An Expert Discussion on Gleason 6 (Grade Group 1) Prostate Cancer - Scott Eggener 

October 4, 2020

Historically called Gleason 6, and more recently referred to as Grade Group 1, is a term that started in the 1960s with Don Gleason's original description. It was more universally adopted by the late 1980s, and the Grade Group system was initiated in 2014. In this conversation with Matthew Cooperberg, MD, MPH, FACS, Scott Eggener, MD offers his perspective on the importance of understanding Gleason 6 or Grade Group 1. Dr. Eggener highlights that histologically it meets the criteria of cancer with an absence of a basal cell layer, but a question worth asking, does it meet the molecular and clinical definitions of a cancer?  Drs. Eggener and Cooperberg review several studies and emphasize the importance of minimizing overdetection and overtreatment.


Scott Eggener, MD, Professor of Surgery (Urologic Oncology) and Radiology, University of Chicago, Chicago, Illinois, USA.

Matthew R. Cooperberg, MD, MPH, FACS, Professor of Urology; Epidemiology & Biostatistics Helen Diller Family Chair in Urology

Read the Full Video Transcript

Matt Cooperberg: Good morning, good afternoon, depending on where you are. Welcome to a Zoom edition of the Uro Today Localized Prostate Cancer Center of Excellence. It's a pleasure to be joined today by Dr. Scott Eggener. Dr. Eggener is the Bruce and Beth White Family Professor of Surgery and Radiology at the University of Chicago, where he is Vice-Chair of the department and also directs the High Risk and Advanced Prostate Cancer Clinic.

What we're going to talk about today is the emerging concept about whether Gleason pattern 3, now being called Gleason Grade Group 1, when it exists as a pure pattern in the setting of low-risk prostate cancer really should be considered cancer, or whether we might think about relabeling it something else. Not a normal finding, but something short of actually putting the cancer label on it. Scott's emerged as a real thought leader on this question, and we are really looking forward to getting his thoughts today. Scott, welcome. Thanks for joining us.

Scott Eggener: Thanks for having me, Matt. It's a topic I'm passionate about and I think is incredibly important and relevant.

Matt Cooperberg: Excellent. I understand you've got a little bit of material to show us to get started.

Scott Eggener: Yeah, hopefully, this is a stimulus for conversation, and happy to share my thoughts. Obviously, you have a lot of knowledge in this space, and we've had many long fruitful discussions on the topic. So historically called Gleason 6 and many people still do call it Gleason 6, but Grade Group 1 is obviously a relatively more recent term that is meaning the same thing. And so a little bit of the biography of it. Most people don't realize that this started in the 60s, and Don Gleason's original description was based on 270 cases, most locally advanced or metastatic. There were competing grading systems and ultimately in the late 70s, Gleason started to win the day, but was more universally adopted by the late 80s. And past is a precursor because regrading and eliminating the cancer label has been done before in Gleason score. And in 2005, we basically eliminated Gleason score 2 through 5 by eliminating patterns 1 and 2. As everyone's probably aware, there were some tweaks to the system in 2014, getting the grade group system initiated.

Historically as many of you know, Gleason 6 means cancer means treatment. I spent most of my training, the most common big case we did was a Gleason 6 cancer radical prostatectomy. And thankfully we've made strides in modifying that, but it's important to understand what is Gleason 6 or Grade Group 1. Histologically it absolutely positively meets the criteria of a cancer. There's an absence of a basal cell layer. But a question worth asking, and we don't have enough time to dive into the details is doesn't meet the molecular and clinical definitions of a cancer? There are many who would argue it does not.

This is not a new topic. This is eight years ago from two powerhouse groups, Johns Hopkins and the University of College of London asking the important question, should we be calling Gleason 6 or Grade Group 1 a cancer?

This has been done in other urological cancers and non-urologic cancers. PUNLMP of the bladder used to be called a cancer. Now it's not. Perhaps the best analogy is the follicular variant of papillary thyroid cancer, which is a fascinating story, a multidisciplinary effort over many years to work through and essentially take away the cancer label from this variant and many, many, many implications of it, including far less surgeries that were considered unnecessary.

I already mentioned Gleason 2 through 5 used to be considered prostate cancer. We don't anymore. It's basically a unicorn. I can tell you simultaneously in the breast cancer community, they're having an ongoing discussion on DCIS of the breast, which is basically their Gleason 6. There are questions on whether it should be called cancer. Can it metastasize? There's even trials ongoing for active surveillance.

Now, what are the data on Gleason 6? Let's first ask can Gleason 6 extend beyond the prostate? A study that we did with our friends at Northwestern, 7,800 surgeries, 2500 were Gleason 6 and the punchline basically is on rereview, modern Gleason 6 was incapable of seminal vesicle invasion. But extracapsular extension 0.2% of the time. So extraordinarily rare.

A study that's gotten a lot of press over the years and thankfully so, 14,000 patients from multiple institutions. The banner headline is not a single case of Gleason 6 in the prostate with a positive lymph node. All the ones historically that had positive nodes by modern grading were considered higher grade.

And then a study of 11,000 men who had a radical prostatectomy for Gleason 6 followed for often a decade or more, and basically not a single patient ever had a metastasis or death from their Gleason 6, suggesting it had not spread beyond the prostate or elsewhere in the body in the years or decades that it was peacefully coexisting in the prostate prior to surgery. So a thought-provoking question that I think we should all ask.
These are literally the definitions from the dictionary. Benign is a mild type or character that does not threaten health or life. Cancer is a malignant tumor that ultimately can invade and spread by metastasis. Ask yourself which one explains our current understanding of Gleason 6.

