Anatomic Pathology / Tumor Percentage in Prostate Cancer
Percentage of Tumor and Tumor Length in Prostate
Biopsy Specimens
A Study of American Veterans
Robin T. Vollmer, MD
Key Words: Prostate cancer; Tumor percentage; Tumor length; Survival; Grade; Needle biopsies; Serum PSA; Tumor size; Age
DOI: 10.1309/AJCP3VUXBYTEY3PU
In this study, the tumors of 451 Veterans Affairs
patients with prostate cancer were examined. In the
biopsy specimens, percentage of tumor and tumor
length were observed in addition to Gleason grade.
The patients were then followed up until death or for
a mean of 4.9 years to see how these measures of the
quantity of tumor in the biopsy specimens related to
overall survival. Cox proportional hazards model
analysis demonstrated that patient age and serum
prostate-specific antigen (PSA) level were related
significantly to overall survival. After controlling for
these 2 variables, percentage of tumor was significantly
related to overall survival (P = .0012), and after
controlling for age and PSA level, tumor length was
significantly related to overall survival (P = .00026).
Nevertheless, these 2 measures did not add prognostic
information, that is, either one or the other was
significant, but not both, probably because they are
closely correlated. The results favor including one or
the other of these 2 quantitative measures in reports
on prostate biopsy specimens with tumor.
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For any biopsy of the prostate, the most important issue
for the patient and his pathologist is the presence of cancer.
Once cancer is found, the patient’s concerns turn to whether
he will die prematurely, whether the tumor will make him
suffer, and what, if any, treatments he should seek. Once the
cancer is found, the pathologist’s concerns turn to issues of
histologic grade and quantity of tumor.
It is therefore no coincidence that the pathologist’s secondary concerns address, at least partly, the secondary concerns of
the patient. For example, the Gleason grading scheme was formulated because it related significantly to overall survival.1 In
addition, many have shown that the combination of histologic
grade and measures of tumor quantity in the initial biopsy specimen relate to outcomes in prostate cancer (see Vollmer2 for
a list of references). However, and in contrast with Gleason’s
initial study of histologic grading, recent studies have favored
outcomes other than overall survival, including tumor stage and
tumor volume. Perhaps the most popular outcome to study has
been biochemical failure,3 an outcome that is difficult to define
and one that is loosely connected to firmer outcomes such as
distant metastases and overall survival.4-7
Thus, to more directly address patients’ concerns about
premature death, I have favored the outcome of overall survival, and it is reasonable to assume that any tumor factors
related to overall survival time should be helpful for deciding whether to treat or which treatments to use. Whereas
most have accepted the Gleason grading scheme, including
the International Society of Urological Pathology consensus
revision,8 as optimal for grading prostate cancer, there is less
consensus on how to measure the amount of tumor in the
biopsy specimens. Methods of measurement include the number of positive cores, fraction of positive cores, percentage of
© American Society for Clinical Pathology
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Abstract
Anatomic Pathology / Original Article
tissue with tumor, and tumor length in millimeters. Recently,
I found that total tumor length provided more information
about overall survival than the Gleason score or the fraction of
positive cores.2 Herein, I report the examination of the relative
prognostic importance of percentage of tumor and total tumor
length in 451 Veterans Affairs patients with prostate cancer
and a mean of more than 4 years’ follow-up.
Materials and Methods
Study Patients
© American Society for Clinical Pathology
Statistical Methods
To relate clinical and histologic variables to overall
survival time, I used Kaplan-Meier plots and the Cox proportional hazards model.9 To relate the percentage of tumor to
tumor length, I used linear regression. All analyses were done
using S-PLUS software (MathSoft, Seattle, WA), and all P
values are 2-sided.
