`EXAMINATION IN THE DETECTION OF PROSTATE CANCER
`
`Masanori Yarnarnoto,” Hatsuki Hibi, and Koji M&ake
`Department of Urology, Nagoya University School of Medicine, Aichi, Japan
`
`Prostate-specific antigen (PSA) is a kallikrein-like serine protease that is secreted exclusively by
`the epithelial cells of all types of prostatic tissue, benign and malignant. Its serum concentration is
`raised in men with prostatic disease including cancer. We have evaluated its usefulness in the
`diagnosis of prostate cancer by measuring serum PSA concentrations in 260 men aged 50 years
`or over. All had abnormalities at digital rectal examination (DRE) involving suspected cancer, signs
`and symptoms of benign prostatic hyperplasia and equivocal findings on DRE, and miscellaneous
`other conditions, including hematospermia, chronic prostatitis and microscopic hematuria.
`Transrectal prostatic needle biopsies were performed in the men with abnormal findings on DRE or
`elevated serum PSA (above 4 ng/ml). Serum PSA ranged from 4.0 to 9.9 ng/ml in 14 (5%) of the
`260 men. Four of the men in this group (31%) who underwent prostatic biopsy had prostate
`cancer. Serum PSA levels greater than or equal to 10.0 ng/ml were found in 8 (3%) of the 260
`men. 5 of these 8 (63%) who underwent prostatic biopsy had cancer. If DRE alone had been used
`to screen the men having biopsies, 4 of the 10 cancers (40%) would have been missed. If PSA
`alone had been used to screen these men, only 1 of the 10 cancers would have been missed.
`Serum PSA measurement was more reliable than DRE for detecting prostate cancer. Since these
`two methods do not always detect the same malignant tumor, the combined use of DRE and PSA
`testing affords a more complete evaluation of the prostate gland for malignant involvement.
`Int J Urol 1994;1:74-77
`
`Key words: prostate specific antigen, prostate cancer, screening
`
`INTRODUCTION
`
`Prostate-specific antigen (PSA) is a serine protease
`isolated from prostatic tissue b y Wang et al.’ in
`1979. This unique glycoprotein is specific for, and
`produced by, all types of prostatic epithelial tissue.
`Since the initial identification and characterization of
`this prostatic marker, numerous researchers have
`investigated the clinical significance of serum PSA
`concentrations. An increased serum PSA was found
`to be a more sensitive indicator of prostatic cancer
`than an increased serum prostatic acid phosphatase,
`the previous “standard” serum marker for prostatic
`malignant involvement.2 Thus, serum PSA has
`replaced serum prostatic acid phosphatase for
`detecting prostate cancer. Currently, serum PSA is
`widely accepted in clinical practice as a sensitive
`marker and has been proposed as a means of
`monitoring the response of prostate cancer to
`therapy. ’
`A recent study by Catalona et al. also suggested
`that measurement of serum PSA is a useful diag-
`nostic tool for detecting prostate cancer.j Measure-
`ment of serum PSA concentrations has several
`advantages over rectal examination or transrectal
`~-
`-~
`Accepted jhr prrblicutio)r ori Xoveuiber 15, 1993. “Requests for
`repririis: Departniem if Urology, Nagoya University, School of
`Medicim, 65 Tsuruniui-cho, Showa-ku, Nagoya, Aichi 466,
`Japall.
`
`~
`
`~
`
`prostatic ultrasonography in screening for prostate
`cancer and is more acceptable to patients than other
`screening procedure^.^ In order to determine the prc-
`dictive significance of PSA and digital rectal exami-
`nation (DRE) in the diagnosis of prostate cancer, wc
`performed this prospective study.
