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The Pathologic Examination of Prostate Tissue
by Jonathan R. Oppenheimer, MD, FCAP
Medical Director and Chief Pathologist, Oppenheimer Urologic Reference Laboratory,
OUR Lab 1854 Air Lane Drive; Suite 17A; Nashville TN 37210
Originally Received January 8, 1997; Last Revised September 30, 1997.
Introduction |
The pathologist |
The pathology laboratory |
Tissue processing of biopsy specimens |
Making the diagnosis |
Interpretation of your pathology report |
The Pathologist as clinical consultant
Introduction
A pathologist is a physician who analyzes tissue
specimens (blood, biopsies, prostates, etc.) that other physicians send
to the pathology laboratory. From the perspective of the patient (and
of many other physicians), the pathologist/laboratory is something like
a black box: in goes the
specimen and out comes set of information leading to a diagnosis. This
article will reveal some of
the inner workings of this mysterious box and show how your pathologist may
assist you and your other physicians in the diagnosis, prognosis, and
treatment of prostate cancer.
The pathologist
Although a patient's prostate biopsy should be examined by a pathologist
who is proficient in interpreting this type of specimen, the patient (and
increasingly the urologist) rarely has the opportunity to choose his
pathologist. While the urologist may know of a pathologist with special
competence in evaluating prostate samples, the insurance company has in
most cases already contracted with a specific commercial laboratory to
handle the specimen, effectively removing the urologist's professional
opinion from this decision. Nevertheless most general pathologists are
well trained and are competent to interpret the great majority of prostate
needle biopsy and prostatectomy specimens. If general pathologists see
enough prostate specimens to gain familiarity with the subtle variations of
normal tissue and the various forms of malignancy, and if they develop a
healthy respect for the hard-to-diagnose cases (i.e., those which need to
be seen by more experienced eyes), they generally provide a valuable service.
The pathology laboratory
The pathology laboratory may be one of many types, ranging from a small
hospital-based
operation with one pathologist, to a multiple-partner group in a large
community hospital or university teaching institution, to a large
commercial corporation employing many pathologists. Generally, the larger
and the more academic the laboratory, the better the chance that one of the
pathologists will have a particular interest in prostate pathology. Some
laboratories may even specialize in urologic disease diagnosis.
A thorough evaluation of tissue takes time as well as expertise.
Unfortunately, the corporatization of medicine has led to laboratory
services being treated as a commodity in which quality is assumed and cost
becomes the decisive factor to the insurers who must pay the bill. Some of
the larger commercial laboratories may focus too much on profit margins, and
their attempts at cost containment may compromise the quality of biopsy
evaluations. Such is the fate of medicine at the close of the twentieth
century.
Becoming an informed consumer, as always, is perhaps the patient's best
defense. If the patient prompts his urologist with the right questions,
he or she
may ask the pathologist to re-evaluate the patient's tissue and thereby
identify
additional diagnostic or prognostic factors.
Tissue processing of biopsy specimens
Immediately after completing the needle biopsy, the urologist places
each of
the tissue core samples into a small vial containing a fixative (usually
10% formalin) which acts as a "pickling solution," preventing the specimen
from degrading and preserving it for further processing. During fixation
the tissue shrinks in size by a factor that must be taken into
account if the
pathologist attempts to calculate the size or volume of the tumor. The tissue
samples are then transferred to the pathology laboratory.
At the laboratory, after further chemical processing, the fixed tissue
is embedded in paraffin
cubes ("blocks") which are then cut with a very sharp knife (a "microtome")
to create
translucently thin sections. These sections are stained with colored dyes
and placed on glass slides for viewing under the microscope. Occasionally
the pathologist finds it necessary to confirm or rule out carcinoma
(cancer) by applying special immunoperoxidase stains which highlight a
specific protein (CK-903 or low molecular weight cytokeratin) which
surrounds benign, but not malignant, glands. These special studies may be
performed on material that is still in the paraffin blocks. The amount of
time that the laboratory is required to store these blocks varies from
state to state and ranges from 5 to 20 years.
At the time of the pathologist's original diagnosis, or later using tissue
remaining in the saved paraffin blocks, he or she may perform additional
tests such as ploidy analysis, which measures the chromosomal content of
malignant cells. Ploidy analysis on prostatectomy specimens has been shown
to be an important prognostic factor in predicting the spread of tumor
outside the prostate and thus the chance of recurrence after surgery. This
test also helps to predict the responsiveness of the tumor to hormonal
treatment.
Recuts are additional slides, prepared exactly like the original ones, from
tissue remaining in the paraffin blocks. They are made either because a
pathologist needs to see more tissue "deeper in the block" to confirm or
rule out a malignant diagnosis, or because slides are to be sent to a
different pathologist for a second opinion (i.e., an outside consultation).
Recutting entails extra expense to the laboratory, but the laboratory
will often absorb
this cost rather than part with its original tissue and slides.
