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Something I don't understand about Gleason scores.

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Posted 5/23/2016 3:10 PM (GMT 0)
The Gleason grading of cancer is the addition of the two most predominate aggressive cancers found.

IE 3+4=7 , 4+5=9, 5+4=9

What I don't understand is why when the larger number, if in the secondary position is down played.
Or is this just in my head? It's I'm sure I've heard others say that they would rather be a 4+5 than 5+4.

In my case 4+5, I know that it means there are more 4 cells than 5s.
But why does that matter?
They are still type 5 cells and they are "very aggressive" as opposed to the "aggressive" 4s.

Are the cells in the secondary position less serious, did they stop reproducing because they are aware that they are outnumbered? /sarcasm
Posted 5/23/2016 3:30 PM (GMT 0)
I would never say that the second number is "downplayed"...and don't think I've ever heard a medical professional refer to it in similar terms. I think your premise is incorrect. I would say it is the second most important number.

It has been shown to be important in unfavorable-risk cases because the proportion/percentage of grade 4 & 5 has been demonstrated to be directly proportional to long term outcome. Here's the conclusion from paper on pubmed titled "The combined percentage of Gleason patterns 4 and 5 is the best predictor of cancer progression after radical prostatectomy."
    The combined percentage of Gleason patterns 4 and 5 is one of the most powerful predictors of patient outcome, and appears superior to conventional Gleason score in identifying patients at increased risk of disease progression. On the basis of our results, we recommend that the combined percentage of Gleason patterns 4 and 5 be evaluated in radical prostatectomy specimens. The amount of high-grade cancer in a prostatectomy specimen should be taken into account in therapeutic decision making and assessment of patient prognosis.



Try out the differences in one of the nomograms.

Post Edited (JackH) : 5/23/2016 12:57:17 PM (GMT-6)

Posted 5/23/2016 3:37 PM (GMT 0)

alephnull said...
The Gleason grading of cancer is the addition of the two most predominate aggressive cancers found.

IE 3+4=7 , 4+5=9, 5+4=9

What I don't understand is why when the larger number, if in the secondary position is down played.
Or is this just in my head? It's I'm sure I've heard others say that they would rather be a 4+5 than 5+4.

In my case 4+5, I know that it means there are more 4 cells than 5s.
But why does that matter?
They are still type 5 cells and they are "very aggressive" as opposed to the "aggressive" 4s.

Are the cells in the secondary position less serious, did they stop reproducing because they are aware that they are outnumbered? /sarcasm


You're right alephnull, the secondary cells just keep on keepin on...

These numbers are meaningful in the context of being in relation to one another.

So...when it's said 4+5 is better than 5+4 it means that in both instances the first number is doing its thing as well as the second number doing its thing.

However...In the 4+5 instance there's fewer 5's than 4's. This is a good thing in that 5's are the worst. And there's fewer of the worst than there are of the the next worst (4's).

In 5+4....there's more of the worst than the next worst. So...in this way...a 5+4 should be worse than a 4+5.
Posted 5/23/2016 3:49 PM (GMT 0)
I've always wondered about that too, Alephnull. If you have for example, a 3+4, that's LOW intermediate risk. But all you need is one grade 4 cell to take a road trip through your body, and set up camp somewhere. In a year or two. You have rising PSA. At least that's what logic tells me.
I suppose a (3+4) means that there's less chance that a grade 4 cell will take hold and grow, than in the case of a 4+3, or a 4+4. ... I suppose.
Posted 5/23/2016 4:09 PM (GMT 0)
I seem to recall that Epstein classifies even the smallest trace of grade 5 cells as G9. My initial diagnosis was G8 (4+4) with tertiary grade 5. Epstein moved me up to a G9 as a result. (But I'm not sure why a 5+4 instead of 4+5. I never asked and figured it didn't really matter...)

As to the what Pratoman asked about the grade 4 cells above is a good question. Is it simply a matter that if there are less grade 4 cells there are fewer to go on a road trip? Or is it more complex than that?
Posted 5/23/2016 4:40 PM (GMT 0)

Pratoman said...

I suppose a (3+4) means that there's less chance that a grade 4 cell will take hold and grow, than in the case of a 4+3, or a 4+4. ... I suppose.

One source for guidance are the cure rates.

A 3+4 has a higher cure rate than a 4+3 and isn't in the same ball park as a 4+4.

It could really be helpful in the fight against this disease if cure rates were even more "efficient". It would be interesting to see the difference in cure rates between a 3+4 pathology that's 95% 3's vs. 51% 3's.
Posted 5/23/2016 6:12 PM (GMT 0)

island time said...
A 3+4 has a higher cure rate than a 4+3 and isn't in the same ball park as a 4+4.

