Journal of Cellular Biochemistry, Supplement 16H:31-43 (1992)

Prostate-Specific Antigen and Diagnosing Early Malignancies of the Prostate Joseph E. Oesterling, M.D. Assistant Professor of Urology, Mayo Medical School & Consultant, Department of Urology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905

Abstract Prostate-specificantigen is a kallikrein-likeserine proteasethat is producedexclusively by the epithelial cells of all types of prostatic tissue, benign and malignant. Physiologically, it is present in the seminal fluid at high concentration and functions to cleave the high molecular weight protein responsible for the seminal coagulum into smaller polypeptides. This action results in liquefactionof the coagulum. Prostate-specificantigenis also present in the serum and can be measured reliably by several different assays. Although the protein is prostate-specific,it is not prostate-cancer-specific.As a result, benign conditions such as benign prostatic hyperplasia, prostatitisand infarction,as well as prostatic intraepithelialneoplasia, can be associated with elevated serum levels of prostate-specific antigen. Approximately 25% of men with benign prostatic hyperplasia have an elevated serum value of prostate-specificantigen, whereas 35%to 40% of patientswith organ-confinedprostate cancer have a level within the reference range. Prostate-specific antigen can identify some cancers not detectable by digital rectal examination; alternatively, this examination can identify cancers not detectable from the serum prostate-specificantigen concentration. Thus, the most complete evaluation of the prostate gland is achieved when both the prostate-specificantigen value and the digital rectal examination are used. The density and the rate of change of serum prostate-specific antigen are new concepts to improve the ability of prostatespecific antigen to detect early prostate cancer. Preliminary results are encouraging, but additional studies are required to determine the true usefulness of these new variables. Thus, in 1992, determination of the prostate-specificantigen value is a valuable new tool for the practicing physician and will be instrumental in our campaign to diagnose clinically significant prostate cancer at an early, curable stage. o 1992 Wiley-Liss, Inc.

Key Words: PIN, prostate carcinoma, PSA density, PSA velocity, screening, tumor progression

Prostate-specific antigen (PSA) is a g l y c o p r o t e i n t h a t was f i r s t i d e n t i f i e d i n seminal plasma by Hara and associates i n 1971 [l]. They r e f e r r e d t o t h i s newly recognized component o f human seminal plasma as y-seminoprotein. Two years l a t e r , L i and B e l i n g [Z] were a b l e t o i s o l a t e and p u r i f y t h i s same p r o t e i n , a l s o from human seminal plasma. They found t h e p r o t e i n t o have a low molecular weight o f approximately 31,000 d a l t o n s , a slow B - m o b i l i t y on e l e c t r o p h o r e s i s , and a h i g h d i f f u s i o n r a t e i n agar medium. They c a l l e d t h i s p r o t e i n E l antigen, according t o i t s m o b i l i t y i n conventional e l e c t r o p h o r e s i s . I n 1978, Sensabaugh [3] f i r s t t r u l y characterized t h i s "semen-specific p r o t e i n " w i t h imnunoe l e c t r o p h o r e t i c analysis. He determi ned that this protein was indeed highly imnunogenic and had several sugar m o i e t i e s ; 01992 Wiley-Liss. Inc.

t h e molecular weight was 30,000 d a l t o n s , and i t s i s o e l e c t r i c p o i n t s ranged from 6.5 t o 8.0. He designated i t p30 because o f i t s mol ecul a r we igh t I n 1979, Wang and colleagues [4] i s o l a t e d an a n t i g e n f r o m p r o s t a t i c t i s s u e , pur f i e d i t , and demonstrated i t s s p e c i f i c i t y w i t h was prostatic tissue. Although it i d e n t i f i e d i n a l l types o f p r o s t a t i c t ssue (normal , benign h y p e r p l a s t ic , and m a l i g n a n t ) , i t c o u l d n o t be found i r a nY o t h e r human t i s s u e . With g e l f i l t r a t i o n and g e l e l e c t r o p h o r e s i s , i t was demonstrated t o have a molecular weight o f 33,000 t o 34,000 dal tons, have a s i n g l e i s o e l e c t r i c p o i n t o f 6.9, and t o e x i s t as a monomer. T h i s r e p o r t f i r s t described t h e p u r i f i c a t i o n o f an a n t i g e n t h a t was p r o s t a t e - s p e c i f i c and d i s t i n c t f r o m p r o s t a t i c a c i d phosphatase. Because o f i t s a s s o c i a t i o n w i t h p r o s t a t i c

.

