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Early Detection of Prostate Cancer


Prostate cancer is unique among the potentially lethal human ma- The concept that adenocarcinoma of the prostate
lignancies in the wide discrepancy between the high prevalence of exists in a latent and a clinical form is supported by
histologic changes recognizable as cancer and the much lower prev- epidemiologic, pathologic, and clinicall evidence. Al-
alence of the clinical disease. Despite the availability of effective though these divergent manifestations of prostate cancel
tests for early detection and of effective treatment for cancers so
have common architectural and cytologic features, the),
detected, the diagnosis usually is not established until the tumor
can be distinguished from each other to some degree
is locally advanced or metastatic. Yet. physicians hesitate to use
by differences in certain pathologic features, such as the
these tests for fear that many cancers found would be latent, of
little threat to the life or health of the host, and treatment could
volume, grade, and invasiveness of the lesion. To appl)
introduce inappropriate morbidity. Latent or “clinically unimpor-
the available diagnostic tests rationallv wr need to know
tant” cancers can be distinguished from those that are clinically the nature of cancers detected with’these tests to de-
important by the larger volume, higher grade, and greater inva- termine whether these cancers are “clinically important”
siveness of the latter. The available tests can detect only those can- or capable of causing morbid or lethal complications if
cers large enough to be palpable. visible on ultrasound, or capable left untreated in men with a sufficiently long life expec-
of elevating: the serum level of prostate-specific antigen. Such can- tancy.
cers are clinically important and should be treated for cure if the ‘We will review the epidemiologic, pathologic, and
life expectancy of the patient is sufficiently long and the morbidity clinical features of latent and clinical prostate cancel
rate of therapy is low. Early detection of prostate cancer using the
and describe the outcome of treatment trials and the
tests that are available today may widen the window of opportunity
available information about the natural history of the
so that treatment indeed becomes possible in those for whom it is
disease to show that prostate canc‘er. when detected
necessary. HUM PATHOL 23:211-222. Copyright G 1992 by W.B.
clinically, is most often a morbid and potentially lethal
Saunders Company
tumor. We will then describe the features of cancers
detected with each of the available diagnostic tests. es-
I’I-ost:ite cancer is unique among the potentially le-
timate the proportion of those cancers rhat are “clini-
I hat human rnali~mancies in the wide discrepancy be-
cally important,” and review the preliminary experience
cween th’r high prevalence of histologic changes rec-
with the use of these tests in early detection trials. Thus,
ognizable as cancer and the much lower prevalence of
our analysis will attempt to provide a rational basis for
( linical disease. Despite the availability of diagnostic tests
the early delection that is essential if the morrality rate
to detect prostafe cancer (digital rectal examination
from prostate cancer is to decline.
/IIRE]. prostate-specific antigen [PSA], and transrectal
~tltrasonogral)~~y [TRUS]) and of effective treatment for
c’ancers detected early (radical prostatectomy or radio- CLINICAL AND LATENT PROSTATE CANCER
therapy), the diagnosis usually is not established until
Clinical Cancer
rhe turrlor is locally advanced or metastatic.. Prostate
c’ancer will kill over 30,000 American men this year, and Epidemiology
the age-specific morrality rate is increasing. Yet, physi- Prostate cancer has become the most common GLIB-
tians hesitate to apply these diagnostic tests in a vigorous cer among American men, and only lung cancer is re-
program of early detection because of their concern sponsible for more cancer deaths.’ The ape-spec.ific
that man\ cancers found would be “latent,” ie, of no mortality rate has slowly increased ol;tar thcb past 50
real threat to the life or well-being of the host. Treatment years,’ and in black American men is ne,lrly double the
of such tumors could result in inappropriate morbidity, rate found in white men.’ Prostate cancer is responsible
md the ‘healrh of the community as a whole could be for nearly 35% of all deaths in men over the age of 55
reduced by suc11 efforts. years.” Since the incidence of prostate I.‘Lmcer increases
more rapidly with age than any other cancel, and the
average age of American men is rising, the number of
patients with prostate cancer is expected to increase
dramatically over the next decade.” Estimates are that
in 199 1 o&r 122,000 men will be diagnosed with pros-
tate cancer and 32,000 will die of the disease in the
United States.’ The mortality rate may underestimate
the morbidity, since endocrine therapy allows 10% of
men with metastatic prostate cancer to live for 10 years

HUMAN PATHOLOGY Volume 23, No. 3 (March 1992)

TABLE 1. Estimated Percentage of Patients in Each Clinical Stage at Diagnosis, Risk of Death From Prostate
Cancer, and Approximate “Cure“ Rate (Lifelong Freedom From Prostate Cancer)
Associated With Each Stage

1O-Year Cancer-
Percentage of Specific Survival Estimated “Cure”
Patients Stage* Prognosis Rate (%) Rate (%)
JO M+ Incurable 10 <I
“0 N+ Rarely turahle 40 15
10 T~LMI, Occasionally curable 60 L’F,
30 T,,,.,N,,W, Often curable NJ 65
10 T,,A,M,, ‘l‘reatment “unnecessary” 05 x5

