ELSEVIER

AGE- AND RACE-SPECIFIC REFERENCE RANGES FOR

PROSTATE-SPECIFIC ANTIGEN FROM A LARGE
COMMUNITY-BASED STUDY*
EDWARD P. DEANTONI, E. DAVID CRAWFORD, JOSEPH E. OESTERLING, COLLEEN A. ROSS,
E. ROY BERGER, DAVID G. McLEOD, FRANK STAGGERS, AND NELSON N. STONE

ABSTRACT
Objectives. To analyze the relationship of age and race to prostate-specific antigen (PSA) levels among
participants in a community-based study.
Methods. A total of 77,700 records of men aged 40 to 79 years were analyzed from a longitudinal study of
PSA conducted during Prostate Cancer Awareness Week 1993 and 1994. Records from 1994 were not
included for men who were tested in 1993. All cases of prostate cancer were excluded. Records with outlier
PSA values greater than 20 ng/mL were eliminated from the analysis (n = 190; 24%).
Results. Mean PSA values (ng/mL) of 1 O-year age groups differed significantly (P <[Link] ] between each
group (ages 40-49, 0.83; 50-59, 1.23; 60-69, 1.83; 70-79, 2.31). In each successively older age group,
PSA variance increased significantly (P = 0.0001 1. Standard deviations (SD) by age group were: 40-49,
0.79; 50-59, 1.33; 60-69, 1.94; and 70-79, 2.35. Significant differences in mean PSA by race were found.
Pairwise differences in mean PSA were found between whites and blacks, whites and Latinos, blacks and
Asians, and Asians and Latinos (P <[Link] 1). No statistically significant differences in PSA variance between
racial groups were found. Age-within-race analysis resulted in consistent statistical significance when com-
paring variance among age cohorts in each race.
Conclusions. Age-specific PSA reference ranges are a result of the increasing mean PSA and increasing PSA
variance in successively older cohorts of men. Mean PSA values differ significantly by race, but differences
in PSA variance do not. The clinical significance of race-specific PSA reference ranges has yet to be deter-
mined. UROLOGY 48: 234-239, 1996.

rostate-specific antigen (PSA) is the most valu- mated 317,100 new cases will be diagnosed, rep-
P able tumor marker for prostate cancer.l The
widespread use of PSA testing among asympto-
resenting a 30% increase over the preceding year.3
An estimated 41,400 deaths will have occurred, a
matic men has catapulted prostate cancer to the 2.5% increase over 1995.3 Much of the increase in
forefront of public awareness and clinical contro- incidence, but not all, is attributable to more and
versy. Between 1980 and 1990, prostate cancer in- better detection methods, particularly the PSA test.
cidence rates increased 50%.’ Although prostate Moreover, better detection is having considerable
cancer mortality rates have also increased, they ap- influence on the stage distribution of prostate can-
pear to be leveling somewhat. In 1996 an esti- cers at time of diagnosis. Many more localized, po-
tentially curable tumors are now being detected,
and the number and incidence of advanced, met-
*This study was funded in part by an unrestricted educational astatic prostate cancers have decreased.4x5
grant from Abbott Diagnostics, Abbott Park, Illinois.
From the Division of Urology, University of Colorado Health The use of PSA as a screening test in asympto-
Sciences Center, Denver, Colorado, the Michigan Prostate Insti- matic men has been questioned because of the un-
tute, University of Michigan, Ann Arbor, Michigan, and the Pros- certainty that detected cancers would inevitably
tate Cancer Education Council progress to clinical disease and that the mortality
Reprint requests: Edward P. DeAntoni, Ph.D., Division of rate from prostate cancer will decline by the de-
Urology, University of Colorado Health Sciences Center, Cam-
pus Box C319, 4200 East Ninth Avenue, Denver, CO 80262 tection of these cancers.6 However, “PSA detecta-
Submitted: January 29, 1996, accepted (with revisions): bility” has been equated with clinically significant
March 15, 1996 cancers.7-9

