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1 Predictors of Upgraded and Upstaged Prostate Cancer in Patients with Gleason score 6 or 7 at Biopsy Shuai Liu1, Jiaqi Wang1, Kejia Ding2,Jiaju Lv3, Sentai Ding4, Jiming Zhao 5, Dongbin Bi6 1 Shuai Liu 1 Jiaqi Wang MD 2 3 Kejia Ding PhD Jiaju Lv 4 PhD Post doctorate Sentai Ding PhD 5 Jiming Zhao 6 Dongbin Bi Associate degree PhD Manuscripts, or the essence of their content, is not previously unpublished and under simultaneous consideration by another journal. Any similar work has not been submitted to or published by another journal. This work has not been submitted/published elsewhere in the same form, in English or in any other language. To Predict the Factors of Upgraded and Upstaged Prostate Cancer in Patients with Gleason score 6 or 7 at Biopsy 2 1 Shuai Liu Doctor Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, P.R. China; 1 Jiaqi Wang graduate student Shandong University, Jinan 250012, P.R. China; 2 Kejia Ding Professor Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, P.R. China; 3 Jiaju Lv Professor Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, P.R. China; 4 Sentai Ding Doctor Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, P.R. China; 5 Jiming Zhao Nurse Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, P.R. China; 6 Dongbin Bi Doctor Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, P.R. China; Correspondence author Dongbin Bi Department of Urology, Provincial Hospital affiliated to Shandong University, 324 Jingwu Street, Jinan, China, 250021. E-mail: [email protected] Tel: 0531-68776310 3 Abstract Objectives: To assess the predictors of upstaged and upgraded prostate cancer in men initially diagnosed with Gleason score (GS) 6 or 7 prostate adenocarcinoma. Methods: The incidence of upstaging and upgrading was assessed in 90 patients who underwent radical prostatectomy (RP) at Shandong Provincial Hospital over the last 13years. We analyzed pretreatment parameters associated with GS discordance and compared with post-prostatectomy variables. Univariate analysis and multivariable logistic regression of men with complete biopsy data (n=90) identified significant predictors of upgrading or upstaging. Abdomen ultrasound prostate volume and PSA density (ultrasonography PSAD) were determined. ROC was performed to determine the significant diagnostic parameters. Results: The overall upgrading and upstaging rate was 45.56 and 31.11%, respectively. PSA (p = 0.011), and PSAD (p = 0.003), extra-capsular extension (p = 0.002) and seminal vesicle invasion (p = 0.000) were significantly associated with upgrading (all p < 0.005). Similarly, fPSA (p = 0.041), F/T (p = 0.002), extra-capsular extension ((P=0.020), clinical stage (p = 0.031) and seminal vesicle invasion (p = 0.000) were associated with upstaging (all p < 0.05). Number and percentage of biopsy cores and clinical stage were all marginally associated with upgraded cancer. ROC curve showed seminal vesicle invasion was associated with upstage, while PSAD, biopsy positive percent and PSA were significant (all P<0.05). Conclusions: PSAD, biopsy positive percent and PSA are apparently associated with upstaged prostate cancer. These patients should be considered for further diagnostic imaging prior to choosing active surveillance. Keywords: Gleason score, prostate cancer, predictor 4 Introduction Prostate cancer (PCa) is the most frequently diagnosed cancer in males and the second leading cause of cancer-related death in males in the United States [1]. Prostate cancer (PCa) usually has extended natural history, with a significant controversy concerning the optimal treatment. Radical prostatectomy (RP) has long been recognized as the most definitive treatment for localized PCa while radiotherapy has shown acceptable efficacy. One of the most important factors influencing treatment choice is the Gleason score (GS) from the initial prostate biopsy [2]. Improved understanding of the potential limitations of prostate biopsy (Pbx) Gleason scoring may allow us to better counsel prostate cancer patients during their treatment decision process. It is estimated that 70% of patients with prostate cancer have low-risk disease, and therefore are more likely to have a favorable prognosis [3]. Determination of whether a patient should be actively treated for low-risk prostate cancer remains