Oesterling

32

tissue only, it was termed "prostatespecific antigen." Subsequently, Wang and associates [5] demonstrated that the PSA found in seminal plasma was imnunologically identical and biochemically similar to that isolated from the prostate gland. Finally, Papsidero and coworkers f6] were able to identify PSA in human serum and verify that this molecule was identical to the one purified directly from prostatic tissue. Thus, from these studies and others [7,8], it became clear that PSA could be measured reliably in the serum and that it was specific for the prostate. Indeed, the only organ-specific serum marker in all of cancer biology had been discovered. BIOHOLECULAR CHARACTERISTICS OF PSA For assessment of the ability of the serum PSA value to identify premalignant and early malignant lesions of the prostate, it is necessary to have a complete understanding of the biomolecular and physiologic properties of this tumor marker. Biochemically, PSA is a single-chain glycoprotein that contains 93x amino acids It is a monomer and 7% carbohydrates [9]. with 240 amino acid residues and 4 carbohydrate side chains (Fig. 1). Evidence suggests that an N-1 inked carbohydrate side chain exists at amino acid 45 (asparagine) and that 0-linked carbohydrate side chains are attached to amino acid 69 (serine), 70 (threonine), and 71 (serine) [lo]. The N-terminal amino acid is isoleucine, and the C-terminal residue is proline. The overall molecular weight is 34,000 daltons, and the isoelectric points range from 6.8 to 7.2 because of various isometric forms [ll]. With use of five murine monoclonal antibodies (1A5, 2A4, 3F1, F5, and 3A12) and an antigen-affinity purified goat polyclonal IgG antibody, the prostate-specific antigenic domain of the PSA molecule has been identified and its three-dimensional structure characterized [9]. In addition, the complete gene encoding PSA has been sequenced and localized to chromosome 19. With the use of PSA cyclic deoxyribonucleic acid fragments as hybridization probes, the gene has been found to be approximately 6 kilobases in size and composed of 4 introns and 5 exons; two major transcription initiation sites also have been identified [12]. An 82% homology has been found between the PSA gene and the human kallikrein-1 gene [13]. Other studies have confi rmed thi s extensi ve homo1 ogy be tween PSA and proteases of the kallikrein family [14,15].

PHYSIOLOGIC PROPERTIES OF PSA Functionally, PSA is a kallikrein-like serine protease that is produced exclusively by the epithelial cells lining the acini and ducts of the prostate gland [8,16]. Using imnunoperoxidase staining techniques, Papsidero and associates [17] demonstrated that within the normal prostate gland, PSA was located only in epithelial cells; none of the other cellular components of the prostate, including the stromal and vascular elements, stained for PSA. Subsequently, Nadji and coworkers [18] detected PSA in the epithelial cells of benign prostatic hyperplasia (BPH) tissue, primary prostate cancer tissue, and metastatic prostate cancer tissue. Normally, PSA is secreted into the lumina of the prostatic ducts and is present in the seminal plasma at high concentrations. In the seminal fluid, PSA is involved directly in the liquefaction of the seminal coagulum that is formed at ejaculation [ls]. Lilja and Laurel 1 [16,19] demonstrated that PSA cleaves this protein rapidly into several basic low molecular weight proteins in concurrence with 1 iquefaction of the coagulum. In a subsequent study, McGee and Herr [20] demonstrated that seminal vesiclespecific antigen, a glycoprotein that is produced by the epithelial cells o f the seminal vesicle, is the substrate for PSA during semen liquefaction. Akiyama and associates [21] and Ban and colleagues [22] found it to possess chymotrypsin-like and trypsin-1 i ke activity. The effect of this proteolytic compound on other body tissues and organs once it is present in the serum in high concentration is unknown.

PSA AND PROSTATIC INTRAEPITHELIAL NEOPLASIA Prostatic intraepithel ial neoplasia (PIN) , also known as atypical hyperplasia and intraductal dysplasia, is characterized by an increased proliferation and dysplasia of the epithelial cells lining the lumina of the acini and ducts [23]. PIN is considered to be a premalignant change in the human prostate and has been demonstrated to be closely related to adenocarcinoma on the basis of imunophenotypic studies [24-281. Brawer 1291 believes that PIN may be responsible for the elevated PSA levels in some patients who have benign prostatic hyperplasia only. To investigate this hypothesis, he and his associates [30] meticulously analyzed the surgical specimens of 81 men undergoing simple prostatectomy (open or transurethral resection) and

Fig. 1. Molecular structure of prostate-specific antigen. (From Oesterling JE: Prostatespecific antigen: a valuable c l i n i c a l tool. Oncology [ W i l l i s t o n Park] 5 no. 4:107-122, 1991. By permission o f Dominus Publlshlng Company.)

i

Oesterling

34

I

Basement membrane

J

I

Grade 1

I

I

1

Very mild Mild

Normal

Moderate

I

Grade 2

I

Severe In situ

I

Grade3

Microinvasive

lw

I

Prostatic intraepithelial neoplasia

Fig. 2. S a l i e n t features o f p r o s t a t i c i n t r a e p i t h e l i a l neoplasia. (From Bostwlck DG, Brawer P r o s t a t i c i n t r a - e p i t h e l i a l neoplasia and e a r l y Invasion i n p r o s t a t e cancer. Cancer 59:788-794, 1987. By permission o f t h e American Cancer S o c i e t y . )

