In prostate cancer, as in life, you roll the dice.
In craps, 3+3 is called a “hard six.” It’s hard because you can only win if you repeat with a combination of 3+3. Any other sixes you roll — 4+2, 5+1 — are losers.
Gleason 3+3 is a hard six in prostate cancer. It is the lowest grade cancer in the traditional Gleason scoring system. Still, to the eye of a pathologist, a Gleason 6 looks like a malignancy.
Now, a few experts are questioning whether this hard six is a cancer at all. Some urologists see a Gleason 6 as a noncancerous growth that has the potential to be invasive, but most likely will never spread to other organs or end up killing a man.
To a patient like me, who has been on active surveillance (AS) for 10 years, a Gleason 6 can create a big medical fuss lasting years with regular prostate-specific antigen (PSA) blood tests, digital rectal exams (DREs), biopsies, and MRIs. It can cause “anxious surveillance” that prompts them to drop AS and undergo unnecessary radical prostatectomy, which poses a potential risk of impotence and urinary incontinence.
The Gleason 6 diagnosis can yield polar opposite recommendations from urologists. Ten years ago, I found this to be the case in the matter of a day.
On December 14, 2010, a local urologist recommended I undergo a radical prostatectomy within the week. When asked, he said he didn’t support active AS, then a relatively new approach for monitoring low-grade prostate cancer.
Only about 6%-10% of candidates in those days opted for AS.
From all 14 of my biopsy samples, there was only one millimeter of Gleason 6, which elicited panic from my urologist and internist.
The next day, I saw Scott Eggener, MD, of the University of Chicago, who had started offering AS only a few years earlier. He told me I really didn’t need surgery and was the “poster boy” for AS.
He shared some research by Laurence Klotz, MD, an AS pioneer from Toronto, showing great outcomes for many men like me who chose to hop on the AS train. I was sold and never looked back.
Eggener predicted my cancer may one day progress where more aggressive treatment may be beneficial but also explained my cancer may ultimately be the same in 10 years, a slow-moving turtle best managed with AS. In fact, four subsequent biopsies failed to find any tumor at all.
These days, about 60% of AS candidates nationwide opt for it, with rates as high as 95% for those with very low-risk prostate cancer and 75% of those with low-risk when cared for by certain urologists or medical practices, said Eggener.
Over the years, he has mentioned to me and others that he thought dropping the “cancer” classification for Gleason 6 was reasonable. He felt Gleason 6 be considered a “precancerous” lesion.
Eggener is now taking it a step further, seeking to change the rules of this game of biopsy craps.
‘The right thing to do’
He told me recently he has decided to dedicate himself to eliminating the cancer diagnosis as a “career goal.” He has recruited Klotz and others, including pathologists, radiation oncologists and radiologists to his team advocating what many may feel is an impossible dream. Eggener knows there is often resistance to change, and it doesn’t happen overnight. However, being in mid-career, he has time on his side.
“I used to whisper the idea after a couple of beers to friends in quiet places, where no one could hear me or impugn me for it. Then, I would start mentioning it to wider audiences, and now I will stand at a podium and tell thousands of people if they’re willing to listen, why I think it’s the right thing to do.”
Eggener said the time to act is now because the evidence overwhelmingly supports his position.
He said while Gleason 6 absolutely meets the histologic criteria of cancer, it doesn’t meet the clinical definition of cancer. It’s not a malignancy that might eventually spread and kill the patient.
“In Gleason 6, it’s basically impossible to spread to other parts of the body. And there’s overwhelming evidence of that,” he said. “I am convinced there’s never been a man in the history of time who’s died from pure Gleason 6 prostate cancer. There’s never even been a case report of it, and for that reason I think men would be better served if Gleason 6 was downgraded, as we’ve done with Gleason 2 through 5.”
If Gleason 6 was considered a precancerous or noncancerous lesion, doctors would monitor patients with PSA or other biomarkers, DREs, and/or MRI in regular check-ups.
“I submit the hypothesis we would ultimately have hundreds of thousands fewer men burdened with the diagnosis of prostate cancer or needing treatment that could impact their quality of life, billions of fewer dollars expended by the healthcare system, and highly likely there would be no increase in prostate cancer deaths across the country as long as men and their doctors continue appropriate follow-up,” Eggener said. “To me, there is clarity. It’s the right thing for public health and for individual men.”
As an example, Eggener said his group at the University of Chicago collaborated with colleagues across town at Northwestern University to study outcomes in 7,800 men who underwent prostatectomies. Of them, 2,500 had prostates with only Gleason 6.
