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2233
COMMUNICATION
International Union
Against Cancer
Workshop on Prostate Markers
Gerald P. Murphy, M.D.,
Alan Partin, M.D., Ph.D.2
1
D.Sc.
1
Pacific Northwest Cancer Foundation, Northwest Hospital, Seattle, Washington.
2
James Buchanan Brady Urological Institute, The Johns Hopkins Hospital, Baltimore, Maryland.
Neuroendocrine Cells
Data presented at the Workshop on Prostate Markers, Vancouver, British Columbia, Canada, July
11–13, 1998.
This meeting was sponsored by the Tumour Biology Committee of the International Union Against
Cancer and supported in part by educational
grants from Hybritech-Beckman, San Diego, California, and Northwest Biotherapeutics, Seattle,
Washington.
The following is a list of workshop participants:
Per-Anders Abrahamsson, M.D., Ph.D., Lund, Sweden; Georg Bartsch, M.D., Innsbruck, Austria;
David Bostwick, M.D., Rochester, MN; Alton Boynton, Ph.D., Seattle, WA; Michael K. Brawer, M.D.,
Seattle, WA; A. T. K. Cockett, M.D., Rochester, NY;
Louis Denis, M.D., Antwerp, Belgium; Lana Grauer,
Ph.D., San Diego, CA; Eric Holmes, Ph.D., Seattle,
WA; Jari Leinonen, Ph.D., Helsinki, Finland; Curtis
Mettlin, Ph.D., Buffalo, NY; Gerald P. Murphy, M.D.,
D.Sc., Seattle, WA; Alan Partin, M.D., Ph.D., Baltimore, MD; Harry Rittenhouse, Ph.D., San Diego,
CA; Peter Snow, Ph.D., Colorado Springs, CO;
Paula Southwick, Ph.D., San Diego, CA; Sai Su,
Ph.D., Seattle, WA; Donald Tindall, M.D., Rochester, MN; and Robert Wolfert, Ph.D., San Diego, CA.
Address for reprints: Gerald P. Murphy, M.D.,
D.Sc., Pacific Northwest Cancer Foundation,
Northwest Hospital, 120 Northgate Plaza, Suite
205, Seattle, WA 98125-7001.
Received July 27, 1998; accepted August 28,
1998.
© 1998 American Cancer Society
Prostatic neuroendocrine cells were first demonstrated in 1944. These
granule-containing cells have functional paracrine, autocrine, and
endocrine capacity. The neuroendocrine cell secretory activity produces products that stimulate prostate smooth muscle cells, benign
prostate epithelial cells, and prostate carcinoma cells. The materials
produced by these cells have been demonstrated to induce focal
differentiation in prostate carcinoma. Prostate specific antigen (PSA)
is coexpressed in some neuroendocrine prostate cells. There are a
number of things that remain unknown regarding such cell types. For
example: 1) the expression of neuroendocrine receptors, 2) correlation between receptors and prognostic factors, 3) relation to androgen
dependence of prostate cells, and 4) correlation with PSA serum
values.
Neuroendocrine cells communicate with peripheral nerves and
with each other. They are involved in the normal regulation of prostate cell growth and the regulation of prostatic secretions. There also
is an interaction between the products of the prostatic stroma and
neuroendocrine cells.
In prostate carcinoma, neuroendocrine differentiation is present
in 7–100% of cases, varying according to fixative and method of
identification employed. These cells are found in association with
nerves and also in such locations as metastatic lymph nodes. Although it is believed that neuroendocrine cells are androgen receptor
negative, this has not been established definitely. There currently are
a diversity of opinions and limited available information. It has been
observed, after antiandrogen therapy, that prostate tumors may have
an increased number of neuroendocrine cells. This situation also is
disputed. In a few limited reports, the levels of neuroendocrine secretory products in the blood have been found to be higher in patients
with androgen independence. It also is believed that these serum
products are not suppressed by androgen ablation therapy or radiation therapy. Whether these products in the tissue have value as an
independent indicator for poor prognosis is unresolved. At the current time, staining prostate carcinoma for neuroendocrine cells is
believed to be an important research project. The future role of
neuroendocrine substances as practical markers are unresolved. Data
were presented at the meeting in Sweden to suggest that in 103 cases,
neuroendocrine staining was related to the Gleason grade of the
primary tumor and, furthermore, that this difference also was related
to survival.
