E. David Crawford, MD

In a recent paper, Eggener et al revisit a decades-old discussion of whether Gleason 6 should be downgraded from cancer (a malignancy) to pre-cancer (a nonmalignancy) because of very low propensity for metastasis (true).

 They make cogent, articulate arguments for “de-cancerizing” group 1. Nevertheless, it is our belief that doing so would create more issues than it solves and lead to increased loss of patients for follow-up as well as potentially missing a segment of more lethal pathologies.

The Gleason system, adapted in the 1960s, has been the gold standard of prostate cancer classification, and it has served us well with certain caveats. Classifying cell types and assigning them grades does have an element of subjectivity, and even Allsbrook Jr et al in an early paper showed there was considerable disparity amongst pathologist reading slides.

 Because of this, the possibility of downgrading (or even upgrading) tumors is always a potential issue.

Gleason grading is an anatomical observation of cellular dysmorphia. Today, we have the added luxury of a plethora of genetic tests that help us substratify anatomical grades from very low to very high risk categories. Lin et al published a Prolaris validation study

 involving CCR (Cell Cycle Risk score) showing that 8% of all commercial Prolaris tests for very low and low risk National Comprehensive Cancer Network categories are above the active surveillance threshold. Myriad has unpublished data showing 37% of pts with Gleason 6 had CCR scores above the active surveillance threshold. Brooks et al published a paper showing the presence of occult high-grade/and or t3+ in otherwise low-risk patients.

 Fifty-five percent of the cohort had grade group 1 disease. Oncotype DX, another genomics company, has data showing that Genomic Prostate Scores of about 5000 patients with grade group 1 fall in the range of 30 to 100, which indicates a greater likelihood of harboring occult high-grade or non–organ-confined diagnosis and a greater potential for disease progression and metastases.

Cancer represents a dysmorphic clonal cell population which, while originally may be homogeneous, ultimately may differentiate into a more heterogeneous aggressive clone. Everyone who has practiced for a long time has patients (admittedly a handful) that went from low-grade grade group 1 to higher grade 3/4/5 or even metastatic. It is unclear whether this is from sampling error and understaging at biopsy, or from the aforementioned cellular grade migration.

We have seen the “throwing of the baby out with the bath water” approach before with the US Preventive Services Task Force (USPSTF) recommending against PSA testing because of over treatment (true) and then upgrading recommendations from a “D” to a “C.” Even with this upgrade, we have seen the preponderance of de novo hormone-sensitive metastatic disease double (from 3% to 6% ) after the USPSTF recommendations. Additionally, many primary care specialties still advise against any prostate-specific antigen testing at all. Does any urologist or genitourinary oncologist agree with that?

The world of oncology is replete with malignancies that are of low metastatic potential and often just observed such as CLL, marginal zone lymphoma, grade 1/2 follicular lymphoma, and myeloma (smoldering) and others. “Real” grade group 1 would fall into that category.

The authors argue for the downgrading of Gleason 6 as a cancer because of over treatment (true) and patient anxiety (perhaps). The concern of downgrading Gleason 6 is that many patients would not comprehend the need for close follow-up and disappear. Thorough counseling and advising a patient of the very low risk and malignant potential of true Gleason 6 generally comforts most patients and sets their mind at ease. Yet they retain the importance of close follow-up and are generally not lost to follow-up.

By downgrading Gleason 6, with all the aforementioned pitfalls with genetic testing, it would lend to the primary care specialties feeling that prostate cancer is a non-lethal disease and should not even be diagnosed (as seen with USPSTF PSA recommendations).

We feel a more appropriate approach would be to retain true Gleason 6 as a cancer of extremely low metastatic potential requiring close follow-up . The utilization of increasing available genomic testing to differentiate good (the majority) from bad actors (the minority), and finally continue strong emphasis on refraining from treatment of all Gleason 6 with low malignant genetics.

1. Eggener SE, Berlin A, Vickers AJ, Paner GP, Wolinsky H, Cooperberg MR. Low-grade prostate cancer: time to stop calling it cancer. 

 Published online April 18, 2022. doi:10.1200/JCO.22.00123

2. Allsbrook Jr WC, Mangold KA, Johnson MH, et al. 

2001;32(1):81-88. doi:10.1053/hupa.2001.21135

3. Lin DW, Crawford ED, Keane T, et al. Identification of men with low-risk biopsy-confirmed prostate cancer as candidates for active surveillance. 

