Eble JN, Sauter G., Epstein JI, Sesterhenn IA - iarc

PSA-related diagnostic strategies.
PSA is elevated beyond the arbitrary cutoff
point of 4.0 ng/ml in the majority of
patients with prostate cancer. It may also
be greater than 4.0 ng/ml in some benign
conditions, including benign prostatic
hyperplasia (BPH). Prostate cancer may
also be present in men with serum PSA
values lower than the above quoted cutoff
points. This may be specifically true
for men considered at higher risk (i.e.,
family history; men with faster doubling
time; and in the United States African
American men). Therefore, serum PSA
lacks high sensitivity and specificity for
prostate cancer. This problem has been
partially overcome by calculating several
PSA-related indices and/or evaluating
other serum markers {1660,1775}. PSA
tests are also useful to detect recurrence
and response of cancer following therapy.
The exact value used to define recurrence
varies depending on the treatment
modality.
Free PSA. The free form of PSA occurs
to a greater proportion in men without
cancer {2607} and, by contrast, the α-1-
chymotrypsin complex PSA comprises a
greater proportion of the total PSA in men
with malignancy. The median values of
total PSA and of the free-to-total PSA
ratio are 7.8 ng/ml and 10.5% in prostate
cancer patients, 4.3 ng/ml and 20.8% in
patients with BPH, and 1.4 ng/ml and
23.6% in a control group of men without
BPH {2506}. There is a significant difference
in free-to-total PSA ratio between
prostate cancer and BPH patients with
prostate volumes smaller than 40 cm 3 ,
but not between patients in these two
groups with prostate volumes exceeding
40 cm 3 {2506}.
Complex PSA. Problems associated with
the free-to-total PSA ratio, particularly
assay variability, and the increased magnitude
of error when the quotient is
derived, are obviated by assays for complex
PSA. Complex PSA value may offer
better specificity than total and free-tototal
PSA ratio {308}.
PSA density
This is the ratio of the serum PSA concentration
to the volume of the gland,
which can be measured by transrectal
ultrasound (total PSA/prostatic volume =
PSA density, PSAD). The PSAD values
are divided into three categories: normal
(values equal or lower than 0.050
ng/ml/cm 3 ), intermediate (from 0.051 to
0.099 ng/ml/cm 3 ) and pathological
(equal to or greater than 0.1 ng/ml/cm 3 ).
The production of PSA per volume of prostatic
tissue is related to the presence of
BPH and prostate cancer and to the proportion
of epithelial cells and the histological
grade of the carcinoma {1476}.
PSA density of the transition zone.
Nodular hyperplasia is the main determinant
of serum PSA levels in patients with
BPH {139,109,1521}. Therefore, it seems
logical that nodular hyperplasia volume
rather than total volume should be used
when trying to interpret elevated levels of
serum PSA. PSA density of the transition
zone (PSA TZD) is more accurate in predicting
prostate cancer than PSA density
for PSA levels of less than 10 ng/ml {625}.
Prostate-specific antigen epithelial
density. The serum PSA level is most
strongly correlated with the volume of
epithelium in the transition zone. The
prostate-specific antigen epithelial density
(PSAED, equal to serum PSA divided
by prostate epithelial volume as determined
morphometrically in biopsies)
should be superior to PSAD. However, the
amount of PSA produced by individual
epithelial cells is variable and serum levels
of PSA may be related to additional
factors such as hormonal milieu, vascularity,
presence of inflammation, and other
unrecognized phenomena {2698, 2941}.
PSA velocity and PSA doubling time
PSA velocity (or PSA slope) refers to the
rate of change in total PSA levels over
time. It has been demonstrated that the
rate of increase over time is greater in
men who have carcinoma as compared
to those who do not {380,381}. This is
linked to the fact that the doubling time of
prostate cancer is estimated to be 100
times faster than BPH. Given the shortterm
variability of serum PSA values,
serum PSA velocity should be calculated
over an 18-month period with at least
three measurements.
PSA doubling time (PSA DT) is closely
related to PSA velocity {1470}. Patients
with BPH have PSA doubling times of 12
± 5 and 17 ± 5 years at years 60 and 85,
respectively. In patients with prostate
cancer, PSA change has both a linear
and exponential phase. During the exponential
phase, the doubling time for
patients with local/regional and
advanced/metastatic disease ranges
from 1.5-6.6 years (median, 3 years) and
0.9-8.5 years (median, 2 years), respectively
{1470,1775}.
Prostate markers other than PSA
Prostatic acid phosphatase (PAP)
PAP is produced by the epithelial cells lining
the prostatic ducts and acini and is
secreted directly into the prostatic ductal
system. PAP was the first serum marker
for prostate cancer. Serum PAP may be
significantly elevated in patients with BPH,
prostatitis, prostatic infarction or prostate
cancer. Serum PAP currently plays a limited
role in the diagnosis and management
of prostate cancer. The sensitivity and
specificity of this tumour marker are far
too low for it to be used as a screening
test for prostate cancer {1660}.
Human glandular kallikrein 2 (hK2)
The gene for hK2 has a close sequence
homology to the PSA gene. hK2 messenger
RNA is localized predominately to
the prostate in the same manner as PSA.
hK2 and PSA exhibit different proteolytic
specificities, but show similar patterns of
complex formation with serum protease
inhibitors. In particular, hK2 is found to
form a covalent complex with ACT at
rates comparable to PSA. Therefore,
serum hK2 is detected in its free form, as
well as in a complex with ACT {2074}.
The serum level of hK2 is relatively high,
especially in men with diagnosed
prostate cancer and not proportional to
total PSA or free PSA concentrations.
This difference in serum expression
between hK2 and PSA allows additional
clinical information to be derived from the
measurement of hK2.
Prostate specific membrane antigen
(PSMA)
Although it is not a secretory protein,
PSMA is a membrane-bound glycoprotein
with high specificity for benign or
malignant prostatic epithelial cells {142,
1125,1839,1842,2412,2846,2847}. This
is a novel prognostic marker that is present
in the serum of healthy men, according
to studies with monoclonal antibody
7E11.C5. An elevated concentration is
associated with the presence of prostate
cancer. PSMA levels correlate best with
advanced stage, or with a hormonerefractory
state. However, studies of the
Acinar adenocarcinoma 167