`
`MATERIALS AND METHODS
`
`Between January 4, 1991 and February 26, 1993, we
`measured serum PSA in 260 ambulatory men, aged
`50 years or over, who had abnormalities at rectal
`examination involving suspected cancer, signs and
`symptoms of benign prostatic hyperplasia and
`equivocal findings on rectal examination, and mis-
`cellaneous other conditions, including hematosper-
`mia, chronic prostatitis, urolithiasis and microscopic
`hematuria. Blood samples were withdrawn before
`biopsy and before or at least 1 week after DRE, since
`this procedure may raise the serum PSA concentra-
`tion. PSA was determined by EIKEN PSA radio-
`immunoassay (EIKEN CHEMICAL CO., LTD.,
`Tokyo, Japan). T h e normal reference range was
`0-4.0 ng/ml. Catalona et al. reported that 6 7 % of
`men with serum PSA values >’ 10 ngiml were found
`to have prostate ~ a n c e r . ~ Thus, we have subdivided
`our patients into 3 groups according to their serum
`PSA (4.0,4.0-9.9, 2 10 ng/ml, respectively).
`
`~
`
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`091 9-81 72/94/01 01 -0074/US$03.00 c Churchill Livingstone Japan 1994
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`T h e indications for prostatic biopsy were an
`abnormal result on DRE or an elevated serum PSA
`(above 4.0 ng/ml). These patients then underwent
`transrectal ultrasonography. If a hypoechoic area was
`found, biopsies were obtained with ultrasound
`guidance. The patients were given enemas containing
`sodium phosphate and sodium biphosphate and
`antimicrobial prophylaxis (oral cefaclor, 250 mg) for
`three days after biopsy. The biopsy was performed
`using an automatic biopsy gun (Bard) fitted with an
`18-gauge biopsy needle.
`Clinical staging consisted of rectal examination,
`determination of serum prostatic acid phosphatase
`levels, and radioisotope bone-scanning with
`confirmatory radiography, if necessary. If the tumor
`was judged to be confined to the organ, it was
`described as stage B; if it was judged to have
`extended through the capsule, but not to have
`metastasized, it was described as stage C ; if it was
`judged to have metastasized, it was described as stage
`D. Correlation coefficients were calculated to
`evaluate the relationship between age, log serum
`PSA, and the diagnosis of cancer. The chi-squared
`test was used to compare the incidence of cancer,
`findings on rectal examination and PSA levels. The
`sensitivity, specificity, positive and negative predictive
`values and overall accuracy of the serum PSA
`measurement and rectal examination as diagnostic
`tests for prostate cancer were evaluated.
`
`RESULTS
`
`For the 260 men participating in the study, the initial
`serum PSA values were < 4.0 ng/ml in 238 (92%),
`4.0-9.9 ng/ml in 14 (5%), and > 10.0 ng/ml in 8
`
`(3%). Table 1 shows these results together with the
`age distribution.
`A total of 22 men with serum PSA values less than
`4.0 ng/ml underwent biopsy when only 1 (4.5%) was
`found to have prostate cancer. Fourteen men with
`serum PSA values of 4.0-9.9 ng/ml underwent biopsy
`and 4 (3 1 %) were found to have prostate cancer. The
`8 men with serum PSA values > 10.0 ng/ml
`underwent biopsy and 5 (63%) were found to have
`cancer (Table 1). Ten men were diagnosed as having
`prostate cancer (overall detection rate, 3.8%). Age
`did not correlate significantly with either serum PSA
`or the diagnosis of cancer.
`Table 2 shows the relationship between the
`findings on DRE and the diagnosis of cancer. The
`percentage of men who proved to have cancer and a
`suspicious DRE was not significant. Table 2 also
`shows the relationship between serum PSA and the
`diagnosis of cancer. The finding of a suspicious result
`was significantly related to cancer (X’ = 4.31, p =
`0.05). If DRE alone had been used to screen the men
`who had biopsies, 4 of the 10 cancers (40%)) would
`have been missed. If PSA alone had been used to
`screen these men, only 1 of the 10 cancers would
`have been missed.
`Table 3 shows the sensitivity, specificity, and
`overall accuracy of rectal examination and serum
`PSA measurement. The advantage of the latter as a
`sole diagnostic test derives from its greater sensitivity,
`specificity and overall accuracy. Serum PSA
`measurement also had a higher positive and negative
`predictive value than DRE.
