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Table of Contents
ORIGINAL ARTICLE
Year : 2019  |  Volume : 30  |  Issue : 6  |  Page : 255-261

Smaller Prostate Volume is Associated with Adverse Pathological Features and Biochemical Recurrence after Radical Prostatectomy


Department of Urology, Texas Tech University Health Sciences Center, Lubbock, Texas, USA

Date of Submission01-May-2019
Date of Decision12-Jun-2019
Date of Acceptance26-Jun-2019
Date of Web Publication23-Dec-2019

Correspondence Address:
Dr. Pranav Sharma
Department of Urology, Texas Tech University Health Sciences Center, 3601 4th Street Stop 7260, Lubbock, Texas 79430
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/UROS.UROS_28_19

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  Abstract 


Introduction: The relationship between prostate cancer (PCa) and benign prostatic hyperplasia is unclear. Reduction in androgenicity and lower intraprostatic growth factor concentrations in smaller prostates may serve a more ideal environment for the development of aggressive tumors. We determined if prostate volume was associated with adverse pathological features, tumor volume, and biochemical recurrence (BCR) in men undergoing radical prostatectomy (RP) for PCa. Materials and Methods: We retrospectively identified 192 men who underwent RP at our institution for PCa from 2010 to 2016 years. Prostate volume was based on RP specimen weight, and cumulative tumor volume was calculated. Means were compared with one-way ANOVA test and proportions with Chi-square analysis. Multivariate logistic regression was performed to determine independent predictors of BCR after RP. Results: Patients with prostate volume >60 g were less likely to have high-risk PCa (Gleason grade group >4) (7.1% vs. 13.4%; P = 0.042), node-positive disease (7.1% vs. 13.4%, P = 0.042), and BCR (10.7% vs. 25.0%, P = 0.002) after surgery. Linear regression showed an inverse relationship between prostate and tumor volume (R = 0.267; P < 0.05). On multivariate logistic regression, prostate volume >30 g (odds ratio [OR]: 0.21, 95% confidence interval [CI]: 0.09–0.88; P = 0.015) and >60 g (OR: 0.14, 95% CI: 0.03–0.74; P = 0.002) were independent predictors of reduced BCR at mean follow-up of 24 months.Conclusions: Smaller prostate volume was associated with adverse pathological features, increased tumor volume, higher incidence of pathological node-positive disease, and increased rates of BCR. Prostate volume should be considered as a prognostic feature when counseling patients with both elevated prostate-specific antigen and newly diagnosed PCa.

Keywords: Adenocarcinoma, pathological features, prostate cancer, prostate volume, radical prostatectomy, tumor volume


How to cite this article:
Buie J, De Riese W, Sharma P. Smaller Prostate Volume is Associated with Adverse Pathological Features and Biochemical Recurrence after Radical Prostatectomy. Urol Sci 2019;30:255-61

How to cite this URL:
Buie J, De Riese W, Sharma P. Smaller Prostate Volume is Associated with Adverse Pathological Features and Biochemical Recurrence after Radical Prostatectomy. Urol Sci [serial online] 2019 [cited 2020 Feb 26];30:255-61. Available from: http://www.e-urol-sci.com/text.asp?2019/30/6/255/273875




  Introduction Top


Benign prostatic hyperplasia (BPH) and prostate cancer (PCa) are two of the most common diagnoses in elderly men, but little is known with regard to the interaction between both diseases.[1] While almost 70% of men develop BPH after the 7th decade of life, PCa also remains one of the most commonly diagnosed malignancies within this same age group.[2] In addition, both pathologies increase in an age-dependent fashion and are influenced by hormone-dependent growth.[3] Published studies have offered conflicting results and theories on the potential relationship between prostate size and PCa severity.

Some studies indicate that smaller prostate gland volume is a negative prognostic feature for PCa.[4] There are several possible explanations. One theory could be a marked reduction in androgenicity and lower overall intraprostatic growth factor concentrations in smaller prostates serving as a more ideal environment for the development of aggressive tumors.[5] Smaller prostates would produce less dihydrotestosterone, which would result in a more hostile environment for tumors to develop.[6] Aggressive prostate tumors may also suppress the production of testosterone, resulting in smaller prostate size.[7] Another theory could be loss of peripheral zone volume in larger prostates secondary to expansion of the transitional zone, resulting in peripheral zone gland destruction and loss.[8] PCas that arise in the transitional zone are more commonly well-differentiated and lower grade.[9] It is also possible that men with larger prostates had their tumors detected at an earlier stage or grade due to prostate-specific antigen (PSA)-driven biopsies, resulting from PSA elevation secondary to BPH (i.e., lead time bias).[10] This suggests that large prostates are more likely to be biopsied, because of an elevated PSA value resulting from benign elements of the gland and not from a significant malignancy.[11]

In this study, we determined if the prostate volume was associated with adverse pathological features (including Gleason grade group and nodal status), tumor volume, and biochemical recurrence (BCR) in men undergoing radical prostatectomy (RP) for PCa.


