The current management for complex urethral strictures commonly uses open reconstruction with buccal mucosa urethroplasty. However, there are multiple situations whereby buccal mucosa is inadequate (eg, pan-urethral stricture or prior buccal harvest) or inappropriate for utilization (eg, heavy tobacco use or oral radiation). Multiple options exist for use as alternatives or adjuncts to buccal mucosa in complex urethral strictures. This article reviews the current state of alternate techniques for urethral stricture treatment besides buccal mucosa, including injectable antifibrotic agents, augmentation urethroplasty with skin flaps, lingual mucosa, colonic mucosa, and new developments in tissue engineering for urethral graft material.
Key points
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Injectable antifibrotic agents may improve rates of recurrence compared with direct vision internal urethrotomy for short urethral strictures.
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Lingual mucosa has similar physiologic and anatomic characteristics to buccal mucosa with promising outcomes from initial clinical trials.
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Colonic mucosa can be harvested in a minimally invasive fashion, thereby increasing its potential use as a graft in complex cases of urethral reconstruction.
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Acellular matrices and tissue-engineered grafts have begun small clinical trials and may eventually provide an off-the-shelf option for urethral reconstruction.
Introduction
The repair of urethral stricture is approached with multiple different techniques, ranging from endoscopic incision to graft placement for open reconstruction, in an attempt to open and maintain a normal urethral lumen. All causes of stricture, including trauma, iatrogenic injury, lichen sclerosus, or prior urethral surgery, have the potential to form long, complex strictures that necessitate extensive reconstruction. Treatment selection ultimately depends on the cause of the stricture, location, length, and the surgeon’s preference and experience level. Shorter strictures are amenable to endoscopic treatment or excision and anastomosis, whereas longer defects require augmentation with oral mucosa grafts or fasciocutaneous flaps. However, clinical scenarios exist whereby the typical buccal mucosa graft or fasciocutaneous flap is insufficient for urethral reconstruction.
Current practice of urethral reconstruction places a premium on buccal mucosa grafts, but additional grafts are available to use as an alternative or adjunct in complex cases, particularly pan-urethral strictures, recurrent strictures when buccal mucosa has been previously harvested, or in patients in whom retrieval of oral mucosa in contraindicated. Buccal mucosa has enjoyed such success that many of the original grafts for urethroplasty, such as extragenital skin, have fallen out of favor. Despite the decreased utilization of skin grafts, the principles of this technique should be continually revisited for inspiration and innovation toward new approaches. Furthermore, tissue engineering and stem cell therapies are promising opportunities to provide off-the-shelf grafts that would preclude the invasiveness and morbidity of tissue harvest for urethral reconstruction.
Introduction
The repair of urethral stricture is approached with multiple different techniques, ranging from endoscopic incision to graft placement for open reconstruction, in an attempt to open and maintain a normal urethral lumen. All causes of stricture, including trauma, iatrogenic injury, lichen sclerosus, or prior urethral surgery, have the potential to form long, complex strictures that necessitate extensive reconstruction. Treatment selection ultimately depends on the cause of the stricture, location, length, and the surgeon’s preference and experience level. Shorter strictures are amenable to endoscopic treatment or excision and anastomosis, whereas longer defects require augmentation with oral mucosa grafts or fasciocutaneous flaps. However, clinical scenarios exist whereby the typical buccal mucosa graft or fasciocutaneous flap is insufficient for urethral reconstruction.
Current practice of urethral reconstruction places a premium on buccal mucosa grafts, but additional grafts are available to use as an alternative or adjunct in complex cases, particularly pan-urethral strictures, recurrent strictures when buccal mucosa has been previously harvested, or in patients in whom retrieval of oral mucosa in contraindicated. Buccal mucosa has enjoyed such success that many of the original grafts for urethroplasty, such as extragenital skin, have fallen out of favor. Despite the decreased utilization of skin grafts, the principles of this technique should be continually revisited for inspiration and innovation toward new approaches. Furthermore, tissue engineering and stem cell therapies are promising opportunities to provide off-the-shelf grafts that would preclude the invasiveness and morbidity of tissue harvest for urethral reconstruction.
Injectables
Although open urethroplasty is the gold standard for treatment of anterior urethral strictures, endoscopic management offers options that are less invasive and can be effective in highly selected patients. Current endoscopic treatments achieve inferior outcomes to open repair, so any improvements in endoscopic platforms that could open this treatment to a broader patient base are intriguing. In addition to stricture incision, multiple antifibrotic medications have been used in attempt to reduce scar formation and inhibit tissue contraction.
