Pathology Patterns Reviews

Prostate-Specific Antigen and the Early Diagnosis of Prostate Cancer

Aaron Caplan, MD, and Alexander Kratz, MD, PhD, MPH
Key Words: Prostate; Cancer; Screening; Prostate-specific antigen

Abstract
With digital rectal examination (DRE), prostatespecific antigen (PSA) is a major screening tool for prostate cancer. PSA is specific for the prostate, but not for prostate cancer. Multiple factors influence PSA value. Determination of PSA levels is not 100% sensitive for prostate cancer, as PSA levels may be normal despite presence of prostate cancer. The cutoff value for PSA of 4.0 ng/mL gives the highest sensitivity and highest specificity. Several modifications of PSA testing have been developed and may be beneficial for select populations. Uncertainty about the natural progression of prostate cancer and inherent limitations of PSA testing make it unclear whether universal screening is beneficial, and the recommendations of various organizations conflict. Randomized studies are in progress to address the role of PSA testing and of modifications of this test in the early detection of prostate cancer.

Prostate cancer is the most frequently diagnosed cancer and the second leading cause of cancer death among men in the United States.1 Almost 200,000 new cases are diagnosed annually, and more than 30,000 men die every year of this disease. The lifetime risk of developing prostate cancer for men is 1 in 6.2 Definitive risk factors for the development of prostate cancer are age (more than 96% of prostate cancer cases occur in men 55 years or older), family history, and African American descent. Possible risk factors include diet and hormonal factors. Since most risk factors for this disease cannot be modified, efforts to reduce mortality related to prostate cancer have focused on early recognition and treatment. Screening for prostate cancer in asymptomatic men is performed most commonly with digital rectal examination (DRE) and assays for prostate-specific antigen (PSA). This article focuses on recent developments in the use of serum PSA levels for the early detection of prostate cancer; PSA measurements in the management of patients already diagnosed to have prostate cancer and other information about PSA3 are not within the scope of this article and will not be discussed.

Biology of PSA
PSA is secreted into the seminal fluid by the luminal epithelial cells of the prostatic ducts, acini, and periurethral glands. Its role is the liquefaction of the seminal coagulum by cleaving 2 seminal vesiclespecific proteins, seminogelin I and II, into several low-molecular-weight soluble protein fragments.4 The exact mechanism by which PSA accesses the bloodstream remains unknown.5 Once in the circulation, PSA assumes one of multiple molecular forms. The majority of PSA
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is complexed with the protease inhibitor alpha1-antichymotrypsin. Most of the remainder of the bound PSA is complexed with alpha2-macroglobulin and other proteins. A smaller proportion is unbound and free. Although very low concentrations of PSA exist in a variety of tissues other than the prostate, serum PSA can be regarded as being organspecific to the prostate.

PSA as a Screening Tool for Prostate Cancer

The measurement of the PSA level has been used as a screening tool for prostate cancer since the mid-1980s. Currently, first-line screening for prostate cancer consists of annual DRE and determination of serum PSA levels. The upper limit of normal for PSA values is generally considered to be 4.0 ng/mL; between 4 and 10 ng/mL is considered borderline, and more than 10 ng/mL is considered high. Patients with a PSA value greater than 4 ng/mL, regardless of DRE results, generally undergo biopsy. The cutoff value of 4.0 ng/mL represents the level at which the highest sensitivity (detection of the largest number of prostate cancers) and highest specificity (exclusion of the greatest number of men without prostate cancer) are present.6 As there is no value of PSA at which the definitive diagnosis of prostate cancer can be made, and a positive finding on DRE is also not 100% specific, biopsy of the prostate is still required for the diagnosis of prostate cancer. PSA testing can give clinicians more than 5 years of lead time in the detection of prostate cancers. Approximately 90% of the tumors detected with PSA screening are clinically localized, and approximately two thirds are still pathologically confined to the prostate. In contrast, tumors detected by DRE alone are clinically localized only 50% to 60% of the time.7 Over the years, PSA testing has been touted as the most important tumor marker for prostate cancer and the most successful tumor marker that currently exists for any form of cancer. However, the clinician using PSA levels for screening for prostate cancer should be aware of several potential problems inherent in this assay. These include the following: 1. Although PSA is relatively organ-specific to the prostate, it is not specific for malignant neoplasms of the prostate. Along with prostate cancer, benign prostatic hypertrophy (BPH), numerous medications, inflammatory conditions, and physical manipulations of the male genitourinary tract can cause temporary and occasionally permanent alterations in serum PSA values Table 1. The major confounding condition in the interpretation of elevated PSA levels is BPH. BPH is a common condition among men older than 50 years and can elevate PSA values.
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Although prostate cancer is associated with a higher increase in PSA serum levels per gram of tissue than BPH,5 the overlap in PSA levels between those with BPH and those with prostate cancer remains extensive.4 Physical manipulations of and inflammatory insults to the genitourinary tract can cause increases in PSA values that take extended periods to correct. This is due to the relatively long half-life (2-3 days) of PSA in serum. Acute and subclinical prostatitis and urinary retention can cause increases in PSA levels, and a 2-fold increase in PSA levels has been reported following vigorous prostatic massage. Following relief of urinary retention, PSA levels have been shown to decrease by 50% within the first 24 to 48 hours. PSA levels return to baseline approximately 6 to 8 weeks after treatment of prostatitis.5 PSA levels generally are unchanged or only minimally increased following DRE, transrectal ultrasonography, and urethral catheterization of the urinary bladder.2 Nevertheless, if samples for the measurement of PSA are needed, it generally is recommended that they be obtained before these procedures to eliminate possible confounding variables. Needle biopsy of the prostate is associated with large increases in PSA levels that may persist for 1 month or longer. Thus, following treatment of acute prostatitis or needle biopsy of the prostate, a waiting period of 4 to 6 weeks before measuring serum PSA levels is advised. Significant increases in PSA levels following ejaculation have been described.8 Therefore, it has been suggested that PSA measurement be deferred for at least 48 hours following ejaculation.9 Finasteride, a 5-alpha-reductase inhibitor that decreases dihydrotestosterone production, has been shown to decrease total PSA levels in patients with BPH by up to 80% and, conversely, in some patients increase levels by 20%. The average perturbation after a 6-month course of this drug is