That's correct...this stuff isn't really applicable/significant for favorable-risk cases, like yours was.



island time said...
It would be interesting to see the difference in cure rates between a 3+4 pathology that's 95% 3's vs. 51% 3's.

I can show you why this isn't all that relevant for favorable risk-cases. The logic is quite straight-forward.

While the specific information you asked about is not available, your first instance of "a 3+4 pathology that's 95% 3's," well, that's just about a 3+3, right? I think you were trying to describe the 3+4 case with the least G-4, so a slightly better case would be results from the set of all 3+3 cases, right? So, looking at a case with 3+3 would be MORE extreme on the favorable side, right?

And your second instance was "a 3+4 pathology that's...51% 3's;" that's 51% G-3 and 49% G-4, so the most G-4 in a 3+4 case, right? So a slightly worse case than this would be results from the set of all 4+3 cases. Right? So looking at a case with 4+3 would be MORE extreme on the unfavorable side.

So, directly to your question, the differences you are asking about would be smaller than the differences between the slightly better 3+3 case and the slightly worse case 4+3. right?

I entered a pair common favorable-risk cases into a nomogram. 60 year old treated with surgery, no RT, no HT. Pathology was no PSM, no SVI, no EPE and no +LN. Pre-surgery PSA was 4ng/mL. Very common. Then I entered 2 difference scenarios of Gleason post-surgical pathology--one was 3+3, the other was 4+3. This is essentially "examining the margins" of 3+4, which was, I believe, your question.

15-year PC specific survival for 3+3 = 99%
15-year PC specific survival for 4+3 = 98%

As I said, the difference between the 2 scenarios you asked about would be less than the differences between these more extreme cases.

The technical term we like to use to described these differences is: "mice nuts."

In other words, small.

Post Edited (JackH) : 5/23/2016 12:56:12 PM (GMT-6)

Posted 5/23/2016 9:14 PM (GMT 0)
My docs basically treated the highest G found. He didn't nuance over the 3/4 vs 4/3. He said the 4 can be bad so let's go after it.
Posted 5/23/2016 9:22 PM (GMT 0)
Thanks all!!

The diff between 98 and 99% may be small statistically, but not to that group of folk in the 1%
Posted 5/23/2016 9:23 PM (GMT 0)

JNF said...
My docs basically treated the highest G found. He didn't nuance over the 3/4 vs 4/3. He said the 4 can be bad so let's go after it.


I hear what you are saying. That's not the current (this decade) thinking amongst the best minds in PC today. The intermediate (G7) cases are now split into two distinctly different groups. Generalizing, the 3+4 cases are favorable-intermediate risk, and 4+3 are unfavorable-intermediate risk. Patients in each group benefit from divergent therapeutic paradigms.

You and your doctor did the right thing by treating your 4+3 case aggressively.
Posted 5/23/2016 11:07 PM (GMT 0)
JackH, can you supply your signature in one of your posts? Were you a 3+4 or a 4+3? J
Posted 5/23/2016 11:28 PM (GMT 0)
Sure, JayMot.

Clinical diagnosis was 3+4, I believe it was 3 out of 13 cores positive, it was a long time ago and I don't remember the percentage in the positive cores, but they were low-ish, I believe all under 50%, and negative DRE. Very typical and common case.

I had an RP, which I did thorough diligence on in terms of picking a treatment and then picking a highly experienced surgeon. Where I failed, or the system failed me, was that before picking a treatment, I should have spent more time understanding whether I really needed treatment or not. I pretty much jumped over that step. In hindsight, I should have started out on AS and waited to see if I really needed treatment or not, but I got zero inputs that this was the most viable (and probably best; not the same thing) choice to start my journey. I might still be on AS today without some of the harms of treatment, or 7 years or so later I may have eventually progressed to the point where I might need treatment, but I could have taken advantage of advances in technique and technology. Post-surgery pathology was also 3+4.
Posted 5/23/2016 11:38 PM (GMT 0)
Yes, a 4+5 can be significantly better than a 5+4. The number that's more prevalent in the core sample goes first. That said, the devil's in the details.

The amount of cancer in each core sample makes a big difference too. If you have a positive core that's 95% 4 and 5% 5 that's a lot different than having 51% 4 and 49% 5. Either way it's a 4+5=9, but it's a very different situation.

Post Edited (Jazzman1) : 5/23/2016 5:47:34 PM (GMT-6)

Posted 5/23/2016 11:49 PM (GMT 0)
I was always taught, that you treat it based on the high number, not the sequence its in. Even in a Gleason 7 (3+4) you treat the "4", not the "3" and the same thing if it were a 4+3.

