Can you die from Gleason 6 PC

The Gleason classification system was designed to provide a prostate cancer dedifferentiation range by low power magnification using microscopic observation of prostate tissue. The five grades represent the loss of glandular architecture as the carcinogenic process evolves from almost a normal structure (well differentiated) to a primitive structure (poorly differentiated).

In simpler words, it is a system based on dedifferentiation as cancer progresses. This process is variable and has the tendency to be slow in proliferating in the majority of cases. This is not to say that every GS 6 will proliferate and kill the patient. Many factors are involved in the development of mutations that drive the metastatic process which is the major cause of death in prostate cancer.

Based on this I searched the medical literature for clarification studies. What follows are several studies that support the premise that dedifferentiation is a stepwise process of variable potential. This fit the know character of prostate cancer: multifocal nd highly heterogeneous. Provided are the source and a summary of the abstracts. Full abstracts are available at PubMed:

Study 1. Brawn PN. The dedifferentiation of prostate carcinoma. Cancer. 1983 Jul 1
15;52(2):246-51. PubMed PMID: 6861069.

Using the M. D. Anderson (MDAH) method of grading prostate carcinoma, 19 of
26 (73%) Grade 1 lesions, 9 of 12 (75%) Grade 2 lesions, and 7 of 8 (88%) Grade 3
lesions dedifferentiated into another grade at the time of the 2nd TURP. Eight
cases that were Grade 4 at the time of the 1st TURP, remained Grade 4 lesions at
the time of the 2nd TURP. Although 10 Grade 1, Grade 2, and Grade 3 lesions did
not change grades, 8 of these 10 cases were less differentiated at the time of
the second TURP than they were at the time of the first TURP. This study suggests
that the usual course of prostate carcinoma is dedifferentiation and that with
dedifferentiation, the likelihood of metastases increases.

Study 2. Brawn PN, Speights VO. The dedifferentiation of metastatic prostate carcinoma. Br J Cancer. 1989 Jan;59(1):85-8. PubMed PMID: 2757926; PubMed Central PMCID: PMC2246976.

The metastases from 41% of the staging lymphadenectomies were entirely
differentiated (gland forming) and an additional 43% were predominantly
(50% or more) differentiated. In contrast, the metastases
from 70% of the autopsies were entirely undifferentiated (non-gland forming) and
an additional 18% were predominantly undifferentiated. Further, five patients
with completely or predominantly differentiated metastases in staging
lymphadenectomies were found to have widespread completely or predominantly
undifferentiated metastases at autopsy 4-7 years later. These findings suggest
that dedifferentiation occurs within metastases and that dedifferentiation within
metastases may be important in understanding the widespread dissemination of
metastatic prostate carcinoma.

Study 3. Adolfsson J, Tribukait B. Evaluation of tumor progression by repeated fine
needle biopsies in prostate adenocarcinoma: modal deoxyribonucleic acid value andcytological differentiation. J Urol. 1990 Dec;144(6):1408-10. PubMed PMID:
2231936.

Repeated fine needle aspiration biopsies of the prostate were taken during a
period of 24 months or more from 84 patients with untreated prostate cancer.
Serial followup regarding modal deoxyribonucleic acid values and cytological
differentiation of the tumor cells was possible in 72 and 78 patients,
respectively. During followup the modal deoxyribonucleic acid values in the tumor
cells changed towards an increased aneuploidy in 17 patients and the cytological
differentiation decreased in 18. These findings of a change in modal
deoxyribonucleic acid values and cytological differentiation of prostate cancer
cells during the course of untreated patients support the concept of a gradual
dedifferentiation of prostate cancer.

Study 4. Draisma G, Postma R, Schröder FH, van der Kwast TH, de Koning HJ.
Gleason score, age and screening: modeling dedifferentiation in prostate cancer. Int JCancer. 2006 Nov 15;119(10):2366-71. PubMed PMID: 16858675.

This studyprovides epidemiological evidence of dedifferentiation as a
major mechanism of progression in prostate cancer. Tumors dedifferentiate during the screen-detectable phase and consequently screening with PSA and early treatment can possibly prevent dedifferentiation.

Study 5. Porten SP, Whitson JM, Cowan JE, Cooperberg MR, Shinohara K, Perez N, Greene KL, Meng MV, Carroll PR. Changes in prostate cancer grade on serial biopsy in men undergoing active surveillance. J Clin Oncol. 2011 Jul 10;29(20):2795-800. Epub
2011 May 31. PubMed PMID: 21632511.

CONCLUSION: A proportion of men experience an upgrade in Gleason score while
undergoing active surveillance. Men who experience early upgrading likely
represent initial sampling error, whereas later upgrading may reflect tumor
dedifferentiation.

It is of extreme importance for us to understand the significance of this. We need to support the postponement of treatment for those that might not benefit from early or unnecessary treatment but at the same time we should not create the notion that all GS 6 are indolent and will not or hardly ever progress . In establishing a good protocol for active surveillance we promote a better quality of life for those men that should just monitor their disease while reducing their risk of progression. I firmly believe that remaining alert is the way to avoid occult progression. One day we will have better tools to avoid this risk, but we are not there yet.

