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EFFECT OF INFLAMMATION AND BENIGN PROSTATIC HYPERPWIA
ON ELEVATED SERUM PROSTATE SPECIFIC ANTIGEN LEVELS
ROBERT B. NADLER, PETER A. HUMPHREY,DEBORAH S. SMITH,WILLIAM J. CATALONA AND
TIMOTHY L. RATLIFT*
From the Division of
SUrgerY and Department of P a t h o b , Washington University school of Medicine, St. Louis, M h u r i
ABSTRACT
Purpose: We quantify the causes of elevated serum prostate specific antigen (PSA) concentrations in men whose prostate biopsies repeatedly showed no cancer.
Materials and Methods: The effects of prostate volume, inflammation, echogenicity on ultrasound and calculi were examined in a large PSA-based screening population of 148 men with
serum PSA concentrations greater than 4.0 ng./ml., findings suspicious for cancer on digital
rectal examination and multiple negative biopsies. These men were selected and compared to 64
men with suspicious rectal examinations, multiple negative biopsies and serum PSA concentrations of 4.0 ng./ml. or less.
Results: The high PSA group had larger prostates (68 versus 33 cc, p = 0.0001) and si@cantly more subclinical prostatic inflammation. Acute and chronic inflammation was more
prevalent in the high PSA group (63%versus 27%,p = 0.0001and 99%versus 77%, p = O.OOO1,
respectively). A simultaneous regression analysis showed that prostatic size accounted for 2396,
inflammation 7%,prostatic calculi 3% and nonisoechoic ultrasound lesions 1%of the serum F'SA
variance.
Conclusions:Prostate volume and inflammation are the most important factors contributing to
serum PSA elevation in men without clinically detectable prostate cancer.
KEYWORDS:
proetatic hypertrophy, inflammation, neoplasm antigem, proetatic neoplasm
Prostate specific antigen (PSA) is a widely used serum
marker for the early detection and monitoring of patients
with prostate cancer.1-4 A drawback to PSA-based prostate
cancer detection is the appreciable false-positive rate. Manipulations of the prostate gland, including prostatic massage, transrectal ultrasonography and needle biopsy, induce
a transient elevation of serum PSA concentrations.5 In addition, nonmalignant conditions, such as benign prostatic hyperplasia (BPH)' and prostatitis,6-8 also have been reported
to contribute to serum PSA elevations. These benign causes
of PSA elevation are problematic in prostate cancer detection
programs that use PSA as a screening test. Although several
reports have suggested that BPH1 and prostatic idammat i ~ n contribute
~ - ~
to elevated serum PSA concentrations, to
our knowledge their relative contributions have not been
formally characterized or quantified.
In a study of PSA-based prostate cancer screening,using a
serum PSA concentration of greater than 4.0 ngJml. as an
indication for transrectal ultrasonography and biopsy, we
observed a 34% prostate cancer detedion rate in volunteers
60 years old and older.10 Many of the prostate biopsy s p 5 mens that did not show cancer revealed inflammation, although there were no symptoms to suggest prostatitis.
We sought to determine the relative contributions of inflammation and BPH to elevated serum PSA concentrations.
We selected a group of men with persistently elevated PSA
concentrations, findings on digital rectal examination that
were suspicious for cancer and no evidence of prostate cancer
on multiple biopsies. These men were compared with respect
to histological evidence of inflammation, ultrasound deterAccepted for publicationJanuary 20, 1995.
Supported in part by a National Kidney FoundationAmerican
Foundation for Urologic Disease Fellowshi an American Cancer
society Fellowship, a r t from Hybritech,fhc., San Die 0, California and Grant €20 C 58193 from the National Cancer fnstitute.
* Requests for reprints: Division of Urology, Washin n Univer6ity Schopl of Medicine, 4960 Children's Place, 10130WgClinic, s t .
Louis, Mlssouri 63110.
mined prostate volume, prostatic calculi and other ultrasound findings to a second group of men who ale0 had suspicious findmga on digital rectal examination and multiple
biopsies showing no cancer but whose serum PSA concentrations were normal.
PATIENTS AND METHODS
High PSA group. In our PSA-1study from July 1, 1989
through June 30,1993, we measured serum PSA concentrations in 10,249 ambulatory men 50 years old or older (mean
age 62.6 2 6.9 years, standard deviation, range 50 to 90).
