 studies for PSA predicting upgrading from bGS ≤ 6 to pGS ≥ 7. DISCUSSION In this systematic review and meta-analysis of 19 stud- ies with high ranking of quality, we identified PSA as a predictor for GSU regardless of the definition of upgrading in patients eligible for curative treatment or AS. The most convincing finding was observed within the subgroup of upgrading from bGS ≤ 6 to pGS ≥ 7 in which all studies consistently verified the predictive performance of PSA on GSU with small heterogeneity (OR = 1.12; 95% CI: 1.11–1.14; P < .05; I2 = 13%; PEg- ger = .239). This review also demonstrated the inaccu- racy of bGS to predict pGS with upgrading occurring in 28.2% of 42193 patients. Gleason upgrading has always been a prolonged invar- iable topic over time. Even if agreement between bGS and pGS has improved over decades(12), due to the na- ture of diagnostic method, the phenomena of Gleason upgrading cannot be eliminated. A systematic review (3) including 14839 patients from 1982–2007 reported upgrading from bGS to pGS was found in 30% (range from 6% to 36%), which had no overlapping population with our review and was comparable with what we had found (28.9%, range from 8.9% to 65.3%). Lyon et.al (13), Porcaro et.al(14), Santok et.al(15) and Sooriakumaran et.al(16) identified 51.5%, 65.3%, 40.4% and 39.6% of patients with GSU partly due to the upgrading from the ‘bottom’ (bGS = 6). Although PSA is typically elevated in high-grade dis- ease, some patients present with the discordant scenario of high-grade disease and low PSA. For Gleason 8–10 disease, these patients with low PSA have a higher risk for PCa death and are more likely to be associated with neuroendocrine genomic features than ones with high PSA(17). High-grade disease could be harboured in these patients which may result in upgrading. However, our pooled results showed that there is a positive linear re- lationship between PSA and GSU. The following two reasons might explain. The proportion of these patients in the population is small which may not influence the linearity of multivariable analysis. The diagnoses of these patients are difficult via PSA screening and these patients might be ineligible for prostatectomy when they are diagnosed. Hence, most of these patients may not be incorporated in the included studies of this re- view. PSA is organ but not cancer specific and hence it may be elevated in patients with large prostate gland or other clinical scenarios such as prostatitis. Counterintuitive- ly, small rather than large prostate volume (PV) was strongly associated with pathologic outcomes includ- ing GSU(18), which was also determined by 2 included studies(19,20) in our review. In 9 articles included(14-16, 20- 25), PV was also incorporated into MVA to adjust for confounders or collinearity. However, PSA was still an independent predictor for GSU. PSA density (PSAD) is the level of PSA divided by the TRUS-determined PV, which is another predictor for risk stratification and prognosis and more likely to be associated with clinical- ly significant PCa(26). Due to PSAD as a better indicator adjusting for PV, it has been reported that PSAD other than PSA was an independent predictor of upgrading (27). Controversially, 3 articles(15,24,25) included in this review demonstrated that PSA was still strongly asso- PSA’s impact on Gleason upgrading-Wang et al. Review 482 Vol 18 No 5 September-October 2021 483 ciated with GSU even when PSAD was incorporated into MVA. However, no matter what we will find from further studies addressing this issue, PSA is a critical factor which urologists or oncologists should be fully considerate to in terms of risk reclassification. All the articles except one(28) incorporated at least one pathologic variable into MVA. Including variables such as the number of positive cores and/or tumor ex- tent in cores improved the predictive performance for a comprehensive risk assessment of GSU. Individu- al differences including racial variation(13,20-22,26), body mass index(13,14, 22-24,26) and comorbidity(13,22) which might potentially affect GSU were also adjusted. Multifarious variables being included in different articles verified PSA as the independent risk factor, but would do so at the cost of inducing the heterogeneity between studies. Heterogeneity among studies focused on upgrading from bGS ≤ 6 to pGS ≥ 7 was acceptable, whilst the variation within subgroup B was significant. The com- bination of different definitions in subgroup B was a major source of heterogeneity. The number of biopsy cores obtained was a vital factor influencing the accura- cy of predicting pGS(29). Most studies adjusted for it or it was an invariant part of study design, however, there were 6 studies(14,19,24,28,30,31) did not do so or report the de- tails, which might contribute to significant variation in outcomes. Given