Age a Big Factor in Prostate Cancer Deaths, Study Finds

Maybe this will give credence to the theory, I'll say fact, just to be me, that gleasons do indeed migrate higher, or at least get more aggressive company as you start aging untreated. Never did psa till 66. Mostly 3 and 4 and teriary 5 on pathology.Bet you when I was 56 I had Pca and bet it was 3's. Just an edu micated guess, which works like facts to me, simpler......

I have never thought that a benign cell just jumped to an 8 or 9. Rather I have suspected that they progress as they mutate. Look at mine....I had 3+3, 3+4, and 4+3. Given more time I am sure that these numbers would continue to progress. I do believe a 6 can stay a 6 for a long time, but I also believe that many a 6 will progress to a 9 or 10 if they aren't interupted by treatment.

I always suspected that PCa doesn't just start as an 8 or a nine but rather start at a low grade and mutate to a higher grade or possibly remain the same. My PSA at the age of 65 was 1.31. At 66 it was 2.45 and jumped to 3.78 14 months later. Should I have had a biopsy at 66 may be my Gleason would have been a 6 or 7 instead of 8.

John T said...
I haven't seen any evidence to suggest that most pc will have a common migration path from a G6 to a G8 or 9 over time. Many G6s will migrate to G7. but there is a lot of evidence to suggest that this may be more to to with biopsy sampling than migration of grades. Most G8s and G9s start as high grade and most G6s stay G6s. There are always exceptions.
JohnT

JohnT,
Where is the evidence to prove that your statement is correct? Reality is very different. The Gleason grading system is based on a process of differentiation by which the normal glandular structure of prostate tissue goes from normal to well differentiated cancer to poorly differentiated cancer in a step-wise process.

Cellular dedifferentiation is associated with DNA changes in which the normal cell content of chromosomes changes in a positive or negative manner. Those ploidy changes are associated with the carcinogenic process. This is from a normal diploid content in normal tissue to an aneuploid content in cancer tissue.

For your statement to be correct men have to be born with high Gleason grades or this carcinogenic process has to be very fast and low grades seldom progress although you admit that some will migrate to GS 7, but most will never progress.

A tumor whose structure is nearly normal (well differentiated) has a biological behavior relatively close to normal and is not very aggressively malignant. At the other extreme, a tumor whose structure has regressed to a more primitive form (poorly differentiated) is aggressively malignant. Those are the two extremes of the Gleason grading system identifying the progressive deterioration of the cancer cell architecture

In most multi-cellular organisms, such as humans, not all cells are alike. As an example, cells that make up the human skin are different from cells that make up organs or glands. And yet, all of the different cell types in the human body are derived from a single, fertilized egg cell through a process of differentiation. Differentiation is the process by which an unspecialized (undifferentiated) cell becomes specialized into one of the many cells that make up the body, such as brain, lung, or prostate cells. During differentiation, certain genes are turned on, or activated, while other genes are switched off, or inactivated. This process is highly regulated. As a result, a differentiated cell will develop specific architectural glandular structures and perform certain characteristic functions. When specialized cells such as prostate cells, undergo genetic mutations, they can in time dedifferentiate and lose their specific architectural structures and characteristics. This is the basis for the Gleason Grading System.

In short, prostate cancer is a multi-step progressive disease with a wide-range, variable time span. In most men the disease progresses slowly, but in others progression is fast and unrelenting. In either case, the common factor is that disease progression is a continuum and, given enough time, it evolves into a lethal disease by the process of dedifferentiation. In his histological observation of tumors, Dr. Gleason recognized the multi-step process that characterizes the heterogeneity of prostate tumors and was able to more closely characterize a patient’s prognosis by grading the two most prevalent patterns present in a tissue sample.

Dr. B. Tribukait and coworkers in Sweden have supported the multi-step progression of prostate cancer with their work on successive needle aspirations of prostate tumors. They evaluated the yearly rate of mutation accumulation as determined by DNA ploidy measurements. In each cell of their bodies, except their germ cells, humans have 23 pairs of chromosomes that dictate the person’s genetic makeup. Normal cells containing 23 pairs of chromosomes are said to be diploid.

Dr. Tribukait was able to show that, as time goes by and mutations accumulate, there is a loss or gain of chromosomes in prostate tumors. This process changes the cells from diploid to aneuploid. Aneuploid cells are cells containing an abnormal number of chromosomes. There is a close relationship between DNA ploidy and Gleason Grades. Higher Gleason Grades are mostly aneuploid and tend to metastasize or invade local tissues more readily.

Further support for this process exists from autopsy results of younger men dying an accidental death. Although the presence of prostate cancer is apparent at even the third decade of life, all those cancers are classified as insignificant and always well differentiated. The implication is that, if those cancers had more time to progress, more aggressive tumors would have developed in time (higher Gleason grades) —which is what typically happens when men are diagnosed at a later point in their lifespan if PSA testing is not used frequently.

Source:
Adolfsson J, Tribukait B.
Evaluation of tumor progression by repeated fine needle biopsies in prostate
adenocarcinoma: modal deoxyribonucleic acid value and cytological
differentiation. J Urol. 1990 Dec;144(6):1408-10.

