Dr. Epstein provides a comprehensive review of the pathology of
prostatic carcinoma and its importance in guiding the clinical
management of treatment for our patients with abnormal prostates
and prostate cancer. Prostate cancer, its evaluation, screening,
and treatment, remain in many aspects the most controversial for
the urologic oncologist. Clearly, our decisions on how we treat
patients with elevated PSA's, abnormal prostate exams, and a diagnosis
of prostate cancer is influenced greatly by the interpretation
of the pathologist of biopsies and radical prostatectomy specimens.
In short, the oncologist and urologist are unable to make intelligent
and accurate recommendations without accurate pathologic review.
Who Needs a Repeat Biopsy?
Although it may seem odd, one of the most frustrating situations
is a patient with an elevated or rising PSA, an abnormal digital
rectal examination, a good candidate for curative therapy, and
a negative prostate biopsy. The risk of prostate biopsy is small.
However, when one considers the overall cost of the procedure,
time off from work, and the anxiety caused to the patient, a recommendation
to repeat the biopsy must not be taken lightly.
As Dr. Epstein so clearly points out, certain criteria help us
decide which men should undergo repeat biopsy and which should
be followed conservatively. Without question, high grade PIN is
one of these criteria. Like the Hopkins group, Brawer and associates
found that men with high grade PIN but no cancer on original prostate
biopsy have an extremely high risk of prostate cancer on subsequent
biopsy . In a previous series of 21 men with PIN, all 10 patients
with grade 2 or 3 PIN had carcinoma on repeat biopsy, whereas
only 2 of 11 had positive subsequent biopsies when their original
biopsy showed grade 1 PIN . In the gentleman with a completely
negative biopsy, I tend to use physical exam and, more importantly,
the velocity of PSA change over time. Carter et al, found an annualized
PSA increase of 0.75ng/mL/year to be a significant cut-off in
determining which men harbored cancer with a previous negative
Catalona demonstrated that men with PSA determinations of greater
than 10ng/mL with a previous negative biopsy had approximately
a 41% chance of having carcinoma found on subsequent biopsy .
Those men that have a subsequent negative second biopsy are unlikely
to have carcinoma found on a third biopsy, and therefore, in my
opinion, should not be rebiopsied unless their PSA continues to
rise at a rapid rate or their physical examination changes significantly,
which occurs in only 4% to 8% of patients.
Who Needs Treatment?
Once cancer is diagnosed the clinician treating the patient needs
to make recommendations based on information received from the
pathologist. This decision is influenced greatly by the pathologist's
interpretation of grade, the number and percentage of each biopsy
involved, and the location of these biopsies. As a urologic oncologist
who sees many men for treatment or second opinion after the diagnosis
is already established, it is extremely difficult when pathologic
reports do not contain all of this information. Several studies
have now established algorithms that help predict stage based
on biopsy grade, the number, location, and amount of cancer in
each biopsy obtained, and PSA value.5 This is extremely important
information in counseling and guiding a patient about the advisability
of several aspects of treatment:
Is a bone scan necessary?
Is nerve sparing radical prostatectomy appropriate?
Is watchful waiting appropriate?
Does radiotherapy have a reasonable chance for cure?
Should neoadjuvant hormonal therapy be used?
Will this patient require a lymph node dissection?
Will this patient likely have pathologic disease outside the prostate,
and possibly require adjuvant radiation or hormonal therapy after
Dr. Epstein points out, as have other authors, that grade is very
important in determining the overall prognosis and success of
therapy. In 1994, the Hopkins group attempted to define which
men might be able to be followed safely with watchful waiting
 based on several criteria, including grade, number of biopsies
positive, amount of cancer per biopsy, and PSA density. The problem
with this algorithm is that prostate biopsies with low grade most
often have the greatest error in determining the final pathologic
grade. Bostwick reported 316 patients diagnosed with prostatic
adenocarcinoma by the 18 gauge automatic spring loaded biopsy
gun and found that prostate biopsies underestimate the radical
prostatectomy specimen grade in 40% of cases. In addition, those
cases most likely to be in error were those with the least amount
of tumor found on prostate biopsy and those with the lowest grade
. In a recent analysis of 88 patients biopsied with the 18
gauge gun at the City of Hope National Medical Center, we found
that 28 patients (32%) had their final total Gleason score upgraded
by at least two points .
In short, I think that healthy men with good life expectancy,
despite having supposed low grade and low volume prostate cancer
should undergo definitive therapy because higher grade and higher
volume disease commonly appear on final pathologic review. The
vast majority of these men will be cured. In addition, this practice
spares them the chronic anxiety of carefully watching their PSA
value while the cancer remains untreated.
Treatment of Men with pT3 and Node Positive Disease
Dr. Epstein points out that the incidence of positive margins
in radical prostatectomy specimens varies widely from institution
to institution. In addition, adjuvant therapy for these gentlemen
with locally advanced disease (pT3) is controversial. Accurate
pathologic interpretation of positive margins and seminal vesical
involvement is extremely important as these men need careful guidance
as to options of possible adjuvant therapy, available prospective
randomized trials, and the increased risk of biochemical recurrence
and eventual metastatic disease.
The treatment of men with pT3 disease with adjuvant radiotherapy
is controversial. To date, no definite benefit has been proven.
In my opinion, these men should be placed on the SWOG/RTOG intergroup
study (SWOG-3794) studying the benefit of adjuvant external beam
radiotherapy so that this question can be answered.
One of the most controversial areas is the treatment of men with
positive micro-metastases to regional lymph nodes found on frozen
section. Dr. Epstein points out in the Hopkins' series that men
with a Gleason sum less than 8 on needle biopsy have a relatively
prolonged interval before distant metastases appear. He advocates
radical prostatectomy in these patients. However, he states that
men with Gleason's grade of 8 to 10 with positive lymph node metastases
will not benefit from radical prostatectomy.
Zincke, and others, reported 370 patients in 1992 with Stage D1
disease who had undergone radical retropubic prostatectomy with
or without adjuvant hormonal therapy with a follow-up of up to
22 years . Those patients with diploid tumors had a significantly
improved survival equal to that of their normal life expectancy
when treated with immediate hormonal therapy following radical
prostatectomy. Although ploidy correlates with grade, not all
men with Gleason's score 8 to 10 will have aneuploid or tetraploid
tumors. Those men with diploid tumors and Gleason's score 8 may
significantly benefit from radical prostatectomy and early adjuvant
hormonal therapy despite their node positive status. In addition,
those men that have undergone pelvic lymph node dissection and
have micro-metastases without radical prostatectomy are often
plagued with symptoms of local progression, not to mention the
anxiety caused by knowing that they will eventually progress.
Since the morbidity of radical prostatectomy is low , it is
justifiable to control the disease locally and give these men
the benefit of the doubt from immediate hormonal therapy in addition
to radical prostatectomy.
In summary, Dr. Epstein provides an excellent review of the pathologic
evaluation of prostatic carcinoma. In addition, he personally
has provided clinicians with invaluable information by his research
and contributions in this field. The role of the pathologist is
crucial when treating the patient with prostate cancer. However,
the questions of who needs treatment and what kind, can only be
determined by the clinician and his overall evaluation of the
patient. For example, two men of the same chronologic age and
same pathology report may require two completely different treatment
plans based on other factors such as comorbidities, voiding and
sexual function or body habitus. Although we are able to make
broad statements about how men of certain pathologic stage generally
do, we must always tailor the treatment to the individual.
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3. Carter HB, Pearson JD, Metter JE, et al: Longitudinal evaluation
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