2234
CANCER November 15, 1998 / Volume 83 / Number 10
There is a cell line called CRL-5813 that is derived
from a lymph node metastasis from a prostate carcinoma patient. The cDNA fragments found were positive for estrogen receptor-␣, and for androgen receptor in this particular cell line. All three chromogranin
secretory products also have been identified. Future
goals relate to the measurement of neuroendocrine
receptors and the mitogenic effects of the neuropeptides produced by these cells. It was further reiterated
that these cells do coexpress PSA. The source of neuroendocrine cells in the prostate is unknown. Although they previously were considered to be stem
cell products, evidence was reported at the meeting
that suggests that these cells may be of ectodermal
origin. Data are required from prospective randomized trials to evaluate whether the expression of these
cells is an independent indicator of disease progression. There may be preliminary information forthcoming from a Radiation Therapy Oncology Group
trial recently completed in North America. However,
further details are unavailable at the current time.
Free Prostate Specific Antigen
A major prospective multiinstitutional study conducted by Hybritech/Beckman of San Diego, California, examined patients who had a serum PSA level
between 4.0 –10.0 ng/mL and a % free PSA (fPSA)
determination. Particular emphasis was made to examine men age ⬎ 50 years (in whom the prevalence of
prostate carcinoma was 4%). In this particular study,
these men also had a negative digital rectal examination. It was noted that this group would equal 10% of
the population of men in a previously conducted total
PSA trial. The proportion of men in this group who
were found to be negative by digital rectal examination with a PSA between 4 –10 ng/mL was 9%. This
group also represented 33% of all the biopsies performed in the initial Hybritech report. A total of 773
men were reported. A cutoff point of ⬍ 25% for abnormal fPSA in this group, as shown, would detect
95% of the tumors. Approximately 20% of the benign
prostatic hyperplasia (BPH) cases would not be biopsied, sparing these patients an unnecessary procedure.
The percentage of fPSA levels was similar in African-American and white patients. As patient age increased, the percentage of fPSA also increased. Using
the 25% fPSA level obviates any need in this study for
age specific cutoff levels because such a level, when
employed, would detect nearly 98% of younger men
with prostate carcinoma. This study found that the
tumors that would not be detected by this test were
located in: 1) older men; 2) men with larger glands
(benign); and 3) men with less aggressive tumors.
The percent fPSA could be used in two different
ways: 1) as a single cutoff point of 25%; and 2) in
individual patient risk assessment, determining that
the lower the percent fPSA, the higher probability of
prostate carcinoma. These levels and the degree of risk
are determined by the prevalence of prostate carcinoma in any particular group. In addition, for the
prediction of favorable pathology in patients with biopsy-proven carcinoma, a fPSA value ⬎ 15% was used
as an effective discriminator.
Additional data were obtained from a multiinstitutional program collected from different countries.
However, the information has not yet been defined
fully. In men with larger prostates, not necessarily in
the screening population, different data may be obtained subsequently. It is possible that the application
of the Hybritech report to a general population may
result in differing observations. This situation is unresolved and further information from this particular
report will be needed. In the chairman’s summary it
was noted that there are reports that fPSA is low in
men with chronic prostatitis, in contrast to other reports that state that acute prostatitis does not affect
fPSA. There are limited reports suggesting that fPSA
may predict capsular penetration and that the advantage of fPSA determinations may be reduced in patients with prostates of smaller size compared, for
example, in patients with prostates ⬎ 40 cc. It also was
noted that the five ␣-reductase acting agents might
equally lower total PSA, as well as fPSA. In the European screening trial currently underway, as a result of
preliminary experiences, digital rectal examination
and transrectal ultrasound have been dropped. All
patients are given a PSA determination and every
screening patient with a total PSA ⬎ 3.0 ng/mL is
recommended for biopsy. Other potential cutoff levels
for % fPSA and total PSA were discussed.
