Understanding your prostate pa... Health Article

What it contains, what it means, and why asking questions about it can lead to better care

At least initially, the pathology report is one of the most important factors in the management of your prostate health, especially if you have been diagnosed with cancer. For example, it can provide valuable information about the location and extent of the cancer, thus helping your physician decide whether to recommend active surveillance, hormone treatment, radiation therapy, or surgery.

With that in mind, you might think that preparing and reading a pathology report would be straightforward — but unfortunately the opposite is true. Pathology reports are not prepared uniformly (compare Figures 4 and 5, for example). In fact, they can vary considerably even within a single institution. They may not be labeled thoroughly or contain enough specifics for you and your doctor to make a good treatment decision.

At the same time, the information that is included in the report may be difficult to decipher. You may also get conflicting interpretations depending on how the report was prepared and who is reading it. It is entirely possible for two pathologists to look at the same biopsy slides and yet disagree about whether you have cancer!

In this article you will learn why such disagreements can happen, what your pathology report should include, and how you can make sense of the information it contains. You will learn when to get a second opinion about the pathology report and why it is sometimes necessary to have a repeat biopsy. And you will learn what questions to ask to obtain the information you need to decide which treatment is best for you.

Deconstructing the report

It is always a good idea to request a copy of your pathology report. A thorough reading will give you the information you need to have informed discussions with your urologist, surgeon, and oncologist, and better guide any decisions you need to make about what to do next.

If the findings on the pathology report are abnormal, it is likely that the diagnosis will fall into one of three major categories:

1. An atypical finding

2. High-grade PIN

3. Prostate cancer (adenocarcinoma).*

An atypical finding means that the pathologist cannot confirm or rule out cancer. Sometimes this finding is reported as "suggestive of" or "suspicious for" cancer but not diagnostic of cancer. This frustratingly equivocal diagnosis usually means that the pathologist looked at the tissue on the slides and saw cells that were not typical, but they were not abnormal enough to classify as cancer (see "What makes it cancer?").

There is no consensus about the correct terminology to use for such lesions. Often you'll see the term atypical small acinar proliferation, or ASAP, but it could also be labeled atypical hyperplasia, atypia, atypical glands, or focal glandular atypia.

Fortunately, such atypical findings are reported in only about 8% of pathology reports, according to a review of 39 studies involving needle biopsy specimens. But the trend toward doing more biopsies and finding smaller cancers has led to an increase in atypical diagnoses. Studies have shown that nearly half of the men who receive such an atypical diagnosis initially will find they have prostate cancer during a follow-up biopsy. This happens regardless of PSA levels or results of a digital rectal exam (DRE), which appear to be unrelated. In addition, compared to other pathologic diagnoses, atypical findings have the highest likelihood of being changed on expert review, usually to a diagnosis of cancer.

High-grade PIN, short for prostatic intraepithelial neoplasia, is another broad diagnostic category. This finding involves a subjective reading of the pathology slides and also generates debate about follow-up and treatment. It is now thought that high-grade PIN might increase a man's risk of developing cancer, but because the steps involved in cancer progression are still elusive, the degree of risk remains unclear. It is usually not considered an important factor when associated with a definitive diagnosis of cancer. For a more complete discussion of this issue, see "Prostatic intraepithelial neoplasia (PIN)."

Beyond these basic distinctions, and sometimes even within them, things can get hazy. The pathologist weighs numerous complex factors when making these broad diagnostic statements, and if you have been given a prostate cancer diagnosis, the report usually contains descriptive information about the type, amount, and grade of cancer found. All of these factors can affect risks and influence treatment decisions.

For all these reasons, your pathology report is not something you should skim but rather scrutinize. It is important to understand every component, discuss how the pathologist arrived at his or her conclusions (or lack thereof), and share the details with every physician involved in your care. The major components of a good pathology report are reviewed here briefly.

Gleason score

If your biopsy finds cancer, the first piece of information you'll want to note is the Gleason score. This numerical value grades prostate tumor cells according to how they look compared with normal cells and how mutated they appear under a microscope, a quality known as differentiation. (Normal cells are well differentiated and cancer cells are not.) Because tumors often consist of multiple cell types, the pathologist assigns two values between 1 and 5: the first to the predominant cell type, and the second to the next-most-prevalent cell type (see Figure 2). The sum, ranging from 2 to 10, is the Gleason score; the higher the number, the more aggressive the cancer.

Figure 2: The Gleason score The Gleason score is a numerical value that grades prostate tumor cells according to how they appear compared to normal prostate cells (a quality known as differentiation). Because tumors often consist of multiple types of cells, the pathologist assigns two values: the first to the predominant cell type, and the second to the next-most-prevalent cell type. These two values are added to come up with the Gleason score. Well differentiated Glandular cells are small, of fairly uniform shape, and tightly packed together. Cells display more varied and irregular shapes and are loosely packed. Moderately differentiated Cells are even more irregular in size and shape and are more dispersed; some cells are fused, and cell borders are less distinct. Poorly differentiated Many cells are fused into irregular masses; some cells (see those darkly shaded) have begun to invade the connective tissue that separates cells. Most of the tumor consists of irregular masses that have invaded the connective tissue.

