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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


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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The content in this section of the Phoenix 5 site was originally developed by CoMed Communications (a Vox Medica company) as part of The Prostate Cancer InfoLink. It is reproduced here with the permission of Vox Medica.

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