Getting the most out of prostate workups
PSA screens and consent
William Check, PhD
Any discussion about detecting and treating prostate cancer starts
and ends with prostate-specific antigen. In its most highly publicized
solo role, as a screening tool, PSA’s performance gets rave reviews.
"PSA screening is clearly effective in detecting prostate cancer
early," says Peter Scardino, MD, chair of the Department of Urology
and head of the prostate cancer program at Memorial Sloan-Kettering
Cancer Center, New York. But PSA doesn’t exit the scene after prostate
cancer has been detected. It also acts as part of an ensemble in
a less dramatic but equally crucial activity—estimating prognosis
and risk of recurrence. And PSA returns to the stage after curative
surgery as the optimal technique for monitoring for recurrence.
"Following radical prostatectomy," Dr. Scardino says, "PSA is
by far the best indicator of recurrence. It gives six to eight years
of warning ahead of conventional studies like physical examination
or bone scan."
While serum PSA’s varied repertoire earns it the starring role
in prostate cancer management, its less famous co-star—surgical
pathology—is equally indispensable. "We actually make the
definitive diagnosis of cancer," says Richard Muller, MD, attending
pathologist at Hartford Pathology, Hartford (Conn.) Hospital. Determining
whether prostatic carcinoma is present is not simple, says Jonathan
Epstein, MD, professor of pathology, urology, and oncology at Johns
Hopkins Medical Institutions, Baltimore. Although Dr. Epstein consults
on 40 to 50 specimens from around the country each day, he finds
that "prostate cancer is probably one of the most difficult cancers
to diagnose." One reason for this difficulty is that the pathologist
gets a limited amount of tissue. To try to compensate for this,
urologists tend to take more needle cores. Ultimately, however,
Dr. Epstein says, the key to avoiding underdiagnosis is "to be very
vigilant, looking for literally just a few malignant glands."
After diagnosis, the surgical pathologist’s analysis of the biopsy
and surgical specimens is an essential component of estimating prognosis
and risk of recurrence. "In both specimens, we make an estimate
of the malignant potential or biological aggressiveness of the tumor,"
Dr. Muller says. Lawrence True, MD, associate professor of pathology
and director of male genitourinary pathology at the University of
Washington, Seattle, expands on this theme. "Once a pathologist
makes a diagnosis of cancer, it is important to provide the clinician
with information to put the patient into a management category,"
he says. "Either the cancer should be handled with the prospect
of cure or the patient is advised that the likelihood of progression
is less and he might not need radical treatment with its potential
When determining treatment options, clinicians rely on the Gleason
score from the biopsy specimen, serum PSA level, and clinical grade.
"Typically these days," says Dr. True, "particularly if radical
surgery is indicated, the clinician will use the Partin nomograms
to present information about the relative likelihood of the patient’s
cancer being more extensive." Named after urologist Alan Partin,
MD, of Johns Hopkins, the Partin nomograms are tables in which PSA,
clinical stage, and Gleason grade in the biopsy specimen are integrated
to predict pathologic stage. In separate nomograms, developed by
Michael Kattan, MD, pretreatment PSA, Gleason score, and clinical
stage are used to predict the probability of biochemical recurrence
preoperatively. Once the surgical specimen is analyzed, the pathologic
findings are used to predict recurrence postoperatively.
Screening for PSA in asymptomatic men
may be a successful way
to detect prostate cancer early. Ninety percent of patients diagnosed
based on an abnormal serum PSA test have localized disease, says
Dr. Scardino, and 80 to 85 percent have pathologically confined
cancer. "Even though randomized prospective trials have not yet
been done to show that PSA screening reduces overall or prostate-cancer-specific
mortality," he says, "because it is capable of detecting prostate
cancer earlier and because results of treating those cancers with
surgery or radiation are so good, we think patients should know
about the possible advantage."