`One man with a serum PSA less than 4.0 ng/ml
`and normal findings on DRE had stage D2, poorly
`differentiated, adenocarcinoma. T h i s patient
`
`Table 1. Seruni PSA concentrations and the incidence of cancer in 260 men.
`Serum PSA concentration (nglml)
`c 4.0
`4.0-9.9
`> 1 0 0
`No with cancer
`No with cancer
`No with cancer
`No
`/No with biopsy
`No
`/No with biopsy
`/No with biospy
`No
`-
`-
`
`011
`01 1
`0
`50-59
`40 (15)
`39
`1
`0
`91
`018
`60-69
`100 (38)
`4
`114
`5
`315
`70-79
`89 (34)
`79
`1 I9
`7
`217
`3
`213
`0
`31 (12)
`29
`014
`80-90
`2
`112
`0
`All
`260
`238
`1 122
`14
`411 4
`8
`518
`Table 2 . Relationship between the results of rectal examination and PSA and the diaptosis of cancer in men who had prostare biopsies.
`No of men
`Normal
`Suspicious
`Rectal exam.
`PSA
`Rectal exam.
`Rectal exam.
`PSA
`10
`10
`4
`6
`9
`34
`34
`10
`24
`13
`~~- __
`
`Age (yrs)
`
`No of men
`(o/. of total)
`
`~~
`
`~
`
`~~
`
`~
`
`~
`
`Diagnosis
`
`-. -
`Cancer
`No cancer
`
`~
`
`_ _ ~
`-
`
`~~~
`
`~~~
`
`PSA
`1
`21
`
`_ ~-
`
`__
`
`-
`
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`lrlt / Ulol 7994:7
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`~~~
`
`~
`
`~~
`
`~
`
`Table. 3. Accuracy of rectal examination and serum PSA measurement in detecting prostate cancer on first biopsy.
`Serum PSA (Yo)
`Rectal examination ( O h )
`Measure'
`-.
`90
`60
`Sensitivity
`Specificity
`29
`62
`Positive predictive value
`20
`43
`71
`Negative predictive value
`95
`Overall accuracy
`36
`68
`'Sensitivity was determined by dividing the number of true positive results by the number of true positives plus thi nuinber of false
`negarives, specifcity by dividing the number of true negative results by the number oftrue negatives plus the number of false positives.
`Positive predictive value was determined by dividing the number of true positive results by the number of true positives and false
`positives combined. Negative predictive value was determined by dividing the number of true negative results by the number of true
`negarives and false negatives combined. Overall accuracy was determined b i dividing the number of true positive and true negative
`results b-y [he rota1 number tested.
`
`~
`
`~
`
`~~
`
`..
`
`underwent biopsy because urinary cytology revealed
`adenocarcinoma. Four men with serum PSA levels in
`the range 4.0-9.9 ng/ml had clinical stages B2, D1,
`D2, and D2. Of 5 men with serum PSA > 10 ng/ml,
`3 had disease confined to the prostate, as determined
`by pathological examination, and the others had
`metastatic bone cancer. No correlation was found
`between serum PSA and tumor stage.
`
`DISCUSSION
`
`Our findings suggest that serum PSA measurement is
`an useful addition to DRE and transrectal ultra-
`sonography for detecting prostate cancer. Although
`all three tests have the ability to predict cancer, serum
`PSA was best. For example, among the 10 men in
`our study group who had cancer, DRE alone would
`have missed 4 (40%). However, if PSA measurement
`alone had been used to screen the men who had
`biopsies, only 1 patient would have been missed.
`Serum PSA measurements are sufficiently sensi-
`tive to be used alone as a screening test for prostate
`cancer (Table 3). T h e specificity of PSA for
`screening is limited because it is elevated in men with
`benign prostatic hyperplasia or p r o s t a t i t i ~ . ' ? ~
`However, PSA, measured in conjunction with DRE,
`is the tool which allows the urologist to diagnose clin-
`ically significant prostate cancer at an early stage. It is
`likely that PSA will play an important role in identify-
`ing men with potentially curable lesions.
