Urethral Strictures

3. DEFINITION, EPIDEMIOLOGY, AETIOLOGY AND PREVENTION

3.1. Definitions

In males, a urethral stricture refers to a narrowed segment of the anterior urethra due to a process of fibrosis and cicatrisation of the urethral mucosa and surrounding spongiosus tissue (“spongiofibrosis”) [11,12]. In the male posterior urethra, there is no spongiosus tissue and at this location the terms stenosis is preferred [11,12]. The definition of meatal stenosis is generally accepted as a short distal narrowing at the meatus, without involvement of the fossa navicularis [12].

There is no universal definition for what constitutes a female urethral stricture (FUS). Female urethral stricture is defined by most authors as a ‘fixed anatomical narrowing’ causing reduced urethral calibre [13,14]. This reduced urethral calibre is variously defined as between < 10 Fr to < 20 Fr [15,16] with the majority of series defining < 14 Fr as diagnostic, compared with a ‘normal’ urethral calibre of 18-30 Fr.

In transgender patients, the term stricture is also used to define a narrowing of the reconstructed urethra despite the absence of surrounding spongious tissue.

3.2. Epidemiology

In males, a sharp increase in incidence is observed after the age of 55 years, with a mean age of 45.1 [17,18].

Overall, the incidence is estimated to be 229-627 per 100,000 males [17]. The anterior urethra is most frequently affected (92.2%), in particular the bulbar urethra (46.9%) [18].

In females, 2-29% of patients presenting with refractory lower urinary tract symptoms (LUTS) have bladder outflow obstruction (BOO) [19-22] of whom 4-20% will have a urethral stricture [21-23]. True FUS therefore occurs in 0.08-5.4% of women with refractory LUTS. There is a markedly increased incidence in women over 64 years of age [24].

After hypospadias repair, meatal stenosis and urethral strictures are reported in 1.3-20% of cases, depending on the severity of the hypospadias and the technique used [25]. There is a significantly higher incidence of this type of strictures in well-resourced countries due to a higher surgical repair rate [26].

Up to 18% of all urethral strictures have been reported to involve the meatus or fossa navicularis, usually due to failed hypospadias repair (FHR), lichen sclerosus (LS), trauma/instrumentation or idiopathic causes [27-30]. Meatal stenosis post-circumcision has been reported in less than 0.2% of children undergoing circumcision as neonates [17].

In female-to-male (FtM) transgender patients (“transmen”), 2-56% will suffer a urethral stricture. Strictures almost exclusively arise at the neomeatus in male-to-female (MtF) transgender patients (“transwomen”) and occur in 4-40% of cases [31].

3.3. Aetiology and prevention

Stricture aetiology differs significantly throughout different regions in the world, due to differences in healthcare quality and environmental and practice patterns [26]. Regardless of geography, urethral stricture disease adversely impacts physical health and quality of life (QoL) [32,33], notwithstanding costs associated with the treatment of primary and recurrent disease [34,35]. The rationale for preventing urethral strictures is to avoid morbidity to the individual and costs to society. Prevention of urethral strictures encompasses reducing the causes of stricture (e.g., infection, trauma, iatrogenic injury) and where this is not possible, mitigating the risk.

3.3.1. Aetiology and prevention in males

a. Sexually transmitted infection

Urethritis due to sexually transmitted infection (STI), in particular gonorrhoea, was previously a major cause of urethral strictures in well-resourced countries accounting for 40% of all cases [36]. The wide-scale promotion of safe sexual practices and easier access to sexual health services, resulting in timely treatment with antimicrobials, is thought to have led to the considerable reduction in the problem [36]. Infective urethritis now accounts for 0.9% to 4.6% of cases in contemporary series from well-resourced countries [36,37] but continues to be the major cause of strictures in low-resourced countries comprising 41.6% of all strictures [38].

