The effect of proliferative hypertrophic scars on determining treatment options for preventing recurrence of vesicourethral anastomotic stenosis after radical prostatectomy: a single-center cross-sectional study

ABSTRACT BACKGROUND: Vesicourethral anastomotic stenosis (VUAS) following retropubic radical prostatectomy (RRP) significantly worsens quality of life. OBJECTIVES: To investigate the relationship between proliferative hypertrophic scar formation and VUAS, and predict more appropriate surgical intervention for preventing recurrent VUAS. DESIGN AND SETTING: Retrospective cross-sectional single-center study on data covering January 2009 to December 2019. METHODS: Among 573 male patients who underwent RRP due to prostate cancer, 80 with VUAS were included. They were divided into two groups according to VUAS treatment method: dilatation using Amplatz renal dilators (39 patients); or endoscopic bladder neck incision/resection (41 patients). The Vancouver scar scale (VSS) was used to evaluate the characteristics of scars that occurred for any reason before development of VUAS. RESULTS: Over a median follow-up of 72 months (range 12-105) after RRP, 17 patients (21.3%) had recurrence of VUAS. Although the treatment success rates were similar (79.5% versus 78.0%; P = 0.875), receiver operating characteristic (ROC) curve analysis indicated that dilatation using Amplatz dilators rather than endoscopic bladder neck incision/resection in patients with VSS scores 4, 5 and 6 may significantly reduce VUAS recurrence. A strong positive relationship was observed between VSS and total number of VUAS occurrences (r: 0.689; P < 0.001). VSS score (odds ratio, OR: 5.380; P < 0.001) and time until occurrence of VUAS (OR: 1.628; P = 0.008) were the most significant predictors for VUAS recurrence. CONCLUSIONS: VSS score can be used as a prediction tool for choosing more appropriate surgical intervention, for preventing recurrent VUAS.


INTRODUCTION
The common feature of urethral stricture, bladder neck stenosis and surgical incision scars is that they develop due to poor wound healing. 1,2 In the pathogenesis of these disorders, many mediators and molecules such as transforming growth factor-β1, basic fibroblast growth factor and plateletderived growth factor play a role. These conditions develop as a result of chronic inflammation. 3 The rate of hypertrophic scar development in the whole population has been reported to be 1.5-4.5%. 4 Although the anterior chest wall and posterior ear are the most common sites for hypertrophic scar formation among anatomical regions, these scars may also be commonly seen elsewhere in the upper body. Individual predisposition, various genetic and hereditary factors and various systemic diseases may also facilitate development of proliferative hypertrophic scars. 4 Although some studies have shown that the presence of hypertrophic scars may be an independent factor for predicting the development of urethral stenosis, we could not find any study that had directly investigated the relationship between proliferative hypertrophic scar formation and vesicourethral anastomotic stenosis (VUAS) after retropubic radical prostatectomy (RRP).

OBJECTIVES
Our aim was to evaluate the existence of this relationship. In addition, we aimed to predict which surgical intervention for VUAS might be more appropriate for preventing recurrent stenosis, depending on the degree of proliferative hypertrophic scar formation.

Patients and study design
Our study was designed as a cross-sectional study after obtaining approval from the local ethics committee (protocol number: 77192459-050.99-E.12077 -7/35; date of approval: November 12, 2019) and written informed patient consent. A total of 573 male patients aged 56-74 years who underwent open RRP due to prostate cancer, operated by the same surgical team between January 2009 and December 2019, were retrospectively evaluated. Our study was conducted in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
We also used a checklist in accordance with the STROBE recommendations (STrengthening the Reporting of OBservational studies in Epidemiology).
Patient demographic data, comorbidities, medical treatments, previous surgeries and clinical data relating to prostate cancer were recorded.
Intraoperative and postoperative complications following radical prostatectomy, the history of VUAS, the time when VUAS developed and the surgical method that was used to treat VUAS were recorded. Data relating to scar status were obtained during routine three-month postoperative follow-up examinations. Among the patients with complete data, those who had previously developed incision scar formation for any reason before surgical intervention to treat VUAS were included in the study. The exclusion criteria are listed below: • Patients with missing data relating to incision scar formation and postprostatectomy follow-up period • Patients who underwent any bladder, prostate or urethral operation prior to radical prostatectomy or development of VUAS • Patients who received radiotherapy in the pelvic region for any reason prior to radical prostatectomy • Patients without incision scar formation on the body for any reason before VUAS • Patients with a history of urethral stricture or bladder neck stenosis prior to radical prostatectomy or those with urethral stricture concomitant with VUAS A flowchart of the study population is shown in Figure 1.
The patients were divided into two groups according to the treatment method for VUAS. The first group consisted of 39 patients who underwent dilatation using Amplatz renal dilators. The second group consisted of 41 patients who underwent endoscopic bladder neck incision and/or resection. Any presence of recurrent stenosis during the follow-up was recorded in both groups.

