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The
PSA test is a blood test that is used to screen for the presence
of prostate cancer. Because PSA is produced by the body and can be used
to detect disease, it is sometimes called a biological marker or tumor
marker. Prostate specific antigen is a protein found in the fluid
portion of blood, called serum. PSA is specific to the prostate. No
other human tissue or body part can make it. PSA levels can be measured
in an individual's serum.
It is normal for men
to have low levels of PSA in their blood; however, prostate cancer or
benign (not cancerous) conditions can increase PSA levels. As men age,
both benign prostate conditions and prostate cancer become more
frequent. The most common benign prostate conditions are prostatitis
(inflammation of the prostate) and benign prostatic hyperplasia (BPH =
enlargement of the prostate).
There is no evidence
that prostatitis or BPH cause cancer, but it is possible for a man to
have one or both of these conditions and to develop prostate cancer as
well.
PSA is only present in men. PSA is present in all normal prostate
tissue. The normal prostate cell holds onto most of the PSA. Very little
leaks into the bloodstream. The small amount that leaks out is what is
measured by the blood test. Prostate cancer cells actually have less PSA
in each cell. However, the cancer cell tends to leak more PSA into the
bloodstream. Knowing this fact, experts developed a range of expected
values in patients with a normal prostate gland. The PSA value should be
less than 4.0. This number reflects the belief that most men, roughly
95%, with normal prostate glands have a PSA value of 4.0 or less. (See
below for age-specific normal values.) Almost any condition that affects
the prostate can make the PSA rise.
The American Cancer
Society and the American Urological Association recommend that men over
age 50 have a yearly PSA. They should also have a rectal examination of
the prostate. High-risk groups should begin screening at age 40 to 45.
Men with a family history of the disease and African Americans fall into
this category.
When evaluating PSA
results, the doctor must also take into account the results of the
rectal exam, the patient's age, previous PSA results, and prostatic
size. For example, findings on a rectal exam must be looked into even if
the PSA result is normal. Recent studies have suggested that the 4.0
level may be too high for younger men and too low for older men. Many
researchers now use the following levels rather than the 4.0 used in the
past. However, more time is needed to assure that these levels are more
accurate.
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AGE |
NORMAL RANGE |
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40 to 50 |
0 to 2.5 |
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50 to 60 |
0 to 3.5 |
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60 to 70 |
0 to 4.5 |
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70 to 80 |
0 to 6.5 |
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If the rectal exam
is normal then the following recommendations are suggested: PSA of 4 or
less. If the PSA level has been measured for the first time and is less
than 4, repeat testing is recommended on a yearly basis. (This number
may be dependent on age. See above for normal values.) PSA between 4 and
10.
If the PSA level
is greater than 4 but less than 10, a diagnostic ultrasound of the
prostate is recommended. If the ultrasound shows no suspicious areas,
the prostate can be monitored through regular testing and exams.
Another option is to take random biopsies from various parts of the
prostate. If observation alone is used, the PSA should be repeated in 4
to 6 months and no later than a year. If the ultrasound shows a
suspicious area, then biopsy of the area needs to be performed. This can
be done at the time of the ultrasound. The patient will need to take
antibiotics ahead of time.
If the PSA is greater than 10, diagnostic ultrasound of the prostate
with biopsies is the recommended course. If the ultrasound shows no
suspicious areas, then random biopsies of the prostate are taken. If the
ultrasound shows suspicious areas, then biopsies of the areas along with
random biopsies need to be done. If previous PSA values are available,
test results will be evaluated differently. The PSA level almost always
rises if cancer is growing. Any PSA level that is rising is suspicious.
However, a high PSA level may not mean that cancer is present. For
example, a male with a stable PSA of 8 over a three-year period is
probably at less risk than a male with a PSA of 2, 4, and 6 over the
same time frame. This is because the second patient's rising levels
suggest growth. This makes it suspicious for cancer. If the first
patient had a negative biopsy when the first high PSA value occurred,
there may be no need to repeat the biopsies. If the PSA level jumped to
10 or 15 for no apparent reason, then repeat ultrasound and biopsies
would be called for. Recent studies suggest that either a 20% rise or a
measurable rise of 0.75 in PSA in one year should prompt a closer look.