MK:

compared t h e p a t h o l o g i c f i n d i n g s w i t h t h e p r e o p e r a t i v e serum PSA l e v e l . P I N was i d e n t i f i e d i n 25 p a t i e n t s (31%). The median PSA l e v e l f o r these men was 4.0 ng/mL (range, 0.3 t o 22.3 ng/mL) compared w i t h 2.1 ng/mL (range, 0.3 t o 4.7 ng/mL) f o r t h e 26 men w i t h BPH o n l y and 5.9 ng/mL (range, 0.92 t o 34 ng/mL) f o r t h e 14 p a t i e n t s w i t h adenocarcinoma i n t h e resected t i s s u e . Lee and colleagues [31] observed s i m i l a r r e s u l t s for patients undergoing transrectal ultrasound-guided biopsy of hypoechoic p e r i p h e r a l zone lesions. The mean prebiopsy serum PSA l e v e l (Pros-Check PSA assay) was 4.0 + 4.0 ng/mL (standard d e v i a t i o n ) f o r 91 men who had BPH t i s s u e o n l y , 9.5 2 10.4 ng/mL f o r 27 p a t i e n t s w i t h P I N i n t h e biopsy specimen, and 84.0 2 377 ng/mL f o r 103 patients whose biopsy specimens were p o s i t i v e f o r adenocarcinoma. A1 though t h e standard d e v i a t i o n s were l a r g e and o n l y 27 p a t i e n t s w i t h P I N were i d e n t i f i e d , t h e n a t u r a l l o g a r i t h m i c PSA values o f men w i t h P I N w e r e s i g n i f i c a n t l y d i f f e r e n t f r o m those o f men w i t h BPH (p < 0.05) and o f men w i t h p r o s t a t e cancer (p < 0.5). Thus, i n some p a t i e n t s i t seems t h a t P I N can be associated w i t h a serum PSA c o n c e n t r a t i o n h i g h e r than t h a t observed f o r BPH alone. T h i s increase i s m o s t l i k e l y due t o a d i s o r g a n i z a t i o n o f t h e basal c e l l l a y e r and perhaps d i s r u p t i o n o f t h e epi the1 i a l basement membrane (Fig. Z), which a l l o w s t h e low molecular weight PSA molecule t o d i f f u s e more e a s i l y f r o m t h e lumina o f t h e a c i n i t o t h e lumina o f t h e adjacent c a p i l l a r i e s o r lymphatics. Another e x p l a n a t i o n i s t h a t t h e r e may be a c o e x i s t i n g adenocarcinoma o f t h e p r o s t a t e t h a t has n o t yet been identified. Several in v e s t i g a t o r s have shown t h a t P I N f r e q u e n t l y i s found i n p r o s t a t e s w i t h adenocarcinoma. Thus, t h e

a s s o c i a t i o n between P I N and a moderately e l e v a t e d serum PSA l e v e l may be o f i n t e r e s t w i t h respect t o e a r l y diagnosis o f p r o s t a t e cancer. However, t h e t r u e s i g n i f i c a n c e o f an e l e v a t e d PSA value i n c o n j u n c t i o n w i t h t h e f i n d i n g o f P I N on biopsy o f t h e p r o s t a t e awaits f u r t h e r investigation.

PSA AND EARLY PROSTATE CANCER When one contemplates use o f t h e PSA concentration f o r the e a r l y detection o f p r o s t a t e cancer o r as a screening t o o l , several c r i t e r i a must be imposed: 1) t h e t e s t being used i s safe and inexpensive so t h a t i t w i 11 have widespread acceptance, 2) t h e disease being sought i s comnon i n t h e p o p u l a t i o n under i n v e s t i g a t i o n , and 3) an e f f e c t i v e treatment i s a v a i l a b l e f o r e a r l y stage disease which w i l l r e s u l t i n a decreased m o r b i d i t y and m o r t a l i t y from t h e disease process. On t h e b a s i s o f o b j e c t i v e data, PSA d e t e r m i n a t i o n f u l f i l l s c r i t e r i o n 1 and p r o s t a t e cancer f u l f i l l s c r i t e r i o n 2. Despite t h e l a c k o f prospective, randomized, c o n t r o l l e d studies, r a d i c a l prostatectomy and r a d i a t i o n therapy a r e presumed t o s a t i s f y c r i t e r i o n 3 and, indeed, are e f f e c t ive treatments f o r organ- con f ined disease. I f PSA i s t o be u s e f u l i n t h e e a r l y detection o f c l i n i c a l l y s i g n i f i c a n t prostate cancer, t h e serum value must be a b l e t o 1) d i s t i n g u i s h c u r a b l e p r o s t a t e cancer from BPH ( s p e c i f i c i t y ) and 2) i d e n t i f y prostate cancer n o t d e t e c t a b l e by d i g i t a l r e c t a l examination ( s e n s i t i v i t y ) . The f i r s t issue can be addressed by comparing t h e serum PSA values o f p a t i e n t s w i t h organ-confined p r o s t a t e cancer ( p a t i e n t s who have t h e g r e a t e s t l i k e l i h o o d of cure w i t h d e f i n i t i v e therapy) w i t h those o f men who have BPH

357

168

Lange e t a l . [34]

Hudson e t a l . [32]

319 75

79

103

79

47

31

185

Organ-conf 1 ned % Prostate ca

391103

14131

a31185

No./total

p


10.1ng/mLt

Prostate s p e c i f i c antigen: a c r i t i c a l assessment o f t h e most useful tumor marker f o r adenocarcinoma of t h e Prostate.

3

3

7

%

10132

a21185

No.ltota1

37 1191319 0.0001

36

32

44

%

Organ-conf ined p r o s t a t e ca

ng1mLt

BPH, benign p r o s t a t i c hyperplasia; ca, cancer; PSA, p r o s t a t e - s p e c i f i c antigen.

