New Frontiers in Urethral Reconstruction
While the success rate of both grafts and penile skin flaps has been established in the literature to be of similar efficacy, there is also significantly higher morbidity associated with the use of such flaps. The increased complexity in harvesting penile skin flaps requires technical expertise and has resulted in the use of full thickness grafts as the augmentation tissue of choice among reconstructive surgeons. There are a number of alternative grafts that can be effectively implemented into the reconstructive urologist's armamentarium for use in particularly complex cases, when there is insufficient buccal mucosa available for augmentation urethroplasty. Lingual grafts, penile and extragenital skin, bladder epithelium, small intestinal submucosa, colonic mucosa, and tissue engineered grafts are all existing potential sources of graft material for patients needing additional tissue for augmentation urethroplasty.
Oral mucosa grafts are the standard grafting material for augmentation urethroplasty as they are accustomed to being wet, and may be resistant to lichen sclerosis. While there is little data regarding lingual mucosa grafts, the characteristics that make buccal mucosa appealing apply to lingual mucosa grafts as well. These full thickness grafts have a thick epithelium, thin lamina propria, and rich, panlaminar vascular plexus, which allows excellent graft take with minimal contracture. The macroscopic architecture of these grafts is identical to buccal mucosa, making this the graft of choice when additional material is needed.
There are notable advantages to harvesting lingual grafts. They are readily available for harvest, have a concealed donor site scar, and can yield two grafts ranging between 7 and 16 cm in length. During graft harvesting, care is taken to dissect between the mucosa and submucosal fat. Both Wharton's duct and the lingual nerve are identified, and care is taken to avoid harvesting mucosa from the floor of the mouth to maintain tongue mobility. Lingual grafts can be harvested from any of three locations on the tongue, the lateral surface, ventral surface, or both the ventral and lateral surface. Harvesting from the ventral location allows the potential for two grafts to be harvested if necessary. After graft harvest, the donor site is closed with absorbable suture and the graft prepared by removing the underlying fibrovascular tissue.
The urethroplasty techniques used with lingual mucosa grafts are similar to buccal grafts, with published reports of one-stage dorsal onlay, dorsal inlay, ventral onlay grafts, as well as a two-stage approach. The short-term outcomes of lingual mucosa grafts appear to be equivalent to buccal mucosa, although there are only a few published reports in the literature. Sharma et al. performed a prospective comparative analysis of lingual mucosa grafts compared to buccal mucosa grafts in 30 patients who underwent a dorsal onlay urethroplasty. The stricture free outcomes were similar at a mean follow-up of 14.5 months. Additionally, there have been a few additional small studies demonstrating success rates of 79–90% with lingual grafts. However the stricture etiology and surgical techniques were heterogeneous in these small studies and follow-up was less than 2 years. Lingual mucosa grafts are an excellent graft material for patients with long strictures due to lichen sclerosis, when there may be an inadequate amount of buccal mucosa available. Das et al. was the first to describe short-term results in 18 patients with lichen sclerosis, and demonstrated an 83.3% success rate in patients with a mean stricture length of 10.2 cm. Similarly, Xu et al. described their experience with one-stage lingual mucosa grafts in 22 patients with lichen sclerosis strictures and demonstrated an 88.9% success rate (mean stricture length 12.5 cm) with a mean follow-up of 38.7 months.
One of the important factors needing validation is the donor site morbidity associated with lingual mucosa harvest. It appears from the small number of studies published, that complications are rare. Initial reports by Simonato et al. reported that patients only complained of slight donor sight pain for 1–2 days, while Das et al. found minimal complications with no functional or esthetic deficiency. Kumar et al. found that all patients were pain free by 6 days, while in patients with bilateral tongue harvest, they temporarily had a higher rate of slurred speech. Sharma et al. published donor site morbidity with long-term changes in speech in patients who underwent bilateral lingual harvest for strictures >7 cm.
Lingual grafts represent an excellent choice as an alternative graft to buccal mucosa in patients requiring long-segment substitution urethroplasty, in patients who have previously had buccal mucosa harvest, or in patients in whom cheek harvest would otherwise be contraindicated. While lingual grafts share all the important characteristics of buccal mucosa, the long-term outcomes of lingual grafts have not been established, as the longest follow-up published to date is 38.7 months. Additionally, while harvesting lingual grafts appears safe, the optimal graft size and location on the tongue has not been established to minimize potential long-term morbidity.
