Sie sind auf Seite 1von 12

Symposium

Early Detection of Prostate Cancer


PETER T. SCARDINO, MD, ROBERT WEAVER, MD,
AND M’LISS A. HUDSON, MD

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

211
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-

212
EARLY DETECTION OF PROSTATE CANCER (Scardino et al)

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
Epidemiology
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

213
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

Prevalence
of Prostate
Cancer
References (%)
46-5 I Percentage of men >50 years old 30
with cancer present
(prevalence of autopsy cancer)
Clinically
46, 48, 51, 52 Estimated proportion of autopsy 6
Important linical Ca
cancer cases that are
20%
“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-
portant”).
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.

214
EARLY DETECTION OF PROSTATE CANCER (Scardino et al)

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

:small
Well-diflerentiated
((;lea\on gwlr
I or2)
Soninwsiv~~

Dipicki
lormal
‘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.

215
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


Dissection
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
Severe

Total
50 (14)

369 (100)
?I

?49
29 (58)

120 (33)
8
i
P
20 c p=.OOl

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

* Percentage of patients with each degree of voiding symptoms.


t
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.)
CHARACTERISTICS OF CANCERS DETECTED

Symptoms
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 Test17.53.56.68.76.82-86
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.

216
EARLY DETECTION OF PROSTATE CANCER (Scardino et al)

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.
l~;~tl~ologi;lc~
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 l.re et al.“”

217
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

218
EARLY DETECTION OF PROSTATE CANCER (Scordino et al)

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
DIST 0~ PROSTATE ‘\ANCERS
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

