Nature of Prostate Cancer in Young Men

[Arnon Krongrad, MD]

Growing up I heard that prostate cancer in young men was uniformly very aggressive. That notion originates in the long-ago days of the pre-PSA era, when we diagnosed prostate cancer with prostate exam and/or bone pain.

In the last 5 years, I have taken care of four men with ages ranging from 31 to 39 at diagnosis; two had family histories and two were sporadic cases. PSA (and I am doing this from memory) ranged from 1.4 to 9 ng/ml before the biopsies. Pathological grades ranged from Gleason score 6 to Gleason score 9. All had clean margins at surgery but I cannot remember the pathological stages (I am not at the office as I type); I believe they were all organ confined (no seminal vesicle involvement). I do recall also a 41-year man with pre-op PSA of 17 ng/ml and Gleason 9 prostate cancer and intravascular invasion who is without evidence of recurrence 6 years later. I see lots of young men with prostate cancer who are a bit older than this bunch who had considerable cancer on pathological exam but who have a good chance of doing well.

Overall, my impression is that young men can survive their prostate cancer. This impression is implicitly reinforced by a recent observation showing that there is no greater likelihood of 5-year progression-free survival in men in their 30s. We won't get into the nuances of what 5-year biochemical progression means. This is only to say that the conventional wisdom about prostate cancer in young men necessarily being very aggressive is probably wrong.

The value of early detection is arguably far greater in younger men than in older men, who are more likely to die of competing illness than younger men. Young men are more likely to regain continence and erections.

But do young men agree to detection? Many but not all, according to a study carried out in general practices in Bristol. That study showed that men aged 45-49 who agreed to prostate cancer testing had a 12% likelihood of PSA greater than or equal to to 1.5 ng/ml; young men had a positive biopsy rate of 21.3%. That is not much lower than what we find in any man with PSA greater than or equal to 4.0 ng/ml.

Dr. Politano, former President of the American Urological Association and a broadly experienced adult and pediatric urologist, tells me of a 9-year old boy who had a radical prostatectomy and reportedly regained erections (that's all I know of that case). OK, so we won't use that to do prostate cancer checks in grade school.

When should we seriously even discuss early detection? In high school?
What do I tell patients whose sons are in their 20s? 30s? 40s?

[Arnon Krongrad, MD]

Jim brings up the real-life complexity of differential diagnosis. Many young men with painful and slow urination have prostatitis, not cancer. There are descriptions of symptoms on the Chronic Prostatitis blog. The point is that the symptoms described above are nonspecific and indeed in most cases have little to do with prostate cancer. This is well illustrated in the story of David Radford, who had an LRP that rid him of 8 years of misery but who did not have cancer (and who had a PSA of 0.9 ng/ml).

We have three "biopsy now" answers. So ...

Let's examine "if there is even a chance." John Barnette, who is a member of this network, was diagnosed with a PSA of 0.4 ng/ml. His biopsy was done on the basis of an abnormal DRE. We know that DRE is not the most reproducible test; another doctor might have called it normal. The point is that risk never really seems to drop to zero.

That's the point, there is always a chance. Remember the case of the nine-year old boy with prostate cancer? Have you noticed that our youngest member is 31-y old? No man is ever off the hook completely. Yet we do not recommend biopsy to every man.

In a sense, what Ralph and Kathy said was that these decisions are never cut and dry. Few cases are as simple as that of the healthy 35-y old man with a PSA of 1.6 ng/ml. There is surely a point at which the patient is too sick or the PSA is too low for us to recommend a biopsy. So we are making binary yes:no decisions in a world of continuums of age, PSA, symptoms, competing illness, mood. There are no absolute answers but we get to pick only absolute and simple actions: do or don't do.

What would I recommend to the healthy 35-y old with a PSA of 1.6 ng/ml?

1) I would repeat the test if this was his only PSA
2) I would do an exam to exclude physical evidence of prostatitis
3) I would refer him to the Diagnosis content on the "New" Prostate Cancer InfoLink
4) I would encourage him to view this video

Would I recommend a biopsy? Yes.

[Ron V]

I will give a brief explanation of what happened to me and it truly sucks...

I was 39 years old when this happened. The only symptom I had was slow and interrupted urine flow. I went to my GP and he ordered a PSA just to be on the safe side. Ends up that it comes back at 6.4. So next I am ordered to go to the Urologist who runs every test he has on me. They stick a camera through my urethra, sonogram of kidneys, DRE. All seems normal. Now we schedule a Biopsy but when the day came he did a quick urinalysis and it ends up I actually have a UTI. He puts me on Levaquin for two weeks . After the two weeks I repeat the PSA and it comes back 4.3.