Ultrasound and biopsy may be needed.
PSA levels alone do not give doctors enough information to distinguish
between benign prostate conditions and cancer but it is the first
screening step for any man over 50. Your physician will take the result
of the PSA test into account when deciding whether to check further for
signs of prostate cancer.
The U.S. Food and Drug Administration (FDA) has approved the PSA test
along with a digital rectal exam DRE to help detect prostate cancer in
men age 50 and older. During a DRE, a doctor inserts a gloved finger
into the rectum and feels the prostate gland through the rectal wall to
check for bumps or abnormal areas. Together, these tests can help
doctors detect prostate cancer in men who have no symptoms of the
disease.
The FDA has also
approved the PSA test to monitor patients with a history of prostate
cancer to see if the cancer has come back (recurred). An elevated PSA
level in a patient with a history of prostate cancer does not always
mean the cancer has come back. A man should discuss an elevated PSA
level with his doctor. The doctor may recommend repeating the PSA test
or performing other tests to check for evidence of recurrence.
It is important to
note that a man who is receiving hormone therapy for prostate cancer may
have a low PSA reading during, or immediately after, treatment. The low
level may not be a true measure of PSA activity in the man’s body. Men
receiving hormone therapy should talk with their doctor, who may advise
them to wait a few months after hormone treatment before having a PSA
test.
For whom might a PSA screening test be recommended?
Doctors’
recommendations for screening vary. Some encourage yearly screening for
men over age 50, and some advise men who are at a higher risk for
prostate cancer to begin screening at age 40 or 45. Others caution
against routine screening, while still others counsel men about the
risks and benefits on an individual basis and encourage men to make
personal decisions about screening.
Several risk factors increase a man’s chances of developing prostate
cancer. These factors may be taken into consideration when a doctor
recommends screening. Age is the most common risk factor, with nearly 70
percent of prostate cancer cases occurring in men age 65 and older.
Other risk factors for prostate cancer include family history, race, and
possibly diet. Men who have a father or brother with prostate cancer
have a greater chance of developing prostate cancer. African American
men have the highest rate of prostate cancer, while Asian and Native
American men have the lowest rates. In addition, there is some evidence
that a diet higher in fat, especially animal fat, may increase the risk
of prostate cancer.
PSA test results
report the level of PSA detected in the blood. The test results are
usually reported as nanograms of PSA per milliliter (ng/ml) of blood. In
the past, most doctors considered PSA values below 4.0 ng/ml as normal.
However, recent research found prostate cancer in men with PSA levels
below 4.0 ng/ml. Many doctors are now using the following ranges,
with some variation:
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PSA |
RANGE |
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0 to 2.5
ng/ml |
low |
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2.6 to 10
ng/ml
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slightly to
moderately elevated |
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10 to 19.9
ng/ml |
moderately
elevated |
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20 ng/ml or
more |
significantly
elevated
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There is no
specific normal or abnormal PSA level. However, the higher a man’s PSA
level, the more likely it is that cancer is present. But because various
factors can cause PSA levels to fluctuate, one abnormal PSA test does
not necessarily indicate a need for other diagnostic tests. When PSA
levels continue to rise over time, other tests may be needed.
There are many
possible reasons for an elevated PSA level, including prostate cancer,
benign prostate enlargement, inflammation, infection, age, and race.
If no other
symptoms suggest cancer, the doctor may recommend repeating DRE (Digital
Rectal Exam) and PSA tests regularly to watch for any changes. If a
man’s PSA levels have been increasing or if a suspicious lump is
detected during the DRE, the doctor may recommend other tests to
determine if there is cancer or another problem in the prostate. A urine
test may be used to detect a urinary tract infection or blood in the
urine. The doctor may recommend imaging tests, such as ultrasound (a
test in which high-frequency sound waves are used to obtain images of
the kidneys and bladder), x-rays, or cystoscopy (a procedure in which a
doctor looks into the urethra and bladder through a thin, lighted tube).
