POINT: Dr. Epstein

The pathologic answer favoring [calling Gleason pattern 3 and Gleason score 6] cancer is that morphologically, it is cancer. There is a loss of basal cells, which is not seen in benign glands. Psychologically and architecturally, it is indistinguishable from higher-grade cancer. You can see perineural invasion, you can see extraprostatic extension – which you don’t see with benign glands – and it merges in with higher-grade cancer. If we look at Gleason score 6 cancer wrapping around a nerve, and if we look at Gleason score 6 invading outside the prostate around the seminal vesicles – this is cancer. Benign glands don’t invade out of the prostate.

Gleason score 6 tumors exist on a molecular continuum with higher-grade cancers; it’s not that they don’t have any molecular features with cancer. If you look at PTEN loss, which is something associated with more aggressive cancer, it’s present in about 5% of Gleason score 6 cancers. Obviously Gleason score 6 has less PTEN loss than higher-grade cancers, but it’s a continuum; it’s not that they don’t have any PTEN loss.

Also, if you look at copy number alterations across the genome, it’s a spectrum across Gleason score 6. Of course, there is an increase [in copy number alterations] among the higher-grade cancers, but it’s not as if there are no copy number alterations among Gleason score 6. That is cancer, it’s just a lower-grade cancer.

Sometimes, in important molecular markers that we look at, Gleason score 6 cancer actually has the same hallmarks as higher-grade cancer: ERG rearrangement is just as common in Gleason score 6 cancer as in Gleason score 7 cancer and above; the relative risk of even Gleason score 8-10 vs. Gleason score 6 for ERG-positive tumors is identical in Gleason score 7 as well. If you look at mutation numbers, Gleason score 6 tumors have mutation numbers similar to those of higher-grade cancers. Again, the emphasis is [that] Gleason score 6 has some of the molecular alterations of cancer, just less so, compared with higher-grade cancer.

Now, let’s take the argument that we’re not going to call it cancer – so what would we call it? One of the terms that has been proposed is “IDLE tumor,” meaning indolent lesion of epithelial origin, or maybe a low malignant potential tumor. Would this make sense if you’re a urologist and you receive a pathology report? An IDLE tumor involving eight cores, 60%-80%, and the patient has a palpable lesion with a PSA [prostate-specific antigen ] above 20? Of course not; you know the patient has cancer, it’s probably an aggressive cancer, and the biopsy just missed the higher-grade lesion.

Also, what happens if you have some cores that have a Gleason score 6 and others of a higher grade? Now, all of a sudden, we don’t call it Gleason score 6 cancer. You’re going to get a pathology report where some of the cores are called an IDLE tumor and some are called Gleason score 7, but we all know that they’re the same tumor. And what happens when we have a tumor that has a mixture of well-formed glands of pattern 3, and poorly formed glands of pattern 4? Is it 3+4 or 4+3? We know it’s all one tumor, and we know that [pattern] 3 has an effect on the tumor, but suddenly we’re saying that if a tumor is all pattern 3, it’s not cancer. If we mix it with pattern 4, then it’s cancer. Again, this is not consistent, and intellectually does not make any sense.

Probably the biggest reason why we want to continue calling Gleason score 6 cancer is the issue of sampling error. If I could have a crystal ball and say that [a] patient has only a Gleason score 6 on the radical prostatectomy, and I’m 100% sure there’s nothing else, I would entertain potentially calling it something other than cancer. But the answer is that about 20% of the time, when we call something Gleason score 6 on a biopsy, it’s Gleason score 7 or higher because of a sampling error. If we don’t call it cancer, and instead use some euphemism for cancer, there will be a significant number of men with Gleason score 6 cancer who won’t be followed as closely, who will drop out of the system, and who will potentially progress to incurable cancer.

The way I look at it, Gleason score 6 cancer is similar to other indolent cancers we have in the body: squamous cell carcinoma, basal cell carcinoma, etc. We call these cancers, but patients have been educated that these are not very aggressive and, for the most part, are not particularly lethal. But they still need to be followed, and patients can deal with this in a rational manner.

So what I think we need is public education. We have to educate patients that most Gleason score 6 cancers can be followed with active surveillance, that they could have a good form of cancer that generally does not cause harm, but that they have to emphasize that there is a risk of having a more aggressive type of cancer that might have been missed, that the cancer could potentially change over time, and that the patient must be followed closely.

I think more and more patients are asking for active surveillance, compared with prior years, and I think urologists need to buy into the concept of “good cancer” to educate the appropriate patients for active surveillance because urologists are the first clinicians that patients typically see following their diagnosis.

One of the problems is that we don’t see Gleason patterns 1 and 2 anymore, so we don’t diagnose Gleason scores 2-5 anymore, for the most part. This makes Gleason score 6 pretty much the lowest cancer we see. The problem is that patients hear they have a Gleason score 6 tumor, they go on the Internet and find out the scale goes from 2-10, and they think their tumor is somewhere in the middle of the range.

Therefore, we are proposing a new grading system. We recently had a meeting in Chicago, which was attended by 85 prostate cancer experts, and this new grading system was accepted to be used, initially, in conjunction with the current Gleason scale. Basically, in the new scale, Gleason scores 2-6 are graded 1 out of 5; Gleason score 3+4=7 would be 2 out of 5; 4+3=7 would be 3 out of 5; Gleason score 8 would be a 4 out of 5; and Gleason scores 9-10 would be a 5 out of 5.

