PNI[Invasion] Progressing to BCR And ... - Advanced Prostate...

Advanced Prostate Cancer

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PNI[Invasion] Progressing to BCR And Possibly to Lethal Pca after a Radical Prostatectomy

Nalakrats profile image

This is in response to one member who has a lingering PSA, after a successful RP, and Scans that showed no disease. The RP was total with the removal of the Seminal Vesicles and clean margins all around with a Dozen Lymph Nodes taken, which were also clean. So our member was confused why his PSA had not reached undetectable. Later to report that in his Surgical report there was PN-Invasion.

So thus the title of this subject. An important determinant of Tumor Behavior is the ability to breach the basement membrane and spread outside the confines of the Prostate.

The classical knowledge of Tumor Metastasis is that of Tumor Spread via Blood Vessels and Lymphatic Fluid. However, Pca has long been recognized to show a propensity to invade and grow along Prostatic Nerves, which lead out of the Prostate to the Pelvic Nexus. This is known as Perineural Invasion. And this has been thought over the years to occur because Nerves provide cancer cells a low Resistance Path[ease of movement] out of the Prostate. Recent Studies of which there are few[or we would be having more discussions on this subject] suggest more Dynamic interaction. Even Pca cells adjacent/near the nerves show increased proliferation compared with those located further away. Thus the conclusion from Meta-Analysis with Pathology Biopsy and Scans show that the Perineural Nerve Space---which is large compared to the nerve itself may very well be a Microenvironment that provides cancer spread and growth and a source of later Metastasis. I have spoken out on the theory that depending on the aggressiveness of the Cancer, Pca might have already entered your bloodstream prior to your DX. I plan to prove that further with a later post. The same can be said for movement into the lymph Fluid. Where we have no scan, Bloodwork, or other tests that can prove this. And why would you even look if you had not been DX? Micro-Metastasis seems to always be in play.

In short, the insidiousness of the disease--->relates IMO to the ability of the cancer cells formed in the Prostate even with a PCA of under 2, in very early stages to enter the body, outside of the Prostate unbeknownst to anyone including the soon to become patient.


62 Replies


Very interesting

My own PSA has stabilized at around 0.5.

This was after concurrent treatment with imrt, ADT, and seeds about 10 years ago.

It was explained to me that not all my non-cancerous prostate cells were killed. For lack of a better explanation, I just accepted that.

Not certain that understanding why helps inform what if anything to do about the situation. Lol

Nalakrats profile image
Nalakrats in reply to cesces

What was explained to you indeed does not make sense.


cesces profile image
cesces in reply to Nalakrats

It does appear to be stable.

I'm not certain what to make of it.

There doesn't seem like there is much to do about it.

What do you make of it?

Nalakrats profile image
Nalakrats in reply to cesces

Closely watch it---remember my discussion about 2 men one 89 and one 90 who both had a major BCR, after being undetectable for 30 years, after an RP-->where was there cancer hiding?


cesces profile image
cesces in reply to Nalakrats


Seems like that's the only practical option.

cesces profile image
cesces in reply to Nalakrats

If it ever reaches 2.0, then maybe I get a scan.

jazj profile image
jazj in reply to cesces

The PSMA PET Scan is very sensitive .5 ng and up. 1 ng I think it's in the low 90% range. That's post RP. Not sure how that translates in the post IMRT setting. I'd look into Realtime MRI Guided Salvage SBRT if I were you.

Thanks for posting.... God help us all 🙏

I had not posted in a long time--even though I have much to write about. It was a personal thing when Greatjohn had died. I wanted to go and shoot 3 of his Doctors. And a couple of more who treated HU members that had harmed or accelerated their Death from Pca when there were other ways out.


Karmaji profile image
Karmaji in reply to Nalakrats

May you explain what went wrong with journey of Greatjohn

I thought he was in good hands....

your comments on this may save others...

Nalakrats profile image
Nalakrats in reply to Karmaji

Sorry, this is private, and he was not!


rogerandme profile image
rogerandme in reply to Nalakrats

Just wondering from your perspective how Great John and others were harmed because I am one year into my treatment and want to make sure I am getting the best treatment for my situation…

Nalakrats profile image
Nalakrats in reply to rogerandme

As I have already said to another member this is private.


rogerandme profile image
rogerandme in reply to Nalakrats

No problem

Hi Nal,

I wholeheartedly agree with your theory.

A few years ago, I read Anthony Horan's book about PCa and several of his published papers. We corresponded. He is now dead, but when he was actively practicing, he practiced at a Veterans' administration facility.