Complexed Prostate Specific Antigen
Two published studies are available in the U. S. from
the Bayer Company and from Hybritech. A number of
previous reports from the 1991 era measuring complexed PSA (C-PSA) are of limited value. C-PSA is the
serum moiety that occurs in greater proportion in
men with carcinoma. In 1997, the Hybritech group
published their assay. The one question concerned
how to measure C-PSA: 1) the sandwich assay, binding
epitopes on PSA and ␣1-antichymotrypsin (ACT); and
2) a competition assay utilizing unlabeled cold antiPSA antibodies (E-Epitope). The assay results, comparing C-PSA with total PSA and fPSA, were reviewed
from recent data. This provided a sensitivity of 94%
and a specificity of 23%. The conclusion of the Hybritech report was that C-PSA did not add to total PSA
UICC Workshop on Prostate Markers/Murphy and Partin
for the detection of tumor. %fPSA was superior to
C-PSA or total PSA within the 4.0 –10.0 ng/mL total
PSA range.
A recent study on the Bayer assay was completed
in Seattle. This study reported the amount of the CPSA. The % C-PSA in this particular data set had the
best receiver operating characteristic (ROC). Comparing the percentage of C-PSA and the percentage fPSA
also may be more useful than C-PSA alone. C-PSA also
is useful for monitoring and staining prostate tumor
cells.
In another study in the 4.0 –10.0 ng/mL range
from Seattle, the best ROC curve was noted using
C-PSA (Bayer assay). Additional combination studies
currently are being considered to evaluate further the
diagnostic potential of C-PSA.
Additional data were presented regarding 35
cases. The conclusions from these studies were: 1) that
C-PSA by itself offers a 10% improvement in specificity
overall and a 17% improvement in the 4.0 –10 ng/mL
total PSA range; and 2) C-PSA may play a role in
obviating unnecessary biopsies in men with a total
PSA ⬍ 4.0 ng/mL.
The Helsinki group reported at this meeting on a
PSA-API ␣-1 protease inhibitor (PSA-API) in the serum. It is possible to combine the proportion of PSAAPI and PSA-ACT or fPSA in the serum over PSA levels
of 4 –20 ng/mL. This may improve the diagnostic accuracy. The group also is measuring nonimmunoreactive PSA. They have measured ␣-2 macroglobulin
(A2M) C-PSA. They have devised a novel immunoflurometric assay for the measurement of PSA-A2M
based on the removal of the immunoreactive PSA in
the serum by immunoabsorption, denaturation of
PSA-A2M at high pH, and the measurement of the
released PSA immunoreactivity by a conventional PSA
immunoassay. ROC analysis suggested the measurement of the ratio of PSA-A2M to total PSA in the serum
improves the diagnostic accuracy for prostate carcinoma compared with an assay for total PSA only.
However, these results are preliminary.
The group also has developed a specific immunoflurometric assay for PSA-ACT based on one monoclonal antibody against PSA and one monoclonal antibody specific for complexed ACT. A monoclonal
antibody specific to the complexed ACT can be developed and used with anti-PSA monoclonal antibodies
in a sandwich assay for PSA-ACT. These monoclonal
antibodies strongly reduced binding with the native
ACT, suggesting they recognize ACT modified during
the complexation. The reduction of the nonspecific
interference due to ACT and due to CG-ACT (a monoclonal antibody that reacts with cathepsin G with ACT)
should allow more reliable use of PSA-ACT assays in
2235
the diagnosis of prostate carcinoma. There were several other interesting observations, namely that the
proportion of PSA-A2M was lower in the serum in
prostate carcinoma patients than in those with benign
disease. Perhaps the sum of the proportions of PSAA2M plus fPSA can be used to reduce the false-positive
results due to BPH. This work is extremely interesting
but at a very early stage in its development.