Table 1 Factors Influencing the Prostate-Specific Antigen Level

Effect on Level Increased Factor Prostate cancer Benign prostatic hypertrophy Needle biopsy of the prostate Acute and subclinical prostatitis Prostatic ischemia and infarction Urinary retention Cystoscopy Prostatic massage Ejaculation Relief of urinary retention Finasteride Digital rectal examination (small increases occasionally seen) Transrectal ultrasonography (small increases occasionally seen) Urethral catheterization Terazosin

Decreased None

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Table 2 Modified Prostate-Specific Antigen (PSA) Measurements

Advantages PSA density Transition zone PSA density PSA velocity Takes into account prostatic volume Controls for transition zonemediated increases in PSA Accounts for rate of change of PSA values over time May be useful in patients with PSA values in normal range to assess the need for biopsy or the need for rebiopsy in a patient with a negative initial biopsy result May increase sensitivity in younger men and increase specificity in older men Increased specificity of testing for men with borderline or intermediate PSA values (4-10 ng/mL) and negative digital rectal examinations Increased sensitivity of cancer detection when PSA values are within normal range Same advantages as free PSA Single test may be able to replace the use of 2 tests (total and free PSA) Reliance on multiple variables for prostate cancer detection Increased specificity over total PSA measurement for men with PSA levels <4.0 ng/mL who have small, potentially curable prostate cancer Disadvantages Measurement of volume is subjective Volume does not equal the epithelial-to-stroma ratio Measurement of volume is subjective Need for multiple PSA determinations Cumbersome calculation

Age- and race-specific PSA reference ranges Free PSA

May decrease specificity in younger men and decrease sensitivity in older men Careful attention to storage and processing of specimen required

Complexed PSA

Difficulties with accuracy of available assays

ProstAsure Index (Global Health Net, Savannah, GA)

Limited clinical data for efficacy

approximately a 50% decrease. Thus, it has been suggested that after prolonged finasteride therapy, PSA values should be multiplied by 2.5,10 2. Although PSA is the most sensitive screening tool presently available for the early detection of prostate cancer, only 65% to 75% of cases of prostate cancer have elevated PSA levels. This means that up to 35% of cases of prostate cancer will be missed by PSA screening, and physicians and patients should be aware that a normal PSA level does not exclude prostate cancer. 3. Interassay and intra-assay variability in PSA measurements have been recognized for some time.11 The PSA concentrations in a given patients specimen, determined with assays from different manufacturers, can vary owing to differences in assay methods, calibration, reagent specificity, and the specificity of PSA antibodies to different molecular forms of PSA found in the patients serum specimen at a given time.11 4. The number of cases of prostate cancer diagnosed each year is far higher than the number of deaths due to this disease. In addition, autopsy studies indicate an even higher incidence of asymptomatic prostatic malignancy in elderly men. This implies that rather than dying of prostate cancer, many patients are dying with this disease. Since treatment options for prostate cancer can be associated with significant morbidity, impaired quality of life, and even mortality, detecting more cases of prostate cancer in earlier stages is not necessarily proof of benefit to patients. 5. Despite the widespread use of PSA testing in screening for prostate cancer, no randomized trials have so
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far demonstrated a reduction in prostate cancer mortality by PSA screening programs.12