  Materials and Methods Top


Data collection

After Institutional Review Board Approval (TTUHSC IRB#: L17-050), we retrospectively identified 192 male patients with primary adenocarcinoma of the prostate who underwent RP with or without pelvic lymph node dissection (PLND) at out institution (Texas Tech University Health Sciences Center) between January 2010 and December 2016 with curative intent. Pathology was confirmed by central histopathological review of prostate core needle biopsies and the RP specimen. We excluded patients with nonadenocarcinoma primary of the prostate or metastatic disease to the prostate, patients with clinical metastatic PCa (confirmed through pathological or radiographic imaging), patients who received prior hormone manipulation with androgen deprivation therapy (ADT) (including 5α-reductase inhibitors) due to its impact on prostate volume, patients who had a prior transurethral resection of the prostate or photoselective vaporization (i.e., GreenLight) laser prostatectomy, or patients who received prior pelvic radiation therapy (XRT).

Sociodemographics and comorbidity indicators (Charlson Comorbidity Index) were collected and abstracted from the initial urology clinic visit. The American Society of Anesthesiologists score was assessed at the time of RP by the covering anesthetist. PSA values were abstracted and recorded based on the most recent serum levels prior to surgery, and PSA density was calculated using the recorded prostate volume from the most recent transrectal ultrasound (TRUS).

The weight of the prostate gland from the RP specimen was used as a surrogate for prostate gland volume in our study given its validated proven accuracy.[12] Tumor volume was calculated using the ellipsoid estimation method (= k [π/6] × length × width × thickness) as described by Noguchi et al.,[13] as it appears to be the most suitable for estimating tumor volume in PCas.[14]

Clinical management and follow-up

All prostate biopsies were performed under TRUS guidance using 6-, 12-, or 14-core templates. We did not routinely use multiparametric magnetic resonance imaging (MRI) of the prostate gland, or MRI/ultrasonography fusion-guided prostate biopsies with lesion targeting to direct the diagnosis and potentially avoid clinical understaging. The surgical approach to RP was dependent on surgeon comfort. A concurrent PLND was performed during RP if the predicated probability of nodal metastases was >2% based on nomograms per the PCa National Comprehensive Cancer Network (NCCN) guidelines.[15]

The length of urethral catheterization was surgeon dependent. Complications were captured through retrospective chart review of the patient's postoperative course (i.e., progress notes and discharge summaries), and subsequent clinic visits up to 90 days after RP. The Clavien-Dindo classification was used to categorize 30- and 90-day complications.

Serum PSA levels were drawn initially at 4–6 weeks after RP, and then, postoperatively, every 3 months for the 1st year, every 6 months during the 2nd and 3rd year, and yearly thereafter. Early salvage pelvic XRT is preferred at our institution over adjuvant XRT in patients with high risk, adverse pathological features (including positive surgical margins [PSM], seminal vesicle invasion [SVI], and extracapsular extension [ECE]); and similarly, early salvage ADT is preferred at our institution over adjuvant ADT in patients with pathological node-positive disease.

Statistical analysis

Our primary endpoint was the development of a BCR (defined as a serum PSA value ≥0.2 ng/ml in two consecutive measurements) postoperatively during the follow-up. Secondary endpoints included incidence of adverse pathological characteristics (ECE, PSM, SVI, lymphovascular invasion [LVI], and higher pathological Gleason grade group) based on the RP specimen, estimated tumor volume, and the incidence of pathological node-positive disease.

Continuous variables were reported as means and standard deviations (SDs), and categorical variables were reported as frequency counts and percentages. Prostate volume was stratified into <30 g, 30–60 g, and >60 g based on predetermined cutoff points. We used the one-way ANOVA test to determine any differences in continuous variables and the Chi-square test for categorical variables. Multivariate logistic regression analysis was performed to evaluate the association of reported variables with our primary endpoint, and odds ratio (OR) with 95% confidence intervals (CIs) were reported.

