0022-5347/98/1593-0899$03.

00/0
THEJOURNAL OF UROLOGY Vol. 159, 899-903.March 1998
Copyright @ 1998 by AMERICAN INr.
UROL~GICALASSOCIATION, Printed in U S A

CHARACTERISTICS OF SCREENING DETECTED PROSTATE CANCER IN

MEN 50 TO 66 YEARS OLD WITH 3 TO 4 NG./ML-. PROSTATE SPECIFIC
ANTIGEN
P. LODDING, G. AUS, S. BERGDAHL, R. FROSING, H. LIMA, C.-G. PIHL AND J. HUGOSSON
From the Urology Division and Department of Pathology, Sahlgrenska University Hospital, Ostra, Gteborg and the Department of
Clinical Chemistry, Lund University Hospital, Malmo, Sweden

ABSTRACT
Purpose: We defined the yield and nature of prostate cancer in the setting of population based,
randomized prostate specific antigen (PSA) guided screening in men with PSA levels between 3
and 4 ng./ml. who were 50 to 65 years old at the time of randomization.
Materials and Methods: Sextant biopsies were performed in 243 men with PSA of 3 to 4 ngJml.
Therapy decisions were based on core cancer length, histological grade and life expectancy.
Results: Of the men 32 (13.2%)had prostate cancer constituting 23%of all of the 137 prostate
cancers to date detected in the first round of our screening study. Age and PSA were similar in
men with and without prostate cancer. Men with prostate cancer had significantly lower free PSA
and free-to-total PSA ratio, and higher PSA density. Cancer was clinical stage T l c in 27 cases and
stage T2 in 5. Hypoechoic areas were noted at transrectal ultrasound in 10 cases. Digital rectal
examination and transrectal ultrasound were normal in 21 cases (66%).To date 14 patients have
undergone prostatectomy. Surgical specimens showed a mean tumor volume of 1.8 cc (range 0.6
to 4.4) and significant amounts of high grade tumor were present in only 3 cases. Margins were
positive in 5 cases, and pathological stage was pT2 in 8 cases and pT3 in 6.
Conclusions: By lowering the PSA cutoff from 4 to 3 ng./ml. an increase in cancer detection by
30% was achieved. While the addition of free-to-total ratio and PSA density may reduce the
number of biopsies by about 15%with sensitivity maintained at 90%, systematic sextant biopsies
were necessary in most of these men as 66% of the tumors were negative on transrectal
ultrasound and digital rectal examination. "he majority of these cancers were clinically signif-
icant and suitable for curative treatment. If therapy decisions are based on the pathological
findings of the biopsies, the risk of treating insignificant cancers seems low.
KEYWORDS:prostatic neoplasms, prostate-specific antigen, biopsy
PSA appears to be the single most cost-efficient primary opsy material and surgical specimens, the diagnostic proce-
tool in prostate cancer screening.' In most screening pro- dures and clinical decisions are described. An attempt is
grams PSA greater than 4 ng./ml. (Hybritech)or equivalent made to evaluate the clinical significance of the tumors and if
is considered abnormal and leads to further evaluation with clinical significance can be predicted from the biopsy mate-
digital rectal examination, transrectal ultrasound and biop- rial.
sies according to various algorithms.2-4 Prostate cancers de-
tected at screening through an increase in PSA alone (clinical PATIENTS AND METHODS
stage Tlc) are clinically significant in the majority of cases Patients and design of screeniw. In the community of
and appear clearly different from the insignificant Gothenburg, Sweden (population 440,000) there were as of
found in autopsy series.5However, the evidence ofthis find- December 31,1994,32,299 men alive who were born between
ing iS mainly based on cases when mean PSA levels among janUary 1, 1930 and December 31, 1944. Following permis-
Tlc tumors are around 10 ng./ml.2-3*6-10 and it is not Clear sion from the ethical committee 10,000 men 50 to 65 years old
whether it also applies to Tlc tumors with low PSA values were, with the of the Swedish National Statistic- Bu-
and therefore Presumably small volumes- It is known from reau, randomized for prostate cancer screening and the re-
clinical studies that prostate cancers detected in men with mainder served as a future controlgroup. Of the men 161
PSA levels below 4 ng./ml. may be clearly significant and well were excluded from screening due to a previous diagnosis of
suited for surgical treatment." At digital rectal examination prostate cancer (54), death or change of residency after the
and transrectal ultrasound guided screening almost 30% of time of randomization. n u s , 9,839 men were actually in-
the detected prostate cancers have been reported to Occur vited to participate in the study and 5,859 (59.5%)accepted
among men with PSA values below 4 nglml.2 to have PSA sampled. Total and free PSA values were ana-
In Our screening study men with d x ~ o r m a PSA
l lyzed. Of the participants 660 (11.3%)had a PSA of 3 nglml.
between 3 and 4 ng./ml. have been systematically biopsied, or mom and we= offered ~ o l o g assessment,
i ~ including
and in this report we focus our attention on the marginal digital rectal examination, transrectal ultrasound (Briiel &
group of screened cases within this PSA interval. The yield of Kjaer 3535 ultrasound machine, 7 MHz. biplane probe model
Prostate cancer, the histopathological characteristics of bi- 8551) and systemic sextant biopsy,12 and 611 (93%)accepted.
The study group for this repok consists of the 243 men-with
Accepted for publication September 5, 1997. PSA levels of 3 to 4 ngJml. who underwent biopsy from
Supported by Grant 3792-Bg6-01XABfrom The Swedish Cancer
Society and by contributionsfrom Wallac ,b k u , F h h d , Abbot January 1995 to June 1996. At the time of biopsy the oldest
Scandinavia AB and Schenng-Plough AB%tockholm, Sweden. men were 66 years old.
899
900 PROSTATE CANCER SCREENING

