Prostate-Specific Antigen Testing in Untreated and Treated Prostatic Adenocarcinoma

Subject Review Prostate-Specific Antigen Testing in Untreated and Treated Prostatic Adenocarcinoma

LESLIE M. RAINWATER, M.D., WILLIAM R. MORGAN, M.D., * Department of Urology; GEORGE G. KLEE, M.D., Ph.D., Section of Clinical Chemistry; HORST ZINCKE, M.D., Department of Urology

The isolation and purification ofprostate-specific antigen (PSA) and the development of a radioimmunoassay for this antigen represent major advancements for the detection of adenocarcinoma of the prostate and the monitoring of response to therapy in patients with this disease. Both monoclonal and polyclonal assays for PSA are available. In attempts to correlate pathologic tumor stage and PSA levels, tumors of higher stage (pathologic stages CI, C2, DI, and D2) have been associated with elevated PSA levels. Increased PSA levels have also been found in patients with benign prostatic diseases (benign prostatic hypertrophy and prostatitis). PSA has been shown to be an excellent marker after radical prostatectomy and for monitoring of radiation therapy. Patients with a persistently elevated PSA level for more than 6 months postoperatively should be assessed for residual or recurrent local or systemic disease. Thus far, routine use ofPSAtesting as a mass screening modality for prostatic cancer has not been considered cost-effective.

tion of survival by systemic (hormonal or chemotherapeutic manipulation) treatment is considered insignificant. Thus, early detection of prostatic cancer by a sensitive and specific tumor marker would be desirable. For prostatic cancer, over the years numerous markers have been used, including acid phosphatase.':" prostatic acid phosphatase.?:? lactate dehydrogenase and isoenzymes.J''i!' creatine kinase BB isoenzymes.v-" carcinoembryonic antigen, 14,15 ~-human chorionic gonadotropin.!" anti-Leu-L!" ~-inhibin or ~-micro­ seminoprotein.F and prostate-specific antigen (PSA) or seminoprotein.Pr'" *Current address: Yale University School of Medicine, Since the 1960s, investigators have attemptNew Haven, Connecticut. ed to isolate antigens specific to prostatic tis22 19 21 Address reprint requests to Dr. Horst Zincke, Department sue. - In 1979, Wang and associates ,23 were able to isolate and purify an antigen specific to of Urology, Mayo Clinic, Rochester, MN 55905.

Currently, prostatic cancer is the most common cancer among men in the United States. In 1990, 106,000 new cases of prostatic cancer are expected, and 30,000 persons are expected to die of this disease.' If diagnosed at a stage that is not beyond regional pelvic lymph node involvement (stage D1 or TO-3, Nl-2, MO), it can be controlled to a large extent by radical surgical excision and adjuvant treatment.v" depending on its pathologic characteristics (in particular, nuclear DNA ploidy pattern). Once distant disease has developed, the probability for prolonga-

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normal, benign, and malignant prostatic tissue. PSA is immunologically and biochemically distinct from prostatic acid phosphatase.F-" it is produced in the prostatic alveolar and ductal epithelial cells and in the embryologic homology of the prostate-the female paraurethral (Skene's) glands." Tissues capable of undergoing prostate-like metaplasia, as seen in cystitis cystica or cystitis glandularis, may stain positive for PSA.26 PSA is a neutral glycoprotein of molecular mass 33,000 to 34,000 kd,24 with kallikrein-like proteolytic enzyme activity responsible for the dissolution of seminal gel formed immediately after ejaculation;" PSA has been localized to the cytoplasmic vesicles, vacuoles, granules, rough endoplasmic reticulum, and lumina of prostatic glands. 27,28 The half-life of PSA reportedly is between 2.2 and 3.15 days, as determined by two separate assay techniques.29,30 PSA levels are generally determined by use of monoclonal (Hybritech Tandem-R, San Diego, California) and polyclonal (Yang Pros-Check, Bellevue, Washington) assay techniques. The monoclonal assay is based on a solid-phase immunoradiometric assay that uses two monoclonal antibodies directed toward two unique sites on the PSA molecule, forming the solidphase PSA-Iabeled antibody sandwich. The polyclonal assay is a competitive radioimmunoassay in which displacement of radiolabeled PSA from polyclonal antiserum is quantitated.i" Although comparison between the two assays with use of similar serum specimens shows a close linear correlation (r = 0.988), the absolute value is 1.85 times higher for the polyclonal assay than for the monoclonal assay.31,32 The normal range for the two assays, however, varies significantly in the opposite direction of the proportional bias, ranging from 0 to 2.5 ng/ml for the polyclonal assay and from 0 to 4.0 ng/ml for the monoclonal assay. Thus, although one assay has an absolute value 1.85 times that for the other assay, such a factor cannot be used to translate from one assay to the other.i" Furthermore, the Pros-Check assay has not been approved by the Food and Drug Administration and can be used only for "research purposes" at the present time. Therefore, investigators should

