, David J. Ralph1 and Giulio Garaffa1
Department of Urology, The Institute of Urology, University College London Hospitals, 16-18 Westmoreland Street, W1G 8PH London, UK
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Peyronie’s disease (PD) was first described by Francois de la Peyronie (1678–1747), who reported a series of patients with “rosary beads of scar tissue” causing curvature of the penis. Peyronie’s Disease is an acquired benign fibrotic disorder involving the tunica albuginea (TA) of the corpora cavernosa of the penis leading to the formation of fibrous inelastic plaques . Peyronie’s Disease is believed to occur in the genetically susceptible individuals and is associated with penile curvature, pain and worsening of erectile function. Peyronie’s Disease has an estimated prevalence of 3–9% in adult men and is frequently associated with cardiovascular risk factors including diabetes, hypertension, dyslipidaemia, and low serum testosterone levels [2–5].
The natural course of PD is not homogeneous and ranges from a spontaneous resolution of all clinical symptoms to severe penile curvature, erectile dysfunction (ED) and the complete inability to engage in penetrative sexual intercourse [1, 3]. However, in most cases, the course of PD can be divided into an acute or inflammatory phase, which is characterized by penile pain and curvature progression and typically resolves within 6–18 months, and a chronic phase, when the inflammation has completely settled. Due to the deformity and the worsening of the quality of erections, PD can have a very negative impact on patient’s self esteem and on his quality of life [1, 6, 7].
This chapter will focus on the management of PD focusing on indications and outcome of the most common surgical techniques.
Aetiology and Natural History of PD
Peyronie’s Disease is considered a wound healing disorder occurring in a presumed genetically susceptible individual whose tunica albuginea responds inappropriately to an inciting event (i.e. trauma, inflammation, infection) with a proliferative, fibrotic reaction resulting in an exuberant, inelastic scar. A closer understanding of the etiopathophysiology is not yet complete. Studies on an animal model suggest that inflammation, TGFβ1 and myofibroblasts play a central role in the formation of PD plaques [8, 9].
Recent literature has rejected the myth that PD can undergo spontaneous resolution while an improvement in the degree of deformity is a quite infrequent occurrence . Commonly, PD is classified into an acute (or inflammatory) phase and a chronic (or stable) phase . During the former, there may be penile pain, even when flaccid, and a penile deformity may become apparent in the erect state. Penile pain resolves spontaneously within 12–18 months of PD onset in most patients. During the chronic phase, since the inflammatory process has settled, pain is absent and the curvature is stable. It should be noted that the natural history of PD is not homogenous and around 30% of patients will experience the sudden onset of a painless deformity .
Clinical Diagnosis and Patient Evaluation
The aim of history taking is to identify the time of onset of Peyronie’s Disease, the presenting symptoms and to understand whether the condition is in the acute or in the chronic phase . Since PD is strongly associated with the presence of cardiovascular disease, it is important to search for the presence of any of the known cardiovascular risk factors [10, 11]. It is also mandatory to assess the quality of the erections, as this is one of the most important factors that need to be taken into consideration when deciding what approach to choose for the management of the condition [1, 3]. Erectile function can be assessed directly questioning the patient and with a variety of tests, including rigiscan or dynamic Doppler ultrasound of the penis. As a degree of cardiovascular disease is quite common in patients with PD, a degree of erectile dysfunction is often present. Other areas of sexual dysfunction including ejaculation, orgasm, and change glans sensation should be also investigated [1, 3, 10, 11].
A careful assessment of the deformity should be carried out in the erect state. The presence of indentation, hinging, or buckling of the erect penis when axial forces are applied, as well as shortening, should be carefully determined. Shortening appears to occur in around 70% of patients presenting with PD and it is one of the most devastating complications for the patient. Stretch penile length represents a good estimate of erect length and it can be easily assessed with the Wessels’ technique , which involves grasping the glans penis and pulling it to full stretch at 90° from the plane of the body [13–15].