The National Cancer Centers Network recommends that, beginning
at age 50, men with a life expectancy of 10 or more years have an
annual digital rectal examination and serum PSA test. If either
is abnormal, prostate biopsy should be done. This recommendation
is supported by the American Urological Association and the American
Cancer Society. Men at high risk—African-Americans and men
with a strong family history of prostate cancer—should have
DRE/PSA screens beginning at age 45.
Dr. Epstein says some Johns Hopkins clinicians follow a more liberal
policy. "Perhaps because we get selected cases, we not infrequently
see prostate cancer in men in their 40s," he says. "So some of our
urologists now offer PSA once at age 40, then again at age 45. If
both tests are low, they test again at age 50. If PSA is under 2
ng/mL at age 50, our studies show you can wait two years to do another
Despite PSA’s widespread acceptance as a screening tool, controversy
remains regarding the extent of its benefit. "It is still too early
to tell asymptomatic men that a routine PSA test will lower the
death rate for prostate cancer," says Gerald Chodak, MD, clinical
professor of surgery at the University of Chicago and director of
the Midwest Prostate and Urology Health Center at Louis A. Weiss
Memorial Hospital, Chicago. Dr. Scardino agrees. "That means that
you can’t fault a physician who sees a 55-year-old man and doesn’t
recommend DRE and PSA testing," he says. "You wouldn’t consider
that medical negligence because those tests are not of clearly proven
medical benefit. We recommend that men be screened, but screening
is not yet ready for prime time as a public health measure." To
handle this ambiguity, Dr. Chodak has introduced consent forms into
his practice. (See "PSA screens and consent.")
In a recent update, the U.S. Preventive Services Task Force reiterated
that evidence is lacking as to whether routine screening for prostate
cancer improves health outcomes. At the center of this dilemma is
the question of whether all prostate cancers detected following
an elevated screening PSA need to be treated. "The majority of cancers
detected by PSA appear to be significant cancers," Dr. Epstein explains.
"But with screening, we are detecting an increasing minority of
small cancers that, when the prostate is taken out, may not have
needed to be removed." In his practice, Dr. Epstein finds that about
25 percent of prostate tumors are 0.5 cc or less in volume. He says
it is "borderline" whether these tumors could have been left behind
without clinically affecting the patient. Men with such small tumors
theoretically are candidates for watchful waiting.
Dr. Muller refers to autopsy studies to make the same point. "If
you take men dying at around age 65, say of a car wreck, about half
on autopsy have a small prostate cancer," he says. "Most of these
men did not have clinical signs of prostate cancer. Yet if you biopsied
this same group, 50 percent would end up with radical prostatectomy."
Dr. Muller also sees postsurgical specimens of less than 0.5 cc
with low Gleason grade (<6) confined to the prostate. "Such
a low-grade tumor has a long doubling time," he says. "In a patient
with a life expectancy of less than 20 years, that tumor may not
have become manifest in the patient’s lifetime."
Unfortunately, there is no certain way before surgery to distinguish
possibly indolent tumors from aggressive ones. In Dr. Muller’s practice,
the most common Gleason scores on biopsy are 3+3, 3+4, 4+3, or 4+4,
with the first two scores accounting for about 80 percent of patients.
"Gleason grade itself doesn’t allow prediction of biological potential
for most patients,"
"Our challenge," says Dr. True, "is to stratify men who are found
to have prostate cancer into those whose cancer should be dealt
with and those whose cancers—based still on limited outcomes
data—don’t need to be treated. We know that many men in the
population have cancers that won’t progress, but we are far from
confident in identifying those individuals."
"We have tried to develop algorithms to identify these insignificant
cancers," Dr. Epstein says. He and his colleagues have identified
a cohort of men whom they are following with repeat biopsies. "We
are more comfortable watching a tumor in an older man," he adds.
In a younger man, a tumor has a longer time to grow. On the other
hand, surgical sequelae, chiefly incontinence and impotence, have
greater impact on younger men.
These uncertainties led to the U.S. Preventive Services Task Force’s
Dec. 2, 2002 update reiterating that "there is insufficient scientific
evidence to promote routine screening [for prostate cancer] for
all men and inconclusive evidence that early detection improves
The scientific evidence included in the update makes a number of
points, such as: "...up to 25 percent of apparently PSA-detected
tumors and more than 25 percent of apparently DRE-detected tumors
were likely in fact to have been detected by serendipity, that is,
an incidental finding from a blind biopsy."