Human Kallikrein
The human kallikrein family contains three very homologous serine proteases including PSA. The hK2
gene was discovered in 1987. The hK2 and hK1 kallikreins show approximately 80% and 60%, respectively, sequence identity with PSA. Like PSA, hK2 is
localized to the prostate and hormonally regulated. In
contrast to PSA, hK2 is a potent enzyme with approximately 20,000-fold more enzyme activity than PSA on
small molecular weight substrates. The current physiologic function of hK2 is not known but its enzyme
specificity may provide important clues. hK2 selectively cleaves arginine residues and readily cleaves the
zymogen form of PSA (proPSA) to produce active PSA,
at least in vitro. One function of hK2 may be to activate
and regulate PSA. hK2 forms complexed with ACT. In
seminal fluid approximately 50% of the hK2 is complexed with protein C inhibitor whereas PSA is nearly
entirely in the free form. Thus far, research has confirmed that hK2 is expressed selectively in prostate
epithelial cells. Androgens for the androgen receptor
can regulate this gene. There also is an interaction
between the androgen receptor and the C-JUN or
C-FOS oncogenes. Vitamin D3 and thyroxine also play
a role in the regulation of this gene. A recent report at
the American Urological Association meeting in San
Diego, California in 1998 by Dr. Kevin Slawin of Baylor
College of Medicine, described reverse transcriptasepolymerase chain reaction (RT-PCR) hK2 results in
293 men after radical prostatectomy. At a follow-up
time of 24 months, there was a difference in the recurrence rates between those men who subsequently
were believed to be positive (14%) versus those men
who were negative. Multivariate analysis with other
parameters, including Gleason score, currently is in
progress. The status of the pelvic lymph nodes measured at radical prostatectomy in 219 patients also
suggested that preoperative RT-PCR hK2 predicts final
lymph node positivity and may predict recurrence.
These initial results will be watched very closely to
observe how follow-up of clinical status correlates
with RT-PCR hK2 and available multiparametric clinical data.
Immunohistochemical studies at the Mayo Clinic
in Rochester, Minnesota have confirmed that the hK2
2236
CANCER November 15, 1998 / Volume 83 / Number 10
protein is expressed specifically in prostate epithelial
cells. In contrast to PSA, hK2 has a lower expression in
BPH than in prostate tumors. However, there was
considerable overlap in the intervals between all three
groups. Basal cells in the prostate virtually were negative. Stroma and urothelium also were negative. Data
with two different antibodies to hK2 were similar in
performance and superior to staining with PSA or
prostate acid phosphatase (PAP). PSA and PAP cell
staining generally was decreased in both prostatic intraepithelial neoplasia (PIN) and prostate tumors. No
prognostic value for hK2 staining was found for patients with lymph node metastasis although virtually
all lymph node metastatic cells stained intensely for
hK2. Hybritech/Beckman then reviewed their hK2 total assay results. The various forms present in seminal
plasma, prostate tissue, and serum were recounted.
The cross-reactivity of PSA and hK2 antibodies to the
homologous antigen remains a potential problem for
antibody selection. The Hybritech/Beckman assay for
total hK2 does not cross-react with PSA in the serum.
In general, monoclonal antibodies to conformational
epitopes for PSA are less likely to cross-react with hK2
and vice versa. Polyclonal antibodies to PSA or hK2
cross-react with the homologous kallikreins. Monoclonal antibodies to linear epitopes on PSA or hK2 are
more likely to cross-react with the other kallikreins,
but can be selected to be specific to either PSA or hK2.
The epitope maps for PSA and hK2 are complex and
the data from various groups will be reported shortly
from recent international workshops. A multiinstitutional study showed that the ratio of fPSA to total hK2
may significantly enhance discrimination between
prostate carcinoma and BPH, especially in the range
of 2.0 – 6.0 ng/mL.
Prostate Specific Membrane Antigen
Prostate specific membrane antigen (PSMA) was identified by the monoclonal antibody 7E11 in 1987. The
cDNA sequence for the coding region of the membrane bound PSMA antigen reactive with 7E11 was
revealed in research completed in 1993. The extracellular domain contains at least two homologies: one to
transferrin receptor and one to NAALADase, an enzyme found in the brain. The antigen exists in at least
two forms: the so-called membrane bound PSMA antigen, and PSM (PSM Prime [PSM⬘]), which has an
alternate start site, lacks the transmembrane region,
and has fewer amino acids as a result. This is found in
the cytoplasm.