b. Inflammation

Lichen sclerosus involves the urethra in 20% of cases [39] and is the most common cause of panurethral stricture disease (48.6%) [18]. The aetiology of LS has not been fully elucidated but is thought to have an autoimmune origin [40]. Lichen sclerosus may be associated with environmental factors and non-autoimmune comorbidities. Uncircumcised men are far more likely to suffer LS than circumcised men (age-adjusted odds ratio [OR] of 53.55; 95% confidence interval [CI]: 7.24-395.88) [41]. Lichen sclerosus is also associated with higher mean body mass index (BMI), diabetes mellitus, coronary artery disease, tobacco usage, hyperlipidaemia, and hypertension [42-44].

c. External urethral trauma

External trauma to the urethra is the second most common cause of stricture formation in adults [36]. The urethra is vulnerable to trauma during certain activities including sport, driving a vehicle, sexual intercourse and during combat. The bulbar urethra is the site most frequently affected by blunt trauma [12], usually as a result of straddle injuries or kicks to the perineum. Penile fracture is associated with a urethral injury in 15% of cases [45]. Motor vehicle accidents are the main cause of blunt injuries to the posterior urethra associated with pelvic fractures [46]. Penetrating injuries of the urethra are uncommon during non-combat situations [47].

d. Iatrogenic urethral injury

Iatrogenic injury to the urethra is one of the most common causes of strictures in well-resourced countries [18,36] accounting for 32-79% of all strictures [36,48]. Preventing iatrogenic urethral injury represents the main way in which urologists can prevent urethral strictures. Iatrogenic urethral injury most commonly results from urethral instrumentation (e.g., catheterisation, cystoscopy), surgery for benign prostatic obstruction (BPO), surgery for prostate cancer, or radiotherapy [37].

d.1 Urethral catheterisation

Urethral strictures are a recognised complication of urethral catheterisation accounting for 11.2-16.3% of all strictures [18,36]. In a meta-analysis by Hollingsworth et al., the pooled percentage of patients who developed urethral stricture or erosion after short-term catheterisation (< 3 weeks) in higher-quality studies was 3.4% (CI: 1-7%) [49]. In studies comprised mainly of men with spinal cord injury with indwelling urethral catheters, the pooled estimate of urethral stricture or erosion was 8.7% (CI: 0.0-18.7%) [49].

Urethral strictures following catheterisation may arise as a consequence of injury during attempts at insertion or during the period a catheter remains in situ. During insertion, the urethra may be injured by formation of a false passage by the catheter tip (29.7%) or inflation of the balloon within its lumen (70.3%) [50]. The rate of urethral injuries due to catheterisation was found to be 3.2 per 1,000 inpatients [51]. A six-month prospective multicentre study found that of 37 patients with catheter-related urethral trauma referred to urologists, 24% continued to perform ISD once weekly and 11% required at least one urethral dilation for urethral stricture [52]. In another follow-up study of 37 patients with catheter-related urethral trauma, 78% of patients developed urethral stricture [50]. The most common locations of trauma are the bulbar and posterior urethra [53].

Catheter-related trauma can be prevented through several measures [54]. Studies have indicated around 25% of all indwelling catheterisations in hospitals were unnecessary and inappropriate [55,56]. Implementation of guidelines [57,58] and specific criteria [59] have been shown to reduce catheterisation rates. Several studies have identified deficits in the knowledge of urethral catheterisation amongst resident doctors [60,61]. This is postulated to be a factor in catheter-related trauma [61]. A targeted training program on urethral catheterisation for nursing staff was shown to be effective in reducing iatrogenic urethral injuries in a prospective single institution study [62].

In addition to guidance and education, another approach to safer catheterisation is modification of the standard Foley catheter. A novel catheter balloon pressure valve safety system was developed to prevent balloon inflation injury though this has not been assessed in comparative studies [63,64]. Bugeja et al., studied the use of urethral catheterisation device (UCD) incorporating a guidewire, in prospective observational cohort study that included 174 patients. The incidence of adverse events was 7% with standard Foley catheterisation vs. 0% with the UCD (no statistical analysis was performed) [65]. A further prospective observational study found that Seldinger technique catheterisation could be used successfully by non-urology trained doctors [66]. These technologies need to be further assessed in prospective raondomised controlled trials (RCTs), incorporating cost-benefit analysis.