In summary, I don’t think we need to change calling Gleason score 6 cancer. We need to change what patients think when they hear that they have Gleason score 6 cancer. Urologists have to reassure and educate patients, and if you modify the grading system to tell someone that they have a grade 1 tumor out of 5 instead of a 6 out of 10, it will help reassure patients and realign the grading system in prostate cancer so Gleason score 6 tumors are more appropriately considered as indolent, but something that still needs following.

Dr. Jonathan I. Epstein is a professor of pathology, urology and oncology at Johns Hopkins University Hospital, Baltimore. He reported no relevant financial disclosures.

COUNTERPOINT: Dr. Rubin

If we were to name Gleason pattern 3 and Gleason score 6 today, we might go with something different. For me, the term “adenoma” comes to mind because adenomas are neoplastic, but we don’t call them cancer.

It’s very important to remind ourselves that if we look at a spectrum of cancer, ranging from indolent to aggressive, many of the [pertinent] studies that we’ve read or heard about are taken from a very discrete, carefully culled set of cancers in patients who were undergoing radical prostatectomies. One should consider that population-based studies are important for this type of evaluation. We should also remind ourselves that nothing in life is zero risk; even going to the gym and running has some risk associated with it, so the fact that we choose to classify something as cancer or an adenoma will always have some risk associated with it.

In a multi-institutional study that Dr. Epstein published recently, he described the risk of Gleason score 6 cancer progressing as approximately 3%. So what does 3% mean? Well, those 3% [of patients] led to prognostic categorizations similar to the ones we just heard about, and one of the important things to remember is that the endpoint here is biochemical recurrence.

A recently published study employed a modeling exercise to look at the meaning of biochemical failure. In that analysis, going from radical prostatectomy to developing biochemical failure, what is the likelihood that you’re going to have metastatic disease? This analysis found no significant association, at least in Gleason score 6 disease, for developing metastatic disease. So that 3% becomes a much smaller risk.

Continuing with Dr. Epstein’s work, he and his associates reviewed around 14,000 cases and identified 22 cases that had Gleason score 6 on the radical prostatectomy but showed metastatic disease. Every one of those cases were rereviewed and upgraded using the new classification system that Dr. Epstein outlined. The conclusion of this analysis was that “in contrast to prevailing assumptions, Gleason score 6 tumors do not appear to metastasize to lymph nodes.”

So what about cancer-specific death? In studies from multiple institutions, where they looked at Gleason score 6 cancers and asked what the likelihood was of dying from prostate cancer vs. competing causes, the former had a very low risk of cancer-specific death in patients 60 years and younger.

We performed similar analysis at the Harvard School of Public Health, Boston, a few years ago, looking at the Physicians’ Health Study and the Health Professionals Follow-Up Study and saw that when we re-created the biopsies and radicals, the scores of Gleason 6 and lower went up to Gleason 7 very often. In a blinded analysis, not one of the Gleason score 6 tumors was associated with lethal prostate cancer.

You’re probably thinking about what we know about conservative management in the setting of localized cancer. I would refer you to the work of Dr. Peter C. Albertsen at the Connecticut Tumor Registry , where by looking at similar types of outcomes between cancer-specific deaths and competing causes, it’s shown that there’s very low risk of dying from prostate cancer with Gleason scores 2-6 (statistics are unadjusted for deaths per 1,000 patients).

From the molecular standpoint – we’ve heard a number of times that various cancers have a risk of somatic alterations. Prostate cancer tends to have a very low number of somatic alterations, but copy number alterations are common, going from localized to advanced. We see driver mutation events occurring more in late-stage cancer, and this is provisional data from 333 localized prostate cancer [cases] from many institutions where it’s been organized from the bottom to the top starting with Gleason score 6.

What we can see is an accumulation of molecular alterations, but what I would highlight is that like adenomas, Gleason score 6 has certain characteristic alterations that we often see without driver events.

And going back to the Physicians’ Health study and the Swedish “Watchful Waiting” study , if we look at all lethal prostate cancers, the vast majority were Gleason score 7 and above. The Swedish cohort was pre-PSA, so some of these Gleason score 6 cancers were probably contaminated because of sampling. Even if we include them and look at principle component analysis, we see that the vast majority of the Gleason score 6 cases cluster together; they’re much more homogeneous, molecularly speaking, compared with the Gleason score 8 cancers that are heterogeneous and spread all over.

Another important analysis that will inform next-generation sequencing studies is to look at subclonal alterations. We believe that the subclonal mutations are the ones that are going to merge in as driver mutations, So what you can do is take the Cancer Genome Atlas data , as we’ve done, and go from Gleason score 6 all the way up to the higher-grade tumors. There are more deletions and genomic focus as you go higher, but also you see that the majority of Gleason score 6 cancers are clonal for these alterations. As you move on up to higher-grade tumors, you start seeing some subclonal emergence of driver lesions.

So I would argue that the Gleason pattern 3 or Gleason score 6 cancers have a very, very low risk of disease compared to other cancer grades and is not associated with death following definitive treatment, and is probably dramatically overtreated. It’s genetically homogeneous, and we see little evidence of subclonal driver mutations in Gleason score 6. So my answer to the question “Should Gleason score 6 be called cancer?” is “no.” But I do agree entirely that we need to have categories of risk, and so Gleason score 6 – or whatever we end up calling it – should be recognized as a group of tumors with a very low risk of aggressiveness.

Dr. Mark A. Rubin is the director of the Institute for Precision Medicine at Weill Cornell Medical College, New York. He reported no relevant financial disclosures.

Dr. Epstein and Dr. Rubin made their remarks at the annual meeting of the Society for Urologic Oncology. Reporter Deepak Chitnis covered their presentation.

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