Percent Tumor Involvement and Risk

of Biochemical Progression After Radical Prostatectomy

Edward N. Rampersaud, Leon Sun, Judd W. Moul, John Madden and Stephen J. Freedland*
From the Division of Urologic Surgery (ENR, LS, JWM, SJF), Duke Prostate Center, and Department of Pathology (JM, SJF), Duke
University Medical Center, and Urology Section, Durham Veteran Affairs Medical Center (SJF), Durham, North Carolina

Purpose: Percent tumor involvement has been associated with biochemical progression in organ confined disease, although
its role in predicting outcome in men with more advanced disease pathology is unclear. We hypothesized percent tumor
involvement may be a good correlate of outcome in all stages of prostate cancer.
Materials and Methods: We examined the association between percent tumor involvement in the radical prostatectomy
specimen and the outcome measures of pathological stage and biochemical progression using multivariate logistic regression
and Cox proportional hazards analysis, respectively, in 2,220 patients from the Duke Prostate Center radical prostatectomy
database.
Results: On multivariate analysis, percent tumor involvement significantly predicted the risk of positive margins (p ⬍0.001),
extracapsular extension (p ⬍0.001), seminal vesicle invasion (p ⬍0.001) and biochemical progression (HR 1.16, 95% CI
1.01–1.33, p ⫽ 0.035). The percent tumor involvement cut points of 5% or less, 6% to 20%, 21% to 50% and greater than 50%
significantly separated men in groups with differing biochemical progression risk (p ⬍0.001). In addition, these cut points
were further able to stratify men among those with organ confined margin negative disease (p ⬍0.001), either positive
margins or extracapsular extension (p ⬍0.001), and those with seminal vesicle invasion (p ⫽ 0.02).
Conclusions: Percent tumor involvement was a significant predictor of biochemical progression and was able to further
stratify men who were already assigned to narrowly defined pathological groups. If confirmed in other studies, percent tumor
involvement may enable the clinician to identify the high risk patient who stands to benefit the most from adjuvant therapy.

Key Words: prostatic neoplasms, prostatectomy, recurrence, disease progression

umor size is a well established prognostic factor in to visually accrue the percentage of each slide examined that

T many types of cancer. Its importance is recognized in

kidney cancer staging with tumors less than or equal
to 4 cm denoted T1 and those greater than 4 cm as T2
lesions.1 Likewise, percent tumor involvement (tumor size
as a percentage of prostate size) is also reflected in the
current form of TNM staging for prostate cancer. Specifically
tumors less than half of 1 lobe are T2a while those greater
than half of 1 lobe are T2b.2 An alternative measure to
percent tumor involvement is tumor volume, which has been
found in multiples studies to hold prognostic value in pros-
tate cancer.3,4 However, other studies have found contradic-
tory results.5 One major problem with measuring true tumor
volume is that it requires specialized procedures such as
whole mounting and computerized digitization that are
time-consuming and require additional equipment and,
therefore, it is not routinely reported by pathologists, at
least at our institution. On the contrary, percent tumor
involvement is reported at our institution, and is relatively
easily provided. This measure simply requires pathologists
Submitted for publication December 13, 2007.
Supported by the Department of Veteran’s Affairs, Department of
Defense and the American Urological Association Foundation/As-
tellas Rising Star in Urology Award.
* Correspondence and requests for reprints: Division of Urology,
Department of Surgery, Box 2626 Duke University Medical Center,
Durham, North Carolina 27710 (telephone: 919-668-8361; e-mail:
steve.freedland@duke.edu).
contains tumor and provide an average. This generally adds
a minimal amount of review time to each case. Furthermore,
percent tumor involvement has been demonstrated to be
associated with biochemical progression in organ confined
disease,6,7 although its role in predicting outcome among
men with more advanced disease pathology has not been
well studied. We hypothesized that percent tumor involve-
ment may be a good correlate of outcome in all stages of
prostate cancer.
MATERIALS AND METHODS
Patient Population
After obtaining institutional review board approval, data
from patients treated with radical prostatectomy between
1990 and 2006 were abstracted into the Duke Prostate Cen-
ter database. Of the 4,581 men in the Duke Prostate Center
radical prostatectomy database we excluded patients who
had received preoperative hormones, chemotherapy or radi-
ation. Patients with missing data for serum PSA, margin
status, capsular extension and percent tumor involvement
were excluded from analysis. This resulted in a study pop-
ulation of 2,220 patients.
The prostatectomy specimens were harvested in the op-
erating room, left and right sides inked with different colors,
weighed, and fixed in formaldehyde overnight at 4C. The
apex and the bladder neck margin were shaved and radially

