Tumor Volume Associated with Recurrence in Prostate Cancer Patients with Seminal Vesicle Invasion

doi:10.4236/oju.2012.223033

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Open Journal of Urology, 2012, 2, 183-187

http://dx.doi.org/10.4236/oju.2012.223033 Published Online October 2012 (http://www.SciRP.org/journal/oju)

Tumor Volume Associated with Recurrence in Prostate

Cancer Patients with Seminal Vesicle Invasion

Paul H. Johnston1*, Timothy A. Masterson1, Liang Cheng2, Michael O. Koch1

1Department of Urology, Indiana University Medical Center, Indianapolis, USA

2Department of Pathology and Laboratory Medicine, Indiana University Medical Center, Indianapolis, USA

Email: *[email protected]

Received July 14, 2012; revised August 31, 2012; accepted September 12, 2012

ABSTRACT

Objectives: To examine predictors of progression-free survival in men with seminal vesicle invasion (SVI) following

radical prostatectomy (RP) for clinically localized prostate cancer. Methods and Materials: Between 1999 and 2009,

1383 men underwent RP at Indiana University. Among them, 115 men were identified with SVI. Disease progression

was defined by a rise in PSA ≥ 0.2 ng/ml, receipt of salvage therapy, progression to metastatic disease, or death. After

excluding 13 patients for receiving adjuvant therapy, 102 were stratified according to surgical margin (SM) and lymph

node (LN) status for Kaplan-Meier analysis of disease progression. Cox proportional hazards analyses of biochemical

progression-free survival were undertaken with respect to margin status, pre-operative prostate specific antigen (PSA),

tumor volume, age, and post-operative Gleason sum. Stem and leaf plot was undertaken for tumor volume by bio-

chemical PFS. Results: Mean age was 61 years, median Gleason sum was 7, mean tumor volume was 9.7 ml, and mean

pre-operative PSA was 13.6 ng/ml. Mean time to disease progression was 17 months. Mean follow-up was 37 months.

Kaplan-Meier analysis revealed statistically insignificant differences in progression-free survival stratified by SM and

LN status (p = 0.12). Cox univariate analyses revealed tumor volume to be a statistically significant predictor of pro-

gression free survival (p = 0.02). Stem and Leaf plot revealed tumor volume to be statistically significantly larger in

patients who experienced biochemical recurrence, compared to those who did not. Conclusion: Tumor volume was

associated progression-free survival in this cohort of SVI patients, while pathologic Gleason sum, PSA, margin and

nodal status were not.

Keywords: Prostate; Neoplasm; Prostatectomy; Seminal Vesicle Invasion; Recurrence

1. Introduction

Seminal vesicle invasion (SVI) is identified in approxi-

mately 3% of prostatectomy specimens in the contempo-

rary prostate-specific antigen (PSA) era [1]. While in-

creased tumor volume has not been shown to be an inde-

pendent predictor of survival on multivariate analysis of

robust radical prostatectomy (RP) data sets, these data

sets were largely comprised of patients without SVI, and

these data sets did not examine the prognostic signifi-

cance of tumor volume with specific reference to SVI

patients [2,3]. Other studies have sought clarification of

the pathologic factors predictive of survival in patients

with seminal vesicle invasion specifically,yet overlooked

the prognostic value of tumor volume [1,4-8]. While tu-

mor volume has been shown to be associated with SVI in

general [9], Epstein showed tumor volume as not predic-

tive of survival in SVI patients [10]. Conversely, Sofer et

al. demonstrated tumor volume greater than 20% to be

predictive of PSA failure in 106 prostatectomy patients

with SVI and negative lymph nodes [11]. Overall, there

remains equipoise with respect to tumor volume’s prog-

nostic role in SVI patients, and with respect to which

clinico-pathologic parameters carry prognostic signifi-

cance for SVI patients in general [7]. This paper seeks to

further explore the clinico-pathologic parameters predic-

tive of progression-free survival (PFS) in patients with

SVI, with specific reference to tumor volume.

2. Materials and Methods

Between 1999 and 2009, 1383 men underwent RP, either

open or robotic, at Indiana University Hospital. After

obtaining IRB approval, age at prostatectomy, pathologic

Gleason sum, pre-operative PSA, tumor volume, seminal

vesicle invasion, surgical margin status (SM+/−), and

lymph node status (LN+/−) were analysed retrospectively.

Where nodal dissection was performed, all nodal tissue

bordered by the pelvic sidewall, Cooper’s ligament, the

external iliac vein, and the hypogastric vessels was re-

*Corresponding author.

P. H. JOHNSTON ET AL.

184

moved. Patients were excluded from analysis for receipt

of adjuvant treatment.

Specimen processing occurred using the whole mount

method for pathological evaluation, as described previ-

ously [12,13]. After surgical extirpation, each prostate

was weighed (g), measured, inked and fixed in formalin.