`Several large-scale studies have been conducted
`recently examining the role of PSA as a screening test
`* As mentioned in the
`for prostate
`introduction, Catalona et al. have evaluated 1,653
`healthy, asymptomatic men, 50 years of age or over,
`with the help of their serum PSA concentrations.
`Thirty-seven were diagnosed as having cancer
`(overall detection rate, 2.2%).j
`In addition, Brawer et al., in a study of 1,249
`symptom-free men, also 50 years of age or over,
`without a family history of prostate cancer, identified
`32 cases of prostate cancer (detection rate, 2.6%).'
`
`Finally, Labrie et al. evaluated the ability of PSA
`to detect prostate cancer in 1,002 men, 45-80 years
`of age, who had been selected randomly from the
`electoral rolls of Quebec City and the surrounding
`area. Using a cut-off of 3.0 ng/ml (Tandem-R assay),
`they obtained a 4.6% detection rate.R
`All these rates are somewhat better than the
`1.3-1.596 reported with DRE. In the Catalona study,
`32% of cancers identified would have been missed
`had DRE alone been used and in our own series,
`40% of cancers would have been missed if DRE
`alone had been used for screening. Brawer's group
`found that 38% of their cancers would not have been
`detected if DRE had been used. We can conclude,
`then, that routine PSA testing of men in the age
`range at risk of developing prostate cancer increases
`the detection rate of this malignancy.
`But PSA is not perfect. T h i s is shown by
`
`Catalona's r e p ~ r t , ~ in which a comparison group of
`300 men underwent prostate biopsy for a variety of
`clinical conditions, including induration, asymmetry,
`equivocal D R E , hematospermia, and chronic
`prostatitis. Serum PSA was measured in 235 of them
`before biopsy. Cancer was found in 61 (26%)) and of
`these, 13 (21%) had a serum PSA in the reference
`range (which for the Tandem-R assay is 0.0-3.9
`ng/ml). These cancers would not have been identified
`had PSA been used to select patients for biopsy.
`Cooner et al. observed similar findings in a series
`of 1,807 men, 50-89 years of age, who attended one
`urology practice for prostate evaluation." Using
`DRE, PSA, and transrectal ultrasonography, the
`investigators found cancer in 263 men. Of these, 52
`(20%) had a normal serum PSA (measured by
`Tandem-R assay).
`Japanese investigators have demonstrated that
`mass screening using PSA and DRE in the Gunma
`Prefecture of Japan is successful in detecting early
`prostate cancer. T h e reported detection rate was
`high. ' I
`In the Labrie study,* in which all patients were
`also evaluated using DRE, PSA and transrectal
`
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`ultrasonography, 16 of 57 (28%) patients found to
`have cancer had a serum PSA of 4.0 ng/ml or less.
`Reliance on serum PSA alone would have meant that
`these 16 cancers would have gone undetected. In our
`present study, only 4 of 10 patients with prostate
`cancer (10%) had a normal PSA level.
`The data from these large investigations and our
`own results indicate that, although PSA can identify
`more cancers than DRE, not all prostate cancers are
`associated with an elevated serum PSA. In fact,
`approximately 20% of all identified prostate cancers
`are accompanied by a normal serum PSA.
`In conclusion, PSA can identify some cancers not
`detectable by digital rectal examination; conversely,
`this examination can identify cancers not detectable
`from the serum PSA concentration. Neither PSA nor
`DRE is sufficiently sensitive or specific on its own to
`be an ideal screening test for early prostate cancer.
`Therefore, cost-effective evaluation of the prostate
`gland is best achieved when both PSA concentration
`and DFE are used. Transrectal ultrasonography is
`more costly and does not contribute appreciably to
`the detectability when the results of both the DRE
`and PSA determinations are normal. Transrectal
`ultrasonography is best reserved for patients who
`have an abnormal DRE or an increased serum PSA.
`
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