219
HUMAN PATHOLOGY Volume 23, No. 3 (March 1992)

REFERENCES
OF PROSTATE ANCERS
1. Boring CC, Squires TS. Tong T: Cancer statistics, 199 1. CA
N = 8,000,OOO
Autopsy Ca 41:19-36, 1991
7,900,000 2. Carter HB, Coffey D: The prostate: An increasing medical
i
problem. Prostate 16:39-48, 1990
3. Seidman H, Mushinski MH. Geib SK, et al: Probabilities of
eventually developing or dying of cancer-United States. 1985. (:A
35:36-56, 1985
C 4. Byar DP: VACURG studies on prostatic cancer and its treat-
Uni ment, in M Tannenbaum M (ed): Urologic Pathology: The Prostate.
Philadelphia, PA, Lea & Febiger, 1977, pp 241-267
100,000 5. Murphy GP, Beckley S, Brady MF, et al: Treatment of newly
Clinicallv I I
diagnosed metastatic prostate cancer patients with chemotherapy
‘mPortarit
20%
Early ‘Stage
A~ agents in combination with hormones versus hormones alone. Cancer
50% 51:1264-1272, 1983
6. Crawford ED: A controlled trial of leuprolide with and without
FIGURE 5. An appropriate screening or early detection pro- flutamide in prostatic carcinoma. N Engl J Med 321:419-424, 1989
gram would increase the yield of previous undetected early 7. Handley R, Carr TW, Travis I). et al: Deferred treatment of
stage clinically important cancers without increasing the de- prostate cancer. Br J Urol 62:249-253, 1988
tection of clinically unimportant cancers. The data from studies 8. Schmidt JD, Mettlin CJ, Natarajan N, et al: Trends in patterns
in which a combination of DRE, PSA, and TRUS was used suggest of care for prostatic cancer, 1974-1983: Results of surveys by th?
that this result can be achieved.“.76.84.85.89.90.95,96 American College of Surgeons. J Urol 136:4 16-42 1, 1986
9. Murphy GP, Beckley S, Brady MF, et al: Treatment of newly
diagnosed metastatic cancer patients with chemotherapy agents in
in patients with a sufficient long life expectancy. We do combination with hormones versus hormones alone. Cancer 5 1: 1264-
not know whether some small prostate cancers are also 1272, 1983
potentially dangerous. As yet, there are no objective 10. Silverberg E: Statistical and epidemiological data on urologic
markers that we can use to distinguish the potentially cancer. Cancer 60:692-717, 1987 (suppl)
11. Catalona WJ: Prostate Cancer. New York, NY. Grunt 8c
lethal small cancers from the truly “latent” small can-
Stratton, 1984
cers. Despite their ability to detect prostate cancer in 12. Gervasi LA, Mata JA, Scardino PT: The prognostic signifi-
more patients at an earlier stage, the noninvasive di- cance of the extent of nodal metastases in prostatic cancer. .J Ural
agnostic tests currently available (DRE, PSA, and TRUS) 142:332-356 . 11989
are relatively insensitive and are incapable of detecting 13. Austenfield MS, Davis BE: New concepts in the treatment
of stage D 1 adenocarcinoma of the prostate. Ural Clin North Am 17:
small, well-differentiated cancers. These tests can detect 867-884, 1990
only those large enough to be palpable, visible on ul- 14. Zincke H, Utz DC, Thule PM, et al: Treatment options for
trasound, or capable of elevating the serum PSA level. patients with stage Dl (T,,,N,,M,) adenocarcinoma of the prostarr.
If Table 4 is accurate, a tumor detected with any of Urology 30:307-3 15. 1987