Combination of the traditional direct vision internal urethrotomy (DVIU) with topical application or injection of an antiproliferative agent has been evaluated for minimally invasive stricture treatment. Antifibrotic agents, including steroids (triamcinolone), mitomycin C (MMC), and hyaluronidase, have all been used to reduce stricture recurrence. The antifibrotic and anticollagen properties of steroids are well documented, and injectable forms are used in treatment of various fibrosis-induced pathologies. MMC has been shown to inhibit cellular proliferation and collagen deposition during scar formation in both in vitro and animal studies. Additionally, MMC has been used clinically for pathologies ranging from nasolacrimal duct obstruction and to vaginal and anal stenosis. Hyaluronidase also possesses antifibrotic properties and has shown benefits in treatment of pulmonary fibrosis, hypertrophic scars, and keloids. Its function is achieved by suppression of fibroblast synthesis of collagen and glycosaminoglycan, which are necessary building blocks for scar formation. Although these agents have a clear theoretic and clinical role for scar management, there are few high-quality studies examining the efficacy of injected antiproliferative agents for anterior urethral strictures.
Triamcinolone has the most published experience, with trials of injected and catheter-coated topical administration dating back to the 1960s. Urethrotomy followed by triamcinolone injection has been shown to be safe and moderately effective. Two small randomized controlled trials evaluated the effect of triamcinolone following urethrotomy for short bulbar strictures (<1.5 cm). Mazdak and colleagues reported stricture recurrence in 21.7% of the triamcinolone group versus 50.0% of the control cohort at a follow-up of 14 months. Meanwhile, Tavakkoli and colleagues reported a lower number of recurrences in the triamcinolone group, but this finding was not statistically significant. A meta-analysis of 8 studies covering 203 patients showed no benefit for catheter-introduced steroids following DVIU, but steroid injection prolonged the time to stricture recurrence.
MMC is also gaining attention as an injectable antiscar agent. The first randomized controlled trial to study MMC following DVIU in short bulbar urethral strictures found a recurrence rate of 10% in the MMC group compared with 50% for DVIU alone. Of note, this study only included 40 total patients and had relatively short follow-up (range 6–24 months). These findings were supported by a recent randomized controlled trial that compared DVIU with MMC to DVIU alone in 151 patients with traumatic anterior urethral strictures measuring up to 2 cm in length. The patients were then followed with retrograde urethrography at 3-month intervals for 18 months. Stricture recurrence was identified in 14% of the MMC group compared with 37% of the control group ( P = .002), and the time to recurrence was 3 months longer in patients treated with MMC ( P = .002).
Although hyaluronic acid has shown antifibrotic effects in animal models, there has been minimal experience in humans. One randomized controlled trial examined the effect of hyaluronic acid and carboxymethylcellulose urethral instillation after DVIU. The experimental group had a significantly lower recurrence rate than controls (9.4% vs 22.9%). These patients were only followed for 6 months, and more data are needed before definitive conclusions can be made for this treatment.
Injection of all 3 drugs simultaneously has also been proposed to reduce stricture recurrence following DVIU. A mixture of 40 mg triamcinolone, 2 mg MMC, and 3000 units of hyaluronic acid were injected into 103 patients with bulbar and penile urethral strictures with no control group. Following one procedure, strictures recurred in 19.4% of cases at a median follow-up of 14 months (range 3–18 months). However, the validity of this study is in question as the lack of a control group precludes any definitive evaluation of this technique.
Other injectable therapies for anterior urethral stricture are in the nascent phase of investigation. Medications that have proven safe and effective for other urologic pathologies are being trialed for urethral stricture. Botox injection following DVIU was reported with modest improvement in short follow-up on 3 patients. Additionally, collagenase Clostridium histolyticum , an injectable therapy for dissolution of Peyronie disease plaques, showed reduction in collagen expression and fibrosis in a rat model of urethral stricture. Animal models have also tested the treatment of urethral strictures with topical bevacizumab, 5-fluorouracil, and halofuginone with promising early results.
Antifibrotic injectables have been steadily growing since their introduction almost 50 years ago, with new agents being continually explored. More rigorous clinical trials to evaluate long-term outcomes and with more clearly defined stricture recurrence criteria are needed to confirm results compared with traditional treatments and to identify optimal patients for endoscopic management. Once the role for injectable treatments is more clearly delineated, their widespread use could allow more patients to avoid the morbidity of open reconstruction.