0022-5347/08/1802-0571/0 571 Vol. 180, 571-576, August 2008

THE JOURNAL OF UROLOGY® Printed in U.S.A.
Copyright © 2008 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2008.04.017
572 BIOCHEMICAL PROGRESSION AFTER PROSTATECTOMY

sectioned to permit evaluation of the margin status parallel RESULTS

to the urethra. The remaining prostate was then sectioned
Demographics
perpendicular to the rectal surface at 3 to 4 mm intervals
The majority of patients were white, had clinical stage T1
and submitted entirely for microscopic evaluation. The tu-
disease, had PSA less than 10 ng/ml and had organ confined
mor involvement of each slide was estimated by the percent
disease on final pathological analysis (table 1).
of the slide consumed with tumor. Estimation of percent
tumor involvement for the entire prostate was accomplished
Predictors of Adverse Pathology
by summing each individual slide and then averaging the
To determine the significant independent predictors of adverse
results from all slides analyzed.
pathological findings after radical prostatectomy we used mul-
Biochemical progression was defined as any increase in
tivariate analysis and found that percent tumor involvement
PSA greater than the 0.2 ng/ml taken after the initial 1
significantly predicted the risk of positive surgical mar-
month postoperative period. Patients who underwent adju- gins (p ⬍0.001), extracapsular extension (p ⬍0.001) and
vant radiotherapy within 6 months after surgery for an seminal vesicle invasion (p ⬍0.001) (table 2). The only other
undetectable PSA were excluded from analysis. Among men factors which significantly predicted all 3 adverse patholog-
who did not have biochemical recurrence, mean and median ical features studied were PSA and pathological Gleason
followup was 5.5 (standard deviation 3.7) and 3.8 years sum.
(range 0 to 15.7), respectively. During that time 571 (25.7%)
men had recurrence. Predictors of Biochemical Progression
On multivariate analysis percent tumor involvement was a
significant predictor of biochemical progression (HR 1.16,
Statistical Analysis 95% CI 1.01–1.33, p ⫽ 0.035, table 3). In addition, the known
The distribution and association of percent tumor involve- prognostic factors of PSA, clinical stage, pathological grade
ment with other clinicopathological variables was evaluated and findings along with prostate weight were also signifi-
using the Mann-Whitney U or Kruskal-Wallis test when cantly associated with progression.
appropriate. PSA, percent tumor involvement and prostate
weight, after log transformation, were analyzed as continu- Determination of PTI Cut Points
ous variables. Race (black or nonblack), clinical stage (cT1, Given that percent tumor involvement significantly pre-
cT2 or cT3/4), pathological Gleason sum (less than 7, 7 and dicted all 3 pathological end points as well as progression,
greater than 7), surgical margins (positive or negative) ex-
tracapsular extension (positive or negative) and seminal TABLE 1. General demographics of men treated with radical
vesicle invasion (positive or negative) were all examined as prostatectomy in the Duke Prostate Center database
categorical variables. No. race (%):
The significant independent risk factors for the binary Black 330 (15.0)
pathological end points of positive surgical margins, extra- Nonblack 1,885 (85.0)
Age:
capsular extension and seminal vesicle invasion were deter- Mean (SD) 62.6 (7.43)
mined using a multivariate backwards stepwise logistic re- Median (IQR) 63.0 (57.6–68.1)
No. younger than 60 (%) 790 (35.6)
gression model. The variables considered for entry into the No. 60–69 (%) 1,058 (47.7)
model were percent tumor involvement, preoperative PSA, No. older than 69 (%) 371 (16.7)
No. clinical stage (%):
age, race, clinical stage, pathological Gleason sum, margin T1 1,558 (79.4)
status, seminal vesicle involvement, prostate weight and T2 386 (19.7)
year of surgery. The variable with the highest p value was T3/T4 19 (1.0)
Diagnosis PSA (ng/ml):
successively eliminated until only variables with a p ⬍0.1 Mean 9.46 (12.9)
were included. Similar analyses were performed to deter- Median 6.4 (4.6–9.6)
No. 4 or less (%) 376 (17.0)
mine the independent risk factors for biochemical progres- No. 4–10 (%) 1,328 (59.8)
sion using a Cox proportional hazards analysis. No. greater than 10 (%) 516 (23.2)
To determine the independent ability of the percent tu- No. biopsy Gleason (%):
Less than 7 1,518 (71.5)
mor involvement cut points to predict biochemical progres- 7 454 (21.4)
sion, we used log rank tests and a Cox proportional hazards Greater than 7 152 (7.2)
No. pathological Gleason (%):
model mutually adjusting for year of surgery, PSA, race, Less than 7 1,012 (45.7)
clinical stage, pathological Gleason sum, positive surgical 7 958 (43.2)
Greater than 7 246 (11.1)
margins, extracapsular extension and seminal vesicle inva- No. ECE (%):
sion. We tested for trend by entering the median percent Pos 639 (28.8)
tumor involvement of each percent tumor volume group as a Neg 1,581 (71.2)
No. SV invasion (%):
continuous term into the model and evaluated the coefficient Pos 196 (8.8)
by the Wald test. A total of 15 men had lymph node positive Neg 2,024 (91.2)
No. biochemical progression (%):
disease. When these men were included or excluded from Pos 571 (25.7)
analysis, the results did not materially change. Therefore, Neg 1,649 (74.3)
these patients were included and assigned the disease pa- No. PTI (%):
Less than 5 682 (30.7)
thology group corresponding to the findings from the pri- 6–20 989 (44.6)
mary prostatectomy specimen. All statistical analyses were 21–50 484 (21.8)
Greater than 50 65 (2.9)
performed using SPSS® 12.0 and STATA® 9.0.
 BIOCHEMICAL PROGRESSION AFTER PROSTATECTOMY 573