the nature of case-control studies, the limitation of study design was also an inevitable reason of heterogeneity. Further prospective, large-scale and well-designed research is needed to determine PSA’s impact on GSU. Experience in GS assignment varies across pathologists especially in different hospitals and regions. Interobserver variability was found to correlate with the accuracy between bGS and pGS(32). In view of pooled analysis of studies, this interobserver variability cannot be eliminated but reflect the true contemporary clinical practice. Except the heterogeneity discussed above, our review still has several limitations. First of all, the quality of the studies varied. Moreover, incomplete retrieval of all research due to inevitable reasons such as no access to full-text, non-extractable data or inappropriate data type. Last but not least, only patients who had under- gone RP were selected for analysis which might not represent the reality. According to our pooled analysis, there are several clin- ical implications of PSA predicting GSU in current clin- ical practice. Patients who are reevaluated to have high probabilities of GSU during AS could adhere to more active follow-up policies in case of delay of treatment. On the contrary, patients with low probabilities of GSU who are unwilling to or could not receive interventions are more inclined to undergo the watchful waiting or AS. These clinical recommendations might give urol- ogists more confidence in clinical decision-making and provide more precise and comprehensive assessment of the risk and more personalized and optimal treatment options for PCa patients. CONCLUSIONS PSA is an independent predictor for Gleason sum up- grading regardless of the definition of upgrading. Pa- tients with high level of serum PSA are at high risk of undergoing pathologic upgrading at prostatectomy. Combined with other risk factors, PSA prompts more accurate risk stratification and helps providers to select optimal therapies for PCa patients. Nevertheless, further robust studies are necessitated to confirm these results. CONFLICTS OF INTEREST: None of the authors have any conflicts of interest to de- clare. APPENDIX https://journals.sbmu.ac.ir/urolj/index.php/uj/libraryFiles/downloadPublic/30 REFERENCES 1. Basiri A, Eshrati B, Zarehoroki A, et al. Incidence, Gleason score and ethnicity pattern of prostate cancer in the multi-ethnicity country of Iran during 2008-2010. Urol J. 2020 May 4. doi: 10.22037/uj.v0i0.5618. Online ahead of print. 2. Delahunt B, Egevad L, Samaratunga H, Martignoni G, Nacey J N, Srigley J R. Gleason and Fuhrman no longer make the grade. Histopathology. 2016;68:475-81. 3. Cohen M S, Hanley R S, Kurteva T, et al. Comparing the Gleason prostate biopsy and Gleason prostatectomy grading system: the Lahey Clinic Medical Center experience and an international meta-analysis. Eur Urol. 2008;54:371-81. 4. Thomsen F B, Brasso K, Klotz L H, Røder M A, Berg K D, Iversen P. Active surveillance for clinically localized prostate cancer--a systematic review. J Surg Oncol. 2014;109:830-5. 5. Briganti A, Larcher A, Abdollah F, et al. Updated nomogram predicting lymph node invasion in patients with prostate cancer undergoing extended pelvic lymph node dissection: the essential importance of percentage of positive cores. Eur Urol. 2012;61:480-7. 6. Oderda M, Gontero P, Sanchez-Salas R, et al. 936 Gleason score upgrading to 8–10 predicts biochemical recurrence in patients undergoing radical prostatectomy: Analysis on 7310 high- risk patient the EMPaCT database. Eur Urol Suppl. 2015;14:e936. 7. Jang W S, Koh D H, Kim J, et al. The prognostic impact of downgrading and upgrading from biopsy to radical prostatectomy among men with Gleason score 7 prostate cancer. Prostate. 2019;79:1805-10. 8. Corcoran N M, Hong M K H, Casey R G, et al. Upgrade in Gleason score between prostate biopsies and pathology following radical prostatectomy significantly impacts upon the risk of biochemical recurrence. BJU Int. 2011;108:E202-10. 9. Chun F K, Steuber T, Erbersdobler A, et al. Development and internal validation of a nomogram predicting the probability of prostate cancer Gleason sum upgrading between biopsy and radical prostatectomy pathology. Eur Urol. 2006;49:820-6. 10. Liberati A, Altman D G, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that PSA’s impact on Gleason upgrading-Wang et al. evaluate healthcare interventions: explanation and elaboration. BMJ. 2009;339:b2700. 11. Luo D, Wan X, Liu J, Tong T. Optimally estimating the sample mean from the sample size, median, mid-range, and/or mid-quartile range. Stat Methods Med Res. 2018;27:1785- 805. 12. Danneman D, Drevin L, Delahunt B, et al. Accuracy of prostate biopsies for predicting Gleason score in radical prostatectomy specimens: nationwide trends 2000-2012. BJU Int. 2017;119:50-6. 