Alternative grafts
Placement of tissue grafts to enlarge or replace the urethral lumen is a long-standing practice for urethral reconstruction. Skin grafts or flaps were some of the original tissues used for urethral reconstruction, but several new sources of graft material have arisen over the past decades. Options include lingual mucosal grafts, bladder epithelium, colonic mucosa, and tissue-engineered grafts, which can all be used for urethroplasty in complex cases.
Genital and Extragenital Skin
Urethral reconstruction with penile skin was first described by Presman and Greenfield in 1953 and gained prominence with preputial skin grafting for hypospadias repair. Penile skin can be deployed as either a flap or graft, which achieve similar efficacy for urethral reconstruction. However, there is significantly less morbidity with the use of grafts, namely, reduced penile skin necrosis and penile torsion. Harvesting well-vascularized penile skin flaps is technically challenging; thus, full-thickness skin grafts have gained the favor of reconstructive surgeons. Genital and extragenital skin grafts are less common in the era of buccal mucosa urethroplasty, but they still play a key role in urethral reconstruction. Although skin grafts should be avoided in patients with lichen sclerosus, they can provide long tissue segments when buccal mucosa has been damaged by tobacco, radiation, or oral leukoplakia or for cases whereby oral mucosa has previously been harvested. Penile skin has the benefits of being elastic, well-vascularized tissue that is devoid of hair. Graft harvest from the penis is relatively straightforward and results in minimal morbidity. A meta-analysis comparing penile skin versus buccal mucosa for urethral reconstruction reported improved outcomes in the buccal mucosa group, achieving 85.9% success compared with 81.8% for penile skin graft ( P = .01). However, it should be noted that the penile skin graft group had an average follow-up almost 2 years longer (64 months skin versus 42 months) and longer stricture length (6.2 cm versus 4.6 cm) than the buccal mucosa cohort. To examine the long-term outcomes of oral mucosa or penile skin graft urethroplasty, Barbagli and colleagues recently published a series of 359 patients followed for a minimum of 6 years. They found a 59.7% success rate for penile skin grafts versus 77.7% for oral mucosa grafts. Furthermore, penile skin grafts were a significant predictor of graft failure on multivariate analysis, even when adjusting for age, stricture length, cause, and previous treatments.
Postauricular skin can serve as an alternative full-thickness graft when oral mucosa and genital skin are inadequate or unavailable for urethroplasty. The best tissue for harvest is located along the lower half of the mastoid and posterior to the tragus, which can yield a graft measuring up to 8 cm from each side. Manoj and colleagues performed anterior urethroplasty on 35 patients and achieved an 89% success rate after 21 months of follow-up. They reported no donor-site complications. For 2-stage hypospadias repairs, Nitkunan and colleagues reported a 97% success rate for graft uptake, with the single failure resulting from keloid formation on the graft, identifying a complication unique to skin grafts. The donor site of this graft is easily visible, and when harvesting this tissue every attempt should be made to maximize cosmesis.
Abdominal skin can also provide full-thickness skin graft for urethral reconstruction. Optimal abdominal skin is located along the flank and lower abdomen, where there are fewer hair follicles. This graft also should be used for patients who have no signs of lichen sclerosus and who lack adequate oral mucosa. It has proven useful as an adjunct to buccal mucosa, as exemplified by Chen and colleagues who combined a dorsal full-thickness abdominal skin graft with ventral buccal mucosa graft for complex bulbar urethral strictures. For patients with strictures greater than 6 cm, they achieved a 100% success rate. In contrast, Liu and colleagues reported on a group of 26 men treated with abdominal wall skin grafts versus 213 treated with other grafts over a median of 59 months of follow-up. The recurrence rate was 53% for the abdominal wall grafts compared with 24% for the others. Multivariate analysis of this cohort identified lichen sclerosus and prior urethroplasty as predictors of recurrence. Although graft type did not predict recurrence in this study, the use of abdominal skin in patients with lichen sclerosus likely influences the poor outcomes observed in these patients. Further studies are needed to elucidate the role of abdominal skin grafts as stand-alone or combination grafts in urethral reconstruction.