22

19

18

46

%

B PH

4.1-10.0

PSA values i n s p e c i f i e d range

From Oesterling JE:

Abbreviations:

38

45

45

%

Organ-conf ined p r o s t a t e ca

nglmLt

4491597 43 1361319 p < 0.0001

1331168

2821357

34/72

No.ltota1

BPH

TTandem-R PSA assay was used t o determine values.

*Both diseases were confirmed h i s t o l o g i c a l l y .

597

-

72

P a r t i n e t a l . [33]

Totals

BPH

Reference

No. o f patients, by disease

0.0-4.0

TABLE I. Prostate-Specific Antigen Values f o r Benign P r o s t a t i c Hyperplasla and Organ-Conflned Prostate Cancer*

36

Oesterling

only. Table I sumnarizes the PSA values for these two groups of patients as determined from three major investigations [32-341. Within each PSA range, there is a statistically significant difference between the PSA values for patients with BPH and those for men with organ-confined prostate cancer (p < 0.0001). Of note, however, is the fact that 43% (136 of 319) of patients with prostate cancer have a PSA value within the normal range, and 25% (148 of 597) of men with BPH have a PSA value above the reference range (0.0 to 4.0 ng/mL). When these data are evaluated statistically (Table 1 1 ) , PSA has a 64% diagnostic accuracy (efficiency) for organ-confined prostate cancer if the serum PSA concentration is more than 4 ng/mL and a 70% diagnostic accuracy if the serum value is more than 10 ng/mL. The positive predictive values are 49% and 75% for serum PSA values of more than 4 and 10 ng/mL, respectively.

When the patient population as a whole i s evaluated, the serum PSA value seems able to distinguish patients with organ-confined prostate cancer from men who have BPH only. However, because of the tremendous overlap i n PSA values between the two groups irrespective of the cutoff level chosen, the serum PSA level, by itself, cannot reliably distinguish patients with early, curable prostate cancer from men with BPH on an individual basis. Thus, PSA determination is not a specific test for early prostate cancer. To determine whether PSA can identify prostate cancers that are not detectable by digital rectal examination, one can review the data of Cooner and associates C35J. These investigators reported on 225 men who presented to their urologic practice for prostatic evaluation and had benign results on digital rectal examination. All men under study also had a serum PSA determin-

TABLE 11. Ability of Prostate-Specific Antigen Level to Distinguish Organ-Confined Prostate Cancer From Benign Prostatic Hyperplasla (Both Histologically Confirmed) % patients at PSA

Statistical parameter Sensitivity Specificity False-negative rate Fa1 se-positi ve rate Diagnostic accuracy (eff i c i ency ) Positive predictive value Negative predictive value

cutoff level >4 >ng j omL ng/mL 57 68

23 96

43

32

77 4

64 49 75

70 75 70

Abbreviation: PSA, prostate-specific antigen. From Oesterling JE: Prostate specific antigen: a critical assessment of the most useful tumor marker for adenocarcinoma of the prostate. J Urol 145:907-923, 1991. BY permission of the American Urological Associ ation, I nc

.

Prostate-Specific Antigen

ation and transrectal u l trasonography. I r r e s p e c t i v e o f t h e serum PSA value, i f a hypoechoic area was identified by t r a n s r e c t a l ultrasonography, a biopsy o f t h e suspicious area was performed. The r e s u l t s a r e sumnarized i n Table 111. O f t h e 225 men i n whom r e s u l t s o f d i g i t a l r e c t a l examinat i o n were negative, 61 (27%) had an e l e v a t e d serum PSA concentration; o f these, 21 (34%) had biopsy-proven p r o s t a t e cancer. Thus, 9.3% (27% x 34%) o f t h e p a t i e n t s i n t h i s s e r i e s had t h e i r p r o s t a t e cancer diagnosed because o f an e l e v a t e d serum PSA concentration. Without question, these data i m p l y t h a t t h e serum PSA value can l e a d t o t h e d e t e c t i o n o f p r o s t a t e cancers n o t i d e n t i f i e d by d i g i t a l r e c t a l examination. Use o f t h e PSA value, however, i s n o t p e r f e c t . With a c u t o f f l e v e l o f 4.0 ng/mL, t h e s e n s i t i v i t y and p o s i t i v e p r e d i c t i v e value o f PSA f o r t h i s group o f men w i t h no evidence o f malignancy by d i g i t a l r e c t a l examination were 75% and 34%, r e s p e c t i v e l y Seven men (4%) had biopsy(Table I V ) . proven cancer d e s p i t e a normal PSA value. C l e a r l y , t h e serum PSA c o n c e n t r a t i o n i s n o t always e l e v a t e d i n t h e s e t t i n g o f cancer; s t a t e d another way, a serum PSA value i n t h e reference range does n o t guarantee t h e absence of a p r o s t a t i c malignancy. Catalona [36] observed similar and associates results. I n a group o f 235 men who had a serum PSA d e t e r m i n a t i o n b e f o r e undergoing p r o s t a t e biopsy f o r c l i n i c a l c o n d i t i o n s ( i n d u r a t i o n , asymnetry, o r hematospermia), 61 (26%) had cancer. O f these, 13 p a t i e n t s

