"Gleason 6 virtually never spreads to other parts of the body"

This topic caught my eye, as it also fits in to some of the other "cancer or not" threads, so I did a little research:

Do adenocarcinomas of the prostate with Gleason score (GS) ≤6 have the potential to metastasize to lymph nodes?

Ross HM, Kryvenko ON, Cowan JE, Simko JP, Wheeler TM, Epstein JI.

Departments of Pathology, Johns Hopkins Hospital, Baltimore, MD 21231-2410, USA.

Abstract

Although rare, there are cases within reported series of men with Gleason score (GS) ≤6 on radical prostatectomies that show pelvic lymph node (LN) metastases. However, there are no studies on whether pelvic LN metastases occur in tumors with GS ≤6 using the International Society of Urological Pathology (ISUP) updated GS system. We performed a search of the radical prostatectomy databases at 4 large academic centers for cases of GS ≤6. Only prostatectomies submitted and embedded in entirety with pelvic LN dissections were included. A combined total of 14,123 cases were identified, of which 22 cases had a positive LN. Histopathologic review of 19 cases (3 cases unavailable for review) showed higher grade than originally reported by the pathologists in all cases. Of the 17 pre-ISUP reviewed cases, 2 were upgraded to 4+3=7 with both cribriform and poorly formed glands. One case was upgraded to 4+3=7 with tertiary pattern 5 displaying cribriform glands, poorly formed glands, and cords of single cells. Eleven cases were upgraded to 3+4=7 with glomeruloid structures and small to large cribriform glands (1 of these also had features of ductal adenocarcinoma). Two cases had tertiary pattern 4 with small cribriform glands. One case had a prominent colloid component that would currently be graded as 4+5=9 because of large cribriform glands and solid sheets of cells within the mucin. Of the 2 post-ISUP cases, 1 demonstrated tertiary pattern 4, and the other showed GS 3+4=7 with irregular cribriform glands. Undergrading is the primary reason for LN positivity with GS ≤6, which has decreased significantly since the adoption of the ISUP grading system in 2005. Of over 14,000 totally embedded radical prostatectomies from multiple institutions, there was not a single case of a GS ≤6 tumor with LN metastases.

Summary: The investigators hypothesize that when using the 2005 International Society of Urologic Pathology classification system, Gleason ≤6 prostate cancer (PCa) cannot metastasize to pelvic lymph nodes. Four large radical prostatectomy databases identified >14 000 cases of Gleason ≤6, with 22 (0.15%) having LN metastasis, of which 19 were available for review. On contemporary re-review, all 19 contained Gleason 4 elements. Therefore, the authors conclude contemporary Gleason 6 cannot metastasize to lymph nodes.
In contrast to prevailing assumptions, GS ≤6 tumors do not appear to metastasize to LNs. Rather, Gleason pattern 4 or 5, as better defined by the current ISUP updated grading system, is required for metastatic disease.

 

My surgeon told me that it is very rare to see a G6 cancer found outside the prostate.  Of all the surgeries he has done, he said he has never seen a G6 that has mestisized.

He then went on to say that if you let G6 go untreated it will eventually change to a G7 and then to G8 and G9, but no one knows how long it will take.  

Now in some men this happens real fast,  but in other men, G6 may takes years and years to change to G7 and so on. 

age is an important factor. If I were in my late 60s or older I'd be willing to gamble that a G6 won't damage me, in my early 40s? no way.

A good AS plan could help alleviate some of the anxiety and uncertainties but besides not giving any guarantee, it also isn't a routine everyone is cut out for. Wasn't an issue with me as a G7 but I wouldn't have gone on AS even as a G6 as a 40 year old.

Forget the exact number but Ralph linked it once. A very large percentage of men get upstaged post surgery from a G6 to a G7. I suppose that developing and providing access to vastly improved diagnostic tools is the first step. At least should be...

You may be interested in recent discussions of this topic on this site:

Is the "cancer" label appropriate for Gleason 6/low risk?

Report suggests changes in the definition of what is cancer

My post 4 up from the bottom of the first page has links to some of the studies about this.

A true G6 will not mastastasize; in a study of 17,000 surgeries not one case was found. A large volume G6 tumor may grow into the rectum wall or bladder if left untreated over a long period. There have been cases where a G6 has morphed into a G7 over time, but again these are rare.
There is a misconception that Gleason grade always starts low and progress into a higher grade so G8s once started as G6s. This is not true as each tumor has its own individual DNA which regulates its grade and growth rate and this rarely changes. the vast majority of upgrades are due to entirely different tumors that have also formed. The vast majority of upgrades are due to a faulty pathology at DX and not from a natural progression to a higher grade. There are also variants, I believe that at least 24 different types have been identified, that appear to be normal, but act in entirely different ways than expected.
So the answer to your question is that it is possible, but not probable.

davidg said...
age is an important factor. If I were in my late 60s or older I'd be willing to gamble that a G6 won't damage me, in my early 40s? no way.