While skin grafts are certainly not a "New frontier" in urethral reconstruction, there is an important use in modern urethral reconstruction for these grafts in patients without lichen sclerosis. Substitution urethroplasty with a penile skin graft was first described in 1953 by Presman and Greenfield, and was ultimately promoted by Devine and Horton using preputial skin for hypospadias repairs. Although the use of penile and extragenital skin grafts has been declining since early 1990s, the use of full thickness skin grafts remains an integral part of the reconstructive urologist's armamentarium. Certain conditions exist which ideally suit the harvest of skin (oral leukoplakia, heavy tobacco use, chewing tobacco, betel nut or pan masala, previous oral radiotherapy, previous oral mucosa grafting, insufficient oral mucosa) for substitution urethroplasty. Penile skin grafts are hairless, elastic, and easy to harvest with minimal donor site morbidity. A recent meta-analysis be Lumen et al. comparing urethral reconstruction with either a penile skin or buccal mucosa demonstrated a success rate of 81.8% vs. 85.9% respectively, P=0.01. The long-term durability of penile skin grafts could not be assessed in this analysis, as the follow-up was only 64 months. However, a recent publication by Barbagli et al. demonstrated the long-term outcomes of 359 patients who had either an oral mucosa or penile skin graft urethroplasty. With a minimum follow-up of 6 years, patients with penile skin grafts had a success rate of 59.7% as compared to 77.7% of patients with an oral mucosa graft.
Postauricular skin is a full thickness graft that can be used for the treatment of anterior urethral strictures when oral mucosa and genital skin are not available. The skin is harvested from the lower half of the mastoid, and should not cross beyond the lower end of the tragus. Manoj et al. has demonstrated the ability to harvest 7–8 cm of full-thickness graft per side, allowing 14–16 cm of graft material if necessary. In 35 patients with a follow-up of 21 months, they demonstrated an 89% success rate, and reported no donor site complications. If harvesting this graft, consideration of the donor site scar should be taken into consideration.
Abdominal skin is another full-thickness skin graft alternative to postauricular skin. This graft should be taken from a hairless area in either the flank or right or left lower quadrant, near the level of the anterior iliac spine. The donor site is closed and the graft prepared by removing all the areolar tissue. The indications for use are similar to postauricular grafts, namely patients without lichen sclerosis in whom oral mucosa and genital skin are not available. A potential use of full thickness skin was described Chen et al. who used a combination of full-thickness skin grafts dorsally in combination with ventral buccal mucosa graft for long segment strictures and reported a 100% success rate in patients with strictures >6 cm with the double graft technique. Further evaluation and longer follow-up will be needed to confirm the preliminary findings of this study.
Another extragenital skin graft option for the treatment of particularly complex, long strictures with severe spongiofibrosis is the use of a meshed split-thickness skin graft. Popularized by Schreiter, these grafts are used in a two-stage approach. In expert hands, these grafts perform exceedingly well in the most complex of cases, with a 79% success rate at 6.5 years follow-up. The overall complication rate with a two stage meshed graft urethroplasty is low, with erectile dysfunction and penile curvature rates reported to occur in 4% and 9% of patients respectively. While these grafts were used before the modern era of buccal mucosa, they currently represent a tiny fraction of urethroplasties performed. However, the mesh graft technique is a useful alternative for the most complex urethral stricture.
Bladder mucosa is a free graft that is available and has been used primarily in the setting of hypospadias surgery. This graft has fallen out of favor both because of the invasive nature of harvest required to obtain the graft, as well as the high rate of stricture recurrence. In particular, meatal problems occur in up to 68% of patients when the graft was exposed to air, and up to 66% of patients required multiple operations to achieve a good result.
While Mundy et al. has described the successful use of intestinal flaps as a salvage procedure for bulbomembranous urethral strictures, colonic mucosa has also been used as a circumferential graft in patients with long segment urethral strictures. Xu et al. reported an 85.7% success rate in 36 patients with a follow-up of 53.6 months (mean stricture length 15.1 cm). However, these patients all underwent a sigmoid resection in order to obtain the graft, raising questions about the practicality of such a technique. We have found that retrieving colonic mucosa for salvage urethroplasty is possible without a bowel resection with a transanal endoscopic micro-surgical technique (TEMS) (Figures 4–8). The TEMS technique was developed by colorectal surgeons for the minimally invasive treatment of early stage rectal tumors and benign polyps high in the rectum (up to 20 cm). We have successfully performed this technique safely in four patients for salvage urethroplasty, with no perioperative complications (Vanni and Zinman unpublished data). At a mean follow-up 13 months (range, 5–19 months), three of the four patients have had a successful outcome, while one patient has required a urethral dilation for recurrent stricture. All four patients have normal bowel function. However, larger patient numbers and long-term follow-up will be important in determining what, if any, role colonic mucosa has in salvage urethroplasty.