100 All 51 52
Exe-ludina ‘I‘,, (stage A I) 1.5 25

* Based on clinical stage. pelvic lymph node dissection. bone scan, and acid phosphatase.’ “~li.‘“.34IYhe UICX staging system is used.“’

and 50% to live for 3 years.“.” These patients require our series of patients treated with combined gold seeds
frequent therapeutic intervention for local and systemic and external beam irradiation therapy, 68% of the
complications of the disease.’ deaths were directly attributable to prostate cancer.‘3
Even patients without pelvic lymph node metastases
Oufcome of Treatment Trials (T:l.qN,,) have a poor prognosis. The risk of disease pro-
Approximately 30% of men with prostate cancer gression by 15 years in our series was 74% and the risk
have distant metastases at the time of diagnosis.’ Despite of death from prostate cancer was 61%.” Whether mul-
the impressive symptomatic response of metastases to timodal therapy can reduce the high mortality rate due
hormonal manipulation (androgen deprivation), the to prostate cancer in patients with locally extensive tu-
survival rate for these patients is dismal: the median mors remains to be seen.
duration of survival is less than 3 years.“.“,s,” By 5 years, Approximately 55% to 60% of prostate cancers are
over 75% and by 10 years, more than 90% of these pa- discovered while still localized (clinical stage A or B),s*”
tients die of their cancer rather than with it.“.” although approximately 20% of these patients have
Approximately 30% of patients with apparently lo- lymph node metastases and will eventually relapse.‘2,‘3
calized prostate cancer (To_d NxM,,) have pelvic lymph The best results of treatment for prostate cancer are
node metastases.“.‘” Virtually all patients found to have among the group of patients whose tumors are clinically
positive pelvic lymph nodes treated with local or regional confined to the prostate and amenable to definitive
therapy show clinical evidence of progression of tumor treatment with radical prostatectomy or irradiation
within 10 years”~“~‘-5 unless additionally treated with therapy. Yet, in 1970 to 1979 the relative survival rate
systemic therapy (androgen deprivation), which has not for patients with localized tumors (To.2NxMo) was 77%
been shown to alter the long-term survival rate (reviewed at 5 years and 63% at 10 years.” After radiotherapy for
by Austenfield and Davis’“). Prostate-specific antigen patients with clinical stage A and B disease (To_eNxMo),
(PSA) levels are elevated within the first 2 years after the cancer-specific mortality rate at 15 years was 34%
to 35%.??.‘” Even among carefully selected patients
radical prostatectomy and pelvic lymphadenectomy in
more than 85% of patients with positive nodes’“-‘s and treated with radical prostatectomy for a small palpable
in 100% of these patients followed for longer periods.lg tumor clinically confined to the prostate, 17% to 20%
The cancer-specific mortality rate for these patients, eventually died of prostate cancer.“.‘s Among node-
whether hormonal therapy is administered early or late, negative patients (To_2NoM,J treated with radical pros-
is approximately 25% at 5 years and 60% at 10 years. tatectomy, indications of eventual treatment failure
Even patients with one single microscopic focus of tumor (positive surgical margins, seminal vesicle invasion, poor
in one lymph node seem to fare as poorly in the long differentiation, or elevated postoperative serum PSA
run as patients with more extensive nodal metastases, levels) are found in at least 25% to 35% of pa-
although long-term data are not available after some tients.“~“~‘g~‘R~3’ In one recent report 28% of stage A
forms of therapy.” Once prostate cancer has spread to and B patients with negative nodes developed local or
the regional nodes, it can rarely be controlled with any distant recurrence 10 years after radical prostatec-
form of local or regional therapy. At least 70% of such tomy. The results of radiotherapy in patients with neg-
patients will eventually die of their cancer rather than ative nodes are similar, with some 20% of patients dead
with it.” of prostate cancer 15 years after treatment.‘“.“‘.“”
Approximately 15% of patients have a locally ex- Summary. Of the spectrum of patients diagnosed
tensive tumor at the time of diagnosis (stage C or with prostate cancer over the past decade (Table l),
T:s..Js.’ ’ and half of these have pelvic lymph node me- approximately 30% will have distant metastases and 30%
tastases.‘z.‘3 The 5-year relative survival rate for patients will have positive lymph nodes or locally extensive cancer
with clinical sta e C cancer (T3_,‘NS) was 66% in a large at the time of initial diagnosis. Of the remaining 40%
national survey 8 and the risk of death from prostate with clinically localized disease, 25% to 35% will have
cancer is approximately 65% to 75% at 15 years.“-” In seminal vesicle invasion or poorly differentiated histol-