clinical and pathological characteristics including patholog-

TABLE 2. Multivariate logistic regression analysis of factors
predicting adverse pathological findings after ical Gleason sum, percent of tumor involvement cut points
radical prostatectomy remained significantly associated with progression for men
with organ confined margin negative disease (p trend ⫽
OR 95% CI p Value
0.006, fig. 2, A) and men with margin positive or extracap-
Pos surgical margins: sular extension (p trend ⫽ 0.01, fig. 2, B), but not among men
PTI 1.99 1.67–2.36 ⬍0.001
SV involvement 2.20 1.43–3.38 ⬍0.001 with seminal vesicle invasion (p trend ⫽ 0.80). For example,
ECE 2.89 2.23–3.73 ⬍0.001 among men with margin positive disease or extracapsular
Yr of surgery 1.15 1.11–1.20 ⬍0.001
Pathological Gleason greater than 7 1.90 1.28–2.83 0.001
extension the 5-year biochemical progression-free survival
Prostate wt 0.61 0.45–0.83 0.002 of men with 5% or less, 6% to 20%, 21% to 50% and greater
PSA 1.31 1.09–1.58 0.004 than 50% tumor involvement was 75% (95% CI 65– 83), 72%
Clinical stage T1/T2 0.69 0.52–0.91 0.010
Pathological Gleason 7 1.32 1.02–1.70 0.031 (95% CI 66 –77), 57% (95% CI 50 – 63) and 22% (95% CI
Nonblack 0.74 0.55–0.98 0.034 7– 43), respectively (p ⬍0.001).
ECE:
PTI 1.94 1.63–2.31 ⬍0.001
PSA 1.46 1.21–1.76 ⬍0.001 DISCUSSION
Pathological Gleason 7 1.79 1.38–2.33 ⬍0.001
Pathological Gleason greater than 7 3.26 2.16–4.93 ⬍0.001 Percent tumor involvement, an easily attained pathological
Margin positivity 2.96 2.29–3.82 ⬍0.001
SV involvement 2.29 1.45–3.63 ⬍0.001 characteristic, has been demonstrated to be associated with
Yr of surgery 0.90 0.87–0.94 ⬍0.001 biochemical progression in men with organ confined dis-
Prostate wt 0.61 0.45–0.83 0.002 ease.6 Percent tumor involvement has also been associated
Clinical stage T1/T2 1.40 1.06–1.86 0.018
SV invasion: with positive surgical margins and early biochemical pro-
PTI 2.60 1.84–3.69 ⬍0.001 gression following prostatectomy.8,9 We further defined the
ECE 2.34 1.50–3.66 ⬍0.001
Pathological Gleason 7 3.35 1.71–6.56 ⬍0.001
association between percent tumor involvement and bio-
Pathological Gleason greater than 7 11.99 5.83–24.62 ⬍0.001 chemical progression in prostate cancer across multiple
Margin positivity 2.14 1.39–3.29 0.001 pathological stages. In addition to finding that percent tu-
PSA 1.45 1.09–1.92 0.009
Prostate wt 0.59 0.34–1.02 0.058 mor involvement was associated with all of the adverse
pathological end points studied, we found that after adjust-
ing for other pathological features, percent tumor involve-
ment was a significant predictor of biochemical progression.
we sought to identify various cut points to stratify patients Furthermore, we identified percent tumor involvement cut
into discrete groups with differing risk of progression. To points that allow for further stratification of patients with
accomplish this we explored various percent tumor involve- organ confined disease, margin positive disease or extracap-
ment cut points by dividing patients into groups based on sular extension, and those with seminal vesicle invasion. If