He argued aggressively against RPs whenever PCa cells were found circulating within the patient's vascular or lymphatic systems. Even if the patient's biopsy indicated early stage PCa, Dr. Horan's opinion was that the PCa cells were already circulating within the patient's vascular and lymphatic systems, so a RP was an unnecessary procedure. Naturally, Horan ran afoul of Dr. Patrick Walsh's opinions concerning RP, and they often clashed at professional functions.

I've had a RARP, and following it, my PSA became undetectable - as expected - for awhile. But, now my PSA is beginning to rise. I agree with Dr. Horan's belief that the RARP did not cure my PCa. The RARP could never erase my disease. Removing my diseased prostate gland simply slowed down the progress of my disease. I believe PCa cells are circulating within my body, and they are quietly searching for a place to grow and begin their next assault. That will be the time when BCR will be identified by the medical establishment, and my follow-up secondary treatment procedures will begin. The RARP bought me some time.

I'll watch for your forthcoming analysis of your theory with interest.

Nalakrats profile image
Nalakrats in reply to ragnar2020

It's been brewing for years--now I have 2 Learned MO's who agree.


Gabby643 profile image
Gabby643 in reply to Nalakrats

and some HU members as well.

Good post - PNI is an indicator of higher risk IMO and warrants more research and consideration in post-pathology staging even if negative on metastases, lymph nodes and margins. Thought I saw a recent study that PNI cases may be 4x the risk of subsequent BCR.

Nalakrats profile image
Nalakrats in reply to PGDuan

I think I saw something else---about leading to Lethal stages.


Great post Nal even though it's not what we like to hear! I thought I was 'in the clear' for eight years post RP, and then my PSA suddenly rose to 0.21. Because of our horrible family history, my older brother demanded a biopsy when his PSA hit 2.5, and sure enough he had this nasty sh*t.

I should have had my prostate chopped out right after my second child was conceived...just useless weight on the drag strip. I'm doing just fine after being minus it for 18 years...maybe I would still be happily married had I gotten rid of it when I was young. Screw prostate glands, they're grossly overrated!

Muffin2019 profile image
Muffin2019 in reply to ronronHU

Definitely better off, I should have had it done in my early 30's, never wanted kids and still single, of course no family history of this cancer or any yet my sister died of lung cancer and my brother has had bladder and colon cancer and still alive.

ronronHU profile image
ronronHU in reply to Muffin2019

My wife and I were practicing the rhythm method when she accidentally got pregnant both times!

Thanks Nal, some interesting research on why this happens-- appears to be a symbiotic relationship between the perineural ganglion cells and the PCa.

Recent research increasingly suggests that PNI is a manifestation of a complex interaction between nerve and cancer cells (3). Ayala et al developed an in vitro model of PNI consisting of co-cultured mouse dorsal root ganglion (DRG) cells and DU-145 prostate cancer cells. This model shows that DRG neurite outgrowth is significantly increased in the presence of prostate cancer cells, with cancer cells subsequently migrating retrograde along the neurites towards the DRG cell bodies (5). Prostate cancer-induced neuronogenesis has since been confirmed in vivo (58). More importantly, nerves have been shown to have a reciprocal effect on prostate cancer growth. On tissue microarrays, prostate cancer cells located near nerves demonstrate a higher proliferative index and lower apoptotic index than cancer cells located further away (6). A phase I clinical trial is currently underway to determine whether periprostatic injection of botulinum toxin A can impair prostate cancer growth (59).

Two candidate mechanisms have been identified to account for the pro-survival effect of PNI. NFΚB and its targets PIM-2 and DAD-1, which together constitute part of an anti-apoptotic pathway, have been shown to be overexpressed in prostate cancer cells associated with nerves compared to those located further away (6). The upstream activator of NFΚB, NCAM, is upregulated in the setting of nerve injury (60). Caveolin-1, a scaffolding protein with anti-apoptotic properties that is expressed by perineural stromal cells during wound repair, has likewise been found to be overexpressed in PNI (61). It is therefore possible that prostate cancer invasion of nerves and subsequent nerve injury results in upregulation of these anti-apoptotic pathways. We did identify a potential novel biological mechanism by which PNI could influence prostate cancer aggressiveness. Our finding of an association between the presence of PNI and increased angiogenesis has not been previously reported in prostate cancer, nor in any other tumors with a propensity for perineural spread, and presents a promising avenue for future study.