these tests is clinically important and should be treated 15. Smith JA, Jr, Haynes TH, Middleton RG: Impact of external
irradiation on local symptoms and survival free disease in patients
for cure if the life expectancy of the patient is sufficiently with pelvic lymph node metastasis from adenorarcinoma of the pros-
long and the morbidity rate of therapy is low. Early de- tate. J Urol 131:705-707, 1984
tection of prostate cancer using the tests available today 16. Hudson MA, Bahnson RR, Catalona WJ: Clinical use of
may widen the window of opportunity so that treatment prostate-specific antigen in patients with prostate cancer. J Ural 142:
loll-1017,1989
indeed becomes possible in those for whom it is nec-
17. Brawer MK, Lange PH: Prostate-specific antigen: Its role in
essary. early detection, staging, and monitoring patients with prostatic car-
The only way to prove the value of screening pros- cinoma. J Endourol 3:227-236, 1989
tate cancers is to undertake a large-scale, randomized 18. Oesterling JE, Chan DW, Epstein JI, et al: Prostate specific
trial comparing the cancer-specific mortality rate in a antigen in the preoperative and postoperative evaluation of localized
prostatic cancer treated with radical prostatectomy. J Ural 139:766-
screened population with that of an unscreened control
772, 1988
group. Screening has been shown repeatedly to detect 19. Stamey TA, Kabalin JN, McNeal JE, et al: Prostate-specific
other cancers at an earlier stage than routine clinical antigen in the diagnosis and treatment of adenocarcinoma of the
practice, but this alone does not justify its performance. prostate. II. Radical prosratectomy treated patients. J Ural 141:1076-
The problems of lead time bias and length time bias are 1083, 1989
20. Lerner SP, Seale-Hawkins C, Carlton CE, Jr, et al: The risk
well known, and the results may be that more tumors
of dying of prostate cancer in patients with clinically localized disease.
are detected in an earlier state, but the mortality rate J Ural 146:1040-1045, 1991
of the disease may not change. 21. Scardino PT: Is radiotherapy effective for locally advanced
Until such a trial is completed, the tests available (stage C or T3) prostate cancer, in Murphy GP, Khoury S (eds): Ther-
for the early detection of prostate cancer cannot be apeutic Progress in Urological Cancers. New York NY, Liss. 1989, pp
223-239
recommended for mass screening of asymptomatic men.
22. Carlton, CE, Jr. Scardino PT: Long-term results after com-
But there is now ample evidence that the addition of bined radioactive gold seed implantation and external beam radio-
PSA and TRUS to DRE will facilitate the early detection therapy for localized prostatic cancer, in Coffey DS. Resnick MI, Dorr
of prostate cancer. If the evidence of benefits and risks FA, et al (eds): A Multidisciplinary Analysis of Controversies in the
is presented to the patient, a physician may reasonably Management of Prostate Cancer. New York, NY, Plenum, 1988, pp
109-121
decide to recommend one or more of these tests to se- 23. Bagshaw MA, Cox KS, Ray GR: Status of radiation treatment
lected individuals considered at increased risk (based on of prostate cancer at Stanford University. Nat1 Cancer Inst Monogr
family history, race, age) of having prostate cancer. 7:47-60, 1988