COPYRIGHT 1996 BY ELSEWER SCIENCE INC 0090~4295/96/$15.00

234 ALL RIGHTS RESERVED PII SOO90-4295(96)00091-X
 Earlier detection of prostate cancers that would of prostatic volume. The operator dependency of
in fact progress to clinical manifestation is simi- TRUS can influence subsequent calculations of
larly questioned because of “lead-time bias”-the prostate volume. Intraindividual variation of PSA
appearance of longer survival with no actual sur- test results has hampered the establishment of
vival benefit from early detection.‘j The null hy- “normal” change in PSA over time. The advantage
pothesis behind lead-time bias is that no cancer of assaying free versus bound PSA is still under
therapy has efficacy: cancer-specific mortality will investigation.
happen at its appointed time. Research has in fact Age-specific PSA reference ranges represent the
documented a “lead-time advantage” of PSA test- attempt to improve the test’s sensitivity and speci-
ing to predict clinical occurrence of prostate can- ficity by the documentation of age-based PSA
cer by as much as 5 to 10 years.“-12 Prior to wide- changes and the recommendation of different cut-
spread PSA testing, a majority of the prostate off points for “normal” PSA and thereby different
cancers that were diagnosed were found to be ad- thresholds for biopsy. Studies have documented
vanced. Advanced prostate cancer is incurable, the correlation of age to PSA.26-29 As men age, PSA
and disease-specific mortality is inevitable unless values increase. This phenomenon has been attrib-
death from competing causes occurs first. Because uted primarily to increasing prostate volume.
advanced prostate cancer is incurable, clinicians Other factors hypothesized as responsible for the
advocate the early detection of prostate cancer increase of PSA with age include prostate infec-
with PSA testing and aggressive treatment of can- tions, prostatic infarction, microscopic prostate
cers that remain confined in the prostatic cap- cancer, and a normal prostatic “aging” process that
sule.13114When a cancer is confined to the prostate may allow increased leaking of PSA into serum.
and surgically excised, the disease rarely pro- There is recent quantifiable evidence of the impact
gresses. l4 of benign enlargement and inflammation on ele-
A shortcoming of PSA as a screening test for the vated PSA values among older men with no evi-
early detection of prostate cancer is the relatively dence of prostate cancer.3o
high number of false-positive results, when the The retrospective comparison of ASRR to the
PSA level is above 4.0 ng/mL but the biopsy is standard reference point of 4.0 ng/mL in “predict-
negative.” Of less concern are false-negative PSA ing” prostate cancer has shown that ASRR does
test results: a positive biopsy with a PSA score of increase sensitivity among younger men (less than
less than 4.0 ng/mL. “False negative” is somewhat 60 years of age) and specificity among older men
of a misnomer, because biopsy would have been (more than 60 years of age) .31,32
indicated as a result of an abnormal digital rectal Racial differences in the incidence of prostate
examination (DRE) and, perhaps, an abnormal cancer have been noted repeatedly. Blacks in the
transrectal ultrasound (TRUS) examination. The United States have the highest incidence of the dis-
positive predictive value of the PSA test has been ease of any racial group.33 Several hypotheses have
shown to be enhanced considerably when con- been proposed to explain this phenomenon. Cir-
ducted with the DRE, and the common recom- culating testosterone levels are higher in blacks,
mendation is that the two tests be performed to- and this may have greater impact on the hormonal
gether. Nevertheless, only 1 patient in 10 with a milieu of the prostate.34,35 The inhibiting role of
suspicious DRE will prove to have prostate cancer vitamin D3 on prostate cancer may be compro-
on biopsy if the PSA is less than 4.0 ng/mL.16,17 mised because of higher melanin levels in blacks.36
When the PSA is 10.0 ng/mL or higher, 50% of Dietary factors may also contribute to these racial
patients will have prostate cancer. The largest per- disparities in prostate cancer incidence.37 Asian
centage of elevated PSA test results falls between Americans have a generally lower incidence of
these two groups in the PSA “gray zone,” 4.1 to prostate cancer than whites and blacks, but they
9.9 ng/mL, where about 25% of men will have exhibit a higher incidence than men in Asia. Pat-
prostate cancer and 75% will have benign prostatic terns of prostate cancer incidence among Latin0
hyperplasia (BPH) . l8 men resemble incidence patterns among whites;
Various analytic techniques have been proposed later stage at diagnosis and higher mortality rates
to improve the sensitivity and specificity of PSA for Latinos may suggest delay in diagnosis rather
testing. These methods include calculations of PSA than racial difference.38
density ( PSAD >, l9 PSAD adjusted for volume of
the transition zone, 2o analysis of PSA velocity METHODS
( PSAV) , 21 free versus bound PSA, 22-25 and the ap-
Data were compiled from 1993 and 1994 records of partic-
plication of age-specific PSA reference ranges
ipants aged 40 to 79 years in a longitudinal study of PSA
(ASRR) .26 conducted during Prostate Cancer Awareness Week which
The calculation of PSAD necessarily involves a has been described previously.3g,40 Age and race were self-
TRUS examination in order to derive an estimation reported. Racial categories on the data instrument were: white