(Enlarge Image)
Figure 4.
Recurrent lichen sclerosis in previous 1 stage buccal mucosa graft.
(Enlarge Image)
Figure 5.
TEMS instruments. TEMS, transanal endoscopic micro-surgical technique.
(Enlarge Image)
Figure 6.
TEMS setup. TEMS, transanal endoscopic micro-surgical technique.
(Enlarge Image)
Figure 7.
Colonic mucosa grafts prior to preparation.
(Enlarge Image)
Figure 8.
Ventral colonic graft onlay.
There is great promise in the field of tissue engineering for the development of an off the shelf graft suitable for urethral reconstruction. While oral mucosa grafts are readily available and adequate for the vast majority of strictures, alternative grafts are needed in the most complex cases. Small intestinal submucosa is a prefabricated, acellular, collagen matrix manufactured from porcine intestinal submucosa. Initial, short-term results in two pilot studies demonstrated success rates between 90–100%. However, at longer follow-up in 25 patients, success was 86% for strictures <4 cm, while in strictures >4 cm no patient had a successful reconstruction. Much research has been performed trying to identify the best scaffold and cell for replacing strictures of the urethra. Autologous tissue engineered buccal mucosa is a promising substitute, and in a pilot study of five patients, all had an initial good result, and at 3 years follow-up, three of the patients had patent urethras. Additionally, synthetic scaffolds have been studied as an off the shelf alternative to human or animal collagen scaffolds. In a study by Raya-Rivera et al., five boys had muscle and epithelial cells seeded onto tubularized polyglycolic acid:poly (lactide-co-glycolide acid) scaffolds. Patients then underwent urethral reconstruction of the tubularized urethras. At a median follow-up of 71 months, all patients had a patent urethra.
Although there has been a tremendous amount of basic science and animal research for tissue engineered grafts, few platforms have advanced to human clinical trial. The problem for any graft in treating a complex urethral stricture is related to the issues of ischemia, fibrosis, and wound contracture. Further study is needed to better elucidate the optimal scaffolds and cell sources to overcome the inherent issues of tissue fibrosis associated with complex urethral strictures.
Alternative Grafts
While the success rate of both grafts and penile skin flaps has been established in the literature to be of similar efficacy, there is also significantly higher morbidity associated with the use of such flaps. The increased complexity in harvesting penile skin flaps requires technical expertise and has resulted in the use of full thickness grafts as the augmentation tissue of choice among reconstructive surgeons. There are a number of alternative grafts that can be effectively implemented into the reconstructive urologist's armamentarium for use in particularly complex cases, when there is insufficient buccal mucosa available for augmentation urethroplasty. Lingual grafts, penile and extragenital skin, bladder epithelium, small intestinal submucosa, colonic mucosa, and tissue engineered grafts are all existing potential sources of graft material for patients needing additional tissue for augmentation urethroplasty.
Lingual Grafts
Oral mucosa grafts are the standard grafting material for augmentation urethroplasty as they are accustomed to being wet, and may be resistant to lichen sclerosis. While there is little data regarding lingual mucosa grafts, the characteristics that make buccal mucosa appealing apply to lingual mucosa grafts as well. These full thickness grafts have a thick epithelium, thin lamina propria, and rich, panlaminar vascular plexus, which allows excellent graft take with minimal contracture. The macroscopic architecture of these grafts is identical to buccal mucosa, making this the graft of choice when additional material is needed.
There are notable advantages to harvesting lingual grafts. They are readily available for harvest, have a concealed donor site scar, and can yield two grafts ranging between 7 and 16 cm in length. During graft harvesting, care is taken to dissect between the mucosa and submucosal fat. Both Wharton's duct and the lingual nerve are identified, and care is taken to avoid harvesting mucosa from the floor of the mouth to maintain tongue mobility. Lingual grafts can be harvested from any of three locations on the tongue, the lateral surface, ventral surface, or both the ventral and lateral surface. Harvesting from the ventral location allows the potential for two grafts to be harvested if necessary. After graft harvest, the donor site is closed with absorbable suture and the graft prepared by removing the underlying fibrovascular tissue.