These men responded to a press release asking healthy men
to participate in a study of PSA measurement as a screening
test for prostate cancer. None had a history of prostate cancer
and those with a history of prostatitis or recurrent u+uy
tract infections were excluded. We did not perform dqptal
rectal examination at the time of the blood test. These preliminary data have been reported previ0usly.23 Serum PSA
concentrations were measured by an immunoenzymatic assay with kits. No further evaluation was performed in men
whose initial levels were 4.0 ngJml. or lower. Rather, the
PSA concentrations were measured again at &month intervals for the duration of the study unless the PSA concentration increased to more than 4.0 ngJml. If the value was
greater than 4.0 ngJml. another blood sample waa collected
to verify the elevation. Men who had 2 serum PSA values
more than 4.0 ngJml. within the 1to 2-week period underwent digital rectal examination and prostate ultrasonography by a senior urology resident or attendhg urologist. If
either of these procedures revealed abnormal or suspiciom
findings, biopsies to include suspicious areas were performed
under ultrasound guidance. If the PSA concentration was
greater than 4.0 ngJml. but digital rectal examination and
ultrasonographic findings were normal no biopsy was performed. Men whose biopsies were normal had serum F'SA
measurements obtained at 6-month intervals.At the time of
407
408
ELEVATED SERUM PROSTATE SPECIFIC ANTIGEN LEVELS
biopsy we evaluated the men for urinary tract infection and tions. This method introduces the variable of a suspicioue
acute prostatitis with a dipstick urinalysis and digital rectal digital rectal examination to the high and normal Pm
examination. If the dipstick urinalysis was positive for blood, groups. However, it is not ethical to perform serial biopsies in
nitrites or leukocyte esterase, urine microscopy was per- men with normal serum PSA concentrations and n o m
formed by a senior urology resident or an attending urologist. digital rectal examination findings. Of our patients 10% had
If significant pyuria or bacteriuria was present, biopsy was a suspicious digital rectal examination. These men undernot done and the urine was cultured. Similarly, we did not went an average of 2.3 ? 0.5 sets of biopsies (range 2 to 4).
Ultrasound measurements. Transrectal ultrasound sperform ultrasonography or biopsies in patients with tenderness on palpation of the prostate suggestive of clinical bac- were performed with either a Bruel & Kjaer model 1846
terial prostatitis. Expressed prostatic fluid was not examined scanner equipped with an 8538 (7 mHz.1 transrectal transbecause these patients were enrolled in a large prostate ducer or a Teknar Proscan scanner with a 7 mHz. transrectal
cancer screening study and had no history of bacterial pros- transducer. All transrectal ultrasound scans were reviewed
tatitis. Repeat digital rectal examination, ultrasonography by 1 person (R.B. N.), and assessed for the presence of isoand biopsy were recommended for men whose PSA concen- echoic, hypoechoic and hyperechoic areas in the peripheral
trations were greater than 4.0 ng./ml. a t a later evaluation. and transition zones of the prostate. The presence of prosTo obtain a group of men with elevated PSA concentrations tatic calculi was also recorded. Prostatic volume was calcuwho had a low probability of having prostate cancer, we lated from photographs taken at transrectal ultrasound u8selected a subset of 148 men with 3 or more sets of negative ing the prolate spheroid formula: 7d6 (transverse diameterp
biopsies and findings suspicious for prostate cancer on digital (anteroposterior dimension).11 We calculated the percentage
rectal examination. These men underwent a mean of 4.0 rt_ of ultrasound scans coded positive for hypoechoic areas, hyperechoic areas, mixed hypoechoic and hyperechoic areas,
1.0 sets of biopsies (range 3 to 7).
Normal PSA group. In our PSA-2 study from May 1, 1991 isoechoic areas and prostatic calculi.