So now we are going to give the Biopsy a second shot. He walks into the office and these are his exact words, "I don't want to give you a biopsy. I don't feel comfortable doing this because you are too young. I've never done this on someone as young as you. I want to put you on Levaquin for SIX (!?!?!?) more weeks and then repeat the PSA." Needless to say I was livid and said no way. The Biopsy is going to happen today. He reluctantly performed it.

Guess what? A week later, positive in 5 out of 8 samples taken and a gleason score of 3+3=6. Unreal right? I had to tell HIM to do it.

I will not mention this Assho..., I mean "Doctor's" name here, but heed my advice...

IF YOU HAVE ANY DOUBTS AT ALL, IF YOUR NUMBERS SEEM STRANGE, FOR THE LOVE OF PETE JUST DO THE BIOPSY!! If not for your health then for your piece of mind..

90 days later I have no prostate.

[Arnon Krongrad, MD]

Again, the complexities of real life, as above. Not all PSA elevation is cancer. In the setting of infection, the likelihood of cancer at any given PSA is obviously lower than without infection. It is no wonder at all that the doctor hesitated and indeed in many cases 6 weeks of Levaquin for a 39-y old with known history of infection would drop the PSA to much lower levels.

Doctors are trained early to "first do not harm." Given that biopsy is invasive and potentially harmful, the instinct to carefully consider it are on target. Thus, the question of doctor hesitation is all around. This is a point that Michael, who is a member of our network, makes well on this local news video.

The question is when is the doctor's hesitation constructive and when is it a reflection of ignorance or improper bias? To answer in any specific case you have to know what is known about the specific symptom or sign.

With a young man with recent urinary infection I would 1) go to prostate biopsy slowly, 2) recommend antibiotics, including possibly a second course, 3) note that a 6-week delay in prostate cancer diagnosis is almost surely not a critical determinant of long-term success, 4) consider the possibility that a biopsy in an acutely infected prostate would put a young man -- possibly without cancer -- into sepsis, hypotension, and organ failure.

The doctor above was almost surely being protective of you. Had the biopsy been 6 weeks later, it's not likely much would have changed. Don't let the events of the last few weeks and the understandable emotion of the times blind you to this.

Again we hear about doctor discomfort as driver of diagnostic recommendation. I wonder if Dr. Consedine would again grace us with discursive thought.

We are talking about very sensitive and at times painful material. Feelings run high and are important. As you express yourself, please remember that this is a very public place and that we have purpose.

1) One purpose is to build bridges. Profanity and public accusations against specific doctors, patients, wives, ministers, hospitals, or anyone else will hurt our purpose.

2) Another purpose is to learn from each other. Remember that we are not writing only to each other. We are writing to the man or woman who are passing by who wishes to stay anonymous. This man or woman may need information or reassurance. To best help ourselves, him, and her we have to talk about issues, not a specific doctor's or patient's behavior and judgment on a given day. Let's use case scenarios to review data and share perspectives.

[PaulC]

I totally agree with you, Jim. I can't think of any reason a man shouldn't learn his baseline PSA at a very young age, and get it re-tested every five years. It's fairly cheap, and if he's going to have a blood draw anyway, it's completely noninvasive. If five hundred tests are done to find one 35-year-old with a PSA of 6 and one 40-year-old whose PSA has octupled to 3.8 in only five years, you've surely paid for the other 498 several times over ... especially since all 498 men with "negative" results now have a datapoint in their portfolio for later comparison.

I'm not so sure about Dr Krongrad's recommendation for a biopsy for men whose PSA indicates a 20% chance of cancer. Aren't there less invasive (and/or less expensive) urine and blood tests that are nearly (>90%) as conclusive?

[Arnon Krongrad, MD]

Most biopsies are done for men whose risk is around 20% - 30%, i.e. with PSA ranging from 2 to 10 ng/ml. Put another way, most labs report a high proportion of negative biopsies. Indeed, if we biopsy only men whose risk is much higher we'd be diagnosing a large proportion of prostate cancers at late stages, i.e. we could do little about it. The time to diagnose prostate cancer is when it is in an early stage, i.e. when PSA is still relatively low, i.e. when more than half the biopsies will be negative.

For what it's worth, and I by no means wish to trivialize it, a biopsy takes 15 minutes to do. When done with some antibiotics and anxiolytics on board and lidocaine injected at the seminal vesicles, it is tolerated well by nearly all men. For a 35-y old as we've discussed here, who is admittedly a rare creature, the value of early detection is theoretically very great, much greater than for an 95-y old. We should not let the scarcity of such men blind us to their existence. Doctors certainly should understand that prostate cancer happens to men in their 30s. When risk is 20%, especially for such young men, it's time to biopsy.