The urethroplasty techniques used with lingual mucosa grafts are similar to buccal grafts, with published reports of one-stage dorsal onlay, dorsal inlay, ventral onlay grafts, as well as a two-stage approach. The short-term outcomes of lingual mucosa grafts appear to be equivalent to buccal mucosa, although there are only a few published reports in the literature. Sharma et al. performed a prospective comparative analysis of lingual mucosa grafts compared to buccal mucosa grafts in 30 patients who underwent a dorsal onlay urethroplasty. The stricture free outcomes were similar at a mean follow-up of 14.5 months. Additionally, there have been a few additional small studies demonstrating success rates of 79–90% with lingual grafts. However the stricture etiology and surgical techniques were heterogeneous in these small studies and follow-up was less than 2 years. Lingual mucosa grafts are an excellent graft material for patients with long strictures due to lichen sclerosis, when there may be an inadequate amount of buccal mucosa available. Das et al. was the first to describe short-term results in 18 patients with lichen sclerosis, and demonstrated an 83.3% success rate in patients with a mean stricture length of 10.2 cm. Similarly, Xu et al. described their experience with one-stage lingual mucosa grafts in 22 patients with lichen sclerosis strictures and demonstrated an 88.9% success rate (mean stricture length 12.5 cm) with a mean follow-up of 38.7 months.
One of the important factors needing validation is the donor site morbidity associated with lingual mucosa harvest. It appears from the small number of studies published, that complications are rare. Initial reports by Simonato et al. reported that patients only complained of slight donor sight pain for 1–2 days, while Das et al. found minimal complications with no functional or esthetic deficiency. Kumar et al. found that all patients were pain free by 6 days, while in patients with bilateral tongue harvest, they temporarily had a higher rate of slurred speech. Sharma et al. published donor site morbidity with long-term changes in speech in patients who underwent bilateral lingual harvest for strictures >7 cm.
Lingual grafts represent an excellent choice as an alternative graft to buccal mucosa in patients requiring long-segment substitution urethroplasty, in patients who have previously had buccal mucosa harvest, or in patients in whom cheek harvest would otherwise be contraindicated. While lingual grafts share all the important characteristics of buccal mucosa, the long-term outcomes of lingual grafts have not been established, as the longest follow-up published to date is 38.7 months. Additionally, while harvesting lingual grafts appears safe, the optimal graft size and location on the tongue has not been established to minimize potential long-term morbidity.
Genital and Extragenital Skin
While skin grafts are certainly not a "New frontier" in urethral reconstruction, there is an important use in modern urethral reconstruction for these grafts in patients without lichen sclerosis. Substitution urethroplasty with a penile skin graft was first described in 1953 by Presman and Greenfield, and was ultimately promoted by Devine and Horton using preputial skin for hypospadias repairs. Although the use of penile and extragenital skin grafts has been declining since early 1990s, the use of full thickness skin grafts remains an integral part of the reconstructive urologist's armamentarium. Certain conditions exist which ideally suit the harvest of skin (oral leukoplakia, heavy tobacco use, chewing tobacco, betel nut or pan masala, previous oral radiotherapy, previous oral mucosa grafting, insufficient oral mucosa) for substitution urethroplasty. Penile skin grafts are hairless, elastic, and easy to harvest with minimal donor site morbidity. A recent meta-analysis be Lumen et al. comparing urethral reconstruction with either a penile skin or buccal mucosa demonstrated a success rate of 81.8% vs. 85.9% respectively, P=0.01. The long-term durability of penile skin grafts could not be assessed in this analysis, as the follow-up was only 64 months. However, a recent publication by Barbagli et al. demonstrated the long-term outcomes of 359 patients who had either an oral mucosa or penile skin graft urethroplasty. With a minimum follow-up of 6 years, patients with penile skin grafts had a success rate of 59.7% as compared to 77.7% of patients with an oral mucosa graft.
Postauricular skin is a full thickness graft that can be used for the treatment of anterior urethral strictures when oral mucosa and genital skin are not available. The skin is harvested from the lower half of the mastoid, and should not cross beyond the lower end of the tragus. Manoj et al. has demonstrated the ability to harvest 7–8 cm of full-thickness graft per side, allowing 14–16 cm of graft material if necessary. In 35 patients with a follow-up of 21 months, they demonstrated an 89% success rate, and reported no donor site complications. If harvesting this graft, consideration of the donor site scar should be taken into consideration.
Abdominal skin is another full-thickness skin graft alternative to postauricular skin. This graft should be taken from a hairless area in either the flank or right or left lower quadrant, near the level of the anterior iliac spine. The donor site is closed and the graft prepared by removing all the areolar tissue. The indications for use are similar to postauricular grafts, namely patients without lichen sclerosis in whom oral mucosa and genital skin are not available. A potential use of full thickness skin was described Chen et al. who used a combination of full-thickness skin grafts dorsally in combination with ventral buccal mucosa graft for long segment strictures and reported a 100% success rate in patients with strictures >6 cm with the double graft technique. Further evaluation and longer follow-up will be needed to confirm the preliminary findings of this study.