Although the original skin grafts were harvested as full-thickness sections, split-thickness skin grafts with mesh support offer a modified approach to skin grafting for augmentation urethroplasty. Schreiter and Noll promoted 2-stage urethral reconstruction with these grafts for patients with long complex strictures and severe spongiofibrosis. Long-term success has been reported as 79% at 6.5 years, even in highly complex strictures. Furthermore, use of meshed grafts cause minimal complications, reporting erectile dysfunction in 4% and penile curvature in 9% of patients following 2-stage urethroplasty. In the current era of buccal mucosa urethroplasty, skin grafts account for a small percentage of overall reconstruction; but they can prove useful in place of or in conjunction with oral grafts for the most complex urethral strictures.
Lingual Grafts
The biological qualities of oral mucosa, including adaptation to a fluid environment and relative resistance to lichen sclerosus, make it ideal for augmentation urethroplasty. Clinical data regarding lingual mucosa grafts are not as extensive as for buccal mucosa, but the similar anatomic and physiologic characteristics make lingual grafts similarly appealing. Both grafts display a thick epithelial layer with thin lamina propria and a robust, pan-laminar vascular bed, which facilitates graft take and minimizes contracture. Because of the similar architecture, lingual mucosa can serve as an ideal substitute when buccal mucosa has already been harvested or as an additional graft for repair of long defects.
Harvest of lingual grafts is equally straightforward as buccal mucosa. The mucosa is readily accessible, can produce 2 grafts from 7 to 16 cm long, and leaves no visible scar at the harvest site. The lateral and ventral surfaces of the tongue can be used as individual grafts or a combination of both sections when larger segments are required. While procuring the graft, the appropriate plane of dissection is between the mucosa and submucosal fat. Identifying the Wharton duct and the lingual nerve as well as the floor of the mouth is critical, as scarring in these sites will reduce tongue mobility postoperatively. Before use, the fibrovascular tissue underlying the graft should be manually removed to help with graft take. Closure of the harvest site with an absorbable suture achieves optimal healing.
Urethral reconstruction with lingual grafts can be performed in the same manner as any urethral reconstruction; with both one-stage (dorsal onlay, dorsal inlay, ventral onlay) or 2-stage approaches a viable option. The studies examining lingual mucosal grafting for urethral reconstruction are summarized in Table 1 . Success rates ranged from 79% to 96%, but most of these studies encompass small numbers with short follow-up. Abdelhameed and colleagues measured the long-term outcomes of lingual grafts in 23 patients, showing 87% freedom from restricture at 66 months of follow-up. Of note, the stricture cause and surgical techniques were heterogeneous in these studies; longer follow-up is needed to determine the long-term outcomes of this graft. Four groups undertook randomized comparisons of lingual versus buccal grafts, shown in Table 2 . Three of them showed comparable success rates between buccal and lingual grafts, but the largest comparison completed by Chauhan and colleagues found lingual grafts superior to buccal grafts with 80% and 69% success, respectively, at 25 months.
| Author | No. of Patients | Average Follow-up (mo) | Stricture Length | Surgical Technique | Success (Definition of Success) | Complications |
|---|---|---|---|---|---|---|
| Simonato et al, 2008 | 29 | 17.7 | 3.6 cm | 1- or 2-Stage onlay | 79.3%, No repeat intervention | None reported |
| Barbagli et al, 2008 | 10 | 5 | 4.5 cm | Dorsal inlay or ventral onlay | 90%, No repeat intervention | Urethrocutaneous fistula (10%) |
| Xu et al, 2010 | 92 | 17 (3–33) | 6.5 cm (2.5–18.0) | 50 Dorsal onlay, 42 tubularized substitute | 96%, No stricture recurrence or need for procedure | Urethrocutaneous fistula (4%) |
| Das et al, 2009 | 30 | 9 (4–12) | 10.2 cm (3.7–16.0) | Dorsal onlay | 83.3%, No repeat instrumentation and peak flow >15 mL/s | Wound infection (7%), extravasation (17%), temporary chordae (3%) |
| Sharma et al, 2010 | 15 | 12 | 2.45 cm | Dorsal onlay | 93%, No postoperative instrumentation | None reported |