Histological coding. One of us (P. A. H.) reviewed histologto December 15, 1993 we measured serum PSA concentrations and performed digital rectal examination in 14,097 ical sections of the prostate needle biopsies in a blinded
ambulatory men 50 years old or older (mean age 60.4 2 7.5 fashion. Inflammation in prostatic tissue was categorized as
years, range 50 to 95). Similar to the PSA-1 study, these men being acute andlor chronic. Acute prostatitis was defined as
responded to a press release asking healthy men to partici- the presence of polymorphonuclear leukocytes within glandpate in a study of PSA measurement as a screening test for ular or ductal lumina, their epithelium andlor adjacent
prostate cancer. Men with a history of prostate cancer, re- stroma (fig. U.12 Chronic nonspecific prostatitis was identicurrent urinary tract infections or bacterial prostatitis were fied as a mononuclear cell infiltrate (lymphocytes, monocytes
excluded. We obtained blood samples before or a t least 1 and plasma cells) in the stroma around prostatic glands."
week after digital rectal examination. Senior urology resi- The chronic inflammatory cells occasionally invaded into the
dents or attending urologists performed all digital rectal glandular epithelium (fig. 2). The inflammation was graded
examinations or transrectal ultrasound guided needle biop- on a 3-tiered scale as 0-none, 1-low grade and 2-high
sies.
grade.
Men with normal PSA concentrations (0to 4 ng./ml.) and
For each subject, all biopsies were combined and the pernormal digital rectal examination findings, or digital rectal centage of specimens coded as showing no, low grade and
examination findings that were abnormal but benign (includ- high grade inflammation for acute and chronic inflammation
ing enlargement with a normal consistency) were not evalu- was calculated. For example, if an individual underwent
ated further. Rather, PSA measurements and digital rectal biopsy 3 times, with 4 specimens ascertained from each biexaminations were repeated at 6-month intervals for the opsy, a total of 12 specimens would be available for coding.
duration of the study unless the PSA concentration became Furthermore, if across all 3 biopsies 6 specimens were coded
elevated (greater than 4.0 ng./ml.) or the digital rectal exam- as showing low grade acute inflammation and 3 specimens
ination was suspicious for cancer.
were coded as showing high grade acute inflammation, the
If either the PSA concentration was elevated (greater than
4 ng./ml.) and/or the digital rectal examination was suspicious for cancer (including induration, asymmetry or irregularity suggesting cancer) subjects underwent 4 (quadrant)
transrectal ultrasound guided needle biopsies (2 apex and 2
base). At biopsy we evaluated the men for urinary tract
infection with dipstick urinalysis and, if positive, also with
urine microscopy. Biopsy was not done in men with prostatic
tenderness on digital rectal examination that was suspicious
for acute prostatitis. Ultrasound findings were recorded but
transreeta1 ultrasound results were not used to determine
whether a biopsy was performed. All 4 quadrants were biopsied even if no suspicious areas on digital rectal examination
or transrectal ultrasound were present. We used a 4-core
rather than a 6-core systematic biopsy technique to minimize
the morbidity in patients with normal findings on digital
rectal examination and ultrasonography. However, according
to standard medical practice we did perform additional biopsies directed at palpable abnormalities and hypoechoic areas.
Men whose biopsies were negative for cancer continued with
serum PSA measurements and digital rectal examination at
6-month intervals.
To obtain a comparison group with suspicious digital rectal
FIG. 1. Acute high grade inflammation in prostate needle biopsy
examination but normal PSA concentrations, we selected a from prostate glands. There is essentially microabscess formation,
with
ag egate of intraglandular neutrophils. In acute prostati?,
subset of 64 men who had 2 or more sets of negative biopsies
n e u t r o r h were also identified in glandular epithelium and in enthat were performed because of susDicious dieital rectal ex- glandu
a r stroma but predominant location was within g l a n r h u
amination-only. All men had normil serum PSA concentra- lumina. H & E, reduced from x400.
0
~
~~
~
~~~
ELEVATED SERUM PROSTATE SPECIFIC ANTIGEN LEVELS
FIG.2. Chronic high grade inflammation in prostate needle biopsy
from periglandular stroma with involvement of glandular epithelium. Chronic inflammatory infiltrate w a s predominantly lymphocytic. H & E, reduced from X400.
respective percentages would be calculated as 25% no inflammation, 50% low grade inflammation and 25% high grade
inflammation. The same method was used to derive percentages for chronic inflammation.
Statistical analysis. Student’s t test was used to compare
the men with persistently elevated and normal PSA concentrations with regard to patient age a t study entry. Prostate
volume was compared between the groups via the MannWhitney U test. Prostate volume was defined as the average
of the 2 most recent ultrasound measurements.