UROLOGY 48 (2)) 1996 235

(n = 70,772); black/African-American (4485); Latino/His-
panic (1543); Oriental/Asian (900); and other. In this report TABLE 1. Mean age and prostate-specific
races are described as white, black, Latino, and Asian. The antigen values, by 1O-year age groups, 40- 79
“other” category represented too few records for analysis. Age Group (II) Mean Age (SD) Mean PSA (SD)
Serum specimens were collected at 250 centers across the
country and processed by Roche Biomedical Laboratories, 40-49 (9,383) 45.34 (2.69) 0.83 ng/mL (0.79)
Inc., with the Abbott IMx PSA assay. P <0.0001*
Cases of prostate cancer were reported by participating cen- 50-59 (24,023) 54.65 (2.87) 1.23 ng/mL (1.33)
ters and were deleted, as were records from 1994 of men also P <0.0001*
tested in 1993. Records of men with an outlier PSA test of 60-69 (28,60 1) 64.45 (2.80) 1.83 ng/mL (1.94)
>20.0 ng/mL were deleted (n = 190, 0.24%) because of the P <0.0001*
potential distortion to the analysis and because of the high
70-79 (15,693) 73.46 (2.69) 2.31 ng/mL (2.35)
probability of unreported prostate cancer. In this subset, the
median PSA was 30.75 ng/mL, the maximum was 1197 ng/ KEY: SD = standard deviation.
mL, and the range was 1176.9. Analysis was conducted on *A statistically signiJicant di;fference (P < [Link] was consistently found when
comparing the mean PSA and the variance (SD) of each age cohort with the mean
77,700 records. In this database, 71,766 (92.4%) had a PSA PSA and the variance of every other cohort.
of 54 ng/mL; 5283 (6.8%) had a PSA of 4.1 to 10.0 ng/mL;
and 651 (0.8%) men had PSA values between 10.1 and 20.0
ng/mL. We cannot assure that every prostate cancer has been
eliminated from these records.
Pairwise comparisons of variability were made utilizing the TABLE II. Mean age and mean PSA (nglmf),
F ratio appropriate for unequal sample sizes. This procedure by race
was performed for variances in PSA across age, race, and age Mean PSA (SD)
Race (n) Mean Age
within race.
When outlier PSA values greater than 20.0 ng/mL were White (70,772) 61.4 1.63 (1.83)
excluded, the resulting distribution of PSA results was not a Black (4,485) 55.5 1.47 (1.87)
normal distribution. Therefore, the nonparametric Kruskall- Latin0 (1,543) 57.3 1.41 (1.79)
Wallis test was used to determine whether there are signifi- Asian (900) 59.9 1.58 (1.80)
cant differences between PSA values. Using the ranked PSA
KEY: SD = standard dewation
values, the Bonferroni test for multiple comparisons deter-
mined pairwise differences, following a significant result of
the Kruskall-Wallis test. The nonparametric Spearman cor-
relation coefficient was also calculated.
Differences in PSA values as a factor of race were
also found. Whites had the highest mean age ( 61.4
RESULTS
years) and highest mean PSA (1.63 ng/mL), fol-
In this large community-based investigation of lowed by Asians (59.9 years, 1.58 ng/mL) and
PSA as a test for the early detection of prostate then Latinos (57.3 years, 1.41 ng/mL) Blacks had
cancer, associations between age and PSA and be- the lowest mean age (55.5 years) yet the greatest
tween race and PSA were observed. variance in PSA values (SD = 1.87). Blacks were
For the entire cohort, the Spearman rank for PSA followed, in descending order of PSA variance, by
and age was 0.33 (r’ = 0.11; P <[Link]). The whites, Asians, and Latinos. Significant pairwise
cohort was separated into four lo-year age groups differences in mean PSA were found between
by decade. All age groups, in both lo-year and T- whites and blacks, whites and Latinos, blacks and
year age groupings, exhibit a normal distribution Asians, as well as Asians and Latinos. All differ-
as demonstrated by frequency distributions with ences were at P <[Link]. No statistically signifi-
skewness and kurtosis values characteristic of the cant differences in PSA variance among racial
normal distribution (Table I). Statistically signif- groups were found (Table 2).
icant differences (P <[Link] > were found among When divided into lo-year age groups, all races
mean PSA values for age groups 40-49, 50-59, demonstrate an increase in mean PSA and PSA
60-69, and 70-79 (Table 1) . Moreover, variances variance. Blacks have the highest mean PSA and
were significantly different among all four age highest variance across all age groups (Table 3).
groups (P <[Link] ) . Variances increase signifi- Age-within-race analysis resulted in consistent sta-
cantly in each successively older age group (P tistical significance when comparing variance
<[Link] ) . Normally, the mean and its standard among the age cohorts within each racial group,
deviation are not statistically related. However, except for the comparison of 60-69 and 70-79
PSA values do not fall within a normal distribu- age categories of both Latinos and Asians. Before
tion: 0.0 ng/mL is the lowest possible value. A suc- stratifying records into lo-year age groups, whites
cessively greater distribution of higher PSA values had the highest overall mean PSA. However, fol-
in older age groups raises the mean PSA, and a lowing stratification, blacks have the highest mean
greater variance (standard deviation) raises the PSA and the greatest PSA variance across all age
upper limits at the 95% confidence interval (CI) groups. Significant differences in PSA variance are
to create the phenomenon of age-specific reference found between whites and blacks across all age
ranges. groups (P <[Link]).