Medicine or surgery may be recommended if the problem is BPH or an
infection.
If cancer is
suspected, a biopsy is needed to determine if cancer is present in the
prostate. During a biopsy, samples of prostate tissue are removed,
usually with a needle, and viewed under a microscope. The doctor may use
ultrasound to view the prostate during the biopsy, but ultrasound cannot
be used alone to tell if cancer is present.
Detection does not always mean saving lives: Even though the PSA test
can detect small tumors, finding a small tumor does not necessarily
reduce a man’s chance of dying from prostate cancer. PSA testing may
identify very slow-growing tumors that are unlikely to threaten a man’s
life. Also, PSA testing may not help a man with a fast-growing or
aggressive cancer that has already spread to other parts of his body
before being detected.
False positive test results (also called false positives) occur
when the PSA level is elevated but no cancer is actually present. False
positives may lead to additional medical procedures that have potential
risks and significant financial costs and can create anxiety for the
patient and his family. Most men with an elevated PSA test turn out not
to have cancer; only 25 to 30 percent of men who have a biopsy due to
elevated PSA levels actually have prostate cancer.
False negative
test results (also called false negatives) occur when the PSA level is
in the normal range even though prostate cancer is actually present.
Most prostate cancers are slow-growing and may exist for decades before
they are large enough to cause symptoms. Subsequent PSA tests may
indicate a problem before the disease progresses significantly.
Using the PSA test to screen men for prostate cancer is controversial
because it is not yet known if this test actually saves lives. Moreover,
it is not clear if the benefits of PSA screening outweigh the risks of
follow-up diagnostic tests and cancer treatments. For example, the PSA
test may detect small cancers that would never become life threatening.
This situation, called overdiagnosis, puts men at risk for complications
from unnecessary treatment such as surgery or radiation.
The procedure used
to diagnose prostate cancer (prostate biopsy) may cause side effects,
including bleeding and infection. Prostate cancer treatment may cause
incontinence (inability to control urine flow) and erectile dysfunction
(erections inadequate for intercourse). For these reasons, it is
important that the benefits and risks of diagnostic procedures and
treatment be taken into account when considering whether to undertake
prostate cancer screening.
The benefits of screening for prostate cancer are still being studied.
The National Cancer Institute (NCI) is currently conducting the
Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, or PLCO
trial, to determine if certain screening tests reduce the number of
deaths from these cancers. The DRE and PSA are being studied to
determine whether yearly screening to detect prostate cancer will
decrease a man’s chance of dying from prostate cancer. Full results from
this study are expected in several years. Scientists also are
researching ways to distinguish between cancerous and benign conditions,
and between slow-growing cancers and fast-growing, potentially lethal
cancers. Some of the methods being studied are:
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PSA velocity:
PSA velocity is based on changes in PSA levels over time. A sharp rise
in the PSA level raises the suspicion of cancer.
Age-adjusted PSA:
Age is an important factor in increasing PSA levels. For this reason,
some doctors use age-adjusted PSA levels to determine when diagnostic
tests are needed. When age-adjusted PSA levels are used, a different PSA
level is defined as normal for each 10-year age group. Doctors who use
this method generally suggest that men younger than age 50 should have a
PSA level below 2.4 ng/ml, while a PSA level up to 6.5 ng/ml would be
considered normal for men in their 70s. Doctors do not agree about the
accuracy and usefulness of age-adjusted PSA levels.
PSA density:
PSA density considers the relationship of the PSA level to the size of
the prostate. In other words, an elevated PSA might not arouse suspicion
if a man has a very enlarged prostate. The use of PSA density to
interpret PSA results is controversial because cancer might be
overlooked in a man with an enlarged prostate.
Free versus complexed (attached) PSA:
PSA circulates in the blood in two forms: free or attached to a protein
molecule. With benign prostate conditions, there is more free PSA, while
cancer produces more of the attached form. Researchers are exploring
different ways to measure PSA and to compare these measurements to
determine if cancer is present.
