Sperling Prostate Center

Gleason 6 Revisited

UPDATE: 7/12/2021
Originally published 6/22/2015

At the time we posted the blog below on Gleason 6 prostate cancer (PCa) tumors that don’t seem to behave like cancer, new terms like “indolent PCa” and “insignificant PCa” were showing up in published studies. The growing use of these terms signaled recognition that a) not every low-risk PCa tumor needs to be treated immediately, and b) some PCa tumors may never need to be treated at all!

The word indolent means lack of activity; in medicine, it means causing little or no pain. Regarding the word significance, we posted a 2016 blog stating that the most widely used definition of insignificance was the Epstein criteria: Tumor volume < 0.2cm, primary (first number) Gleason < 6, and organ-confined PCa. Anything above those criteria was considered significant. In other words, small localized tumors that are composed largely of Gleason 6 PCa are generally safe for Active Surveillance that included routine interval monitoring by means of PSA blood tests and multiparametric MRI of the prostate. In addition to PSA and MRI, more recent tissue and urine tests at the time of biopsy offer biomarkers that can reveal genomic evidence distinguishing between indolent vs. aggressive PCa.[i, ii], This gives doctors and patients a very high degree of confidence when considering holding off on treatment—maybe forever.

On the other hand, we posted a cautionary statement based on studies of patients whose Gleason 6 tumors eventually appeared to move into a higher PCa grade. The truth is, we are not yet at a point where we can predict with 100% certainty that an individual’s Gleason 6 will never progress. The solution, then, for thousands of men considering Active Surveillance is focal therapy such as our Focal Laser Ablation. This “male lumpectomy” approach is a middle ground between no-treatment and whole-gland treatment. It offers greater peace of mind (as well as the possibility of lifelong cancer control with no further treatment) than living with untreated PCa in the gland.

In the 6+ years since the original blog below, focal therapy is a giant step toward the life and lifestyle PCa patients desire.


When is a cancer not a cancer? That is the question when it comes to Gleason 6 (3 + 3) prostate cancer (PCa). It’s a hot topic that has a lot of researchers and clinicians stumped. While the majority of urologists and radiation oncologists view Gleason 6 as true PCa, there is high level international debate on the subject.

What is the Gleason score?

The Gleason score (or Gleason grade) system was developed in the 1960s by pathologist Donald Gleason at the Minneapolis VA Hospital. Tissue specimens obtained from a prostate needle biopsy are examined under a microscope. What’s being scored is the appearance of the cells, that is, on a scale of 1 to 5, how much do they appear like normal cells, and how much like cancer (where 1 is normal). It is not a genetic or molecular evaluation, but rather a structural evaluation based on five patterns.

Pattern 1 – The tissue has small, well-formed closely packed glands that are considered to behave normally.

Pattern 2 – The glands are still well-formed but they are larger with more tissue between them.

Pattern 3 – The glands are still recognizable but the cells are darker; some have left the glands and are beginning to infiltrate surrounding tissue. This is considered a moderately differentiated PCa.

Pattern 4 –There are few recognizable glands. Many cells are behaving as invasive tumor cells, and are considered a poorly differentiated PCa—it is quite advanced in its development as cancer.

Pattern 5 – There are few or no recognizable glands, and is a full-blown aggressive cancer.

The biopsy samples are tiny threads of tissue captured in a hollow needle core. The Gleason score is always reported as a sum of two numbers. When a pathologist views each core sample, he/she is looking for the largest percentage with > 50% abnormal pattern; that pattern’s score will be the 1st number because it is the dominant pattern. The next largest sample (percentage of abnormal cells between 5 – 50%) will be the 2nd number. The two scores are summed. Here are a few examples:

Gleason 3 + 3 = 6

Gleason 3 + 4 = 7

Gleason 4 + 3 = 7

There are two sums that equal 7, but 4 + 3 is more worrisome than 3 + 4, because the dominant pattern is more extensive and aggressive than the secondary pattern.

