Sunday, June 12, 2011

Perineural Invasion On Prostate Biopsy: How It May Change The Game Plan

A reader recently asked me to share my thoughts on perineural invasion found on a prostate biopsy.  In formulating my response to this question, I was surprised that I did not cover this topic sooner.  After all, perineural invasion (PNI) is found in approximately 30% of biopsies.  The presence of PNI on a prostate biopsy can sometimes be a sign that the prostate cancer found on the biopsy may be just the tip of the iceberg in terms of the cancer within the prostate.  As such, PNI can change both the prognosis and treatment course for men with newly diagnosed prostate cancer.  In this post, I will describe PNI and explain its impact on treatment plans and prognosis.

Defining Perineural Invasion

Before I explain the importance of perineural invasion, we must first be on the same page as to what this finding on a prostate biopsy actually means.  The presence of PNI means that the pathologist has seen prostate cancer cells surrounding or tracking along a nerve fiber within the prostate.  The importance of this finding becomes apparent when you realize that nerves within the prostate travel outside of the gland through microscopic holes within the prostate capsule.  The capsule, as you may remember from my previous post about positive margins, is the outer covering of the prostate.  This covering serves as a barrier preventing the spread of cancer outside of the prostate, at least for a while.  Because nerves travel through holes in the capsule, prostate cancer growing around these nerves can follow them all the way out of the prostate without needing to overcome the resistance of the capsule.  As a result, the presence of PNI on a biopsy portends a higher likelihood of prostate cancer that has or will escape the prostate gland.  Studies have, indeed, validated this theory while also demonstrating other negative impacts of PNI.

The Impact of Perineural Invasion on Final Pathology

Numerous clinical studies have compared the final pathologic findings (after radical prostatectomy) of those patients with and without PNI on initial biopsy.  The results are very striking.  Large studies have demonstrated that men with PNI have a 2-3 times higher rate of extracapsular extension (prostate cancer outside of the gland) and nearly twice the likelihood of positive margins after prostatectomy when compared to men without PNI on their prostate biopsy.  That means that the presence of PNI at least doubles the chance of T3 disease in a man undergoing treatment for what is clinically localized, T2 disease.  In addition, numerous studies have demonstrated that PNI on biopsy is associated with higher grade disease (Gleason 8-10) on final pathology even when only low grade disease (Gleason <7) is found on biopsy. In fact, one study demonstrated that over 40% of men with PNI and low grade disease on biopsy are subsequently found to have high grade disease on final pathology after prostatectomy.  The reason for this disparity appears to be sampling error, with high grade disease not caught in the original biopsy specimens.  Hence when a prostate biopsy demonstrates Gleason 6 disease and PNI, there is a high likelihood that higher grade, more aggressive cancer is present in the prostate but was not detected.  Other studies have also demonstrated a higher risk of seminal vesicle invasion and lymph node metastases in men found to have PNI.

Perineural Invasion and Prognosis After Prostatectomy
Given the significant adverse impact of PNI on final pathology, it is not surprising that PNI has also been demonstrated to negatively affect prognosis after surgery.  One study out of Johns Hopkins followed 1256 men with prostate cancer for an average of 3 years after radical prostatectomy.  Out of this patient population, 188 men (15%) were found to have PNI on prostate biopsy.  Even over this relatively short follow up period, men with PNI on biopsy were found to have three times the likelihood of PSA recurrence as compared to those men without PNI. Similar findings were reported in 6 out of 10 studies of the impact of PNI on men undergoing radical prostatectomy for prostate cancer.  Not surprisingly, men with low risk prostate cancer (Gleason 6, T1-T2a, and PSA<1O) and PNI are three times more likely to require salvage radiation than their low risk counterparts without PNI.

Perineural Invasion and Prognosis After Radiation Therapy

The prognosis after radiation therapy, as well, appears to be negatively impacted by the presence of PNI on prostate biopsy.  One study followed 381 men undergoing radiation therapy for localized prostate cancer, 86(23%) of whom were found to have PNI on prostate biopsy.  After 5 years of follow up, 69% of men without PNI were free of cancer as compared to only 47% of men with PNI.  When dividing men into risk categories, the study demonstrated that only 50% of men with low risk prostate cancer (Gleason 6, T1a-T2a, PSA <10) and PNI were free of cancer at 5 years of follow up.  This rate of cancer free survival was lower than the 53% rate achieved by men with high risk prostate cancer (Gleason 8-10 or T2c-T4 or PSA >20) but without PNI.  Hence, the presence of PNI could instantly transform an otherwise low risk prostate cancer into a high risk disease.  Such findings were validated in 5 out of 10 large studies of men treated with radiation therapy.  Interestingly, one large study of men undergoing brachytherapy for prostate cancer did not demonstrate a difference in treatment outcomes of men with and without PNI.  Of note, however, is that men selected for brachytherapy generally have lower risk disease than those who undergo external beam radiation.