Catheter diameter is suggested as a possible contributing factor to urethral stricture due to a pressure effect on the urethral wall [67]. Decreasing the catheter size from 22 Fr to 18 Fr significantly decreased the risk of fossa navicularis strictures (6.9% vs. 0.9%, p=0.02) after radical prostatectomy (RP) [68]. Catheter material may also have an influence on the occurrence of stricture. In the 1970s/80s several comparative studies in patients undergoing cardiac surgery demonstrated that non-coated latex catheters were associated with a greater incidence of urethritis and more stricture formation than silicone catheters [69-71]. Other studies showed no difference [72-74]. Modern latex catheters have polymeric coatings [75] due to the concern with regards to stricture alongside the risk of hypersensitivity and the demonstrable in vitro toxicity of latex. Prolonged urethral catheterisation has also been implicated in the aetiology of stricture (e.g., poly-trauma, burns patients) [48].

d.2 Transurethral prostate surgery

Urethral stricture following transurethral prostate surgery occurs in between 4.5-13% of patients [76], whereas bladder neck stenosis (BNS) occurs in between 0.3-9.7% [77]. Transurethral surgery is the most common cause of iatrogenic urethral stricture accounting for 41% of all causes [48]. The most common location for urethral stricture is the bulbomembranous urethra, followed by the fossa navicularis and penile urethra [78,79]. Postulated mechanisms include friction at the penoscrotal junction, lack of adequate lubrication, repetitive ‘in and out’ movement of the resectoscope, breach of mucosal integrity leading to urine extravasation and monopolar current leak due to inadequate resectoscope insulation [80]. Bladder neck stenosis may be related to excessive and/or circumferential resection and the use of relatively large resection loops which may generate excessive heat in small intraurethral adenomas leading to scarring [77,81]. Stenoses of the posterior urethra may also be due to a prolonged period of post-operative inability to void [82].

d.2.1 Risk factors for development of urethral stricture and bladder neck stenosis

Several risk factors for the development of urethral stricture and BNS following transurethral prostate surgery have been identified. Both prostatic inflammation (OR: 4.31) and operative time > 60 min (OR: 4.27) were found to be independent predictors of stricture after monopolar transurethral resection of prostate (TURP) [83]. In terms of bipolar TURP, slower resection rate (OR: 0.003), intraoperative urethral mucosa rupture (OR: 2.44) and post-operative infection were shown to be independent predictors (OR: 1.49) [84,85]. A larger-calibre endoscopic sheath (26 Fr vs. 24 Fr) was associated with a greater risk of bulbar urethral stricture following monopolar TURP (11.4% vs. 2.9%, p=0.018) [86]. Room temperature irrigation solution was associated with a greater risk of urethral stricture following combined transurethral resection and vaporisation of the prostate compared to body temperature irrigation (21.3% vs. 6.3%, p=0.002) [87].

Bladder neck stenosis is known to occur more frequently in smaller prostate glands after both monopolar and bipolar TURP [88,89]. Lee et al., found that adenoma weight was an independent risk factor for BNS after monopolar TURP [89]. Meanwhile, Tao et al., found total prostate volume (< 46.2 g) (OR: 1.5), but not resected gland weight, to be an independent risk factor [84].

d.2.2 Incidence of urethral stricture and bladder neck stenosis with different energy modalities

A SR and meta-analysis by Cornu et al., showed no significant differences in urethral stricture and BNS rates by energy modality (monopolar, bipolar, holmium laser enucleation, photoselective vaporisation) [76]. In another meta-analysis assessing outcomes of thulium (Tm:Yag) laser and bipolar TURP, no difference in urethral stricture and BNS rates were found between the two modalities [90]. The presence of potentially confounding factors such as endoscopic sheath diameter, energy setting used, procedural length and length of follow-up make inter-study comparisons between energy modalities problematic. Overall, there is no strong evidence that any single modality is associated with a clinically significant higher incidence of urethral stricture and BNS than others. Selection of modality should be based on a comprehensive evaluation of clinical safety and efficacy. A summary of incidences of urethral stricture and BNS with different modalities is presented in Table 3.1.

