Pathogenesis of Radical-Prostatectomy-Associated Morbidity

Pathogenesis of Radical-Prostatectomy-Associated Morbidity: History

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Subjects: Andrology

Contributor:

Dorin Novacescu

Alexandru Nesiu

Razvan Bardan

Silviu Constantin Latcu

Vlad Filodel Dema

Alexei Croitor

men’s sexual health
erectile dysfunction
radical prostatectomy
cavernous nerve injury
rat model
neuregulins (NRGs)

1. Introduction

Prostate cancer (PC) is the second most frequent malignancy (after lung cancer) in men worldwide, with continuously increasing incidence rates. Currently accounting for ~3.8% of all deaths caused by cancer in men, prostate cancer represents the fifth leading cause of death worldwide [1]. Important developments for urological malignancies in general [2,3,4], and PC in particular, include improved diagnostic technologies and fundamental scientific understanding of pathogenesis, as well as steadily evolving clinical tools for screening/early detection and risk stratification/therapeutic decision-making. In addition, superior and highly specific clinical methods are available for PC diagnosis, which include Prostate Specific Antigen (PSA) screening, multi-parametric magnetic resonance imaging (mpMRI), PSA isoforms, and micro ribonucleic acid (microRNA). These methods have greatly facilitated early detection [5]. Subsequently, mortality rates were significantly diminished, especially in developed countries (~10.1/100,000 people in Western Europe in 2018 [1]), where these emerging clinical tools were more swiftly integrated. This improvement in oncological outcomes has resulted from more organ-confined disease at initial diagnosis and allowing for immediate curative treatment, i.e., radical surgery or radiotherapy [6]. Unfortunately, only modest improvements have been achieved regarding surgical-treatment-associated morbidity. Postoperative functional complications remain quite frequent and still severely impact quality of life for PC survivors [7].

Radical prostatectomy (RP) is the most widely recommended curative therapeutic procedure for patients with intermediate-to-high-risk prostate cancer and a life expectancy of at least 10 years [8]. Despite the advancements in surgical techniques and postoperative management, no significant change has been observed regarding the probability of erectile function (EF) recovery after surgery over the last decade [9]. Simultaneously, as we entered the current era of mostly curative therapeutic management of PC, mean age at initial diagnosis of PC has decreased, while overall life expectancy has steadily increased. Therefore, RP-associated morbidity, due to intraoperative lesions of the cavernous nerve (CN) plexus, has now begun affecting much younger patients. Thus, currently, especially when tumor loco-regional extension allows for the use of a nerve-sparing RP technique, postoperative functional recovery has become the most important surgical goal. Due to the predisposing inherent regional pelvic anatomy, even in the hands of the most experienced surgeon, regardless of surgical technique or approach used, a certain degree of CN damage usually occurs during RP [10]. Additional strategies are required to improve EF outcomes after RP, seeing as contemporary treatment modalities, i.e., penile rehabilitation protocols, only provide a quicker recovery of EF, not a better rate of recovery overall [11]. Active research, aiming to better comprehend and hopefully identify a curative treatment for CN-lesion-related pathology, is currently ongoing. Even so, for the moment, the pervasive need for a significant improvement in the clinical management of post-RP ED remains unaddressed and requires further analysis.

2. Pathogenesis of Radical-Prostatectomy-Associated Morbidity

The oncological goal of RP is to achieve a complete removal of the cancerous prostate tissue in order to cure the patient of PC. The surgical procedure involves removing the entire prostate, with its capsule intact, alongside the seminal vesicles and distal vas deferens, followed by vesico-urethral anastomosis. Additionally, bilateral ilio-obturatory pelvic lymphadenectomy may also be required in high-risk cases. Surgical approaches have greatly evolved, from open perineal/retropubic approaches to the newer laparoscopic and robot-assisted techniques. Importantly, the increased complexity of the procedure, the associated reconstructive surgical challenges, and the inherent anatomical particularities of the pelvic region greatly facilitate the occurrence of significant postoperative complications. Thus, the overall goal of this surgery is not only radical oncological excision, but also the preservation of the patient’s quality of life, to the greatest extent possible [15].