My doctor has always said, that a Gleason 7 can be very unpredictable to treat, where in many cases a Gleason 8, while more serious, tends to respond to aggressive treatment better.

I was downgraded from a 4+3 to a 3+4 back in 2008, which should have been a good thing. I will state for a fact (on my case only) that my Gleason 7 has been very aggressive from day one and continues to be so. The only time I was/have ever been unpredictable was at my 90 days post surgery PSA, believe Feb. of 2009, when it came in at .05. It is now and has been in XX.XXX numbers for the past 5 years. When I was told of the .05, my surgeon was alarmed (I thought it was good news at the time), he said I was headed for trouble. And he was exactly right.

Post Edited (Purgatory) : 5/23/2016 5:55:41 PM (GMT-6)

Posted 5/23/2016 11:50 PM (GMT 0)
The primary and secondary scores are assessed this way:
Primary grade - assigned to the dominant pattern of the tumor (has to be greater than 50% of the total pattern seen).
Secondary grade - assigned to the next-most frequent pattern (has to be less than 50%, but at least 5%, of the pattern of the total cancer observed).
Tertiary grade - increasingly, pathologists provide details of the "tertiary" component. This is where there is a small component of a third (generally more aggressive) pattern.

So, yeah, the primary/secondary assessment can be a big deal, though with type 5 it seems if there's any of it the risk is much higher. Even tertiary, probably less than 5%, is important.

My 5+4 means 2 of my cores had over 50% type 5 cells. That's a lot. The 4+5s don't specify how much of the view the secondary 5 actually covered, but it's somewhere between 5 and 50%. So, primary/secondary can mean quite a bit about the amount of the baddies in there.
Posted 5/24/2016 10:53 AM (GMT 0)
In my mind, the most important component is the curative rate based on statistics for the various Gleason and stages.

What that represents is the clinical understanding and ability to treat the various cell types.

For prostate cancer, there are 3 components. (1) Disease Functionality and (2) Ability to Treat and (3) Quality of Life

That being said, new data needs to start replacing the old data since science/medicine are moving at break neck speeds these days where PCa is concerned and a lot of the old data is what is used to generate the nomograms.

Obviously, type 5 cell structures are the most agressive, with type 4 being #2, and so on.

When we start talking about 4+3 or 3+4, and so on, in my mind, a type 4 is a type 4, and will functionally do what type 4's do, regardless of the proximity of type 3 structures. Given the growth rate differentials, in my mind, a 3+4 or 4+3 will some day become a 4+3 or 4+4 with 3+3 unless there is some intervention.

At what point does a 3+5=8 become a 5+5=10 with 3+3=6? My mind just rolls over and over trying to understand the functionality and differentiation. Glad there are well educated scientists and doctors out there to tell me.

Posted 5/24/2016 11:22 AM (GMT 0)
I've seen other comments by other experts that repeat the suggestion about how a 4+3 is a peculiar beast and often difficult to deal with. Others have said where the dominant pattern is higher than the secondary, such as Redwing's case with the 5+3, is unusual and challenging.

Some docs do, in fact, treat the high number regardless of where it lands...and that sounds like a solid, conservative medical opinion. In other words, treat the worst case scenario from the start. Some percentage of the time it might not have been necessary...but the rest of the time it is. Making those calls is what they get paid the big bucks for, IMO.

And we couple that with Epstein's research that indicates that G3 cells don't tend to mutate to G4s...that G4s spring up on their own from the base tissue (not sure where G5's come from..do they mutate from G4 or show up on their own?), and we see how significant the G4 really is.

It is confusing, and then when you couple this confusion with the risk categories (low risk, low intermediate, high intermediate, etc) along with the staging assessments, you might as well be speaking chinese.

In the end, our individual categories actually tell a unique story that is ours alone to experience.
Posted 5/24/2016 11:36 AM (GMT 0)

Newton451 said...

That being said, new data needs to start replacing the old data since science/medicine are moving at break neck speeds these days where PCa is concerned and a lot of the old data is what is used to generate the nomograms.

You do know, don't you, that the major nomograms ARE refreshed, updated and validated with current data sets every couple of years?
Posted 5/24/2016 11:49 AM (GMT 0)
Nope. I wasn't aware. Thanks Jack.
Posted 5/24/2016 11:54 AM (GMT 0)

Newton451 said...

When we start talking about 4+3 or 3+4, and so on, in my mind, a type 4 is a type 4, and will functionally do what type 4's do, regardless of the proximity of type 3 structures. Given the growth rate differentials, in my mind, a 3+4 or 4+3 will some day become a 4+3 or 4+4 with 3+3 unless there is some intervention.