Pathology. All specimens of prostate cancer were reviewed J

I .... I . . . . I

by 1 pathologist (C.-G. P.). Maximum core cancer length and 0

o Benign,nod
maximum percentage of cancer in the cores were recorded. If 45 - 0 0 Benign,palpablenodule .
2 or more adjacent cores contained cancer the sum of the
cancer lengths of the 2 cores containing the most tumor Cancer,n o d
tissue was noted and, for the estimation of the percentage of Cancer,palpable nodule
cancer within these cores, was divided by the sum of the total 0

length of the 2 cores. If cancer was detected in several non- 35

adjacent cores only the core with the longest cancer area was n o
recorded. The prostatectomy specimens were fixed in forma- @ 30 O O D O 0

lin and the whole gland was then serially blocked in trans-
verse planes at 5 mm. intervals. Tumor area was measured g 2 5
with a 2 mm. grid. Tumor volume was estimated by multi- a :
plying the sum of the tumor areas in consecutive slides by 5 20 :
mm. To make conservative estimations no shrinking factor
was used. Gleason grades and score were noted. In biopsies 15 :
the area percentage of grade 4 or 5 tumor was estimated, and
in surgical specimens the volume percentage of grade 4 or 5 -
tumor was estimated. 10
m
Clinical management. Curative treatment was suggested
to patients with low co-morbidity and a life expectancy of
more than 10 years with tumors judged significant. Clinical
0
0
.
4
significance was considered if core cancer length was 3 mm. 0
or greater on any biopsy, combined core cancer lengths of 2 0 ,05 ,1 ,15 ,2 2 5
adjacent biopsies were 3 mm. or greater, tumor was palpable
PSA density
or tumor contained Gleason grade 4 or 5. Patients were
liberally subjected to re-biopsy of the tumor area129 13 if pri- FIG. 1. Scattergram shows free-to-total (FIT)ratio and PSA den-
mary biopsies were equivocal. Radical retropubic bladder sity for each of 243 biopsied men. Observations are subdivided ac-
neck sparing prostatectomy combined with bilateral lymph cording to bio sy outcome (benign or cancer) and digital rectal ex-
amination fin& s (normal or palpable nodule).
node dissection were performed.