Yes. I agree. Following my RP and after follow up with surgeon ( low key, job done, actually G9 so lucky we operated). After that I was busy dealing with recovery and side effects for a while but I would reread my post surgery report occasionally and note the phrase 'peri neural invasion'. No sort of invasion sounded good to me but information on what it meant was hard to find but I knew early on - G9, PNI - this isnt done. All your friends and family tell you how you are looking good, recovering great, dont worry about this or that side effect....But ultimately BCR within 12 mths, ADT and RT. Work through another couple of years of treatment and side effects, lowering PSA. Once again, youre looking good, well done etc etc but you reread that report - G9, PNI - then the regular insidious PSA creep recommences. And so Advanced PCA and round 3 ......

Hi Nal. Was this post only for Gleason 8 and above or happened to lower scores too? Thank you.

PGDuan profile image
PGDuan in reply to Ralph1966

Hu Ralph, A surprise, but it happened to me… I was PSA 11 GS 4+3 and negative on margins and lymph nodes, but PNI.

I am wondering whether PN happened in my case. I was initially diagnosed with Gleason 3 + 3 cancer, which was treated by seed implant in June 2011. My PSA dropped to 0.1 in about 15 months from pretreatment PSA of 3.4. In 2016, my PSA started going up. DRE, biopsy, and MRI confirmed an extra-capsular cancerous mass about an inch in diameter attached to the prostate capsule. It was treated with cyberknife and Lupron for nine months with PSA dropping promptly to 0.1.

Unfortunately, that was not the end of the story. In 2018, I was diagnosed with metastasis in multiple pelvic and abdominal lymph nodes diagnosed by PET/CT scan and biopsy of a lymph node. My PSA was 4.5 in November 2018 when I started ADT treatment. Currently, I am on second ADT break.

Coming back to my question, is it possible that not all cancer cells in the prostate were killed by the seeds. Those cells escaped using PN. Or, was it more aggressive cancer was present just on the capsule.

Nalakrats profile image
Nalakrats in reply to dac500

Hard to tell, other in my general discussions--I believe as do others that Pca cells escape the Prostate before a DX is confirmed that you have PC. The routes are PNI, Blood Vessels, and Lymph fluid.


Does Actinium- 25 Destroy PN?

Outside my area of knowledge.


I am in this catagory. I thought all pathology was really good after RARP but was positive for PNI. I had no clue what that meant until this post!! PSA was >.01 for one year. I then started T (as I had been on this for years with low T that really had an effect mentally, focus, etc) I did have BRC after 6 months, recently did SRT, 10 months out PSA .02. Doing all I can re supps (sulforaphane, MCP, Pom Juice, Fisetin, melatonin high dose, etc) in hope it stays there or lower at my 1 year PSA next month. Crap! I thought I might be almost done.

It is a bitch! Sorry!


Seems to me there is no cure for prostrate cancer unless you are really luckey I remember Mgr JOE TOREY of the YANKEES HAD PROSTRATE CANCER 1998,had surgery and radiation by DR CATALONA a leader in the field never heard of a reccurance thank god..

Not everyone has a recurrence. To be Pca-free means to me that all the Pca cells are either removed or killed. There are theories re: Stem Cells. As well as even having a few Cancer cells left after dual treatment that just eventually die, as they have no ability to hook up with each other-->they then get into the bloodstream, and when going thru the heart time after time, the turbulence of the Heart kills them eventually.


SViking profile image
SViking in reply to Nalakrats

Thank you for the detailed analysis. So what’s the solution once and then is diagnosed with prostate cancer? Should everyone automatically get systemic treatment?

Nalakrats profile image
Nalakrats in reply to SViking

Systemic treatment is a definite help early on. I know one Onco-Urologist--that as soon as possible after surgery, and removing everything that can be determinative, has his patient's next stop to be a Full-blown course of Chemo, as soon as possible. He has a good track record.


Dr A believed that and started a trial for adjunctive chemotherapy immediately. Unfortunately there were not enough takers in the trial, so it was stopped lacking funding. He has written extensively on this.


Jimbo59 profile image
Jimbo59 in reply to Nalakrats

My pt3a clear margins case path report included the phrase "established extraprostatic extension and established extraprostatic Perinural Invasion."This prompted me to add aduvant RT to my treatment even although my post psa result was <0.01. I felt that the micrometastases were probably out there and just hoped that they were still in range of aRT zone. This was in 2015 at the age of 58. All psa tests since have been <0.1 and <0.025 more recently so glad to have avoided a reccurance so far and maybe ever.

I exercise hard and often on road and mountain bike as one of my ways of hopefully killing off any dormant cells that may be floating about...

