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Prostate-specific antigen testing for prostate cancer: Practical Interpretation of Values

Abstract: The mere mention of prostate cancer strikes fear in the hearts of men. Fortunately, prostate-specific antigen (PSA) is now a recognized tumor marker that can indicate but not exclude the presence of this potentially fatal disease. In this article, Drs. Randrup and Baum explain the nature of PSA and the practical application of serum PSA determination. Also discussed are three PSA-based strategies for early diagnosis and guidelines for interpreting PSA values in the primary care setting

In men, prostate cancer is the most common malignant disease and the second most frequent cause of cancer-related death. More than 200,000 new cases are diagnosed and 38,000 men die of the disease each year in the United States1. With the "graying" of America, these numbers are likely only to increase. Urologists agree that patients with organ-confined disease and a life expectancy of 10 years or more have the best chance of cure of prostate cancer. Although controversy regarding the value of screening for prostate cancer persists Physician82, at present about 70% of patients with diagnosed prostate cancer have disease that is localized to the prostate gland, where it is potentially curable by surgery or radiation therapy.

Prostate-specific antigen (PSA) was discovered to be a component of healthy human prostate tissue in 1970.3 and found to be present in human seminal fluid in 1971 4. In 1986, PSA testing became clinically available. Because of its specificity for prostatic tissue, PSA is the best tumor marker available for prostate cancer.

PSA as a tumor marker

PSA is an enzyme that hydrolyzes the coagulum of ejaculate and therefore has a function in male fertility5. This glycoprotein has a molecular weight of about 34,000 d, contains 240 amino acids, and is chemically similar to kallikrein. It is produced exclusively by the epithelial cells of the acini and ducts of the prostate gland. Since small amounts of PSA pass into the vascular system, this enzyme is also present in the serum of healthy men.

When prostatic cells are injured, increased in number, or altered by disease or prostatic manipulation, the permeability of the epithelial cell membrane increases and the serum PSA level rises correspondingly. These changes can occur with prostatic adenocarcinoma, prostatic intraepithelial neoplasia, benign prostatic hyperplasia, prostatitis, perineal trauma, vigorous prostatic massage, rigid cystoscopy, and transurethral resection of the prostate gland.

Unfortunately, both benign prostatic hyperplasia and prostate cancer increase the serum PSA level. Consequently, the serum PSA level lacks the specificity needed to detect prostate cancer. In other words, this enzyme is organ-specific but not disease-specific. Nevertheless, the serum PSA level typically is increased in many cases of prostate cancer and so is measured and used as a "tumor marker."

Two PSA assays

Available at present are two commercial assays for PSA: monoclonal Tandem-R (Hybritech Inc., San Diego) and polyclonal Pro-Check (Yang Laboratories, Bellevue, Washington). The Tandem-R assay is by far the more widely used of the two. (Unless stated otherwise, Tandem-R is the assay referred to in subsequent discussion.) Physicians' knowledge of which of the two assays is being used is important because of the difference in their ranges of normal values: 0 to 4 ng/mL for Tandem-R and 0 to 2/5 mg,: for Pro-Check.

PSA has a half-life of two to three days. As a result, determination of the baseline PSA level should be delayed for two to three weeks after prostatic manipulation, such as prostate biopsy or surgery, transrectal ultrasound, or cystoscopy. A similar delay of PSA measurement is unnecessary after a simple digital rectal examination, which does not elevate the PSA level like it does the prostatic acid phosphatase level6.

Interpretation of PSA values

Measurement of the serum PSA level is done to (1) screen for prostate cancer in asymptomatic patients, (2) aid in diagnosing prostatic adenocarcinoma, and (3) follow the natural course of the disease and the response to therapy in patients known to have prostate cancer.

There is no set PSA value that enables physicians to diagnose prostate cancer, but a serum PSA level greater than 10 ng/mL is highly suggestive of the disease. Elevations that are caused by benign prostatic enlargement, prostatitis, urologic manipulation, or prostatic trauma are almost always below 20 ng/mL. PSA readings have no upper limit and can reach 10,000 ng/mL or more. In general, however, a PSA value of 100 ng/mL is, in al likelihood, a sign of metastatic prostate cancer.

As already pointed out, a normal PSA level does not exclude the diagnosis of prostate cancer. In these cases, the tumor burden may be too small to produce biochemical evidence of the cancer's existence. On rare occasions, a large malignant tumor may also be accompanied by a low PSA level. In these cases, the cell population of the tumor may be so undifferentiated that it is unable to synthesize the complex PSA molecule.