controversial, as multiple studies have reported that a considerable proportion of men qualifying for active surveillance (AS) have aggressive tumor features at RP [4,5]. Pathological upgrading and upstaging of prostate cancer RP are more likely to represent initial misclassification than true disease progression [6].While Bul et al. [7] showed that the Prostate Cancer Research International Active Surveillance (PRIAS) criteria independently predicted decreased incidence of upstaging, it did not predict decreased upgrade or biochemical recurrence (BCR). Furthermore, Thong et al. [8] determined that pathological upgrade was significantly associated with extraprostatic extension, positive surgical margins, and seminal vesicle involvement. While patients with GS7 PCa have long been considered to have a more aggressive disease course than GS ≤ 6 tumors, GS7 tumors are heterogeneous in their biologic behavior. Several reports suggested that GS4+3 cancers have a threefold increase in lethal outcomes compared to GS3+4 cancers. Simultaneously, a significant difference in recurrence-free survival rates was found between them [9,10] . The objective of this study was to examine the pathologic outcomes in men with GS 6 or 7 PCa who underwent RP and to identify preoperative factors including biopsy features that impact the incidence of upgrading and upstaging. These results in turn may aid in therapeutic management of patients with GS6 or7 tumor at initial diagnosis. Methods 5 Patients After obtaining Shandong Provincial Hospital institutional review board approval, the data of 90 patients who had at least 12 core biopsies, Gleason Score 6 or 7 and underwent radical RP over the last 13 years were analyzed retrospectively. All biopsy and RP specimens were reviewed by a genitourinary pathologist. Pathologic stage and GS were examined postoperatively. Upstaging of PCa was defined as pathologic stage T3–T4, and upgrading as the pathologic GS ≥ 7 (4+3). PCa was identified and graded according to the definitions of the 2005 consensus conference of the International Society of Urological Pathology [11]. Patients with no biopsy slide or incomplete data were excluded. Statistical Analysis SPSS 19.0 for Windows was used for data analysis. Student’s t-test was used for continuous variables and Pearson χ 2 test and Fisher’s exact test for categorical variables. Logistic regression analysis was used for multivariate analysis and for statistical significance. A receiver-operating characteristic (ROC) curve was used to determine the optimal PSAD, biopsy positive status and PSAD cutoff yielding the highest combined sensitivity and specificity A p value < 0.05 was considered statistically significant. Results Over-all upgrading and upstaging incidence We analyzed pretreatment parameters associated with GS discordance and compared immediate with post-prostatectomy outcome variables. Of the 90 patients undergoing RP, the overall upgrading and upstaging rate in our institution of Gleason 6 or 7 prostate cancer was 45.56 and 31.11%, respectively. Preoperative factors Univariate analysis shows that free PSA (fPSA) and free/total PSA ratio (F/T) were significantly associated with upstaging (p= 0.041, 0.011, Table 1). Age (p = 0.964), BMI (p = 0.172), PSA (p = 0.110), PSAD (p = 0.061), smoking status (p = 0.664), drinking status (p = 1.000) and hypertension (p = 0.495) were not statistical significant with upstaging (all p > 0.05, Table 1). Additionally, in Table2, TPSA and PSAD were dramatically associated with upgrading (p = 0.004, 0.002), while age (p = 0.820), BMI (p = 0.397), fPSA (p = 0.192), F/T (p = 0.062), smoking (p = 0.089), drinking (p = 0.741) and hypertension (p = 0.750) showed no statistical significance with upstaging (all P > 0.05, Table 2). 