RESULTS TABLE2. Separate and combined findings at digital rectal

Prostate cancer was detected in 32 of the 243 men (13.2%), examination and transrectal ultrasound, and their predictive
constituting 23% of all 137 cancers detected in the first round values in 243 bwpsied men with PSA of 3 to 4 ng. lml.
of our screening study (table 1). There were no significant
differences between men with benign and malignant biopsies
in regard to age or PSA level. Prostate volume was signifi- Digital rectal examination 27 (84) 190 (90) 12
cantly smaller in men with cancer. Mean PSA density was normal
significantly higher in subjects with cancer, while mean free Palpable nodule 5 (16) 21 (10) 19
Transrectal ultrasound 22 (69) 176 (83) 11
PSA and free-to-total PSA ratio were significantly lower. Of normal
the 32 men with malignant biopsy outcome 30 (94%) had a Hypoechoic area 10 (31) 35 (17) 22
free-to-total ratio of 27% or less (fig. 1). Digital rectal examination 21 (66) 167 (79) 11
Digital rectal examination and transrectal ultrasound + transrectal ultra-
sound normal
findings are listed in table 2.Of the prostate cancer group 21 Palpable nodule and/or 11 (34) 44 (21) 20
(66%) had normal findings on digital rectal examination and hvwechoic area
transrectal ultrasound, and no T3 tumors were found. A
clinical stage T2 nodule was not significantly associated with
malignant biopsy outcome (chi-square p = 0.357)but a hy-
poechoic area on transrectal ultrasound was significant (chi- Surgery was done in 14 patients, 4 received radiotherapy
square p = 0.0466). and 4 are scheduled for surgery. Ten patients are under
Primary biopsy data are listed in table 3. Only 2 tumors observation because of severe co-morbidity (2),unwillingness
showed areas of grade 4 or 5, and Gleason score 3 + 3 was the to undergo curative treatment (3)and suspicion of insignifi-
most frequent pattern. Biopsy was repeated in 20 men, in- cant tumor (5).For the operated patients the clinical and
cluding 15 who had a single positive primary biopsy and 11 histopathological data are listed in table 4. None of these
who had core cancer lengths 3 mm. or less. &-biopsies were tumors was of insignificant size (less than 0.5 cc) and mean
positive in 17 of the 20 cases (85%). tumor volume was 1.8cc (median 1.1).High grade tumor was
present in more than 5% of the tumor volume only in 3 cases.
Six patients had a pT3 tumor and margins were positive in 5.
TABLE1. Descriptive data (mean values) on 243 bwpsied men with Lymph nodes were free of metastasis in all cases and all bone
PSA of 3 to 4 ng. Iml.
scans were negative.
p Value (unpaired DISCUSSION
Benign Ca 2-tailed Student’s
t test) As many as 23% of all cancers detected in our PSA guided
No. pts. 211 32 screening study occurred in men with PSA of 3 to 4 ng./ml.
Age (yrs.) 59.4 59.0 0.645 From previous studies it is well known that a substantial
Pmstatevol.attransreetal 40 34 0.037 proportion of patients with localized prostate cancer have a
ultrasound (cc)
PSA (nglml.) 3.39 3.45 0.320 serum PSA below 4 ngJml. Mettlin et a1 reported prostate
Free PSA (nglml.) 0.69 0.55 0.005 cancer in 29% of their cases, which were selected based on
Free-to-btal ratio (%) 20.4 16.1 0.003 pathological findings at digital rectal examination and/or
PSA density (nglmllgm.) 0.10 0.12 0.003
transrectal ultrasound,2 and Catalona et a1 found prostate
 PROSTATE CANCER SCREENING 901
TABLE3. Data on primary biopsy outcome i n all 32 men missed cancers were significant, as 1 was removed and found
with cancer to be a 0.58 cc, Gleason 3 + 3 tumor and the other was
No. Pts. treated conservatively due to co-morbidity but the biopsy
Core Ca length (median 4.2 mm., range showed 10.5 mm. of cancer with 14% grade 4 tumor. The
019-21.5):* free-to-total ratio, particularly in combination with PSA den-
Less than 3 12 sity, is of value in increasing the specificity of a single PSA
3-10 14 test in this low interval, which can reduce the number of
Greater than 10 6
o/o Ca on biopsies (median 27, range 1-88):t
unnecessary biopsies by about 10 to 20%.14. However,
Less than 25 15 the optimal free-to-total ratio and PSA density cutoff values
25-50 10 need to be further clarified.
Greater than 50 7 We found no age variation between patients with benign
Gleason score:
4 or Less 8
and malignant biopsy outcome. In fact, using the age ad-
5 4 22 justed reference ranges proposed by Oesterling et a1,20 we
7 or Greater 2 would have missed 27 cancers (84%)(fig. 2).
% Grade 4-5: Is the detection of these tumors of any value to the pa-
0 30
15 1
tients, or are we detecting clinically insignificant tumors?
30 1 Histological grade (Gleason grades 4 and 5) and tumor vol-
No. pos. cores: ume (usually with a cutoff value of 0.5 cc) are the 2 most
1 17 important determinants of the clinical significance of pros-
2 6
3 5
tate cancer. Tumor volume is intimately associated with the
4 4 serum PSA level. The exact interpretation of these parame-
Miimum cancer length found in a single core or, if ters, however, remains controversial.3.8.9.12.13.19,2i-24The
risk of detecting insignificant cancers a t biopsy has been
contained cancer, the sum of the core cancer lengths of those 2 cores.
iMaximum core cancer length divided by the total biopsy length of the discussed12.'3.19.2"27 and among Tlc cancers 11 to 30% are