PSA-based strategies for early diagnosis

Attempts to improve the usefulness of PSA in early diagnosis of prostate cancer have resulted in several strategies of reading and interpreting PSA values. However, because their reference ranges, for normal values are more controversial than the "0 to 4" normal range currently used as the standard, these strategies have not been universally accepted or applied7.

Age-specific PSA

This strategy corrects the normal range of PSA values on the basis of age, with patients separated by decade of life, extending from the fifth decade through the eighth. Normal PSA reference values, by decade, are as follows: 40 to 49 years, 0 to 2.5 ng/mL; 50 to 59, 0 to 3.5; 60 to 69, 0 to 4.5; and 70 to 79, 0 to 6.5.

According to a recent article8, the evidence supports the theory that the standard normal reference range for serum PSA values is not adequate to account for age-dependent variations in prostate volume and PSA production and secretion. Proponents of this theory maintain that a small PSA increase is more significant in a young patient than in an older one. Thus, they believe that use of the age-specific PSA strategy improves the sensitivity of this tumor marker in young men and it specificity in older men.

PSA rate of change

Unlike a single PSA reading, serial PSA determinations (typically obtained once a year) add a new dimensiion to th einterpretation of PSA values. The rate of change (i.e., of increase) of the PSA level may suggest a neoplastic disease process within the prosate gland rather than benign enlargement7. For example, a man whose PSA values are 3.5, 4.5 and 7 ng/mL in three consecutive years is at greater risk for malignant prostatic disease than perhaps is a man whose readings have been stable at 7 ng/mL for the last three years. In general, an upward trend in the PSA level in which the rate of increase is 0.75 ng/mL or more per year, or 20% or more per year⁹, is considered abnormal and requires further investigation.

PSA Density

Given a mild elevation of the PSA level (e.g., 8 ng/mL in a 65 year-old man), the smaller the prostate gland on rectal examination, the higher the chances that the patient has prostate cancer, since with a small prostate gland, the elevation in PSA level cannot be explained on the basis of benign enlargement. Marked benign prostatic hyperplasia may account for the elevated PSA value.

This notion is expressed by the concept of PSA density¹⁰, which is calculated after prostate volume is determined by transrectal ultrasound. The serum PSA value is divided by prostate value (in cubic centimeters) to obtain a density ratio. A normal density ratio is 0.15 or less. At a given PSA value, the larger the natural size of the prostate gland, the smaller the density ratio. PSA density ratios that exceed 0.15 suggest prostate cancer.

The chief advantages and disadvantages of these three PSA-based strategies for early diagnosis of prostate cancer are summarized in Table 1. All three reference ranges were established to permit early diagnosis of prostate cancer.

Practical applicaton of PSA testing

For primary care physicians, the main application of the PSA test is screening. PSA-based follow-up and monitoring of patients with diagnosed prostate cancer is, for the most part, the domain of urologists and oncologists.

In the hope of optimizing detection of early and curable prostate cancer, the American Cancer Society and the American Urological Association currently recommend that all men 50 years of age or older should have a PSA test and rectal examination11. The same recommendation holds for men 40 to 49 years of age who are black or have a family history of prostate cancer (in father, brother or uncle) and thus are considered at increased risk for malignant disease of the prostate gland.

Physicians should refer all patients with an abnormal PSA value for urologic evaluation. Whether a PSA value is normal or abnormal can be decided on the basis of either the standard normal reference range of 0 to 4 ng/mL, the use of which is appropriate for patients of all ages regardless of the presence of other medical conditions or one of the PSA-based strategies: age-specific PSA, PSA rate of change, or PSA density.

Effects of finasteride therapy on PSA level

Finasteride (Proscar), the 5-apha-reductase inhibitor widely used to manage benign prostatic hyperplasia, decreases PSA levels quite consistently to half of the baseline value in patients treated with the drug for six months or longer^6,12. Follow-up with annual standard PSA determinations can be continued in such patients, but physicians need to remember that the actual PSA value is double the amount measured. For example, a PSA level greater than 2 ng/mL in a patient receiving long-term finasteride therapy should be considered abnormal and warrants urologic referral.

PSA monitoring of patients with prostate cancer.

Radical prostatectomy or definitive radiation treatment, both of which are done with curative intent, should result in unmeasurable levels of PSA in serum. Measurement, however, should be delayed until two to three weeks after such therapy to avoid falsely high readings related to the long half-life of PSA.

In patients undergoing androgen deprivation therapy, which is used as a palliative measure for advanced prostate cancer, PSA levels are generally not undetectable. Usually, they show a precipitous decline from pretreatment levels and may be in the normal or mild-moderate range. The important consideration in these patients is that the serum PSA level remain basically stable during follow-up. A definite upward trend in the PSA level discloses the presence of a prostate cancer that is unresponsive to hormonal control an dcalls for additional therapy.

