0022-5347/01/1653-0757/0

THE JOURNAL OF UROLOGY® Vol. 165, 757–760, March 2001

Copyright © 2001 by AMERICAN UROLOGICAL ASSOCIATION, INC.® Printed in U.S.A.

Original Articles

THE INCIDENCE OF PROSTATE CANCER IN A SCREENING

POPULATION WITH A SERUM PROSTATE SPECIFIC ANTIGEN
BETWEEN 2.5 AND 4.0 NG./ML.: RELATION TO BIOPSY STRATEGY
RICHARD J. BABAIAN,* DENNIS A. JOHNSTON, WILLIAM NACCARATO, ALBERTO AYALA,
VIJAYA A. BHADKAMKAR AND HERBERT A. FRITSCHE, JR.†
From the Departments of Urology, Biomathematics, Pathology and Research Laboratory Medicine, The University of Texas, M. D.
Anderson Cancer Center, Houston, Texas, and Dade Behring, Inc., Newark, Delaware

ABSTRACT

Purpose: It has recently been suggested that the diagnostic threshold for the prostate specific
antigen (PSA) assay be lowered to enhance prostate cancer detection. A 22% incidence of prostate
cancer has been reported in men with PSA between 2.5 and 4.0 ng./ml. We designed a study to
confirm this observation.
Materials and Methods: Men who participated in our free early detection program and who had
serum PSA between 2.5 and 4.0 ng./ml. were asked to undergo prostate biopsy. Of 268 eligible
men 151 (56%) agreed to participate in this free trial. All men underwent biopsy using an 11-core
multisite directed biopsy scheme. All biopsy cores were color coded for location specificity and
examined by 1 pathologist.
Results: Cancer was identified in 24.5% (37 of 151) of the men biopsied. The median age of men
with cancer was 62 years (range 43 to 74). Conventional systematic sextant biopsies, which
accounted for 6 of the 11 cores, detected 73.0% (27 of 37) of the cancers and the alternate site
biopsies identified the remaining 10. Gleason score was 6 in 25 men, 3 ⫹ 4 in 5, 4 ⫹ 3 in 4 and
8 or greater in 3 (median Gleason score 6). There were 14 men who had 1 core positive for cancer,
9 had 2 and 14 had more than 2 (median number of positive cores 2). Of the 14 men with 1
positive core 11 had a less than 3 mm. focus of cancer and 8 had only a positive alternate site
biopsy. There were 11 cases of abnormal results on digital rectal examination, 5 of which were
cancer, and 31 cases of abnormal results on ultrasonography, 13 of which were cancer. Median
biological variability in PSA was ⫾15% (range 0.4% to 440.0%).
Conclusions: We found a significant incidence of cancer (24.5%, 37 of 51) in men with serum
PSA between 2.5 and 4.0 ng./ml. In our study 67.6% of the detected cancers were significant
based on the biopsy data. If the PSA threshold is lowered the conventional systematic sextant
technique may be preferable to an extended strategy.
KEY WORDS: prostate-specific antigen, mass screening, incidence, biopsy

