Co-expression and impact of

prostate specific
PSA is a 33 kDa glycoprotein of the
kallikrein family of proteases [19]. It is found in normal,
hyperplastic and malignant prostate tissue, and is not
specific biomarker for PC [20]. It is secreted into the
lumen of prostatic duct to liquefy the seminal coagulum
[21]. In invasive adenocarcinomas, disruption of the normal
glandular architecture and loss of the polarity of
prostatic cells appear to allow PSA increased direct leakage
into peripheral circulation [22]. PSA is the most
widely used serum marker for the diagnosis and followup
of PC [23]. Unlike serum PSA, there are drawbacks
to use tissue PSA, like for example, the loss of expression
of tissue PSA associated with advanced disease and
the development of androgen-independent prostate cancer
(AIPC) [20,24].

Protein Specific Antigen (PSA) merupakan glikoprotein berukuran 33 kilo dalton (kDA)
yang termasuk dalam golongan protease kallikrein. PSA terdapat pada jaringan prostat
normal, hiperplasia dan maligna(kanker). PSA disekresikan melalui lumen kelenjar(ductus)
prostat ke dalam cairan sperma. Pada kanker prostat adenocarcinoma yang invasif, rusaknya
kelenjar dan jaringan prostat dapat menyebabkan kenaikan kadar PSA yang dilepaskan ke
peredaran darah perifer. Kadar PSA pada serum paling sering digunakan sebagai
penanda(marker) dalam mendiagnosis dan mengetahui efek terapi kanker prostat. Berbeda
dengan kadar PSA pada serum, hilangnya ekspresi PSA pada jaringan prostat menandakan
perkembangan kanker prostat yang lebih parah yaitu kanker prostat yang sudah tidak
bergantung lagi dengan androgen atau Androgen Independent Prostate Cancer (AIPC).
PSA is highly expressed in hyperplastic
tissues. This is in part, thought to be due to the
differences observed in several biological features
between peripheral and transition zone of the prostate
gland [2]. Although, the majority of the glandular tissue
in prostate is located in the peripheral zone, the PSA
tissue is secreted at higher levels by benign prostate
epithelium arising exclusively in the transition zone
compared to prostate cancer developing mainly in peripheral
zone [36,22].

Tingkat ekspresi PSA yang tinggi terjadi pada jaringan prostat yang mengalami hiperplasia.
Walaupun kelenjar prostat terdapat pada zona perifer, ekspresi PSA yang tinggi ini terdapat
pada epitel prostat di zona transisi. Hal tersebut berbeda dengan kanker prostat dengan
ekspresi PSA yang tinggi pada zona perifer.

From pro-prostate specific antigen

PSA menjadi penanda tumor (tumor marker) pertama yang disetujui lembaga Food and Drug
Administration (FDA) di Amerika Serikat untuk deteksi dini kanker prostat dan banyak digunakan di
seluruh dunia. Padahal, pada perkembangannya PSA tidak pernah bisa menjadi marker terbaik untuk
mendeteksi kanker prostat. Hal tersebut disebabkan oleh rendahnya spesifitasnya terutama pada kadar awal
PSA serum antara 4ng/ml 10ng/ml. Peningkatan kadar PSA yang bisa menjadi penanda tumor hanya
pada kadar awal PSA serum 4ng/ml. Fakta ini karena rusaknya membran basal epitel prostat dapat
meningkatkan kadar PSA serum. Kerusakan membran basal prostat tidak hanya terjadi pada kanker prostat,
tetapi juga terjadi pada tumor jinak prostat dan trauma fisik pada prostat.
rostate specific antigen (PSA) is the first USA Food
and Drug Administration (FDA)-approved tumor
marker for early detection of prostate cancer (PCa) and it
is now in widespread clinical use.1-3 The widespread use
of PSA screening has had a tremendous impact on all
aspects of the management of PCa. However, PSA has
never been a perfect marker for the detection of PCa. One
of the main drawbacks of PSA is its low specificity and
low positive predictive value, especially when PSA level
ranges between 4 ng/ml and 10 ng/ml.4-6 This makes it
very hard to find an universal appropriate diagnostic
cut-off point, not to mention biopsy-detected PCa (in
some cases, high-grade cancers included) is not rare
(approximately 15.2%) among men with PSA levels
lower than well-accepted cut-off point 4 ng/ml.7 This lack
of specificity is partially due to one biologic fact that
destruction of the basement membrane of epithelial cells
of the prostate may result in excessive escape of PSA into
the circulation. Thus, PCa, benign prostate diseases, as
well as physical trauma of the prostate, can result in
significant increases of serum PSA.8 On the other hand,
application of PSA-based screening for over a decade has
resulted in a stage migration to more organ-confined
tumors at the time of diagnosis and lower but more
irrelevant PSA levels.