Making the diagnosis
Fortunately, there are objective criteria which pathologists use to make
the diagnosis of cancer, but these are most easily applied on the largest
and most easily diagnosable lesions. Most pathologists now practicing were
trained before the current popularity of thin needle core biopsies.
As a consequence, many pathologists have never had formal training in the
interpretation of
such specimens. This lack of training partly explains the considerable
variation in the ability of pathologists to diagnose small lesions and to
assign consistent Gleason scores.
Fortunately (for themselves as well as their patients), pathologists learn
to be conservative in their diagnoses. There is nothing more embarrassing
(or costly to the pathologist) than making a diagnosis of cancer only to
find that the subsequently removed prostate is free of disease. Therefore,
pathologists who lacks the confidence to be definitive may undercall a
lesion, using words like "atypical," "suspicious," and "can't rule out." A
repeat biopsy may well provide the evidence necessary to make an
unequivocal diagnosis, but could perhaps have been avoided if the original
biopsy specimens had
been reviewed by someone with more experience. Caution is indeed the better
part of valor and even the most expert of prostate pathologists must
occasionally offer less than definitive diagnoses.
The same psychology that may lead a pathologist to hesitate in making a
diagnosis of cancer may be responsible for the problem of undercalling the
Gleason score (see below) when a definitive positive (cancer) diagnosis is
made on a very small lesion. The author's experience at Johns Hopkins
Hospital was
that most "2 + 2 = 4" biopsies sent for evaluation were actually 3 + 3 = 6
biopsies that had been undergraded by a general pathologist. This
phenomenon decreases the predictive value of aids such as the
Partin tables and the
Narayan tables, compilations of results from previous patients. These
tables use readily available data (typically Gleason score, clinical stage,
and PSA level) to suggest the likelihood that surgery will remove all the
tumor.
Another reason for sub-optimal diagnosis is that the pathologist might overlook
a microscopic focus of carcinoma, prompting a need for an additional
biopsy to make
the diagnosis or giving false assurance that cancer has been ruled out.
Fortunately, there have been fewer misinterpretations of a benign entity
as a
malignant one since such cases have become more widely publicized in
pathologic circles. A much more common occurrence is the failure to
identify prognostic factors (such as extensive intravascular,
extraprostatic, or significant perineural tumor involvement) that might rule out or at
least call into question aggressive treatments designed to be curative.
Interpretation of your pathology report
All prostate cancer patients are advised to obtain a copy of their own
pathology report(s); your pathology report is your
information and you have every right to have it. A careful reading of its
contents will make you a more informed patient, better able to formulate
rational treatment decisions with the aid of your urologist, surgeon, and
oncologist.
Furthermore, asking the laboratory or the urologist for a copy of the
report serves other purposes. It demonstrates your interest in being an
active participant in the important decisions that must be made, perhaps
fostering better discussion between you and your doctor. In addition, the
request will often cause the pathology laboratory to review the slides,
and can
give the pathologist the opportunity to identify additional diagnostic and
prognostic factors.
A complete report of a needle biopsy should include:
- Your name and associated individual identifiers (age, patient number,
etc.)
- The accession number of the case (usually in the form of "S-year-number,"
e.g., S-96-16258)
- A gross description of the specimen (including the number and size
of the tissue cores) removed from the prostate and received by the
laboratory
- The diagnosis, which reduced to its most basic form is either benign
(normal), atypical/suspicious, or malignant (cancer)
- The name and signature of the responsible pathologist along with the name
and address of the laboratory.
If the pathologist finds only benign (non-cancerous) tissues in the biopsies, it
may be useful for him to mention other clues he sees (e.g., marked
inflammation or signs of infection) that may explain an elevated PSA.
While such findings cannot prove that cancer is not present in an
unsampled portion of the prostate, they might indicate to the urologist
that a trial of antibiotics may be in order to treat a possible prostatic
infection (prostatitis). If the PSA then returns to normal, an unnecessary
repeat biopsy may be avoided. The PSA level may rise as a result of
the biopsy procedure, but it should decrease to
baseline levels in 4 to 6 weeks.
Many benign conditions mimic the appearance of prostate cancer. The two
most troublesome to pathologists are atrophy and a marked inflammatory
reaction called
granulomatous prostatitis. Your urologist can explain these conditions to
you if they
appear in the pathologist's report.
High-grade prostatic intraepithelial neoplasia (PIN),
although itself a
nonmalignant condition, often occurs in conjunction with cancer. A repeat
biopsy on men with a previous diagnosis of high-grade PIN demonstrates cancer in up
to half of the cases. Low-grade PIN is not important and probably should
not even be mentioned in the biopsy report.