Statistical analysis was performed with the Statistical Package for the Social Sciences software package (IBM Corporation, Armonk, NY, USA). All tests were two-sided, with P < 0.05 considered to be statistically significant.


  Results Top


Relevant sociodemographics, clinical, and disease-specific characteristics of our study population stratified by prostate volume are shown in [Table 1], intra- and post-operative characteristics are shown in [Table 2], and pathological characteristics are shown in [Table 3]. The mean PSA was 10.2 ng/mL, and PSA density was 0.33 ng/mL/cc with 40% of patients having clinical low-risk disease per NCCN guidelines.[15] Due to the late adoption of robotic surgery at our institution, the majority of radical prostatectomies were performed open through a retropubic approach (63%). Overall, the 30-day complication rate was 29.7%, and the 90-day complication rate was also 29.7%. The incidence of high-grade (Clavien > III) complications was 0% and 9.4% at 30- and 90-day after surgery, respectively. Mean prostate volume based on the weight of the RP specimen was 46.5 g, and mean tumor volume was 6.6 cc. Only 57.3% of patients had organ-confined disease on the final pathology with 12.5% of patients having the node-positive disease after PLND.
Table 1: Patient sociodemographics, clinical, and disease-specific characteristics

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Table 2: Intraoperative and postoperative characteristics

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Table 3: Pathological characteristics

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Patients with a prostate volume >60 g were more likely to be older (mean age: 66.1 vs. 61.4 years; P = 0.007) with longer operative times (mean time: 272 vs. 229 min; P = 0.002) and more intraoperative blood loss (mean estimated blood loss: 1119 vs. 671 cc; P = 0.010). PSA density was also significantly higher in patients with a prostate volume <30 g compared to patients with a prostate volume >60 g (0.50 vs. 0.30 ng/mL/cc; P < 0.05).

On multivariate analysis, larger prostate volume (based on the prostate weight) as a continuous variable was associated with less PSM (OR: 0.97, 95% CI: 0.95–0.98; P = 0.003), less SVI (OR: 0.92, 95% CI: 0.88–0.96; P < 0.05), less ECE (OR: 0.98, 95% CI: 0.96–0.99; P = 0.038), and less LVI (OR: 0.93, 95% CI: 0.90–0.96; P < 0.05) when accounting for patient age, race, body mass index, comorbidities, prebiopsy PSA, clinical tumor stage based on digital rectal examination (DRE), and clinical Gleason grade group. Patients with prostate volume >60 g were also less likely to have high-risk PCa (Gleason grade group >4) (7.1% vs. 13.4%; P = 0.042) and node-positive disease (7.1% vs. 13.4%, P = 0.042). Linear regression showed an inverse relationship between prostate and tumor volume (R = 0.267; P < 0.05) [Figure 1].
Figure 1: Prostate versus tumor volume

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BCR (defined as a serum PSA value of ≥0.2 ng/ml in two consecutive measurements) was experienced by 44 patients (22.9%) during a mean follow-up of 24 months). Patients with prostate volume >60 g were less likely to have BCR (10.7% vs. 25.0%; P = 0.002) after surgery. On multivariate logistic regression, prostate volume >30 g (OR: 0.21, 95% CI: 0.09–0.88; P = 0.015) and >60 g (OR: 0.14, 95% CI: 0.03–0.74; P = 0.002) were independent predictors of reduced BCR [Table 4]. Pathological Gleason grade group, tumor stage, nodal stage, and surgical margin status were also independently associated with BCR. Increasing PSA density was associated with adverse pathological features and BCR on univariate analysis due to inverse collinearity with prostate volume, but this significance was lost for the primary and secondary endpoints after adjusting and controlling for prostate volume on multivariate analysis.
Table 4: Predictors of biochemical recurrence

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Mean time to PSA recurrence was 15.3 months (SD: 17.8 months), and mean PSA at the time of salvage therapy was 1.0 ng/mL (SD: 0.99 ng/mL). Early salvage pelvic XRT was utilized in 39 patients (20.3%) for BCR and ADT was initiated in 19 patients (9.9%). Only 12 patients (6.3%) developed clinical metastatic disease (predominantly in the bone) during available follow-up, and 4 patients (2.1%) died of PCa.


  Discussion Top


In this study, we demonstrated that in our cohort of men undergoing definitive surgical resection with RP for the treatment of nonmetastatic, primary prostatic adenocarcinoma, and smaller prostate volume was associated with more aggressive pathological features, a higher incidence of node-positive disease, and increased rates of BCR.