Chi-square statistics were used to compare the proportion
of cases in each group coded positive (at any biopsy) for
prostatic calculi, nonisoechoic lesions, and acute and chronic
inflammation. Fisher’s exact tests were used when small cell
sizes precluded use of the chi-square test.
For the subset of men with a t least 1 ultrasound scan coded
positive for prostatic calculi, the percentage of each individual’s total number of ultrasound scans coded positive for
prostatic calculi was compared between study groups using
Mann-Whitney U tests. Similar comparisons were made for
the subset of scans coded positive for nonisoechoic lesions
(that is comparing percentage of biopsies coded positive for
hypoechoic, hyperechoic, and mixed hypoechoic and hyperechoic lesions), acute inflammation (that is comparing percentage of biopsy specimens coded positive for acute inflammation overall, low grade acute inflammation and high grade
acute inflammation) and chronic inflammation (that is comparing percentage of biopsy specimens coded positive for
chronic inflammation overall, low grade chronic inflammation and high grade chronic inflammation).
Combining the 2 study groups, a hierarchical regression
analysis was used to predict mean PSA concentration based
on patient age at study entry, prostate size, prostatic calculi
(present in a t least 1 biopsy specimen versus absent in all
specimens), nonisoechoic lesions (present in a t least 1 biopsy specimen versus absent in all specimens), acute inflammation (low or high grade acute inflammation present in at
least 1 biopsy specimen versus absent in all specimens) and
chronic inflammation (low or high grade chronic inflammation present in at least 1 biopsy specimen versus absent in all
specimens). For each subject mean PSA concentration was
computed as the average of all PSA measurements immediately preceding each biopsy. The distribution of mean PSA
was normalized via log transformation. Significance tests for
the multiple correlation coefficient (R‘) were calculated at
each step of the hierarchial model. A semi-partial R2 was also
computed and tested for significance as each predictor was
409
entered. The semi-partial R2 represents the increase in dependent variable variance accounted for by a specific predictor, controlling for all previously entered predictors.13 For
this analysis, the semi-partial R2 values associated with
acute and chronic inflammation were of particular interest; a
significant semi-partial R2 would indicate a significant increment in prediction of mean PSA concentration above that
explained by patient age, prostate size, presence of prostatic
calculi and presence of nonisoechoic lesions. Significance
tests were also computed for the final regression coefficients
after the inclusion of all predictors.
We also performed a simultaneous regression analysis to
determine the unique contribution of each predictor in explaining mean PSA concentration while controlling for all
other predictors. This analysis differs from the hierarchical
analysis in that the semi-partial R2 values represent the
unique proportion of mean PSA variance explained by each
predictor simultaneously controlling for all other predictors.13 In this analysis, semi-partial R2 values are not dependent upon the order that predictors are entered into the
model. Regression coefficients resultant from the simultaneous analysis equal the final regression coefficients in the
hierarchical model after the inclusion of all predictors.
To determine whether we had induced either acute or
chronic inflammation through multiple biopsies, we used
chi-square statistics to compare the percentage of men without acute inflammation by number of biopsies and percentage of men without chronic inflammation by number of biopsies. We also computed again the simultaneous regression
analysis predicting mean PSA including data from only the
initial biopsy.
RESULTS
Patient age a t study entry. The 2 study groups differed
significantly with regard to patient age at study entry. Mean
age at study entry for the men with persistently elevated
PSA concentrations was 67.0 t 5.9 years (range 5 2 to 81)
versus 63.9 ? 7.2 years (range 50 to 78) for those with normal
PSA concentrations the Student t test (210) = -3.2, p =
0.002).
Prostate size. A s expected, the men with persistently elevated PSA concentrations had significantly larger prostates
(mean volume 68.1 2 27.3 cc, range 21 to 154.6) than those
without elevated PSA levels (mean volume 32.5 2 12.8 cc,
range 11.8 to 87.4, z = -9.5, p <0.0001). Median average
PSA concentration for the men with significantly elevated PSA
levels was 6.6 ng./ml. versus 1.1 ng./ml. for those with normal
PSA values.