A systematic review analysing different techniques used for BPH surgery, showed the lowest incidence of urethral strictures in enucleation procedures, followed by B-TURP and ablation, and M-TURP. However, after twelve months of follow-up there were no significant differences in stricture rate [91].

Table 3.1: Incidence of urethral stricture and bladder neck stenosis by transurethral modality (adapted from Chen et al. 2016 )

d.2.3 Interventions to prevent urethral stricture and bladder neck stenosis

Sciarra and colleagues conducted a single-blind RCT (n=96) to assess the use of rofecoxib for stricture prevention following TURP. At twelve months follow-up a urethral stricture was found in 17% and 0% of cases in the placebo and rofecoxib groups, respectively (p=0.0039) [92]. Chung et al., conducted a single blinded RCT (n=180) evaluating the effect of urethral instillation of hyaluronic acid (HA) and carboxymethylcellulose (CMC). Urethral stricture on urethrography was diagnosed in 1.25% and 8.64% of patients in the treatment and placebo group respectively (p=0.031). Further RCTs are needed to confirm these findings and the safety of the pharmacological interventions.

Several earlier comparative studies assessed whether routine preliminary urethrotomy with an Otis urethrotome prevented the incidence of stricture following TURP [93-96]. Only one of these reported at least twelve month follow-up, finding no significant difference in stricture rate in patients undergoing TURP alone vs. Otis urethrotomy followed by TURP (21% vs. 14%) [97]. Others have suggested performing internal urethrotomy where there are pre-existent meatal or urethral strictures [98].

Adjunctive transurethral incision of the prostate (TUIP) at the end of TURP to reduce the rates of BNS was studied by Lee et al. [89]. A total of 1,135 patients of whom 667 underwent TURP and 468 underwent TURP plus TUIP were retrospectively studied. At median follow-up of 38 months, the incidence of BNS was 12.3% for the TURP group vs. 6.0% for the TURP plus TUIP group (p < 0.001). In glands < 30 g, the incidence of BNS in the TURP vs. the TURP plus TUIP group was 19.3% and 7.7%, respectively (p < 0.05). The clinical efficacy and safety of additional surgical interventions to prevent urethral stricture and BNS need to be confirmed in larger prospective RCTs before their use can be recommended.

d.3 Radical prostatectomy

Radical prostatectomy has been associated with vesico-urethral anastomosis stricture (VUAS) in 0.5-30% of patients [77], though most modern series report it in the range of 1-3% [99]. The risk of stricture formation after salvage RP is notably higher (22-40%) [100]. Most VUAS develop within the first two years [100,101]. A 2012 meta-analysis by Tewari et al., showed no significant difference in VUAS between open-, laparoscopic and robotic RP [102]. In contrast, a more recent analysis of a national cohort in the UK found that VUAS rate after robotic RP was 3.3%, which is significantly lower than following laparoscopic (5.7%) or open RP (6.9%) [103]. These findings are consistent with an earlier similar study conducted in the USA [104]. The difference in VUAS rates may be explained by the level of experience and surgical volume of surgeons [105]. The cohort studies represent “real world” data, including all levels of surgical experience and surgical volumes whereas the meta-analysis is based on clinical studies. Thus, the better outcomes for robotic RP in the population studies may be related to the shorter learning curve [106].

d.3.1 Risk factors for development of vesicourethral anastomosis strictures

These include higher grade cancer, more advanced stage, higher prostate volume, coronary artery disease, obesity, hypertension, diabetes mellitus, previous bladder outlet surgery and older age [99,107,108]. Surgical factors include the use of non-nerve-sparing technique, anastomotic urine leak, increased operative time and increased estimated blood loss [99,107,108]. In addition, low-volume surgeons (< 40/year) were shown to have higher VUAS rates, 27.7%, compared to high-volume surgeons (> 40/year), 22% [109].

d.3.2 Interventions to prevent vesicourethral anastomosis strictures

Srougi et al., studied bladder neck mucosal eversion in a prospective RCT of 95 patients. No significant difference was found in rates of VUAS at twelve months follow-up [110]. A meta-analysis by Kowelewski et al., comparing interrupted vs. continuous vesico-urethral anastomosis suturing found no difference in VUAS rates [111]. Another SR by Bai et al., compared barbed sutures to conventional sutures, and although heterogeneity across studies precluded meta-analysis, no patients developed VUAS with either approach [112].