After fixation, the apex and the base of the prostate were

amputated and sectioned in the vertical, parasagittal

plane at 3 - 5 mm intervals, assessing for tumor involve-

ment. The seminal vesicles were amputated parallel to

the base of the prostate, sectioned parallel to the junction

of the prostate at 3 mm intervals, and embedded entirely

for histologic examination. The prostate was then sec-

tioned perpendicularly in 5 mm increments along its long

axis from the apex to the base of the gland. All slides

were reviewed by a single pathologist (LC). Pathological

staging of each specimen was undertaken using the 2010

TNM staging system. Tumor grade was assigned ac-

cording to 2005 ISUP classification system [14]. Tumor

volume was estimated using the grid method [15], and

maximum tumor diameter was recorded using the great-

est cross-sectional dimension (cm) of the dominant tumor.

Using analysis of variance, all 102 SVI patients were

stratified into SM+ and SM− groups, and LN+ and LN-

groups, and analyzed for differences in age at RP, patho-

logic Gleason sum (trichotomous variable), pre-operative

PSA, tumor volume, and prostate weight. This same

grouping was then used forKaplan-Meier survival analy-

sis, with respect to PFS.Additionally, Cox proportional

hazards analyses of PFS were undertaken for the 83 pa-

tients with respect to margin status, pre-operative PSA,

tumor volume, age, and pathologic Gleason sum. Finally,

stem and leaf plot was undertaken for tumor volume by

biochemical PFS. Disease progression was defined by a

rise in the PSA ≥ 0.2 ng/mL, receipt of salvage therapy,

development of distant metastases, or death from prostate

cancer. Statistical calculations were performed using

STATA statistical software (College Station, Texas), and

a p-value of less than 0.05 was chosen as significant.

3. Results

From the original cohort of 1383 patients, 115 (8.3%)

were identified with SVI. After exclusion of 13 SVI pa-

tients for receipt of adjuvant therapy (7 received adjuvant

androgen deprivation and adjuvant chemotherapy, 3 re-

ceived adjuvant androgen deprivation only, and 3 re-

ceived adjuvant radiation), the remaining 102 SVI pa-

tients were analysed, and their clinico-pathologic char-

acteristics are seen in Table 1. Mean age was 61 years,

median Gleason sum was 7, mean tumor volume was 9.7

mL, and mean pre-operative PSA was 13.6 ng/mL. Mean

time to disease progression was 17 months. Mean follow-

up was 37 months, 81.3% had a pelvic lymph node dis-

section at time of prostatectomy, and the margin-positive

rate was 43%. 56 (54.9%) patients experienced bioche-

mical recurrence, 43 (42.2%) patients were without evi-

dence of biochemical recurrence at last follow-up, and 3

(2.9%) patients received salvage radiation and were

deemed to have recurred.

Of the 102 patients analysed, 54 (52.9%) had isolated

SVI without positive surgical margins (SM−) or pathol-

ogically confirmed lymph node involvement (LN−). Of

the remaining 48 (47.1%) patients with SVI, 38 (37.3%)

patients had specimen-confined disease with positive sur-

gical margins (SM+), and 10 (9.8%) patients had pathol-

ogically confirmed lymph node involvement (LN+).

Following patient stratification into these three subgro-

ups, Kaplan-Meier analysis with respect to recurrence-

free survival revealed non-statistically significant differ-

ences in recurrence-free survival (p = 0.12). When as-

sessing for predictors of biochemical failure in all pa-

tients, univariate and multivariate analyses were per-

formed (Table 2). Tumor volume proved significant on

univariate analysis. Stem and leaf plot revealed tumor

volume to be statistically significantly larger in patients

who experienced biochemical recurrence (BCR), com-

pared to those who did not (p < 0.001).

Table 1. Clinico-pathologic characteristics of 102 patients with SVI.

Parameter All Patients (n = 102)SM−/LN− (n = 54)SM+/LN− (n = 38) LN+ (n = 10) p value

Mean Age at Prostatectomy 61 (44 - 74) 61 (44 - 74) 62 (45 - 73) 63 (53 - 74) 0.75

Gleason Sum (%)

≤6 3 (3) 67 (66) 2 (4) 1 (3) 0 (0)

7 30 (31) 42 (78) 19 (50) 6 (60)

≥8 10 (18) 18 (47) 4 (40)

0.009

Mean Tumor Volume (mL) 9.7 (0.2 - 38.0) 5.7 (0.2 - 32) 14.2 (1.2 - 38) 14.4 (3.6 - 29.3) <0.0001

Mean Pre-op PSA 13.6 9.8 (2.9 - 39.9) 18.5 (3.8 - 150) 14.8 (6.5 - 31.6) 0.06

Mean Prostate Weight (g) 44.5 (20 - 100) 43 (25 - 95) 44.4 (20 - 76) 52 (26 - 100) 0.21

P. H. JOHNSTON ET AL. 185

Table 2. Cox proportional hazards analyses of clinico-pathologic 83 patients with SVI.