220
EARLY DETECTION OF PROSTATE CANCER (Scardino et al)

24. Holzman M, Carlton CE, Jr, Scardino PT: The frequency 51. Breslow N, Chan CW, Dhom G, et al: Latent carcinoma of
and morbidity of local tumor recurrence after definitive radiotherapy prostate at autopsy in seven areas. Int J Cancer 20:680-688, 1977
for stage C prostate cancer. J Ural 146:1578-1582, 1991 _’ 52. Scardino PT: Early detection of prostate cancer. Urol Clin
25. Bapshaw MA. Cox RS, Ramback TE: Radiation theranv for North Am 16:635-655, 1989
localized p&ate cancer: Justification by tong-term follow-up: ‘Ural 53. Chodak GW, Schoenberg HW: Progress and problems in
Clin North Am 17:787-802, 1990 screening for carcinoma of the prostate. World J Surg 13:60-64, 1989
26. Mench HR, Garfinkel L, Dodd GD: Preliminary report of 54. Thompson IM, Maj MC, Fair WR: Screening for carcinoma
the National Cancer Data Base. CA 41:17-l 8, 199 1 of the prostate: Efficacy of available screening tests. World J Surg 13:
27. Lepor H, Kimball AW, Walsh PC: Cause-specific actuarial 65-70, 1989
survival analysis: A useful method for reporting survival data in men 55. Chodak GW, Keller P, Schoenberg HW: Assessment of
with clinically localized carcinoma of the prostate. J Urol 14182-84,
screening for prostate cancer using digital rectal examination. J Urol
1989
141:1136-1138, 1989
28. Gibbons RP, Correa RJ, Brannen GE, et al: Total prostatec-
56. Lee F, Littrup PJ, Torp-Pedersen ST, et al: Prostate cancer:
tomy for clinically localized prostatic cancer: Long-term results. J Urol
Comparison of transrectal US and digital rectal examination for
141:564-566, 1989
screening. Radiology 168:389-394, 1988
29. Walsh PC, Lepor H: The role of radical prostatectomy in the
57. Scott R, Jr, Mutchnik DL, Laskowski TZ, et al: Carcinoma
management of prostatic cancer. Cancer 60:5261537, 1987 (suppl)
of the prostate in elderly men: Incidence, growth characteristics and
30. Paulson DF. Moul IW. Wahher PI: Radical nrostatectomv
clinical significance. J Urol 101:602-607, 1969
for clinical stage T&,M,, p;ostatic adenoc&cinoma: Long term ret
58. Babaian RJ, Troncoso P, Ayala A: Transurethral resection
suits. J Urol 144: 1180-l 184, 1990
zone prostate cancer detected at cystoprostatectomy. Cancer 67:1418-
31. Lange PH, Ercole CJ, Lightner DJ, et al: The value of serum
prostate-specific antigen determinations before and after radical 1422, 1991
prostatectomy. J Ural 141:873-879, 1989 59. Whitmore WF, Jr: Natural history and staging of prostate
32. Scardmo PT, Wheeler TM: Local control of prostate cancer cancer. Urol Clin North Am 11:205-220, 1984
with radiotherapy: Frequency and prognostic significance of positive 60. McNeal JE: Origin and development of carcinoma in the
results of postirradiation prostate biopsy. Nat1 Cancer Inst Monogr prostate. Cancer 23:24-34, 1969
7:95-103, 1988 6 1. Carter HB, Piantodosi S, Isaacs JT: Clinical evidence for and
33. Bagshaw MA: Radiation therapy for cancer of the prostate, implications of the multistep development of prostate cancer. J Ural
in Skinner DC, Lieskovskv G (eds): Diagnosis and Management of 143:742-746, 1990
Genitourinary &cer. Phiadelphia, PA, !?aunders, 1988, p”p425-445 62. Stamey TA, McNeil JE, Freiha FS, et al: Morphometric and
34. George NJ: Natural history of localized prostatic cancer clinical studies on 68 consecutive radical prostatectomies. J Ural 139:
managed by conservative therapy alone. Lancet March 5:494-497, 1235-1241, 1988
1988 63. Greene DR, Egawa S, Neerhut G, et al: The distribution of
35. Scardino PT, Shinohara K, Wheeler TM, et al: Staging of residual cancer in radical prostatectomy specimens in stage A prostate
prostate cancer. Ural Clin North Am 16:713-734, 1989 cancer. J Ural 145:324-329, 1991
36. Myers MH, Ries LA: Cancer patient survival rates: SEER 64. McNeal JE, Redwine EA, Freiha FS, et al: Zonal distribution
program results for 10 years of follow-up. CA 39:21-32, 1989 of prostate adenocarcinoma: Correlation with histological pattern and
37. Whitmore WF, Jr: Natural history of low stage prostatic can- direction of spread. Am J Surg Path01 12:897-906, 1988