The prostate specific antigen (PSA) assay is widely used detecting cancer.5, 6 However, a lower threshold would signif-
throughout the world to detect prostate cancer. The estab- icantly increase the number of men who would become can-
lished absolute cutoff value commonly used to differentiate didates for biopsy.
the risk between cancer and no cancer is 4.0 ng./ml.1 The Approximately 12% of all men have PSA in the range of 2.5
limitations of this marker, specifically its false-negative and to 4.0 ng./ml., and presumably the vast majority do not have
false-positive rates, are well known. Numerous investigators this disease and even fewer would have clinically significant
have attempted to enhance the sensitivity and improve the prostate cancer.7 To our knowledge the relationship between
specificity of the PSA assay through various enhancements, curable prostate cancer and serum PSA has not yet been
including volume and age based indexes.2– 4 These modifica- clearly defined. About 30% of men with PSA 4.1 to 10 ng./ml.
tions have added little, if any, to our diagnostic armamen- have extraprostatic extension of cancer at prostatectomy,
tarium.4 Some investigators have suggested lowering the and this finding is associated with a less favorable outcome
diagnostic threshold to increase the sensitivity of PSA in compared with those with organ confined disease.8 Will low-
Accepted for publication September 15, 2000. ering the PSA threshold significantly improve outcome with-
* Financial interest and/or other relationship with Astra Zeneca out overtreatment of some patients compared to the outcome
and Bayer. achieved using the conventional PSA 4.0 ng./ml. threshold?
† Financial interest and/or other relationship with IMI, Inc., The task of investigators today is to enhance detection,
Tosoh, dia Dexus and Bayer.
thereby improving outcome, minimizing unnecessary biop-
Editor’s Note: This article is the first of 5 published in this sies and identifying those specific patients who would benefit
issue for which category 1 CME credits can be earned. In-
structions for obtaining credits are given with the questions from therapeutic intervention.
on pages 942 and 943. As a result of the challenge to lower the 4.0 ng./ml. PSA
757
758 SERUM PROSTATE SPECIFIC ANTIGEN VALUE AND ITS RELATION TO BIOPSY STRATEGY

threshold, we designed a study to determine the incidence of

prostate cancer in men with PSA 2.5 to 4.0 ng./ml. who partic-
ipate in early detection programs. Furthermore, because of the
emergence of new biopsy strategies to enhance cancer detection,
we compared the systematic sextant biopsy and an 11-core
multisite directed biopsy in this patient population.