Presence ofprostatic calculi. Of 147 men with persistently
elevated and 64 with normal PSA concentrations 146 (99.3%)
and 59 ( 9 2 . 2 9 ) ,respectively, had a t least 1 ultrasound scan
coded positive for prostatic calculi (table 1, Fisher’s exact test
p = 0.01). One man with persistently elevated PSA concentrations was excluded from this analysis due to unavailability of ultrasound measurements. For the 205 men with prostatic calculi the mean percentage of ultrasound specimens
coded positive for prostatic calculi (77.0 t 22.7, range 25.2 to
100.0) did not differ between those with or without elevated
TABLE1. Influence
of
uarrous benign prostate conditions on serum
PSA concentrations
No. High
PSA ( 4 )
I147 pts.*)
No. Normal
PSA “2 1
I64 pts.)
p Value
59 (92 2 )
0.01
146 199.31
Prostatic calculi present
61 195.31
0.02
Nonisoechoic lesions present
147 1100.0)
17 127.4):
0.0001
Any acute inflammation
92 162.61
0.0001
145 (98.61
48 177.4lf
Any chronic inflammation
* Ultrasound measurements and histological coding unavailable for 1 man.
+ Total patients 62. histological coding unavailable for 2 men.
ELEVATED SERUM PROSTATE SPECIFIC ANTIGEN LEVELS
410
PSA concentrations (81.2 2 24.6, range 33.3 to 100.0, z = 1.3, p <O.OOOl). The presence of prostatic calculi also added significantly to the model (semi-partial R2 = 0.03, p = 0.0009).
p = 0.19).
Presence of nonisoechoic lesions. All of the men with per- However, the actual predictive increment was minimal (that
sistently elevated PSA concentrations and 61 of 64 (95.3%) is presence of prostatic calculi accounted for 3% of the variwith normal concentrations had at least 1 ultrasound scan ance in PSA concentration after controlling for patient age
coded positive for nonisoechoic lesions (table 1, Fisher's exact and size). The presence of nonisoechoic lesions did not add
test p = 0.02).Among the 208 men with nonisoechoic lesions significantly to the prediction of PSA concentration.
Controlling for all previously entered predictors, the addithe mean percentage of ultrasound scans coded positive for
these lesions was significantly greater for those with persis- tion of acute inflammation contributed significantly to the
tently elevated PSA concentrations (table 2, z = -2.4, p = model (semi-partial R2 = 0.08, p <O.OOOl). The significant
0.02). However, when nonisoechoic lesions were subdivided increment (semi-partial R2)indicates that acute inflammainto hypoechoic, hyperechoic and mixed types differences tion explained 8%of the variance in PSA over and above that
between the persistently elevated and normal PSA groups predicted on the basis of patient age, prostate size, presence
were observed only for men with mixed lesions ( z = -2.3, p = of prostatic calculi and presence of nonisoechoic areas. The
addition of chronic inflammation also added significantly ta
0.02).
Presence of inflammation. Of 147 men with persistently the model (semi-partial R2 = 0.01, p = 0.015). However, the
elevated and 62 with normal PSA concentrations 92 (62.6%) predictive increment was relatively minor (that is chronic
and 17 (27.4%0),
respectively, had at least 1 biopsy specimen inflammation accounted for 1%of the variance in PSA concoded positive for acute inflammation (table 1, chi-square [ 11 centrations, controlling for all previously entered variables).
The results from the simultaneous regression analysis are
= 21.6, p <0.0001). In contrast, nearly all of the men with
high PSA concentrations 198.6%)and the majority with nor- also presented in table 4. Prostate size uniquely accounted
mal levels (77.4%)had at least 1 biopsy specimen coded for 23% of the variance in mean PSA concentration (semipositive for chronic inflammation (table 1, chi-square [ l ] = partial R2 = 0.23, p <O.OOOl), presence of prostatic calculi
27.8, p <0.0001). One man with high PSAconcentrations and accounted for 3%(semi-partial R2 = 0.03, p = 0.001), pres2 with normal levels were excluded from these analyses due ence of acute inflammation accounted for 6%(semi-partial R2
= 0.06, p <0.0001) and presence of chronic inflammation
to unavailability of histological coding.