This was a paper that many dozens of urologic oncologists put together with the summary basically metastatic potential is negligible. Many people have suggested renaming Gleason 6. Laura Esserman, Ian Thompson suggested IDLE, indolent lesion of epithelial origin for Gleason 6 and even some items within breast and thyroid. I'm the biggest fan of INeRRT, and for full disclosure it's because it's the one that I came up with. But indolent neoplasm rarely requiring treatment. And then some friends with sophomoric humor came up with PENIS, and I'll let you read it there.

So I think one of the most important initiatives of our generation of those who manage prostate cancer are looking for ways to minimize unnecessary over detection and over treatment. I know this sounds crazy, particularly from someone whose practice is largely based in prostate cancer, but I look for reasons not to have to screen, not to have to biopsy and not to have to treat a man. I think we've got a number of tools available, all based on data, to help transform the landscape.

And then lastly, on a totally separate topic is if a man does require treatment, there are many ongoing clinical trials, even randomized ones with FDA oversight as registration trials to see if we can come up with safer, but equally efficacious ways of treating prostate cancer.

So lastly, I'll just close with who wants change? Everyone wants change. But it is understandably more difficult to make those changes when you've been doing the same thing for a long period of time. And then important to understand sometimes your heart needs more time to accept what your mind might already know.

Matt Cooperberg: Excellent. Thank you for the overview. So let's talk about some of the arguments against, because obviously we've been having this conversation for a couple of years and we've seen public talks like this. I think one of the most common arguments tends to be that the data on the biologic and clinical inertness, if you will, of Gleason 6 is all based on prostatectomy series where the prostate has been removed. We're usually talking about making these decisions based on biopsy rather than prostatectomy, and we might be under-sampling higher cancer. So what do we do with that argument?

Scott Eggener: Yeah, that's the most common blowback I get, and it is totally appropriate. Totally understandable. But I think it's a separate issue. That's a limitation of our sampling, of our imaging, of our biopsy detection rather than Gleason 6 itself. Obviously, you, I, and many others know the Holy Grail would be if you had some magic urine serum imaging test that said there's only Gleason 6 in the prostate, and then it's a no-brainer what you do. But correct. But those older path studies where historically 20 to 30% of the patients had higher grade or extracapsular extension when on biopsy it only showed Gleason 6, you and I both know we've gotten so much better with imaging, restaging biopsies, potentially genomic biomarkers. We're not at 100% accuracy, but we're way better than our historical precedents.

Matt Cooperberg: So if we did go down this pathway, how would we follow inert? In other words, it's one of the other arguments against, is that we can't call this normal. It's not normal. It doesn't look normal. I don't think anybody's been arguing that it should be called normal. It just should be called something that is not cancer. The analogy that I've liked is the colon cancer model, where if you have a polyp in the colon, we remove the polyp, but nobody would ever consider taking out the entire colon or doing aggressive radiation therapy. But you still treat the polyp and then you do more frequent sigmoidoscopies and colonoscopies than you would have had the polyp not been found. Basically, does a patient with an inert or idle tumor still undergo a typical active surveillance protocol as would a patient where they Gleason 6 cancer today? Or do we follow it differently? How do you think these should be managed?

Scott Eggener: Yeah, it might be a lame answer, but it really depends on the patient. There are some patients with really low volume Gleason 6 that don't have any of the other concerning risk factors. They've got a low volume by millimeters. Their PSA density is low. Their total PSA is relatively low. Their DRE is normal. I kind of think of them as just screening them and checking a PSA regularly. There's obviously other people that have higher volume and some of the other risk factors, and you follow them more closely. It's no different than what we do on our surveillance protocols, where there are good data now on certain patients that might need a restaging biopsy every one to two years versus every four years. You tailor the strategy based on all the information you have integrating it with their age, life expectancy and other important factors.

Matt Cooperberg: I do want to spend one extra minute on the biology because I think it's fascinating. But the more we look at these, whether we're talking about RNA expression on DNA alterations on a whole host of biologic assays, the more difficult it is to find features that distinguish them from normal surrounding prostate tissues. So, I mean, do you have a sense that there's a threshold that we need to hit to prove their biologic normalcy? The broader question is what will it take to convince the pathologists and the other stakeholders that we should consider a change in nomenclature?

Scott Eggener: Yeah. I don't have card-carried expertise as a basic scientist or a molecular biologist. Frankly, I've leaned on some of the data you and your group have produced on this, on the biology of it. It is very interesting. I think this is a years' long process, and it absolutely is multidisciplinary. It's incredibly important to have the basic scientists, and most importantly, the pathologist along. When I talk to my colleagues in thyroid cancer who have successfully removed the cancer label from that follicular type of papillary thyroid, they said the main driving force was getting the pathologists on board. And so as you know already, there is a drive in the US in the very early stages of starting that effort. I think most importantly, it's a conversation that should be had. I see it as a public health issue and a conversation we need to have amongst our community. We'll see how it plays out.

Matt Cooperberg: Excellent. It's a really important space to watch, and I really appreciate your leadership in this area. Hopefully, we will continue the conversation over the years to come, ideally in person soon. It'll be great to see you soon, hopefully in 2021, when the world gets back to some kind of new normal. Any concluding thoughts?

Scott Eggener: Thanks for covering the topic and anyone who's listening, email, tweet at me, and quite honestly the blowback and the questions and the conversation are more important than just any agreement you might have.

Matt Cooperberg: Absolutely. Hopefully this is the conversation that we and others can help catalyze and really drive some meaningful change. Somebody that was at our last one on made the comment that this could be one of the most impactful things we could do in prostate cancer in our lifetime. I definitely continue to agree with that statement. Looking forward to the future.

Scott Eggener: Thanks again.

Matt Cooperberg: Thanks.