Penemuan bentuk molekul PSA yang lain pada serum di tahun 1990an mampu meningkatkan
spesifitas PSA sebagai penanda pasti kanker prostat. PSA berada pada serum dalam bentuk
bebas atau free PSA(fPSA) dan berikatan dengan molekul lain atau complexed PSA (cPSA).
PSA serum sebesar 70 90 % berikatan dengan protease inhibitor membentuk cPSA.
Protease inhibitor tersebut adalah alpha1-antichymotrypsin (PSA-ACT),10-12 alpha2-
macroglobulin (PSA-A2M), and alpha1-protease inhibitor (PSA-API). fPSA akan lebih
meningkat pada tumor jinak prostat dibanding pada kanker prostat. Nilai
Rasio(perbandingan) fPSA dan total PSA dapat digunakan untuk mendiagnosis kanker prostat
dengan spesifitas lebih baik, sehingga dapat mengurangi biopsi yang tidak perlu. Peningkatan
kadar PSA serum dapat menjadi penanda kanker prostat jika rasio fPSA dan PSA total 0,15-
0,25 dengan kadar awal PSA total 4-10 ng/ml.
fPSA pada serum terdiri atas:
1. Proenzyme PSA atau prekursor PSA (pPSA) yang berhubungan dengan adanya
kanker prostat. Kadar normal proPSA serum adalah 33 % dari fPSA.
2. Benign PSA (BPSA) yaitu PSA yang sudah sedikit terdegradasi dan berhubungan
dengan adanya Benign Prostat Hyperplasia (BPH). Kadar normal BPSA serum adalah
28 % dari fPSA.
3. Inactive atau intact PSA (iPSA)yaitu PSA yang tidak aktif lagi. Kadar normal iPSA
serum adalah 39 % dari fPSA.
pPSA disekresikan oleh epitel prostat berupa 244 asam amino ke dalam lumen kelenjar
prostat. pPSA ini akan diubah menjadi PSA mature oleh enzim human kallikreins (hK)-2, hK-
4 dan hK-216 dengan melakukan post translasi proteolitik 7 asam amino awal pPSA. Hasil
degradasi tersebut yang menjadi mature PSA adalah -1 pPSA,-2pPSA,-4pPSA,-5pPSA dan
-7pPSA, sedangkan -3pPSA dan -6pPSA belum ditemukan dalam serum.
Figure 1, PSA is normally secreted from the prostate
luminal epithelial cells as proPSA, an inactive proenzyme
containing a 244-amino acid, seven additional amino acid
pro-leader peptide compared to 237 amino acids of
mature PSA. Immediately after its release into the lumen,
the pro-leader part is removed and converted to its active
form by the effect of human kallikreins (hK)-2 and hK-4.
Partial removal of this leader sequence has led to the
identification of other truncated forms of proPSA.
Truncated PSA refers to proPSA in which any of the
normal seven amino acids in the pro-leader peptide have
been removed. Thus, theoretically seven isoforms of
proPSA should exist. However, only [1], [2], [4],
[5], [7]pPSA were found in the serum of men. There is
still no evidence of [3], [6]pPSA existence.19-21 The
truncated forms of proPSA are assumed to result from
post-translational proteolytic cleavage of the pro-leader
peptide. All forms of truncated proPSA containing any of
the pro-leader amino acids remain enzymatically inactive.
The pro-leader peptide of proPSA isoforms is removed
extracellularly to produce active, mature PSA. Other
prostate-localized kallikreins such as hK216 or prostin17
are considered to be responsible for the conversion and
activation of proPSA. The conversion of proPSA to PSA
is very efficient, and no proPSA forms have been found
in the seminal plasma.
The
discovery of different PSA molecular forms in the serum
in the early 1990s renewed clinical research to enhance
the specificity of PSA. PSA circulates in the serum in free
and complex forms (Figure 1). About 70%90% of PSA
that leaks into the serum is complexed with serum
protease inhibitors, which is termed as complexed PSA
(cPSA). cPSA is bound to protease inhibitors such as
alpha1-antichymotrypsin (PSA-ACT),10-12 alpha2-
macroglobulin (PSA-A2M), and alpha1-protease inhibitor
(PSA-API). Approximately, 65%95% of the PSA is
bound to ACT (PSA-ACT) whereas free PSA represents,
on an average, only 5%35% of the total PSA (tPSA).13-15
The relative amount of free PSA tends to be increased in
benign disease compared to PCa. The ratio of free PSA
(fPSA) to total PSA (%fPSA) is being used routinely to
increase specificity for PCa and to reduce unnecessary
biopsies.16,17 However, there is no significant
improvement in detection of PCa when %fPSA varies
from <15% to >25% with total PSA values between 4.0
and 10.0 ng/ml. Diagnostic grey zone still exists. It has
been an urgent need to find new serum markers that at
least linked to PCa or even better, helped in the prognosis
and grading of this ubiquitous disease.

Ekspresi -5 pPSA dan -7 pPSA) pada jaringan kanker prostat dan prostat normal tidak berbeda secara
signifikan. (-2)pPSA lebih tinggi diekspresikan pada kanker prostat daripada prostat normal. Ekspresi
pPSA pada zona perifer dan transisi juga tidak berbeda secara signifikan.

Chan et al29 applied specific mABs to proPSA to perform

immunohistochemical staining (IHS) on specimens of
prostate needle biopsies showing high-grade prostatic
intraepithelial neoplasia (HGPIN, 22 sections),
adeno-carcinoma (30 sections), 17 radical prostatectomy
and three open prostatectomy specimens identified from
the surgical pathology files of Johns Hopkins Hospital.
Their results confirm that the [5/7]pPSA mAB showed
little difference between cancer and benign glands, and
the mAB to [2]pPSA stained cancer tissue more strongly
than benign tissue. Benign atrophic glands often showed
negative or weak/patchy staining. No difference was
found in the staining pattern between benign glands in the
peripheral zone and transition zone. This study is the first
one to demonstrate that mABs to proPSA can be used as
specific IHS for benign and malignant prostatic tissues.
Their results suggest that [2]pPSA appears to be
preferentially more concentrated in cancer tissue than in
benign glands, correlating with previous tissue extract
studies.29

Immunohistochemical Detection of
Prostate-specific
Antigen Expression in Primary Urothelial
Carcinoma of the Urinary Bladder
PSA merupakan protease serine yang disekresikan oleh epitel prostat dan jaringan lainnya
seperti pada epitel periuretral, kelenjar perianal dan kelenjar cowper. PSA berfungsi untuk
mencairkan cairan seminalis agar sperma dapat diejakulasikan. Ekspresi PSA pada jaringan
tumor secara imunohistokimia dapat mengidentifikasi kanker metastase dari kanker prostat.
Prostate-specific antigen (PSA) is a 33-kDa serine protease
that is secreted by prostatic epithelium and non-prostate
tissues, such as epithelial lining of the periurethral and
perianal glands, urachus remnant and cowpers glands (1). It
functions in the liquefaction of seminal coagulum to allow
the release of spermatozoa. Because of its role in the
detection and prognosis of prostate cancer, PSA remains the

only serum biomarker recommended by the American

Cancer Society for use in the screening of malignancies (2).
In addition, immunohistochemical analysis of PSA
expression in tumor tissue is generally successfully applied
in the identification of the prostatic origin of metastatic
carcinoma (3) and the distinction between poorly
differentiated prostatic cancer and urothelial carcinoma in the
bladder neck region (3-5).