The discussion focused on the advantages of
PSMA as a marker given that it is an integral membrane protein. This property makes it ideal for cell
harvesting, imaging, and therapeutics. Other ques-
tions focused around the mechanism of 7E11 binding
and its expression outside the prostate. Two reports
were reviewed from the Mayo Clinic that used the
7E11 antibody for staining of radical prostatectomy
cases as well as lymph nodes. The confidence limits
for the staining results were quite narrow in contrast
to those reported the previous day for hK2. There was
no background staining in contrast to previous reports
published elsewhere. This is believed to be due to
technical differences. The Mayo Clinic investigators
use overnight incubation for the antibody in contrast
to other more arduous and perhaps artifact-creating
endeavors. The basal cells were not stained. Immunoreactivity was enhanced on the luminal surface of the
prostate epithelial cells again in contrast to the diffuse
staining with hK2. High grade prostate carcinoma
showed enhanced expression. There is heterogeneity
observed in low grade prostate carcinoma. Again, this
is in contrast with results published elsewhere. The
antibody is a reliable staining agent and has the ability
to differentiate between BPH, PIN, and adenocarcinoma.
Another report dealt with the characteristics of the
entire PSMA molecule and monoclonal antibodies
formed to different regions. There are at least ten
potential glycosylation sites on the antigen. 7E11 recognizes the first six amino acids from the N-terminal
of the protein that are distributed on the cytosolic side
of the membrane. Pacific Northwest Cancer Foundation/Northwest Hospital in collaboration with Northwest Biotherapeutics and Hybritech/Beckman has
created more than 32 monoclonal antibodies to the
extracellular domain. These have unique properties
and provide multiple opportunities for diagnosis and
therapy. PSMA expressing 7E11 positive cells also are
found in semen, and are increased in amount relative
to those staining for cytokeratin 8-18 in the presence
of malignancy and increased tumor size.
Alternate splicing as a factor in the propagation of
PSMA also was reviewed. RT-PCR with PSMA and
PSM⬘ can be performed. The PSM⬘ from normal prostate is slightly different from that derived from the
LNCAP cell line material. The PSM⬘ is higher in normal
prostate tissue compared with that found in prostate
carcinoma. It is further down-regulated by androgen
in LNCAP cells. The clinical value of the use of RT-PCR
for detecting hematogenous circulating prostate cells
in prostate carcinoma patients remains unresolved.
There are three main problems: 1) modes of protocol
(e.g., choice of primers) and PCR conditions such as
the number of cycles; 2) diffuse expression of genes
under various conditions affects the performance of
the assay; and 3) technologic problems that relate to
sampling issues also are present.
UICC Workshop on Prostate Markers/Murphy and Partin
Further research has been done by the Hybritech/
Beckman group to identify PSM⬘ in the cytosol fraction from LNCAP cells. PSMA as a specific molecule
has a great number of properties and currently is
being used for visualization of lymph node metastases
in nuclear medicine tests. It doubtless is a matter of
time until a serum assay is available to test the ability
of PSMA to detect prognostic factors at both early and
late events in the patient with prostate carcinoma.
Artificial Neural Networks
Preliminary data from artificial neural networks involving diagnosis, screening data, prostatectomy results, and recurrence rates were presented. The data
were preliminary and no conclusion was reached.
However, the potential ability of artificial neural networks to provide a means for further discrimination
was discussed and presented. Several early data sets
from patients with prostate carcinoma at various
stages of early diagnosis and advanced disease had
some interesting features. Throughout the presentation, two major prognostic factors were identified.
These were the Gleason grade and PSMA serum values
as determined by Western blot analysis. This was in
marked contrast to other previously reported factors
that have been enumerated in various studies, such as
PSA, total PSA, fPSA, age, race, and other pathologic
findings. It is too early to reach conclusions from such
tests, but the results raise important questions for
current and future study.
Total Prostate Specific Antigen, Free Prostate Specific
Antigen, Complexed Prostate Specific Antigen, and hK2
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