Surgical procedure for vesicourethral anastomosis in retropubic radical prostatectomy
A non-bladder neck sparing approach was used to remove the prostate. A 2/0 absorbable multifilament suture in a 'tennis racquet' fashion, to a size of 22 French (Fr), was used for bladder neck reconstruction. After the mucosa had been everted over the bladder neck with 4/0 absorbable sutures, vesicourethral anastomosis was performed using six 1/0 absorbable multifilament sutures at the 2, 4, 6, 8, 10 and 12 o' clock positions, over a 20 Fr Foley catheter.
The urethral catheter was left in place for three weeks.

Dilatation technique using Amplatz renal dilators
Under regional or local anesthesia and in the lithotomy position, a 0.038-inch stiff hydrophilic guidewire was manipulated beyond the stenosis, through cystoscopy, and was advanced into the bladder. Sequential dilatation was performed using Amplatz renal dilators from 10F to 26F with an 8F stylet. During the dilatation, the Amplatz dilators were advanced by means of rotation towards the bladder with use of a lubricant. After dilatation, an 18 Fr urethral catheter was inserted with guidance through a guidewire and was maintained there for 5 days. A three-month self-catheterization protocol was recommended after removal of the catheter. If necessary, sclerotic areas of the bladder neck were resected with a 26 F resectoscope. These resections were performed deeply at the 3 and 9 o' clock positions. After both procedures, an 18 Fr urethral catheter was inserted and maintained there for 5 days. A three-month self-catheterization protocol was recommended after removal of the catheter.

Diagnosis of postoperative vesicourethral anastomotic stenosis
The patients presented with complaints such as weak urinary flow rate, dripping after urination, incontinence, residual urinary sensation and inability to completely drain the bladder after radical prostatectomy.
Occurrences of weak urinary flow (Qmax < 10 ml/sec) were determined through uroflowmetry and post-micturition residual urine through ultrasonography. Retrograde urethrography was used to make the differential diagnosis between VUAS and concomitant urethral stricture and to identify the location and length of stenosis.
Because contrast did not adequately pass the proximal urethra or bladder neck in cases of very tight stenosis, voiding cystourethrography was performed if necessary, by passing a small feeding tube into the bladder. Alternatively, anterograde urethrography was performed by placing a suprapubic tube. Urodynamic testing was performed to evaluate bladder capacity, compliance and detrusor contractility whenever there was suspicion of bladder dysfunction.
The definitive diagnosis was made by means of cystourethroscopy, using a 17 Fr cystoscope. Although urethral dilatation to 22

Follow-up and Analysis
Patients who underwent open retropubic radical prostatectomy due to prostate cancer, operated by the same surgical team between January 2009 and December 2019, were retrospectively evaluated for this study (n = 573).
Data on 88 patients who underwent surgical intervention because of development of post-prostatectomy VUAS were recorded.
Among them, 80 patients with complete data who had previously developed incision scar formation for any reason before surgical intervention for VUAS were included in the study.
A total of 80 patients with complete data were found to be eligible for the study, and they were divided into two groups: -Dilatation using Amplatz renal dilators (n = 39), -Endoscopic bladder neck incision and/or resection (n = 41).
Because the number of cases was small in both groups, patients whose data were fully accessible were included in the study without randomization.
The presence of recurrent VUAS over a median follow-up of 72 months was recorded in both groups.
Demographic, clinical and pathological data were evaluated.
Statistical evaluation was performed between the two treatment groups.

Excluded Patients (n: 8)
-Patients with missing data relating to incision scar formation and postprostatectomy follow-up period (n = 2).
-Patients who underwent any bladder, prostate or urethral operation prior to radical prostatectomy (n = 1).
-Patients who received radiotherapy in the pelvic region for any reason prior to radical prostatectomy or development of VUAS (n = 1).
-Patients without incision scar formation on the body for any reason before VUAS (n = 2).
-Patients with a history of urethral stricture or bladder neck stenosis prior to radical prostatectomy or those detected as presenting concomitant urethral stricture with VUAS (n = 2). VUAS = vesicourethral anastomotic stenosis. Figure 1. Flowchart of the study population.
Fr via a catheter was tried as the initial management, endoscopic intervention was required in resistant cases. Incision scar and cystoscopy images from a single patient are shown in Figure 2.
Surgical success in both groups was defined as having no evidence of recurrence (Qmax more than 15 ml/sec; post-micturition residual urine < 50 ml) at the 1 st , 3 rd , 6 th and 12 th postoperative months and every three-month follow-up. Obstructive symptoms, Qmax smaller than 10 ml/sec and any need for repeated surgical urethral interventions were defined as recurrence.

Statistical analyses
The In multivariate analysis, VSS score (OR: 5.380; P < 0.001) and time until occurrence of VUAS (OR: 1.628; P = 0.008) were found to be the most significant determinants for predicting recurrence of VUAS (Table 3).