Despite fact that PSA may be a specific marker for

prostatic differentiation (3-5), ectopic expression of PSA has
been reported in a variety of non-prostatic tumors (6-16),
most commonly in breast cancer (6-9) and salivary gland
neoplasms (10-12). Other non-prostatic tumors reported to
express PSA include adenocarcinoma of the urinary bladder
(13), melanomas (14), acinar cell carcinoma of the pancreas
(15) and lung cancer (17, 18). Interestingly, Mai et al.
demonstrated a phenotypic alteration in the urothelial
carcinoma of the bladder when it spreads into the prostate.
All ten primary urothelial tumors of urinary bladder were
negative for PSA, whereas six tumors invasive to the prostate
were focally positive (19). Urothelial cancer cells thus might
exhibit PSA expression through mesenchymalepithelial
interaction in the prostatic stroma.

Selain itu ekspresi PSA pada jaringan juga terjadi pada kanker payudara, kelenjar saliva,
kandung kemih, melanoma, acinar penkreas dan paru-paru.

PSA merupakan penanda kanker prostat yang paling sering digunakan.

PSA is the most important and clinically useful marker for
prostate cancer. In non-prostatic tissues, however, ectopic
expression of PSA has been observed in anal glands of male
patients, urethral glands, cystitis cystica/glandularis, and in
a minority of nephrogenic adenoma of the prostatic urethra
(6-16). The non-prostatic neoplasms reported to express
PSA include breast cancer (6-9), salivary gland neoplasms
(10-12), adenocarcinoma of the urinary bladder (13),
melanomas (14), acinar cell carcinoma of the pancreas (15)
and lung cancer (17, 18).
In this cohort study, cytoplasmic expression of PSA was
observed in some large, invasive urothelial tumors. Such
expression, although rare (1.4%), is quite different from that
of prior reports showing absolutely negative staining for PSA
in the urothelial carcinoma of the bladder (4, 5, 19, 23).
Several explanations may account for the discrepancy, such
as differences in the primary antibody used, the efficiency of
antigen retrieval, or the sensitivity of immunostaining

reagents. Mai et al. proposed that mesenchymaepithelial

interaction induced by prostatic stroma may play a role in
the unusual PSA immunoreactivity in bladder lesions (19,
23). This interpretation, however, is not valid in our cases,
since all these PSA-positive urothelial tumors were located
in the posterior, lateral, trigone, or dome areas of the bladder.
In addition, non-mucinous glandular differentiation in
urothelial carcinoma was not included in our study. Thus, the
molecular mechanism underlying PSA expression in
urothelial carcinoma remains to be elucidated.
Tremblay et al. showed that PSA (HK3) antiserum may
cross-react with other members of the kallikrein family,
especially with HK2 (24). This possibility is being tested in
vitro. Alternatively, prostatic differentiation can be detected
in the cystitis cystica/glandularis of the bladder mucosa,
whereas adjacent surface uroepithelium or transitional cell
nests were negative for PSA (16). The phenomenon suggests
a broad metaplastic potential in various differentiated but
embryologically related tissues (16). Therefore, prostatic
differentiation in the urinary tract may not be ectopic or as
rare as previously proposed (25, 26).

Is Prostate-Specific Antigen Velocity Useful in Early

Detection
PSA velocity (PSAV)
Since the beginning of the prostate-specific antigen (PSA) screening
era, PSA velocity (PSAV) has been investigated for its use in early
detection. Over time, our understanding of PSAV has evolved, and
our use of this summary of PSA growth has changed. Early on, the
primary concern about the PSA test was its lack of specificity in
older men and men with benign prostatic hypertrophy (BPH).
Initial studies of PSAV focused on reducing false-positive tests in
these populations. In a well-known analysis of data from stored
serum samples in the Baltimore Longitudinal Study of Aging
(BLSA), Carter et al. ( 1 , 2 ) showed that the PSA growth rate was
higher in cancer patients than in men with BPH and normal prostates
and proposed a PSAV threshold of 0.75 ng/mL per year to distinguish
prostate cancer from BPH in men with elevated PSA levels.
Thus, PSAV was initially used to restrict the definition of a positive
PSA test so as to reduce the likelihood of unnecessary biopsies.
With the passage of time, overdetection and overtreatment
have emerged as the most pressing problems of the PSA screening
era, and substantial effort is being devoted to identifying markers
that will reliably distinguish indolent cancers from those that
should be treated. Although several tissue markers are being studied
closely for their use in guiding treatment decisions following
diagnosis, PSAV is currently under scrutiny as a serum marker that
might be useful even earlier at the point of biopsy referral.
The intense focus on PSAV as a screening biomarker is due to
two recent developments. First, results from the Prostate Cancer
Prevention Trial (PCPT) show clearly that no single PSA cutoff
separates men at high risk of prostate cancer or high-grade disease
from men at low risk ( 3 ). Rather, there is a continuum of risk, and
the frequency of high-grade disease at low PSA levels can be nontrivial.
Second, several recent studies have shown that high prediagnosis

PSA Velocity (PSAV) serum digunakan untuk mendiagnosis kanker prostat terutama pada
kadar awal PSA total serum yang rendah dengan nilai PSAV lebih dari 0,35 ng/ml per tahun.
Selain itu, Nilai PSAV yang lebih besar dari 2 ng/ml per tahun mengindikasikan kanker
prostat dengan prognosis buruk.
PSAV is strongly associated with poor disease-specifi c
survival following diagnosis and have suggested that PSAV may be
useful in identifying those men with low PSA values who are at risk
of harboring a potentially lethal tumor. For example, D Amico
et al. ( 4 , 5 ) found that PSAV greater than 2.0 ng/mL per year in the
year before diagnosis was independently associated with a dramatically
increased risk of prostate cancer death (adjusted hazard ratios
[HRs] = 10 and 12) following treatment with radical prostatectomy
or external beam radiation therapy. In a recent study of BLSA data,
Carter et al. ( 6 ) also found a strong association between survival
and higher PSAV as early as 10 15 years before diagnosis (adjusted
HR = 4 per 1.0 ng/mL per year increase in PSAV). Based on this
fi nding, they proposed that a PSAV threshold of 0.35 ng/mL per
year be used in screening men with low PSA levels to increase
detection of potentially lethal tumors during the window of
curability.