ogy or an dewed postoperative PSA level, making long- likely to die of metastatic disease. The potential for full
term control of the cancer unlikely. A fourth of all those expression of the disease in older men will . always
patients will have small foci of well-differentiated tumor be limited by the likelihood of death from other- causes.”
found incidentally at transurethral resection of the While these conclusions are applicable to the population
prostate (stage Al) and for all but very young patients studied, the high rate of local progressic)n over a short
interventieon is unnecessary. In summary. the techniques period belies the latent nature of clinically detected lo-
of diagnosis and therapy used over the past 20 years calized prostate cancer even in elderly patients.
result in death from prostate cancer in half of all patients Whitmore et at reported the outcome of expectant
within 10 vears’” and local or systemic progression of management of 75 patients with predominantly well-
the disease in more than two thirds of patients (Table differentiated clinical stage B tumors.“’ While the cri-
I ). If patients with stage Al (ToaNoMo) are considered teria for the selection of these patients is not clear, each
to have latent cancer and are excluded, the results are patient was apparently followed without treatment for
even worse. Because the tumor is so often detected in a minimum of 1 year from the time of diagnosis with
an advanced stage, treatment has had little impact on no apparent change in the tumor.“’ Using an actuarial
the eventual outcome. Considering the poor results of analysis, nearly all patients showed local progression
therapy for the population of patients diagnosed with withrn I5 years while fewer developed distant metastases.
prostate caner in recent decades, it is no wonder that Within the period of follow-up (24 to 298 months), 1 1
some autlhorities question whether any form of treat- patients died of prostate cancer, 18 of other causes, and
ment favorably alters the natural history of the dis- seven were lost to follow-up. Thus, local progression,
t.aSe,‘E.:\H even within this select group of favorable patients, was
inexorable although distant rnetastases and death from
prostate cancer were more difficult to predict.
Despite anecdotal reports of the benign behavior Johansson et al ernphasized the slow rate of pro-
of clinicallv detected prostate cancer, recent reports of gression and low rate of death from prostate cancer
unselected, properly staged, carefully followed patients observed in 223 patients.“” During a mean observation
who received no treatment until progression was doc- period of 78 rnonths, only 29% of the patients showed
umented or symptoms appeared show that prostate evidence of progression (9% distant, 20% local only)
c-ancer, when detected clinically, progresses slowly but and 37% died (7% of prostate cancer). Howe\,er, these
relentlesslv in the absence of treatment and threatens patients were older (mean age, 72 years) than patients
the life oif’the host.7.I I.:{-1.:~‘1-~‘1 with comparable stage tumors in fiorth America, and
Handley et al reported a large series of patients death from other causes was common. The period of
managed by deferred treatment.7 Although 75% of their observation was too short (mean, 7 years) for evaluation
patients had clinically localized disease at the time of of the total impact of prostate cancer on mortality. Death
diagnosis, only 30% survived 5 years compared with the from clinically localized prostate cancel is rare in the
expected survrval rate of 65% for an age-matched pop- first 5 to 7 years after diagnosis; over 40% of the cancer
ulation. Two thirds of all deaths within 5 years were due deaths that will ever occur do so after 10 years.“‘,“’ Fur-
to prostate cancer. Although the policy was to defer thermore, moderately and poorly differentiated turnors
treatment until the patients became symptomatic, only were selectively excluded from this series. During the
I 1% survived 5 years without requiring any further first 2 years of accrual only patients with grade I turnors
treatment and 17% of the patients died of cancer with- were included, and these are the only patients followed
out ever having received hormonal therapy. These in- beyond 7 years. Finally, a third of the Z!.‘< patients were
vestigators concluded that a deferred treatment policy stage Al (T,,,), a group for whom therapy is not usually
was clearly temporary; most patients became symptom- recommended; their 5-year progression rate was only
atic soon after diagnosis and some suffered death as 9.3%. In contrast, 36% of the T,,,, tumors and 38% of
their first symptomatic event. the T,.? tumors progressed within 5 yeai-s.‘“’
(George reported an apparently favorable outcome Summnq. Small, clinically detectable prostate can-
of a no treatment policy in 120 patients.“” Only 19% cers have a slow doubling tirne, approximately 2 years
required treatrnent for symptomatic local progression; in published reports.““.“” However, all studies that have
distant progression occurred in 1 1% and death from followed untreated patients for long periods show that
prostate cancer occurred in 4%, whereas 40% died of progression is inexorable, with local recurrence often
other causes. However, this was an elderly group of se- preceding distant metastases.‘.““.4” Clinically localized
lected patients (mean age, 74.8 years). The length of prostate cancer is not a benign disease; it has a slow but
follow-up was not stated and no details were provided steadily progressive natural history.
about the stage or grade of the tumors. Nevertheless,
84% of the patients developed evidence of local pro- Latent Cancer
gression measured by palpation. The actuarial rate of
distant metastases (estimated from the published curves)
was approximately 45% and the actuariat cancer-specific Approximately 30% of men over the age of 50 years
mortality rate was approximately 35% at 5 years. George who have no clinical evidence of prostate cancer harbor
concluded that “the progression of localized prostatic foci of cancer within the prostate (Table 2).4”.47..57This
c’ancer is indeed predictable-but the prediction is that remarkably high prevalence of prostate cancer at au-
growth will he slow and regular and the patient is un- topsy, seen in no other organ, makes ir thf. most common

HUMAN PATHOLOGY Volume 23, No. 3 (March 1992)

TABLE 2. Estimates of the Prevalence of Prostate N=8,000,000

Cancer in a Population of Men Over 50 Years of Age
Who Might Be Targets for Screening