Results
Survival and Percentage of Tumor in Biopsy Specimens
zFigure 1z shows the distribution of percentage of tumor
in the study population, and it demonstrates an exponential
distribution much like that of tumor length.2 For 49% of the
cases, the percentage of tumor was less than 5%; 14% of the
cases had a percentage of tumor between 5% and 10%; 17%
of cases were between 10% and 20%, 5% between 20% and
30%, 7% between 30% and 40%, 2% between 40% and 50%,
and just 6% of cases were more than 50% of tumor. Thus,
most men with prostate cancer in this study had a limited
amount of tumor.
zFigure 2z shows a Kaplan-Meier plot of the probability
of survival at last follow-up vs the percentage of tumor in
the needle biopsy specimens of the prostate. The plot demonstrates that biopsy specimens with higher percentages of
tumor were associated with a lower probability of survival,
and a univariate Cox model analysis demonstrated that this
zTable 1z
Characteristics of the Study Population
Characteristic
Result
No. of patients
Mean (range) age (y)
Primary treatment
Surgery
Radiation
Other
Mean (range) of serum prostate-specific antigen (ng/mL)*
Mean (range) of total number of biopsy cores
Mean (range) of biopsy Gleason score
No. of deaths
Mean (range) follow-up in patients alive at last follow-up (y)
Mean (range) percentage of tumor in biopsy
specimens
*
451
63 (42-87)
310
105
36
10.6 (0.1-99.2)
8.3 (2-16)
6.6 (5-10)
52
4.9 (0.5-15.2)
14.4 (0.1-90)
Units given are conventional; to convert to Système International units (µg/L),
multiply by 1.0.
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The study patients comprised 451 men whose prostate
cancer was diagnosed by needle biopsy. All of the diagnoses
were made by me, and, in addition, I prospectively recorded the
Gleason score, the number of cores with tumor, the total tumor
length in millimeters,2 and an estimate of the percentage of tissue with tumor. Specifically, the percentage of tumor present
was estimated as the fraction of all tissue occupied by tumor
multiplied by 100, and this estimate was obtained subjectively,
that is, without formal measurements or reliance on tumor
length. Nevertheless, if tumor was present in several separate
slides (blocks), the percentage of tumor in each slide was estimated separately, summed, and then finally divided by the total
number of slides (blocks) to achieve an overall average.
Tumor length comprised the total tumor length in millimeters for all core biopsy specimens containing tumor and
was measured as before.2 Two foci of tumor in a single set
of cores were measured separately if they were separated by
lobules of benign glands or by gland-free expanses of benign
stroma, and this decision was made subjectively, relying on
my experience with evaluating previous prostatectomy specimens. All of the men were patients in the Durham Veterans
Affairs Medical Center (VAMC). Of the 451 patients, 310
were treated with radical prostatectomy, 105 primarily by
external beam radiation therapy, and 36 as needed by other
methods, including hormonal therapy. In general, information
about clinical stage was not uniformly documented in their
medical records; however, I assumed that all patients treated
by surgery or radiation therapy had clinically localized tumor,
because the standard of practice routinely excluded these
treatments for patients with evidence of metastatic tumor.
The only inclusion criteria for the study were the diagnosis of prostate cancer, a measurement of tumor length, and
an estimate of the percentage of tumor. (Gleason grade was
present in all the cases.) The only exclusion criterion for the
study was a prostate-specific antigen (PSA) level exceeding
100 ng/mL (100 µg/L), because I judged that when such
high values of PSA were present, the amount of tumor in
the needle biopsy specimens would be considered of minor
importance. Thus, all 451 men in this study had initial values
of PSA less than 100 ng/mL (100 µg/L). I obtained survival
data from hospital records or public records of deaths, and
the study was approved by the local VAMC Institutional
Review Board. Other details about these study patients and
their tumors are given in zTable 1z.
Vollmer / Tumor Percentage in Prostate Cancer
1.0
Survival Probability
250
No. of Cases
200
150
100
50
0.8
0.6
0.4
0.2
0.0
0
0
20
40
60
0
80
20
40
Discussion
Although many older men get cancer of the prostate, just
a fraction of them die of this tumor. Thus, the diagnosis of
prostate cancer does not by itself imply shortened survival
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zTable 2z
Two Cox Model Analyses*
Variable
Coefficient
Model with percentage of tumor (LR = 32)
Patient age
Serum PSA level
Percentage of tumor
Model with tumor length (LR = 33)
Patient age
Serum PSA level
Tumor length
0.0552
0.427
0.0190
0.0501
0.451
0.0199
P
.011
.022
.0012
.020
.013
.00026
LR, likelihood ratio of the model; PSA, prostate-specific antigen.