236 UROLOGY 48 (21, 1996

 TABLE Ill. Mean PSA values (SD), race by age
40-49 SO-59 60-69 70-79
White 0.82 (0.77) 1.2 (1.3) 1.8 (1.9) 2.3 (2.3)
n 7,553 21,921 26,719 14,979
Black 0.87 (0.92) 1.4(1.6) 2.0 (2.4) 2.5 (2.7)
n 1,377 1,582 1,112 414
Latin0 0.73 (0.71) 1.3(1.6) 1.8(2.1)* 2.0 (2.3)*
n 314 607 468 154
Asian 0.85 (0.57) 1.3(1.6) 1.8(1.9)* 2.3 (2.3)*
n 139 313 302 146
KEY: SD = standard deviation.
* Age groups between which no statistical significance was found between either mean PSA or PSA variance. Most age
group comparisons were signijicant at the 0.05 level.

TABLE IV. Age-specific PSA reference are comparable to those recommended by this
ranges, by race (95% Cl) seminal study by Oesterling et aI. and that have
been applied in follow-up studies42 (Table 5).
Age White Black Latin0 Asian Other reports have documented this association of
40-49 O-2.3 O-2.7 o-2.1 O-2.0 PSA concentration with age.“-” Increasing PSA
50-59 O-3.8 o-4.4 o-4.3 o-4.5 variability with age has been reported earlier and
60-69 O-5.6 O-6.7 O-6.0 o-5.5 has led to the recommendation that the upper lim-
70-79 O-6.9 o-7.7 O-6.6 O-6.8 its of normal should be lowered for men under age
KEY: Cl = confidence interval. 60 and raised for men over age 60.43
The present study has attempted to demonstrate
that age-specific PSA reference ranges are a result
of the increasing mean PSA and the increasing PSA
TABLE V. Comparison of age-specific PSA variance in successively older cohorts of men.
reference ranges (95% Cl) Mean PSA differs significantly by race, but racial
Age Current Study Oesterling et a/. * differences in PSA variance do not. The impor-
40-49 O-2.4 O-2.5 tance of different mean PSA values by race remains
50-59 O-3.8 o-3.5 to be determined. Thus, race-specific PSA refer-
60-69 O-5.6 o-4.5 ence ranges remain a version of age-specific PSA
70-79 O-6.9 O-6.5 reference ranges.
KEY: Cl = confidence interval. Because the level of PSA production depends on
* Reference 26. the quantity of prostate cells, a logical explanation
for an age-associated increase in PSA levels in men
who have no evidence of prostate carcinoma is the
Table 4 shows race-specific PSA reference ranges increasing volume of the prostate with age.26z29
(by lo-year age groups), at the upper 95% CL However, not all men experience continued pros-
Blacks have the highest upper limits for all age tate growth. Moreover, a recent study found that
categories except in the SO-59 age group. The a higher risk of prostate cancer (determined by
ASRR for Latin0 and Asian men demonstrate having two first-order relatives with prostate can-
greater variability above and below the ASRR for cer) does not contribute to generalized over-