PROSTATE-SPECIFIC ANTIGEN TESTING 1119

indicate which PSA technique has been used because the two assays are not quantitatively equivalent. Several factors have been shown to cause an increased serum PSA level: benign prostatic hypertrophy; prostatic cancer; manipulation of the prostate during prostatic surgical procedures, cystoscopy, diagnostic massage, or palpation; acute or chronic prostatitis; and prostatic infarction.Pv" Recent evidence from a prospective study by Brawer and associates." however, refutes the theory that a normal, nonvigorous rectal examination results in a falsely increased PSA or prostatic acid phosphatase finding.

REVIEW OF LITERATURE PSA and Tumor Stage.-Few investigators have reported a correlation between pathologic tumor stage and PSA. In a report on 74 patients, Ercole and associates"? attempted to increase the specificity ofPSA in the detection ofprostatic cancer by increasing the upper limit of a "normal" PSA level to 10 ng/ml. None of the 24 patients with pathologic stage AI, A2, or B1 prostatic cancer had an elevated PSA level, but 33% of patients with pathologic stage B2 and only 15% with stage C1 had an elevated PSA level preoperatively. Of patients with pathologic stages C2, D1, and D2, however, 86%, 71%, and 98%, respectively, had a PSA level of more than 10.0 ng/ml. Oesterling and associates.P'' using a concentration limit of 4.0 ng/ml, found that approximately 45% of 103 patients with pathologic stages A and B prostatic cancer had an elevated PSA level. With tumors of higher stage, 65%, 78%, and 100%, respectively, of the 75 patients with pathologic stages C1, C2, and D1 had an elevated PSA level. In a subsequent report from the same institution, Partin and colleagues'" increased the sensitivity while decreasing the specificity by using a value of2.8 ng/ ml as the upper limit of normal for PSA. Of 185 patients with pathologic stages A and B, 45% were found to have an elevated PSA level; with tumors of higher stage, 85% and 98% of patients with pathologic stage C+ and D1, respectively, had an elevated PSA level (Table 1). Other investigators have correlated clinical stage with

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1120 PROSTATE-SPECIFIC ANTIGEN TESTING

Table I.-Level of Prostate-Specific Antigen (PSA) in Various Studies of Pathologically Staged Prostatic Cancer

Study Partin et aP8 Oesterling et al 3 0 Rainwater et al (unpublished data) Ercole et al 3 7

No. of patients

Concentration limit (ng/ml)*

350 178

2.8 4.0

548 74

4.0 10.0

A+B

A

Patients with elevated PSA: no. (%) Bl B2 C+

84/185 (45) 47/103 (46) 0/14 (0)

42/65 (65) 0110 (0)

132/168 (79) 2/6 (33)

Dl

94/111 (85) 40/58 (69)

53/54 (98) 17/17 (l00)

186/229 (81) 14/27 (52)

82/86 (95) 12/17 (71)

*Hybritech Tandem-R.