Published studies have offered conflicting results and theories on the potential relationship between prostate size and PCa severity. Freedland et al. studied a cohort of 1602 men that were treated with RP between 1988 and 2003 years.[6] The authors found that prostate weight inversely correlated with the presence of PSM, ECE, and high-grade disease (defined as Gleason score >7). This translated to a lower biochemical progression rate in men with larger prostates (>100 g) over a median follow-up of 34 months. These results have also been reproduced using prostate volume based on TRUS as a surrogate for prostate size. Kassouf et al. reported an association between patients with a larger prostate volume (>50 cc) and a reduced incidence of tumor upgrading on RP specimens compared to their preoperative biopsy report as well as a smaller tumor volume although this difference did not reach statistical significance (P = 0.06).[9] Most recently, Hong et al. correlated smaller prostate size based on MRI-measured prostate volume with higher pathologic Gleason score, ECE, and PSMs on univariate analysis,[16] and de Gorski et al. found that the detection rate of clinically significant PCa (>1 core of Gleason 3 + 4 = 7 or 3 + 3 = 6 with >4 mm cancer core length) by MRI/TRUS fusion-guided biopsy was 77% for prostate glands <30 g, but only 34% for prostate glands >55 g.[17] Conversely, Kulkarni et al. observed no association between gland size and Gleason score on RP specimens.[18] Although larger prostates were more likely to have lower biopsy grade cancers, TRUS volume was not associated with Gleason score upgrading after RP, and this initial association was attributed to sampling error. The authors also argued that smaller prostates increased the sensitivity of detecting high-grade tumors at biopsy but not high-grade tumors at the time of RP. D'Amico et al., however, reported a 7.5-fold increased odds of high-grade disease among men with prostates <20 g versus ≥100 g, and this relationship remained significant even after excluding men with PSA-detected tumors (clinical stage T1c) and examining only men with abnormal DREs.[19]

One theory regarding the association between prostate size and adverse pathological features could be a marked reduction in androgenicity and lower overall intraprostatic growth factor concentrations in smaller prostates serving as a more ideal environment for the development of aggressive tumors.[5] Aggressive prostate tumors may suppress the production of testosterone, resulting in smaller prostate size.[7] Another theory could be loss of peripheral zone volume in larger prostates secondary to expansion of the transitional zone, resulting in peripheral zone gland destruction and loss.[8] It is also possible that men with larger prostates had their tumors detected earlier due to PSA-driven biopsies resulting from PSA elevation secondary to BPH (i.e., lead time bias).[10] This suggests that large prostates are more likely to be biopsied due to an elevated PSA value resulting from benign elements of the gland and not from a significant cancer.[11]

In our study, patients with smaller prostates were more likely to experience BCR, with a prostate volume >30 and >60 g being independent predictors of reduced BCR. Hong et al. also observed this relationship, noting that larger prostate volume at RP was associated with lower risk of BCR. Moschini et al. also noted this association although it was only significant in men with intermediate-risk PCa defined by the D'amico risk classification system.[20]

There are several potential limitations with our study. It is retrospective, so all confounding variables may not be accounted for. There was no standardization with regard to indication for prostate biopsy based on PSA, number/location of cores taken, and surgical treatment favored over radiation, or active surveillance. We did not routinely use prebiopsy markers or MRI to guide management, so there was risk of clinical understaging. PLND was not performed uniformly across out study population, so the finding of increased rate of lymph node involvement with smaller prostate size would be difficult to interpret, and further evaluation would be necessary. Finally, the cumulative tumor volume was calculated from the RP specimen and may be underestimated in patients with significant extraprostatic disease.


  Conclusions Top


Smaller prostate volume was associated with adverse pathological features, increased tumor volume, higher incidence of pathological node-positive disease, and increased rates of BCR. Although the pathophysiology behind this phenomenon is still not well understood, further larger scale prospective studies are necessary to validate its impact and understand the mechanism. In addition, prostate size should be considered as a prognostic feature in counseling patients with both elevated PSA and newly diagnosed PCa.

Acknowledgments

The authors would like to acknowledge the contribution of the Texas Tech University Health Sciences Center Clinical Research Institute for their assistance with this research.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Kulkarni GS, Lockwood G, Evans A, Toi A, Trachtenberg J, Jewett MA, et al. Clinical predictors of Gleason score upgrading: Implications for patients considering watchful waiting, active surveillance, or brachytherapy. Cancer 2007;109:2432-8.  Back to cited text no. 18
    
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    Figures

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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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