“We couldn’t find a single patient with Gleason 6 growing into the seminal vesicle, and the likelihood of it extending outside of the lining or the capsule of the prostate was 0.28%,” he said.
He cited a study led by Jonathan Epstein, MD, director of surgical pathology at Johns Hopkins in Baltimore, of more than 14,000 men. He said none of those with Gleason 6 had cancer identified in the lymph nodes.
Klotz divides the Gleason 6 nomenclature issue into two parts: the social/political and the scientific.
On the former, he said: “Imagine how much easier life would be if you didn’t have to explain to a patient that he had cancer but didn’t need treatment. And probably the result would be less overtreatment insofar as there’s still a controversy in some people’s minds about whether these patients should be treated or not. So, that’s the driver.”
He said the science is complex. Everyone agrees that Gleason 6 resembles a cancer under the microscope.
Generally, a hallmark of cancer is metastases. Gleason 6 doesn’t metastasize, but, Klotz said, neither do basal cell carcinoma of the skin nor gliomas in the brain.
“The lack of metastasis is not by itself a reason to say it’s not cancer. So then the second clinical parameter is invasion. It’s not common but you do see invasion outside the prostate occasionally with Gleason 6 prostate cancer. So, that’s a problem,” Klotz said.
He said about 2% of patients with low-grade Gleason 6 have serious genetic aberrations in their cancer cells, suggesting the cancers may be more aggressive. “It’s a small proportion but it’s not zero,” he said. These cells probably mutate to a higher Gleason pattern before they metastasize.
On the other hand, some tumors have been reclassified as noncancerous. Klotz said papillary urothelial neoplasm of low malignant potential (PUNLMP) is probably the best model of cancer being redefined as a noncancer. Eggener said it has also occurred in thyroid cancer (follicular variant of papillary thyroid cancer) and been debated for ductal breast carcinoma in situ.
Will dropping the “cancer label” from Gleason 6 be accepted by urologists, let alone by genitourinary pathologists? Others have proposed such a change in the past but failed because of opposition from the pathologists — the umpire in biopsy reading — but also many urologists.
I asked several experts and got a mixed response.
Bert Vorstman, MD, a retired Florida urologist and outspoken critic of the “prostate cancer industry,” said, “We cannot keep the Gleason label as it is associated with the cancer word, and we can’t keep the cancer tag as it is bogus [as he wrote in 2016] and needlessly terrorizing.” He favors renaming Gleason 6 as age-related prostatic neoplasia.
Urologist Peter Carroll, of the University of California San Francisco, another AS pioneer, favors leaving Gleason 6 as cancer, taking a philosophical view about cancer and society.
“I always point out that some men with 3+3 disease are harboring higher-risk tumors. Telling a patient he does not have cancer risks incomplete follow-up and the risk of significant progression over time which could be a real problem. All AS series, including our own at UCSF, have identified predictors of progression and its likelihood. You simply can’t write the diagnosis off. But to me, it’s a larger issue that confronts society’s perception of cancer in general, not just prostate cancer,” he said.
“We can try and rename low-grade prostate cancer, but I think it just confuses the issue rather than confronts the need for society to recognize that cancer is a spectrum of disease. We have taken a similar approach to heart disease, diabetes and other diseases. Not everyone with diabetes needs insulin and not everyone with cardiac disease needs a stent or bypass surgery. For many it is lifestyle change only.
“We also have to realize that we are rapidly changing early detection strategies to try and minimize the detection of very low-grade, low-volume cancers in the first place,” he said.
William Catalona, MD, professor of urology at Northwestern, has been a major figure in urology over the past 30 years and the father of mass PSA screening. He was a major opponent of AS and has debated the topic with Klotz many times. He concedes that he lost most of the debates and in recent years has become a supporter of what he calls “appropriate AS.”
Catalona told me he opposes reclassifying Gleason 3+3 as noncancerous. “If somebody has an elevated PSA and gets a biopsy that shows one or two cores of Gleason 3+3 prostate cancer, it’s really not correct to tell them that they don’t have cancer and that they don’t require enhanced surveillance,” he said.
Catalona disputes claims that there are no documented cases of Gleason 3+3 being life-threatening. “All men with Gleason 3+3 are at substantial risk of their disease being underestimated.”
He said that because of the well-recognized risk of biopsy sampling error, urologists remain justifiably concerned about the significant possibility of unrecognized undergrading. “They see it frequently, when Gleason 3+3 turns out to be Gleason 7-10,” he said.