There are many less invasive and less informative tests. I am aware of no study in which another test was "positive" and used as a basis for radical prostatectomy, from which diagnosis would be confirmed and the noninvasive test's positive predictive value would be shown to be 100%, as it is with biopsy.

Paul, you've responded to part of this rather long and winding discussion: when to do PSA. The second part, was what to do with a healthy, happy, asymptomatic 35-y old with a reproducible PSA of 1.6 ng/ml. He reflects an amalgamation of the four young men with prostate cancer I describe in the introduction (see above). Do you have a recommendation for him?

PS: I didn't understand the octupling business.

PPS: Amazing, but today I was told of a 15-y old boy with prostate cancer. He apparently presented with symptoms, had treatment (I assume RP but am not sure), and is "doing well." Not as young as the nine-year old I described above, but ... jeez!

[Charlie Royce]

Ok I have a contribution to this as well. At 39 I had no symptoms whatsoever when my Doc suggested a PSA at a routine physical. I had no PSA history. My Urologist then suggested biopsy just because that is what he did. I was diagnosed and found Dr K. What I had at the time was the anxiety mentioned earlier in this post. What I did not have was the 27 replies to this forum to really analyze the right decision for me.

As individuals dealing with diagnosis it seems impossible for any Doctor to
leave out all the options. Before I met Dr K I talked with another Urologist that chose to wait over 5 years after his diagnosis and I personally still couldn't wait to have mine removed.

I stress this as my personal reaction to the diagnosis. Another patient would react differently. I believe a study on anxiety in these situations would be a waste. And a study of Doctors dialog with patients would be equally diverse based on attitudes and perceived anxiety in patients. Doctors I believe will always err on cautions side, but now they can refer patients to actual feedback that allows for more constructive decision making. I certainly would have read every word of this forum, but still would have wanted it out.

Eventually science will trump this discussion. In the meantime, these forums are the best possible addition to an early PSA that is available.

[PaulC]

Here's is what I meant by "octupled in five years": If a 40-year-old with PSA of 3.8 had already been monitoring his PSA every five years since age 20, he would already know at this point whether the data set resembled A or B:

• A: {age 20: 3.2; age 25: 3.1; age 30: 3.7; age 35: 4.1; age 40: 3.8}
  No reason to think this variation is anything but noise.
• B: {age 20: <0.1; age 25: <0.1; age 30: 0.1; age 35: 0.5; age 40: 3.8}
  Consistent with a worrisome PSA DT of about 16 months.

To translate this to the hypothetical 35-year-old with a PSA of 1.6: If he had already been monitoring his PSA every five years since age 20, he would already know at this point whether the data set resembled A, B, or C:

• A: {age 20: 1.7; age 25: 1.5; age 30: 1.6; age 35: 1.6}
  No worries; no reason to do anything for another 5 years.
• B: {age 20: <0.1; age 25: 0.2; age 30: 0.5; age 35: 1.6}
  I would recommend a biopsy.
• C: {age 20: 0.2; age 25: 0.2; age 30: 0.2; age 35: 1.6}
  I would look carefully for signs and symptoms of inflammation and perhaps prescribe a course of antibiotics. In any case, I'd advise a repeat PSA in four weeks, with instructions on refraining from sex, enemas, or anal play for several days preceding the test. I would follow with a PCAPlus or biopsy if the elevation persisted.

In the absence of any baseline data to strongly suggest a recent progression, my recommendation for the 35-year-old would be to refrain from biopsy for the time being, to obtain a less invasive (and possibly less expensive) test such as PCA3Plus or EPCA when it becomes available, and to monitor PSA every year.

[Arnon Krongrad, MD]

Some brief points:

1) PSA velocity correlates with risk of a positive biopsy. However, PSA velocity does not correlate with risk of positive biopsy independently of absolute PSA. A man with PSA 1.6 ng/ml has a risk of something like 20%. One has to decide if that level of risk warrants a biopsy.

2) The tests you cite, to the best of my knowledge, were tested against biopsy results. The question we would need answered for our patient is how do they perform before biopsy? Forget negative predictive value, which is not known even for PSA (how many "negative" PSAs -- low level PSAs -- are true negatives; would require doing radical prostatectomy for men with very low PSAs; not on the horizon). But what about positive predictive value (risk that a level at a given threshold defined as "positive" is a true positive)? We have mountains of data on PSA's PPV but none on the PPV of the other tests. I don't know what they mean in this setting.

