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The Prostate 28:295-299 (I 996)
Prostatic Acid Phosphatase Levels (Enzymatic
Method) From Completely Sectioned, Clinically
Benign, Whole Prostates
P.N. Brawn, D.W. Jay, D.M. Foster, D. Kuhl, V.O. Speights, E.H. Johnson,
M. Riggs, M.L. Lind, K.S. Coffield, and B. Weaver
Department of Pathology, Veterans Administration Medical Center, University of
Michigan, Ann Arbor (P.N.6.); Department of Pathology, Veterans Administration Medical
Center (D.WJ., D.K, E.H.1.) and Departments of Pathology (V.O.S.), Statistics (M.R), and
Urology (KS.C.), Scott & White Memorial Hospital, Texas A M University School of
Medicine, and Department of Pathology (6.W.), Veterans Administration Medical Center,
Templejunior College, Temple, Department of Nuclear Medicine (D.M.F.), Veterans
Administration Medical Center, Institute of Biomedical Studies, Baylor University, Waco,
and Department of Research and Education (M.LL), Kelsey-Seybold Clinic,
Houston, Texas
ABSTRACT:
Clinically benign, whole, untrimmed prostates were obtained from 104
patients at autopsy, completely sectioned, and examined microscopically. The histological
and gross findings of the prostate were correlated with premortem prostatic acid phosphatase levels (PAP, enzymatic method, ACA, Dupont Co.) to determine how often carcinoma of the prostate (CAP) affected PAP levels and to identify other findings within the
prostate associated with elevated PAP levels. Sixty (58%)prostates did not have CAP, 34
(33%)had CAP smaller than 1 ml in volume, and 10 (10%)had CAP larger than 1 ml in
volume. PAP levels were elevated (greater than 1 U/L) in 8 of the 60 (13%)prostates without
CAP, in 2 of the 34 (6%) prostates with CAP smaller than 1 ml, and in 1 of the 10 (10%)
prostates with CAP larger than 1 ml. These differences were not statistically significant.
Likewise, a statistically significant correlation between PAP levels and patient age, patient
race, severe inflammation, or high grade prostatic intraepithelial neoplasia (PIN) was not
found. However, there was a statistically significant correlation between PAP levels and
prostate weight (P < 0.OOOl).This study suggests that PAP cannot distinguish between
patients with clinically undetected CAP and patients without CAP. Furthermore, elevated
PAP levels are often not due to metastatic CAP and additional evidence should be present,
even in patients with known CAP, before an elevated PAP level is considered to be conclusive evidence of metastatic CAP. 0 1996 Wiley-Liss, h c . *
KEY WORDS:
prostate carcinoma, acid phosphatase, atypical hyperplasidadenosis,
prostatic acid phosphatase, prostatic intraepithelial neoplasia
INTRODUCTION
levels are
prostate-specific antigen
valuable but have limitations, i.e., the inability to
detect most carcinoma Of the prostate (CAP) -less
than 1 d in volume and lack of specificity for CAP
[l]. Although another serum test, prostatic acid
@ 1996 Wiley-Lss, Inc. *This article is a US Government work
and, as such, is in the public domain in the United States of America
Received for publication December 24, 1994; accepted April 27,
,mE
Il7.I.
Address reprint requests to Peter N. Brawn, Department of Pathology, Veterans Administration Medical Center, University of
Michigan, Ann Arbor, MI 48105.
296
Brawn et al.
phosphatase (PAP, enzymatic method) has been
available for decades, it is unknown how often PAP
is elevated in patients with clinically undetected CAP
or in patients without CAP. Furthermore, the
frequency and etiology of elevated PAP levels in
patients without CAP, using fully sectioned prostates, have not been reported. Since most patients, at
one time or another, receive at least one serum PAP
determination, it remains important to be able to
interpret normal, borderline, or elevated PAP levels,
regardless of the PSA level. To further our understanding of PAP, this study correlated serum PAP
levels with the histological and gross findings from
completely sectioned, clinically benign, whole prostates.
MATERIALS AND METHODS
Whole, untrimmed prostates were obtained from
104 consecutive autopsies which fulfilled the following criteria: 1) They did not have a history of CAP, 2)
digital examinations of the prostate had been done
within 1 year of death and were not suspicious for
malignancy, and 3) stored serum had been drawn
within 72 hr prior to death and frozen at the time of
autopsy.
These 104 prostates include 100 prostates that had
not been used in a study before and 4 prostates that
had been included in a prior study of PSA [11. These
whole, untrimmed prostates included the entire prostate, both seminal vesicles, approximately 1 cm of
bladder neck, and a small amount of tissue beyond
the surgical capsule. The prostates were untrimmed
because the adjacent tissue was thought to be essential for evaluating whether CAP or other histological
findings extended beyond the prostate. The prostates
accounted for 75% of the weight of the untrimmed
specimens as previously described [l]. The untrimmed prostates were weighed, fixed in formalin
for at least a week, completely cross sectioned perpendicular to the urethra at 3 mm intervals, cut with
a microtome, placed on large slides, and stained as
previously described [2].