of Prostate
References (%)
46-5 I Percentage of men >50 years old 30
with cancer present
(prevalence of autopsy cancer)
46, 48, 51, 52 Estimated proportion of autopsy 6
Important linical Ca
cancer cases that are
“clinically important” 100,000
(0.2 x 30%)
53-56 Actual t-ate of detection with l-3
DRE, PSA, +TRUS FIGURE 1. Distribution of prostate cancers If the prevalence
l-3, 10 Annual incidence rate in men 0.31 of adenocarcinoma among men more than 50 years of age is
250 years old 30%‘ then approximately 8 million American men harbor foci
I-3, 10 Annual mortality rate in men 0.09 of cancer in their prostate. Yet, in 1990 only approximately
>50 years old 100,000 men were diagnosed with the disease (“clinical can-
cer”) and the other 7.9 million were considered to have inci-
Note. The estimated prevalence varres more than 3004old de- dental or “autopsy” cancer. Based on the pathologic features
pending on the presumed prevalence of clinically important cancer. of prostate cancer found at autopsy46 and on the lifetime risk
Abbreviations: DRE, digital rectal examination; PSA, prostate- of developing prostate cancer.52 we estimate that approxi-
specific antigen; TRUS, transrectal ultrasound. mately 20% of these cancers are “clinically important” (that
is, they will threaten the life or well-being of the host if not treated
effectively), and 80% are truly latent cancer (“clinically unim-
malignancy in human beings.“* The age-specific preva-
lence of prostate cancer in cystoprostatectom
mens confirms the findings in autopsy studies. Uqt;
the Stanford series, 25 of 66 prostates (38%) contained of every 14.5 will die of prostate cancer (Table 3).‘”
cancer.“” Although the ratio of prostate cancer deaths to the de-
Yet, the estimated number of men diagnosed with velopment of histologic evidence of the disease is much
clinical prostate cancers in 1985 was only approximately greater (one in 14.5 rather than one in 323) when viewed
86,000, which represents only 1.05% (86,000 of in this perspective, it is apparent that most histologic
8,193,OOO) of the men estimated to have cancer present (“autopsy”) cancers do not progress within the normal
in the prostate (Fig 1).5? There were an estimated 25,500 life expectancy of the host. Yet, these cancers found at
deaths from prostate cancer in 1985, which is only 0.3 1% autopsy have all of the cytologic and architectural fea-
of these men. Thus, only one of 95 men with cancer tures of the disease detected clinically.““-“‘.“‘,“”
was diagnosed with the disease, and only one in 323
died of the disease that year (Table 2). This enormous Pathologic Features
discrepancy between the high prevalence of the disease Detailed pathologic examination of cancers found
at autopsy and the low incidence of the disease clinically at autopsy and of clinically detected cancers do, however,
has provided a theoretical basis for a policy of “no show important differences between autopsy-detected
treatment” and has stymied efforts at early detection and clinically detected cancers in the volume, grade,
and screening,“8,5”,“4,5”
and invasiveness of the tumor.~6,48,4’1..51,.57
Most cancers
This apparent discrepancy, however, has been ex- found at autopsy are small, well differentiated, and show
aggerated by the failure to consider the effect of time. no tendency to invade normal structures ( rostatic cap-
Although the clinical incidence of prostate cancer is low sule, seminal vesicles) (reviewed by Dhom” B). Others are
(approximately 0.31% per year for men more than 50 larger, less well differentiated, and do invade normal
years old), the lifetime risk of developing prostate cancer structures. The prevalence and proportion of these
for a man 50 years old in 1985 was 9.51%3 (Table 3). larger, proliferative cancers are greater in older men,
Similarly, the annual mortality rate for men more than
50 years old in 1985 was only 0.09%, but the lifetime
risk of dying of prostate cancer was 2.89%. In 1985 a
TABLE 3. The Lifetime Risk of Developing or of Dying of
50-year-old man was expected to live to the age of 75. Prostate Cancer for a 50-Year-Old White Man in 1985
Autopsy data confirm that prostate cancer is not found
in every 75-year-old man but in only approximately Lifetime
42%.5’ For a 50-year-old man, therefore, we can estimate Risk (Yo) Ratio
that the lifetime risk of developing cancer in the prostate Lifetime risk of developing “autopsy” cancer5p: 42
is approximately 42%, the risk of developing the disease Lifetime risk of developing clinical cancer’: 9.51
clinically is approximately 9.5%, and the risk of dying Lifetime risk of dying of prostate came?: 2.80
from the disease is approximately 2.9%. Over their life- Note. The ratios indicate that for every death from prostatecancer,
times, then, one of every 4.4 men who harbors cancer 3.3 men will he diagnosed with the clinical disease and 14.5will develop
in his prostate will develop the disease clinically and one histologic evidence of cancel- in the prostate dur-ing their lifetime.


TABLE 4. Geographic Variations (8.4- to 10.8-Fold) TABLE 5. Features That Help Distinguish Ciinicalty
in the Incidence and Mortality Rates of Clinical Important From Unimportant Prostate Cancers
Prostate Cancer (Per 100,000 Men&r)
(Iinicall~ Clinically
Important C:nimportant

((;lea\on gwlr
I or2)

‘1 rmsitirm ~onr

cer in men over the age of 50 years would be approxi-

mately 20% of the 30% of men more than 50 years of
ill black Americans. and in geographic regions with a age with prostate cancer, or 6% rather tlhan 30% (prev-
higher clinical incidence of and mortality rate from alence at autopsy) or 0.31% (annual incidence) (Table
prostate ‘cancer, while the smaller, nonproliferative 2). These are the clinically important (IFig 2) but cur-
c.mcers are more uniform with age, ethnic group, and rently undetected cancers that would be the appropriate
geographic region (Table 4)” (reviewed by Dhom’s and targets of an early detection program and could rep-
Scardino”‘). These observations strongly support the resent as many as 1.6 million men in the United States
c’c)ncept of a multistep process in the pathogenesis of alone, a staggering figure unless one considers that 2.0%
prostate cancer in which latent cancers have progressed of 50-vear-old men alive today (or approximatelv
through s~ome but not all of the steps necessary for full 790,OOiI in this country alone) will eventually die oi
malignant expression.“’ prostate cancer.” To prevent these deaths we may have
Since some cancers found at autopsy have the fea- to detect and treat two to three patients for every death
tures of clinical cancers”.4H.‘,1.6” and some cancers de- prevented.
trcted clinically have the features of autopsy or latent The proper goal of an early detection program is
cancers (for example, stage A, or To,),““-“” we have found not to detect all prostate cancers, but only IO detect
il more helpful to describe prostate cancers as “clinically those that are potentially morbid or lethal (the clinically
important” (ie, threatening the life or well being of the important cancers), which we estimate have a prevalence
host within his remaining life expectancy) or “clinically of approximately 6% (20% of cancers prevalent in the
unimportant” (ie, a latent cancer of no threat to the prostate in men more than 50 veal-s old., or all the can-
host).“’ At the light microscope level, tumor volume, cers, except To,, that will even&allv he detected as clin-
grade, am1 invasiveness are some of the features that
help to distinguish clinically important from unimpor-
tant cancers (Table 5). Llnfortunately, no objective
nlarkers of progression in human prostate can&r have
been established,7” hut additional features that seem to DIRT IBUTI~N OF PROSTATE LANCERS
he strongly associated with the biologic behavior of I
prostate cancer are the DNA ploidy status of the tumor, I N=8,000,000 ;
the degre’r of PSA production (serum PSA level), and, I i AutoDsY ca
possibly, the Lone of origin of the turnor within the
prostate (‘Table 5).
The proportion of prostate cancers present in the
population of men over 50 years old that are clinically
importanl is difficult to determine precisely, but infor-
mation available from detailed morphometnc studies of
prostate cancers found at autopsy and in cystoprosta-
tectomy series suggests that approximately 20% of
these currently undetected cancers are clinically im-
portant based on the features listed in Table 5
FIGURE 2. Of the clinically detected cancers nearly half are
(I;ig l).’ 1,;‘-IH4!1.5I..-,:!.r,7.l>ll advanced (Table 1). Approximately 40% are early stage and
Goal of a,? Early Detection Program may be curable, and 10% are focal, well-differentiated stage
A, (T,,) and may be “clinically unimportant.” Of the large pool
If OUI‘ estimates are correct, the prevalence of clin- of undetected but clinically important cancers, similar propor-
ic-ally impl:)rtant but presently undetected prostate can- tions are estimated to apply.