New information about PSA

Most commercially available assays for PSA only measure the total PSA level. Available now is a new PSA assay¹³ (Dianon Systems, Stratford, Connecticut) that can distinguish between the two major forms of PSA: (1) free PSA (f-PSA) and (2) PSA complexed with alpha-1 antichymodtrypsin (PSA-ACT). f-PSA accounts for 10% to 40% of the total PSA level and the PSA-ACT complex, 60% to 90%. This new test can measure the f-PSA molecule. In patients with prostate cancer, the amount of f-PSA decreases and the amount of PSA-ACT complex increases.

Recent studies Physician^8,13 Physician^8,14 have demonstrated the usefulness of measuring the ratio of f-PSA to total PSA. If the ratio of f-PSA to total PSA times 100% is less than 25%, benign prostatic hyperplasia rather than prostate cancer is the more likely diagnosis. The test is very useful in men whose total PSA level is in the gray zone. (4 o 10 ng/mL). In addition, it helps differentiate prostate cancer from benign prostatic hyperplasia an dincreases the sensitivity and specificity of PSA as a tumor marker.

Conclusion

Physicians now have at their disposal a very useful tool for early diagnosis of prostate cancer: measurement of prostate-specific antigen (PSA) levels in serum. Although PSA is not the ideal tumor marker that we physicians all wish we had, it may help- guide us in identifying and manging prostate cancer, which currently is the most common malignant disease found in men.

References

¹Boring CC, Squire TS, Tong T. Cancer statistics, 1993. CA Cancer J Clin 1993;43(1):7-26.

²Chodak GW. Questioning the value of screening for prostate cancer in asymptomatic men. (Editorial) Urology 1993;42(2):116-8.

³Ablin RJ, Soanes WA, Bronson P, et al. Precipitating antigens of the normal human prostate. J Reprod Fertil 1970;22(3):573-4.

⁴Hara M, Koyanagi Y, Inoue T, et al. Some physico-chemical characteristics of "gamma-seminoprotein," an antigenic component specific for human seminal plasma: forensic immunological study of body fluids and secretion. Nippon Hoigaku Zasshi 1971;25(4):322-4.

⁵Stamey TA, McNeal JE. Adenocarcinoma of the prostate. In: Walsh PC, et al, eds. Campbell's urology. 6th ed. Philadelphia: Saunders, 1992:1159-221.

⁶Ruckle HC, Klee GG, Osterling JE. Prostate-specific antigen: critical issues of the practicing physician. Mayo Clin Proc 1994; 69 (1): 59-68

⁷Mettlin C, littrup PJ, Kane RA et al. Relative sensitivity and specificity of serum prostate specific antigen (PSA) level compared with age-referenced PSA, PSA density and PSA change: data from the American Cancer Society National Prostate Cancer Detection Project. Cancer 1994; 74(5) 1615-20

⁸Osterling JE, Jacobsen SJ, Chute CG, et al. Serum prostate-specific antigen in a community-based population of health men; establishment of age-specific reference ranges. JAMA 1993; 270 (7): 869-4

⁹Brawer MK, Beatie J, Wener MH, et al. Screening for prostatic carcinoma with prostate specific antigen: results of the second year. J Urol 1993; 150(1): 106-9

¹⁰Benson MC, Whang IS, Pantuck A, et al. Prostate specific antigen density: a means of distinguishing benign prostatic hypertrophy and prostate cancer. J Urol 1992; 147(3 pt 2): 815-6

¹¹Mettlin C, Jones G, Averette H, et al. Defining and updating the American Cancer Society guidelines for the cancer-related check-up: prostate and endometrial cancers. CA Cancer J Clin 1993; 43(1):42-6

¹² Guess HA, Heyse JF, Gormley GJ. The effect of finasteride on prostate-specific antigen in men with benign prostatic hyperplasia. Prostate 1993; 22(1):31-7

¹³Christensson A, Bjork T, Nilsson O et al. Serum prostate specific antigen complexed to alpha-1 antichymotrypsin as an indicator of prostate cancer. J Urol 1993; 150 (1): 100-5

¹⁴Catalona WJ, Smith DS, Ratliff TL, et al. Measurement of prostate-specific antigen in serum as a screening test for prostate cancer. N Engl J Med 1991; 324(17): 1156-61

Reprinted with permission from Postgraduate Medicine, The McGraw-Hill Companies, Inc., February 1996 Eddy Randrup, M.D., Neil Baum, M.D.

Dr. Baum is associate clinical professor of urology at Tulane University School of Medicine and Louisiana State University School of Medicine, both in New Orleans.

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Reprinted with permission from Neil Baum MD, neilbaum.com.

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