core(s) involved. reported to have a volume of less than 0.5 cc.6-9 The need to
predict clinical significance from the biopsy specimens is
especially great when dealing with Tlc cases within the
cancer in 22% of biopsied men with PSA of 2.6 to 4.0 ng./ml. lowest PSA ranges.
and normal digital rectal examination.14 The study of Cata- We have basically applied the guidelines of Dietrick et a125
lona et a1 differs from ours in that patient age was an average to predict tumor size (and significance) with some modifica-
of 6 years older, only 36%of the cases within the studied PSA tions. Some authors have argued that core cancer length is
interval were actually biopsied, as opposed to more than 90% not predictive of the pathological stage and that biopsy find-
in our study, and participants were volunteers rather than ings of less than 3 mm. of cancer can represent significant
randomized and population based. These differences may tumors that should be aggressively treated.27-29 This finding
account for the higher cancer frequency reported in their may be true, especially in cases with higher PSA levels
study. and/or palpable lesions in which small core cancer lengths
Of all of our men with serum PSA between 3 and 4 ng./ml. are more likely to reflect sampling errors. The outcome of our
13.2%were diagnosed with prostate cancer. In these early re-biopsies, which on most occasions confirmed a core cancer
tumors digital rectal examination and transrectal ultrasound length of 3 mm. or more, tends to support this finding fur-
findings were generally negative. If a positive digital rectal ther. However, in this group of patients with low PSA a
examination and/or transrectal ultrasound had been re- conservative approach is appropriate12.13.25.26 and no harm
quired to proceed with biopsies, as in some screening pro- is likely to occur by attempting to confirm equivocal primary
gram~,~.4,15 21 of the 32 cancers (66%) would have been biopsy findings by re-biopsy. Using our criteria, we seem to
missed. Our findings that digital rectal examination and avoid over treatment of insignificant tumors. In fact, our
transrectal ultrasound are weakly or not at all significantly findings indicate that screening detected cancers of predom-
related to malignant biopsy outcome in cases within this PSA inantly clinical stage Tlc associated with a low serum PSA
interval and have poor positive predictive value agree with are significant, frequently serious tumors, which preferably
those of Colberg et a1.16 should be treated with curative intent if the patient is oth-
In our program the only criterion for biopsy was a serum erwise healthy and not too old.6,'O Indeed, patients subjected
PSA of greater than 3 ng./ml. Since all men with palpable to radical prostatectomy with preoperative serum PSA levels
nodules are likely to be biopsied regardless of PSA density of 4 ng./ml. or less were recently shown to have a 5-year
and free-to-total ratio in any screening program, it is of relapse-free survival of 89%,while the corresponding figure if
particular interest to evaluate whether the use of PSA den- serum PSA were 4 to 20 ng./ml. was only about 609L.30
sity and free-to-total ratio separately or combined can reduce Of the 10 patients who are not currently scheduled to
the number of biopsies in men with normal digital rectal receive curative treatment only 5 have been considered to
examination while maintaining an acceptable sensitivity of have insignificant tumors. Thus, assuming that we have the
at least 90%.Among our 217 men with normal digital rectal same accuracy at predicting tumor significance from the bi-
examination a PSA density cutoff of 0.057 to proceed with opsy material in all patients as in those who have undergone
biopsy would have reduced the number of biopsies from 217 prostatectomy, only 5 of the 32 cancers (16%)would be insig-
to 196 (lo%),while 2 of 27 cancers would have been missed nificant. This figure is surprisingly low in this select group of
(sensitivity 93%). Thus, PSA density alone seems to be of patients and it is comparable to figures reported in uns-
limited value to determine the need for biopsy in this low elected studies on Tlc tumors as a group6-9 and by Catalona
PSA interval. These observations are in agreement with et al on men with PSA of 2.6 to 4 ngJml.14 Long-term fol-
those of Presti et a1.17 lowup of patients judged to have insignificant tumors is im-
The use of a free-to-total ratio cutoff of 26%among the men portant to rule out the possibility of under treatment, espe-
with normal digital rectal examination would reduce biopsies cially in younger men.
from 217 to 190 (12%) while missing 2 cancers (sensitivity Our cancer cases differed, probably due to patient selec-
93%). Using a combination with a cutoff of 0.075 for PSA tion, from those in a large clinical study of referred prostate
density and 21.5% for free-to-total ratio the optimal reduc- cancer patients with PSA of 4 ngJml. or less." Noldus and
tion (217 to 172, 21%)of biopsies was obtained in our study Stamey reported that only 30% of patients had a normal
while maintaining a sensitivity of 93%. However, the 2 digital rectal examination, mean tumor size was 2.3 ec and
902 PROSTATE CANCER SCREENING