6 Biopsy factors Pathology results showed that clinical stage was associated with upstaging (p = 0.031, Table 3), while the number of positive cores (p = 0.640) and percentage of biopsy cores (p = 0.640) were not associated with upstaging (Table 3) The detailed comparison of biopsy features between patients who were upgraded versus those who were not upgraded is shown in Table 4. Although not statistically significant, there was a marginal association between the number of positive cores, percentage of biopsy cores, clinical stage and the risk of upgrade (p = 0.049, 0.050, 0.052, Table 4). Pathological factors As shown in Table 5, extra-capsular and seminal vesicle extension were significantly associated with upstaging (p = 0.020, 0.000) but not nodal status (p = 0.452) or Abdomen ultrasound prostate volume (p = 0.586) .We found that extra-capsular extension and seminal vesicle extension were associated with upgraded PCa (p = 0.002, 0.000, Table 6). As showed in Table 6, nodal status (p = 0.286) and Abdomen ultrasound prostate volume (P = 0.970) were not significantly associated with pathological upgrade. Logistic regression analysis of clinicopathologic factors Table 7 shows the logistic regression analysis of upstaging with other parameters, which are listed from the most significant to least significant values: seminal vesicle (p = 0.000) and extra-capsular extension (p = 0.040). There was no relationship between upstaging and GS ≥7 at the fPSA, F/T, or clinical stage.(p = 0.666, 0.230, 0.394) Similarly, Table 8 summarizes the logistic regression analysis of upgraded PCa with other parameters, which are listed from the most significant to the least significant values: extra-capsular extension (p = 0.004) and percentage of biopsy cores (p = 0.020). There was no relationship between upgrading and GS ≥7 at the seminal vesicle, PSA, or PSAD. (p = 0.998, 0.551, 0.394) ROC curve analysis of upstaging and clinicopathologic factors As shown in the Fig. 1 and Table 9, ROC curve analysis indicated that seminal vesicle was associated with upstaging. The AUC of upstaging variables are clinical stage (0.579), fPSA (0.565), F/T (0.450), extra-capsular (0.397) and seminal vesicle (0.248). (p = 0.232, 0.329, 0.061, 0.068, 0.000).The AUC of seminal vesicle < 0.5 suggests little diagnostic significance. ROC curve analysis of upgrading and clinicopathologic factors PSAD (p = 0.001), biopsy-positive status 7 (p = 0.002) and PSA (p = 0.004) were significant. The AUC of upgraded variables included PSAD (0.703), biopsy positive percent (0.693) and PSA (0.676) (Fig. 2 and Table 10). PSAD, PSA and biopsypositive percentage were highly significant diagnostically. Discussion In the present study, 45.56% (28) of the total patients were upgraded to Gleason 7 to 10 and 31.11% (41) were upstaged to T3-T4/N0-1 disease. Kang DI et al previously reported upstaging rates of 10.2– 12.5% in men who fulfilled the AS criteria [12]. In contrast to the upstaging risk, the reported upgrading rate in our study was not significantly different from the published studies. Previously, Moussa et al. [13] reported that 26.8% of patients with GS3+4 cancers were upgraded after RP. We found that PSA, PSAD, seminal vesicle and extra-capsular extension were significantly associated with upgrading and upstaging (n=90, all p < 0.05). The PSA level was significantly higher in the upgraded group (p = 0.011) consistent with the reports published by Freedland et al. [14] and Tilki et al. [15] .Multivariate models indicated that inclusion of PSAD instead of PSA significantly increased predictive accuracy of upgrades [16]. We also found that PSAD has lower p value than PSA in predicting upstaging. Kundu et al. determined that patients with a higher PSAD showed more aggressive clinically localized prostate cancer [17]. Wong et al. [18]reported outcomes in a large multicenter RP cohort using two different sets of AS criteria (Toronto and PRIAS). Among 410 patients qualifying for PRIAS, an overall upgrading rate of 57.3% and an overall upstaging rate of 12.4% were reported. Increasing PSA level and clinical stage 2 were predictors of high-risk disease. Smaldone et al. [19] reported pathological outcomes of RP in patients qualifying for two different AS protocols and found upgrading in 20–27% and upstaging in 6–8%. Recently, the number of biopsy cores emerged as an independent predictor of pathologically insignificant PCa and unfavorable disease at RP [20] suggesting that the extent of initial biopsy sampling improved patient selection and surveillance strategy [21]. However, Pinthus et al. demonstrated no difference in the number of Pbx cores in patients with concordant GS or those who were upgraded. We also found that a number of positive cores (p = 0.049) and maximum percentage of biopsy cores (p = 0.049) were all marginally associated with upgrade. Freedland et al [22] reported that men with a small prostate were found to have more advanced