Nalakrats profile image
Nalakrats in reply to Jimbo59

I do not know if exercising kills off Dormant Pca cells--My guess is you got the Bastards early on. Good for You--I wish I had your benefits.


jazj profile image
jazj in reply to Jimbo59

This is my plan. I estimate I've got about a 50/50 chance of ending up in your exact situation and early salvage SBRT + ADT are shown to be potentially curative, or at least will help buy the most time to let better treatments emerge. I would seriously consider aRT even with just positive surgical margins. Although can you even have positive surgical margins and still be pathological T2?

jazj profile image
jazj in reply to Nalakrats

I agree that negative scans, even PSMA, are no guarantee PCa isn't going to linger and grow places that treatment did not reach. Your anecdotal evidence about the people decades later getting a recurrence I'm sure are statistically low, but of course not impossible. I think it is good you point out: "Not everyone has a recurrence." I'm not a fan of local therapies like HIFU, Laser, etc. I think they are just inferior ways out for people that are petrified of radiation or surgery. I think they can only be curative in a very limited type of case. I think it's better at primary treatment decision time to assume the primary treatment, no matter what it is, will fail (not good from a psychology standpoint but more pragmatic) and go aggressive and go early (both primary and secondary if needed.) The decision between hot flashes and/or permanent erectile dysfunction and death are pretty obvious. wrote :"PCa might have already entered your blood stream and lymph even before your diagnosis"

This is a known physiological fact that in every human being there are cancer cells which circulate in blood and lymphatic fluid ...but the body's defense mechanisms keep their numbers in check and hence not much growth.

It is a constant war between immune system and cancer whether diagnosed or not. Interestingly, in many men cancer remains undiagnosed for many years and decades. (in my own case, I did not get diagnosed for 12 years and had a normal life with PSA in 40+range 12 years ago. Why? Whereas in many men, PCa gets diagnosed quickly and spreads very quickly...We do not know what causes these individual differences. I guess there are many factors which make these individual differences such as genetics, diet, environment, stress, general health status...just to name a few.

So, if every ones blood already have cancer cells circulating then every one is metastatic literally from the get go.

Nalakrats profile image
Nalakrats in reply to LearnAll

That what you say is a generalized theory--of yin and yang-->that there is an equilibrium of cancer cells in the blood at all times. If this was so---we have Blood tests that can pick up the tiniest amount of DNA or DNA pieces of dying dead cells--and the most sophisticated Cancer Tumor Cell Count methods can count 1 cancer cell in 7mls of blood. So the theory of always having cancer cells IMO has nothing to do with a developed Tumor in the Prostate so small as to be undetectable--and yet the cells that make up the structure of that Tumor can find their way into our blood supply--->regardless of PSA. And where they go, is a you guess it scenario. As our blood goes everywhere. Remember I mentioned a long time ago about @750,000 gallons of blood coursing thru any one point in the body in a year. That number just astounds me, about our Heart-->whose extreme turbulence upon its beating process--->to a cancer cell is like that cell going over Niagra Falls without a barrel.


ragnar2020 profile image
ragnar2020 in reply to Nalakrats

Hi Nal,

I had never thought about the turbulence created in one's heart and how that agitation affects the blood cells. I've always marveled at the amazing strength of the cardiac muscles and how that little pump just keeps functioning 24/7/365 no matter how many bad things we've done to it during our lifetime.

Thanks for thinking about this stuff and putting the info out there for us to contemplate....

Nalakrats profile image
Nalakrats in reply to LearnAll

I am saying that from a very small tumor yet to be felt in a DRE, or determined with a PSA---that the cells of the Tumor itself---that they will eventually be a pain in your ass and cause you to go to war, as they will have already entered the Blood--in many cases.


I had ductal hystology.g9..pni mets to pelvic ramus and L 3,4,5.....i know without a doubt the pni was gateway...nal has confirmed my suspicions.....and now i fight best i can....cancer was only found in right quadrant...outer edge i guess of prostate..Just my 2 shillings....thanks nal...

You are welcome!

Interesting post, and an unfortunate one too

You know the saying that the horse has already escaped the paddock. But it seems it's more like the tiny fish has escaped the hatchery.

This PCa is a bastard.

Well thought out Nal! You know that I firmly believe based on the knowledge of my Research and Professor Medical Oncologist shared with me in 2004. I had not considered nerves in the same category as the vascular and lymphatic systems; only because it was not discussed. However it makes sense.

I remember the day in 2004, when Dr. A said, “In your case it mattered not whether you had surgery or radiation, your were metastatic before original diagnosis a year old. The reason spread through micro-metastasis!