No published study of PSA or PSAV answers the key questions

that must be addressed to determine whether PSAV
is going to be useful in population screening for prostate
cancer.

Even if PSAV differs dramatically between individuals with

and without prostate cancer or between those with lethal and

nonlethal cancers, this does not automatically imply that

PSAV will be useful in early detection of prostate cancer.

Loss of Prostate-specific Antigen Expression in Prostate Cancer

Ekspresi PSA yang tinggi pada kanker prostat berhubungan dengan rendahnya angiogenesis
pada jaringan kanker tersebut. Hal tersebut dapat disebabkan oleh efek PSA atau memang
fenotipe kanker yang nonangiogenic. PSA dapat menyebabkan perubahan Lys-plasminogen
menjadi molekul angiostatin yang menghambat angiogenesis. PSA juga berperan dalam
mengontrol aktivitas proliferasi sel tumor pada tahap awal. Pengontrolan PSA ini akan
terganggu oleh adanya faktor pertumbuhan (growth factor) lainnya seperti integrins dan
adhesion molecules yang dapat menigkatkan PSA serum, pertumbuhan infiltratif sel tumor
dan metastase.
In conclusion, the high PSA expression in prostate cancer
cells that is accompanied by low intratumoral angiogenesis,
could be interpreted as the result of either a direct vascular
suppressive action of PSA, or the coexistence with a nonangiogenic
phenotype. The first hypothesis seems more likely and
confirms the in vitro observation that PSA is able to convert
Lys-plasminogen to biologically active angiostatin-like fragments
that inhibit angiogenesis. The vascular suppressive action
of PSA could explain some of the growth characteristics of
prostate cancer, i.e., the low MVD and the slow proliferation
rate. PSA could, theoretically, play the role of a regulator of the
proliferative activity of prostate cancer in early stages of the
disease. A loss of this controlled balance, that is apparently
maintained by the contribution of other growth factors, like the
integrins and adhesion molecules, could lead to an increase in
PSA levels, tumor growth, and tumor metastasis. It would be
certainly interesting to examine by retrospective analyses in the
future whether serum PSA is of any significance in predicting
tumor response to therapy, knowing that an increased therapeutic
efficacy would be theoretically anticipated because of its
vascular suppressive action. With regard to MUC1, this is an
important molecule, the depolarized expression of which relates
to a high intratumoral angiogenesis in prostate cancer, a fact that
may suggest coactivation of angiogenic and migration pathways
of these parameters in human cancers.

Precursor of prostate-specific antigen

Ekspresi -5pPSA dan -7 pPSA, p63 dan racemase pada HGPIN dan kanker adenocarcinoma
prostat lebih tinggi daripada jaringan prostat normal.
In conclusion, the different staining patterns
for [5/7] pro-PSA in benign and neoplastic
cells might be used in conjunction with high
molecular weight keratin, p63 and racemase
to distinguish BPE from HGPIN and
adenocarcinoma, particularly when racemase
staining is negative. Both isoforms are
sensitive markers for prostatic epithelium,

making them possible candidates for

investigating carcinomas of unknown origin,
particularly in cases in which PSA staining is
negative and the level of suspicion is high. The
expression of [2] and [5/7] pro-PSA
increases incrementally from BPE to HGPIN
and adenocarcinoma, indicating that these
markers might be useful for studying
carcinogenesis of the prostate.

Psa43
Kanker prostat merupakan kanker dengan penderita terbanyak dan penyebab kematian ke 2
akibat kanker di Amerika Serikat. PSA adalah glikoprotein yang termasuk golongan
kallikrein protease serine dan berukuran 34 kDa. PSA dihasilkan oleh epitel jaringan prostat
normal,tumor jinak dan kanker. PSA juga dapat ditemukan pada cairan seminalis, serum dan
urin.
Prostate cancer (PCa) is the most common form of
cancer and the second leading cause of cancer death
among US men, with an incidence of slightly less than
190,000 new cases and mortality of around 29,000 in
20081. Since 1995 the incidence has been increased by
1% annually, whereas mortality decreased by 4%2. International
incidence rates vary more than 65-fold time,
from a low-risk (China) to a high-risk range population
in US1,3.
PSA is a glycoprotein which belongs to the kallikrein
family of neutral serine proteases, weighing approximately
34 kDa4. It is a product of secretion of the prostate
epithelium produced by normal, benign and cancerous
cells5. Moreover, PSA is present in the seminal fluid, serum
and urine6.
Flocks was the first who experimented with the an

antigens
in the prostate7. Thereafter, the presence of the
precipitative antigens in prostate was reported by Ablin
et al8. The first description of PSA referred to a prominent
protein in human seminal plasma as seminoprotein9.
Furthermore, Wang et al purified a tissue-specific antigen
Prostate antigen10, which was at the beginning measured
quantitatively in the blood11.

Pemantauan kadar PSA serum menjadi salah satu faktor yang dapat memprediksi keadaan
patologis yang lebih parah pada kanker prostat dan menjadi pemantau keberhasilan terapi
kanker prostat. Kadar normal PSA serum adalah 0 4 ng/ml. Peningkatan kadar PSA dapat
mengindikasikan adanya kanker prostat. Walaupun demikian, tidak adanya peningkatan kadar
PSA juga bisa terjadi pada kanker prostat. Peningkatan kadar PSA serum juga bisa
disebabkan oleh infeksi, iritasi dan hiperplasia pada prostat.
As a screening tool PSA is known predictive factor of
adverse pathologic findings12 and outcome after primary
treatment13,14. Normal PSA levels are defined as between
0-4.0 ng/ml15. Increased levels of PSA may suggest the
presence of prostate cancer. However, prostate cancer can
also be present in the complete absence of an elevated
PSA level, in which case the test result would be a false
negative16. PSA levels can be also elevated due to the
prostate infection, irritation, benign prostatic hypertrophy

(BPH), i.e. enlargement or recent ejaculation17, in which

cases it may again give false positive results18.