METHODS

Between September 1998 and September 1999, 3,172 men

participated in a free early detection program at The Univer-
sity of Texas, M. D. Anderson Cancer Center. Total serum
PSA was obtained before the digital rectal examination using
the TOSOH‡ immunometric assay. Serum PSA in the range
Schema of prostate depicts 11 sites of biopsy strategy. R Base,
of 2.5 to 4.0 ng./ml. was detected in 322 (10.2%) men. Of these right base (sextant). R Mid, right mid (sextant). R Apex, right apex
men 268 were eligible to participate in the study based on the (sextant). L Base, left base (sextant). L Mid, left mid (sextant). L
eligibility criteria of age between 40 and 75 years, no prior Apex, left apex (sextant). RAH, right anterior horn. LAH, left ante-
prostate biopsy, screening PSA 2.5 to 4.0 ng./ml. regardless of rior horn. RTZ, right transition zone. LTZ, left transition zone. ML,
midline.
bladder outlet obstructive symptoms, life expectancy 5 years
or greater, no history of bleeding dyscrasia, no anticoagulant
therapy, no medication or food supplement that could de-
zone. A sextant biopsy site only was positive in 27% (10 of 37)
crease or increase serum PSA, except saw palmetto, and no
of men with cancer. Positive biopsy results in sextant and
history of transurethral resection of the prostate or open
alternate sites were observed in 46% (17 of 37) of patients. A
prostatectomy. These 268 men were asked to undergo a pros-
repeat biopsy was recommended in 10 men for either intra-
tate biopsy at no charge.
prostatic epithelial neoplasia (5) or atypical suspicious
A total of 151 (56%) men agreed to participate in this
glands (5). The repeat biopsy was positive for cancer in 2 of 4
institutional review board approved study and signed an
men.
informed consent. All 151 men underwent an 11-core multi-
The distribution of a positive biopsy site in all 37 patients
site directed biopsy (see figure).9 Any hypoechoic area or
and in those 12 with clinically insignificant cancer based on
abnormal digital rectal examination finding that was not
the 2 biopsy strategies is shown in the table. Only 1 core
biopsied with the 11-core technique was also biopsied. Me-
positive for cancer was seen in 14 men, 8 of whom had a
dian time from initial screening PSA to biopsy was 60 days
positive alternate site. Gleason scores were 6 in 12 patients,
(range 2 to 213). No interval PSA values were obtained be-
7 (4 ⫹ 3) in 1 and 8 in 1. The length of cancer in these biopsies
tween the initial PSA and time of biopsy. All biopsy cores
was 3 mm. or less in all 12 patients with a Gleason score of 6.
were color coded with dye and submitted in 3 separate con-
Of 9 cases with 2 cores positive for cancer Gleason score was
tainers, including 1 marked right, 1 left and 1 alternate sites,
6 in 6, 7 (4 ⫹ 3) in 2 and 8 in 1. Of 14 cases with 3 or more
to reduce cost and enable accurate identification of the origin
cores positive for cancer, including 1 with 7 positive cores,
location of each core. All biopsies were reviewed by 1 pathol-
Gleason score was 7 in 5 (3 ⫹ 4 in 4 and 4 ⫹ 3 in 1) and 8 in
ogist.
1. The designation of clinically significant disease was based
All patients underwent a digital rectal examination and
on the definition proposed by Terris et al, that is more than
transrectal ultrasonography of the prostate immediately be-
1 positive core, Gleason score 7 or greater or a cancer focus in
fore biopsy. The prostate gland volume was determined by
1 core greater than 3 mm.11 All 37 cases could have been
the elliptical method. No patient was excluded from study
evaluated by this definition and, using these criteria, 67.6%
because of an abnormal digital rectal examination or trans-
(25 of 37) could have been classified as having clinically
rectal ultrasonography. Demographic information, including
significant disease. Clinically significant cancer was detected
patient age, ethnicity, PSA history, family history of prostate
in 1 patient by only a sextant biopsy compared to 2 using only
cancer and use of any medication or food supplement that
an alternate site biopsy strategy. A positive biopsy at sextant
could influence the PSA value, such as finasteride, saw pal-
and alternate sites was observed in 22 patients.
metto and any androgen or estrogen, dehydroepiandros-
To date, 19 men have undergone radical prostatectomy,
terone, herbs and vitamins, was recorded. Tumor volume in
including 14 at our institution. The tumor volume was 0.5 cc
the radical prostatectomy specimens was determined by a
or less in 8 patients (mean 0.18, range 0.03 to 0.36) and
previously described computer assisted volumetric pro-
greater than 0.5 cc in 6 (mean 1.27, range 0.61 to 3.29). The
gram.10 We statistically analyzed the relationship between
pathological stage was pT2 in 12 patients and pT3 in 2. A
variables using the chi-square statistic.
positive margin of resection was questionably focal in the
patient who had the largest tumor, which was present in
RESULTS
extraprostatic tissue. Of the men with tumor volume 0.5 cc or
Overall, cancer was detected in 24.5% (37 of 151) of the less Gleason score was 6 in 4 and 7 in 4. Of the 6 patients
men biopsied. The median age of all 151 men was 62 years with tumor volume greater than 0.5 cc Gleason score was 6 in
(range 43 to 74). There was no difference in the median age 2, 7 in 3 and 9 in 1. Radiation therapy was selected by 6
of the men with positive or negative biopsy (64 versus 62 patients, watchful waiting by 3, 6 patients were undecided as
years). The ethnic distribution of the men in our study was to which therapeutic option to choose and 1 was lost to
75% (114 of 151) white, 17% (26 of 151) black and 7% (11 of followup.
151) Hispanic. The cancer incidence was 26% (30 of 114) Mean total prostate gland volume as determined by ultra-
among white men, 23% (6 of 26) among black men and 9% (1 sound showed a significant difference (p ⫽ 0.016) between
of 11) among Hispanics. Conventional systematic sextant patients with cancer (37.6 cc) and those who had a negative
biopsies, which accounted for 6 of the 11 cores in our biopsy biopsy (45.7 cc). Mean gland volume in patients with only a
scheme, detected 73.0% (27 of 37) of the cancers. Cancer was positive alternate site was 39.2 cc compared to 31.1 cc and
detected only in an alternate site in 27% of cases, including 8 40.5 cc in those who had a positive sextant site biopsy or
in the anterior horn right and/or left and 2 in the transition positive alternate and sextant sites. These differences were
not significantly different.
‡ TOSOH Medics, San Francisco, California. Results of the digital rectal examination were abnormal
 SERUM PROSTATE SPECIFIC ANTIGEN VALUE AND ITS RELATION TO BIOPSY STRATEGY 759
Location of positive biopsy cores in patients with cancer and those with clinically insignificant cancer
Pos. Biopsy Site
Biopsy Strategy
Anterior Horn Transition Zone Apex Mid Base