| Abdelhameed et al, 2015 | 23 | 66 (60–72) | 4.6 cm | 15 Dorsal onlay, 8 ventral onlay | 87%, No restricture on RUG, no postoperative instrumentation | Wound infection (17%), extravasation (4%), oral numbness (39%), postvoid dribbling (13%) |
| Li et al, 2016 | 56 | 34.7 (10–58) | 5.6 cm ±1.6 | 42 Ventral onlay, 14 Snodgrass inlay | 78.6%, No restricture or fistula | Urethrocutaneous fistula (12.5%), neourethral stricture (9%), meatal stenosis (4%) |
| Author | No. BMG | No. LMG | Avg F/U (Range) | Avg Stricture Length (Range) | Success (Definition of Success) |
|---|---|---|---|---|---|
| Sharma et al, 2013 | 15 | 15 | 14.5 mo | 8.1 cm | 86.7% BMG vs 93.3% LMG No stricture on urethroscopy, flow >15 mL/s |
| Chauhan et al, 2016 | 52 | 50 | 25.0 mo | 6.5 cm (3.2–13.5) | 69.2% BMG vs 80.0% LMG No obstructive voiding or instrumentation |
| Lumen et al, 2016 | 29 | 29 | 30.0 mo (17–43) | 5.0 cm (1–18) | 82.8% BMG vs 89.7% LMG No stricture, fistula, or urethral manipulation |
| Maarouf et al, 2013 | 23 | 21 | 20.8 mo (12–24) | 6.8 cm | 78.2% BMG vs 76.1% LMG No postoperative procedure |
Lingual mucosa grafts can be especially useful in patients with lichen sclerosus, who are prone to long and recurrent strictures. Some pan-urethral strictures are longer than the available buccal mucosa is able to repair, whereas others will have recurrence of their stricture after bilateral buccal graft urethroplasty and need subsequent reconstruction. Das and colleagues reported short-term outcomes on 30 patients undergoing lingual mucosa urethroplasty, of whom 18 had lichen sclerosus. Their overall success rate was 83.3% with an average follow-up of 9 months. Furthermore, Xu and colleagues analyzed one-stage lingual mucosa grafting, specifically in patients with lichen sclerosus–induced strictures averaging 12.5 cm in length. They also reported positive results, achieving 90.9% success rate in 22 patients with lichen sclerosus with 38 months of follow-up.
Although lingual mucosa has notable positive characteristics, its use does may cause appreciable patient morbidity. Several studies have specifically investigated postoperative pain and disability at the harvest site. Pain in the mouth was mostly limited to the first 1 to 2 days, and all patients were pain free by postoperative day 6. As would be expected, bilateral lingual graft harvest caused a slight increase in postoperative pain. Also of note, harvest of lingual grafts longer than 7 cm or bilateral grafts was more likely to cause long-term speech changes. Lumen and colleagues compared the postoperative morbidity of lingual versus buccal graft harvest and found that the functional impairment (ie, difficulty eating or speaking) were higher in lingual grafts through the first 2 weeks postoperatively, but there was no difference in long-term sequelae between the two groups. Graft-site morbidity for studies comparing buccal and lingual mucosa grafts is compiled in Table 3 .
| Early Postoperative (<1 wk) | Intermediate Postoperative (3–6 mo) | Late Postoperative (1 y) | ||||
|---|---|---|---|---|---|---|
| Buccal Graft | Lingual Graft | Buccal Graft | Lingual Graft | Buccal Graft | Lingual Graft | |
| Bleeding | 6/67 (9%) | 9/65 (14%) | 0/67 (0%) | 0/65 (0%) | 0/67 (0%) | 0/65 (0%) |
| Oral pain | 72/104 (69%) | 40/100 (40%) | 1/81 (1%) | 0/79 (0%) | 0/67 (0%) | 0/65 (0%) |
| Mouth tightness | 68/90 (76%) | 23/86 (27%) | 13/94 (14%) | 2/94 (2%) | 0/67 (0%) | 0/65 (0%) |
| Speech difficulty | 50/119 (42%) | 84/115 (73%) | 12/94 (13%) | 14/94 (15%) | 0/67 (0%) | 4/65 (6%) |
| Altered sensation | 88/119 (74%) | 52/115 (45%) | 25/117 (21%) | 12/115 (10%) | 2/67 (3%) | 0/65 (0%) |
| Difficulty chewing | 54/96 (56%) | 57/94 (61%) | 22/94 (23%) | 12/94 (13%) | 0/67 (0%) | 0/65 (0%) |
| Reduced tongue protrusion | 5/38 (13%) | 36/36 (100%) | 0/15 (0%) | 3/15 (20%) | 0/67 (0%) | 2/65 (3%) |
Related posts:
Management of Urethral Strictures
Definition of Successful Treatment and Optimal Follow-up after Urethral Reconstruction for Urethral Stricture Disease
Cost-effective Strategies for the Management and Treatment of Urethral Stricture Disease
The Nontransecting Approach to Bulbar Urethroplasty
Management of Panurethral Stricture
Effect of Lichen Sclerosis on Success of Urethroplasty
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