RalphV

Thanks for the thoughtful contribution, Ralph.  It reaffirms my feeling that prostate cancer is a disease that we should never minimize.  G6 or G9, it's all serious business.

 

John T said...
DanO,
Dr Scholz is one of the most highly regarded prostate oncologists in the US and has 30 years treating and researching prostate cancer and only prostate cancer. If anyone understands how tumors form and grow he is the person. If he says that G6s remain G6s and don't progress I would take that to the bank, especially when there is no evidence to support another viewpoint.
Many patients on this board have had small G8 tumors discovered early. It is very doubtful that they started as G6. It is not unusual for a G6 patient to go 20 or more years without treatment and it is rare for a patient to die of a G6 cancer. If cancers progressed as you suggest these patients would have died years earlier. It may be illogical to you, but the DNA of the cancer you have is the DNA that stays with that cancer and determines how it will act. It is not at all unreasonable to expect that if one has a predisposition to prostate cancer that other tumors will not form somewhere along the line and it is well known that PC is a multifocal disease and that if you have one tumor there are mostl likely more. A patient can have a G6 tumor in one place and a G8 in another, in fact this is very common. Tumors that start independently can also grow into one another appearing as one tumor, but are actually multiple tumors.
JT

First of all let me apologize to you John. I did not read every post before I replied, I should have. I assure you that my post directly after yours was coincidence. Had I read your post relaying Dr Scholz opinion I would have worded my post differently, though I still would have posted my doubts about tumor grade stasis.

I also apologize for helping to derail the initial question.

Thanks Ralph for posting some study info concerning my question. The fact that there are studies asking whether grades de-differentiate indicate there is disagreement in academia. My opinion is not out of left field.

be well...

Ralph,
This doesn't sound logical. The tumor size of any gleason grade is a function of psa doubling time and time. There is a constant psa per cc of tumor for each gleason grade. If given a 2cc G6 tumor with a 2 year doubling time, in 6 years it will be 16cc. It will continue to double in size at the same rate until it eventually breaks out of the prostate. A g6 can be large or small, so can a G9. It's size depends of it's internal doubling time and the length of time it has been growing. Higher grade gleasons may have more volume when they are discovered, because their psa doubling time is fast, this is why they are dangerous. They also give off lower amounts of psa per cc of volume so they are discovered later.
Strum describes this very well in his book. If you know the size of a tumor and it's gleason grade and have 3 years of psa history to determine doubling time, one can calculate the size that a tumor will be at every stage of a man's life from that point on.

Ralph, thank you for such an extensive search. I read and have a few comments to make about the following study and what I consider are its weakneses:

Brawn PN, Speights VO. The dedifferentiation of metastatic prostate carcinoma


- comparing lymphoadenectomies from a set of patients, and then an entirely different set of patients at autopsy: it is like comparing apples and oranges. Only 9 patients "made" the both groups, and in that group, in 2 patients at autopsy metastasis could not be identified, in another 2 patients the metastatic cancer was still differentiated at autopsy, and in 5 patients cancer went from differentiated in lymph nodes to undifferentiated cancer at autopsy. 5 is hardly a high number of subjects for a meaningful conclusion, but it can serve as sort of a "case study" example, in which circumstances a deeper analysis would have been required.

- prostate tissue was never compared to the distant metastasis, only samples from lymph nodes. So, it is possible that the "undifferentiated" prostate tissue gave "undifferentiated" metastasis even though lymph node samples appeared "differentiated" (?)

-it is hard to translate this "differentiation" lingo into Gleason grading, in other words, one cannot draw a concusion from this study that Gleason 3 morphs into Gleason 4 or 5.

Special Lady,
You were correct in pointing out that PC in lymphnodes is different from PC in the prostate. The Gleason grade is only used on Prostate tissue and lymphnode tissue is not graded because of that reason. Later upgrading of Gleason grades is not evidence of tumors morphing. PC is multifocal with multiple tumors forming in different locations. Higher grade tumors are normally found along with lower grade tumors on post op pathology and in biopsies. We assume the tumor morphed, but most likely it is a new tumor.
If anyone has a good relationship with an expert pathologist, it would be helpful if we had his opinion on the issue.
JT

Ralph,
Before any calculations are made the psa from benign prosate tissue is subtracted using the formula .066X prostate size in cc.
On page 158 "Primer on Prostate Cancer" Strum describes two software programs. One to calculate tumor volume and the other to obtain projected outcomes using AS by using tumor volume and PSADT. One program was created by Di'Amico. They take into account the different amounts of psa generated by the different gleason grades as each Gleason grades produces a different ratio of psa per cc of tumor volume with the higher grades producing less psa.
I also emailed both Oppenheimer and Bronkhoff with the question of G6s; hope they will answer.