37

(21%) had a normal serum PSA value. Thus, if PSA had been used t o decide who should have biopsy, 21% o f t h e cancers i d e n t i f i e d would have been missed. Taken together, these r e s u l t s i n d i c a t e t h a t t h e PSA value can i d e n t i f y some p r o s t a t e cancers n o t d e t e c t e d by d i g i t a l r e c t a l examination b u t t h a t n o t a l l cancers a r e associated w i t h an e l e v a t e d serum PSA level. Thus, PSA i s n o t an e n t i r e l y s e n s i t i v e t e s t f o r e a r l y p r o s t a t e cancer. Nevertheless, can t h e r o u t i n e use o f t h e serum PSA l e v e l increase t h e d e t e c t i o n r a t e of p r o s t a t e cancer? Recently, two l a r g e - s c a l e s t u d i e s have been conducted t o examine t h e r o l e o f PSA d e t e r m i n a t i o n as a screening t e s t for p r o s t a t e cancer [36,37]. A t Washington Louis, Catalona and University i n St. associates [36] evaluated 1,653 healthy, asymptomatic men w i t h a serum PSA determin a t i o n ; cancer was diagnosed i n 37 men, and t h e o v e r a l l d e t e c t i o n r a t e was 2.2%. Brawer and colleagues [37] a t t h e U n i v e r s i t y o f Washington i n S e a t t l e s t u d i e d 1,249 men; they i d e n t i f i e d 32 p a t i e n t s w i t h p r o s t a t e cancer, and t h e d e t e c t i o n r a t e was 2.6%. These values a r e somewhat b e t t e r than t h e r a t e s o f 1.3% t o 1.5% reported f o r d i g i t a l I n t h e Washington r e c t a l examination [38]. University study, 32% o f t h e cancers i d e n t i f i e d would have been missed i f d i g i t a l r e c t a l examination alone had been used. The S e a t t l e group found t h a t 38% o f t h e cancers would n o t have been i d e n t i f i e d i f d i g i t a l r e c t a l examination had been used t o screen

TABLE 111. Serum P r o s t a t e - S p e c i f i c Antigen Level and Biopsy R e s u l t s f o r 225 Men With Benign R e s u l t s o f D i g i t a l Rectal Examination

Serum PSA, ng/mL 0.0-4.0

%

No.

164

96

157

4

7

43

74

32

26

11

18 225

44 -

8 -

56 -

10 -

p a t ie n t s

4.1-10.0

>

10.0 Total

Biopsy r e s u l t s Ben ign Cancer

No. o f

88

197

Abbreviation:

PSA, p r o s t a t e - s p e c i f i c antigen.

M o d i f i e d from

Cooner WH,

%

12

No.

28

Mosley BR, R u t h e r f o r d CL Jr, Beard JH, Pond HS,

Bass RB Jr, T e r r y WJ: C l i n i c a l a p p l i c a t i o n o f t r a n s r e c t a l ultrasonography and p r o s t a t e s p e c i f i c a n t i g e n i n 139:758-761,

1988.

t h e search f o r p r o s t a t e cancer.

J Urol

Oesterling

38

the population under study. Thus, use of the PSA value in a screening capacity will increase the detection rate of prostate cancer. However, not all the additional cancers identified by the PSA level are 1 ow-vol ume, organ-conf i ned, curabl e tumors, nor are they found only in men with a minimal life expectancy of 10 years. In the screening study from Seattle, 2 (6%) of the 32 men found to have cancer had clinical stage C disease; 30 (94%), however, were thought to have organ-confined disease. Sixteen (50%) underwent surgical exploration: one (6%) had stage D 1 cancer and six (38%) had pathologic stage C disease. Six other patients in the series with newly diagnosed cancer were followed expectantly because of poor health o r advanced age. Perhaps only men with a life expectancy of 10 years o r more should be included in early detect i on programs. These data relating to the ability of the serum PSA value to detect early prostate

cancer indicate that 1) patients with early, curable prostate cancer can have serum PSA values similar to those of men with obstructive BPH, 2) the PSA level can identify prostate cancers not detectable by digital rectal examination, 3) digital rectal examination can identify prostate cancers not detectable by the serum PSA value, and 4) overall, the PSA value can identify more prostate cancers than digital rectal examination when both are used in a screening capacity. Neither, however, is sufficiently sensitive nor specific to be used alone a s a screening test for prostate cancer. Thus, the PSA value seems to identify some cancers, digital rectal examination identifies some tumors, and the lesions identified are not necessarily the same lesions. I n 1992, the most complete, yet cost-effective, evaluation of the prostate gland is achieved when both determination of the PSA value and digital rectal examination are used together.

TABLE IV. Ability of Prostate-Specffic Antigen Level to Detect Prostate Cancer in Men With Benign Results of Digital Rectal Examination % patients at PSA

Stat i s t i cal parameter ~

~

_

~

_

_

~~

Sensitivity Specificity False-negative rate Fa1 se-posi tive rate Diagnostic accuracy (efficiency) Positive predictive value Negative predictive value

cutoff level > 4 ng/mL ?igh’i!L ~

75 79 25 21

36 96 64 4

79 34 96

88 56 91

Abbreviation: PSA, prostate-specific antigen. Data from Cooner WH, Mosley BR, Rutherford CL Jr, Beard JH, Pond HS, Bass RB Jr, Terry WJ: Clinical application of transrectal ultrasonography and prostate specific antigen in the search for prostate cancer. J Urol 139: 758-761, 1988.