To distinguish the condition between BPH and prostate

cancer (in order to minimize unnecessary biopsies in
men without cancer) and slow the fast growing cancers,
various PSA markers have been used: PSA velocity, ageadjusted
PSA, PSA density (PSAD) and free versus attached
PSA.

PSA density (PSAD) dihitung nilainya dengan membagi PSA serum dengan volume prostat
yang diukur dengan transrectal ultrasonography. PSAD menjadi salah satu penentu prognosis
dan pemantau keberhasilan terapi kanker prostat.
The PSA density can be calculated when the PSA value
in ng/ml is divided by the prostate volume measured by

transrectal ultrasonography (US-PSAD), or by its weight

measured from the prostatectomised specimens in grams
(PW-PSAD). However, the goal should be to improve the
specificity of PSA testing for prostate cancer screening, at
the same time preserving its sensitivity19

Concluding the incorporation of the PSAD into the

work-up for the risk assessment might provide useful
prognostic information in addition to the grade, stage
and PSA level in patients with prostate cancer. Prostate
specific antigen density measurements can be useful in
determining the aggressiveness of the clinically localized
prostate cancer, and might be used as an adjunct in
predicting insignificant cancers, their outcome after local
therapy and further prognosis of the patients.
The PW-PSAD is not clinically useful to predict the
adverse pathologic features, since in this case the prostate
has already been removed. The strong correlation
between US-PSAD and PW-PSAD strongly suggests the
usefulness of the US-PSAD as a prognostic tool in the
treatment and follow up of the prostate cancer.

Role of Prostate-Specific Antigen Change Ratio at

Initial Biopsy as
Rasio (perbandingan) kadar PSA serum sesudah biopsi dan sebelum biopsi (PSA change
ratio) pada biopsi pertama dapat menjadi penanda kanker prostat. Jika PSA change ratio 3
4, maka dapat diindikasikan adanya kanker prostat. Jika PSA change ratio kurang dari 3,
maka biopsi ulang harus dilakukan untuk memastikan diagnosis.
PSA change ratio is thought be a predictive factor for prostate cancer. If
the PSA change ratio was less than 3.0-4.0, repeat biopsy should be considered to confirm
the diagnosis.

Psa35

Although baseline PSA value and rate of PSA change are prognostic factors for lethal prostate cancer,
they are poor predictors of lethal prostate cancer among patients with localized prostate cancer who are
managed by watchful waiting

psa 32

PSA double time (PSADT) adalah waktu yang dibutuhkan untuk terjadinya peningkatan
kadar PSA serum sebanyak 2 kali kadar PSA serum awal. Nilai PSADT yang singkat (< 3
bulan) paska terapi kanker prostat menunjukkan kegagalan terapi. Nilai PSADT lebih dari 15
bulan menunjukkan keberhasilan terapi kanker prostat dengan prognosis baik. Walaupun
demikian, penentuan keberhasilan terapi dan prognosis tetap tidak bisa hanya berdasarkan
PSADT saja. Penilaian gleason score (histopatologi) harus tetap dilakukan bersama PSADT.
Regardless of the definition of failure used, or
the method by which PSADT is calculated,
PSADT has been shown to be significantly
associated with the time to metastases
and cancer-specific death. The optimum
thresholds for PSADT for clinical decisionmaking
continue to be investigated, and a
single threshold is unlikely for all cases.
However, the currently available data suggest
that PSADT is most useful at the ends of the
spectrum. An extremely short PSADT after
therapy (e.g.

3 months) is associated with

significantly worse clinical outcomes, whereas
patients with a relatively long PSADT (e.g.

15 months) are unlikely to die from their

disease. While PSADT is a significant predictor
of outcomes, it should be incorporated with
other important clinical and pathological
factors, e.g. the Gleason score, to optimally
assess the prognosis for the individual
patient.

Psa27

PSA velocity enhanced the detection of high-grade cancer in men

who had PSA levels >4 ng/mL. These findings, in conjunction with life expectancy,
may be used when deciding which men should not be recommended for
prostate biopsy despite a PSA level >4 ng/mL.

Psa24
Prostate cancer is the second most frequently diagnosed cancer of men (899 000 new cases, 13.6% of the total)
and the fifth most common cancer overall. Nearly three-quarters of the registered cases occur in developed
countries (644 000 cases). Incidence rates of prostate cancer vary by more than 25-fold worldwide, the highest
rates are in Australia/New Zealand (104.2 per 100,000), Western and Northern Europe, Northern America, largely
because largely because the practice of prostate specific antigen (PSA) testing and subsequent biopsy has
become widespread in those regions. Incidence rates are relatively high in certain developing regions such as
the Caribbean, South America and sub-Saharan Africa. The lowest age-standardised incidence rate is estimated
in South-Central Asia (4.1 per 100,000).
With an estimated 258 000 deaths in 2008, prostate cancer is the sixth leading cause of death from cancer in
men (6.1% of the total). Because PSA testing has a much greater effect on incidence than on mortality, there is
less variation in mortality rates worldwide (10-fold) than is observed for incidence (25-fold), and the number of
deaths from prostate cancer is almost the same in developed and developing regions. Mortality rates are
generally high in predominantly black populations (Caribbean, 26.3 per 100,000 and sub-Saharan Africa, ASRs
18-19 per 100,000), very low in Asia (ASR 2.5 per 100,000 in Eastern Asia for example) and intermediate in
Europe and Oceania.

The incidence of prostate cancer in different parts of

the world differs quite markedly (GLOBOCAN, 2002).
The factors responsible for the differences remain unclear.
The age-standardized rates (world standard) of the
incidence of prostate cancer could range from 124.8 and
90.9 per 100,000 in USA and Sweden, respectively, to
12.6 per 100,000 in Japan and 1.7 per 100,000 in China
(GLOBOCAN, 2002). Although the incidence of prostate
cancer in Singapore is not as high as that of the USA or
the Nordic countries, it is on the rise. Prostate cancer is
now the fifth most frequent cancer among Singaporean
males, and the incidence has been increasing steadily over
the last 35 years. The average annual rate of increase
between 1968 and 2002 was 5.6%, with the last 10 years
having seen a relatively steeper increase. The age-adjusted
risk of this cancer in 1998-2002 was 17.4 compared to
4.2 per 100,000 in 1968-1972 (Seow et al., 2004). What
could be the factors that could have contributed to this
increase especially after the 1990s? One possible reason
could be the use of the prostate-specific antigen

psa17

Tingginya kadar PSA serum terendah (nadir level) dan singkatnya waktu yang dibutuhkan
untuk mencapai kadar PSA serum terendah setelah terapi blokade maksimal androgen (MAB)
berhubungan dengan tingginya progesivitas dan prognosis buruk kanker prostat.