* Coefficients are given for just the significant variables in 3-variable models. The
serum PSA level was used with a natural logarithm transformation; and age,
percentage of tumor, and total tumor length were coded as continuous variables.
The LR provides a measure of how well the model fit the survival results.
80
60
40
20
0
0
2
4
6
8
10
12
Square Root of Tumor Length
zFigure 3z Plot of the percentage of tumor vs the square
root of tumor length. The square root transformation was
used to demonstrate a nearly linear relationship and to obtain
approximate normality to the residuals for the accompanying
linear regression analysis.
© American Society for Clinical Pathology
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association was significant (P = 4.2 × 10–6). Nevertheless,
univariate Cox model analyses also demonstrated that patient
age (P = .0008), serum PSA level (P = 7 × 10–7), and tumor
length (P = 6 × 10–8) were significantly associated with survival. The biopsy Gleason score, coded as 6 or less vs 7 vs
more than 7, was of borderline significance (P = .048).
zTable 2z shows 2 Cox model analyses, the first using
the percentage of tumor as the measure of tumor quantity and
the second using tumor length. Both models demonstrate that
the quantity of tumor was significantly related to overall survival after controlling for the effects of patient age and serum
PSA level. With the presence of age, serum PSA level, and
quantity of tumor present as explanatory variables, Gleason
score (coded as described) provided no additional prognostic
information (P > .7). The model likelihood ratios provide a
measure of how well the Cox models fit the survival data.
Because both models had similar likelihood ratios, because
both models had similar coefficients for patient age and serum
PSA level, and because both measures of quantity of tumor
had P values of similar magnitude, the results suggest that
tumor length, as a prognostic variable, provides no more than
a modest advantage over percentage of tumor. Furthermore,
using both variables together provided no significant additive
information (P > .1). These results suggest that the percentage
of tumor and tumor length were closely related to one another,
and this is demonstrated in zFigure 3z, which is a plot of percentage of tumor vs the square root of tumor length. The scatter plot shows a strong positive association between percentage of tumor and tumor length (P ~ 0 by linear regression).
80
zFigure 2z Kaplan-Meier plot of the probability of survival
at last follow-up vs the percentage of tumor in biopsy
specimens of the prostate. The faint upper and lower lines
give 95% confidence intervals.
Percent Tumor
zFigure 1z Percentage of tumor in biopsy specimens of the
prostate.
60
Percent Tumor
Percent Tumor
Anatomic Pathology / Original Article
© American Society for Clinical Pathology
Regardless, this preliminary study shows once again that
the quantity of tumor in needle biopsy specimens relates to
overall survival. Thus, prospective studies of outcomes for
prostate cancer and studies designed to select and test new
molecular genetic markers for prostate cancer should include
an estimate of the overall percentage of tumor present or total
tumor length. Otherwise, one risks identifying an expensive
marker for outcomes only to discover later that it is no better
a prognosticator than the quick and cheaply obtained estimate
of percentage of tumor. Because I have not been able to demonstrate superiority of one measure over the other, some may,
for the moment, want to include both measures in their data.
Finally, I recommend that pathologists routinely include in
their reports of positive biopsy specimens an estimate of the
overall percentage of tissue replaced by tumor.
From Laboratory Medicine, Veterans Affairs and Duke University
Medical Centers, Durham, NC.
Address reprint requests to Dr Vollmer: Laboratory Medicine
113, VA Medical Center, 508 Fulton St, Durham, NC 27705.
References
1. Gleason DF. Histologic grading and clinical staging of prostatic
carcinoma. In: Tannenbaum M, ed. Urologic Pathology: The
Prostate. Philadelphia, PA: Lea & Febiger; 1977:171-198.