Modified PSA Measurements

A number of strategies have been developed to address some of the pitfalls inherent in the use of PSA levels for the early detection of prostate cancer. None have yet found wide acceptance in clinical practice, and most are still undergoing clinical trials Table 2. PSA Density PSA density (PSAD) was first introduced as a way to further distinguish prostate cancer from benign prostatic disease in patients with PSA values in the borderline range and negative DREs.5 The definition of PSAD is the ratio of the serum concentration of PSA to prostatic volume as measured by transrectal ultrasound.4 The ratio relies on the fact that prostate cancer releases more PSA per volume of prostatic tissue into the circulation than does BPH.5 Studies using PSAD for prostate cancer screening have led to conflicting results. This might be the result of interobserver variation in estimating prostatic volume owing to the subjectivity of this technique.1 Therefore, PSAD is not widely used by clinicians. Transition Zone PSA Density Another volume-dependent index studied for its ability to enhance prostate cancer detection in patients with
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borderline/intermediate PSA levels is the transition zone PSA density (PSA-TZ). The PSA-TZ relies on the principle that the transition zone is almost exclusively the region of the prostate enlarged in BPH. Because most PSA leakage into serum emanates from the transition zone, it is this region that is the main determinant of PSA levels in patients with BPH.4,13 The PSA-TZ is calculated by dividing the total PSA measurement by the ultrasonographically determined transition zone volume, giving a value in nanograms per milliliter per cubic centimeter. Although initial results have been promising,1,5,14 this method still relies on subjective interpretation of ultrasonographic volume measurements, thereby limiting reproducibility. PSA-TZ remains an investigative tool in prostate cancer diagnosis.5 PSA Velocity The concept of PSA velocity is based on the finding that the rate of change of PSA values over time is greater in men with prostate cancer than in men with other diseases of the prostate. 15 Statistically significant differences in PSA velocity in men diagnosed with prostate cancer, compared with men with BPH or control subjects, were detected up to 10 years before their diagnosis.15 PSA velocity is calculated using 3 PSA measurements taken over a 2-year period, or at least 12 to 18 months apart. Limitations of this method include the need for multiple PSA determinations and the necessity for cumbersome calculations. Age- and Race-Specific PSA Reference Ranges An increase in serum PSA levels with age has been observed and is thought to be largely related to increased glandular volume.1 This observation has led to the development of different normal reference ranges for patients of different ages. The use of age-specific PSA reference ranges has different results in different age groups. In younger men, a number of studies have shown that age-specific PSA reference ranges may increase sensitivity for cancer detection. However, by increasing sensitivity, invariably, the specificity decreases. Thus, these reference ranges also may increase the number of unnecessary biopsies in this population. In older men, age-specific PSA reference ranges increase the specificity of PSA for the detection of prostate cancer but, alternatively, could increase the number of cancers missed.5 It has been reported that African American men have increased PSA values compared with white men, regardless of age, clinical stage, and histologic grade.16 Some speculate that this difference is due in part to an increased volume of tumor at the time of diagnosis in African American men in comparison with their white counterparts.17 Results are mixed regarding the usefulness of age- and race-specific PSA reference ranges. More investigation is
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needed. Neither the US Food and Drug Administration nor the manufacturers of PSA assays approve of or recommend these reference ranges.5 Free PSA PSA circulates in bound and free forms in the serum. Multiple investigators have found that as the percentage of free PSA decreases, the probability of having cancer increases.5 The calculation of the percentage of free PSA to total PSA (the free PSA ratio) has been shown to be clinically useful by increasing specificity in patients with borderline or intermediate PSA values (4-10 ng/mL) and negative DREs. A number of studies have also shown the free PSA ratio to increase the sensitivity of cancer detection when PSA values are within the normal range. However, it is still unclear how large a role free PSA will ultimately have in the diagnosis of prostate cancer. Complexed PSA The proportion of PSA bound to alpha 1 -antichymotrypsin is elevated in the serum of men with prostate cancer compared with healthy men and those with benign prostatic disease.18 Assays using this principle are now in clinical studies to assess their clinical usefulness. ProstAsure Index Last, the ProstAsure Index (Global Health Net, Savannah, GA) is a new, serum-based, neural networkderived test. It mathematically analyzes multiple variables, including total PSA, prostate acid phosphatase, creatine kinase-BB isoenzyme, and patient age, in a nonlinear manner.1 Prospective, early-detection clinical trials are needed to further evaluate this new modality.