2018; 36(6):310.e7-310.e13. doi:10.1016/j.urolonc.2018.03.011

4. Brooks MA, Thomas L, Magi-Galluzzi C, et al. Validating the association of adverse pathology with distant metastasis and prostate cancer mortality 20-years after radical prostatectomy. 

2022;40(3):104.e1-104.e7. doi:10.1016/j.urolonc.2021.10.005

 is a member of the Cancer Clinical Research Unit at Princess Margaret Cancer Centre and an affiliate scientist at Techna Institute for Advancement of Technology for Health in Toronto, Canada. 

 is a professor of urology; epidemiology & biostatistics and Helen Diller Family Chair in Urology at the University of California, San Francisco. 

 is the Bruce and Beth White Family Professor of Surgery anddirector of the High Risk and Advanced Prostate Cancer Clinic at the University of Chicago, Illinois. 

 is a professor of pathology at the University of Chicago. 

 is an attending research methodologist at Memorial Sloan Kettering Cancer Center in New York City, New York.

We would like to thank Harris et al for their interest in our work. The authors provide an excellent summary of the main counterarguments to eliminating the term 

 when describing a prostate tumor with only pattern 3 disease (ie, Gleason 6, Grade Group 1). Indeed, many of these arguments have been made before in the published literature.

 We address these below. We also encourage readers to review the entirety of our proposal.

 You have to call Gleason 6 cancer because of the possibility of misgrading due to inadequate sampling: “Patients [may go] from low-grade grade group 1 to higher grade 3/4/5…[due to] sampling error…at biopsy.”

 This is intrinsic to any sampling and applies similarly to any indolent diagnosis. For instance, as is often the case, we biopsy a patient who has underlying prostate cancer but only find high-grade prostatic intraepithelial neoplasia (HGPIN). That would not be an argument for calling HGPIN a cancer, and by the same token, should not be an argument for calling Gleason 6 a cancer.

 Possibility of misgrading due to variation in pathological assessment: “Classifying cell types and assigning them grades does have an element of subjectivity, [there is] considerable disparity amongst pathologist[s].”

 Similar to the previous point, this also applies to non-cancer diagnoses. There are cases where 1 pathologist would categorize a given lesion as atypical small acinar proliferation (ASAP) that another pathologist would say is cancer. That does not imply we should call ASAP a cancer; the same holds for Gleason 6.

 Possibility of low grade becoming high grade rapidly: “Everyone who has practiced for a long time has patients that went from low-grade grade group 1 to higher grade 3/4/5…[due to] cellular grade migration.”

 Again, this also applies to non-cancer diagnoses. Everyone who has practiced for a long time has patients (albeit extremely rare) who have gone from benign findings on biopsy to high-volume aggressive disease. Indeed, there are extraordinarily rare cases in which men have repeated and extensive negative biopsies and then present with metastatic disease. That a prostate with Gleason 6 can subsequently harbor higher-grade lesions that lead to metastases does not warrant it being termed 

 because premalignant conditions can also progress.

Possibility of Gleason 6 metastasizing: “Everyone who has practiced for a long time has patients that went from low-grade grade group 1 to even metastatic.”

 The purported scenario is incongruent with contemporary published literature, since rates are consistently <1% and as low as 0.1% at 15 years,

 highlighting that progression of Gleason 6 to metastases is extremely rare. To our understanding, there are no cases reported in the literature of men with solely Gleason 6 (at prostatectomy) who have had metastases or died. Therefore, it is important to underscore the goal of screening or surveillance is (or should be) to identify potentially meaningful higher-grade lesions. However, nearly every aforementioned patient referred to our practice in such a scenario (Gleason 6 on biopsy with eventual metastases) had not been followed by generally accepted surveillance protocols. Thus, these cases (which can occur due to unsampled higher-grade cancer) are more reflective of suboptimal assessments or follow-up rather than highlighting a lethal potential of Gleason 6. If “everyone who has practiced for a long-time” has experienced this, a well-annotated series of these men would be a welcome addition to the literature.

 Some low-grade cancers are actually aggressive based on genetic tests: “37% of patients with Gleason 6 have Cell Cycle Risk scores above the active surveillance threshold (unpublished).”