2. Vollmer RT. Tumor length in prostate cancer. Am J Clin Pathol.
2008;130:77-82.
3. Cookson MS, Aus G, Burnett AL, et al. Variation in the
definition of biochemical recurrence in patients treated for
localized prostate cancer: The American Urological Association
prostate guidelines for localized prostate cancer update panel
report and recommendations for a standard in the reporting of
surgical outcomes. J Urol. 2007;177:540-545.
4. Pound CR, Partin AW, Eisenberger MA, et al. Natural
history of progression after PSA elevation following radical
prostatectomy. JAMA. 1999;281:1591-1597.
5. Freedland SJ, Humphreys EB, Mangold LA, et al.
Risk of prostate cancer–specific mortality following
biochemical recurrence after radical prostatectomy. JAMA.
2005;294:433-439.
6. Thames H, Kuban D, Levy L, et al. Comparison of alternative
biochemical failure definitions based on clinical outcome
in 4839 prostate cancer patients treated by external beam
radiotherapy between 1986 and 1995. Int J Radiation Oncology
Biol Phys. 2003;57:929-943.
7. Vollmer RT, Montana GS. The dynamics of prostate-specific
antigen after definitive radiation therapy for prostate cancer.
Clin Cancer Res. 1999;5:4119-4125.
8. Epstein JL, Allsbrook WC Jr, Amin MB, et al. The 2005
International Society of Urological Pathology (ISUP) consensus
conference on Gleason grading of prostate cancer. Am J Surg
Pathol. 2005;9:1228-1242.
9. Hosmer DW, Lemeshow S. Applied Survival Analysis: Regression
Modeling of Time to Event Data. New York, NY: Wiley; 1999.
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time. This study, like its predecessor,2 demonstrates that men
who die prematurely after the diagnosis of prostate cancer
have a greater quantity of tumor in the needle biopsy specimens. In fact, the quantity of tumor as measured by percentage of tumor present or total tumor length provides stronger
prognostic information about overall survival than does
patient age, serum PSA level, or Gleason score. The fraction
of men who have more than 30% of the tissues in a biopsy
specimen replaced by tumor or who have greater than 20 mm
of tumor length tend to die sooner, but fortunately, as Figure
1 demonstrates, this is a small fraction.
This study, however, does not demonstrate which of
these 2 measures of tumor quantity is better than the other,
and it demonstrates that the 2 measures are closely related to
one another. The percentage of tumor is easier and quicker to
estimate than total tumor length, and it requires neither a calibrated eyepiece micrometer nor elaborate measurements. If
one evaluates each slide with tumor independently, as I have
done in this study, then estimating the percentage of tumor
on the slide is relatively easy. Sometimes, it helps to proceed
stepwise through a mental algorithm. On a given slide with
tumor, first consider if the percentage of tumor constitutes
less than or more than 50% of the tissue. If it is less than
50% (as most are), is it less than or more than 25%? Then
by proceeding in such a stepwise manner, I have been able to
comfortably narrow the estimate of tumor on a single slide to
within 5% to 10% increments. After including 0% estimates
for the slides without tumor, one simply averages these estimates over all of the slides. I have also informally observed
that pathology residents can obtain close consensus estimates
of the percentage of tumor present.
On the other hand, estimating the percentage of tumor is
clearly a more subjective process than measuring total tumor
length with an eyepiece micrometer. Furthermore, it is possible
that some of the significance of the association between percentage of tumor and overall survival in this study was due to
my being the only observer. In other words, the percentage of
tumor could suffer as a prognostic variable in comparison with
total tumor length if it were to be recorded by different pathologists, because the variance in the process would increase.
Although formal interobserver studies regarding tumor
length and percentage of tumor are needed to address such
issues, I have not studied this, because I was the only
full-time surgical pathologist at the VAMC during this
prospective study. In addition, because the mean follow-up
in censored patients in the present was just 4.9 years, it is
possible that longer follow-up and more observed deaths
could demonstrate greater importance for the Gleason score
and for showing which of these 2 methods for measuring the
amount of tumor is better.