Why pathologists may disagree

Nancy Ferrari

Senior editor, Harvard Health

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,” below). 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.

Variations in practice

Amin M, Boccon-Gibod L, Egevad L, et al. Prognostic and Predictive Factors and Reporting of Prostate Carcinoma in Prostate Needle Biopsy Specimens. Scandinavian Journal of Urology and Nephrology Supplement 2005; 216:20–33. PMID: 16019757.

Egevad L, Allsbrook WC Jr, Epstein JI. Current Practice of Diagnosis and Reporting of Prostate Cancer on Needle Biopsy Among Genitourinary Pathologists. Human Pathology 2006;37:292–97. PMID: 16613324.

Epstein JI, Srigley J, Grignon D, et al. Recommendations for the Reporting of Prostate Carcinoma. Virchows Archiv: An International Journal of Pathology 2007;451:751–56. PMID: 17674043.

Kao J, Upton M, Zhang P, Rosen S. Individual Prostate Biopsy Core Embedding Facilitates Maximal Tissue Representation. Journal of Urology 2002;168:496–99. PMID: 12131296.

Ohori M, Kattan MW, Koh H, et al. Predicting the Presence and Side of Extracapsular Extension: A Nomogram for Staging Prostate Cancer. Journal of Urology 2004;171:1844–49. PMID: 15076291.

Rubin MA, Bismar TA, Curtis S, et al. Prostate Needle Biopsy Reporting. American Journal of Surgical Pathology 2004;28:946–52. PMID: 15223967.

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 1).

Table 1: When to consider a second biopsy

It’s always wise to seek a second opinion about your original biopsy, by having another pathologist review your pathology report and your biopsy slides. In the following circumstances, you may want to consider undergoing a second biopsy, possibly at a medical facility that performs saturation biopsies.

Situation during initial biopsy Why it is a concern
Only six cores were taken during the original biopsy. The standard number today is 12; some centers take 20.
Your cores were not individually labeled. This can cause confusion about the location and aggressiveness of the cancer.
Anatomic location, indicating where the cores came from, is not included in the pathology report. Location of the cancer helps guide treatment decisions, as it helps to determine how aggressive the cancer is and what type of side effects you may experience after treatment.
Your combined Gleason score is 4 or lower. This type of score is rare. Studies have shown that when these biopsies are later reviewed by expert urologic pathologists, the score usually rises, meaning the cancer is worse than was initially thought.
You are told you have an atypical finding, so cancer cannot be confirmed or ruled out. Great disagreement exists about what constitutes an atypical finding; about half of men who initially have this diagnosis will eventually discover they have prostate cancer.
You are told you have high-grade PIN. A follow-up biopsy is always recommended; the question is when.

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.

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.

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).

Originally published Oct. 1, 2007; last reviewed April 27, 2011.


  1. Don

    Please give Glen a hug for me. And if you can somehow wrap your arms auornd yourself, that can be from me, too. Peaceful, healing vibes are heading westward as we speak

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