Two large randomized trials in the United States—the National
Cancer Institute-sponsored Prostate, Colorectal, Lung and Ovarian
Screening Trial and the Prostatectomy Intervention Versus Observation
Trial are testing whether screening followed by radical treatment
reduces death. Also ongoing is the European Randomized Study of
Screening for Prostate Cancer. None of these trials will produce
outcomes data for several years.
Even if the trial results are unequivocal, they may not affect
clinical practice. "There is a certain psychological element that
can obviate all our clinical studies," Dr. Muller says. "The clinician
is up against it in advising a patient with low-grade tumor on biopsy,
slightly elevated PSA, and our assessment that the tumor is not
very big. Often those patients don’t want to hear that they have
only a 10 percent chance of having a biologically aggressive tumor.
They say, ’I am not going to wait for this to kill me.’ They want
Dr. True concurs. "According to my clinical colleagues," he says,
are men who, though they may initially elect to have their tumor watched,
decide after a while they just can’t live with it and either want
it out or want
"Until we have a very accurate way of predicting
which tumors are biologically aggressive," says Dr. Muller, "most
men will be treated."
Attempts to improve the specificity of PSA screening have focused
on following up serum total PSA results in the equivocal range—4
to 10 ng/mL, where the probability of cancer on biopsy is 25 percent
or less—with measurement of percent free PSA (%fPSA), the
form not complexed to proteins. Performing biopsies on only those
samples with <25% fPSA avoids about 20 percent of biopsies
in this group while missing five percent of cancers.
"There was great enthusiasm a couple of years ago that the free-to-bound
ratio would further stratify patients into likelihood of cancer
being present and being more extensive," Dr. True says. "My impression
is that that test is not routinely used now because it is not all
that powerful." Dr. Scardino finds %fPSA useful primarily for the
patient who has borderline PSA, such as 4.1; or who has a very large
prostate on DRE, where he suspects PSA may be low for the size of
the prostate; or who has a negative biopsy, to help decide whether
to perform repeat biopsy.
Further compromising PSA’s accuracy, values below the accepted
cutoff may not be safe. Dr. True has seen cases with total PSA levels
under 4 ng/mL in which cancer is fairly extensive and may even have
high-grade components and higher stage. "These cases are rare,"
he says, but they exist.
Dr. Partin recently studied the use of %fPSA testing on total
PSA results between 2 and 4 ng/mL (J Urol. 2002; 168: 504-508).
In this setting, three to five biopsies were needed to find one
cancer, compared with three biopsies needed to detect one cancer
using %fPSA on total PSA in the 4 to 10 ng/mL range. Of 41 cancers
detected when total PSA was 2 to 4 ng/mL, six had a Gleason score
of five and 28 had a Gleason score of six.
Data have also suggested that the converse of %fPSA, which is
complexed PSA (cPSA), can replace total PSA and %fPSA in the diagnostic
setting. Dr. Scardino acknowledges that claims for cPSA are "scientifically
correct." However, he says, "I think its appeal is going to be limited."
First, physicians are already widely informed about total PSA and
would have to be re-educated about the meaning of a given level
and cutoffs. Second, "The value of total PSA extends well beyond
diagnosis to prognosis and following patients after therapy," he
says. "To shift to complexed PSA just for one setting, we would
have to redo all staging and prognostic nomograms."
Before prostate biopsy, a rise in total
PSA must be confirmed.
"PSA can vary from week to week and month to month," Dr.
Scardino notes. If the rise is confirmed, ultrasound-guided needle
biopsy of the prostate is performed. "We recommend taking at least
six and preferably 10 to 12 cores," he says. "Cores should be labeled
as to where they came from to help plan treatment or if results
are equivocal, repeat biopsies can be done in the same area."