HUMAN PATHOLOGY Volume 23, No. 3 (March 1992)

TABLE6. Patients With Moderate or Severe

Obstructive Voiding Symptoms at the Time of
Diagnosis of Prostate Cancer (Stages B and C, or T,_J
Were More Likely to Have Pelvic Lymph Node
Metastases (P < .OOOl)

Results of Pelvic Lymph

Degree of Obstructive
Voiding Symptoms N (%)* Negative Positive (%)t

None 171 (46) 135 36 (21)

Mild 55 (15) 35 20 (36)
Moderate 93 (25) 58 35 (38) 6 c I

50 (14)

369 (100)

29 (58)

120 (33)
20 c p=.OOl

l --* Negllglble Sx (226)
Substantlal Sx (n=143)

* Percentage of patients with each degree of voiding symptoms.

t Percentage of patients with lymph node metastases.
Data from Meacham et aLa 01 ’ ’ ’ ’ ’ ’ ’ ’ ’ ’
0 5 10
Time (Years)
ical cancers) (Fig 2) (Table 2). We will review below the FIGURE 3. Freedom from distant metastasis after treatment
pathologic features of cancers detected with the available (radiotherapy) for clinically localized (stages B and C, or T,.
noninvasive diagnostic tests (symptoms, DRE, PSA, ul- ,N,M,) prostate cancer based on the degree of obstructive
voiding symptoms at the time of diagnosis. Patients with sub-
trasound, and combinations of these) and estimate the stantial (moderate or severe) obstructive symptoms had a sig-
proportion that are clinically important. nificantly worse prognosis. (Reproduced with permissionBO:
Meacham RB, Scardino PT. Hoffman GS, et al: The risk of distant
metastases after TURP vs needle biopsy in patients with localized
TECHNIQUES FOR EARLY DETECTION AND prostate cancer. J Urol 142:320-325, 1989, @ by American Uro-
logical Association, Inc.)

Digital Rectal Examination
Prostate cancer is a notoriously silent disease with
few early symptoms. Symptoms associated with bladder The DRE traditionally has been considered the most
outlet obstruction are commonly present in men over accurate test for the detection of prostate cancer. Digital
the age of 50 years and are often ascribed to benign rectal examination has been demonstrated to be more
prostatic hyperplasia (BPH). Indeed, BPH is more com- sensitive, more specific, and to have a greater efficiency
mon than prostate cancer: the lifetime risk of a 50-year- than a variety of laboratory tests available in the 1970s7”
old man requiring a prostatectomy for symptomatic However, few of these laboratory tests are still in clinical
BPH is 20% to 25%.* However, symptoms of bladder use today. In one study patients were hospitalized for
outlet obstruction also develop in men with prostate urinary symptoms and were not asymptomatic subjects
cancer. In a series of 300 consecutive men hospitalized of a screening program; prostate cancer was detected
for obstructive voiding symptoms, Guinan et al diag- in 23%, considerably more than expected in a screening
nosed prostate cancer in 23%?” trial.
In our own series of 5 10 men treated with radio- Digital rectal examination has been used to detect
active gold seed implantation and external beam irra- prostate cancer in several large series, and the detection
diation for TOb-TJ cancer (stages AB, B, and C), 234 (46%) rates range from 0.8% to 1.4% (Table 7).““m56.8” Although
had a transurethral resection of the pstate for symp- 67% to 88% of these tumors are clinically localized,
toms of bladder outlet obstruction. ’ Of the patients
with a palpable (T,.,) cancer, 143 (39%) had moderate
or severe obstructive voiding symptoms at the time of TABLE7. Results of Early Detection Programs Using
diagnosis. These patients had a greater chance of having Each Diagnostic Test17.
lymph node metastases (Table 6) and developing distant
metastases (Fig 3) than comparably staged patients DRE (%) TRW (%) PSA (%)
without obstructive voiding symptoms, confirming the Positive predictive value 22-36 15-41 “‘L-35 (>4)*
clinical observation that patients with prostate cancer 65-67 (>lO)
Detection rate 0.8-1.4 2.3-3.1 2.2
who have obstructive voiding symptoms at presentation Clinically localized 53-88 58-100 96 (4- 10)
are more likely to have locally advanced disease and a 77 (>lO)
poor prognosis. s1 While there are no objective data de- 56-72 (4-10)
scribing the detailed pathologic characteristics of pros- Pathologically confined 37-77 56-68 8-33 (10)
tate cancers that are detected because of the develop-
Abbreviations: DRE, digital rectal examination; TRUS, tramrectal
ment of urinary symptoms, such symptoms are likely to ultrasound; PSA, prostate-specific antigen.
be of little use in the early detection of prostate cancer. * Numbers in parentheses refer to the level of PSA.