I also remember those scary black and white videos of marijuana, the Communists and cancer from the '60s. It's no wonder "in your mind" this is what you think, because you've been successfully conditioned in society to think that "cancer" equates to certain pain, suffering and death.

In real life, however, it's different...particularly for prostate cancer. A high-grade PC may grow in you if you've got the right environment to feed it in your body and not enough resistance to fight it back on a daily basis, or it may not; and you may already have some low-grade PC or not. It doesn't "morph" in the way it seems like in your mind.

Post Edited (JackH) : 5/24/2016 5:57:49 AM (GMT-6)

Posted 5/24/2016 12:57 PM (GMT 0)
My take on the whole G thing is, "a little G9 can definitely spoil your day".

it does not really matter if the primary is 4 or 5, to my "mind" a G9 is BAD!.

.
Posted 5/24/2016 1:38 PM (GMT 0)

PSA3DOT7 said...
My take on the whole G thing is, "a little G9 can definitely spoil your day".

it does not really matter if the primary is 4 or 5, to my "mind" a G9 is BAD!.



Definitely agree with you.


4+5 versus 5+4, not much, or any, difference in approach. Both are "high-risk" category (a.k.a "BAD") along with 4+4; grouped together because of similar outcomes/approaches.

3+4 versus 4+3, more significant difference, and very different approach. Completely different risk categories.


It's important to note at this point that risk categories are defined by more than just Gleason scores, but any doctor who treats favorable-intermediate risk PC the same as unfavorable-intermediate risk PC in this decade should be fired, or should go ahead and retire. That's just the old mode of "one-size-fits-all" which went out with bell-bottoms.
Posted 5/24/2016 1:54 PM (GMT 0)
I think it is far more individualized than that. As has been pointed out the proportions of the scores can make a considerable difference as can other factors like age, general health, PSA at dx, family history, percentage of cores etc. There is always a line midway between two classifications at which prudence says to round up.

I am all for evidence based treatment, but let's not take the doctor's judgement and experience out of the consideration.. I think this is particularly valid when surgery is not the treatment. We know that about 30% of biopsies are upgraded after the pathology. So if I was 3+4 using radiation as a treatment I feel it would be prudent to consider treating as if I were 4+3, because there is always a strong probability that I am.
Posted 5/24/2016 2:06 PM (GMT 0)

JNF said...
We know that about 30% of biopsies are upgraded after the pathology. So if I was 3+4 using radiation as a treatment I feel it would be prudent to consider treating as if I were 4+3, because there is always a strong probability that I am.



You are extrapolating inappropriately.

3+4 (depending on other case characteristics) is typically a favorable-intermediate risk case.

Studies have shown that Gleason scores of low-risk cases (not other risk categories) with a single biopsy reading get changed about 50% of the time post-operatively...about half of those are downgraded, and about half of those upgraded.

So if a newcomer presented the "logic" you mentioned, I would first ask him which prostate cancer expert pathologist re-read his prostate biopsy slides, because that will significantly reduces the risk of upgrade. (Of course, this is why it is "Step-0" in the sticky thread...it's that important that one should do it before "Step-1.") Then I would ask if they have also eliminated walking across streets...because after all they might get hit by a truck.

The rule of thumb...anyone with favorable-risk PC who pursues aggressive treatment based on a single biopsy not read by a PC expert pathologist is at an elevated risk of being overtreated.
Posted 5/24/2016 3:13 PM (GMT 0)
This is a good example where personal involvement and education is very important in making treatment decisions. Multiple opinions are likely to bring different suggestions that the patient must sort out. I don't agree that doctors should be fired for not 100% following non-statutory standard of care protocols where there are inherent grey areas. If that is the case, then I suggest that every surgeon that operates on low risk should be fired and probably hung for good measure!

One guidance from my urologist was that in his extensive experience the situation is usually worse than the initial dx indicates, thus the significant number of recurrances. When I asked this of the two other urologists, two radiation oncologists, and one medical oncologist they all concurred. The message was clear to me and I favored the more aggressive approach as my wife was going through major treatment for her second breast cancer in the same breast. My concern level to go after the cancer was clear.

In many medical treatments there are rarely clear absolutes. Particularly in PCa where we have so many different treatment methods and biological variations of the cancer, many of which are unknown in the basic biopsy such as ploidy, that can have effects on treatment efficacy. It remains, in my opinion, that in many cases it just isn't cut and dried and the judgment of the doctor and patient must be guided by broad evidence but not restricted by the same broad evidence. At the end of the day, two identically dx'd people can choose different level of treatment aggressiveness based on their personal considerations. They can also decide not to treat. None of this should be laid on the doctor.
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