Full cross sections were examined histologically
for the presence of CAP, inflammation, prostatic
intraepithelial neoplasia (PIN), and atypical hyperplasia/adenosis (AHA). Unequivocal evidence was
required for the diagnosis of CAP. CAP was strictly
separated from AHA, atypical atrophy, sclerosing
adenosis, atypia caused by inflammation, mesonephric hyperplasia, and cribriform hyperplasia
[3-91.
Inflammation was divided into three categories:
minimal to none, moderate, and severe. Minimal to
no inflammation was defined as occasional collections of inflammatory cells, usually lymphocytes, pri-
marily in prostatic stroma with minimal involvement
of prostatic glands. Moderate inflammation involved
a larger portion of the prostate and could be acute,
chronic, or both. Moderate inflammation, in any location, did not completely fill one low-power (5 mm)
microscopic field. Severe inflammation could be
acute, chronic, or both and was defined as inflammation which completely filled at least one low-power
microscopic field.
PIN was categorized as low grade (PIN 1) and high
grade (PIN 2-3) and was characterized by cytological
abnormalities of prostatic glands without major architectural disturbances [lo]. AHA was categorized as
mild, moderate, and severe as has been described in
numerous studies [3,4,6]. AHA is characterized by
architectural disturbances of prostatic glands without
significant cytological abnormalities.
PAP levels were determined by the enzymatic
method (ACA, Dupont Co., normal 0-1 UL).Sample
stability has been previously described [11,12]. Necessary precautions were taken to ensure sample integrity. Validity of data was assured through repetitive testing, either initially or longitudinally, or both.
Statistical analyses were performed using the
Kruskal-Wallis test and Pearson product-moment
correlations. P values < 0.05 were considered to be
statistically sigruficant.
RESULTS
The 104 patients included 89 white (including Hispanic) and 15 black patients with an average age of 69
years (range 38-96 years). Ninety-three had PAP levels between 0-1 U/L and 11 had PAP levels above 1
UL.The characteristics of these latter 11 patients are
presented in Table I.
Patients Without CAP
Sixty of the 104 patients did not have CAP. Fifty
were white and 10 were black. These patients had an
average age of 66 years (range 38-95 years) and an
average untrimmed prostate weight of 35.3 g (range
15-152 g). Flfty-two of these 60 (87%) patients had
PAP levels between 0-1 U/L while 8 (13%)had PAP
levels above 1 U/L (mean and median PAP levels for
these 60 patients were, respectively, 1.58 U/L and
0.37 U/Lwith a range from 0.01 to 45 UL).
Patients With CAP
Fourty-four of the 104 (43%)had CAP. Thirty-nine
were white and five were black. These patients had
an average age of 73 years (range 55-96 years) and an
average untrimmed prostate weight of 39.3 g (range
16-103 g).
Thirty-four of these patients had CAP less than 1
PAP Levels in Whole Prostates
297
TABLE 1. Characteristics of the I I Patients With Elevated PAP Levels*
Age/
Race
Prostate
weight
untrimmed
(GMS)
65W
58W
5OW
59w
64W
77w
66B
81B
71W
67W
79w
PAP
U/L
CAP
35
1.16
33
22
26
49
40
36
32
116
57
152
1.24
1.41
2.57
3.03
3.71
6.38
7.57
11.60
14.47
45.0
YES
0.25 ml
NO
NO
NO
NO
NO
NO
YES 7.0 ml
NO
YES 0.2 ml
NO
Additional
histology
Cause of
death
High grade PIN
ASVD
None
None
High grade PIN
High grade PIN
High grade PIN
Prostatic infarct
Moderate inflammation
Prostatic infarct
None
High grade PIN
ASVD
Esophageal carcinoma with metastases
Pneumonia
Post surgical hemorrhage
Emphysema
Perforated GI ulcer and emphysema
Alzheimers
Leukemia
Lymphoma
ASVD
‘ASVD, atherosclerotic vascular disease; GI, gastrointestinal.
ml and 2 of these 34 patients had elevated PAP levels
(mean and median PAP levels for these 34 patients
were, respectively, 0.78 U/L and 0.32 U/L with a
range from 0.01 to 14.47 U/L).
Ten of these patients had CAP larger than 1ml and
one of these had an elevated PAP level (mean and
median PAP levels for these 10 patients were, respectively, 1.1U L and 0.43 U/L with a range from 0.16 to
7.57 UL).
Additional Categories of Patients
andor Specimens
Three untrimmed prostates weighed 80 g or more
while 101 weighed less than 80 g. Two of the three
weighing more than 80 g had elevated PAP levels.
Twenty-two prostates had severe acute and/or
chronic inflammation and three of these had elevated
PAP levels. Eighty-two did not have severe acute
and/or chronic inflammation and eight of these had
elevated PAP levels.