TABLE 8. Characteristics of Cancers Detected With palpable induration correlates well with the total volume
Each Diagnostic Test in Patients With Clinically of tumor”” nor with the area of cancer on the posterior
Localized Prostate Cancers Treated With surface of the prostate.!“’
Radical Prostatectomy, and for Latent
Asymmetry and induration, as well as a discrete hard
Cancers Detected Incidentally at Autopsy
nodule, are included in the tindings on I)RE that may
or in Cystoprostatectomy Specimens
__.__ be judged suspicious for prostate CYIIK~I‘. but these
findings lack specificity for cancer. The positive predic-
tive value of a palpable abnormalit\; is on,lk 22%, to 36Yo
(Table 7). Yet, the most serious 1in;itation of DRE is its
lack of sensitivity (false-negative results). For example,
approximately 10% to 20% of transurethral resections
performed for benign prostatic hypertroph~ in patients
with no palpable abnormality suggestive of cancer un-
cover an incidental cancer of the prostate. Digital rectal
examination detected only 12 of 22 cancers found in ;I
screening study, while TRUS found 20.““ Goner et al
detected cancer by TRUS in 12.4% of 22.5 men, none
of whom was ‘:juclged by the urologist tl:) have a suspi-
ciously palpable lesion.““g Goner et at later reported
that 25% of the cancers found in men examined h>
TRUS were not palpable (Table 9).“”
Thus, DRE is relatively insensitive and nonspecific.
staging revealed that many were, in fact, not Cancers detected by palpation are relatively large, man)
confined to the prostate gland.9”,54 In our own series of are late in their- development and no longer curable.
9X clinical stage B (T,.,) radical prostatectomy speci- and some are so small they would fit OUI definition of
mens, 63% extended through the capsule and 18% into clinically unimportant cancers.
the seminal vesicles.x7 These cancers ranged in size from
0.45 to 19.2 cc (mean, 4.04 cc), although we occasionally
Prostate-Specific Antigen
have encountered palpable cancers as small as 0.04 cc.88
Stanley et al reported that palpable clinical stage B can- The on]!. study using PSA as the primarv test to
cers in patients with negative lymph nodes ranged from screen for prostate cancer was conducted by Catalona
0.01 to 25 cc (mean, 5.4 cc).‘” Nonpalpable cancers et al, who determined serum levels in 4,293 self-referred
discovered in cystoprostatectomy specimens by these patients,‘t’,x’l Overall, serum levels higher than 4.0 ng/
same investigators ranged from 0.00 1 to 1.1 C‘C(mean, mL (Hybritech monoclonal I-adioimrnunoassa~; Hybri-
0.1 cc) and all were confined to the prostate.‘” Thus, tech, San Diego, CA) were detected in .516 patients
palpable cancers clinically confined to the prostate are (12%). These patients were asked to ret.urn for a DRE
one to two orders of magnitude larger, on average, than and TRUS to determine the need for a Ileedle biopsy.
latent cancers (Table 8) and most already extend outside The overall cancer detection rate in the published series
the l,rostate_:‘“.;;.“7.~~~ was 2.2% (Table i).” Cancer was detected in 26% of
Not only does DRE detect cancer relatively late, the men with a PSA level of -1.0 to 10.0 ng/ml.. Nearly
there is only a weak correlation between the size of the all of these tumors (96%) were clinically localir.ed, and
cancer estimated by DRE and the actual volume of can- the tumor was confined to the prostate in 72% of these
cer present. Tumors palpable as small nodules (1.5 cm patients who had a radical prostatectomv. Callcer was
or half of one lobe) are generally smaller than larger detected in 66% of patients with a serum level higher
palpable tumors, but the overlap is substantial.“’ Neither than 10.0 ng/mL. While 77% of these cancers were clin-
the absolute nor the relative dimensions of an area of ically localized, only 33% of the patients who had a rad-

TABLE 9. The Detection of Prostate Cancer in Studies Using a Combination of Digital Rectal Examination.
Prostate-Specific Antigen, and Transrectal Ultrasound With Transrectal Ultrasound-Guided Eliopsy
of Any Suspicious Hypoechoic Lesion: Influence of Abnormal Digital Rectal Examination or
Prostate-Specific Antigen (>4.0 ng/mL) on Results
____ _______~
Abnormal ~rRtIS Puwnragc No. of Patknts With Gmrer and
N (%) Biopsy Performed PPV TRUS With Cancc~ Percentage of All <Lmwrs Dvterted (%)

DRE+. PSAt 438 (I 7) 0!I 3i 55 “11 (I!31

DRE+. PSA- 446 (17) ti7 15 10.:; 16 (121
DRE-. PSAt 487 (IX) 19 “7 I3 63 (171
DRE-, PSA-~ 1265(48) “I 12 2.5 .‘<‘)
_ (VI
All patients ‘_‘634 17 31 14.5
__-- ~~

Abt~revi;ltic,n\. TRIJS. transrec tal ultrasound; PfV, positive prrdictive slur of h~poechoic lesion t m TRUS: LIKE. di@at u’t tal txunination;
PSA. prostar-specific antigen.
Data front (:ocmer et al”“~“” ;md et al.“”

