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PAP - Making a Comeback as a Prognostic Indicator (May 2003)
Unless my personal experience is unusual, most clinicians managing
prostate cancer have not ordered the serum prostatic acid phosphatase
(PAP) test for quite a while. The authors of the paper "Long-Term Outcomes
after Treatment with External Beam Radiation Therapy and Palladium 103 for
Patients with High Risk Prostate Cancer" (CANCER, February 15, 2003, p.
979) have presented convincing data that is likely to change our usage.
This excellent paper by Dr. Michael Dattoli (co-authored by Drs. Larry
Wood and Kent Wallner, both from the University of Washington) finds that
a pretreatment PAP level of >2.5 ng/ml "the strongest predictor of
failure" (P = 0.0001) compared to Gleason sum (P = 0.04) and PSA (P =
0.04). The normal range for PAP was up to 2.5 ng/ml. The PAP was
especially useful in the prognosticly difficult group with PSA between 4
and 20 ng/ml. Their study involved 161 men treated between 1992 and 1996
(median follow-up: 7 years) with clinical Stage T1 - T3 PC, Gleason sum
>7, and PSA level >10 ng/ml who received 41 Gy external beam radiotherapy
to a limited pelvic field followed by a palladium 103 brachytherapy boost.
Failure was defined as never achieving a nadir PSA of <.2 ng/ml, or rising
to exceed that value. All failing patients underwent a repeat prostate
biopsy and all biopsies were negative for residual PC, thereby
establishing in the best possible way that the failure was due to systemic
micrometastatic disease. The pretreatment PAP test will certainly have to
be incorporated in the stratification of future trials and would also be
informative in management of individual patients. This study derives
further strength because it stands on the shoulders of several earlier
studies that came to the same conclusion about the prognostic usefulness
of the PAP test.
Moul (J Urol, 1998, March) found the pretreatment PAP predictive of
pathologic stage and first serological recurrence in 295 men post radical
prostatectomy (RP). The disease free survival at 4 years was 78.8% for men
with a PAP < 3 ng/ml, compared to 38.8% for those with PAP > 3 ng/ml. The
usefulness of PAP was independent of PSA value, and was particularly
useful (P = 0.012) in the group with PSA > 10 ng/ml. In another study, Han
(UROLOGY, 2001, April) analyzed the post RP outcome of 1681 men with
clinically localized disease and found that men with a pretreatment PAP of
<.4 had a 77% likelihood of freedom from biochemical recurrence at 10
years compared with 44% for those with PAP >.5. (The normal range for PAP
in this study was 0 - .8 U/L.) In their study 90% of the men were clinical
Stage T1C - T2 with 75% Gleason sums <7 and 95% were PSA<20.
What is PAP ? PAP is significantly different from PSA, which is an enzyme
(a serine protease) secreted into the lumen of the prostatic acini by the
surrounding glandular epithelium and dispatched via ducts to enter the
urethra where it serves to liquify the coagulum of the ejaculum. In
contrast, the PAP is an intracellular signaling enzyme (a protein tyrosine
phosphatase - a deactivator of signaling) in prostate cells and is
associated with cellular differentiation. The genes for both PAP and PSA
are under the control of androgen receptor signaling. One of the
challenging unknowns yet to be fully deciphered is what signaling
mechanisms account for the continued production of PAP and secretion of
PSA in the PC cells in "androgen insensitive" prostate cancer when
signaling via the androgen receptor continues independent of testosterone
stimulation.
In seeming paradox to the clinical usefulness of the PAP test wherein a
high value predicts for treatment failure, the PAP content in malignant
prostate cells is less than in their benign counterparts. The
comparatively lower PAP content in malignant cells may be consistent with
our knowledge that a high content of PAP inhibits a prostate cell's
response to the proliferative stimulus from growth factors emanating from
the surrounding support cells. There is strong evidence that in the
androgen deprived state, one source of stimulation to the androgen
receptor comes from growth factors working through the ErbB-2 receptor on
the PC cell. The resulting implication is that when cellular PAP content
is high, as in the benign state, cellular sensitivity to growth
stimulation signaling is reduced. The converse of this inverse
relationship may be to allow growth stimulation to be more effective in
the malignant cell. There is much yet to be learned about the cellular
function of prostatic acid phosptatase, however, these several studies
have shown the PAP test has useful practical applications.
Bottom Line: The PAP test has returned to a useful place in the
pretreatment evaluation of outcome for primary treatment of prostate
cancer. «
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