Immediately the pathologist’s first hurdle arises—the small
amount of material available. Each core is about one-half inch by
a few millimeters and represents about 1/1,000 of the prostate gland.
To compensate, urologists are expanding the amount of sampling.
Dr. True cites a urologist colleague’s opinion that 12 biopsy cores
are now standard.
Urologists at Johns Hopkins also think that six biopsy cores are
inadequate, says Dr. Epstein, and take 12 or even 18. For a man
who is considering watchful waiting, for whom it is critical not
to miss an aggressive tumor, clinicians may take up to 30 cores
under outpatient anesthesia. Still, Dr. Epstein says, "even with
more extensive sampling, the problem of limited tissue persists."
Making diagnosis even more difficult, says Dr. Epstein, is that
prostate cancers often do not form a solid mass like breast or colon
cancers, "but grow by insinuating themselves among benign tissue.
So a needle biopsy often shows only a few malignant glands among
an overwhelming number of benign glands." Prostate cancers also
can have a deceptively benign appearance. And there are numerous
mimics of high- and low-grade prostate cancer, such as adenosis
The key to recognizing prostate cancer is to look for a constellation
of features, says Dr. Epstein. Architectural factors arguing in
favor of cancer include small, crowded glands between larger benign
glands. Positive nuclear features are prominent nucleoli, nuclear
enlargement, hyperchromasia, and mitotic figures. Dark cytoplasm
is also characteristic of malignancy, as are intraluminal crystalloids
and blue and dense eosinophilic intraglandular or intraluminal secretions.
Three features are pathognomonic of prostate cancer—perineural
invasion, mucinous fibroplasia, and glomerulations (much like a
kidney glomerulus)—but they are infrequent.
Findings that should make the pathologist hesitate to call cancer
are atrophic features, inflammation, and adenosis, all of which
are benign mimickers of prostate cancer. High-grade prostatic intraepithelial
neoplasia may be a precursor lesion of prostate cancer or a mimic
of invasive cancer, "but you would not call it invasive cancer,"
Dr. Epstein says. "As a precursor lesion, its natural history is
unknown, so you wouldn’t want
to subject the patient to surgery or radiation if only PIN is present."
Diagnosis is aided by ancillary immunochemical tests that label
basal cells, which are present in benign glands but absent in cancer.
Two basal cell markers are 34betaE12 (high-molecular-weight cytokeratin)
and a relatively new marker, p63. "We use both in a given case,"
Dr. Epstein says. "One may work better." Although it may sound straightforward
to say that a biopsy containing tissue in which both stains are
absent indicates the presence of cancer, Dr. Epstein warns, "Many
benign glands include some mimickers of cancer where one does not
always see these markers. So the absence of basal cells is not always
An even newer marker called AMACR (alpha methylacyl-CoA racemase),
one of the first developed using molecular techniques, is the first
marker present in cancerous but not benign glands. Again, however,
in practice, interpretation is not quite so straightforward. Some
noncancerous lesions are positive for AMACR, most typically high-grade
PIN but sometimes even adenosis or atrophy stains.
"You have to use all immunostains in light of what the lesion
looks like under routine light microscopy with H&E," Dr. Epstein
says. Using histological features plus existing markers will resolve
the "vast majority" of prostate biopsies, all but about five percent,
he says. If results are mixed, Dr. Epstein reports it as "small
focus of atypical glands suspicious of cancer but not diagnostic."
Typically, he adds, unless the patient is very old, repeat biopsy
is recommended since approximately 50 percent of these men will
be found to have cancer on repeat biopsy.
After diagnosis, the next step is to estimate the probability
of progression based on total PSA plus Gleason score, clinical stage,
and amount of cancer tissue present. Extent of cancer is expressed
as linear length of tissue or an estimate of percent of malignant
tissue present, such as the fraction of cores involved or how many
millimeters of cancer are seen in each core.