Davidg I agree with you 100%.
In the words of Dr. Sorace from Datolli cancer center during my consult.
At the time I was a G6 and not the G7 that I am now.
"at your age (52) you are not going to out run this and are going to need treatment"

The study that John T and Yooper mentioned has always bugged me a bit because it demonstrates a relationship at one point in time but it has a title that seems to draw unwarranted inferences about the future.

What they show, very conclusively, is that whenever there are metastases to lymph nodes there are gleason grade 4 cells present in the pathology, that is if there are mets then the Gleason score will always be 7 and up.

But to make the claim that is, at least, implied by their title you would also have to show that Gleason scored 6 tumors never progress to higher grades. It's an interesting relationship but it sounds more reassuring than it is. It's a bit like reassuring a father as his daughter dresses for the Prom that virgins never get pregnant. The forum rules do not allow the discussion of whether or not there has been an exception but, as a general rule it is true... but not, actually, that reassuring.

John T said...
There is a misconception that Gleason grade always starts low and progress into a higher grade so G8s once started as G6s. This is not true as each tumor has its own individual DNA which regulates its grade and growth rate and this rarely changes. the vast majority of upgrades are due to entirely different tumors that have also formed.

I'm not agreeing or disagreeing -- I remain skeptical until there's more evidence. We know that the genes that are currently activated do change all the time. It is the function of microRNAs to turn on and off different parts of the DNA -- and there is ongoing research about their use in cancer therapy. Various kinases, that regulate cell growth and replication, are varyingly inhibited and activated over time and in response to the cell's environment. Cancer cells have a high ability to mutate in response to environmental stress.

Sowalsky et al. examined only 4 TMPRSS:ERG fusion positive tumors. Not all PC tumors display such fusion. They stayed on the fence on whether the G4s emerged sequentially or in parallel from a common ancestor. "These findings establish that a subset of G3 tumors progress to G4 or emerge from a common precursor."

Likewise, VanderWeele et al. only examined four subjects. While there was some overlap in the DNA sequencing, they came down on the side of parallel development from a common ancestor, "These data support a model of parallel evolution of lower and higher Gleason score disease, rather than progression from Gleason 6 to higher Gleason scores."

If there is a common ancestor, what is it? We know that there seem to be prostate cancer stem cells in very low concentrations in some tumors. Is it these that give rise to G3s, G4s and G5s? If so, why one and not the others? What is the process that drives this evolution, and how can we detect and interfere with it? Similarly, are G3s sometimes amped into G4s and G5s by aberrant microRNAs or the tumor microenvironment and what drives such a process? I think there are lots of unknowns about the natural history of PC, and it may be different in different people.

In the meantime, I agree that true G3s are safe until they're not, just as PDA's prom queen remains a virgin until she's not. And just as we might chaperone the prom queen, the G3s bear chaperoning with Active Surveillance.

Post Edited (Tall Allen) : 8/2/2013 2:47:19 PM (GMT-6)

Tall Allen,
Elegant explanation. Thank you. With continued research, we will one day understand the true nature of PCa in all its variations. From there a "risk assessment" will be very reassuring as a man decides his course of treatment. For now, we must stay the course and be ever vigilant. For me, as a Gleason 6, I was fortunate that there was no upgrade post op and I continue to hope for no BCR and no metastases. All of these articles make me feel better but the door is not closed on the possibilities of a failed original treatment. Fingers crossed and maybe my eyes are a little crossed too with all these scientific terms on DNA, RNA, clonal progressions, etc.

 

Yooper,

The title of the study said...
Do adenocarcinomas of the prostate with Gleason score (GS) ≤6 have the potential to metastasize to lymph nodes?

What they found is that they do not have the potential to do so in a single step. But my question is -- do they have the potential to metastasize in two steps -- step 1) progress to Gleason 7, step 2) metastasize? There is some question about whether Gleason 6 has the ability to become Gleason 7. This study strongly suggests that it won't metastasize until it does. But if it can then a diagnosis of Gleason 6 (even if completely correct) wouldn't guarantee that the tumor would remain indolent and not eventually metastasize.

Have fun at the lake.

Highlander,

Actually, I don't see the possibility of progression as posing that big a problem for AS per se. As long as the progression from Gleason grade 3 to grade 4 is gradual and men are monitored closely and you try to switch men to treatment before their presumably Gleason 6 tumors grow outside the prostate, then you can probably follow an AS protocol while staying within the usual risk envelope that comes with AS.

And, I think it's possible to get all wrapped up in the question of progression, and whether or not it is actually possible, and miss a larger point. We don't get pathology reports signed by God telling us that Gleason 6 cancer is all that is present. We get biopsy reports that tell us that the pathologist looking at the tiny little samples we gave him of our prostate saw Gleason 6 cancer and didn't see Gleason 7. If we do another biopsy a year later and see Gleason 7 (or 8 or 9) we have no way of knowing if it was a case of progression or if the higher grade cancer was there before and the biopsy needles just missed it. This issue of progression tends to get lost in the uncertainty of diagnosis. Until such time as we have much better diagnostic tools -- imaging that reliably finds tumors and scores them, or genetic or metabolic markers that tell us accurately what is present -- the question of progression will be interesting but somewhat beside the point.

All of which makes the statement I started this thread off with seem a little meaningless and, IMHO, dangerous.