Download Predictors of Upgraded and Upstaged Prostate Cancer in Patients

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Manuscripts, or the essence of their content, is not previously unpublished and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. Prostate cancers scored as Gleason 6 on prostate biopsy are frequently
Gleason 7 tumors at radical prostatectomy: Implication on outcome. J Urol 2004;176:979–84.
[3] Hayes JH, Ollendorf DA, Pearson SD et al. Active surveillance compared with initial treatment for
men with low-risk prostate cancer: a decision analysis. JAMA 2010; 304: 2373–80
[4] Thaxton CS, Loeb S, Roehl KA, Kan D, Catalona WJ. Treatment outcomes of radical prostatectomy
in potential candidates for 3 published active surveillance protocols. Urology 2010; 75: 414–8
[5] Mitsuzuka K, Narita S, Koie T, et al. Pathological and biochemical outcomes after radical
prostatectomy in men with low-risk prostate cancer meeting the Prostate Cancer International: active
Surveillance criteria. BJU Int 2013; 111: 914–20
[6] Bul M, Zhu X, Valdagni R ,et al. Active surveillance for low-risk prostate cancer worldwide: the
PRIAS study. Eur Urol 2013; 63: 597–603
[7] Bul M, Zhu X, Rannikko A ,et al. Radical prostatectomy for low-risk prostate cancer following initial
active surveillance: results from a prospective observational study. Eur Urol 2012; 62: 195–200
10
[8] Thong AE, Shikanov S, Katz MH, et al. A single microfocus (5% or less) of Gleason 6 prostate cancer
at biopsy-can we predict adverse pathological outcomes? J Urol 2008; 180: 2436–40
[9] Stark JR, Perner S, Stampfer MJ, et al. Gleason score and lethal prostate cancer: does 3+4 = 4+3? J
Clin Oncol 2009; 27: 3459–3464.
[10]Chan TY, Partin AW, Walsh PC, Epstein JI: Prognostic significance of Gleason score 3+4 versus
Gleason score 4+3 tumor at radical prostatectomy. Urology 2000; 56: 823–827.
[11]EpsteinJI, AllsbrookWCJr, AminMB, EgevadLL.The 2005 International Society of Urological
Pathology(ISUP) Consensus Conference on Gleason grading of prostatic carcinoma. AmJSurg Pathol
2005;29:1228–42.
[12] Kang DI, Jang TL, Jeong J ,et al.: Pathological findings following radical prostatectomy in patients
who are candidates for active surveillance: impact of varying PSA levels. Asian J Androl 2011; 13: 838–
841.
[13] Moussa AS, Li J, Soriano M, Klein EA, Dong F, Jones JS: Prostate biopsy clinical and pathological
variables that predict significant grading changes in patients with intermediate and high-grade prostate
cancer. BJU Int 2009; 103: 43–48.
[14] Freedland SJ, Kane CJ, Amling CL, Aronson WJ, Terris MK, Presti JC Jr: Upgrading and
downgrading of prostate needle biopsy specimens: risk factors and clinical implications. Urology 2007;
69: 495–499.
[15] Tilki D, Schlenker B, John M ,et al: Clinical and pathologic predictors of Gleason sum upgrading in
patients after radical prostatectomy: results from a single institution series. Urol Oncol 2011; 29: 508–
514.
[16] Oh JJ, Hong SK, Lee JK ,et al. Prostate-specific antigen vs prostate-specific antigen density as a
predictor of upgrading in men diagnosed with Gleason 6 prostate cancer by contemporary multicore
prostate biopsy. BJU Int 2012; 110: E494–9
[17] Kundu SD, Roehl KA, Yu X, Antenor JA, Suarez BK, Catalona WJ. Prostate specific antigen density
correlates with features of prostate cancer aggressiveness. J Urol 2007;177:505–9.
[18]Wong LM, Neal DE, Johnston RB ,et al. International multicentre study examining selection criteria
for active surveillance in men undergoing radical prostatectomy. Br J Cancer 2012; 107: 1467–73
[19] Smaldone MC, Cowan JE, Carroll PR, Davies BJ. Eligibility for active surveillance and pathological
11
outcomes for men undergoing radical prostatectomy in a large, community based cohort. J Urol 2010;
183: 138–43
[20]Villa L, Salonia A, Capitanio U, et al. The number of cores at first biopsy may suggest the need for a
confirmatory biopsy in patients eligible for active surveillance- implication for clinical decision making in
the real-life setting. Urology 2014;84:634–41.
[21]Bul M, Zhu X,Valdagni R, et al. Active surveillance for low-risk prostate cancer worldwide: the
PRIAS study. Eur Urol 2013;63:597–603.
[22] Freedland SJ , Isaacs WB , Platz EA, 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
[23]Dong F, Jones JS, Stephenson AJ, Magi-Galluzzi C, Reuther AM, Klein EA. Prostate cancer volume
at biopsy predicts clinically significant upgrading. J Urol 2008;179: 896–900.
[24]Freedland SJ, Isaacs WB, Mangold LA, et al. Stronger association between obesity and biochemical
progression
after
radical
prostatectomy
among
men
treated
in
the
last
10
years.ClinCancerRes2005;11:2883–8.
[25]Efstathiou JA, Chen MH, Renshaw AA, Loffredo MJ, D'Amico AV. Influence of body mass index on
prostate-specific antigen failure after androgen suppression and radiation therapy for localized prostate
cancer. Cancer2007;109:1493–8.
[26]Busch J, Magheli A, Leva N, et al. Higher rates of upgrading and upstaging in older patients
undergoing radical prostatectomy and qualifying for active surveillance.BJU Int. 2014 Oct;114(4):517-21.
[27] Iremashvili V, Pelaez L, Manoharan M, Jorda M, Rosenberg DL, Soloway MS: Pathologic prostate
cancer characteristics in patients eligible for active surveillance: a head-to-head comparison of
contemporary protocols. Eur Urol 2012; 62: 462.
[28] Cooperberg MR, Carroll PR, Klotz L: Active surveillance for prostate cancer: progress and promise.
J Clin Oncol 2011; 29: 3669.
[29]. Freedland SJ, Kane CJ, Amling CL ,et al.: Upgrading and downgrading of prostate needle biopsy
specimens: risk factors and clinical implications. Urology 2007; 69: 495.
[30]. 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.