Sixty-two had high grade PIN while 42 did not.
Five patients with high-grade PIN had elevated PAP
levels while six patients without high-grade PIN had
elevated PAP levels.
Statistical Analysis
There were no statistical differences in the median
PAP levels of prostates without CAP, prostates with
CAP less than 1 ml, and prostates with CAP larger
than 1 ml (P = 0.38) (Fig. 1).
,
There were no statistical differences in the median
PAP levels of the prostates with severe acute and/or
chronic inflammation compared to prostates without
severe acute and/or chronic inflammation (P = 0.18).
There was a sigruficant correlation between untrimmed prostate weight and PAP levels (r = 0.65; P
less than 0.0001) (Fig. 1).
There was no significant correlation between patient age and PAP levels (P = 0.36). There was no
racial difference in PAP levels between white and
black patients (P = 0.08).
There was no sigruficant correlation between highgrade PIN and PAP levels (P = 0.14) (median PAP
levels of 0.34 U/L for patients with high-grade PIN
and 0.39 U/L for patients without high-grade PIN).
DISCUSSION
This study found elevated PAP levels in 11 of 104
patients with clinically benign prostates. Eight of
these elevations occurred in patients without CAP
while the remaining three occurred in patients with
clinically unsuspected CAP. Statistically sigruficant
differences in PAP levels were not found between
patients without CAP, patients with CAP smaller
than 1 ml, or in patients with CAP larger than 1 ml.
Furthermore, patient age, patient race, severe acute
and/or chronic inflammation, or high-grade PIN were
not statistically correlated with PAP levels. The only
statistical correlation between PAP levels and the
gross or histological findings of the prostate was
prostate weight (P < 0.0001).
Possible etiologies for elevated PAP levels were
identified in five cases. These were 1)an untrimmed
prostate weighing 152 g (there is a correlation be-
298
Brawn et al.
0
X
al
o
Y
CONCLUSIONS
0
o
Oo0
0
l
o
o NoCA
x
CAc 1 mi
C A > l mi
0
20
40
60
mal percentages of elevated PAP levels in elderly
men.
80 100 120 140 160
This study confirms that PAP (enzymatic method)
is of little value in detecting CAP in clinically benign
prostates. Furthermore, this study is the first to document, through complete sectioning of the prostate,
that a surprisingly large percentage of elderly men
have elevated PAP levels in the absence of CAP and
that it is often impossible to identify with certainty
the etiology of the elevated PAP levels. Consequently, additional evidence, even in patients with
known CAP, should be present before an elevated
PAP is attributed to metastatic CAP.
Weight of Untrimmed Prostates (gm)
ACKNOWLEDGMENTS
Fig. 1.
Semi-log of PAP levels vs. untrimmed prostate weights.
tween PAP levels and prostate weight), 2) an untrimmed prostate weighing 116 g which also had a
prostatic infarct (both prostate weight and prostatic
infarcts [13] are correlated with PAP levels, 3) one
case with lymphoma and another case with esophageal carcinoma with metastases (Foti et al. [12] reported that 10 of 37 males and 14 of 53 females with
nonprostatic malignancies had elevated PAP levels,
and 4) one case with both lymphoma and prostatic
infarct (both findings associated with elevated PAP
levels).
Etiologies for the elevated PAP levels could not be
identified with certainty in the remaining six cases.
Specifically, indwelling bladder catheters were an unlikely source of elevated PAP levels since patients
with and without indwelling catheters had similar
PAP levels. Likewise, digital examinations of the
prostate were an unlikely source of elevated PAP levels since few patients had digital examinations of the
prostate within 1 week of death and none of these
examinations were prostatic massages performed by
urologists.
Foti et al. [14] found that 12%,15%,29%,and 60%
of men with Stage A, B, C, and D CAP had elevated
PAP levels (enzymatic method). While PAP is often
elevated in Stage D CAP (metastatic CAP) and may
be elevated in Stage C CAP (extension beyond the
prostatic capsule), the current study suggests that
PAP cannot detect Stage A or Stage B CAP (organ
confined CAP). Our finding of an 11% incidence of
elevated PAP levels in patients with clinically benign
prostates may indicate that the 12% and 15% incidences of elevated PAP levels reported by Foti et al.
[14] for Stage A and Stage B CAP represent the nor-
The authors thank the Dupont Co. for donating
the reagents used in this study.
REFERENCES
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11. Panteghini M, Pagani F, Bonora R Pre-analytical and
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PAP Levels in Whole Prostates
enzymatic activity and by radioimmunoassay. Clin
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13. Brawn PN,Foster DM, Jay DW, Kuhl D, Speights VO,
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serum prostate-specific antigen and prostatic acid
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14. Foti AG, Cooper JF, Herschman H, Malvaez RR: Detection of prostatic cancer by solid-phase radioimmunoassay of serum prostatic acid phosphatase. N Engl J
Med 2971357-1361, 1977.
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