Prostate-Specific Antigen

RATE OF CHANGE I N SERUM PSA VALUE I f t h e a b i l i t y o f PSA t o d e t e c t e a r l y , curable p r o s t a t e cancer i s t o be improved, t h e f o l l o w i n g c a p a b i l i t i e s o f t h i s tumor marker need t o be enhanced: 1) t o d i s t i n g u i s h organ-confined p r o s t a t e cancer from BPH because both c o n d i t i o n s occur i n t h e same age range and 2) t o i d e n t i f y nonpalpable p r o s t a t e cancer i n a r e l i a b l e manner. To t h i s end, C a r t e r and associates [39] examined t h e concept o f " r a t e o f change i n serum PSA." They conducted a retrospect i v e a n a l y s i s o f 54 men who had been f o l l o w e d i n t h e B a l t i m o r e L o n g i t u d i n a l Study o f Aging f o r a minimum o f 7 years before BPH o r p r o s t a t e cancer was diagnosed o r b e f o r e t h e e x c l u s i o n o f any p r o s t a t i c disease was established. The c o n t r o l group consisted o f 16 men who had no p r o s t a t i c disease, t h e second group had 20 men who underwent a simple prostatectomy and had a h i s t o l o g i c diagnosis o f BPH, and t h e t h i r d group consisted o f 18 p a t i e n t s w i t h biopsy-proven p r o s t a t e cancer. A l l men underwent a complete h i s t o r y , p h y s i c a l examination, and l a b o r a t o r y e v a l u a t i o n every 2 t o 2.5 years. Stored serum obtained from each v i s i t was used for determining the serum PSA concentration. I n t h i s unique study, t h e i n v e s t i g a t o r s demonstrated t h a t t h e r a t e o f change was more u s e f u l than t h e a c t u a l serum PSA l e v e l f o r d e t e c t i n g p r o s t a t e cancer. By u s i n g r a t e o f change, they found t h a t p r o s t a t e cancer could be detected years b e f o r e i t was diagnosed by o t h e r methods. A t 5 years b e f o r e d i a g n o s i s - - a t a t i m e when t h e serum PSA l e v e l s d i d n o t d i f f e r s i g n i f i c a n t l y between s u b j e c t s w i t h BPH and those w i t h p r o s t a t e cancer--the r a t e o f change i n PSA was markedly g r e a t e r i n t h e p r o s t a t e cancer group as compared w i t h c o n t r o l s (p < 0.01) and BPH s u b j e c t s (p < 0.01) (Table V; Fig. 3). With a c u t o f f o f more than 0.75 ng/mL p e r y e a r f o r t h e r a t e o f change, t h e s p e c i f i c i t i e s f o r distinguishing prostate cancer from BPH and from c o n t r o l s were 90% and loo%, r e s p e c t i v e l y . These a r e markedly b e t t e r than what i s observed f o r t h e serum PSA concentration. The s e n s i t i v i t y f o r t h e r a t e o f change, however, was n o t s i g n i f i c a n t l y b e t t e r than t h a t f o r t h e serum PSA concentration. T h i s important observation i n v o l v i n g r a t e o f change i n serum PSA value w i l l undoubte d l y have v a l u a b l e i m p l i c a t i o n s as more and more p a t i e n t s r e t u r n a n n u a l l y f o r a serum PSA determination and digital rectal

39

examination. Thus, an increase i n the serum PSA l e v e l f r o m 2.1 ng/mL t o 3.4 ng/rnL i n 1 y e a r i s s i g n i f i c a n t and may lead t o t h e detection o f a c l i n i c a l l y significant, but p o t e n t i a l l y curable, p r o s t a t e cancer, even though b o t h values a r e w i t h i n t h e reference range. A1 though these d a t a a r e p r e l iminary, they do i n d i c a t e t h a t t h e r a t e o f change may improve t h e a b i l i t y o f t h e PSA value t o d e t e c t e a r l y p r o s t a t e cancer. More e x p e r i ence w i t h t h i s concept may a l s o i d e n t i f y a percentage change p e r u n i t o f t i m e t h a t i s s i g n i f i c a n t f o r r e c o g n i z i n g p r o s t a t e cancer and d i s t i n g u i s h i n g p r o s t a t e cancer f r o m BPH only. Because PSA expression i s under hormonal r e g u l a t i o n [40], i t a l s o may be worthwhile t o incorporate the p a t i e n t ' s s t a t e o f androgenic s t i m u l a t i o n , perhaps t h e serum f r e e and t o t a l t e s t o s t e r o n e l e v e l s , i n t o these new v a r i a b l e s .

PSA DENSITY Another technique f o r improving t h e a b i l i t y o f t h e PSA value t o d e t e c t e a r l y p r o s t a t e cancer i s t o c o r r e l a t e t h e serum PSA c o n c e n t r a t i o n w i t h t h e p r o s t a t i c volume. Indeed, a m i l d l y e l e v a t e d serum PSA l e v e l associated w i t h a small p r o s t a t e gland may be i n d i c a t i v e o f cancer, whereas the same value i n a p a t i e n t w i t h a l a r g e gland may be 20 I8 -I

16

\

14

E

cl)

=

12

a a

10

a €

'

8

8

6 4

2 n

"

20

15

10

5

0

Time prior to diagnosis, years Fig. 3. Serum p r o s t a t e - s p e c i f i c antigen (PSA) concent r a t i o n as a f u n c t i o n o f time before diagnosis o f p r o s t a t i c condition. Note S i g n i f i c a n t increase i n serum value years before t h e diagnosis o f e i t h e r l o c a l / r e g i o n a l o r metastatic cancer was established. BPH, benign p r o s t a t i c hyperplasia. (From Carter e t a l . [39]. By permission o f t h e American Medical Association.)

