Pathology Title of Lecture
AY 2018-2019 Instructor’s Name (Name, MD, other-post-nominals)
1st Shifting Exam MM/DD/YYYY
OUTLINE
Serum and Urine Markers for Prostate Cancer
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LEARNING OBJECTIVES
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I. SERUM PROSTATE-SPECIFIC ANTIGEN
 PSA is a member of the kallikrein family of serine proteases that
is synthesized uniquely in the epithelial cells of the prostate gland
and its expression is regulated by the androgen receptor.
 PSA has a high cancer sensitivity and tissue specificity which
makes it the most potent tumor marker for prostate cancer.
 Normal reference range: 0-4 ng/mL
 Studies suggest that it has a sensitivity of atleast 80% and a
specificity of around 50%
 Lack of cancer specificity in distinguishing prostate cancer and
nonmalignant prostate lesions is the main drawback with PSA
(elevated PSA in BPH, acute prostatitis and infarction)
 Annual PSA screening is recommended both by the American
Urological Association and the American Cancer Society for all
men
 Complete removal of the prostate should result in an
undetectable PSA level, while incomplete resection of the gland
(not persistent disease) might result in measurable levels of PSA.
 Any increase in measurable PSA after a successful radical
prostatectomy would indicate prostate cancer recurrence or
metastasis.
 A transient and modest increase of PSA may occur during
radiation therapy which should not be misinterpreted.
 Early diagnosis of prostate cancer with PSA has resulted to
20% decrease in death cases, though with a high risk of
overdiagnosing.
 Methods to improve the performance of serum PSA
measurement for the early detection of prostate cancer:
 PSA in combination with digital rectal examination (DRE) or
transrectal ultrasound
 PSA fractions (i.e., free and bound) have been used to
increase the sensitivity and specificity of elevated serum PSA
in the diagnosis of prostate cancer
A. FREE PSA, COMPLEX PSA AND PERCENTAGE
OF FREE PSA
 PSA is capable of complexing into stable forms with various
endogenous protease inhibitors collectively called complexed
PSA (cPSA):
 alpha 1-antichymotrypsin (ACT)
 serum PSA exist largely (up to 90% of total PSA) in
complex with this as PSA–α1-antichymotrypsin (PSA-
ACT) which is readily detectable by most immunoassays.
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 α2-macroglobulin (to which it binds covalently)
 escapes detection by most immunoassays.
 α-protease inhibitor (API)
 The noncomplexed forms, known as free PSA (fPSA), are
unreactive with plasma protease inhibitors.
 Measurement of fPSA and the calculation of percentage of
fPSA is done using the equation below:
%fPSA = [fPSA/tPSA] × 100
 This has an inverse relationship with prostate cancer risk,
which have been used to help to differentiate BPH from
prostate cancer.
 fPSA ratio helps improve the specificity for prostate cancer
detection in men with PSA levels between 4-10 ng/mL,
reducing unnecessary biopsies.
 In BPH cases, the fPSA is higher than in cases with prostate
cancer.
 fPSA has recently been shown to exist in at least three
molecular forms:
 proPSA
 BPSA
 inactive “intact” PSA (iPSA).
 In prostate cancer, cPSA is generally increased in serum
with a corresponding decrease in fPSA.
B. PSA DOUBLING TIME, VELOCITY AND DENSITY
 Cancer is a growth process, and it seems reasonable to suppose
that the rate of change of a tumor marker would be a more
sensitive marker of disease aggressiveness than an absolute
level.
 The time (in months) required for the PSA value to double is
known as the PSA doubling time.
 PSA doubling time can predict recurrence after radical
prostatectomy in androgen-independent prostate cancer
patients.
 The rate of PSA increase over time is PSA velocity (PSAV)
 It is the PSA difference divided by the number of years.
 Typically as ng/mL/year.
 It has been shown that a PSA velocity of 0.75 ng/year or
greater is a strong predictor of cancer with a specificity of
95%.
 It has also been proven that PSA velocity may be a useful
tool in predicting prostate cancer risk and need for biopsy
when PSA levels are in between 2-4 ng/mL
II. URINE MARKERS
A. URINE PROSTATE CANCER ANTIGEN 3
 Prostate cancer antigen 3 (PCA3) is a prostate-specific gene
that is an average 66 times overexpressed in prostate cancer
cells compared with normal prostate cells.
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 Assays were developed to measure the relative amount of PCA3
RNA over PSA RNA using quantitative reverse transcription-PCR
or direct RNA amplification.
 Aptima PCA3 Assay – an assay based on the principle of
target capture followed by transcription-mediated amplification
and uses calibrators to quantify PCA3 and PSA RNA copy
number to provide a PCA3 score (ratio of PCA3 RNA/PSA
RNA).
 Specificity ranges from 71% to 80%; Sensitivity ranges from 50%
to 61%.
 PCA3 has the advantage compared with PSA, that it is
independent of prostate volume, because PCA3 is correlated
with tumor volume, and may even predict extracapsular tumor
extension.
B. URINE HYPERMETHYLATED GLUTATHIONE S-
TRANSFERASE pi 1 GENE
 DNA hypermethylation has been demonstrated to be one of the
most common molecular alterations in prostate cancer
Patho Title of Lecture
 More than 90% of cancers have hypermethylated promoters
in one or more genes.
 Specificity is up to 98%; sensitivity is up to 75% in prostate cancer
 Higher frequency of GSTP1 methylation in the urine of men with
stage III vs. II disease suggests increased frequency of
hypermethylation with increased stage.
C. URINE FUSION GENE VARIANTS
 A family of new genes resulting from the fusion between the
androgen-regulated transmembrane serine protease gene
(TMPRSS2) with genes members of the E26 transformation-
specific (ETS) family of oncogenes was made using a new
biostatistical method called cancer outlier profile analysis.
 The TMPRSS2– E26 transformation specific-related gene (ERG)
fusion transcripts have been identified in 40%–80% of prostate
cancers.
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