Screening Recommendations
PSA testing remains controversial because it is not known whether PSA screening saves lives. The perceived benefits of early detection must be measured against the known risks of treatment-related morbidity, such as incontinence and impotence. In prostate cancer, uncertainty about the natural progression of disease and the efficacy of specific treatments makes it unclear whether early diagnosis will equal lower mortality. The American Cancer Society and the American Urological Association have endorsed annual examinations for early detection of prostate cancer with DRE and PSA, beginning at the age of 50 years, for asymptomatic men with at least a 10-year life expectancy. These agencies also recommended that for men with a strong family history of prostate cancer (2 or more affected first-degree relatives, eg, father
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and brother) and men of African American descent, testing commence at the age of 45 years. Although many physicians in the United States have followed these screening recommendations, support was not and still is not unanimous. Even though the Food and Drug Administration has approved PSA testing for the early detection of prostate cancer, both the US and Canadian Preventive Services Task Forces do not advocate routine screening and recommend against the routine use of PSA for screening. The American College of Physicians and American Society of Internal Medicine recommend that screening decisions should be individualized for each patient. A number of large-scale, randomized controlled trials are underway that should address questions about the treatment and progression of prostate cancer and aid in the evaluation of PSA measurement as an early detection instrument. In the interim, physicians should counsel men on an individual basis about the risks and benefits of prostate cancer screening in relation to their personal risk factors for the development of this disease. Despite personal biases, physicians should encourage their patients to make their own informed decisions.
From the Division of Laboratory Medicine, Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston. Address reprint requests to Dr Kratz: MGH Division of Laboratory Medicine, 55 Fruit St, Gray 235, Boston, MA 02114.

References
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4. Montironi R, Mazzucchelli R, Algaba F. Prostate-specific antigen as a marker of prostate disease. Virchows Arch. 2000;436:297-304. 5. Polascik TJ, Oesterling JE, Partin AW. Prostate specific antigen: a decade of discovery: what we have learned and where we are going. J Urol. 1999;162:293-306. 6. Carter HB, Epstein JI, Chan DW, et al. Recommended prostate-specific antigen testing intervals for the detection of curable prostate cancer. JAMA. 1997;277:1456-1460. 7. Glode LM. Early prostate cancer diagnosis and therapy. Adv Intern Med. 2000;45:41-64. 8. Tchetgen MB, Song JT, Strawderman M, et al. Ejaculation increases the serum prostate-specific antigen concentration. Urology. 1996;47:511-516. 9. Henry JB. Clinical Diagnosis and Management by Laboratory Methods. 19th ed. Philadelphia, PA: Saunders; 1996. 10. Gormley GJ, Ng J, Cook T, et al. Effect of finasteride on prostate-specific antigen density. Urology. 1994;43:53-59. 11. Hortin GL, Bahnson RR, et al. Differences in values obtained with 2 assays of prostate specific antigen. J Urol. 1988;139:762-765. 12. Carter HB, Pearson JD. Prostate-specific antigen testing for early diagnosis of prostate cancer: formulation of guidelines. Urology. 1999;54:780-786. 13. Hammerer PG, McNeal JE, Stamey TA. Correlation between serum prostate-specific antigen levels and the volume of the individual glandular zones of the human prostate. J Urol. 1995;153:111-114. 14. Zlotta AR, Djavan B, Marberger M, et al. Prostate specific antigen density of the transition zone: a new effective parameter for prostate cancer prediction. J Urol. 1997;157:1315-1321. 15. Carter HB, Pearson JD, Metter J, et al. Longitudinal evaluation of prostate-specific antigen levels in men with and without prostate diseases. JAMA. 1992;267:2215-2220. 16. Morgan TO, Jacobsen SJ, McCarthy WF, et al. Age-specific reference ranges for prostate-specific antigen in black men. N Engl J Med. 1996;335:304-309. 17. Moul JW, Sesterhenn IA, Connelly RR, et al. Prostatespecific antigen values at the time of prostate cancer diagnosis in African-American men. JAMA. 1995;274:1277-1281. 18. Brawer MK, Cheli CD, Neaman IE, et al. Complexed prostate specific antigen provides significant enhancement of specificity compared with total prostate specific antigen for detecting prostate cancer. J Urol. 2000;163:1476-1480.

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