Essentially, there are two major types of complications, which occur after RP, in the late postoperative setting, namely, obstructive, i.e., anastomosis stenosis, urethral strictures, meatal stenosis; and functional, i.e., impotence and incontinence. Regarding obstructive complications, multiple endoscopic treatment modalities are available and offer a reasonable rate of success. Confoundingly, regarding post-RP functional complications, even though in recent years, mainly due to technical and conceptual advancements in RP surgical strategy, the rate of urinary incontinence has steadily decreased, post-RP ED remains disproportionally prevalent [16]. Post-RP ED usually occurs due to the almost unavoidable intraoperative damage of the regional autonomic innervation, especially during dorsolateral prostatic dissection. This damage may be mechanically induced (nerve division, crush, or stretching), or secondary to thermal damage, ischemia, and/or local inflammatory responses [14], with subsequent Wallerian degeneration of injured nerve fibers and dysregulation of neuromodulated tissue oxygenation. These complications are more difficult to treat and, until now, no specific curative treatment protocol has been developed.

Conversely, the ever-growing arsenal of both biomarkers and modern multimodal imaging [17] has indeed greatly facilitated PC diagnosis, clinical staging, and risk stratification, as well as RP surgical planning. Specifically, mpMRI and targeted biopsies have revolutionized the diagnosis and management of PC. MpMRI, a combination of anatomical imaging techniques (T2-weighted imaging) and functional imaging techniques (dynamic contrast-enhanced MRI, diffusion-weighted MRI, and magnetic resonance spectroscopy), offer superior imaging capabilities that enable the accurate identification of suspicious areas in the prostate gland, thus reducing unnecessary biopsies and increasing the detection of clinically significant PC [18]. Targeted biopsies, guided by mpMRI, are more accurate in detecting PC lesions and have a higher yield of clinically significant disease than traditional systematic biopsies [19,20,21]. Furthermore, mpMRI can aid surgeons during robotic RP by providing detailed anatomical information on the location and extent of the cancer within the prostate gland and accurately predicting the location and extent of extraprostatic extension, seminal vesicle invasion, and lymph node metastasis, which are all important factors to consider when planning the nerve-sparing technique (i.e., intra, inter, or extrafascial nerve sparing) [22,23,24].

2.1. Predisposing Anatomic Considerations

In human males, the inferior hypogastric plexus, also known as also known as the pelvic plexus, represents the central innervation hub of the pelvic cavity. Constituting a complex network of nerves, located near the base of the bladder, anterior to the rectum, the inferior hypogastric plexus emerges as a result of the convergence and intermingling of sympathetic fibers from the lumbar sympathetic ganglia and parasympathetic fibers from the sacral spinal cord, which provide autonomic innervation to the main pelvic viscera, i.e., the bladder, rectum, and male reproductive organs—seminal vesicles, vas deferens, prostate, and penis. Additionally, and distinctly, this plexus also contributes to the sensory innervation of the perineum and anus [25].

The anatomic relationships of the inferior hypogastric plexus are complex and involve multiple structures within the pelvic region. Some of the key anatomic relationships of the inferior hypogastric plexus include proximity to the bladder base and postero-inferior bladder wall, anterior aspect of the rectum, and proximity to major blood vessels (aorta and the internal iliac arteries) [25]. Overall, the anatomic relationships of the inferior hypogastric plexus are complex and involve multiple structures within the pelvic region. Understanding these relationships is important for the diagnosis and treatment of a variety of pelvic conditions.

The CNs are a pair of parasympathetic nerves, which arise from the inferior hypogastric (or pelvic) plexus and run along the lateral aspect of the prostate, entering the corpus cavernosum at the base of the penis. They are responsible for the regulation of blood flow into the erectile tissue and play a crucial role in the physiological mechanism of sexual arousal and erection. More specifically, the CNs comprise small myelinated and unmyelinated nerve fibers, responsible for the regulation of parietal smooth muscle tonus within the penile blood vessels, and are thus able to increase the blood flow to the corpus cavernosum, resulting in penile erection [27]. Thus, extensive damage to the CNs will result in ED. Therefore, the anatomy of the CNs is crucial for normal sexual function and their proper functioning is essential for maintaining sexual health.