Catalona cited research on mice published last month showing that several years after successful treatment of tumors, stress hormones can trigger cancer in residual cells that had been dormant throughout the body.
“It’s a fairly rare occurrence, but there are some men who will undergo a radical prostatectomy or even radiation therapy, and they will remain free of recurrence for 10, 11, 12, 13, 14 years,” he said. “And then suddenly, the tumor will start progressing, and they can even develop metastases. And this also exists in other types of cancer, interestingly, in kidney cancer, in melanoma, and in a sense in cancers that seem to respond to immunotherapy.”
Catalona said most of the urology community currently is seeking to “make AS less intense and burdensome, but not to the extreme of reclassifying the disease as not being cancer.”
Pathologists likely will resist any new classification system suggesting Gleason 6 isn’t serious.
Epstein and his Hopkins colleagues previously shepherded a major change that resulted in a new classification system in 2014. The six in Gleason 6 seemed high to begin the scoring to many patients. The International Society of Urological Pathology then created the five-grade classification system in which Gleason 6 was moved to the semantically less frightening Grade Group 1.
However, Epstein told me he is sticking with the cancer designation for Grade Group 1/Gleason 6: “Morphologically and genetically, Gleason score 6 is cancer with the ability to invade tissues. If one could have a crystal ball and say that when Gleason score 6 is seen on biopsy, there is only Gleason 6 in the prostate then I would feel that one could reclassify Gleason score 6 cancer as ‘noncancer.’
“However, biopsy Gleason score underestimates disease grade and extent in a significant percentage of cases. Although multiparametric MRI leads to decreased undergrading, it still exists even with improved imaging. If Gleason 6 on biopsy were not labeled as cancer, the potential for higher-grade or more extensive disease might be ignored, and physician recommendations (or compliance with recommendations) for immediate treatment or careful monitoring when appropriate might not occur.”
But pathologists aren’t unanimous either.
Edward Uthman, MD, past president of the Texas Society of Pathologists and an adjunct professor of pathology at the University of Texas McGovern Medical School, said, “For me, if something can’t kill the patient, it’s not cancer. Thus, Gleason 3+3 doesn’t metastasize, so it should not be called cancer. Glioblastoma doesn’t metastasize (or rarely does), but it can and does kill the patient by local invasion of the brain, so it is properly regarded as cancer. Epstein is correct in a strict sense, but the word ‘cancer’ conveys a popular meaning that does not include an entity that behaves like Gleason 3+3.”
George D. Lundberg, MD, former JAMA editor and a pathologist, said of the Gleason 6 tumors: “The fear is that a ‘real cancer’ might pop up later, so calling Gleason 6 cancer probably more reflects sampling error than a change in the cancer called Gleason 6.”
He favors identifying these lesions as “incidentalomas” or “indolentomas.”
The war begins
So battle lines are drawn for a great debate in medicine that could have a major impact on men with low-risk prostate lesions. There are about 90,000 such men diagnosed each year in the U.S. and 600,000 worldwide.
Personally, as someone who has lived for a decade with a Gleason 6 diagnosis, I support eliminating the cancer designation.
A cancer diagnosis, even one considered low-risk, can change one’s definition of self and can trigger anxiety.
As Lundberg said: “Many lesions that were called ‘cancer’ really were not cancers at all in behavior, and this fact began to be recognized in large numbers of patients. These unfortunate victims have experienced massive psychological and physical harm and costs without any clear benefits achieved by finding and treating their ‘noncancers.'”
Why torture men needlessly with a cancer diagnosis?
Catalona responded: “The reason is that if they are not as lucky as you have been, they may recognize the true nature of their life-threatening cancer in time to be cured.” (For the record, I talked to Catalona, one of the best surgeons in the urology game, in 2013 about my case. He advised me then that AS would be a mistake. But he now concedes that it has worked for me, even though it may not for other men.)
Eggener’s advice spared me from unnecessary prostate surgery and potential lifestyle changes 10 years ago. Now he tells me he wished he could have saved me from the first biopsy and the subsequent ones.
My hope is Eggener has a winning roll.
But I’ll give Catalona the last word: “I’ll trust that you will be disappointed in this hope, but if you are correct, a material proportion of men (and their families) will experience unnecessary suffering and death from prostate ‘noncancer.'”
Howard Wolinsky is a Chicago-based author and journalist who has written about his journey on active surveillance since 2016. His new book is Contain and Eliminate: The American Medical Association’s Conspiracy to Destroy Chiropractic.
Last Updated January 08, 2021