Barring extreme circumstances (he also has multiple sclerosis), the next 35 y old with a 20% risk of a positive biopsy who comes into my office is getting a recommendation for biopsy. No way I let him walk out the door without him understanding that I have no way to know 1) if he has prostate cancer without a biopsy and 2) if he has prostate cancer when his period for effective treatment expires.

[PaulC]

With respect to point #1: I don't see the utility of PSA velocity as opposed to PSA doubling time, and I frankly wonder if it has been used because of mathematical ignorance. If an investment pays $100 in a year, you have no idea whether it's a great investment on a stake of $500, or a lousy investment on a stake of $10,000. The whole point is the rate of change (second derivative), not the absolute difference (first derivative).

With respect to point #2: I suspect I'm ignorant on this, and would appreciate having it explained to me. Yes, I think they were tested against biopsy results and pathology results; how else can you calibrate a new instrument except against a well-understood old instrument? Until you have accumulated more data on how well the new instrument performs, it is necessarily less certainly reliable (although possibly more accurate) than the old instrument. This doesn't strike me as an argument against using the new instrument, especially if it is less invasive less expensive, and potentially more accurate once it has gained acceptance and widespread calibration.

[Arnon Krongrad, MD]

I think we agree on point one: velocity is not useful here. As for doubling time, I am not sure I've seen it tested as an independent contributor to risk assessment after PSA has been included in the regression model (I am aware that it correlates with post-treatment prognosis, but that is a univariate model and wholly different context from which in any event we'd better not extrapolate). I am not ready to use velocity or doubling time as a modifier to my primary risk assessment.

PSA was characterized in virgin populations. Its positive predictive value is established. All the many new tests are being tested against biopsy proven prostate cancer. How was the cancer first detected? Biopsy after PSA. The question is this: if the PSA result says the risk is 20%, can the new test modify that assessment?

Back to our 35-y old. We know from PSA that his risk is 20%. To keep me from recommending a biopsy, I would want a New Test that discriminates this kind of cohort into sub-cohorts that have risks of 2% and 98%. In other words, I'd want a mathematical model that showed me that New Test was independently associated with the binary outcome of cancer-yes-or-no-by-biopsy. It's not enough that the New Test correlates with cancer-yes-or-no-by-biopsy. It has to help me discriminate what I know from the PSA. I have not seen an analysis to show that New Test does that (let alone found a nomogram that breaks down risk by age, DRE, PSA, and New Test). So I am not ready to apply it. Let us not confuse interesting research and conceptual breakthroughs with tools useful at the bedside (disclosure: I cannot keep up with the literature, try as I might. If I have missed the analysis I need, somebody please enlighten me).

As we get into tests, from DRE to PSA to all the news that's fit to cut and paste, we'll want a statistician. We almost got one this week but no cigar. What we got is Rhonda. So the week closes on an upnote after all.

[Kathy Meade]

I am not a scientist but the NCI says that there is not enough proof that screening or treatment saves lives. You are saying that there is not enough proof to justify waiting 6 months for additional information that could avoid a young man from experiencing life altering side effects. In my mind the arguments are similar. Both work against the risk/benefit evaluation that men should be doing prior to deciding about treatment.

Your practice is not the same as most urologists. You do not see patients over a long term. Are we talking about your practice or the practice of all urologists?.

What we hear not infrequently is that doctors rush patients into treatment and those patients after the fact sometimes wonder when they are dealing with the realities of the side effects if they should have slowed down. Expectations and lack of understanding is usually the reason this happens. How can the system needs change to minimize the problem?

I wonder is there any proof that waiting 6 months does harm to the ultimate survival for patients? Biopsies are not without potential problems. Transrectal prostate needle biopsy with ultrasound guidance has become the standard for the diagnosis of prostate cancer.1 Common postprocedural complications including limited hematuria, hematospermia and hematochezia have been reported.2 Most studies have low rates of more significant complications such as urinary tract infection, urinary retention and sepsis.3,4 We report on an unusual case of life-threatening rectal hemorrhage after transrectal prostate biopsy. http://www.nature.com/pcan/journal/v6/n2/full/4500645a.html

[Arnon Krongrad, MD]

Missing cancer at age 35 is life altering. And as for the NCI, it does not say. Maybe people working at the NCI say. And of course there is never enough proof; we always want more. But beyond platitudes, epidemiology, discussions about my practice, and other urologists, here is the issue: young men get and die of prostate cancer. One sits in your office. He has a 20% risk. What is the recommendation for him? Mine is clear.