every 5% of percent tumor involvement as 5% or less, 5.1% to confirmed in other studies, these data suggest that percent
10.0%, 10.1% to 15.0%, etc. The percent tumor involvement tumor involvement can help prognosticate the risk of recur-
groups were examined as categorical variables in a Cox rence and help identify men who are at the highest risk who
proportional hazards analysis and categories with similar would then be good candidates for clinical trials of adjuvant
hazard ratios for progression were combined. This resulted therapy aimed at reducing the risk of progression.
in percent tumor involvement being divided into 4 groups of Staging of other types of cancer often involve the actual
5% or less, 6% to 20%, 21% to 50% and greater than 50%. tumor size. For example, in kidney cancer tumor size less
Overall, percent tumor involvement cut points were signifi- than 4 cm is T1 whereas size greater than 4 cm is T2 dis-
cantly associated with biochemical progression (log rank ease.1 In prostate cancer some virtue is given to the size of
p ⬍0.001, fig. 1). This remained true even after adjustment for the tumor in relation to the size of the organ (ie T2a vs T2b).
multiple clinical and pathological characteristics (p trend ⫽ However, among men with pathologically organ confined
0.008). Men with 5% or less tumor involvement had a 5-year disease the subtle distinction between T2a and T2b does not
biochemical progression-free survival of 87% (95% CI 84 – always provide accurate risk stratification.10 Indeed, the
89) compared to 23% (95% CI 14 –34) among men with a greatest prognostication is taken from extra-organ involve-
percent tumor involvement greater than 50%. ment (ie T3). An alternative measure of tumor size would be
to assess tumor volume. Indeed, tumor volume has been
Role of PTI Cut Points When Already
Stratified by Pathological Features
Given that the percent tumor involvement cut points were
TABLE 3. Multivariate Cox proportional hazards model of factors
significantly associated with outcome, we further sought to
predicting biochemical progression after radical prostatectomy
determine whether they remained associated with progres-
sion among groups of men within narrowly defined patho- Odds
Ratio 95% CI p Value
logical groups. Specifically, we examined whether percent
tumor involvement cut points predicted progression among Pathological Gleason 7 1.55 1.23–1.95 ⬍0.001
Margin pos 1.62 1.32–2.00 ⬍0.001
men with organ confined margin negative disease, those Pathological Gleason greater than 7 2.70 2.01–3.65 ⬍0.001
with either margin positive or extracapsular extension and PSA 1.62 1.41–1.85 ⬍0.001
SV involvement 1.61 1.22–2.11 0.001
patients with seminal vesicle invasion. When this was done Prostate wt 0.65 0.51–0.84 0.001
percent tumor involvement cut points were significantly as- Yr of surgery 0.95 0.92–0.99 0.005
sociated with progression in all 3 pathological groups Clinical stage T1/T2 0.77 0.61–0.96 0.022
PTI 1.16 1.01–1.33 0.035
(p ⱕ0.02). Moreover, even after adjustment for multiple
574 BIOCHEMICAL PROGRESSION AFTER PROSTATECTOMY

