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.
Dr. Jonathan I. Epstein
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.