Pelvic surgery in general, be it for prostate, bladder, or colorectal malignancies, commonly results in a high incidence of ED due to trauma of the CNs, the principal autonomic innervation of the penis [14]. Notwithstanding recent advancements in both surgical techniques (nerve-sparing procedures) and equipment (robot-assisted approach), these types of neurological lesions remain prevalent and virtually unavoidable, with less than 40% of patients regaining EF, sufficient for sexual intercourse, following bilateral CN-sparing surgery [14,28,29]. However, regardless of surgical technique and/or approach used, the incidence of post-RP ED remains high and represents a serious problem, especially in young patients [30]. Thus, in the era of early detection, with mostly curative initial treatment for prostate cancer, age at diagnosis has decreased, while life expectancy has steadily increased. Postoperative functional recovery has become the most important surgical goal when performing RP.

2.2. Pathophysiology of Erectile Dysfunction following Nerve-Sparing Radical Prostatectomy

In the physiological setting, the pelvic plexus is the origin of innervation for erection. The CNs contain parasympathetic and sympathetic fibers, with the proximal ganglionic area containing both myelinated and unmyelinated fibers. This conformation gradually changes distally, with fewer myelinated fibers being represented, until the point of crural entry, where the CNs are almost exclusively composed of unmyelinated axons. Therefore, unmyelinated axons represent the part of CN fibers which provide the neurotransmitters for penile innervation, the most important one being nitric oxide (NO) [14,31,32]. Sexual stimulation produces NO release at the level of these fibers, which will then induce an increase in oxygenated blood flow to the erectile tissue, by relaxing parietal arterial and arteriolar smooth muscle fibers [33]. The increased blood flow produces distension forces acting upon the endothelium, leading to a sustained nitric oxide synthase (eNOS) release from endothelial cells. This mechanism is crucial for erection prior to intercourse as well as the long-term maintenance of corporal health [34]. Even in the hands of the most experienced surgeon, regardless of the surgical technique or approach used, a certain degree of CN damage occurs during RP [35]. This nerve injury can result from retraction injury during surgery, electrocautery damage, neural vasculature disruption, or rampant local inflammation post compression trauma [36]. This surgical trauma is the causal agent of impaired parasympathetic penile function, manifested as ED [37].

Postoperative nerve damage will induce tissue hypoxia, which in turn leads to a decrease in NO production, thus creating a vicious circle, while also diminishing, simultaneously, the production of anti-fibrotic protective mediators [30], resulting in fibrous connective tissue buildup with smooth muscle apoptosis. These fibrotic changes, which are irreversible, diminish tissue elasticity and make penile expansion difficult [35]. Thus, acute intraoperative lesions of the CNs initiate a chronic, irreversible, vicious circle of structural and metabolic modifications within the cavernous tissue.

In addition to vaso-occlusive disease, it is possible that the deposition of collagen is due to cellular apoptosis of smooth muscle (not of the endothelium), particularly in the subtunical area, causing dysfunction of the veno-occlusive mechanism of the corpus cavernosum. These mechanisms underlie the etiology of the massive corporeal venous leaks that follow [39], thus adding a secondary venogenic component of ED. Therefore, while the occasional use of erectogenic pharmacotherapy will likely produce a transient erection, especially early after surgery, an underlying long-term deterioration of the normal physiologic processes involved in penile erection is already underway [39].

In summary, post-RP ED is caused by interference with the neurological mechanisms that facilitate cavernosal oxygenation, leading to fibrosis. A timely re-establishment of tissue oxygenation via neurologically modulated mechanisms is paramount. Currently available management options for post-RP ED all share the same rationale of re-establishing tissue oxygenation, but do not address the causal issue, i.e., CN damage, only the consequences in a later, postoperative setting, making clinical applications, such as standardized perioperative systemic prophylaxis of CN lesions, a very desirable outcome.

This entry is adapted from the peer-reviewed paper 10.3390/jcm12062208

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