cer and the impact of early detection. Ural Clin North Am 17:689- 65. Christensen WN, Partin AN, Walsh PC, et al: Pathologic
697, 1990 findings in clinical stage A2 prostate cancer. Cancer 65:1021-1027,
38. Hinman F, Jr: Screening for prostatic carcinoma. J Ural 145: 1990
126-130, 1991 66. McNeal JE, Villers AA, Redwine EA, et al: Histologic differ-
39. Johansson JE, Adami HO, Andersson SO, et al: Natural his- entiation, c’ancer volume, and pelvic lymph node metastasis in ade-
tory of localized prostatic cancer. A population-based study in 223 nocarcinoma of the prostate. Cancer 66: 1225-l 236, 1990
untreated patients. Lancet April 15:799-803, 1989 67. Gleason DF, Mellinger GT, The Veterans Administration
40. Whitmore WF, Jr, Warner JA, Thompson IM, Jr: Expectant Cooperative Urological Research Group: Prediction of prognosis for
management of localized prostatic cancer. Cancer 67: 1091-1096, 1991 prostatic carcinoma by combined histological grading and clinical
41. Norlen BJ: Epidemiology: Is prostate cancer mostly a “be- staging. J Urol 111:58-64, 1974
nign” tumor? Stand J Urol Nephrol 110:71-75, 1988 (suppl) 68. Rip011 E, Greene D, Tobon A, et al: Deoxyribonucleic acid
42. Larson A, Norlen BJ: Five-year follow-up of patients with ploidy, tumor volume and prostate specific antigen in localized prostate
localized prostatic carcinoma initially referred for expectant treatment.
cancer. J Ural 145:252A, 1991 (abstr 160)
Stand J Urol Nephrol93:19-30, 1985 (suppl)
69. Nativ 0, Myers RP, Farrow GM, et al: Nuclear deoxyribo-
43. Schroeder FH, Carpentier PJ, Maksimovic PA, et al: Trans-
nucleic acid ploidy and serum prostate specific antigen in operable
rectal ultrasonography (TRUS)-Volumetric applications to prostatic
prostatic adenocarcinoma. J Urol 144:303-306, 1990
carcinoma, in Resnick M, Watanabe H, Karr JP (eds): Diagnostic Ul-
70. Greene DR. Taylor SR, Wheeler TM, et al: DNA ploidy by
trasound of the Prostate. New York, NY, Elsevier, 1989, pp 124-128
image analysis of individual foci of prostate cancer: A preliminary
44. Stamey TA, Kabalin JW: Prostate specific antigen in the di-
report. Cancer Res 51:4084-4089, 1991
agnosis and treatment of adenocarcinoma of the prostate. I. Untreated
patients. J Ural 141:1070-1075, 1989 71. Blute ML, Nativ 0, Zincke H, et al: Pattern of failure after
45. Barnes R, Hadley H, Axford P, et al: Conservative treatment radical retropubic prostatectomy for clinically and pathologically lo-
of early carcinoma of prostate. Urology 14:359-362, 1979 cahzed adenbcarcinoma of the prostate: Influence-of tumor debxy-
46. McNeil JE, Bostwick DG, Kindrachuk RA, et al: Patterns of ribonucleic acid nloidv. T Urol 142: 1262-l 265. 1989
progression in prostate cancer. Lancet January 11:60-63, 1986 : 72. WinklerHZ,‘R&twater LM, Myers RP, et al: Stage Dl pros-
47. Franks LM: Latency and progression in tumors: The natural tatic adenocarcinoma: Significance of nuclear DNA ploidy patterns
history of prostatic cancer. Lancet 2:1037-1039, 1956 studied by flow cytometry. Mayo Clin Proc 63:103-122, 1988
48. Dhom G: Epidemiologic aspects of latent and clinically man- 73. Forsshmd G, Zetterberg A: Ploidy level determination in high
ifest carcinoma of the prostate. J Cancer Res Clin Oncol 106:210- grade and low grade malignant variants of prostate carcinoma. Cancer
218, 1983 Res 50:4281-4285, 1990
49. Kabalin JN, McNeil JE, Price HM, et al: Unsuspected ade- 74. Lee S, Cut-tin SM, Paulson DF, et al: Flow cytometric deter-
nocarcinoma of the prostate in patients undergoing cystoprostatectomy mination of ploidy in prostatic adenocarcinoma: A comparison with
for other causes: Incidence, histology and morphometric observations. seminal vesicle involvement and histopathological grading as a pre-
J Urol 141:1091-1094, 1989 dictor of clinical recurrence. J Urol 140:769-774, 1988
50. Montie JE, Wood DP, Ir, Pontes JE, et al: Adenocarcinoma 75. Adolfsson J, Ronstrom L, Hedhtnd P, et al: The prognostic
of the prostate incystoprostatectomy speccmens removed for bladder value of modal deoxyribonucleic acid in low grade, low stage untreated
cancer. Cancer 63:381-385, 1989 prostate cancer. J Urol 144:1404-1407, 1990