PSA level, but the upper limits of normal have varied from 1.79 to 24.0 ng/ml with the monoclonal or polyclonal assay (Table 2).23,29,39-45 PSA and Prostatic Noncancerous Disease.-Increases in PSA levels have been detected in patients with benign prostatic diseases (Table 3). Patients with uncomplicated benign prostatic hypertrophy have an elevated PSA level in 21 to 68% of cases. 23,30,37,44 Robles and associates" reported PSA levels in patients with the following conditions: complicated benign prostatic hypertrophy, PSA levels that ranged from 0.4 to 212 ng/ml (mean, 22.5 ng/ml); acute prostatitis, 0.2 to 124 ng/ml (mean, 18.1 ng/ml); and chronic prostatitis, 0.2 to 11.8 ng/ml (mean, 2.9 ng/ml). Overall, 171 of 290 patients (59%) with uncomplicated and complicated benign prostatic hypertrophy had an elevated PSA level of more than 4.0 ng/ml. PSA and Monitoring ofTreated Prostatic Cancer.-PSA is an excellent biochemical marker for monitoring the response to treatment of prostatic cancer. The effect of hormonal (diethylstilbestrol) treatment, luteinizing hormone releasing hormone antagonist, radiation therapy, and radical prostatectomy has been demonstrated both immunohistochemically and serologically.46-48 Siddall and co-workers'" were able to distinguish responders and nonresponders to a luteinizing hormone releasing hormone antagonist by the median level of PSA at 12 months of 3.0 ng/ml and 155 ng/ml, respectively. After radical prostatectomy, PSA levels decreased to the range in female subjects (0.0 to 0.2 ng/ml) in 96% of patients with pathologic stage A and B lesions, 75% with pathologic stage C (capsular penetration), but only 19% of pathologic stage

C+ and D1 (seminal vesicle or lymph node involvement, respectively), an indication that adjuvant treatment in the form of hormonal or radiation therapy may be necessary in these patients." In a study of 174 patients who underwent radical prostatectomy, Hudson and colleagues'" noted that 87 of 98 patients (89%) with organconfined tumors had undetectable PSA levels (less than 0.6 ng/ml), as did 33 of 47 patients (70%) with capsular penetration or positive margins and only 10 of 29 patients (34%) with pathologic stage C+ and D1lesions. Stamey and associates-? administered a course of radiation therapy to the pelvis of four patients who had pathologic stage C or D1 tumors and persistently elevated PSA levels after radical prostatectomy. Three of these patients responded favorably-PSA levels were in the undetectable range within 9 to 44 months of follow-up. In a subsequent study from the same institution, Kabalin and co-workers'" reported that 23 of 27 patients (85%) with prostatic cancer who received primary curative radiation therapy had a PSA level above the normal range; 21 ofthese 23 patients (91%) had biopsy specimens positive for residual adenocarcinoma. The other four patients had PSA levels in the normal range and normal findings on rectal examinations; however, they had focal areas of hypoechogenicity on ultrasonography and biopsy evidence of adenocarcinoma. Thus, an elevated PSA level after radiotherapy for curative intent is highly suggestive of residual disease; however, a normal PSA level does not exclude persistent adenocarcinoma. Routine Screening With PSA.-Routine screening for the early detection of prostatic

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Table 2.-Level of Prostate-Specific Antigen (PSA) in Various Studies of Clinically Staged Prostatic Cancer

Study 23

No. of patients

Wang et al Hudson et al 3 9

442 146

Robles et al 4 0 Siddall et al 4 1 Emtage et al 4 2 Guinan et al 4 3 Stamey et al 2 9 Seamonds et al 4 4 Wang & Kawaguchiv"

78 151 136 118 127 40 59

Concentration limit (ng/ml) 1.79* 4.0* 10.0* 10.0* 10.0* 10.0* 24.0* 2.5t 2.6t 5.0t

Patients with elevated PSA: no. (%) Al 5/8 (62) 1/3 (33) 1/10 (10) 7/12 (58) 5/7 (71) 2/2 (100)

A2

B

27/34 (79) A + B: 64/103 (62) A + B: 37/103 (36) 2/3 (67) 6/8 (75) A + B + C: 39/91 (43) A + B + C: 34/43 (79) 5/21 (24) 70/70 (100) 1/1 (100) 10/10 (100) 23/24 (96)

C

D

43/56 (77) 296/344 (86) C + D: 31/43 (72) C + D: 27/43 (63) 19/21 (90) 40/43 (93) 55/60 (92) 87/93 (94) 8/15 (53) 66/72 (92) 23/23 (l00) 22/22 (100) 4/4 (100) 18/18 (100) 15/15 (l00) 18/18 (100)