HUMAN PATHOLOGY Volume 23, No. 3 (March 1992)

ical prostatectomy had an organ-confined cancer (Ta- The high prevalence of BPH and the frequent elevation
ble 7).7ti of PSA in patients with BPH and prostatitis lead us to
Serum PSA levels have been shown to correlate recommend biopsy for such patients only in the presence
generally with the volume, clinical stage, and pathologic of an abnormal DRE or TRUS, or when the prostate
stage of prostate cancer, although there is a wide range gland is disproportionately small relative to the patient’s
of PSA values associated with any given volume or PSA level or the PSA level rises over time.
stage. 16-19.s1,44Except at extremely high levels, PSA is
not predictive of the features of the cancer in the in- Transrectal Ultrasonography
dividual patient. In a small series from our institution,
normal serum PSA levels (<4 ng/mL) were associated The introduction of TRUS has provided physicians
with small volume cancers (0.1 to 3.6 cc; median, 0.85 with an effective way to see the internal anatomy and
cc), low Gleason grade, low risk of extracapsular exten- pathology of the prostate gland.“’ Initial studies re-
sion (27%), and DNA diploid tumors in 56%.6s Prostate- ported low specificity and sensitivity for the detection
specific antigen levels of 4 to 10 ng/mL were associated of cancer.“s With the availability of high-frequency bi-
with larger cancers (0.4 to 13.8 cc; median, 1.30 cc), planer probes and with increased experience among
higher grade, and greater risk of extracapsular extension sonographers, the accuracy of detection of rostate
(44%); 66% were nondiploid. Prostate-specific antigen cancer by TRUS has improved markedly.““s4s”~g g,” Most
levels higher than 10 ng/mL were uniformly associated urologists today would find it difficult to care for patients
with a nondiploid cancer (see also ref 69), which was with prostate diseases without TRUS.“” The predomi-
large (2.4 to 16.8 cc; median, 8.6 cc), high grade, and nant appearance of prostate cancer on ultrasonography
extending through the capsule in 87%.68 Thus, PSA lev- is hypoechoic relative to the normal peripheral zone of
els of 4 to 10 ng/mL will identify cancer pathologically the prostate.“8~““,‘0”
confined to the prostate in 56% to 72% of patients, but Transrectal ultrasonography has been used to
if the level is more than 10 ng/mL, 67% to 92% will screen for prostate cancer in several large series and
have locally advanced cancer (Table 7). Therefore, while has consistently been shown to increase detection when
more specific, using a PSA level higher than 10 ng/ml compared with DRE. Lee et al examined 784 self-re-
may not offer an effective technique for early detection. ferred men using both DRE and TRLJS.‘” Overall, 77
There are other theoretical limitations to the use biopsies were performed because of an abnormal TRUS
of this serum marker for early detection. A normal and 39 because of an abnormal DRE. Cancer was de-
serum PSA level does not exclude the diagnosis of can- tected in 22 patients or 2.8% of men screened (Table
cer. False-negative results are common, and a third of 7). Digital rectal examination detected cancer in 10 pa-
men treated with radical prostatectomy for prostate tients (1.3%) and TRUS detected cancer in 20 patients
cancer have a normal serum PSA level.‘“*‘” Cooner and (2.6%). The positive predictive value of a hypoechoic
other investigators have reported normal PSA levels in lesion on TRUS was 26% for both TRUS and DRE in
20% of their patients with cancer who had an abnormal this series, within the range reported by others (Ta-
DRE and/or TRUS (Table 9).‘“,“” Moreover. false-pos- ble 7).53s4
itive results are also common since PSA levels are often The 20 tumors detected by ultrasound in Lee et
elevated in men with common benign conditions, such al’s series ranged from 0.72 to 2.4 cm in average di-
as BPH or prostatitis. Brawer and Lange reported a ameter (corresponding roughly to a volume of 0.2 to
negative biopsy result in 40% of patients with a PSA 7.2 cc), and 17 (77%) of the 20 were less than 1.5 cm
level of 4.0 ng/mL and in 19% of those with a level of in diameter. Surgical staging of 14 of these 17 tumors
10 ng/mL. ” Moreover, in the absence of an abnormal confirmed negative lymph nodes in all; six patients un-
DRE or TRUS, an elevated PSA level provides no in- derwent radical prostatectomy and five tumors were
formation about the location of a possible tumor. To confined to the prostate pathologically.‘” Mettlin et al
find the tumor, the physician must perform multiple screened 2,425 men in a similar trial and detected cancer
systematic core biopsies of the prostate, in which case in 57 (2.4%).s5 Digital rectal examination detected 58%
a certain number of coincidental, clinically unimportant of the cancers and TRUS detected 77%. Overall, 93%
cancers may be detected and unnecessarily treated. of the cancers detected by TRUS were clinically confined
In summary, PSA levels have proved to be extremely to the prostate and approximately 68% of those treated
useful in the early detection of prostate cancer, es- with radical prostatectomy were pathologically confined
pecially when combined with DRE or TRUS. Patients (Table 7).
with abnormal rectal or ultrasound findings are much In a large study comparing ultrasound images of
more likely (32.8%) to have cancer if their PSA level is the prostate with whole mount serial sections of radical
elevated than if the level is normal (4.6%) (Table prostatectomy specimens, Shinohara et al described the
9). ‘7s4,8g.96When the PSA level is 4 to 10 ng/mL and characteristics of cancers detected sonographically.HH!”
the DRE or TRUS is abnormal, a detected cancer will Overall, 68% of the clinically detected cancers were vis-
almost always have the pathologic features of a clinically ible sonographically. Cancers that could be seen as hy-
important cancer.‘“‘“,“*.““.‘” Prostate-specific antigen poechoic lesions were larger, less well-differentiated, and
levels of 10 ng/mL are highly predictive of the presence located in the peripheral zone, in contrast to cancers
of cancer and usually warrant a prostatic biopsy re- not visible on ultrasound (isoechoic). The smallest tumor
gardless of the results of the DRE or TRUS. At inter- seen was 4.4 mm in the pathologic specimen (0.04 cc),
mediate levels, however, the false-positive rate is higher. and this tumor was palpable. Only 19% of the tumors