Our results suggest that higher PSA nadir level and shorter TTN following
MAB are associated with higher risk of disease progression and poorer survival in patients
with metastatic, hormone-sensitive prostate cancer. Furthermore, these two
variables have a synergistic effect on the outcome.

Psa16

Biopsi ulang harus dilakukan pada kadar PSA serum yang tidak berubah atau meningkat,usia tua,
volume prostat yang kecil dan nilai PSA density yang tinggi.

The second biopsy is strongly recommended when PSA level shows no

change or increase, age is older, prostate volume is smaller or PSA density is higher

psa11

Rendahnya protein dan tingginya lemak pada makanan yang dikonsumsi menimbulkan
kenaikan kadar PSA.

a lower percent protein intake and higher percent fat intake

had an elevated PSA level, although the magnitude of these
associations was small

psa22

Kadar testosterone serum tidak berhubungan dengan peningkatan PSA, resiko kanker prostat
dan agresivitas kanker prostat.

serum testosterone at the time of diagnosis was

unrelated to PSA elevation, prostate cancer risk, and aggressiveness

psa25

Skrining kadar PSA serum tidak terbukti dapat mendiagnosis secara dini kanker prostat.
In a nationally representative sample, we
found that despite the lack of clear evidence of benefit,
PSA testing for prostate cancer screening has increased
dramatically, especially among black men and younger
men.
Arch Intern Med. 2007;167

Psa27

PSA velocity enhanced the detection of high-grade cancer in men

who had PSA levels >4 ng/mL. These findings, in conjunction with life expectancy,
may be used when deciding which men should not be recommended for
prostate biopsy despite a PSA level >4 ng/mL.

Peningkatan nilai PSAV sebelum diagnosis berhubungan dengan kanker prostat derajat tinggi
pada kadar PSA serum awal < 3ng/ml. Peningkatan tersebut juga mengindikasikan adanya
invasi kanker prostat pada vesikal seminalis dan kelenjar getah bening pada pelvis.
It has been demonstrated that a change in the
serum PSA level during the year before diagnosis
(PSA velocity) is associated significantly with adverse
pathologic factors, including high-grade cancer identified
at prostatectomy, seminal vesicle invasion,
positive pelvic lymph nodes, time to PSA recurrence,
and prostate cancer-specific and all-cause mortality
after surgery5 or after external beam radiation therapy.
6 However, although a change in the PSA level
during the year before diagnosis had clinical utility
as a prognostic factor, PSA velocity did not contribute
independent information for the prediction of
high-grade disease in men from the Prostate Cancer
Prevention Trial, in which the PSA level at study
entry study was required to be <3 ng/mL.7

These findings differ from early studies of PSA

velocity in men with higher PSA levels, in whom
higher PSA velocity was a strong predictor of newly
diagnosed prostate cancer.8,9 A recent report from
the Prostate, Lung, Colorectal, and Ovarian Cancer
Screening Trial indicated that there was a significant
association between PSA velocity and the presence of
cancers with Gleason scores from 7 to 10 among
men who were diagnosed with cancer.10 However,
the association of PSA velocity in men with higher
PSA levels in conjunction with detection of highgrade
cancer has not been assessed among men who
have not yet been diagnosed with cancer.

Psa31

Biopsi berulang juga dapat menyebabkan peningkatan kadar PSA serum tanpa adanya kanker
prostat. Hal ini membuktikan prosedur biopsi berulang pada peningkatan kadar serum PSA
sampai ditemukannya gambaran histopatologi kanker prostat adalah salah. Hasil normal
pemantauan (skrining) kadar PSA serum juga sering membuat kanker prostat tidak terdeteksi.
Repeat biopsies also exacerbate this verification bias. When
a biomarker is tested, there are positive test results for individual
patients in whom, at biopsy, no disease is found. This is a
major problem for this subpopulation: men screened for prostate
cancer who test positive for a biomarker but have a negative
biopsy result are likely to undergo multiple repeat biopsies
during follow-up. Rarely are biomarker studies updated with
respect to these later events. A more insidious predictive bias
involves those people whose biomarker (e.g., PSA) findings
are elevated. These men often undergo a biopsy and, if the
result is negative, also often undergo many biopsies over the
ensuing years. Because the likelihood of cancer detection is
directly related to the degree of prostate sampling, an elevated
PSA level leads to repeated biopsies until cancer is found. In
contrast, a PSA measurement in the normal range results in
less frequent ascertainment and a higher risk of a missed cancer
diagnosis.

Deteksi dini kanker prostat berdasarkan kadar PSA serum lebih tepat pada ukuran volume
prostat yang kecil.
Moreover, the size of the prostate gland (i.e., its volume)
varies from patient to patient. Successful cancer detection is
more likely in a smaller than a larger prostate; this produces a
bias in the evaluation of PSA screening that is related to the
presence and size of the cancer as well as the size of the
prostate itself.25

psa32

Regardless of the definition of failure used, or

the method by which PSADT is calculated,
PSADT has been shown to be significantly
associated with the time to metastases
and cancer-specific death. The optimum
thresholds for PSADT for clinical decisionmaking
continue to be investigated, and a
single threshold is unlikely for all cases.
However, the currently available data suggest
that PSADT is most useful at the ends of the
spectrum. An extremely short PSADT after
therapy (e.g.

3 months) is associated with

significantly worse clinical outcomes, whereas
patients with a relatively long PSADT (e.g.