*Hybritech Tandem-R. tYang Pros-Check.

cancer was recently reviewed. 50 By using only digital rectal examinations for routine screening, the overall detected incidence ofl.7% among the 811 patients examined was determined to be cost-effective. Furthermore, Cooner and associates'" performed transrectal ultrasonography on 225 prostates thought to be benign on palpation; sonographically, 96 (42.7%) had areas suggestive of cancer and thus a biopsy was performed. Cancer was detected in 28 patients (12.4%) or 29.2% of the 96 biopsy specimens obtained. In this overall group of 225 patients, PSA was less than 4.0 ng/ml in 7, 4.1 to 10.0 ng/ ml in 11, and more than 10.0 ng/ml in 10 of the patients with biopsy-proven cancers but palpably benign prostates. In a follow-up report, Cooner and colleagues'" reported on 1,035 patients with palpably benign prostates. Of 275 patients with sonographic evidence suggestive of cancer, 54 (19.6%) were found to have adenocarcinoma. Of 105 patients with an elevated PSA level (more than 4.0 ng/ ml), 37 (35.2%) had a biopsy specimen positive for adenocarcinoma; of 170 patients with a normal PSA level, 17 (10.0%) had biopsy evidence of adenocarcinoma.

eratively to correlate Mayo pathologic tumor stage (Fig. 1) with PSA level (Rainwater LM, Zincke H, Morgan WR, Myers RP, Klee GG: Unpublished data). Of 65 patients with pathologic stage B1 (pT1), 42 (65%) had elevated PSA levels (overall range, 0.2 to 53.2 ng/ml). Of 168 patients with organ-confined tumors of larger volume-pathologic stage B2 (pT2)-132 (79%) had an elevated PSA level (overall range, 0.4 to 89.1 ng/ml). Tumors of higher stage-C or C+ (pT3 or pT4)-with capsular penetration (C, pT3), seminal vesicle involvement (C+, pT3), bladder neck or rectal involvement (pT4), or residual tumor were associated with increased elevations of PSA levels; of 229 patients, 186 (81%) had elevated PSA levels (overall range, 0.3 to 239 ng/ml). Among 86 patients with tumors and lymph node involvement-pathologic stage D1 (pT2-4, Nl-2, MO)-82 (95%) had an elevated PSA level (overall range, 0.6 to 209 ng/ml). In a recent Mayo Clinic study, 53 a correlation was found between the tumor nuclear DNA ploidy pattern and serum PSA in 71 patients who had undergone radical prostatectomy. All patients with a DNA tetraploid and DNA aneuploid histogram pattern had an elevated PSA level. In contrast, 35% of tumors with a MAYO CLINIC EXPERIENCE DNA diploid histogram had a PSA level within We reviewed the records of 548 patients who the normal range (0.0 to 4.0 ng/ml). Preoperaunderwent radical retropubic prostatectomy for tive PSA levels were significantly and indepenadenocarcinoma between January 1987 and dently correlated with tumor nuclear DNA ploidy December 1988 at our institution for whom a pattern. As we have previously noted, DNA PSA measurement (Hybritech Tandem-R; nor- ploidy analysis of prostatic cancer correlates mal range, 0 to 4.0 ng/ml) had been done preop- significantly with outcome of disease in patients

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1122 PROSTATE-SPECIFIC ANTIGEN TESTING

Table 3.-Level of Prostate-Specific Antigen (PSA) in Various Studies of Patients With Prostatic Noncancerous Disease

Study Oesterling et apo

No. of patients 72

Ercole et aP 7

357

Hudson et aP9

168

Robles et al 4 0 Guinan et al 4 3

290 117

Concentration limit (ng/ml)" 4.0 10.0 4.0 10.0 4.0 10.0 10.0 24.0

Patients with elevated PSA: no. (%) Control subjects BPHt or prostatitis

Male

Female

0/48 (0) 0/48 (0)

0/21 (0) 0/21 (0)

37 (51) 7 (10) 75 (21) 3 (1) 35 (21) 3 (2)