If a malignant diagnosis is made, it is imperative that a
Gleason grade be
assigned. The grade describes how closely the malignant glandular
microstructures resemble normal ones, with a lower number being closer to
normal and describing a tumor with less potential to spread. The Gleason
score is the sum of the two Gleason patterns which the pathologist believes
best characterize the tumor. Thus a score of 3 + 4 = 7 means that the
pathologist sees predominantly pattern 3 and a secondary pattern of 4. The
"grade" is really a synonym for the "pattern," but unfortunately is used
(even by pathologists) to mean "score." Putting this information in the
form of a mathematical equation helps to prevent misunderstanding.
An accurate assessment of Gleason grades and score is the single most
useful factor in predicting the course of the disease and the probable
outcome. For this reason, pathologists should provide these numbers. Terms
like "low grade tumor" or "moderately differentiated adenocarcinoma" are
not as reproducible and do not substitute for Gleason grade and score.
The pathologist should indicate the amount of tumor present on each core
(measured as percent of core involvement and length in millimeters) as well
as the particular location involved (apex, base, transition zone, side of
prostate, etc.) since this information may be useful in estimating the
total size of the tumor and in predicting the extent of tumor (staging)
found after possible prostatectomy.
Seminal vesicle involvement, tumor cells located within blood vessels
(called intravascular involvement), and extraprostatic extension of
malignant glands may occasionally
be identified in needle cores. In addition to assigning an accurate Gleason
grade, a pathologist who has had experience
correlating routine slides with formal ploidy studies can often make a good
estimate of DNA ploidy (a determination of gross chromosome
abnormalities) simply by evaluating the routinely stained glass slide.
The pathologist should note the presence of perineural invasion, a phenomenon
in which the tumor is present within a nerve and follows the course of that
nerve. The significance of perineural invasion (sometimes also called
perineural involvement) is controversial at present. Although it has been
associated with extension of the tumor beyond the capsule of the prostate,
it is my personal opinion at this time that this risk is only
of considerable significance if it applies to the large-sized nerves
located outside the prostate or if the perineural component of the tumor
demonstrates a Gleason pattern of 4 or 5. (Note: This is a Gleason
pattern, not a Gleason sum.)
If your biopsy report contains the phrase "outside consultation," the
pathologist recognized the case as difficult and sent it to another
institution for a second opinion.
Pay particular attention to words such as "atrophy," "atypical
hyperplasia," "atypia," or "atypical glands," all of which indicate that
the pathologist may have seen something abnormal in the specimen.
Don't be concerned about mention of "rectal" or "colonic" tissue; such a
finding is irrelevant. Small fragments of bowel lining (mucosa) are very
common in needle core biopsies since the needle has to punch through this
tissue to get to the prostate. The body quickly produces more mucosa to
plug up the tiny hole.
Postsurgical pathology reports
One of the most important pieces of information to be obtained from the
postoperative pathology report is the assessment of surgical margins and
of capsular penetration. "Organ-confined" tumor is tumor within the
confines of the
anatomical prostate (i.e., within the outer shell of the "walnut").
Established capsular penetration means that more than a few glands are
found outside the normal confines of the prostate.
When the surgeon removes the prostate, he often includes a thin rim of
nonprostatic soft tissue that surrounds the prostate. The outer aspect of
this soft tissue constitutes the surgical margin. A report of negative
margins means that the pathologist found no evidence of cancer at the outer
edge of the tissue the surgeon removed. Conversely, a finding of positive
margins means that all cancer cells might not have been removed.
One may take such information as the presence of capsular penetration and
the status of surgical margins and combine it with Gleason score and PSA to
estimate whether the cancer was or was not completely removed by surgery.
Such a determination may suggest the early use of additional salvage
treatments such as radiation and/or hormonal therapy.
If hormonal therapy has preceded the surgery (neoadjuvant therapy), careful
examination of the removed tissue will tell if the therapy was successful
in stopping the growth of the cancer, or whether hormone-insensitive cancer
cells have continued to proliferate. Pathologists should not attempt to
establish Gleason grades on such hormonally-treated tissue; the changes
resulting from the hormone treatment cause an artificial increase in
perceived grade.
Other items of note that may appear on the postsurgical pathology report
include seminal vesicle involvement, intravascular involvement, involvement
of nerve twigs at the periphery of the gland, size of tumor nodule(s) with
calculation of volumes, presence of intraductal features, and the
percentage of poorly differentiated tumor (Gleason pattern 4 and above)
within the tumor.
The pathologist as clinical consultant
Your pathologist may help you and your care-givers in the interpretation of
such laboratory tests as free PSA, PSA velocity, and prostatic acid
phosphatase (PAP). They may also help to evaluate the ultrasensitive PSA
tests that warn of early tumor recurrence. This information can help you
and your urologist in the decision to initiate adjuvant therapy early, when
it may be most effective.
Understanding your pathology and laboratory reports will help you become a
more active and informed participant in the medical decisions that will
affect your future. Your pathologist can help you in this process.
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