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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%.
DEFINITIONS.
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.
FURTHER READING.
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
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