15 months) are unlikely to die from their

disease. While PSADT is a significant predictor
of outcomes, it should be incorporated with
other important clinical and pathological
factors, e.g. the Gleason score, to optimally
assess the prognosis for the individual
patient

psa expression 7

Reseptor androgen (AR) diekspresikan pada tumor primer dan metastase kanker prostat. AR
akan mengaktifkan ekspresi gen yang berpengaruh pada pertumbuhan,difrensiasi dan
pengontrolan pertumbuhan epitel prostat. PSA merupakan serine protease mirip chymotrypsin
yang ekspresinya juga diaktifkan oleh AR. Ekspresi PSA terdapat pada jaringan prostat
normal. Ekspresi PSA meningkat pada hiperplasia dan radang prostat (prostatitis). Setelah
berikatan dengan androgen, AR berpindah menuju nukleus untuk berikatan dengan Androgen
Responsive Elements (ARE) pada promoter gen PSA.
The AR is found to be expressed in the
majority of prostate cancer samples, both the primary and
metastatic sites, and also including those with androgenrefractory
status. The AR activates gene expression that is
involved in the growth, differentiation, and maintenance of
prostate epithelium. Prostate-specific antigen (PSA), a chymotrypsin-
like serine protease, is a well-known AR-regulated gene
in the human prostate gland and is often increased in
hyperplastic and inflammatory lesions (4, 5). PSA has the
ability to cleave proteins that affect cell migration and
metastasis. Currently, serum PSA is widely used as a marker
for the diagnosis of prostate cancer and disease progression.
Upon binding to androgen, the AR translocates into the nucleus
and binds to the androgen responsive elements (ARE) on the
PSA promoter. In addition to the PSA gene, the expression of
several other genes has been found to be up-regulated via ARmediated
signaling in prostate cancer (3). Prostate cancer
therapy is dependent on the stages of the tumor and AR
expression.

PSA mampu merusak glikoprotein matriks ekstraseluler seperti fibronectin dan laminin
yang membuat sel tumor bisa bermigrasi dan bermetastase. PSA dapat mengaktifkan
urokinase-type plasminogen activator yang juga memperkuat kemampuan sel tumor untuk
berinvasi. Pada kanker prostat, Hypoxia Inducible Factor (HIF-1) bersama AR dapat
meningkatkan ekspresi PSA untuk meningkatkan progresifitas sel tumor.
PSA can cleave proteins that affect cell migration and
metastasis (3). For instance, PSA has the capacity to cleave
extracellular matrix glycoproteins such as fibronectin and
laminin and facilitate prostate cancer cell invasion (39). PSA
can cleave and activate the urokinase-type plasminogen
activator, which enhances tumor cell invasion (40). In prostate
cancers, HIF-1 might cooperate with the AR to activate the
expression of PSA and then facilitate prostate cancer invasion
and progression.

Urutan letak gen PSA adalah (KLK-1)-(PSA)-(hGK-1) sepanjang 60kb pada 19q13.2-13.4.
Gen hGK-1 juga diekspresikan pada prostat dan berjarak 12 kb dari gen PSA. Gen KLK-1
diekspresikan pada pankreas dan ginjal dan berjarak 31 kb dari gen PSA.
The
PSA gene is a member of the human kallikrein gene
family. Further members of the kallikrein gene family
are the hGK-1 gene, which is also expressed in the
prostate, and the tissue kallikrein gene (KLK1), which
is expressed in the pancreas and kidney (36). The
three genes are clustered in the order [KLK-1]-[PSA]-
[hGK-1], in an area of 60 kb on human chromosome
19q13.2-13.4 (7). The PSA and hGK-1 genes are separated
by 12 kb; the distance between KLK1 and PSA,
which are transcribed from opposite strands, is approximately
31 kb (7). PSA expression does not only
show cell-specificity, but is also tightly regulated by
androgens, as mediated by the androgen receptor
(AR) (812). The strong tissue specificity makes the
PSA promoter a good candidate through which to
deliver therapeutic genes in prostate cancer.

Androgen Respon Elements (ARE) merupakan binding site AR dan berada pada proksimal
promoter gen PSA.
Two functionally active AR-binding sites (androgen
response elements or AREs) were identified in the
proximal PSA promoter, at positions 2170 (ARE-I) and
2394 (ARE-II), respectively (11, 13). Although the
proximal PSA promoter, including ARE-I and ARE-II, is
more active in LNCaP prostate cells than in nonprostate
cells, its activity is relatively low. This low level of
activity suggested that the proximal PSA promoter is
not sufficient to account completely for androgen regulation
of the endogenous PSA gene, as observed in
LNCaP cells (11).

Psa expression 3

PSA merupakan serine protease mirip chymotrypsin yang disintesis pada jaringan prostat
normal, hiperplasia dan kanker.
ARE-I dan ARE-II terletak pada proksimal promotor gen PSA, sedangkan ARE-III terletak
pada 24 kb dari promotor gen PSA. ARE-III ini merupakan enhancer element core (AREc)
yang penting dalam ekspresi PSA.
Prostate-specific antigen (PSA)1 is a chymotrypsin-like serine
protease synthesized primarily by normal, hyperplastic

and malignant prostatic (13). PSA expression is tightly regulated

by androgen through the action of androgen receptor (AR)
(2, 4, 5). Upon binding to androgen, AR translocates into the
nucleus and binds to the androgen response elements (AREs)
on the PSA promoter, where it interacts with other transcription
factors and activates PSA gene transcription. Cleutjens et
al. (6, 7) have identified three AREs within the 5.8-kb PSA
promoter. ARE-I and -II are located within the proximal region
of the promoter, whereas ARE-III is contained within a 440-bp
strong enhancer element core (AREc) located at 24.2 kb of the
promoter (79). Recently, additional non-consensus AREs have
been identified within the AREc enhancer element. This study
proposes that androgen regulation of the AREc in prostate cells
might involve the formation of AR and prostate-specific factor
nucleoprotein complexes on the multiple non-consensus AREs
in the enhancer region (10).