For the 109 men with acute inflammation table 3 presents accounted for 1%(semi-partialR2 = 0.01, p = 0.015).Patient
the mean percentage of biopsies coded positive for low grade, age and presence of nonisoechoic lesions did not uniquely
high grade and any acute inflammation. Overall, the men explain a significant proportion of variance in mean PSA
with high PSA concentrations had a significantly greater concentration. Of most interest is the semi-partial R2 value
percentage of biopsy specimens positive for acute inflamma- for acute inflammation. The decrease in the semi-partial R2
tion (z = -2.2, p = 0.02).However, this difference was due value from 0.08 in the hierarchical analysis to 0.06 in the
mainly to a significantly greater percentage of specimens simultaneous analysis indicates that there is a slight overlap
with low grade acute inflammation (z = - 1.9, p = 0.05).High (that is 2%)in the mean PSA variance explained by acute and
grade acute inflammation occurred rarely and the incidence chronic inflammation. However, the larger semi-partial R2
value found for acute inflammation within the simultaneous
did not differ between the groups (z = -0.09, p = 0.9).
For the 193 men with chronic inflammation table 3 also analysis confirms that acute inflammation may be a more
presents the mean percentage of biopsies positive for low important predictor of the serum PSA concentration than
grade, high grade and any chronic inflammation. Overall, the chronic inflammation.
The final regression coefficients for predicting the log of the
men with high PSA concentrations had a significantly
greater percentage of biopsy specimens positive for chronic mean PSA are shown in table 5. Controlling for every other
inflammation (z = -4.3, p <0.0001). Similar to the findings predictor, increased prostate volume, presence of prostatic
for acute inflammation, this difference was due mainly to calculi, acute inflammation and chronic inflammation were
a significantly greater percentage of specimens with low significantly associated with increased serum PSA concengrade chronic inflammation (z = -3.7, p = 0.0002).High grade trations.
To determine if serial biopsies induced acute or chronic
chronic inflammation was found in only a small percentage
of biopsy specimens and did not differ between the groups inflammation, we examined each set of biopsies indepen(Z = -1.8, p = 0.08).
dently to assess the percentage of inflammation. There was
Multivariable regression models for predicting log (mean no induction of acute inflammation with serial biopsies for
PSA). The results from the hierarchical regression analysis the high or normal PSA groups (p = 0.66 and p = 0.69,
are presented in table 4. The hierarchial analysis was per- respectively). There was some induction of chronic inflammaformed to determine whether inflammation significantly in- tion in the high PSA group for 5 sets of biopsies. The perfluenced PSA concentrations. While relative contributions of centage of men without chronic inflammation decreased from
all variables are determined, the outcome is influenced by the 28 to 12%for 5 sets of biopsies (chi-square [4] = 10.6, p =
order of entry into the model. Thus, prostate size, presence of 0.03). However, when evaluating the subset of men with 5 or
calculi and presence of nonisoechoic lesions were entered as more biopsies, the proportion of men without chronic inflamcontrolling contributors to evaluate the contribution of in- mation decreased dramatically after biopsy 1 but remained
flammation. As previously reported, prostate size was a pow- consistent thereafter. There was no induction of chronic inerful predictor of the log of the mean PSA, accounting for 34% flammation in the normal PSA group for 3 sets of biopsies (p
of the variance in PSA concentration (semi-partial R" = 0.34, = 0.34). To validate further that we did not induce inflam-
. Mean percentage of
_TABLE
_ ~2_
_____
ultrasound studies coded positive for nonisoechoic lesions for the subset of men with nonisoechoic lesions
-----
--__.-____
Mean
Ultrasound Lesion
______~_~__
SD ~range)
?
High PSA I147 pts.*)
Normal PSA (61 pts.1
_________
88.1 r 17.9(20.0-100.0)
Nonisoechoic
Hypoechoic
Hyperechoic
Mixed hypoechoic and hyperechoic
' Ultrasound measurements unavailable for 1 man.
_.
64.2 z 28.1 10.0-1oo.n)
2.3 Z 7.5
10.0-33.9)
21.6t 22.2 [o.o-ioo.n1
~
~
~
78.7 :24.9133.3-100.0)
56.8 :
37.6 10.0-100.0~
6.3 z 16.4 (0.0-50.01
15.6 z 25.3
-~
-10.0-100.0)
p Value
----
ll.02
0.2
0.2
0 0 2.