 Large cohorts of active surveillance patients with long-term follow-up, without MRI or genomics, show negligible prostate cancer-specific death rates, even though these cohorts would presumably have had 37% categorized as “high-genomic risk.” There is zero high-level evidence supporting the notion that immediate treatment of patients with low-grade disease but high genomic risk lowers cancer morbidity or mortality compared with treatment if or when progression to high-grade disease occurs. Additionally, the thresholds reported on these tests have not been validated to predict long-term mortality outcomes. Although genomics clearly have a role to play in prostate cancer risk stratification, their routine use in clinically low-risk prostate cancer would lead to massively increased costs, significant rates of overtreatment, and is not endorsed by guidelines.

 We can solve the problem of overtreatment: “counseling…generally comforts most patients and sets their mind at ease…continue strong emphasis on refraining from treatment of all Gleason 6.”

 We have been trying for many decades to limit radical treatment of low-grade cancer. Although progress has been commendable, it has been lamentably slow and heterogeneous. Contemporary US data from the American Urological Association Quality Registry show 50% of men with low-risk (Gleason 6) disease are treated radically.

 For some providers, this percentage is still 100%.

 Not calling it cancer may lead to patients not being careful with active surveillance: “Many patients would not comprehend the need for close follow-up and disappear.”

 This is a highly speculative assumption without robust supportive evidence. Moreover, this would be an argument that could be applied to other non-cancerous conditions, such as a HGPIN, ASAP, or even a colon polyp. We do not think polyps should be called cancer just so patients are assiduous in getting a follow-up colonoscopy; the same is true for Gleason 6, we should not call it cancer.

 Guilt by association with the US Preventive Services Task Force (USPSTF) recommendation against screening.

 Conflating our proposal with no screening whatsoever is rather unfortunate. We are certain the authors agree that ongoing “screening” of men with erstwhile Gleason 6 is quite different than no screening whatsoever. Again, the USPSTF is actually an argument in favor of our proposal. The USPSTF explicitly cited declining rates of overtreatment for low-grade disease in its 2018 revision from a “D” to a “C” recommendation. These trends would only increase if Gleason 6 disease was no longer described as cancer. We underscore that re-labeling aims to further improve the benefit:harm ratio of prostate-specific antigen screening by minimizing overdiagnosis (as opposed to underscreening).

In summary, most of the arguments raised for retaining the “cancer” label for Gleason 6 disease are equally applicable to benign or precancerous findings. Gleason 6 with “high genomic risk” leads to early or unnecessary radical therapies in far too many men. Lastly, we return to our main point: the 

 of labeling an inert disease as “cancer” is not innocuous. Millions of men have experienced the trauma of being told “you have cancer,” and a high proportion were nudged towards treatment as a result, with negligible potential benefit but a meaningful risk of persistent side effects and deleterious consequences in their quality of life. We feel strongly removing the 

 label from Gleason 6 will, as a practical measure, on balance do far more good than harm. It is an important conversation for our community to engage in and advocate for.

1. Epstein JI. Is Grade Group 1 (Gleason score 3 + 3 = 6) adenocarcinoma of the prostate really cancer? 

2022;32(1):91-95. doi:10.1097/MOU.0000000000000945

2. Eggener SE, Berlin A, Vickers AJ, Paner GP, Wolinsky H, Cooperberg MR. Low-grade prostate cancer: time to stop calling it cancer. 

Published online April 18, 2022. doi:10.1200/JCO.22.00123

3. Tosoian JJ, Mamawala M, Epstein JI, et al. Active surveillance of grade group 1 prostate cancer: long-term outcomes from a large prospective cohort. 

2020;77(6):675-682. doi: 10.1016/j.eururo.2019.12.017

4. Eggener SE, Rumble RB, Armstrong AJ, et al. Molecular biomarkers in localized prostate cancer: ASCO guideline. 

2020;38(13):1474-1494. doi:10.1200/JCO.19.02768

5. Cooperberg M, Meeks W, Fang R, et al. active surveillance for low-risk prostate cancer: time trends and variation in the AUA Quality (AQUA) Registry. 

2022;207(suppl 5):e740. doi:10.1097/JU.0000000000002609.03

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"We feel a more appropriate approach would be to retain true Gleason 6 as a cancer of extremely low metastatic potential requiring close follow-up," write Harris et al.

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E. David Crawford, MD

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