d.4 Prostate radiation and ablative treatments

Urethral strictures occur in 1.5% of patients undergoing external beam radiation therapy (EBRT), 1.9% having brachytherapy (BT) and 4.9% who receive combination EBRT-BT at around four years follow-up [113]. These strictures typically occur in the bulbomembranous urethra [114]. As opposed to RP, stricture incidence after irradiation increases with time [100,113]. For the ablative treatments, the stricture incidence after cryotherapy and high-intensity focused ultrasound (HIFU) is 1.1-3.3% and 10.3%, respectively [100,115]. The use of these modalities in the salvage setting is associated with increased risk of stricture formation: 3-10% after salvage EBRT, 5-12% after salvage cryotherapy and 15-30% after salvage HIFU [100]. Due to the increasing utilisation of prostate irradiation (EBRT, BT) and ablative treatments (cryotherapy, HIFU), an increasing number of respectively radiation-induced and ablative treatment-induced strictures are expected [116].

d.4.1 Risk factors for the development of radiation strictures

Awad et al., performed a multivariate meta-regression analysis including 46 studies, finding combining ERBT + BT and length of follow-up to be significant predictors of urethral stricture following prostate radiation [113]. Factors not shown to predict urethral stricture included biochemical equivalent dose, age, and androgen deprivation therapy [113]. Previous TURP was not included in the analysis, but has been found to be an independent predictor of stricture (HR: 2.81) in a previous multivariate analysis from a single institution [117] as well as PSA level < 10 ng/ml (HR: 0.47) [118].

d.4.2 Interventions to prevent radiation induced urethral strictures

Delaying adjuvant or salvage EBRT by nine months is associated with lower rates of urethral stricture (HR: 0.6) [119]. This has to be balanced with risk of delaying treatment in terms of cancer control [77]. In BT, it has been reported that downward movement of needle applicators occurs between fractions [120]. This may explain why strictures occur below the prostatic apex [118] in the so called “hot spot” [121]. Several measures taken together are thought to have contributed to a reduction in urethral stricture formation with BT including reduction of dose to the “hot spot”, more careful needle placement, avoiding midline insertion and the introduction of plastic needles rather than steel [113].

e. Failed hypospadias repair

Although urethral strictures after hypospadias repair are sometimes considered as iatrogenic [36], they are a very specific subtype and should be considered as a separate entity. The main reasons for this are the absence of spongiosus tissue at different levels within the penile urethral segment, and the lack of high-quality local tissues for urethral reconstruction [122].

f. Congenital

The diagnosis of a congenital urethral stricture can only be made in the absence of other possible aetiology, such as iatrogenic, inflammatory, and traumatic causes [123]. Congenital strictures are thought to be consequent to incomplete or incorrect fusion of the urethra formed from the urogenital sinus with the urethra formed following closure of the urethral folds. They typically have a deep bulbar location and are usually short. In general, congenital strictures are diagnosed at a young age (Moorman’s ring or Cobb’s collar).

g. Idiopathic

Idiopathic strictures are seen in 34% of all penile strictures and in 63% of all bulbar strictures [124]. Unrecognised trauma is thought to be a possible aetiology of idiopathic urethral strictures [26].

3.3.2. Aetiology in females

The cause of FUS was idiopathic in 48.5%, iatrogenic in 24.1%, resulting from prior urethral dilations, difficult/traumatic catheterisation with subsequent fibrosis, urethral surgeries (mainly diverticulum surgery, fistula repair and anti-incontinence procedures) and trauma (mainly following pelvic fracture) in 16.4% [125-137]. Radiation therapy and infections are rare causes of FUS [138]. The most common segment of urethra affected is the midor mid-to-distal (58%). Panurethral strictures are rare (4%) [15,125,127,128,130-132,137,139].

For further information see online supplementary Tables S3.1 and S3.2.