The Gleason score is one of the most important factors in determining whether the cancer is likely confined to the prostate and how aggressive it is (see Table 3 for a quick guide to what the scores mean).

Number of cores

An ideal report also specifies how many samples, or cores, were removed during the biopsy. The standard number of cores used to be six: three from the right side of the prostate and three from the left. However, this limited sampling meant that cancerous portions of the prostate, if there were any, might be missed. As a result, as many as one in four patients eventually diagnosed with prostate cancer was told, on the basis of the initial biopsy, that he did not have cancer — meaning that the test provided a false-negative finding.

Today, most doctors agree that an initial biopsy should include at least 10 to 12 core samples. In certain situations, some doctors recommend doing a saturation biopsy, which typically removes 12 to 14 cores — and sometimes as many as 20 or more — but less agreement exists about this practice.

Anatomic location

Ideally, the pathologist who prepares your report will have separated and labeled the core samples according to what part of the prostate they came from. This labeling will tell you and your doctors whether the cells came from the right or left side and whether they were drawn from the apex (counterintuitively, at the bottom), mid zone (middle), or base (top) of the prostate. In a saturation biopsy you may see even more detailed labels, such as RMA and RMB to differentiate between the right mid zone near the apex and the right mid zone closer to the base. Similarly, the report may refer to three zones: the peripheral, central, and transition zones (see Figure 3). All of this information can be invaluable in helping to determine the general location of the tumor, which helps guide treatment decisions.

Figure 3: Zones of the prostate To help your doctor more precisely determine the location of prostate cancer or another condition, such as high-grade PIN, your pathology report may name specific areas. For example, it may refer to the apex, located at the bottom of the prostate; the base, at the top; or the mid zone, the area between the apex and base. Alternatively, it may note three zones: the peripheral zone (1), the central zone (2), and the transition zone (3). Seventy percent of prostate cancers arise in the peripheral zone. Few arise in the anterior prostate.

Extent of cancer

In addition to paying attention to the number of cores taken, you'll want to look at how much cancer was found. This information may be provided as the number of positive cores, the length of cancer in millimeters among all cores, the percentage of cancer per core, the fraction of positive cores, or the total percentage of cancer in the entire specimen. Regardless of the type of measurement, your doctor can use this information to determine the likelihood that the cancer is confined to the prostate or has spread.

Clinical data

In the clinical portion of the report, you may see notes from your physician to the pathologist offering any relevant information about why the biopsy was performed and what the physician is looking for.

Gross description

Your pathology report should also include a gross description with such important identifying information as the container in which the tissue was shipped to the department, length of various pieces of tissue, their color, and how the tissue is labeled.

Don't be alarmed if you see mention of rectal or colonic tissue. Small fragments of bowel lining (colonic mucosa) are common in needle core biopsy specimens since the needle has to poke through this tissue to get to the prostate.

Comments

Sometimes, you will find notes to your physician or urologist in a section labeled "Comments." This may be an important source of additional information such as whether the pathologist has found high-grade PIN or any atypical tissue. This section may also describe various features of the tissue and offer clues about the pathologist's thinking, especially if the final diagnosis is not entirely clear.

Identifying details

Last, the report should include identifying information such as your name, age, and patient number, and the date, as well as the name and signature of the pathologist who prepared the report, the name of the person who performed the biopsy, and the name and address of the laboratory.

Why pathologists may disagree

Consider this all-too-common scenario: One pathologist decides a cancer diagnosis is "definitive," but another, looking at the same biopsy results, calls it "suspicious," but not necessarily cancer. Who is right, and why do pathologists disagree?

The main reasons for disagreement are explored briefly below (and you can read more about these issues by consulting the studies listed in "Variations in practice"). Some disagreements involve objective factors, such as how biopsies are done. Usually, though, pathologists disagree when it comes to interpretation and judgment — both subjective qualities.

The pathologist's experience level and subtle biases also come into play. One small study has shown that factors such as the age of the pathologist — as well as the age of the patient — can play a role in whether or not an ambiguous finding is diagnosed as cancer. This study found that pathologists older than 50 were more likely to require greater evidence of abnormalities before diagnosing cancer than were their younger peers, and that some pathologists were more likely to diagnose cancer in men 70 or older than in those younger than 60.

Suffice it to say, it's always a good idea to ask a second pathologist to review your pathology report and take a second look at your biopsy tissue (usually contained in slides that can be transported from one medical facility to another). This ensures that at least two pathologists agree on the diagnosis, which will give you and your doctor more confidence in developing a treatment plan. However, in certain circumstances you may want to undergo a second biopsy (see Table 4).

Variability in sampling and labeling

There is little uniformity among medical facilities with regard to the number of cores removed during a biopsy and how they are labeled. Sometimes the cores are submitted to the pathology lab in two containers labeled simply "right" and "left," referring to the side of the prostate they were taken from. Or worse, the cores are jumbled in a single container without any location specified. In this situation you may end up with an overall Gleason score that averages all involved needle biopsy specimens as if they were one long positive core. This is far from ideal, and may be one reason to consider having a biopsy repeated.