DISCUSSION
The incidence of VUAS after open RRP has been found to range from 0.4% to 32% in different series. 6,7 The incidence has been decreasing through the help of surgical techniques and new technological developments over recent years. 8 The rate of VUAS was found to be 1.1% after robotic assisted laparoscopic radical prostatectomy (RALP), whereas it was reported as 4.7% in a series that underwent laparoscopic radical prostatectomy. 9 Most studies have only reported on the patients who underwent treatment for VUAS, so the rates in the literature are considered to be lower than the true incidence. 10 Although there are studies reporting that the development of VUAS is significantly reduced by means of bladder neck protection methods during RALP, 11 there are also contradictory findings suggesting that preservation of the bladder neck reduces VUAS rates. 10,12 Symptomatic   Amplatz renal dilators that are used for tract dilatation in percutaneous renal surgeries have begun to be used for dilatation of urethra or bladder neck strictures, as an alternative method. 19 The success rates for this technique have been reported as 73-92.3% at 21-month follow-up. 19 According to our results, the recurrence rates were 20.5% and 21.9%, respectively, in patients who underwent dilatation using Amplatz renal dilators and endoscopic bladder neck incision and/or resection at a median follow-up of 72 months.
The presence of a poorly healed median sternotomy incision scar has also been shown to be associated with poor wound healing in urethral tissue. It has been reported that patients with advanced median sternotomy scars develop longer segmented and frequently recurrent urethral stenosis after urethral manipulations. 20 There have not been enough studies investigating any similar relationship with VUAS, but we observed a strong positive relationship between VSS and development and recurrence of VUAS. Although a cutoff value for the VSS score has not been defined for a description of hypertrophic scars, the most accepted score has been 4, in various studies. [20][21][22] A maximal abdominal scar width > 10 mm has been found to have an eight-fold greater likelihood of VUAS after open RRP. 8 In accordance with this information, we observed that median VSS scores were higher in patients with recurrence of VUAS (6 versus 3; P < 0.001).
Some authors have stated that although urethral dilatation and endoscopic laser incision and/or resection can significantly cure VUAS, residual fibrotic tissue may be left. Using electrocautery to provide hemostasis has also been associated with new fibrosis triggered by thermal damage. 13,19 This may be a risk factor for development of new fibrosis and recurrent stenosis. 13 Although holmium laser incision or plasma-button vaporization of VUAS has been reported to have significantly higher success rates, 13,14 there have also been studies contradicting this, in which it was reported that there were no significant differences in the results from the holmium laser, electrocautery or cold knife incision. 23 According to our findings, dilatation using Amplatz renal dilators gave rise to less risk of recurrent fibrotic stenosis than did diathermic incision and resection, even in patients with high susceptibility to development of proliferative hypertrophic scars.
The rate of recalcitrant VUAS with more than three unsuccessful endoscopic interventions has been reported to be 25-30%. 24  Radiotherapy that is used for adjuvant or salvage treatment is also a predisposing factor for development of necrosis and fibrosis of the bladder neck, due to progressive obliterative endarteritis. 29 In our study, we excluded patients who had undergone radiotherapy, and also those with urethral stricture or bladder neck stenosis prior to RRP, in order to form a homogeneous patient group.
Taking a critical view, the utility of VSS may not seem significant enough, given that minimally invasive surgical techniques for prostate cancer that reduce the rate of VUAS have been developed. Nonetheless, although minimally invasive techniques do not give rise to incision lines that are as long as in open surgery, proliferative hypertrophic scars may also develop at the trocar sites in these methods. Therefore, although the rate of VUAS is decreased through minimally invasive surgery, it is still likely to be seen. Based on the relationship between proliferative hypertrophic scar formation and VUAS in our study, we think that our findings may also guide clinicians in choosing a more appropriate surgical intervention that can reduce the likelihood of recurrence, even in cases of VUAS following minimally invasive surgery.
Although our study revealed a novel prediction, its retrospective nonrandomized design with a limited number of patients and a relatively short follow-up period in a single center is its main limitation. Moreover, although our VUAS rates were consistent with traditional open RRP rates, they were higher than what is seen in robotic surgery data, and are too high for a modern series. In plasma button vaporization and injection of antifibrotic agents or steroids into the incision site were not used in this study. We also were unable to evaluate the relationship between the success rates of these methods and the presence of proliferative hypertrophic scars. Lastly, in similar studies in the literature, patients with a scar on the anterior chest wall were included because this body area is more likely to develop hypertrophic scar formation. However, we also included patients who had previously developed incision scars for any reason, in areas other than this one. Although we evaluated these scars through VSS, this can be considered to be a limitation in terms of standardization.

CONCLUSION
The VSS score can be used as a prediction tool for choosing a more appropriate method for individualized treatment among patients at higher risk of scarring. We present our findings as "preliminary results" because it was not easy to obtain comprehensive results, due to the limitations of our study. Nevertheless, because the relationship between proliferative hypertrophic scar formation and development of VUAS had not been investigated before, we think that our preliminary results may be a step towards further studies.