Exact plaque location should be noted, but measurements of its size have proven to have no impact in terms of treatment outcome [1, 3, 11]. The most important part of the clinical diagnosis is to visually assess the penis in the erect state in order to obtain an accurate and objective measure can of the deformity. It appears that the most reliable technique involves the intracavernosal administration of a vasoactive agent in order to induce a pharmacological erection. Once rigidity is achieved, the degree of curvature is best measured with a goniometer, and a simple string can be used to measure girth at the base, corona, and any area of indentation or hourglass narrowing [1, 3, 11].
Non-surgical Management of Peyronie’s Disease
After more than 250 years, management of PD still remains one of the most controversial issues in andrology . Currently surgery represents the most effective and reliable treatment for Peyronie’s Disease and its aim is to guarantee a penis straight and rigid enough to achieve penetrative sex . However, surgery is not able to restore the pre-Peyronie’s disease the size and the shape of the penis and is invasive. On the other hand, the nonsurgical management of PD is less invasive, but it is far less effective than surgery.
Several nonsurgical therapies including a variety of oral, topical and injectable agents, as well as more innovative approaches such as extracorporeal shock wave lithotripsy, have been tested over the years [1, 3, 11, 16]. Nevertheless, as is frequently the case when a variety of different treatments are available for a single disease, the evidence showing the efficacy of each one of these therapies in the management of PD has been scarce. The value of many published studies has been questioned as most of them were not well controlled, often were formed by a small number of patients and with limited reports on objective measures of curvature change .
Potassium Para-aminobenzoate (POTABA)
POTABA was introduced as a treatment for Peyronie’s disease in 1959. However, data concerning its mode of action and efficacy are limited [17, 18]. Recent papers showed a significant reduction in plaque size but no change in pain or improvement of the curvature. POTABA seems to be helpful in stabilizing the plaque and preventing curvature progression during the early stage of PD [19, 20].
A recent placebo controlled study showed that tamoxifen is ineffective in the treatment of PD .
Colchicine is an anti-inflammatory agent with inhibitory effects on neutrophil microtubules. Although initial studies showed that colchicine might be also effective in the early phase of PD [24, 25], recent placebo controlled studies have showed no benefit . However, the combination of colchicine and Vitamin E was shown in another double-blinded, randomized trial to induce significant improvements in plaque size, curvature, and pain during the initial phase of PD .
Phosphodiesterase Type 5 Inhibitors (PDE5i)
PDE5i has been shown to counteract the development of plaques in a rat model of PD and there have been several unpublished reports on the use of daily phosphodiesterase type 5 inhibitors including tadalafil indicating potential benefits for PD . In a recent studies, tadalafil in combination with verapamil or with extracorporeal shock wave therapy (ESWL) was shown to lead to a significant decrease in plaque size and to an improvement in IIEF scores when compared to either group alone [31, 32]. Further placebo-controlled trials are necessary before this class of drugs can be recommended to treat men with PD.
Intralesional dexamethasone was initially used for PD in the 1950s with the aim to decrease plaque size and penile pain. However, subsequent studies did not replicate earlier findings, and the authors believe that the therapeutic effects were due to the mechanical effects of the injection and not to the action of the drug itself [33–37].
In the last 10 years, intralesional injection of collagenase clostridium histolyticum (CCh) was one of the most commonly studied therapies for PD . Intralesional CCh (Xiaflex®; Auxilium, Chesterbrook, PA, USA) is a purified mix of two collagenases that leads to a breakdown of the collagen fibers when injected into the penile fibrotic plaque . Prospective, randomised, placebo-controlled study demonstrated clinical benefit with the use of intralesional injections of collagenase , recent studies have reported significant decreases in deviation angle, in plaque width and length accompanied by low overall rates of serious adverse events [39, 40]. Overall, these well-designed trials have led to intralesional CCh becoming the only FDA-approved drug for PD .
In in-vitro studies, verapamil has shown to interfere with Peyronie’s plaque derived fibroblast cellular proliferation and Levine et al. reported that intralesional verapamil injection induces a significant reduction in penile curvature [42–44]. These encouraging results have been confirmed by two subsequent studies while one failed to demonstrate any effectiveness of this treatment. Further large-scale comparative studies are needed for ILV to become a standard of care or an FDA-approved therapy.