RalphV




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The article fails to differentiate between two very different types of patients:

Case A: A 75 year old who has been getting screened regularly since age 60 earlier, has had "normal" PSA all this time, and then their PSA begins to rise and they are biopsied, and then diagnosed with PC.

Case B: A 75 year old who has never had a screen and never would. They are only getting tested now because they are symptomatic.

It should not surprise anyone that the "case B" patients are disproportionately advanced and metastatic relatively to prostate cancers found in younger men, virtually all of whose cancers are now found by screening. However this tells us little about the aggressiveness and progression of disease in "case A" patients. it tells us more about screen-detected vs. symptomatic cancers than it tells us about old men vs. younger men.

Because these cases are not discussed separately, it could well be that everything in the article is true, and that older men who were screened consistently until they reach an advanced age, still tend to have less aggressive tumors that they die with, and not from.

Proscap,
Why is there a need to differentiate between the two cases? The article is set to demonstrate that “contrary to common belief, men age 75 and older are diagnosed with late-stage and more aggressive prostate cancer and thus die from the disease more often than younger men”

“They analyzed 464,918 records of men diagnosed with prostate cancer between 1998 and 2007, known as the "PSA era" because of a strong inclination to recommend the PSA test during that time.” That large population includes both of your cases.

“The analysis showed that when age groups are broken down into smaller sections, men 75 or older represented only 16 percent of the male population above age 50 and 26 percent of all cases of prostate cancer -- but 48 percent of cases of metastatic disease at diagnosis and 53 percent of all deaths. In general, higher grade cancer seemed to increase with age, the study said.”

In spite of all the hoopla about the widespread use of PSA here, this is one more indication that a great number of men age 50 and above never are tested with PSA and therefore are currently diagnosed with advanced PCa.

RalphV

John,
Look at it another way. I have told the story of my friends father here that had a recurrence of prostate cancer 29 years after his initial therapy. When the second diagnosis came about it was Gleason 10. Is it reasonable to think that he always had Gleason 10 prostate cancer for 29 years and it suddenly became aggressive?

I am no geneticist so I will not comment on the probability that this was possible. But it seems highly unlikely that he always had G10 disease for 29 years.

There is no logical reason to suspect that a normal cell will only mutate once, multiply into a single grade without mutating into a more aggressive grade. I do agree that many biopsies miss the more aggressive tumor. And that is likely more common. But there is plenty of evidence that mutations continue to happen to healthy prostate cells and cancerous prostate cells.

Tony

JohnT,
PCa Incidence is driven by the use of PSA testing. The higher the PSA test use, the higher the incidence.
That said, using your example of 200,000 new diagnosis and 30,000 PCa deaths (in round figures) we can do some calculations. Given that most PCa diagnosed today is early disease and 2/3 are treated with surgery or radiation, most of them should be “cured” as they were never destined to die of PCa. (Don’t laugh yet!)

That leaves 68,000 men. Many of these 20% to 25% (17,000) have higher grade disease and we will get back to them shortly, That leaves 51,000 men diagnosed with prostate cancer that never get localized treatment and probably constitute the population that undergoes WW or AS and ultimately might or might not get some kind of treatment.

The 17,000 men diagnosed with advanced PCa will mostly get treated with HT and eventually fail therapy. This group will constitute some 57% of the yearly deaths attributed to PCa. That leaves the 51,000 men that mostly decide to treat the disease expectantly and conservatively.

Most of these men are part of what is considered early disease because of the “widespread” use of PSA testing and depending on age at diagnosis they would live 10 years or more without treatment and with slow signs of progression. As time goes by and approach 15 years after diagnosis, PCa progression and its symptoms starts to affect this population and some 25% of them will die of PCa while the rest dies of cardiovascular disease, diabetes or other cancers.

Now we all know that those 2/3 that are treated with very early cancers (that are overtreated and were never destined to die of the disease), do eventually fail treatment and some die of PCa. The question is then: were these men overtreated as reported or was their disease more aggressive and eventually progressed after treatment? Take your choice and move the numbers of those that died around to fit the actual deaths. The point here is that early disease given enough time will progress through the range of GSs if the patient doesn’t die of something else. Given the new recommendations, if approved as written, less of these early potentially curable cancers will be diagnosed and more men will eventually die.

That is supported by what is happening in countries in which the use of PSA is limited. There the ratio of deaths to incidence is much higher than here and it is common to diagnose men with very advanced disease which is the group with the highest risk of a PCa specific death. For years they kept saying that “most men die with prostate cancer than from prostate cancer”, but if health improvements in cardiovascular disease, diabetes and smoke cessation take effect, that saying will be a thing of the past without PSA testing.

RalphV

Purgatory said...
He joked about that if every man with PC could live to be 125 years old, there would be 100% mortality rate from PC, but of course, that's not going to happen.

125 doesn't appear to be nearly old enough....200 might be.

Casey, the 125 was my doctor's hypothetical number, where did yours come from?

Casey, that's not what he said, and you know it. You are taking things out of context.

Here the mod hat is ON.

Gentlemen, lets remain civil.