No markers currently help with prognosis. "Even though we have
identified candidates, right now we have no markers that we can
say with confidence stratify patients," Dr. True says. "DNA ploidy
and proliferation and cell cycle markers, such as ki67 and p27,
have been proposed, but none has been validated prospectively in
Dr. True is part of a research group, the Pacific Northwest Prostate
Cancer SPORE (specialized program of research excellence), that
received NIH funding to investigate markers for prostate cancer
likely to metastasize to bones and to grow through androgen blockade,
thereby exhibiting hormonal independence. The group will search
for new gene products using the same molecular methods used to discover
AMACR. "Our goal is to identify new immunohistochemical tools for
practicing pathologists," Dr. True says.
Dr. Scardino estimates that at Memorial
Center about 600 men per year are treated with
surgery, about 500 with external beam radiation therapy, and about
100 with brachytherapy seed implants. Radical prostatectomy is effective
for prostate cancer localized to the prostate or immediate periprostatic
tissue, stages T1-T3a, while external beam radiation therapy can
be used in locally extensive cancers, stages T3b or T4. "In some
patients you could flip a coin," Dr. Scardino says. "Others are
better suited for surgery or radiation."
If a man who is receiving anticoagulation for atrial fibrillation
has radiation therapy, he may suffer radiation proctitis and rectal
bleeding that would be difficult to control. If he has surgery,
it would be safe to stop Coumadin for a short time and resume it
post-surgery. On the other hand, Dr. Scardino would be reluctant
to perform surgery on a man with a history of pulmonary embolism,
who is more appropriately treated with external beam radiation therapy.
Brachytherapy is appropriate for a limited group of patients—men
with favorable low-risk cancers who do not have a large prostate
or a high level of bladder outlet obstruction.
When disease is less extensive, a surgeon may perform a nerve-sparing
version of radical prostatectomy, which takes less soft tissue around
the periphery of the prostate in an attempt to spare the nerves responsible
for erectile and ejaculatory function and urinary control. "Tumors
Gleason grade >3+4 are more likely to have tumor outside the
prostate," Dr. Muller says.
Dr. Scardino believes most prostate cancers suitable for surgery
are candidates for a nerve-sparing operation, with the neurovascular
bundle needing to be resected in roughly 10 to 30 percent of patients.
Determining where the tumor extends requires DRE and biopsy results,
sometimes supplemented with endorectal MRI. Sparing one or two nerves
raises the probability of recovering erectile function from virtually
zero to 30-50 percent and 70-90 percent respectively. "These are
extremely small, delicate nerves," Dr. Scardino says, "and it is
very easy to injure them. So while they are often preserved, they
can be damaged, which compromises recovery of function." Success
of nerve-sparing surgery thus depends on the surgeon’s skill. Dr.
Scardino and his colleagues published data last year showing substantial
variations in outcomes from radical prostatectomy (N Engl J
Med. 2002; 346: 1138-1144). "Generally the busier surgeons
get better outcomes," Dr. Scardino says. "Still, even among the
busier surgeons there were disturbing variations. Radical prostatectomy
is an unforgiving operation."
Hormonal therapy is important in treating metastatic prostate
cancer. "Hormonal therapy is very effective in placing prostate
cancer in remission and in reducing its size," Dr. Scardino says.
"But it is not curative. Given enough time, prostate cancer will
always learn how to grow in the absence of androgens." No data demonstrate
a clear advantage to giving hormonal therapy early after diagnosis.
Because of its adverse effects—reduced libido, osteoporosis
if given long-term, and decreased muscle mass—Dr. Scardino
favors saving hormonal therapy until later, but certainly before
the disease becomes symptomatic. "That way we gain as much length
of life but avoid side effects," he says.
Hormonal therapy is also used to treat localized cancer in conjunction
with radiation. Administered before radiation, it shrinks tumor
and improves long-term disease-free survival in men with large high-grade
cancers or high PSA. A few studies also suggest that men with localized
but aggressive tumors benefit further when given hormonal therapy
for two to three years after radiation therapy.