Huge strides have been made in understanding the varieties of prostate cell lines and how they differ. Studies on men with Gleason 6 who go on active surveillance (AS) show that some have tumors that never progress. Imaging shows that their tumors don’t grow, and biopsy shows that their Gleason score doesn’t progress higher. These cancers are called “indolent” which means they appear to be inactive. Since all cancers are known to eventually spread uncontrollably without treatment, what are we to make of biopsy-proven cancer cells that defy that belief? After all, there is no guarantee that a single Gleason 6 cell wouldn’t mutate into a rogue form of PCa and begin quickly replicating itself. On the other hand, if a patient has an indolent tumor, why put him through an aggressive treatment with its risks of side effects that damage quality of life if his PCa never would have shifted gears?

A rather large group of authors (Eggener et al. 2015) weighed in on this matter after an extensive review of the literature.[iii] They note that while Gleason 6 is the most widely diagnosed form of PCa due to PSA screening, “…considerable debate exists regarding the genetic features, clinical significance, natural history, metastatic potential and optimal management.” They ask if it meets “…commonly accepted molecular and genetic features of cancer.” In short, are we finding cancers that don’t need to be treated?

The authors point out that this is a big enough concern to consider ways to cut down on overdiagnosis of Gleason 6, such as

…modifications to PSA-based screening strategies such as targeting high-risk populations, decreasing the frequency of screening, recommendations on screening cessation, incorporation of remaining life expectancy estimates, shared decision-making, novel biomarkers, and eliminating PSA screening entirely.

They support a strategy of observation in the form of AS as a way for patients and their doctors to monitor and manage Gleason 6, since this avoids exposure to the risk of side effects. We know, however, that many patients find AS psychologically challenging, fearing that a time bomb is ticking in their pelvic bed; at the same time, they dread TRUS re-biopsies, which can be unpleasant and inaccurate.

At the Sperling Prostate Center, we are in dialogue with global experts on the issue of Gleason 6 as indolent or potentially dangerous. We recognize that the jury is still out. Help is on the way in the form of genomic testing that is increasingly available and that can identify biomarkers signaling the roughly 15% of Gleason 6 cancers that are more lethal than meets the eye (on the microscope). Our Center offers a way to support AS via the integration of 3T multiparametric MRI, which can detect a shift from an insignificant to a significant tumor, and in conjunction with periodic blood tests such as PSA, fPSA and tPSA, or urine tests (PCA3) we have given hundreds of men peace of mind knowing that if an idle cancer starts to “wake up” we can do an mpMRI targeted biopsy to get a close look at the cellular activity.

Thus, we can offer today’s Gleason 6 PCa patient the best pathway to track disease activity while enjoying peace of mind.

NOTE: This content is solely for purposes of information and does not substitute for diagnostic or medical advice. Talk to your doctor if you are experiencing pelvic pain, or have any other health concerns or questions of a personal medical nature.

[i] Kohaar I, Chen Y, Banerjee S, Borbiev T. A urine exosome gene expression panel distinguishes between indolent and aggressive prostate cancers at biopsy. J Urol. 2021 Feb;205(2):420-425.
[ii] Cooperberg MR, Cowan JE, Lindquist KJ, Kobayashi Y et al. Multiple Tissue Biomarkers Independently and Additively Predict Prostate Cancer Pathology Outcomes. Eur Urol. 2021 Jan;79(1):141-149.
[iii] Eggener SE, Badani K, Barocas DA et al. Gleason 6 Prostate Cancer: Translating Biology Into Population Health. J Urol. 2015 Apr 4. pii: S0022-5347(15)03689-7. doi: 10.1016/j.juro.2015.01.126. [Epub ahead of print]


About Dr. Dan Sperling

Dan Sperling, MD, DABR, is a board certified radiologist who is globally recognized as a leader in multiparametric MRI for the detection and diagnosis of a range of disease conditions. As Medical Director of the Sperling Prostate Center, Sperling Medical Group and Sperling Neurosurgery Associates, he and his team are on the leading edge of significant change in medical practice. He is the co-author of the new patient book Redefining Prostate Cancer, and is a contributing author on over 25 published studies. For more information, contact the Sperling Prostate Center.

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