No. pos. biopsy cores Ca:

Alternate only 9 2 – – –
Sextant only – – 7 5 5
Both 19 5 11 8 6
No. pos. biopsy cores clinically
insignificant Ca:
Alternate only 5 2 – – –
Sextant only – – 2 1 2

and suspicious for cancer in 11 (7.3%) men, including 6 (5.5%) value to 2.5 ng./ml. will increase the disease specific survival
who had negative and 5 (13.5%) who had positive biopsy rate remains to be determined. However, it has been amply
results. Results of transrectal ultrasonography were abnor- demonstrated that treatment outcome for surgery and radi-
mal in 31 (20.5%) men, including 18 (15.8%) with negative ation therapy is associated with preoperative PSA, with pa-
and 13 (35.1%) with positive biopsy results. Of the 136 men tients with PSA less than 4 ng./ml. fairing better than those
evaluable for a family history of prostate cancer 23 (22%) with PSA 4.1 to 10 ng./ml.14, 15
with negative biopsy results had a family history of prostate Comparison of the conventional systematic sextant biopsy
cancer compared with 12 (34.3%) who had positive biopsy strategy and an 11-core multisite directed scheme revealed
results. This difference was not significant (p ⫽ 0.1863). A cancer detection rates of 17.9% and 24.5%, respectively. An
total of 20 patients reported taking saw palmetto, including 4 alternate biopsy site only was positive in 10 patients. Clini-
(10.8%) with cancer and 16 (14%) with a negative biopsy cally insignificant disease based on the previously stated
result. criteria was detected in 12 patients, 7 (58.3%) of whom had
A history of PSA testing was available for only 46 men only a positive alternate site. In addition, only 8% (2 of 25) of
because of inability to recall prior PSA values. Of the 39 men the significant cancers would have gone undetected if only
who could recall PSA history and who had negative biopsy the conventional systematic sextant biopsies were per-
results 36 consistently had values greater than or equal to formed. These data suggest that extended biopsy strategies
2.0 ng./ml. but less than 4.0 ng./ml., and 3 had levels consis- could be avoided in men with PSA between 2.5 and 4.0
tently less than or equal to 2.0 ng./ml. Of the 7 men with ng./ml. in an attempt to minimize the diagnosis of insignifi-
positive biopsy results 1 had PSA 4.8 ng./ml. and 6 had PSA cant cancers without jeopardizing the detection of significant
2.0 to 4.0 ng./ml. cancer.

DISCUSSION
CONCLUSIONS
There are relatively few studies that document the inci- A significant number (24.5%) of men with serum PSA in
dence of prostate cancer when the PSA assay value is 2.5 to the range of 2.5 to 4.0 ng./ml. have prostate cancer and based
4.0 ng./ml. In 1996 Shroder et al reported a 14% incidence of on current clinical criteria the majority (70%) of these can-
PSA in the reflex range of 1 to 3.9 ng./ml., and 28% of these cers are clinically significant. Furthermore, if a decision is
men had cancer.12 In a larger study from Washington Uni- made to perform a biopsy when serum PSA is between 2.5
versity biopsy in 36% of men in a screening population with and 4.0 ng./ml., the conventional systematic sextant tech-
PSA 2.6 to 4.0 ng./ml. revealed cancer in 22%. As is readily nique may be preferable to an extended schema to decrease
apparent, these findings are similar to those found in men the detection of clinically insignificant cancers. A more de-
with PSA between 4.1 and 10 ng./ml.13 Our finding of a 24.5% finitive answer regarding the optimum biopsy strategy in
positive biopsy rate is in agreement with these previous these patients awaits larger multi-institutional studies.
reports.
The significance of our study is that approximately 56% of
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