disease and be at greater risk for progression after RP than those with larger glands. We could not confirm such a finding. However, Dong et al. demonstrated that 8 patients with higher tumor volume at biopsy were at increased risk for GS upgrade. Specifically, Dong et al. determined that patients with more than 5% of the biopsy tissue positive for prostate cancer, greater than 1 biopsy core or greater than 10% of any core positive for prostate cancer, showed an increased risk of GS upgrade [23]. The Dong et al. single institution study is limited by the relatively small patient population (268 patients). We found no significance of prostate volume in predicting upgrading (p = 0.970) or upstaging (p = 0.586). Increasing BMI was associated with shorter time to PSA treatment failure after RP [24] and androgen suppression therapy or radiation therapy for clinically localized PCa[25] Pathological upgrading and upstaging were significantly higher among older (≥65 years) vs younger (< 65 years) patients (53.1% vs 44.1% and 12.2% vs 7.2%, respectively). Higher prostate-specific antigen levels and increasing age were independent predictors of upgraded cancer in patients aged <65 years[26]. However we failed to confirm these conclusions. As debates continue on appropriate criteria for AS, this paper serves as an important reminder that nearly 40% of biopsy Gleason 3+3 and cT1c-T2a patients who generally qualified for AS may have pathologic Gleason 3+4 disease and an additional 7% percent may be harboring Gleason ≥4+3 or T3b4/N0-1 disease. The challenge for clinicians is to identify these patients prior to the initiation of AS, for which the current criteria were neither sensitive nor specific. [27] In the Lotz phase II study, 50% of patients who progressed to treatment with AS eventually relapsed, raising the suspicion of aggressive disease at presentation and whether treating the disease earlier could have altered the outcome. [28] A previous, smaller study showed patients upgraded at prostatectomy had a relative risk of 1.86 (1.302.46) for biochemical progression at six years, [29]. Another study showed progression-free survival in patients upgraded from Gleason 6 to Gleason 3+4 or 4+3 at prostatectomy similar to patients with biopsy 3+4 and 4+3 disease, respectively, at five years. [30] The retrospective nature of our study was a limitation, and the data were analyzed in selected patients who underwent RP, suggesting inherent bias of a retrospective design and a selection bias. However, RP is necessary to confirm the pathological characteristics of insignificant PCa. Further, our study was limited to reporting oncologic outcomes and PCa-specific mortality due to lack of biochemical and progression-free survival data, which might be more important than the adverse pathological characteristics. ROC curve shows no variables of diagnostic significance associated with upstaging, while 9 higher PSAD, biopsy-positive status and PSA were apparently significant. Finally, due to small sample size, no optimal cutoff value of variables predicting upstaging and upgrading was provided in the ROC curve. Acknowledgment This study was supported by the grants from Chinese prostate cancer database, the Natural Science foundation of Shandong province (project number:2014ZRB14513), the science and techonolgy research foundation of Shandong province Shandong affiliated to Shandong University (project number: 2014WS0353 and Provincial Hospital 2014WS0341) and the science and techonolgy research foundation of Jinan (project number:201121060). Conflicts of interest No conflicts of interest References [1]Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics. CA Cancer J Clin 2014;64:9–29. [2] Pinthus JH, Witkos M, Fleshner NE, et al. 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Pinthus JH, Witkos M, Fleshner NE ,et al: Prostate cancers scored as Gleason 6 on prostate biopsy are frequently Gleason 7 tumors at radical prostatectomy: implication on outcome. J Urol 2006; 176: 979 12 Figure legends Fig .1 ROC curve of upstaging variables associated with prostate cancer upgrade The upstaging variables include fPSA, F/T, Extra capsular, Seminal vesicle invasion and clinical stage Fig. 2 ROC curve of variables associated with prostate cancer upgrade The upgrading variables include PSA, PSAD, Extra capsular and Biopsy positive percent.