13. Lyon T D, Turner II R N, Yabes J G, et al. Preoperative statin use at the time of radical prostatectomy is not associated with biochemical recurrence or pathologic upgrading. Urology. 2016;97:153-9. 14. Porcaro A B, Siracusano S, Luyk N D, et al. Low-risk prostate cancer and tumor upgrading in the surgical specimen: analysis of clinical factors predicting tumor upgrading in a contemporary series of patients who were evaluated according to the modified Gleason score grading system. Curr Urol. 2017;10:118- 25. 15. Santok G D R, Raheem A A, Kim L H, et al. Prostate-specific antigen 10-20 ng/mL: a predictor of degree of upgrading to ≥ 8 among patients with biopsy Gleason score 6. Investig Clin Urol. 2017;58:90-7. 16. Sooriakumaran P, Srivastava A, Christos P, Grover S, Shevchuk M, Tewari A. Predictive models for worsening prognosis in potential candidates for active surveillance of presumed low-risk prostate cancer. Int Urol Nephrol. 2012;44:459-70. 17. Mahal B A, Yang D D, Wang N Q, et al. Clinical and genomic characterization of low- prostate-specific antigen, high-grade prostate cancer. Eur Urol. 2018;74:146-54. 18. Freedland S J, Isaacs W B, Platz E A, et al. Prostate size and risk of high-grade, advanced prostate cancer and biochemical progression after radical prostatectomy: A Search Database Study. J Clin Oncol. 2005;23:7546-54. 19. Epstein J I, Feng Z, Trock B J, Pierorazio P M. Upgrading and downgrading of prostate cancer from biopsy to radical prostatectomy: incidence and predictive factors using the modified Gleason grading system and factoring in tertiary grades. Eur Urol. 2012,61:1019-24. 20. Kassouf W, Nakanishi H, Ochiai A, Babaian K N, Troncoso P, Babaian R. Effect of prostate volume on tumor grade in patients undergoing radical prostatectomy in the era of extended prostatic biopsies. J Urol. 2007;178:111-4. 21. Quintana L, Ward A, Gerrin S J, et al. Gleason misclassification rate is independent of number of biopsy cores in systematic biopsy. Urology. 2016;91:143-9. 22. Jalloh M, Myers F, Cowan J E, Carroll P R, Cooperberg M R. Racial variation in prostate cancer upgrading and upstaging among men with low-risk clinical characteristics. Eur Urol. 2015;67:451-7. 23. Lee S, Jeong S J, Hwang S I, et al. Clinical value of core length in contemporary multicore prostate biopsy. PLoS One. 2015;10:e123704. 24. Porcaro A B, Luyk N D, Corsi P, et al. Association between basal total testosterone levels and tumor upgrading in low and intermediate risk prostate cancer. Urol Int. 2017;99:215-21. 25. Gofrit O N, Zorn K C, Taxy J B, et al. Predicting the risk of patients with biopsy Gleason score 6 to harbor a higher grade cancer. J Urol. 2007;178:1925-8. 26. Freedland S J, Wieder J A, Jack G S, Dorey F, deKernion J B, Aronson W J. Improved risk stratification for biochemical recurrence after radical prostatectomy using a novel risk group system based on prostate specific antigen density and biopsy Gleason score. J Urol. 2002;168:110-5. 27. Magheli A, Hinz S, Hege C, et al. Prostate specific antigen density to predict prostate cancer upgrading in a contemporary radical prostatectomy series: a single center experience. J Urol. 2010;183:126-31. 28. Bullock N, Simpkin A, Fowler S, Varma M, Kynaston H. Narahari K. Pathological upgrading in prostate cancer treated with surgery in the United Kingdom: trends and risk factors from the British Association of Urological Surgeons Radical Prostatectomy Registry. BMC Urol. 2019;19:94. 29. Coogan C L, Latchamsetty K C, Greenfield J, Corman J M, Lynch B, Porter C R. Increasing the number of biopsy cores improves the concordance of biopsy Gleason score to prostatectomy Gleason score. BJU Int. 2005;96:324-7. 30. Gokce M I, Tangal S, Hamidi N, Suer E, Ibis M A, Beduk Y. Role of neutrophil-to-lymphocyte ratio in prediction of Gleason score upgrading and disease upstaging in low-risk prostate cancer patients eligible for active surveillance. Can Urol Assoc J. 2016;10:E383-7. 31. Martin N E, Chen M H, Zhang D, Richie J P, D'Amico A V. Unfavorable intermediate-risk prostate cancer and the odds of upgrading to Gleason 8 or higher at prostatectomy. Clin Genitourin Cancer. 2017;15:237-41. 32. Allsbrook Jr W J, Mangold K A, Johnson M H, et al. Interobserver reproducibility of Gleason grading of prostatic carcinoma: urologic pathologists. Hum Pathol. 2001;32:74-80. 33. Freedland S J, Kane C J, Amling C L, et al.. Upgrading and downgrading of prostate needle biopsy specimens: risk factors and clinical implications. Urology. 2007;69:495-9. 34. Pietzak III E J, Kabarriti A E, Mucksavage P, et al. The presence of high-grade prostatic intraepithelial neoplasia or atypia on prostate biopsy does not adversely affect prostatectomy outcomes for patients otherwise eligible for active surveillance. Urology. 2014;84:1442-7. PSA’s impact on Gleason upgrading-Wang et al. Review 484