Another extragenital skin graft option for the treatment of particularly complex, long strictures with severe spongiofibrosis is the use of a meshed split-thickness skin graft. Popularized by Schreiter, these grafts are used in a two-stage approach. In expert hands, these grafts perform exceedingly well in the most complex of cases, with a 79% success rate at 6.5 years follow-up. The overall complication rate with a two stage meshed graft urethroplasty is low, with erectile dysfunction and penile curvature rates reported to occur in 4% and 9% of patients respectively. While these grafts were used before the modern era of buccal mucosa, they currently represent a tiny fraction of urethroplasties performed. However, the mesh graft technique is a useful alternative for the most complex urethral stricture.
Bladder Mucosa
Bladder mucosa is a free graft that is available and has been used primarily in the setting of hypospadias surgery. This graft has fallen out of favor both because of the invasive nature of harvest required to obtain the graft, as well as the high rate of stricture recurrence. In particular, meatal problems occur in up to 68% of patients when the graft was exposed to air, and up to 66% of patients required multiple operations to achieve a good result.
Colonic Mucosa
While Mundy et al. has described the successful use of intestinal flaps as a salvage procedure for bulbomembranous urethral strictures, colonic mucosa has also been used as a circumferential graft in patients with long segment urethral strictures. Xu et al. reported an 85.7% success rate in 36 patients with a follow-up of 53.6 months (mean stricture length 15.1 cm). However, these patients all underwent a sigmoid resection in order to obtain the graft, raising questions about the practicality of such a technique. We have found that retrieving colonic mucosa for salvage urethroplasty is possible without a bowel resection with a transanal endoscopic micro-surgical technique (TEMS) (Figures 4–8). The TEMS technique was developed by colorectal surgeons for the minimally invasive treatment of early stage rectal tumors and benign polyps high in the rectum (up to 20 cm). We have successfully performed this technique safely in four patients for salvage urethroplasty, with no perioperative complications (Vanni and Zinman unpublished data). At a mean follow-up 13 months (range, 5–19 months), three of the four patients have had a successful outcome, while one patient has required a urethral dilation for recurrent stricture. All four patients have normal bowel function. However, larger patient numbers and long-term follow-up will be important in determining what, if any, role colonic mucosa has in salvage urethroplasty.
(Enlarge Image)
Figure 4.
Recurrent lichen sclerosis in previous 1 stage buccal mucosa graft.
(Enlarge Image)
Figure 5.
TEMS instruments. TEMS, transanal endoscopic micro-surgical technique.
(Enlarge Image)
Figure 6.
TEMS setup. TEMS, transanal endoscopic micro-surgical technique.
(Enlarge Image)
Figure 7.
Colonic mucosa grafts prior to preparation.
(Enlarge Image)
Figure 8.
Ventral colonic graft onlay.
Acellular Matrix/Tissue Engineering
There is great promise in the field of tissue engineering for the development of an off the shelf graft suitable for urethral reconstruction. While oral mucosa grafts are readily available and adequate for the vast majority of strictures, alternative grafts are needed in the most complex cases. Small intestinal submucosa is a prefabricated, acellular, collagen matrix manufactured from porcine intestinal submucosa. Initial, short-term results in two pilot studies demonstrated success rates between 90–100%. However, at longer follow-up in 25 patients, success was 86% for strictures <4 cm, while in strictures >4 cm no patient had a successful reconstruction. Much research has been performed trying to identify the best scaffold and cell for replacing strictures of the urethra. Autologous tissue engineered buccal mucosa is a promising substitute, and in a pilot study of five patients, all had an initial good result, and at 3 years follow-up, three of the patients had patent urethras. Additionally, synthetic scaffolds have been studied as an off the shelf alternative to human or animal collagen scaffolds. In a study by Raya-Rivera et al., five boys had muscle and epithelial cells seeded onto tubularized polyglycolic acid:poly (lactide-co-glycolide acid) scaffolds. Patients then underwent urethral reconstruction of the tubularized urethras. At a median follow-up of 71 months, all patients had a patent urethra.
Although there has been a tremendous amount of basic science and animal research for tissue engineered grafts, few platforms have advanced to human clinical trial. The problem for any graft in treating a complex urethral stricture is related to the issues of ischemia, fibrosis, and wound contracture. Further study is needed to better elucidate the optimal scaffolds and cell sources to overcome the inherent issues of tissue fibrosis associated with complex urethral strictures.
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