Alteration of PSA cutoff level:
Some researchers have suggested lowering the cutoff levels that
determine if a PSA measurement is normal or elevated. For example, a
number of studies have used cutoff levels of 2.5 or 3.0 ng/ml (rather
than 4.0 ng/ml). In such studies, PSA measurements above 2.5 or 3.0 ng/ml
are considered elevated. Researchers hope that using these lower cutoff
levels will increase the chance of detecting prostate cancer; however,
this method may also increase overdiagnosis and false positive test
results and lead to unnecessary medical procedures.
Protein patterns:
Scientists are also studying a test that can rapidly analyze the
patterns of various proteins in the blood. Researchers hope that this
technique can determine if a biopsy is necessary when a person has a
slightly elevated PSA level or an abnormal DRE.
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Prostate-Specific Antigen (PSA), Complexed |
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Other
PSA tests that measure just the free or complexed portion are also
available.
The
relative proportions of free and complexed PSA are thought to be
different in prostate cancer when compared with other prostatic
diseases. Men with cancer are thought to have a smaller proportion of
free PSA and more complexed PSA than men with other benign prostatic
diseases such as benign prostatic hyperplasia (BPH) or prostatitis,
which can also lead to abnormal total PSA test results.
Free
or complexed PSA tests are provided by some laboratories usually in
addition to the total PSA test. They have often been used as reflex
tests following a raised total PSA test result. The results are then
expressed as the percentage of free PSA compared with the total amount
of PSA detected. Any results below a cut-off are thought to be
suggestive of prostate cancer. These free or complexed PSA tests are
designed to be used when the total PSA test result is marginally raised,
and not in cases where the total PSA test result is very high and
suggestive of advanced prostate cancer.
The
introduction of free PSA (fPSA) testing has introduced a greater
level of specificity in identifying early prostate cancer. In 1998, the
FDA approved fPSA testing as a diagnostic aid for men with total PSA
values between 4.0-10.0 ng/mL. This has often been the diagnostic gray
zone for total PSA testing and fPSA may aid in the stratification. In
general, “At any percent free PSA level, one could be a lot more
reassured in the man with the small prostate…if somebody has a really
low percent free PSA, 10 or 12, no matter how big or how small their
prostate is, then you worry. And if a patient has a really high free PSA,
say 30%, no matter how big or small his prostate is, you can feel
reassured,” (William Catalona, M.D., Urologist at Barnes
Hosptial, Washington University, St. Louis).
But
fPSA levels between 10-25% are another gray zone as the table
illustrates. Additional testing on the horizon includes complexed PSA
and human glandular kallikrein (hK2) to fPSA ratio.
Probability of
Prostate Cancer Based Upon Test Results
(Modified from Hybridech, Inc.) |
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Standard PSA |
Probability of cancer |
Percent free PSA |
Probability of cancer |
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0-2 ng/mL |
1% |
0-10% |
56% |
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2-4 ng/mL |
15% |
10-15% |
28% |
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4-10 ng/mL |
25% |
15-20% |
20% |
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>10 ng/mL |
>50% |
20-25% |
16% |
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>25% |
8%
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Prostate-Specific Antigen (PSA),
Free/Total Ratio |
PSA represents a major indicator for
the diagnosis and management of prostate cancer. However, within the
range of
4-10 ng/mL, in which 75% of men do not have cancer, the PSA
lacks specificity. At this range, 4 men require a biopsy to identify 1
man with cancer.
Stenman et al studied this problem and reported in 1991 that men with
prostate cancer had more complexed prostate-specific antigen (cPSA) than
fPSA, in contrast to men with BPH. After the development of an
immunoassay, investigators demonstrated that the ratio of free-to-total
prostate-specific antigen (f/tPSA) was lower in men with prostate
cancer.
In the PSA range of 4-10, total prostate-specific antigen (tPSA)
segregates adequately between men with or without cancer. The f/tPSA is
more discriminatory.
A 7-institution study investigated 63 men with BPH, 30 men with prostate
cancer (prostate size >40 cm3), and 20 men with small prostates. All of
the PSA levels were 4-10 ng/mL. The median f/tPSA proportion was 0.188
(in BPH), 0.159 (in prostate cancer [prostate size >40 cm3]), and 0.092
(in small prostates).