Knowing the anatomic location of any cancerous tissue is important for a number of reasons. This information helps to determine whether cancer is unilateral (confined to one side of the prostate) or bilateral (affecting both sides), and to estimate how likely it is that the cancer has spread or might do so in the future.

For instance, if cancer-containing cores are removed from the base of the prostate gland, the tumor is probably located near the seminal vesicle, which stores prostatic secretions and semen. (If cancer is in the seminal vesicle, it has migrated out of the prostate, signaling that more-widespread cancer may be present.) On the other hand, if the cancer is at the apex, it may impinge on the bladder neck or lower bladder, posing challenges for the surgeon, who wants to remove the entire cancer without affecting continence. Clearly these represent very different scenarios when it comes to treatment and potential side effects such as erectile dysfunction or incontinence.

In addition, the anatomic location of specimens helps pathologists recognize and try to avoid certain diagnostic pitfalls: for instance, the tendency to confuse benign seminal vesicle tissue with high-grade PIN at the base of the prostate, or to mistake the Cowper's gland, located adjacent to the urethra, for cancer at the apex. Details about location are also useful in making sure the same site is targeted in a repeat biopsy. In addition, mapping the distribution of cancer may help in planning the field of radiation therapy or influence decisions about nerve- or bladder-neck–sparing surgery during radical prostatectomy.

Another reason for knowing the location of the cancer is that this information can help determine whether extracapsular extension (ECE) — the spread of prostate cancer beyond the outer lining of the prostate — has occurred. Scientists have developed mathematical models known as nomograms that use systematic analysis of biopsy results from each lobe of the prostate, combined with PSA levels and digital rectal exam results, to predict the likelihood of ECE before planning treatment. (See "What's a nomogram?" for more information.)

Pathology reports may also vary in the way that they describe the extent of cancer. Sometimes you'll see the measurement noted as a percentage of positive cores, other times as a percentage of tissue in the positive cores, and other times as a length of cancerous tissue in positive cores. It's not clear which measuring system is best. Even more problematic, many reports omit this type of information completely, leaving your doctor without details that could help determine whether the cancer is confined to the prostate or has spread beyond its surrounding capsule or into other areas of the body.

Variations in Gleason scoring

Different pathologists may also assign a different Gleason score to the same biopsy sample. Pathologists determine the grade of a lesion visually. Therefore, the score is only as good as the pathologist examining the tissue, as well as the quality of the tissue itself. One pathologist may grade a given biopsy a 3 + 4 (moderate risk) while another may interpret the same tissue as 4 + 3 (higher risk; see Table 3). In other situations, the discrepancy is even greater, to the point where one pathologist calls the cells cancer and another does not.

Another slippery area involves small amounts of cancer limited to a specific area, with a single Gleason pattern. Different pathologists report this finding in different ways. Some may assign a total Gleason score, while others may note only a single pattern. Others may not score it at all.

Different opinions about perineural invasion

Your pathology report may contain a finding of perineural invasion (PNI). Not to be confused with PIN, PNI describes cancer that tracks along or around a nerve. There is no consensus as to the clinical significance of such a finding.

One small study, involving 42 highly experienced urologists, found that most did not consider a finding of PNI important and fewer than half thought it should even be included in a pathology report. But 10 of the urologists — almost a quarter of the group — thought that PNI was clinically important, and said it would guide their treatment recommendations. For example, they said they would not perform nerve-sparing surgery on the side of the prostate where PNI was found on needle biopsy. Interestingly, the more radical prostatectomies the surgeons had performed, the more likely they were to consider PNI clinically important. (For one physician's thoughts on PNI, see "Another perspective on PNI.")

Problems distinguishing benign mimics

Numerous benign mimics of prostate cancer exist, but these can be difficult to distinguish from cancer. The most common mimics are partial atrophy of tissue and crowded benign glands. Others include complete atrophy of tissue, adenosis, seminal vesicle tissue, and granulomatous prostatitis. If you see any of these terms on your report, be assured they are no cause for apprehension. But they can be tricky for pathologists to identify.

Because of the challenges posed by benign mimics, a diagnosis of cancer will often be verified by immunohistochemistry (IHC), which uses certain antibodies to stain for cancer or its mimics. Just be aware that occasionally this process can produce both false-positive results (indicating cancer is present when it is not) and false-negative results (ruling cancer out when it is present).

Questions to ask before deciding on treatment

It should be clear by now that pathology reports vary in large part because the clinical features they analyze often require some subjective interpretation. This means it's important to question the findings and make sure you understand them.

Start by studying your pathology report closely. Circle anything that doesn't make sense to you. Let your doctor know how much you know, and ask questions until you are satisfied that you understand the report and both the pathologist's and your physician's thinking.

In particular, look for information about the location and extent of your cancer. If the information is not available in the report, find out why. If your report appears to be incomplete or has not been closely examined or explained, do not hesitate to get a second opinion or request a second biopsy (see Table 4).

Table 5 provides some suggestions about what questions to ask. Although it may feel uncomfortable at first to question your doctor, keep in mind that learning the answers will help you work with your doctor to make the best treatment decisions. After all, you are the one who has to live with the consequences.