He went on to explain the term which I had never heard nor read before. He further told me that the only way to kill metastatic cancer was through early and total systemic treatment with chemotherapy and ADT. This was 18 years ago and the modern “silver bullets” were either not developed or in early stages of trials. Although as the years passed they were always in his arsenal, yet I never needed. Some of his patients did. Reminds me I need to call Cmdrdata to see how he is doing.....

I am a realist and know that new treatments have been developed or tried depending on the scope of disease. And some are working and keeping this bastard disease at bay, in 2004, the general methodology was palliative treatment only to increase longevity and essentially died of something unrelated to Stage 4 PCa. However, I see very little has changed from this original goal.

Yes, I concur in a Great John’s story, like so many others, he was initially treated by a doctor who did not specialize in Genitourologic Cancers. This is the major reason that I sought out Academia and Research - the guys who were on the cutting edge, up on their “game” and teaching new Medical Oncologists. No doubt money for research enters into their research. ..... this was highlight to me about 2010 when I wore a Breast Cancer Awareness t-shirt. I learned the facts of life about research dollars..... in reflection, the same trial that I participated in 2004, mirrors the treatment that my cousin received in 2019 fir Stage 4 Breast Cancer. At the same medical school where I met Dr A. The major difference - Research funding.

Which leads to another gem....... Dr A told me that Prostate Cancer and Breast Cancer are closely related hormonal cancer.... more than most realize....,,

Anyway Nal, your post and explanation mirrors what was shared with me years ago. I just had not considered a third path to spread. However, it makes sense with everything that I have learned from Dr. A.


Thanks for the Comments--I hope to discuss the micro-metastasis via the Blood supply in-depth. I have mentioned it before--but I am working on an opus. It is not ready for prime time yet.


I had brca gene test didnt have enough to matter....good for kids....but it did say i expressed gene for highr risk of.....breast cancer......being mine was ductal crbiform....wahla......its sane cribiform ad breast cancer.....i believe....just ended up in my prostate......or did it travell via pin from other part of body.....too much for me to phathom....but ...

Very knowledgeable commentary thanks everyone going to see Dr morris at sloan on Tuesday hopefully he can can work something out on my second recurance still have not hit 0.2 yet so to early for scans

I notice you mention the possibility of spread even with PSA below 2. After RP in 2016 and years of ADT, my PSA has settled in right at 1.0 . Do you feel that with grade group 5, and multiple lymph node mets, I could be experiencing progression even with a low PSA of 1.0 ?

PS. I did have PN, lymph node, and extraprostatic extension spread at time of RP

ragnar2020 profile image
ragnar2020 in reply to joeguy

Hi Joeguy,

IMO, I'd ask my docs for an annual PSMA-PET CT if they'll order it. It's new for Medicare to pay since 12/21, and normally there is reluctance to order it with a PSA under .4, but according to the RO who oversaw my PSMA PET C/T last year, he has seen distant micro-mets discovered in guys having a PSA below .2. PSMA PET C/T scans are changing the course of PCa care at the imaging phase of planning.

joeguy profile image
joeguy in reply to ragnar2020

Im still a little too young for medicare. but I did pay out of pocket for a PSMA scan 1 1/2 years ago. At that time, it showed no bone mets, but several lymph nodes from pelvic area to periaorta area. Would like to have another PSMA scan, but the last on cost me $2200. I will probably hold off on another until im closer to trying LU177 treatment. A CT scan last year showed that lymph mets had reduced in size, but there were more of them...... not sure what to think about that.

Fred312 profile image
Fred312 in reply to joeguy

Now that PSMA scans are FDA approved, the price has gone up. My doc told me it is abt 20K without insurance. MSK offered it for 6K before FDA approval.

joeguy profile image
joeguy in reply to Fred312

Sounds about right.... the medical industry is a racket

jazj profile image
jazj in reply to joeguy

Insurance should cover it now. My private PPO Insurance did. Required pre-approval. $18K! I had read like $2,500 for Ga68 before I found out about insurance now covering it. Gee, I wonder why medical costs are out of control in this country. Insurance paying for it? Charge them at least 3-5X more.

Nal...... your post spoiled my day at the nudist camp.....Sigh......Thanks!!!

Good Luck, Good Health and Good Humor.

j-o-h-n Monday 05/09/2022 7:12 PM DST

Nalakrats profile image
Nalakrats in reply to j-o-h-n

Did you go around with your Schmeckel for all to see?


Gabby643 profile image
Gabby643 in reply to j-o-h-n

Good one😎

Not since it became a schwanz.........

Good Luck, Good Health and Good Humor.

j-o-h-n Monday 05/09/2022 9:13 PM DST

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