This implies that prostate size is an important variable in selecting a
cutoff value for fPSA.
For men whose prostates are smaller than 40 cm3,
a percent fPSA of 0.137 or lower is used to detect 90% of the cancers,
and 76% of the negative biopsy findings can be eliminated.
For men with
prostates larger than 40 cm3, a cutoff of 0.205 allows detection of 90%
of the cancers, and 38% of the negative biopsy findings can be
eliminated.
If the patient has a normal-sized prostate on DRE, a value
of 0.234 is necessary to detect 90% of the cancers, sparing 31.3% of the
patients an unnecessary biopsy.
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Prostate-Specific Antigen (PSA),
Ultra sensitive
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| Ultra sensitive prostate
specific antigen (PSA) assays allow a lower limit of detection
(less than 0.01 ng/ml) than standard PSA assays.
PSA sampling should not be performed for at least 6 weeks after
prostatic biopsy. This test should not be used for prostate
cancer screening. This procedure does not provide serial
monitoring; it is intended for one-time use only.
This test is intended for use as
an aid in the management of patients following surgical or
medical treatment for prostate cancer. The use of PSA as an aid
in the management of prostate cancer patients after treatment
has been well documented.
The frequency of cancer recurrence
correlates with the degree of cancer progression at the time of
treatment.
It has been estimated that cancer relapse following
radical prostatectomy occurs in 3% to 11% of patients where the
tumor is confined to the prostate. Fifteen percent to 40% of
patients with tumors extending beyond the prostatic capsule will
have cancer recurrence and to 30% to 66% for patients with
positive surgical margins or invasion of seminal vesicles will
experience relapse. Biochemical recurrence, defined as
increasing PSA levels after treatment, can be observed much
earlier than clinical signs of tumor recurrence.
Persistent
elevation of PSA following treatment or an increase in a
post-treatment PSA level has been found to be indicative of
recurrent or residual disease.
The lead time for
the detection of cancer may be increased by months, or even
years, through the use of ultrasensitive PSA. The ultrasensitive PSA test has a functional sensitivity of 0.01 ng/mL,
which is an order of magnitude greater than that of other
conventional assays (0.1 ng/mL).
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Prostatic Acid Phosphatase (PAP) |
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This is not a screening test for prostate cancer. Acid phosphatase
levels rise only after prostate cancer has metastasized.
Acid phosphatase is
an enzyme found throughout the body, but primarily in the prostate
gland. Like all enzymes, it is needed to trigger specific chemical
reactions. Acid phosphatase testing is done to diagnose whether prostate
cancer has spread to other parts of the body (metastasized), and to
check the effectiveness of treatment. The test has been largely
supplanted by the prostate specific antigen test (PSA).
The male prostate gland has 100 times more acid phosphatase than any
other body tissue. When prostate cancer spreads to other parts of the
body, acid phosphatase levels rise, particularly if the cancer spreads
to the bone. One-half to three-fourths of persons who have metastasized
prostate cancer have high acid phosphatase levels. Levels fall after the
tumor is removed or reduced through treatment.
Tissues other than
prostate have small amounts of acid phosphatase, including bone, liver,
spleen, kidney, and red blood cells and platelets. Damage to these
tissues causes a moderate increase in acid phosphatase levels.
Acid phosphatase is
very concentrated in semen. Rape investigations will often include
testing for the presence of acid phosphatase in vaginal fluid.
Laboratory testing measures the amount of acid phosphatase in a person's
blood, and can determine from what tissue the enzyme is coming. For
example, it is important to know if the increased acid phosphatase is
from the prostate or red blood cells. Acid phosphatase from the
prostate, called prostatic acid phosphatase (PAP), is the most medically
significant type of acid phosphatase.
Subtle differences
between prostatic acid phosphatase and acid phosphatases from other
tissues cause them to react differently in the laboratory when mixed
with certain chemicals. Laboratory test methods based on these
differences reveal how much of a person's total acid phosphatase is
derived from the prostate.
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