As use of high-dose 3-D conformal radiation therapy increases,
however, use of adjunctive hormonal therapy may decrease. "At high
radiation doses, such as 81 Gray, beneficial effects of hormonal
therapy before radiation are doubtful," Dr. Scardino says. Hormonal
therapy confers no apparent advantage when used before surgery,
according to the results of five
With the resected radical prostatectomy specimen, the pathologist
can make a much better determination of prognosis. One criterion
is degree of extension: Is the tumor confined to the prostate? Has
it invaded the seminal vesicles or pelvic lymph nodes? Did the surgeon
remove the entire lesion or is the tumor at the margin? A more accurate
determination of Gleason grade is also possible. "After surgery,
we have the entire specimen to look at," says Dr. Epstein, "whereas
on needle biopsy, we are confronted with sampling error and might
undercall the Gleason score."
Dr. Muller points out that no posttreatment specimen is available
after radiation therapy. "That makes the estimate of Gleason grade
in biopsy tissue of paramount importance," he says. Gleason grade
by itself without pathologic stage is an indicator of biological
aggressiveness. "But," Dr. Muller says, "it is much more satisfying
to me to get the radical prostatectomy specimen and determine pathologic
stage." Recent work has shown that the combination of pathologic
stage and Gleason score on the prostatectomy specimen predicts a
patient’s probability of biochemical failure (Cancer. 2001;91:
Dr. True notes the importance of being able to recognize prostate
cancer after localized or systemic therapy. "Many times the clinician
will go back to biopsy the prostate to evaluate success of treatment,"
he says. Histologic changes caused by therapy can make this a challenging
task. With hormonal blockade or brachytherapy, cancer cells are
typically shrunken and inconspicuous. "After brachytherapy especially,
benign glands often have a degree of atypia that we are not used
to seeing in benign glands," Dr. True says. To avoid mistaking therapy-induced
changes for cancer, the pathologist must become familiar with those
changes. Immunostains for basal cell markers are also helpful in
Assuming that post-therapy PSA has declined
limits, any subsequent rise in PSA is interpreted as a sign of recurrence.
Radical prostatectomy removes the entire prostate gland, so the
only source of PSA would be recurrent tumor, Dr. Muller notes. With
radiation therapy, however, some prostate tissue remains, so it
is a little less clear-cut that every PSA rise after radiation therapy
is a sign of recurrent tumor and a biopsy may be performed.
Dr. True adds one more consideration. "We are becoming more aware
that there is a spike of PSA about 18 months after implantation
of brachytherapy seeds," he says. "We have now had anecdotal experience
in up to a dozen patients that if nothing further is done, PSA will
drop to undetectable levels over the next year."
For recurrent cancer after radiation therapy, hormonal therapy
is the standard treatment, Dr. Scardino says. For recurrence after
radical surgery, treatment depends to a great extent on when the
PSA rises and how rapidly this occurs. If PSA levels start to climb
within two years of surgery and increase rapidly, that suggests
metastasis, for which hormonal therapy is indicated. PSA levels
that rise later and go up more slowly suggest local regrowth, and
it is reasonable to use radiation to kill that tumor. A look back
at the pathology can also be useful. For a more aggressive cancer—high-grade,
poorly differentiated, growing into seminal vesicles or lymph nodes—a
recurrence is more likely to be metastatic. What is not usually
helpful is radiology: When PSA is first elevated, the tumor is so
small that it is impossible to detect with a radiologic study. "If
you do give radiation for recurrence after surgery," Dr. Scardino
says, "we know that you must start before PSA gets to 2 ng/mL. After
that, virtually no patients can be cured. And we prefer to start
radiation before PSA reaches 0.5 ng/mL."
To better detect malignant prostate lesions in the future, Dr.
Muller looks to the detection of oncogenes. "My hope is that we
could do an analysis on the biopsy specimen of genetic lesions in
each individual’s tumor," he says. Combining that genetic analysis
with classic parameters—serum PSA, Gleason grade, and extent
of tumor—may provide a more accurate estimate of each tumor’s
biological potential and make it possible to tailor therapy based
on that patient’s risk.
"We are just now starting to study those genetic parameters,"
William Check is a medical writer in Wilmette, Ill.