.~
ELEVATED SERUM PROSTATE SPECIFIC ANTIGEN LEVELS
41%
TABLE3. Mean percentage of biopsy specimens coded positive for inflammation for the subset of m n with intlammation
Mean
Inflammation
2
SD (range)
High F'SA
Normal PSA
28.0 2 18.9 (9.0-100.0)
26.2 2 16.7 (0.0-80.0)
2.7 f 8.2
(O.W.0)
19.9 2 13.8 (8.0-57.0)
17.3 2 7.5 (8.3-33.3)
2.7 2 7.8 (0.0-28.6)
p value
Acute:'
b Y
LOW
High
Chronic:t
46.1 2 22.6 (12.5-87.5)
0.0001
42.5 f 21.3 (12.5-87.5)
0.0002
High
3.6 2 9.9 . (0.0-42.9)
0.08
* Total of 92 men with high B A levels (histological coding unavailable for 1) and 17 with normal PSA levels (histological coding unavailable for 2).
t Total of 145 men with high PSA levels (histological ading unavailable for 1) and 48 with n o d PSA levels (histological coding unavailable for 2).
b Y
64.3 2 23.2 (12.5-100.0)
57.1 5 23.4 (0.0-100.0)
7.2 2 15.9 (0.0-100.0)
LOW
-
0.02
0.05
0.9
TABLE4. Cumulative R2 and semi-partial d predicting log (mean
PSA)
Semi-partial Ra
Independent Variable
R2
Hierarchical Simultaneous
-
Pt.age
prostate size
Prostatic calculi present
Nonisoechoic lesions present
Acute inflammation present
Chronic inflammation present
* p <0.01.
t p <0.0001.
$ p <0.001.
8 p <0.05.
-
0.0457'
0.3846t
0.41687
0.4252t
0.5047t
0.5192t
0.3389t
0.0322$
0.0084
0.0795t
0.01456
0.006
0.2271t
0.0251*
0.0087
0.0554t
0.01458
TABLE5. Final regression coefficientsfor pwdkting log (mean
PSA)
Final Regression
Independent Variable
SE
Coefficient
Intercept
F't. age
Prostate size
Prostatic calculi present
Nonisoechoic lesions present
Acute inflammation present
chronic inflammation present
* p <0.0001.
t p <0.01.
-2.2286
0.0037
0.0170*
0.9438t
0.7834
0.4784:
0.4802$
0.6219
0.0076
0.0017
0.2916
0.4103
0.0994
0.1953
$ p ~0.05.
mation, we computed again the simultaneous regression
analysis predicting mean PSA including data from only the
initial set of biopsies. In this analysis, which controlled for all
other variables, prostate size and acute inflammation remained significant predictors of the serum PSA level (semipartial R2 = 0.26,p <O.MN)l for prostate size and semi-partial
R2 = 0.04,p = 0.002for presence of acute innammation).
DISCUSSION
It is firmly established that prostate cancer can cause an
elevation in serum PSA concentrations. However, as we have
shown previously, clinically detectable prostate cancer accounts for only 34% of serum PSA elevations.10 There are
limited data evaluating other factors as possible causes of
serum PSA elevation, especially in patients in whom there is
reasonable certainty that clinically detectable prostate cancer is not present. Our results suggest that prostate volume
is an important cause of PSA elevation. Our results also
provide quantitative demonstration that acute and chronic
inflammation not associated with clinical bacterial prostatitis or symptomatic nonbacterial prostatitis is an important
contributor to elevated PSA concentrations. Prostatic calculi
and nonisoechoic areas identified on ultrasound scans, both
of which may be surrogate markers for inflammation, also
are associated with PSA elevation.
Stamey et a1 previously demonstrated that BPH W ~ San
~~
important contributor to PSA elevation.' Our data strongly
support BPH associated prostate enlargement as the most
powerful benign contributor to PSA elevation. In our study
group (median PSA 6.6 ng./ml.) the mean prostate volume
was 68.1cc in men with high PSA concentrations compared
to 32.5 cc in those with normal concentrations (median PSA
1.1ng./ml.). Despite the fact that all subjects with elevated
PSA concentrations had 3 or more sets of negative biopsies
(mean 4.01, the possibility that undiagnosed microscopic
prostate cancer was present cannot be excluded. In this regard we previously showed that the cancer detection rate on
biopsies 4 to 7 is approximately 696.9 Given this caveat,
simultaneous regression analysis showed prostate volume in
the absence of demonstrable prostate cancer to be a significant and important contributor to PSA elevation.