97 (33) 6 (5)

*Hybritech Tandem-R. tBPH = benign prostatic hypertrophy.

who have pathologic stage Dl (pTO-3, N1-2, MO) lesions." None of the patients with a DNA diploid tumor and adjuvant hormonal treatment had progression of the tumor, whereas patients with DNA tetraploid and aneuploid tumors died of prostatic cancer despite administration of adjuvant hormonal treatment. Thus, patients with a normal PSA level seem more likely to have a DNA diploid tumor, which is known to be associated with the most favorable prognosis.v'v" The duration of follow-up for our 548 patients with preoperative PSA levels has been insufficient to substantiate these findings at this time. In another Mayo study, Morgan and co-workers recently analyzed the preoperative and postoperative PSA levels in 180 patients who had undergone radical prostatectomy (Morgan WR, Zincke H, Rainwater LM, Myers RP, Klee GG: Unpublished data). In this study group, 75 patients had pathologic stage A or B lesions, 83% of whom had a PSA level of 0.2 ng/ml or less (female levels) postoperatively. Of 75 patients with pathologic stage C+ tumors, 78% had female PSA levels postoperatively. Of30 patients with pathologic stage Dllesions, 90% had PSA levels of 0.2 ng/ml or less postoperatively; however, all had undergone adjuvant orchiectomy at the time of radical prostatectomy. For patients with stage C or D1 tumors, 37 had adjuvant orchiectomy, 14 had adjuvant radiation therapy, and 47 had no adjuvant therapy, with 97%, 86%, and 68% having female PSA levels, respec-

tively. Thus, adjuvant orchiectomy seems to result in better control of advanced prostatic cancer than does adjuvant radiotherapy, as determined on the basis ofPSA levels. Whether this finding will translate to a lower rate of progression and, thus, possibly prolonged survival remains to be determined. Recently, studies have produced evidence that PSA expression is hormonally regulated-that is, dependent on a milieu with the presence of the male hormone testosterone or dihydrotestosterone.v-" Hence, PSA levels may be unreliable in patients treated hormonally. The half-life of PSA has been reported to be approximately 3 days. Occasionally, however, we have noted that the PSA concentration was not at female levels (0.0 to 0.2 ng/ml) at the time of 3- or 6-month follow-up but that it slowly and gradually declined during a 6- to 12-month period. Specifically, of 1,806 patients who underwent radical retropubic prostatectomy for stages A through C disease, 161 had a sustained decrease in postoperative PSA levels on serial measurements. Ofthese 161 patients, however, only 3 had not received adjuvant treatment (radiation therapy, hormonal therapy, or both), which might have accounted for the decrease. All three patients had their PSA levels measured early in our laboratory's experience with PSA determinations. Furthermore, several patients with pathologic stage B2 (pT2) and C+ (pT3) lesions have had normalization ofPSA to

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DESCRIPTION Incidental finding in TURP specimen

MAYO UlCC SYSTEM SYSTEM

:S 1 cm 3 tissue

> 1 em" tissue

Tumor is :S 2 em. in diameter and confined to one lobe

Tumor is

A, } A2 ToNoMo

8,

T.~~. ~

u~'I

> 2 em. in diameter and/or

present In both lobes

Tumor extends beyond the prostatic capsule Seminal Vesicle not involved

~

CC + T 3-.NoMo

~~ ,/1

seminal Vesicle involved (+)

Tumor Stage A, 8, or C with pelvic node involvement

TO~N1-2MO

02

To-.N.Mo-,

Tumor Stage A, 8 or C with pelvic and/or distal node involvement or distant metastases

~..

((,.;:,. nod,

0,

\

~

~~_Ie

..,o""

'.mph

nocN .ndlor

'.sel

dt'~n1

tl'WIt ..