Oesterling

40

i n d i c a t i v e o f BPH Only. To i n v e s t i g a t e t h i s concept, Benson and associates [41,42] d e f i n e d a new variable--"PSA d e n s i t y . " It is the quotient of the serum PSA c o n c e n t r a t i o n d i v i d e d by t h e volume o f t h e p r o s t a t e gland as determined by t r a n s r e c t a l u l trasonography. I n a p r e l i m i n a r y study o f 61 p a t i e n t s [41], these i n v e s t i g a t o r s found t h i s v a r i a b l e u s e f u l f o r d i s t i n g u i s h i n g men w i t h BPH from p a t i e n t s w i t h p r o s t a t e cancer. The mean PSA d e n s i t y f o r t h e 41 p a t i e n t s w i t h c l i n i c a l l y l o c a l i z e d p r o s t a t e cancer was 0.58, whereas t h e mean value f o r t h e 20 men w i t h BPH was 0.04 (p < 0.0001). In t h e study, 33 of 33 p a t i e n t s w i t h a PSA d e n s i t y more than 0.12 had p r o s t a t e cancer; o n l y 2 p a t i e n t s w i t h p r o s t a t e cancer had a PSA d e n s i t y l e s s than 0.05. I n f a c t , 10 (83%) o f t h e 12 p a t i e n t s w i t h p r o s t a t e cancer and a normal serum PSA c o n c e n t r a t i o n had an elevated PSA d e n s i t y value. With regard t o

TABLE V.

t h e p a t i e n t s w i t h BPH, 19 (Y5%) o f t n e 20 had a PSA d e n s i t y l e s s than 0.1. The h i g h e s t PSA d e n s i t y value f o r any o f t h e p a t i e n t s w i t h BPH was j u s t 0.117. These same investigators also developed a p r o b a b i l i t y p l o t t h a t a l l o w s the p r a c t i c i n g p h y s i c i a n t o estimate t h e p r o b a b i l i t y o f a p a t i e n t having p r o s t a t e cancer g i v e n t h e PSA d e n s i t y (Fig. 4). T h i s concept o f PSA d e n s i t y may have i t s g r e a t e s t value f o r p a t i e n t s w i t h a PSA value t h a t i s e i t h e r i n t h e upper normal range o r m i l d l y e l e v a t e d (between 4.0 and 10.0 ng1mL). Benson and colleagues [42] learned t h a t p a t i e n t s w i t h a serum PSA concentration i n t h e " m i l d l y e l e v a t e d range" who have an e l e v a t e d PSA d e n s i t y a r e a t increased r i s k f o r having p r o s t a t e cancer, whereas p a t i e n t s who have a concomitant l o w PSA d e n s i t y are u n l i k e l y t o harbor a malignancy i n t h e prostate. I n t h i s manner, PSA d e n s i t y may

Rate of Change i n Serum P r o s t a t e - S p e c i f i c Antigen Level Rate o f change by group, ng1mL p e r y e a r Local I Controls BPH regional M e t a s t a t ic

I n t e r v a l before diagnosis, y r 0-5 5-10

0.03

0.12

0.88

5.35

0.01

0.27

10-15

0.02

0.09 0.09

1.33 0.30

0.14

M o d i f i e d from C a r t e r e t a l . [39]. 100 i

a,

0

c

lu

80

0

a,

3

c)

60

v)

2

Q c

0

> c .-

alu

40 20

I)

2

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o 0

0.2

0.4

0.6

0.8

1.o

1.2

PSA density F l g . 4. P r o b a b i l i t y o f p r o s t a t e cancer as a function o f p r o s t a t e - s p e c i f i c antigen (PSA) density. For a PSA density o f 0.15, t h e r i s k o f p r o s t a t e cancer I s approximately 12%. (From Benson e t a l . [42]. By permission o f the American Urological Association.)