How Perineural Invasion Can Change the Treatment Plan

Given the significant impact of PNI on final pathology and prognosis, it seems obvious that the presence of PNI can influence the treatment course chosen by patients and their doctors. A study of surgical approaches in men with PNI demonstrated that removing the nerves on the side of the prostate with PNI on biopsy led to a positive margin rate of 11%.  In contrast, the positive margin rate was 100% when the nerves were spared on the side of PNI.  Of note, a recent study from Johns Hopkins reported that nerve sparing did not impact positive margin rates or prognosis in men with PNI.  This data needs to be taken with an enormous grain of salt however in that all men in the study were operated on by Dr Patrick Walsh, the urologist credited for the development of the modern day open radical prostatectomy.  It would see unlikely (at best) that such outcomes could be replicated by the typical urologist performing the surgery.  As a result, most urologists will sacrifice nerve sparing in order to assure negative margins in men with PNI.  In addition, given the high likelihood of positive margins and T3 disease, urologists often counsel patients with PNI on biopsy that they may likely need to undergo radiation therapy following radical prostatectomy.  Similarly, radiation oncologists treating men with PNI often approach them as high risk patients regardless of clinical stage, PSA, or Gleason score.  As a result, they often treat men with PNI with a combination of radiation and hormonal therapy rather than radiation therapy alone.  In addition, they may also use dose escalation as part of their radiation protocol.

Take Home Message

Perineural invasion is a very significant finding on a prostate biopsy.  It often indicates high risk prostate cancer, even in men with seemingly low risk disease.  PNI is also usually associated with a poorer prognosis, leading to a higher risk of recurrent disease.  As a result, men with prostate cancer that are found to have PNI on prostate biopsy are often provided with more aggressive therapy, whether it be in the form of surgery or radiation.  Understanding the significance of PNI on prostate biopsy is crucial to formulating a successful battle plan against prostate cancer.

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  1. Hi Doctor,

    That was a great description for PNI, thank you. In my final pathology I had both PNI and vascular invasion. Any thoughts on vascular invasion and what it may mean for development of mets? Thanks

    Bill Manning

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  2. Bill: thanks for the feedback. While I cannot give individualized advice I can say that vascular invasion on prostatectomy pathology, like PNI on prostate biopsy, has been associated with more aggressive disease and likelihood of recurrence.

  3. Hi Doc,
    Thank you for the very interesting discussion on PNI. What you failed to mention however, was that although PNI is certainly not good news, neither overall mortality nor PCa-specific mortality is affected by PNI. Do you agree?

  4. Scott: I know of one study from 2007 that did demonstrate a difference in cancer specific survival. Nonetheless, I dont think that is the important aspect of PNI. Most urologists use PNI on a prostate biopsy as a warning sign that a particular cancer is more aggressive than otherwise would be expected from Gleason score etc. As such, it leads urologists and radiation oncologists to proceed with more aggressive treatment protocols in hopes of minimizing the increased risk of cancer recurrence and associated POTENTIAL decreased cancer specific survival. I would not think of PNI as a prognosticator of future survival but, rather, a sign that more aggressive treatment and follow up should be considered. Hope that helps.

    Prostate Doc

  5. Very informative. So having open rp, with successful bilateral nerve sparing , negative margins but perineural invasion present, would that indicate the need for follow up treatment? Gleeson 6, pT2cNx. Everyone seems to just ignore pni on a path report.

  6. Dear ProstateDoc,
    Had a radical prostatectomy last Aug 2012.
    Pre Surgery: Gleason 6, T2, PSA 4.5
    Pathology Post Report: PNI present, Gleason 6 (3+3) pT2, all lymph nodes negative, bladder neck negative, seminal vesicle negative, and negative margins
    Post Surgery: PSA < 0.1 at ~2 months
    Just wondering if you could help explain risk of recurrence with presence of PNI and negative margins.

  7. Have 2 remarks on your write up.
    First of all, what you call PNI is supposedly Pn1, written thus to oppose: pN0 and pN1, where Pn1 is Perineural Invasion 0 or 1 and pN0 or pN1 being the Lymph node invasion.
    Secondly, you fail to mention that the perineural invasion when found after RP maybe either Intra or Extra-prostate, thus when the pathology returns:
    pT2c, GS (3+3=6), PSA 2,96 at biopsy
    The final report after the RP is now: PSA 2,42
    pT3a, pN0 (0/16, 9R+7L), L0, V0, Pn1, R0, GS (4+3=7a), classification GIIa, and subsequently the Pn1 is confirmed to be intra-Prostate.
    You surely will agree that this diagnosis and future treatment maybe substantially different from one with Pn1 extra-Prostate?
    Would you please write about the Progensa PCA3 test (FDA approved 12feb2012) which saved my life by establishing a 111-score on a scale of 4 to 125 thus indicating PCa to be be found with 95% surety on an following up by Biopsy. It stopped the useless biopsy taking where the possibility of ent- metastases as a consequence of a useless biopsy. In Holland the aim is to let the MD do the DRE and PCA3 test, to obtain simple and quick differentiation between BPH, PCa and PCa free clients by not having to keep more than 80% of non PCa men is suspense! BTW the test will even locate men with very low PSA values! As low as sub <1 PSA.

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