skip navigation barphoenix 5 - to help men and their companions overcome issues created by prostate cancer
main menu   -   articles   -   prostate   -   stories   -   sexuality   -   resources   -   glossary   -   search

Prostate Specific Antigen:
The Current Prostate Cancer Controversy

by Ralph Valle
(reprinted with permission of the author)

Prostate-specific antigen, better known as PSA has revolutionized the world of prostate cancer. Some consider it the best marker for cancer in existence while others view it as a dangerous indicator because of its role in detecting cancers, that according to them, are so minute that should not be treated. Most of the argument is economic in principle with many experts on both sides of the equation supporting very logical positions. Who is right and who is wrong? That question is left for you to decide, and in supporting one position or the other you will find yourself alternating between the supporting arguments on both sides.

What is the cause of this furor?

PSA is a serine protease, a glycoprotein secreted exclusively by the epithelial cells of the prostate and also in minute quantities by the periurethral glands.

In 1970, Ablin R.J. et al. identified two separate prostatic tissue-specific antigens. One of the antigens was identified as prostatic acid phosphatase, while the other, the forerunner of the current PSA remained unnamed. In 1971, Hara et al. identified a protein in seminal fluid. They called it gamma-seminoprotein.

A few years later (1979) Wang, Chu et al. purified the antigen from prostatic tissue and named it prostate-specific antigen. Both proteins were the same, with distinct biomolecular and physiological properties. These researchers were the first to demonstrate the relationship of PSA to prostate cancer. Normal prostate epithelial cells and benign hyperplastic tissue produce more PSA than malignant prostatic tissue.

The reason that PSA is expressed in higher numbers in advanced disease is consistent with the above statement due to the higher volume of tumor cells present in advanced prostate cancer. The exact mechanism on how PSA ends up in blood serum is not exactly understood but the "leakage" is promoted by tissue abnormalities within the prostate that allow the enzyme to travel through the cell stroma into the bloodstream via capillaries and lymphatic pathways. The main known biological function of PSA is the cleavage of the major gel-forming proteins semenogelin and fibronectin to increase sperm motility.

The PSA Test-How they do it.

The commercial PSA assays measure this glycoprotein in the serum using immunoassays. The discrepancy of results between different commercial assays is well recognized and causes a lot of problems in diagnosing and properly staging PCa. The standardization of these assays will eliminate or at least minimize most of these problems. The commercial assays use different techniques to measure PSA. Some are immunoradiometric, some are enzyme immunoassays and one is a chemiluminescent immunoassays.

The description of the Hybritech Inc Tandem-R assay which was approved by the FDA for detection of PCa is representative and as follows:

The assay is a solid-phase, two site, monoclonal antibody immunoradiometric assay. The PSA in serum binds to a unique monoclonal antibody fixed on a plastic bead. Simultaneously, a separate distinct epitope of the PSA molecule is detected with a second radiolabelled monoclonal antibody. Six calibrators are used in this test at different concentrations covering the range of the test. Radioactivity is quantitated using a gamma ray counter and concentration is calculated from a standard reference curve using a plot of total counts per minute versus the log of the dose (ng/ml), connecting a straight line between each of the calibrator points.

PSA and Age

PSA is also age dependent, as we get older the PSA tends to increase and therefore the normal range varies with age. The following is a guideline adjusted for age:

 	Age 40-49       0.0-2.5 ng/ml 
 	Age 50-59       0.0-3.5 ng/ml
 	Age 60-69       0.0-4.5 ng/ml
 	Age 70-79       0.0-6.5 ng/ml

Note: The normal 4.0 ng/ml is no longer recognized as the cutoff point.

It is important to recognize that the real value of the PSA test in early detection is based on establishing a baseline PSA value and regularly, on a yearly basis, measuring the PSA to observe changes from the baseline value. Incremental changes of 0.75 ng/ml in a year should be investigated. A trend is more important and one must always remember that PSA is not specific for cancer. A high PSA could be caused by infection, prostate enlargement, manipulation or even urine retention. Never react to ONE variance.

Another important function of the PSA test is in maintenance after treatments. A PSA measurement after a radical prostatectomy is a sign of residual disease and normally requires further treatment. The same is true of all other therapies including hormonal suppression. In other words, PSA is a valuable tool to watch disease progression and help decide on treatment options as early as possible.

PSA and its Forms.

In 1990, Christensson et al. discovered that PSA exists in more than one form circulating in serum. These forms are: Free PSA (PSA-f), bound PSA (PSA-ACT) and complexed PSA (PSA-MG). Since the complexed form, PSA-MG is not immunoreactive, it is not measured by any of the available commercial assays at the present time. Total PSA is the result you get when they draw your blood and they use a commercial assay. It is a combination of PSA-f and PSA-ACT.

Other PSA Tests.

PSA II is an assay that measures both the total PSA (by commercial assay) and also the free PSA by using an investigational immunoradiometric assay.

The theory behind the use of this test is based on the fact that the percentage of free PSA is lower in patients with untreated PCa than in patients with BPH.

In other words, the higher the ratio of PSA-f to total PSA the less probability of cancer. This test can help discriminate between BPH and PCa. In the 4.0 to 10.0 ng/ml. PSA range, at a cutoff of 20% free/total PSA ratio, the sensitivity is 80% and specificity of 49% with a 95% confidence interval. One interesting observation is that in developing this test, the researchers found no PCa patients with 25% or higher ratio of free/total PSA.