I am nowhere near the expert on PCa that JohnT and Ralfinaz are, but I do have on obervation on this topic.

What I derive from this thread is that as a group we should be very careful about assuring newcomers, freshly diagnosed as Gleason 6, that they'll likely be "just fine"; that their cancer is likely "indolent"; that even if it spreads, it's unlikely to cause a problem because Gleason 6 cancers have a tough time surviving outside the prostate; that they are surely good candidates for AS rather than surgery; and that their Gleason 6 will very likely alwayrs remain Gleason 6 and not morph into a higher Gleason grade.

All those things may be true.......I'm not arguing the truth of any of these assertions.

But I've noticed that a lot of men are looking for any possible excuse to avoid the unpleasantries associated with biopsies, surgeries, and radiation.  If all they take away from their visit to HW is an impression that they are more likely to die with their Gleason 6 than because of it and that it's hardly even a cancer at all, I think that's a very bad message we've sent.

The message I would prefer they take away is that they MUST be sure their situation is comprehensively looked at, and that it is almost certain that their physician will be in a better position to advise them than anyone here on HW.  He knows their medical history; he has put hands on (an in) their bodies; he has even looked at things like fingernails, eyes, earlobes, skin that tell a wise doctor a lot about a person's general health.  We know none of these things. 

When the rest of the world seems intent on doing away with screenings; when we hear more and more about the horrible side effects than we do about the benefits; when we're constantly warned about overtreatment....I feel that we, as men who have experienced this cancer, are in a unique position to tell other men that this is a serious business, even if it's "only" Gleason 6.  After all, it's an undeniable truth that something like 30,000 men will die of prostate cancer this year. 

If we, as prostate cancer survivors, don't stress the seriousness of this disease...who will?  I think we can do that and still warn the newly-diagnosed that they must educate themselves and choose their treatment wisely.  I'm not sure that's the message we've been sending lately, though.  Just my opinion, and I'm sure not shared by all.

This is a good discussion of different viewpoints and no one is suggesting that anyone take any action without being directed by a medical professional. It is also prudent to note that many doctors up not up to date on the latest diagonostics or treatments for PC and it is wise to seek confirming recommendiations or second opinions, hopefuly from a doctor that specializes in only prostate cancer.
These are some comments by Dr Strum on PSA:

"The psa level stands out as the major tool in the management of PC. It serves as the marker or indicator of PC activity throughout the course of PC. It informs us of the response to various treatments and is the single most important product produced by the prostate cancer cell."

"However, despite the incredible value of psa and psa dynamics, there are pitfalls in solely relying on psa. This relates to an understanding of the degree of agressiveness and stage. When Gleason scores 8-10 have been identified, psa loses much of its value as a tumor marker; other indicators of disease such as PAP, CGA CEA and NSE are biomarkers that better reflect the cellular activity of a more aggressive and less differentiated tumor cell population"

"The dynamics of PSA, such as PSA velocity and PSA doubling time are reflections of cell growth. A high PSAV and short PDADT are more consistant with a systemic disease and is true at time of DX and also with recurrance of psa after any form of treatment"

I wanted to mention a friend of mine because his case seems to disagree with at least one impression here: that if you have a G6, the cancer has not spread very far, or does not spread very far.

In his case, he was biopsied with a G6, and he opted for surgery. After RRP, although the entire organ was removed, he had positive margins and capsule penetration. The tumor size was significant, although I do not have details of the % of the organ that was involved. After some time of undetectable PSA, he had a BCR. He has decided to do AS and not opt for radiation. His doubling time started out at least 18 months, and has been increasing with time.

It sounds to me that he has a G6 that may stay a G6, and it appears to not be a particularly aggressive type (based on the doubling time). However, the tumor did spread significantly within the prostate and managed to exit the organ.

I think that in the next decade, with gene sequencing and the collection of statistics regarding correlation with various cases of aggressiveness of PC, we will have a lot more visibility into the 24 or so types of PC that they know are out there. Perhaps some G6 develop into G10 given time, and others never go past G6. Perhaps it has more to do with the particular type of PC you have (of the 24 or so they have identified) than anything else. Perhaps they will be able to let you know just how aggressive your type is, and the days of relying primarily on a biopsy will be behind us. One can hope.

Casey, your post was definitely not one that I was referring to. You were clear that G3+3 is not necessarily low-risk.

In my friend's case, unfortunately, he will probably never undergo RT, because he watched his father (who had a different type of cancer) die from complications from it. I just keep praying that it IS non-aggressive. At least he has a long doubling time in his favor.

Im-Patient, you are now a third person on this thread who reports "extensive G6". HD_Rider had a PNI with a G6, and questionabout it had an extensive tumor, also a G6.

Perhaps we can agree at least on the fact that G6 tumors can definitely grow and should be very closely monitored in people on AS, preferably with MRI imaging.

Ralph.

I am guessing you have been living with PCa longer then 1992. That is just when you found out about it. Correct? So maybe 25 or 30 years? You are my role model if so.

Lol