Relatively little is known about the effects of prostatic
idammation on serum PSA levels, especially inflammation
not associated with acute bacterial prostatitis. Previous investigators have reported prostatic inflammation prevalence
rates of 5 to 98% based on needle biopsies, autopsy and
transurethral prostatectomy specimens.14-"3 By studying
subjecta with multiple negative biopsies, we not only decreased the possible contribution of coexistent small prostate
cancers but also increased the amount of tissue sampled in
each prostate, thus enhancing our ability to detect focal areas
of inflammation. By the eligibility criteria of our study, these
men had no known history of bacterial or nonbacterial prostatitis. It was not part of the study design to evaluate the
expressed prostatic secretions either microscopically or by
culture in these patients who had a negative urinalysis and a
digital rectal examination not suspicious for prostatitis.
We took several measures to ensure that we did not induce
inflammation with the serial biopsies. We compared groups
with high and normal PSA concentrations, and analyzed the
data with respect to only the first set of biopsies, confirming
that prostate s u e and acute inflammation were the most
important predictors of PSA elevation. Finally, we analyzed
the data for the induction of inflammation and found no
evidence of increased acute inflammation with serial biopsies. We did, however, find some increase in chronic inflammation with serial biopsies but the change occur& mainly
between biopsies 1and 2. Thus, inflammation induced with
serial biopsies did not account for the resulta observed. Performance of multiple biopsies provides better sampling of the
prostates with time to detect small foci of inflammation and
also more accurately excludes the presence of d t carcinoma.
Only a few reports investigate the relationship between
serum PSA concentrations and prostatic inflammation.
Brawn et al reported on 105 autopsy cases with premortem
PSA concentrations and digital rectal examination findings
that were not suspicious for prostate cancer within 1 year of
death.9 They found a statistically sigdicant difference in the
proportion of patients with PSA concentrations greater than
4.0 ng./ml. plus severe acute andlor chronic inhmmation
compared to all other patients (50% versus 222,p = 0.032).
412
ELEVATED SERUM PROSTATE SPECIFIC ANTIGEN LEVELS
Prostatic calculi, also associated with inflammation and
However, 37 of the 105 patients had cancer. Of 96 patients
without cancer a t autopsy or with cancer volumes less than 1 prostatitis, uniquely explained 3% of the variance in PSA
cc 16 (17%)had severe acute and/or chronic inflammation Concentrations. The high prevalence of prostatic calculi in the
and 8 (50%)had serum PSA concentrations greater than 4 normal PSA group (92%)may account for some of the susping./ml. However, this was not a screening population. Some cious findings on rectal examination. Although prostatic calpatients had either prostate cancer, an indwelling urethral culi and nonisoechoic ultrasound lesions are prevalent, they
catheter or clinical prostatitis that could have affected the account for only a small percentage of variance in mean PSA
concentrations (3%and 1%,respectively) with only the presobservations.
Neal et al performed biopsy in 6 of 10 patients who pre- ence of calculi being significant.
sented with clinical prostatitis.7 Mean serum PSA concentraCONCLUSIONS
tion was 28.5 ng./ml., which persisted (less than 4.0 ng.lml.1
for 8 weeks after treatment. Two patients had cancer and 6
BPH, prostatic inflammation, presence of prostatic calculi
had acute or chronic prostatitis. In monkeys Neal et al dem- and mixed prostatic ultrasound lesions are significantly asonstrated an elevation in serum PSA concentrations 5 to 7 sociated with elevated serum PSA concentrations in men
days after the induction of acute prostatitis. The PSA con- without demonstrable prostate cancer. BPH is the most imcentrations subsequently normalized as the prostatitis re- portant nonmalignant process responsible for PSA elevation.
solved. Moon e t al found that the human prostatic carcinoma However, prostatic inflammation, especially low grade acutecell line, LNCaP, when infected with bacteria in vitro did not and chronic inflammation, also has an important role. To a
increase PSA production, which suggested that infection and lesser extent, prostate calculi and nonhomogeneous ultrainflammation increase serum PSA concentrations by affect- sound lesions, possible surrogate markers for inflammation
ing the natural anatomical and physiological barriers to PSA and BPH, also are associated with elevated PSA concentradiffusion between the prostatic glandular tissue and the tions.
bloodstream. 19
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