<5% 6-20% 21-50% >50%

Percent PSA Free Survival

100
90
80
70
60
50
40
30
20
10
0
0 5 Years 10 15
<5% 555 252 49 2
6-20% 558 274 69 2
21-50% 141 77 22 2
>50% 6 4 1 0

Log-rank, p<0.001
FIG. 1. Actuarial 15-year Kaplan-Meier estimates of biochemical progression rates segregated by percent tumor involvement. Log rank
p ⬍0.001.

examined in depth as a predictor of biochemical progres- the observation linking percent tumor involvement with
sion.4,11,12 However, in practice, tumor volume is often cal- progression for men with adverse pathological features.
culated by the percent of tumor involvement multiplied by Specifically, when stratified by pathological findings, per-
prostate weight. For example, at our center the pathologists cent tumor involvement remained significantly predictive
routinely record percent tumor involvement but not tumor of progression for those with organ confined disease, positive
volume. To accurately measure tumor volume, as opposed to surgical margins or extracapsular extension, and those with
calculating it based upon tumor percent involvement, in- seminal vesicle invasion.
volves whole mount sectioning with tumor digitization. Pathological traits such as Gleason grade greater than 7,
Therefore, to do this is time-consuming and requires addi- extracapsular extension, seminal vesicle invasion, and
tional equipment. As such, we would suggest that examining higher preoperative serum PSA are all well established
both parameters (percent tumor involvement and prostate characteristics of higher risk and recurrent tumor behav-
weight) separately may be more informative. Indeed, both ior.13,14 These characteristics have been used to develop
parameters were significantly linked with progression. various nomograms for the prediction of biochemical recur-
Ramos6 and Carvalhal7 et al previously identified an rence with varying reliability.15 Given that recent data sug-
association between percent tumor involvement and bio- gest early use of adjuvant rather than salvage therapy may
chemical progression in the setting of pathologically organ improve long-term outcomes, the goal of prognostication is to
confined disease. We confirmed their findings and extended rapidly identify those patients who are at the highest risk of

A B
Percent PSA Free Survival

<5% 6-20% 21-50% >50%

Percent PSA Free Survival

<5% 6-20% 21-50% >50%

100 100
90 90
80 80
70 70
60 60
50 50
40 40
30 30
20 20
10 10
0 0
0 5 Years 10 15 0 5 Years 10 15
<5% 679 298 54 3 <5% 118 45 4 0
6-20% 986 433 106 3 6-20% 369 149 34 2
21-50% 484 194 56 2 21-50% 249 96 27 1
>50% 65 13 6 1 >50% 18 5 1 0