Hellstrom et al. conducted a single-blind, multicenter, placebo controlled, parallel study that showed that intralesional IFN alpha-2B may be beneficial for men with Peyronie’s disease . These findings offer the largest and best-controlled trial of intralesional therapy for Peyronie’s disease, as well as support its use and demonstrates the lack of clinical benefit following intralesional injection of saline. It is significantly more costly than verapamil and has been associated with flu-like side effects. However, a recent study failed to demonstrate any efficacy of intralesional injection of IFN alpha-2B . Further studies are needed to better compare its efficacy to other treatments and to assess its functional significance for patients.
Other Non-invasive Therapy
Penile Traction Devices
It is well-documented that gradual expansion of tissue by traction, also known as mechanotransduction , results in the formation of new connective tissue by cellular proliferation in several tissue models including bone, muscle and Dupuytren’s scar [53–55]. However, penile traction has proved to have insignificant role in the management of PD [56, 57].
Surgery represents the gold standard of treatment and should be offered during the chronic (stable) phase of PD. The aim of surgery is to provide a penis straight and rigid enough to allow the patient to perform penetrative sexual intercourse. The main indications for surgery are: (1) stable disease; (2) compromised or inability to engage in coitus due to deformity and/or ED; (3) extensive plaque calcification; (4) failed conservative treatment [1, 58].
Appropriate preoperative counselling is necessary to guarantee an acceptable postoperative satisfaction rates. Patients must be aware that the aim of surgery is to create “functionally straight” of the penis, defined as a curvature of less than 10–20° and, more important, that a loss of penile length will always occur. In addition, there may be diminished rigidity, which may be consequence of PD itself, of the associated cardiovascular risk factors, or of the surgical approach. Loss of penile sensation may also occur in patients who have undergone PD surgery [1, 3, 11]. This may be the result of several of factors including lack of engorgement of the glans and damage of the branches of the penile dorsal nerve following surgical procedures involving dissection of the neurovascular bundle (NB). Lack of engorgement of the glans is usually a consequence of poor arterial inflow secondary to systemic atherosclerosis or diffuses infiltration of the NB or urethra by the fibrotic PD plaque [1, 3, 11].
Surgical Approach Selection
The choice of surgical technique is driven by different preoperative factors that are: (1) the severity of the curvature, (2) penile length and (3) the quality of erections [59–61]. When rigidity is sufficient for a sexual penetration, with or without pharmacological supports, the curvature can be adjusted either by shortening the longer side of the penile shaft using tunica plication techniques, or lengthening the shorter concave side performing a plaque incision/partial excision followed by grafting of the resulting defect. Tunical plication techniques are commonly selected when there is a curvature of less than 60° without hourglass deformity and when the supposed loss of length will be less than 20% of total penile erect length [59–61]. Patients who have complex curvature either greater than 60°, and/or in presence of an hourglass deformity, plaque incision or plaque excision and grafting is chosen.
Tunica albuginea plication procedures are developed to obtain straightening of the shaft by shortening the longer, convex side of the penis. This surgical approach, which has been originally described in 1969 by Nesbit for penile congenital deformities, can be applied to PD and includes the excision of a piece of tunica albuginea at the point of maximum curvature followed by approximation of the tunical edges to produce a shortening effect [62, 63]. Several modifications of the Nesbit technique were described, which do not include the excision of the tunica albuginea reducing the possible injury to the underlying corpus cavernosum. Plication approaches are simple, minimally invasive, and tend to preserve potency in most patients but they can result in further penile shortening, which has been shown to be particularly significant if the curvature corrected is more than 60° or in presence of complex deformity [1, 3]. Furthermore, significant hinge and hourglass deformities cannot be corrected adequately with these techniques and therefore an adequate patient’s selection is paramount in order to achieve satisfactory results.
This technique is a modification of the Essed-Schroeder technique. It consists of two (16 dot)  or three (24 dot) pairs of parallel Essed-Schroeder plications according to the curvature degree. The plication sutures are applied along the convex side of the shaft, starting from the point of maximum curvature and are initially left loose. The sutures are then tied after the induction of an artificial erection. After the pair of sutures applied at the point of maximum curvature has been tied, the degree of deformity is reviewed. If the curvature is adequately corrected, the other sutures are not tied; if a curvature persists, the remaining pair(s) of sutures is tied in order till the shaft is sufficiently straightened.