Kadar PSA serum akan meningkat kembali pada kanker prostat yang sudah tidak terpengaruh
oleh androgen (Androgen Independent Prostate Cancer). Kondisi ini terjadi karena adanya
mutasi atau amplifikasi AR yang tidak lagi spesifik hanya berikatan dengan androgen. Selain
itu, aktivasi AR dapat dilakukan oleh like insulin-like growth factor-1 dan keratinocyte
growth factor.
PSA is a serum marker for prostate cancer. It has been
shown that serum PSA is proportional to tumor volume and
correlates positively with the clinical stage of the disease (11).
Progression of prostate cancer to androgen independence is
commonly associated with a rebound of serum PSA (12). PSA
elevation in hormone-refractory prostate tumors has been attributed
to: 1) mutations and/or amplifications of AR (1318)
that broaden its ligand specificity and/or enhance tumor cells
responsiveness to androgen, respectively (19); 2) androgenindependent
(AI) activation of the AR by growth factor signaling
pathways like insulin-like growth factor-1 and keratinocyte
growth factor, which would elicit AR-mediated transcriptional
activation (20, 21).

Psa13
Tingkat ekspresi AR oleh androgen dipengaruhi oleh polimorfisme CAG repeat pada gen AR.
Semakin pendek CAG repeat akan meningkatkan ekspresi AR yang berhubungan dengan
tingginya resiko terjadinya kanker prostat. Adanya genotip alel G/G pada gen AR juga
meningkatkan resiko terjadinya kanker prostat. PSA memiliki 2 efek yang berlawanan dalam
proses karsinogenesis kanker prostat yaitu meningkatkan proliferasi sel dan menghambat
angiogenesis.
As androgens are critical for the development and progression
of prostate cancer, Coetzee and Ross (18) had hypothesized
that variation in transcriptional activity by the AR related to
polymorphic CAG repeats influences prostate carcinogenesis.
They suggested that smaller CAG repeats might be associated
with a higher level of receptor transactivation, thereby increasing
the risk of prostate cancer.

the G/G genotype was associated with more advanced

disease. Our data support the hypothesis of an ambivalent role

of PSA during prostate carcinogenesis (13,14). PSA seems to

have both stimulatory effects on prostatic cell proliferation
(13) as well as anti-angiogenic properties (14).

PSA sebagai IGFBP-3 protease dapat meningkatkan IGF-I dan IGF-II yang mampu
merangsang proliferasi sel prostat. Polimorfisme adenin atau guanin gen PSA terutama pada
ARE-I berpengaruh pada perbedaan resiko terjadinya kanker prostat, karena perbedaan
affinitas AR terhadap adenin dan guanin. Polimorfisme guanin gen PSA menurunkan resiko
terjadinya kanker prostat.

Data indicating a role of PSA as an IGFBP-

3 protease, thereby increasing bioavailable IGF-I and IGF-II,
which may have stimulatory effects on prostatic cell proliferation
(13). But on the other hand, PSA may function in tumours
as an anti-angiogenic protein (14).
The PSA expression is regulated by androgens, as mediated
by the AR. At least three AREs have been identified in the
PSA gene promoter, at positions 170 (ARE-I), 394 (AREII)
and approximately 4200 (ARE-III) in a far upstream
enhancer region, respectively. A single nucleotide polymorphism,
an adenine to guanine substitution at position 158 in the
ARE-I sequence of the PSA gene has been described (15). It
has been hypothesized that the AR binds the two PSA alleles
(A and G) with differing affinity and may, thereby, differently
influence prostate cancer risk

the control of PSA

Peran PSA adalah mendegradasi protein seminal dengan berat molekul yang tinggi. PSA juga
berperan dalam pengaturan proliferasi sel prostat dengan meningkatkan kadar insulin like
growth factors.

One of
its roles is to degrade high molecular weight seminal
vesicle proteins that otherwise would form seminal coagulates
(Allhoff et al., 1983; Lilja, 1985; Leo et al.,
1991). Alternatively, it appears to be involved in prostate
growth regulation by cleaving insulin-like growth factor-binding proteins and thereby
increasing the bioavailability
of insulin-like growth factors

Kadar PSA serum sangat kecil dibanding PSA yang dihasilkan prostat. Peningkatan kadar
PSA terjadi jika terjadi kerusakan pada membran basal epitel prostat seperti pada prostatitis,
Benign Prostat Hyperplasia (BPH) dan kanker prostat. Selama ini, kadar PSA serum < 2,5
ng/ml diharuskan melakukan biopsi berulang kali sampai ditemukan gambaran histopatologi
kanker prostat. Padahal 80 % pasien dengan kondisi tersebut tidak pernah menunjukkan
gambaran histopatologi kanker prostat. Kadar PSA serum > 15ng/ml lebih dapat
menunjukkan adanya kanker prostat, tetapi tetap harus didukung oleh pemeriksaan rectal
yang menunjukkan peningkatan ukuran prostat.
Kadar PSA dan bentuk molekul PSA lainnya dalam serum tidak dapat menjadi penanda
(tumor marker) pada deteksi dini dan diagnosis kanker prostat. Kadar PSA serum harus tetap
didukung oleh pemeriksaan lainnya, seperti digital rectal, histopatologis, Magnetic
Resonance Imaging (MRI) dan lain-lain. Pemeriksaan - pemeriksaan tersebut untuk
mencegah adanya biopsi berulang dan overtreatment. Walaupun demikian, kadar PSA dalam
serum tetap menjadi penanda terbaik untuk mengetahui keberhasilan terapi kanker prostat.

Kanker prostat merupakan kanker yang paling sering terjadi pada laki-laki dan urutan
ke 5 kanker dengan angka kejadian tertinggi di dunia. Selain itu, kanker prostat juga berada
pada urutan ke 6 jumlah kematian terbanyak akibat kanker di dunia. 1 Kanker prostat
merupakan keganasan yang paling sering diderita oleh pria di Amerika Serikat dan Eropa.
Pada 10 tahun terakhir terlihat peningkatan insiden kanker prostat, termasuk di Indonesia. 2
Jumlah penderita kanker prostat di Indonesia menjadi yang tertinggi ke 5 diantara jumlah
penderita kanker jenis lainnya yang terjadi pada laki - laki. 1 Kanker prostat juga menjadi
penyebab kematian terbanyak ke 5 pada laki-laki yang mengidap kanker di Indonesia. 1 Oleh
karena itu, pencarian metode medis terbaik untuk deteksi dini, diagnosis dan mengobati
kanker prostat terus dilakukan.