Log-rank, p<0.001 Log-rank, p<0.001

FIG. 2. Actuarial 15-year Kaplan-Meier estimates of biochemical progression rates of cases of organ confined margin negative disease
segregated by percent tumor involvement (A) and cases of positive surgical margins or extracapsular extension (B). Log rank p ⬍0.001.
 BIOCHEMICAL PROGRESSION AFTER PROSTATECTOMY
progression and who may stand to benefit the most from
adjuvant therapy.16 As such, the identification of discrete
percent tumor involvement cut points creating 4 risk groups
is of clinical importance as it allows us to better delineate
the risk of biochemical progression. Moreover, the fact that
tumor percent involvement can further stratify men even
after they are grouped by standard pathological character-
istics and adds information even after controlling for multi-
ple clinical and pathological factors including pathological
tumor grade, suggests that it can be used clinically to iden-
tify the highest risk patients who should then be considered
for adjuvant therapy clinical trials. Specifically, tumor per-
cent involvement appears to potentially have the greatest
clinical value for men with either positive surgical margins
or extracapsular extension without seminal vesicle invasion.
Within that group we could identify a group with a 75%
5-year biochemical progression-free survival risk. These
men are less likely to receive significant benefit from adju-
vant therapy due to low recurrence risk. Alternatively, we
also identified a group with similar pathological stage, but a
22% 5-year biochemical progression-free survival risk.
These men would be ideal candidates for adjuvant therapy
due to the high recurrence risk.
Prostate weight, in concordance with the findings from
prior studies, was significantly predictive of biochemical pro-
gression.17,18 However, due to its inconsistent association
with other pathological findings and our a priori hypothesis
that percent tumor involvement would be the best predictor,
it was not the primary focus of this study. Future study is
needed to identify clinically relevant cut points regarding
prostate weight.
Limitations of our study include incomplete followup data
such that PSA doubling time, development of metastatic
disease and death were not available. However, we used
time to biochemical progression as our primary end point
because earlier progression has been linked with risk of
prostate cancer death.19 Certainly the methods used to as-
certain percent tumor involvement are imperfect. The more
precise method would be to section the tissue then have the
percent tissue involvement digitally measured. Whether
more accurate measurements would improve prognostica-
tion enough over the current method to justify the added
time needed to attain them is unknown. Unfortunately the
percent of tissue with cancer on the diagnostic biopsy was
not available. Therefore, we are unable to comment on the
degree of association between tumor burden on biopsy and
that found at the time of radical prostatectomy. Finally,
given the intra-observer and inter-observer variability in
pathological assessment, these results require validation in
other datasets.
CONCLUSIONS
Percent tumor involvement has not been well studied as a
pathological characteristic in the prediction of prostate can-
cer outcomes. It is a relatively inexpensive and easily deter-
mined parameter during routine pathological analysis of
prostatectomy specimens, and requires no additional equip-
ment. Identification of 4 risk groups with differing biochem-
ical progression outcomes even after pathological staging is
known and adjustment for other key prostate cancer char-
acteristics provides the clinician with additional information
for the prognostic armamentarium. Percent tumor involve-
575
ment appears to be most useful in men with intermediate
risk disease based on pathological findings of a positive
surgical margin or extraprostatic disease. As more evidence
accumulates that adjuvant therapy may be better than sal-
vage therapy, the use of percent tumor involvement may
enable the clinician to identify the high risk patient who
stands to benefit the most from adjuvant therapy.
Abbreviations and Acronyms
ECE ⫽ extracapsular extension
PSA ⫽ prostate specific antigen
PTI ⫽ percent tumor involvement
SV ⫽ seminal vesicle
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EDITORIAL COMMENT
Following the interpretation of pathological findings after
radical prostatectomy, physicians and patients want to
know, “Now what?” It seems almost weekly that a new
predictive table or nomogram or neural network sprouts,
and it is then touted as new or improved or updated. Keep-
ing track of them can be difficult and determining which one
may be more or less useful can many times depend on the
situation. Undoubtedly these predictive tools have an impor-
tant informative role but depend not only on the type of
systematic statistical approach taken to analyze the clinical
scenario but also as much on the actual data points exam-
ined.
The authors attempt to clarify and establish an associa-
tion between prostatic cancer tumor volume and the risk of
biochemical progression after radical prostatectomy. In
more than 2,200 evaluable patients pathologist estimated
percent tumor volume correlated with the risk of a positive
surgical margin, extracapsular extension and seminal vesi-
cal involvement. At a variety of cut points the estimated
tumor volume stratifies patients into varying risk groups of
progression. Interestingly these findings were not based on
whole mount evaluations of calculated tumor volume, and it
is unclear if this more exact and time-consuming method
would prove more or less predictive. As with any series the
widespread applicability of this visual estimate is yet un-
known as well.
It makes teleological sense that the more tumor seen by
the pathologist, in some manner, begets a worse tumor. How
could it not? However, ultimately what is important to the
patient is how clinically useful this pathological finding will
become and in what specific patient characteristic profile the
percent tumor volume should be used. Future series will
determine how percent tumor volume will become inte-
grated in our predictive armamentarium. As in previous
series these authors have provided an important service of
capturing and examining data that provide the initial key
groundwork for clinically useful information for patients
and treating physicians.
Sam S. Chang
Department of Urologic Surgery
Vanderbilt University Medical Center
Nashville, Tennessee