The PSA RT-PCR is a totally different type of test. RT-PCR technology is common in molecular testing. By using PSA derived primers the researchers at Columbia University used RT-PCR technology to try to detect micrometastatic cells circulating in serum and identify extraprostatic disease at the staging level. This test is also investigational and once fully developed and refined can potentially help in avoiding unnecessary treatments (RP and RT done on systemic PCa patients).The positive predictive value of PSA RT-PCR in the Columbia series was 77%.


Sensitivity: Is the capability of a test to identify the presence of disease expressed as the ratio of true positives to the sum of true positives and false negatives.

Specificity: Is the capability of a test to identify the absence of disease expressed as the ratio of true negatives to the sum of true negatives and false positives.

Positive predictive value: Is the capability of a test to identify patients with disease among all patients demonstrating positive results.


Ablin RJ, Soanes WA, Bronson P, Witebski E: Precipitating antigens of the normal human prostate. J Reprod Fertil 1970; 22: 573 - 574.

Ablin RJ, Bronson P, Soanes WA, Witebski E: Tissue- and Species-specific Antigens of Normal Human Prostatic Tissue. Journal of Immunology. Vol 104, No 6, June 1970

Hara M, Inorre T, Fukuyama T: Some physico-chemical characteristics of gamma- seminoprotein, an antigenic component specific for human seminal plasma. Jap J Legal Med 1971; 25: 322 - 324

Wang MC, Valenzuela LA, Murphy GP, Chu TM: Purification of a human prostate specific antigen. Invest Urol 1979: 17: 159 - 163.

McCormack RT, Oesterling JE et al.: Molecular forms of Prostate-specific antigen and the human kallikrein gene family: A New Era. UROLOGY /May 1995/ Volume 45, Number 5

Stamey TA: Second Stanford Conference on International Standardization of Prostate-specific Antigen Immunoassays: September1 and 2, 1994. UROLOGY /February 1995/ Volume 45 Number 2

Gann PH, Stampler MJ et al. : A Prospective Evaluation of Plasma Prostate-Specific Antigen for Detection of Prostatic Cancer. JAMA, January 25, 1995-Vol 273, No 4

Ploch NR and Brawer MK: How to use Prostate-Specific Antigen. SUPPLEMENT TO UROLOGY /February 1995/ Volume 43, Number 2

Schambeck CM, Schmeller N et al. : Methodological and Clinical Comparisson of the ACS Prostate-Specific Antigen Assay and the Tandem-E Prostate-Specific Antigen Assay in Prostate Cancer. UROLOGY 46 (2), 1995

Brawer MK: Prostate-Specific Antigen: Critical Issues. UROLOGY Symposium /December 1994/ Volume 44, Number 6A

Anderson JR, Zweiback E et al. : Age-Specific Reference Ranges for Serum Prostate-Specific Antigen. UROLOGY 46 (1), 1995

Partin AW and Osterling JE: The Clinical Usefulness of Prostate-Specific Antigen: Update 1994. The Journal of Urology Vol. 152 1358-1368, November 1994

Osterling JE, Lilja H et al. :Free, Complexed and Total Serum Prostate-Specific Antigen: The Establishment of Appropriate Reference Ranges for their Concentrations and Ratios.The Journal of Urology, Vol 154, 1090-1095, September 1995

Luderer AA, Thiel R et al. : Measurement of the Proportion of Free to Total Prostate- Specific Antigen Improves Diagnostic Performance of Prostate-Specific Antigen in the Diagnostic Gray Zone of Total Prostate-Specific Antigen. UROLOGY 46 (2), 1995

Jiang Y, Chapin RS et al. : A rapid RT-PCR method for detection of intact RNA in formalin-fixed paraffin embedded tissues. Nucleic Acids Research, 1995, Vol. 23, No. 15 3071-3072

Katz AE, Buttyan R et al. : Molecular staging of prostate cancer with the use of an enhanced reverse transcriptase-PCR assay. Urology, 43: 765, 1994

Cama C, Katz AE et al. : Molecular staging of prostate cancer II. A comparisson of the molecular application of an enhanced reverse transcriptase polymerase chain reaction assay for prostate-specific antigen versus prostate-specific membrane antigen. The Journal of Urology, Vol 153, 1373-1378, May 1995

Israeli RS, Fair WR et al. : Sensitive detection of prostatic hematogenous tumor cell dissemination using prostate-specific antigen and prostate-specific membrane-derived primers in the polymerase chain reaction. The Journal of Urology, Vol. 153, 573-577, March 1995

Catalona WJ, Hudson MA, Scardino PT, Dalkin BL. et al.: Selection of optimal prostate specific antigen cutoffs for early detection of prostate cancer. Comment in: J Urol 1994 Dec; 152(6 Pt 1):2046-8, Comment in: J Urol 1995 Sept; 154(3):1145-6

Ralph Valle
January 1996

Go to
PSA Menu


main menu   -   articles   -   prostate   -   stories   -   sexuality   -   resources   -   glossary   -   search

This information is provided for educational purposes only and does not replace or amend professional medical advice. Unless otherwise stated and credited, the content of Phoenix5 (P5) is by and the opinion of and copyright © 2000 Robert Vaughn Young. All Rights Reserved. P5 is at <>. P5's policy regarding privacy and right to reprint are at <>.