Tunica Albuginea Plication (TAP)
The tunica albuginea plication (TAP) a series of parallel incisions are made on the superficial layer of the tunica albuginea at the point of maximum curvature. The edges of the two parallel incisions are then approximated .
This technique uses the Heinke-Mikowitz principle where a vertical incision is closed transversely in order to shorten the convex side of the penis. As the transversal closure of the tunica albuginea guarantees a degree of widening, this technique should be offered to patients who have slight penile indentation not requiring plaque incision/excision and grafting .
Incision or Partial Excision and Grafting Techniques
Surgical grafting techniques consist of plaque incision or partial excision followed by grafting of the defect. Complete excision of the plaque should be avoided, as it is related with an excessively high rate of erectile dysfunction due to a compromised veno-occlusive mechanism [1, 69]. In particular, larger grafts, men older than 60 years old, and those with ventral grafting also appear to have a higher risk of post-operative erectile dysfunction. Therefore, modern techniques try to reduce the degree of the excision and several authors believe that excision should be avoided completely if possible and rather make a simple releasing incisions at the point of maximum curvature [1, 70–73].
Several types of grafts are available for PD surgery with advantages and drawbacks in terms of availability, antigenicity and cost effectiveness. They are classified in three categories: synthetic, autologous tissue and extracellular matrix [74–76].
The most common synthetic grafts are Goretex and Dacron while the most common autologous materials are saphenous vein, dermis, buccal mucosa, rectus fascia and fascia lata. Bovine and cadaveric pericardium, porcine small intestine submucosa (SIS) and cadaveric fascia lata are the extracellular matrix grafts [74–76].
The main disadvantage of synthetic grafts is their immunogenicity, which translates in a significantly increased infection rate, and leads to the formation of dense fibrosis. Donor size morbidity and limited availability and increased operative time are, instead, the downsides of autologous graft .
Extracellular matrix grafts or xenografts instead represent the material of choice when grafting is required as they are not associated with donor site morbidity, limited availability and immunogenicity and they appear to have similar mid-term outcome results as compared to autologous grafts .
The operative procedure is done essentially the same way for all grafting techniques, regardless to the type of graft used. After an artificial erection is created to demonstrate the exact location of the curvature, the penis is degloved using a circumferential subcoronal incision. Buck’s fascia containing the neuro-vascular bundle is then elevated, either from a pair of parallel paraurethral incisions allowing elevation of Buck’s fascia dorsally, or by coming through the bed of the deep dorsal vein.
Once Buck’s fascia is properly elevated the artificial erection is repeated, in order to identify precisely the point of maximum deformity. Although surgeons differ in their approach as to whether a simple modified double Y-like relaxing incision should be made at the point of maximum curvature or whether partial plaque excision is recommended, particularly when there is significant indentation and/or calcification, the goal is to remove as little plaque as possible, but to allow proper correction of the deformity by expanding the tunica albuginea in both girth and length.
If adequate straightening is not achieved with a single graft, further straightening should be achieved by plicating the tunica albuginea on the side opposite to the incision, although this may cause further shortening. Additional incisions and grafting are highly discouraged, as this is likely to further impair the quality of the erections [76–88].
The geometric principle approach initially described by Egydio  represents a useful tool to locate the exact point where to perform the tunical incision and to precisely identify the size and shape of the graft required. This technique has proven extremely useful, as proper sizing of the graft allows a complete correction of the deformity using a single patch in the vast majority of patients and therefore additional plications are usually not necessary.
Once the graft is positioned, Buck’s fascia is reapproximated to provide support over the graft and to provide a haemostatic effect.
In order to minimize postoperative contracture of the graft, which has been reported to occur by the vast majority of Authors regardless of the grafting material used, early postoperative stretching of the graft is actively encouraged. Graft contracture can be prevented with the administration of phosphodiesterase type 5 inhibitors (PDE5i) , which are usually started 7–10 days after surgery and maintained for 6 weeks, in order to enhance nocturnal erections, stretch the tissue, encourage nourishment of the graft, and possibly reduce the risk of postoperative ED .