Sperling Prostate Center

How Much Gleason Pattern 4 Is Worth Worrying About?

UPDATE: 11/5/2021
Originally published 4/4/2016

In the 5+ years since we posted the blog below, a new grading system called Gleason grade group has simplified the two-number system, which was confusing for patients. For example, in Gleason 7 prostate cancer (PCa), what’s the difference between 3+4 = 7 and 4+3 = 7? In the new system, Grade Group 2 (3+4) is more favorable risk than Grade Group 3 (4+3). The difference is, when pattern 4 is listed first, it means a greater proportion of 4 than 3. This indicates the disease is evolving in an aggressive direction.

Besides the news about the new grading system, there’s also a new realization about a specific PCa cell formation that appears to be more prevalent in Gleason pattern 4. Cribriform PCa is a “… pattern of invasive prostate cancer [that] is associated with adverse pathologic features and leads to uniquely adverse outcomes. Sixteen papers and numerous abstracts have reached these conclusions concordantly.”[i] It has been suggested that the presence of any amount of cribriform cell architecture automatically be designated as at least Gleason pattern 4.

That said, not all Gleason pattern 4 has cribriform cells. Thus, by way of updating the original blog, we would add the question, “What type of Gleason Pattern 4 is worth worrying about?” In other words, if biopsy slides are positive for cribriform PCa, it should be a red flag that worry is well justified, and aggressive treatment should be considered. scenarios…


When it comes to the debate over significant vs. insignificant prostate cancer (PCa), these are interesting times. For instance, some experts are now suggesting that Gleason 6 (3+3) PCa does not behave like cancer. By this they mean that not all cases of Gleason 3+3 grow in size or become more aggressive. They raise the question, if Gleason 3+3 doesn’t progress, does it need to be treated? And if it doesn’t, then it is considered insignificant.

So what makes a PCa tumor “significant”? There is no clear definition. However, the presence of Gleason pattern 4 (GP4) usually sends up a red flag. Here are the possible Gleason scores with pattern 4, in order from least aggressive to most aggressive:

Gleason 3+4

Gleason 4+3

Gleason 4+4

Gleason 4+5

Note that Gleason 3+4 is the least worrisome because there is a greater percentage of GP3 as indicated by being the primary (first) number. But how much GP4 should a patient be worried about? Put another way, what percent of GP4 is likely to be a predictor of recurrence after treatment?

I came across a study that actually measured percentages of Gleason pattern 4 in needle core biopsy specimens.[i] It’s rather astonishing to think that a percentage of certain cell types can be accurately measured in a microscopic thread of cancer. The authors sought to establish a cut-off point above 6% GP4 that would correlate with increased risk of recurrence. They obtained their data from radical prostatectomy (RP) patients for whom they had biopsy records so they could compare pre-RP Gleason percentages with RP patients who eventually experienced post-surgery disease progression, or rising PSA. They included the following variables in their statistical analysis:

  • Quantity of GP4 in biopsy cores
  • Number of positive cores
  • Percentage of core tissue scored as positive for PCa
  • Pre-op PSA
  • Perineural invasion (PNI) at time of RP
  • Clinical stage

What they found is good news for patients with Gleason 3+3, or patients with GP4 less than 6%. These two types of patients “did not differ significantly in terms of biochemical PSA recurrence…” However, patients with 6-25% GP4 tissue, 26-49% GP4 tissue, Gleason 4+3 were more likely to experience recurrence. They concluded, “Our data suggest that the quantity of GP 4 tissue in GS 7 cancer has clinical significance.” They caution that more research is needed, but raise the question as to whether the percent of GP4 “should be included in standard pathology reports.”

I don’t think we’ll resolve the issue of significant PCa any time soon, but perhaps there’s a message here that GP4 greater than 6% should definitely have 3T multiparametric MRI and genomic analysis before making a treatment decision.

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] Iczkowski KA, Paner GP, Van de Kwast, T. The New Realization About Cribriform Prostate Cancer. Advances in Anatomic Pathology. 2018 Jan; 25(1):31-37.
[ii] Kir G, Seneldir H, Gumus E. Outcomes of Gleason score 3 + 4 = 7 prostate cancer with minimal amounts (<6%) vs ?6% of Gleason pattern 4 tissue in needle biopsy specimens. Ann Diagn Pathol. 2016 Feb;20:48-51.


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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