Prostate-Specific Antigen

41

t h a t PSA d e t e r m i n a t i o n and d i g i t a l r e c t a l examination be used t o g e t h e r when e v a l u a t i n g t h e p r o s t a t e gland f o r malignancy. In a d d i t i o n , t h e new concepts o f "PSA d e n s i t y " and " r a t e of change i n serum PSA" a r e being developed t o improve f u r t h e r t h e a b i l i t y o f t h e PSA value t o diagnose e a r l y p r o s t a t e cancer and t o d i s t i n g u i s h i t f r o m BPH. A1 though the preliminary results are encouraging, a d d i t i o n a l s t u d i e s w i l l be necessary t o c o n f i r m t h e t r u e usefulness o f these two new v a r i a b l e s . I n t h e i n t e r i m , the most prudent approach when e v a l u a t i n g a man 50 years o r o l d e r i s t o b o t h determine t h e serum PSA concentration and perform a digital rectal I f r e s u l t s o f b o t h are normal, examination. t h e p a t i e n t should be f o l l o w e d up w i t h annual evaluations monitoring palpable changes i n t h e p r o s t a t e and t h e r a t e o f I f results change i n t h e serum PSA l e v e l . of d i g i t a l r e c t a l examination a r e unremarka b l e and t h e serum PSA l e v e l i s m i l d l y e l e v a t e d (4.1 t o 10.0 ng/mL) , t r a n s r e c t a l u l trasonography should be performed. The e c h o g e n i c i t y o f t h e gland can be examined, and t h e volume o f t h e p r o s t a t e can be determined f o r c a l c u l a t i n g t h e PSA density. I f an a b n o r m a l i t y cannot be i d e n t i f i e d by d i g i t a l r e c t a l examination o r t r a n s r e c t a l ultrasonography b u t t h e PSA d e n s i t y i s elevated, t h e p a t i e n t should undergo a If t h e systematic biopsy o f t h e prostate. r e s u l t s o f d i g i t a l r e c t a l examination a r e normal and t h e serum PSA l e v e l i s markedly

become a u s e f u l t o o l f o r h e l p i n g p h y s i c i a n s decide which p a t i e n t s w i t h a h i g h normal o r m i l d l y e l e v a t e d serum PSA l e v e l t o s u b j e c t t o p r o s t a t e b i o p s y and which t o f o l l o w w i t h annual evaluations.

CONCLUSIONS Without question, PSA d e t e r m i n a t i o n i s a v a l u a b l e new t o o l f o r t h e c l i n i c i a n and c l e a r l y has a r o l e i n t h e e a r l y d i a g n o s i s o f clinically significant p r o s t a t e cancer. When used i n a screening c a p a c i t y , t h e PSA value can d e t e c t approximately t w i c e as many cancers as d i g i t a l r e c t a l examination. The PSA l e v e l , however, i s n e i t h e r s u f f i c i e n t l y s p e c i f i c nor s e n s i t i v e t o be t h e " p e r f e c t " It screening t e s t f o r p r o s t a t e cancer. l a c k s s p e c i f i c i t y because i t i s produced by all types o f p r o s t a t i c tissue--normal, h y p e r p l a s t i c (BPH), and cancerous. It i s PSA l a c k s not prostate-cancer-specific. s e n s i t i v i t y because i t i s produced by e p i t h e l i a l c e l l s and secreted i n t o t h e p r o s t a t i c d u c t a l system; v e r y l i t t l e e n t e r s t h e general c i r c u l a t i o n . I t i s o n l y when t h e r e has been a s i g n i f i c a n t derangement i n the a r c h i t e c t u r a l pattern o f the prostate gland t h a t PSA can d i f f u s e f r o m a c i n i i n t o t h e stroma and e n t e r t h e systemic c i r c u l a t i o n through t h e lymphatics and c a p i l l a r i e s . Thus, n o t a l l p r o s t a t e cancers produce an e l e v a t e d serum PSA concentration. Because o f these shortcomings w i t h t h e serum PSA c o n c e n t r a t i o n , i t i s recomnended

Algorithm for Utilization of DRE, Serum PSA, and TRUS in the Early Detection of Clinically Significant Prostate Cancer

-

DRE PSAa DRE and serum PSA determination for all men 250 years of age

Normal

s4 0

Normal

4 1-100-

Diagnostic Action

Annual evaluation TRUS ~

~

c

Sextant biopsy'

Biopsy lesion PSAD determinationb

,5

Normal

TRUS

>loo-

Abnormal

*

1-year reevaluation

Biopsy lesion Sextant biopsyC

TRUS-guided biopsy

a Tandem4 PSA assay, ng/mL b Serum PSA concentraltonlprostate volume c Three cores from each side (base. mid-prostate, apex)

Fig. 5.

Algorithm f o r t h e e a r l y d et ection o f c l i n i c a l l y s i g n i f i c a n t p r o s t a t e cancer w i t h d i g i t a l r e c t a l examination (DRE). serum prostate-specific antigen (PSA) l e v e l , and t r a n s r e c t a l PSAD, p rost ate-specific antigen density. (From Cupp and Oesterling ultrasonography (TRUS). [38]. By permfssion o f the American Urological Assoclation.)

Oesterling

42

elevated (more than 10.0 ng/mL), the patient should be subjected to transrectal ul trasonography and biopsy of any suspicious lesions. If no discrete, hypoechoic areas are visualized, a systematic biopsy of the prostate should be done. An abnormal result of digital rectal examination, irrespective of the serum PSA level, signals that biopsy should be done on the area in question. This approach for evaluating the prostate gland is sumnarized by the algorithm in Figure 5. As we progress through the 1990s and head into the 21st century, PSA is clearly the "standard" tumor marker for prostate cancer. The routine use of PSA determination in the population at risk for the development of prostate cancer should increase the detection rate of early, organ-confined lesions--tumors that are curable with definitive therapy. Indeed, the discovery of PSA is one of the most significant advancements in the field of urology in recent times. Until a "prostate-cancerspecific antigen" is identified (one that appears in the serum as soon as the cancer achieves biologic significance), we will continue to use the only organ-specific tumor marker in all of cancer biology--PSA. REFERENCES

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36.

37.

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42.

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