Analysis Parameter Hazard Ratio 95% CI p Value

Univariate Age 1.04 0.99, 1.1 0.13

PSA 1.00 0.99, 1.0 0.44

Tumor Volume 1.04 1.0, 1.1 0.02

Gleason Sum (<7 vs. 7 vs. 8 or more) 2.1 0.99, 4.5 0.05

SM 1.19 0.55, 2.6 0.65

Multivariate Age 1.03 0.97, 1.1 0.39

PSA 1.0 0.98, 1.0 0.73

Tumor Volume 1.08 0.99, 1.2 0.07

Gleason Sum (>7 vs. 7 vs. 8 or more) 2.42 0.95, 6.1 0.06

SM 0.63 0.21, 1.9 0.40

4. Comment

In this retrospective cohort of SVI patients, tumor vol-

ume was associated with PFS on univariate analysis,

while margin status, age, pathologic Gleason sum and

pre-operative PSA were not. Stem and leaf plot confirms

smaller tumor volume to be associated with longer bio-

chemical progression-free survival in SVI patients. Addi-

tionally, Kaplan-Meier analysis failed to demonstrate

survival differences for SVI patients according to margin

and node status.

Epstein et al. [16] defined SVI as penetration of the

muscular wall of the SVI as opposed to peri-vesicle in-

volvement of tumor, based upon differential survival for

these two pathologic findings. Furthermore, they sug-

gested that the staging definition of SVI need specify

involvement of the distal, free end of the vesicle, once

again on the basis of differential survival. This sugges-

tion was supported by Debras et al. [17], who confirmed

a worse prognosis for such patients. SVI has been further

subclassified, although this subclassification does not

affect prognosis in a statistically significant manner [18].

This study reveals an association between tumor vol-

ume and recurrence for SVI patients. This association

can help clinicians prognosticate biochemical recurrence

post-prostatectomy, but further research need be done

before a pre-operative MRI revealing a large tumor vol-

ume in a patient known to harbour SVI would cancel

surgery.

In addition to contributing to the relatively sparse lit-

erature on the predictive role of tumor volume in patients

with SVI, this study sought to further clarify the predic-

tive role of Gleason sum for such patients. Gleason sum

is a crucial prognostic indicator of biochemical recur-

rence for RP patients in general [19], and for SVI pa-

tients this has largely been the case [1,4-6,10]. In reveal-

ing differences in Gleason sum on Analysis of Variance

of 102 SVI patients stratified by node and margin status,

despite no evidence of survival differences upon Kap-

lan-Meier analysis of these same strata, our study fail-

sadds to add further credence to Gleason sum as a pre-

dictor of survival in SVI patients, but does not necessar-

ily support the small body of work which suggests Glea-

son sum is not predictive of survival in SVI patients [8,11].

Our study offers no clarification with respect to the

predictive role of positive surgical margins for SVI pa-

tients. Generally speaking, a positive surgical margin at

the time of RP is a negative prognostic indicator [20].

Several papers focusing on PFS in patients with SVI and

negative lymph nodes have demonstrated a prognostic

value to margin status under these circumstances [1,5,6,

8,10], while others have shown no such value [4,11]. Our

work further confuses the issue, as a predictive role for

margin status was not demonstrated on Cox multivariate

analysis of all RP patients, nor was a survival difference

demonstrated in the Kaplan-Meier analysis of SVI pa-

tients in particular.

In much the same manner, this study does not improve

upon the controversy surrounding pre-operative PSA’s

predictive role for SVI patients. PSA is a well-known

prognostic indicator of biochemical recurrence for pro-

statectomy patients in general [19] and several publica-

tions have shown a predictive value to pre-operative PSA

where SVI patients have negative lymph nodes [4,6,11].

Conversely, others demonstrate no predictive value for

such patients [1,5,8,10]. In failing to demonstrate differ-

ential PSA values for SVI patients stratified by node and

margins status, we are unable to comment on PSA’s role

in the lack of survival difference seen on Kaplan-Meier

analysis of these same strata of SVI patients. It’s worth

noting the p-value for in this case was close to signifi-

cance, and it may be that our study size was simply

P. H. JOHNSTON ET AL.

186

underpowered to reveal statistical significance.

The authors acknowledge this study’s retrospective

nature is subject to the selection bias inherent in its de-

sign. Furthermore, pelvic lymph node dissection was not

undertaken in 18.6% patients. While nodal dissections in

all patients would be advantageous from a statistical

analysis point-of-view, the finding of pathologic SVI was

not routinely anticipated pre-operatively, thus the deci-

sion to forgo nodal dissection in a subset of the cohort is

reflective of real-world oncologic decision-making. It

must also be noted that a mean follow-up of 37 months is

relatively short for prostate cancer, although a mean time

to progression of 17 months suggests that the vast major-

ity of patients who were going to progress biochemically

had done so by the time mean follow-up was reached.

Furthermore, given the high-risk nature of SVI patients

as a whole, follow-up as observed in this study is likely

adequate for the endpoint of biochemical recurrence.

Finally, it is worth acknowledging that a more robust

data set of SVI patients would be helpful in further de-

lineating the role of tumor volume as a prognostic patho-

logic parameter [1].

5. Conclusion

This data set fails to demonstrate progression-free sur-

vival differences for men with SVI, according to surgical

margin and lymph node status. While there remains equi-

poise in this patient population with respect to which

clinico-pathologic parameters confer survival advantage,

this paper suggests lower tumor volume is advantageous

to patients with SVI at the time of RP.

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