less than 10 mm in maximum transverse diameter in Twenty-five percent of the cancers were not palpable
the pathologic specimen were seen on the sonogram and 20% had a normal PSA level; 8% of the cancers
compared with 82% of larger tumors. Thirty percent to detected were in men with a normal DRE and normal
35% of cancers detected by DRE or transurethral re- PSA (Table 9). Nevertheless, 47% of the men were sub-
section of the prostate cannot be seen by ultrasonog- jected to a prostatic biopsy in this series, ranging from
raphy. Ultrasound was unable to demonstrate 65% of 99% of those with an abnormal DRE and PSA to 21%
stage A tumors, which tend to be located anteriorly and when both were normal.
are small, well differentiated, and often multifocal. Only Cooner’s data may not be applicable to a population
10% of tumors with Gleason scores 2 to 4 and 19% of subjected to mass screening. The prevalence of cancer
those less than 10 mm in diameter were seen in our in these patients, 14.5%, is much greater than one would
series. expect in the general population of men over the age
In a later series we examined the pathologic features of 50 years. Others have used this diagnostic triad with
of cancers visible sonographically and compared these different results. Lee et al found cancer in 2.8% of 784
to cancer-s palpable by DRE. Cancers that were both men and Mettlin et al in 2.4% of 2425 men who re-
palpable and visible by ultrasound were large (median sponded to a public offer of a screerling.‘“,8” In both
volume, 4.. 15 cc), high grade (median Gleason grade 7), series the detection rate was higher than that reported
nondiplolld (97%), and frequently extended through the for DRE alone but lower than our theoretical target of
capsule (85%) and into the seminal vesicles (33%). Can- 6% prevalence of clinically important cancer in men
cers that were visible by ultrasound but not palpable more than 50 years of age. Based on the pathologic
were smaller (1.72 cc), lower grade (Gleason 6), non- characteristics of cancers found, and the results of lim-
diploid (86%), and extended through the capsule in 57% ited field trials with the available diagnostic techniques
and into the seminal vesicles in 14%. Cancers that were for the early detection of prostate cancer, we c’an reject
palpable but not visible on ultrasound demonstrated the concern that screening of selected populations is
similar histologic features (1.70 cc, grade 6, 50% non- detecting more cancers only by detecting clinically un-
diploid, and 50% with extracapsular extension). important, histologic cancers that are of little threat to
In general, the size of a hypoechoic cancer corre- the life or well-being of the host (Fig 4). The use of
sponds reasonably well with the actual size of the tumor DRE, PSA, and TRUS for the early detection of prostate
measured in the surgical specimen,“‘,“” although not all cancer in appropriate patients promises to increase the
investigators have been as successful making this cor- overall detection rate of clinically important, early stage,
relation.“” The best available technique for estimating curable, but previously undetected prostate cancer
the volume of a prostate cancer, if it is visible on the (Fig 5).
sonogram, is to measure it planimetrically on the trans-
verse images.
Perhaps the most important use of TRLJS in the SUMMARY
early detection of prostate cancer is as a guide for di-
rected needle biopsies of the prostate.““,“” The ease of Studies of the pathology of prostate cancer found
use and low morbidity rate of this procedure has dra- at autopsy or in the clinic, the natural history of the
matically changed the approach to patients suspected disease, and the results of treatment trials leave little
of having prostate cancer. room for doubt that large cancers, particularly those
In summary, TRUS can detect some nonpalpable that are not well differentiated or that invade outside
cancers, but rarely are these smaller than 0.2 cc, roughly the prostate, will prove lethal if no1 effectively treated
equivalent to a diameter of 7 to 8 mm (Table 7). The
range of size, grade, invasiveness, and DNA ploidy status
of palpable and sonographically visible tumors is similar.
Tumors detected by TRUS alone are not so small as to
be consid.ered clinically unimportant. The limitation of
ultrasound is not that small clinically unimportant can- N = 8,000,OOO
c-ers will be detected, but that some larger, clinically Autopsy Ca
important, and treatable cancers will be missed. These
data provide a firm foundation for the use of TRUS in
the early detection of prostate cancer.

Combined Use of Digital Rectal

Examination, Prostate-Specific Antigen, and
Transrectal Ultrasonography

Digital rectal examination, PSA, and TRUS are each

limited in the ability to detect prostate cancer. The in-
tegration of these methods into a diagnostic triad has FIGURE 4. Some physicians caution against ‘early detection of
prostate cancer ding the available diagnostic tests because
enhanced the early detection of prostate cancer. Cooner they fear that most additional cancers detected (indicated by
examined 2,634 men referred for urologic evaluation the dotted line labeled “screening”) would be clinically unim-
and obtained a diagnosis of cancer in 383 (14.5%).“” portant or latent cancers of no threat to the host.3853,54.59’02

HUMAN PATHOLOGY Volume 23, No. 3 (March 1992)

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N = 8,000,OOO
Autopsy Ca 41:19-36, 1991
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Clinicallv I I
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HUMAN PATHOLOGY Volume 23, No. 3 (March 1992)

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