TABLE4. Descriptive data on 14 patients subjected to radical retropubic prostatectomy

Biopsy* Specimen

Pt. No. c:r 4bCa Gleason % Tumor Gleason 9%

?:zl PT
Age stage (nglml.) Density

~ ~~
Ratio
2:s bneh
(mm.)t
COWS
Grades
+ score
Grade4
or 5
Vol.
(cc)
Grades
+ Score
Grade4
or 5 Invasion ~ar’ns
No. Stage

51 Tlc 3.91 0.13 17.9 1.2 10 2+2=4 0 1.2 3+2=5 0 No Yes 6 Pm

52 Tlc 3.54 0.16 10.2 13.8 79 3+2=5 0 2.9 3+2=5 0 No Yes 1 pT3
55 Tlc 3.35 0.09 13.9 7 56 3+3=6 0 0.7 3+4=7 13 No No 1 Pm
56 Tlc 3.3 0.07 25.8 5.1 28 3 + 3 = 6 0 0.6 3+3=6 0 No No 2 Pm
57 T2b 3.87 0.24 8.3 8 52 3+3=6 0 3.2 3+3=6 0 No No 2 pT3
58 Tlc 3.66 0.15 6.6 15.6 86 3+4=7 30 3.0 3+4=7 30 Yes Yes 1 pT3
58 Tlc 3.17 0.11 16.4 2 10.2 57 3+3=6 0 1.0 3+3=6 0 No No 1 Pm
60 Tlc 3.09 0.10 17.5 2 8.0 30 3+3=6 0 0.6 3+2=5 0 No No 7 Pm
60 Tlc 3.52 0.10 9.2 3 2.0 12 3+3=6 0 1.0 3+3=6 0 No No 2 pT3
62 Tlc 3.77 0.11 8.0 3 7.7 41 3+2=5 0 1.0 3+3=6 0 No No 2 pT2
63 Tlc 3.36 0.15 11.6 3 8.2 46 3+2=5 0 1.4 3+2=5 0 No Yes 1 pT3
63 Tlc 3.88 0.13 11.9 1 2.1 16 3 + 3 = 6 0 0.8 3+1=4 4 No No 3 Pl-2
64 T2b 3.62 0.08 15.2 3 18.1 60 3+ 3=6 0 4.4 3+3=6 2 Yes Yes 1 pT3
65 T2b 3.69 0.07 22 2 21.5 88 3+3=6 0 3.0 3+4=7 28 NO NO 2 Pm
* In rebiopsied cases listed data refer to the most serious biopsy outcome.
t The maximum core cancer length found in a single core or, if two adjacent cores contained cancer, the sum of the core cancer lengths of those 2 cores.
$ Maximum core cancer length divided by the total biopsy length of the core(s) involved.

r = I
62
80 0 0 0 tate cancers detected in a multimodality early detection pro-
3 3.1 3.2 3.3 3,4 3,5 3.8 3.7
PSA (ng/rnl)
FIG. 2. PSA level and age for 32 men with prostate cancer. Only
right lower quadrant represents patients who would be considered to
have abnormal age related PSA values (see text).
tumors with a volume of less than 0.5 cc, judged to be insig-
nificant, occurred in 9%. our study, which represents con-
secutive patients from an unselected population based group
of screened men 50 to 65 years old at randomization, the
hmors Were smaller and p ~ d o - ~ t b ’ clinical stage T1c,
and high grade tumors were less frequent.
CONCLUSIONS
We have shown that prostate cancers are relatively fie-
quent in men with PSA between 3 and 4 ngJml., constituting
about 25% of all screening detected cancers in our study.
These tumors require systematic sextant biopsies regardless
of digital rectal examination and transrectal ultrasound find-
ings to be detected but the number of biopsies can be reduced
by about 10 to 20%, maintaining a sensitivity of more than
90%, by also considering free-to-total ratio and PSA density.
Based mainly on careful estimations of core cancer length
and histological grade of the biopsies, it is possible to exclude
accurately a tumor volume of less than 0.5 cc and at least
over treatment in this group of patients can be safely
avoided. The majority of these tumors are small but clearly
significant and well suited for curative treatment.
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