Fig. 1. Correlation of Mayo Clinic staging and Union Internationale Contre Ie Cancer (UICC) staging in cancer ofthe prostate. TNM = tumor, nodal involvement, distant metastatic involvement; TURP = transurethral resection of the prostate. (From Zincke H, Fleming TR, Furlow WL, Myers RP, Utz DC: Radical retropubic prostatectomy and pelvic lymphadenectomy for high-stage cancer ofthe prostate. Cancer 47:1901-1910,1981. By permission of the American Cancer Society.)

undetectable levels by 3- or 6-month follow-up and subsequent elevations (more than 0.2 ngl ml) at 12 to 18 months, presumably antedating clinical evidence of recurrent local disease, distant disease, or both. CONCLUSION The isolation and purification of PSA and the development of a monoclonal radioimmunoas-

say for this antigen represent major advancements in the diagnosis of adenocarcinoma ofthe prostate and the monitoring of response to therapy in patients with this cancer. PSA is specific not merely for prostatic cancer but for prostatic tissue, including prostatic pathologic changes such as uncomplicated and complicated benign prostatic hypertrophy, acute and chronic prostatitis, and prostatic infarction. Furthermore, vig-

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1124 PROSTATE-SPECIFIC ANTIGEN TESTING

orous manipulation of the prostate with massage, instrumentation, catheterization, or biopsy can cause a transient elevation in the PSA level, although such a result does not usually occur on a normal diagnostic palpation of the prostate." Some clinicians have suggested that a period of3 weeks (based on the half-life ofPSA of approximately 3 days) after manipulation of the prostate should be allowed for false elevations in PSA to return to premanipulation levels. This guideline, however, may apply only to the patient who has had more than a normal diagnostic palpation of the prostate. Elevations in PSA level without prior extensive manipulation ofthe prostate may be indicative of a prostatic abnormality that necessitates further evaluation. With the advent of ultrasonography of the prostate, which allows visualization of the entire gland, areas not previously detectable by palpation are now. accessible. With ultrasonic guidance, these areas of the prostate can undergo biopsy with much greater accuracy than with finger-guided biopsies alone. Nevertheless, 25 to 50% of prostatic cancers are not even detectable by ultrasound studies because of their is 0 echoic appearance; thus, in such cases, palpation of the prostate by an experienced investigator is necessary. Our previous dependence on a digital rectal examination-which is associated with more than a 50% error rate alone-together with a "blind" and potentially traumatic needle biopsy with use of the Vim-Silverman needle is now outdated. Today, digital rectal examination with the availability of PSA testing and ultrasound-guided small needle prostatic biopsies have considerably improved our ability to detect prostatic cancer in many patients at an earlier stage. This combination of modalities has also proved particularly valuable in the diagnosis of "incidental" (stage A) cancers-namely, in those patients who have disease even though prostatic examination on rectal palpation reveals normal findings. By identifying disease at an early stage (localized or stage B2 or less), the potential for cure can be enhanced. For instance, in our experience with more than 700 patients with pathologic stage B2 or less disease who have

undergone radical prostatectomy, cancer-related death rates as late as 15 years postoperatively can be expected to be 7% or less." Currently, skillful digital rectal examination ofthe prostate may still be the best single screening technique for most prostatic cancers. Any suggestive finding should promptly lead to PSA testing and ultrasonographic examination ofthe prostate; abnormal findings on either test may then be followed by ultrasound-guided biopsy of the prostate (Fig. 2). The use of ultrasound per se or of routine PSA testing as a mass screening modality for prostatic cancer is at present considered not cost-effective. Finally, a most important statement can be made about postprostatectomy PSA levels. Any patient with a persistently elevated PSA level (more than 0.2 ng/ml) after a reasonably long period (beyond 6 months) postoperatively should be considered to have persistent or recurrent disease-locally, systemically, or both. Rarely is residual benign tissue responsible for such an increase in PSA levels after surgical treatment of prostatic cancer. In the group of patients who have received both surgical and hormonal treatment, investigators should remember that PSA expression is affected by hormonal therapy.Fv" Thus, PSA testing alone without performance of other usual laboratory tests (such as acid phosphatase, bone scanning, and roentgenography) cannot be recommended.

US prostate

II

Prostate Bx

II

Yearly check

Fig. 2. Algorithm for approach to patient with normal or increased level of prostate-specific antigen (PSA). Bx = biopsy; US = ultrasonography.

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1126 PROSTATE-SPECIFIC ANTIGEN TESTING

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