“When it comes to prostate cancer (PCa), perhaps the single most important thing a patient should know is the degree to which his PCa is dangerous.” I posted that declaration in a 2020 blog on the Gleason Grade Group system. A precise diagnosis allows treatment to be tailored to the disease, but it appears that low-risk PCa is not as easy to diagnose as one would think.

There is universal agreement that such a creature as low risk PCa exists. Tissue from a prostate biopsy is graded (Gleason score) based on the appearance of abnormal cells. The more they resemble normal tissue, the lower the Gleason score. The Prostate Cancer Foundation offers a good explanation of both Gleason grading and Grade Group, showing that low-risk PCa can be defined either way:

• PCa less than or equal to Gleason grade 3+3=6
• Grade Group 1 (GG1)

Debate over what to call GG1 Prostate Cancer

Universal agreement evaporates, however, over the issue of how dangerous it is. To put it bluntly, is Gleason grade 3 (or GG1) truly cancer? Debate continues over questions such as a) does Gleason 3+3 behave like cancer, b) can GG1 progress to a higher grade, or c) does it have invasive capabilities? There are distinguished experts like these two, who propose that GG1 does not behave like cancer, and perhaps should not even be called cancer:

1. Laurence Klotz (Clinician, researcher; Sunnybrook Health Sciences Center) – “… we know much more about how the molecular genetics of Gleason 3 and 4 compare, and they are like night and day. … The corollary of that is the metastatic potential of Gleason 3 is now acknowledged to be essentially zero.”^[i]
2. Matthew Cooperberg (Urology professor, researcher; University of California San Francisco) – “GG1 is not normal—but neither is it cancer. It is a premalignant finding indicating close surveillance but rarely immediate treatment. In 2023, its definition and label should reflect this contemporary understanding of its place on the biological continuum.”^[ii]

On the other hand, there are worthies who maintain that GG1 is true cancer:

1. Jonathan Epstein – (Pathology professor, researcher; Johns Hopkins) – “…morphologically, GG1 may be indistinguishable from GG2 to GG5 and GG1 is invasive (lacks basal cells), can show perineural invasion and extraprostatic extension; molecularly, GG1 has many of the hallmarks of prostate cancer … There is strong support for retaining the carcinoma designation for GG1.”^[iii]
2. Panel of experts (Clinicians, oncologists, biologists; Netherlands Cancer Institute) – “We characterized the molecular activity of the androgen receptor protein, which drives prostate cancer disease, in low-grade tumors. Our results show that these tumors are true cancers and are clearly separate from benign prostate tissue despite their low clinical aggressiveness.”^[iv]

While the jury is still out, the all-important question remains: how can we match treatment to low risk PCa if we don’t really know what it is? Hence the call for more utilization of Active Surveillance (AS). “Grade group 1 (GG1) primary prostate cancers with a pathologic Gleason score of 6 are considered indolent and generally not associated with fatal outcomes, so treatment is not indicated for most cases.”^[v] Both Klotz and Cooperberg are advocates for going on AS in order to avoid clobbering a mouse with an elephant gun—until there’s clear evidence of PCa activity (meaning signs of progression to a higher grade as indicated by rise in PSA, multiparametric MRI, and biopsy).

However, not everyone shares their view. Dr. E. David Crawford, an expert on PCa, believes AS is being encouraged for too many low-risk patients. In a presentation to a 2023 meeting of the Large Urology Group Practice Association (LUGPA), he implied that neither current diagnostics nor GG1 PCa itself can be completely trusted: “… for those under surveillance, a commitment must be made to diligently monitor their condition due to the likelihood that approximately one-third of these patients may harbor a more aggressive condition.”^[vi] Ironically, AS itself carries burdens; a study of over 8,000 AS cases with an average of 48 months of follow-up found that 51% discontinued it for various reasons. While a rise in PSA triggered a move to treatment for some, others quit due to anxiety or the burden of monitoring.^[vii]

Perhaps this is why Crawford and a growing number of urologists are so positive about focal therapy as a way to destroy low-grade PCa while preserving quality of life. Biologic research may yet tell us with certainty if Gleason 3 cells are truly cancer or not—but no matter what name it goes by, it certainly is not normal prostate tissue. For patients with GG1 PCa who don’t like the idea of cancer possibly growing in their body, nor the idea of prostatectomy or radiation, the Sperling Prostate Center offers three state of-the-art MRI-guided in-bore focal treatments: Focal Laser Ablation, TULSA, and Exablate Prostate. Contact us for more information on how we can best match focal therapy to your individual situation.

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.

References

[i] Klotz, Laurence. “Active Surveillance: From Biology to Bedside. Who fails, why, and how can we prevent this?” Presented at the 2nd Annual International Prostate Cancer Update (Beaver Creek, CO), Jan. 27, 2018. https://grandroundsinurology.com/active-surveillance-from-biology-to-bedside/
[ii] Cooperberg, Matthew. “Prostate Cancer Grade Group 1 Should Be Followed as a Neoplasm, Not a Cancer.” AUA News, Dec. 6, 2023. https://auanews.net/issues/articles/2023/december-2023/prostate-cancer-grade-group-1-should-be-followed-as-a-neoplasm-not-a-cancer
[iii] Epstein JI. Is Grade Group 1 (Gleason score 3 + 3 = 6) adenocarcinoma of the prostate really cancer? Curr Opin Urol. 2022 Jan 1;32(1):91-95.
[iv] Linder S, Severson TM, van der Mijn KJC, Nevedomskaya E et al. Grade Group 1 Prostate Cancers Exhibit Tumor-defining Androgen Receptor-driven Programs. Eur Urol. 2023 Nov;84(5):455-460.
[v] Ibid.
[vi] https://www.onclive.com/view/dr-crawford-on-the-evolving-role-of-active-surveillance-in-prostate-cancer
[vii]Timilshina N, Komisarenko M, Martin LJ, et al. Factors Associated with Discontinuation of Active Surveillance among Men with Low-Risk Prostate Cancer: A Population-Based Study. J Urol. 2021 Oct;206(4):903-913.