221
HUMAN PATHOLOGY Volume 23, No. 3 (March 1992)

76. Catalona WJ, Smith DS, Ratliff TL, et al: Measurement of 89. Lee F, Torp-Pedersen S, Littrup PJ, et al: Hypoechoic lesions
prostate specific antigen in serum as a screening test for prostate of the prostate: Clinical relevance of tumor size, digital rectal exam-
cancer. N Engl J Med 324:1156-1161, 1991 ination, and prostate-specific antigen. Radiology 170:29-32, 1989
77. Greene DR, Wheeler TM, Egawa S, et al: A comparison of 90. Lee F, Torp-Pedersen ST, Siders DB, et al: Transrectal ul-
the morphological features of cancer arising in the transition zone trasonography in the diagnosis and staging of prostatic carcinoma.
and in the peripheral zone of the prostate. J Ural 146: 1069-1076. Radiology 170:609-615. 1989
1991 91. Shinohara K, Scardino PT. Carter SStC, et al: Pathologic
78. Thompson T, Kadmon D, Timme TL, et al: Experimental
basis of the sonographic appearance of the normal and malignant
oncogene-induced prostate cancer. Cancer Sutv 11:55-7 1, 1991
prostate. Ural Clin North Am 16:675-69 1, 1989
79. Guinan P, Bush I, Ray V, et al: The accuracy of the digital
92. Catalona WJ, Bigg SW: Nerve-sparing radical prostatectomy:
rectal examination in the diagnosis of prostate carcinoma. N Engl J
Evaluation of results after 250 patients. J Ural 143:538-543, 1990
Med 303:499-503, 1980
80. Meacham RB, Scdrdino PT, Hoffman GS, et al: The risk of 93. Carter SStC, Talley D, Egawa S, et al: Accurate preoperative
distant metastases after TURP vs needle biopsy in patients with lo- determination of prostate cancer volume in clinically localized disease.
calized prostate cancer. J Ural 142:320-325, 1989 J Ural 14 1:276A, 1989 (abstr 427)
81. Bretas F, Scale C. Cantini M, et al: Obstructive voiding symp- 94. Spigelman SS. McNeal JE, Freiha FS, et al: Rectal examination
toms indicate a poor prognosis for patients with prostatic cancer. J in volume determination of carcinoma of the prostate: Clinical and
Ural 135:240A. 1986 (dbstr 546) anatomical correlations. J Ural 136: 1228-l 230, 1986
82. Shabsigh R, Carter SStC. Egawa S, et al: Transrectal ultra- 95. Cooner WH, Mosley BR, Rutherford CL, Jr, et al: Clinical
sound and/or digital guided biopsy of the prostate. J Ural 14 1:282A, application of tramrectal ultrasonography and prostate-specific antigen
1989 (abstr 449) in the search for prostate cancer. J Ural 139:66-69, 1988
83. Catalona WJ, Ratliff TL, Yuan JJ: Serum prostate specific 96. Cooner WH: Prostate-specific antigen, digital rectal exami-
antigen as a first-line screening test for prostate cancer. J Ural 143: nation, and transrectal ultrasonic examination of the prostate in pros-
313A, 1990 (abstr 499) tate cancer detection. Monogr Ural 12:3-13, 1991
84. Cooner WH. Mosley BR, Rutherford CL, Jr, et al: Prostate 97. Rifkin MD: Ultrasound of the Prostate. New York, NY, Raven,
cancer detection in a clinical urological practice by ultrasonography. 1988
digital rectal examination, and prostate specific antigen. J Ural 143:
98. Waterhouse RL, Resnick MI: The use of transrectal prostatic
1146-l 154, 1990
ultrasonography in the evaluation of patients with prostatic carcinoma.
85. Mettlin C, Lee F, Drago J, et al: The American Cancer Society
J Urol 141:233-239. 1989
National Prostate Cancer Detection Project: Findings on the detection
99. Carter SStC, Scardino PT, Shinohara K: Advances in urologic
of early prostate cancer in 2425 men. Cancer 67:2949-2958. 1991
ultrasound. Ural Clin North Am 16:617-867, 1989
86. Oesterling JE, Chan DW, Epstein Jl, et al: Prostate specific
antigen in the preoperative and postoperative evaluation of localized 100. Lee F. Gray JM, McLeary RD, et al: Transrectal ultrasound
prostatic cancer treated with radical prostatectomy. J Urol 139:766- in the diagnosis of prostate cancer: Location, echogenicity, histopa-
772, 1988 thology, and staging. Prostate 7:117-129, 1985
87. Rosen M, Lapin S, Goldstone L, et al: The frequency of 101. Palken M. Cobb OE, Warren BH, et al: Prostate cancer:
extracapsular extension and positive surgical margins in radical pros- Correlation of digital rectal examination, transrectal ultrasound, and
tatectomy specimens. J Ural 143:3 15A, 1990 (abstr 505) prostate specific antigen levels with tumor volumes in radical pros-
88. Shinohara K, Wheeler T. Scardino PT: The appearance of tatectomy specimens. J Ural 143:1155-l 162, 1990
prostate cancer on transrectal ultrasonography: Correlation of imaging 102. McClennan BL: Transrectal ultrasound: Is the technology
and pathological examinations. J Ural 142:76-82, 1989 leading the science? Radiology 168:571-577, 1988