whites. Racial differences in ASRR for PSA are growth of the prostate, but that estrogens do influ-
masked when included with a predominantly ence at least transitional zone volume.44
white population. The variability in PSA as men age suggests a cau-
tionary note when considering the clinical implica-
DISCUSSION tions of age-specific PSA reference ranges. The upper
limits of age-specific PSA reference ranges are based
Controversy surrounds the interpretation and on extending mean PSA levels upward two standard
utility of age-specific PSA reference ranges to en- deviations to establish a 95% confidence limit (CL).
hance the clinical interpretation of PSA.41 Oester- However, the distribution of PSA values in any age
ling and colleagues conducted a study of 471 men group is not a normal distribution: absolute 0.0 ng/
in rural Minnesota, between the ages of 40 and 79 mL is always the lowest value. The degree of varia-
years, and found a direct correlation of serum PSA tion in PSA values increases with each older age co-
concentration and age (r = 0.43) .26 The age-spe- hort. That is, men in their 70s exhibit more vari-
cific PSA reference ranges from the current study ability in PSA values than men in their 60s who, in

UROLOGY 48 (21, 1996 237

 in the general population, has influenced the pa-
wfmL
40-4g 0%F---- 4 7 19.4 rameters of age- and race-specific PSA reference
50-59 ranges. The use of age-specific PSA reference
nglmL
ranges may be less sensitive among older men be-
-I cause poorly differentiated cancers in small-vol-
20.0
ume prostates would not leak sufficient PSA to
70-79 l-1 I 6-A cross a threshold higher than 4.0 ng/mL, and such
m 20.0
- Maximum PSA
reference ranges may be less sensitive because of
the greater PSA variance among older men.
FIGURE 1. PSA quartiles by 1 O-year age cohorts. Box Race-specific PSA reference ranges reflect differ-
plot of PSA values measured in 77,700 study pat-tici-
ences in mean PSA and age-related PSA variance.
pants, 1993 to 1994, including men aged 40 to 79
years without diagnosis of prostate cancer. Records for However, although statistically significant differ-
individuals tested in 1993 were omitted from the group ences were found in the mean PSA and PSA vari-
of records for 1994. ance between whites and blacks, for example, the
clinical significance of this finding remains un-
clear. Greater PSA variance among blacks leads to
ng/mL
higher upper limits of race-specific PSA reference
6
7.5, ranges, but to have higher reference ranges for
/
7t blacks would seem to make the PSA test less sen-
6- sitive in the population that has had the highest
incidence of prostate cancer in the world. More
study on racial differences in PSA is warranted.
PSA4
3-
-
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