Investigation of the role of intra- and peri-prostatic nerves in urinary continence and prostate cancer progression

© 2017 Dr. Fairleigh ReevesBackground Prostate cancer is a prevalent disease that causes significant morbidity and mortality. Although radical prostatectomy offers excellent disease control, it is associated with significant side effects in some men. One of the most debilitating of these is urinary incontinence. This is usually thought to be due to external urethral sphincter (rhabdosphincter) deficiency. However, the underlying cause of sphincter weakness is not clear. In order to minimise the risk of post-prostatectomy incontinence, clarity of the underlying pathophysiology is required. The neuroanatomy of male urinary continence is incompletely understood. The periprostatic nerves may be involved in the maintenance of normal continence and thus involved in the pathophysiology of post-prostatectomy incontinence. Beyond their fundamental role in tissue innervation, nerves have a complex relationship with pathology. Perineural invasion is an important mechanism for extra-prostatic cancer spread. However, conflicting evidence exists regarding the ability of perineural invasion in a radical prostatectomy specimen to predict disease recurrence. Recently, there is a growing body of evidence to suggest the autonomic nervous system exerts a regulatory effect in cancer (including prostate cancer). Methods A systematic review and meta-analysis was undertaken to investigate if sparing the neurovascular bundle at radical prostatectomy is associated with post-operative urinary continence outcomes. Following from this, three complementary anatomical studies were undertaken to investigate the innervation of the male urethral rhabdosphincter. These were done to investigate potential mechanisms for neurologically mediated post-prostatectomy incontinence. Study methodology included fresh cadaveric dissection, histological evaluation of periprostatic nerve distribution in radical prostatectomy specimens and intraoperative nerve conduction studies. Analysis of prospectively collected data from men treated for clinically localized prostate cancer was interrogated to investigate the relationship between perineural invasion in a radical prostatectomy specimen and clinicopathological variables including biochemical recurrence. More detailed, histological analysis of intraprostatic nerves in radical prostatectomy specimens was undertaken to describe the autonomic nerve subtypes involved in perineural invasion, and those nerves in surrounding normal prostate tissue. These subtype nerve counts were compared against routine clinicopathological variables including recurrence, to evaluate their clinical relevance and determine their role in predicting biochemical recurrence after radical prostatectomy. Results Meta-analysis revealed that sparing the neurovascular bundle during radical prostatectomy is associated with improved continence recovery up to six months post-operatively, but not with long-term outcomes. Fresh cadaveric dissection demonstrated pudendal supply to the male urethral rhabdosphincter, but was neither able to confirm nor exclude the possibility of intrapelvic innervation. Histological evaluation of radical prostatectomy specimens demonstrated the presence of somatic nerves travelling alongside the prostate, which may represent motor fibres destined for the rhabdosphincter. This was supported by evidence from intraoperative neurophysiological studies that demonstrated functional innervation to the male urethral rhabdosphincter travels with the neurovascular bundle in some men. Presence of undifferentiated perineural invasion in radical prostatectomy specimens was not associated with biochemical failure, in the large prospective cohort studied. On histological analysis of intraprostatic nerves in prostate cancer, the majority of nerves were of a mixed bundle type (sympathetic and parasympathetic). Sympathetic non-perineural invasion nerves and non-adrenergic, non-nitrergic perineural invasion nerves and were both found to be independent predictors of biochemical recurrence. Conclusion Nerve sparing should be considered in men with pre-operative erectile dysfunction in the context of appropriate oncological risk stratification, as it may result in improved early continence rates. This thesis supports the hypothesis that in some men, in addition to chief somatic supply via the perineal branch of the pudendal nerve, there exists intrapelvic somatic nerves, which travel in close proximity to the prostate to supply the male urethral rhadbosphincter. Preservation of these intrapelvic somatic continence nerves may provide one explanation for the association between nerve sparing and improved early urinary continence rates. Future research should seek to ascertain the frequency of this anatomical variation in a large cohort in order to inform surgical technique for the optimisation of continence outcomes. The presence of routinely reported perineural invasion at radical prostatectomy does not aid post-operative risk stratification. However, increased density of specific nerve subtypes can be used in predicting recurrence after prostatectomy. This provides further evidence for a relationship between the nervous system and prostate cancer. A greater understanding of the interactions between prostate cancer and nerves will help clarify their role risk stratification and may lead to future therapeutic targets