Use of Small Intestinal Submucosa Graft for the Surgical Management of Peyronie’s Disease

Use of Small Intestinal Submucosa Graft for the Surgical Management of Peyronie’s Disease L. Dean Knoll* From the Center for Urological Treatment and Research, Nashville, Tennessee

Purpose: We report on the long-term followup of porcine small intestinal submucosal graft as a closure material for the tunica albuginea after plaque incision. Materials and Methods: A total of 162 patients with at least a 12-month history of Peyronie’s disease with penile curvature of 60 degrees or more were evaluated. Patient age ranged from 33 to 69 years (mean 52). Preoperatively all patients underwent intracavernous injection and photographic documentation of curvature. Surgisis® ES, derived from porcine small intestine, was immersed in normal saline and was used to graft the tunical deficit after plaque incision using a subcoronal incisional approach. Results: Surgical correction of penile curvature was achieved in 148 of 162 patients (91%). At a mean followup of 38 months (range 6 to 96) 79% of the patients were fully potent with 21% requiring assistance. No reports of intraoperative penile shortening, long-term pain, infection, bulging at the graft site or evidence of a local immunogenic rejection reaction have been noted. Conclusions: Surgisis grafts for the coverage of cavernous defects after Peyronie’s plaque incision allow for satisfactory clinical results in long-term followup. The ease of surgical handling and placement, no associated comorbidities from harvesting techniques, and no adverse reactions make this material an anatomical and functional tunical substitute. Key Words: penis; penile induration; transplants; intestine, small

eyronie’s Disease is characterized by the formation of a nonexpansive fibrous plaque on the tunica albuginea and the underlying corpus cavernosum. The fibrous plaque thickens and contracts the tunica albuginea, causing a focal bend in the erect penis, and often producing pain and/or erectile dysfunction. In some cases penile curvature can inhibit the ability to engage in sexual intercourse. Originally assumed to affect only 0.5% to 3.2% of men,1 the prevalence is now estimated at as high as 8.9%.2 ED, which affects 20% to 54% of men with PD and may be purely mechanical in nature,3 is associated with vascular abnormalities in the penis in 61% to 70% of men with PD.4 Multiple treatment options for PD are currently available and include minimally invasive interventions such as intralesional verapamil injections, radiotherapy or shock wave therapy, but these have generally shown limited and unpredictable success. When the plaque proves refractory to these treatments, when penile curvature is severe or when ED is mechanical, surgical treatments are considered the best option to correct the defect. Among the most important factors for determining the form of surgical treatment are erectile function and penile hemodynamics. Only patients with adequate penile vascular status and erectile function can be considered candidates for a reconstructive option. Many techniques have been described for the surgical correction of PD. Tunical plication procedures are used suc-

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Submitted for publication April 17, 2007. * Correspondence and requests for reprints: Center for Urological Treatment and Research, 345–23rd Ave. North, Suite 212, Nashville, Tennessee 37203 (telephone: 615-327-2055; e-mail: dknoll23@ yahoo.com).

0022-5347/07/1786-2474/0 THE JOURNAL OF UROLOGY® Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION

cessfully but the consequential penile shortening is not always acceptable. Sometimes, especially in cases when PD is accompanied by ED, the placement of an inflatable prosthetic device is desirable since correction of the penile curvature does not correct the ED.5 Grafting procedures with various materials combined with incision or excision of the plaque have become the standard technique for the correction of the most severe curvature.6,7 Candidates for surgical correction should have chronic, stable disease, a greater than 60-degree curvature with significant penile shortening, the absence of ED and the inability to achieve intromission during intercourse.7 A number of graft materials have been used for the correction of tunical defects, all with varying effectiveness. The comorbidities associated with the harvesting of autologous dermal tissue and vein grafts, combined with the extensive preparation necessary for implantation are obvious disadvantages to these materials. Permanent synthetic materials are associated with a high rate of fibrosis and can often be palpated by patients.8 Thus, a biologically derived material that is able to incorporate natural functional tissue into the tunical defect is desirable. This ideal material has not yet been described, but the ECM derived from porcine small intestine (Surgisis ES) has been used successfully with short-term outcomes as an effective tunical substitute for the surgical management of severe penile curvature secondary to PD.9 SIS is an acellular extracellular matrix biomaterial. It contains the structural collagens of the ECM, as well as associated matrix factors that contribute to functional wound healing, cell signaling and tissue remodeling.10 –12 In

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Vol. 178, 2474-2478, December 2007 Printed in U.S.A. DOI:10.1016/j.juro.2007.08.044

SUBMUCOSAL GRAFT FOR PEYRONIE’S DISEASE animal models and in clinical use it has proven effective in restoring site specific function and architecture to the area in which it has been implanted in a process that has been described as smart tissue remodeling.13 In urology it has been successfully used in the surgical management of stress urinary incontinence14 and PD with short-term followup.15 The purpose of this study is to report the successful longterm outcome of plaque incision and Surgisis ES grafting for the management of severe penile curvature secondary to PD. MATERIALS AND METHODS Between August 1998 and August 2006 a total of 162 patients with PD underwent surgical treatment with incision of the plaque and Surgisis ES grafting. Patient age ranged from 33 to 69 years (mean 52). The mean interval between disease onset and surgery was 16 months (range 12 to 30). Candidates for surgery had stable disease for at least 9 months with curvature of at least 60 degrees. Patients also had to achieve an erection sufficient for intercourse and have a degree of curvature not allowing for vaginal penetration. Preoperative Evaluation Preoperative evaluation included a detailed medical and surgical history of symptom duration and progression, status of penile rigidity, ability to engage in sexual intercourse, and history of penile trauma or surgery. No patients experienced penile pain with or without an erection at surgery. Patients with pain were treated medically and were excluded from analysis. All patients had full penile rigidity but were unable to obtain intromission due to penile curvature. Patients with ED (ie those who required pharmacological assistance or a vacuum device to obtain full rigidity) were excluded from analysis as were those who presented with hourglass deformities of the penis. The physical examination by palpation determined the extent and location of the plaque. Plaque sizes varied and by ruler measurement of width and length ranged from 1.5 ⫻ 4.0 to 3.0 ⫻ 6.0 cm. All patients received an intracavernosal injection with 10 to 20 ␮g prostaglandin E1 with genital self-stimulation. Photographic documentation of the curvature was recorded at home and in the office at the time of ICI. All patients were able to achieve full rigidity with ICI requiring pharmacological reversal with 1:100,000 epinephrine. Patients had curvature 60 degrees or greater as measured using a protractor (range 60 to 100 degrees). Preoperative biothesiometry was performed in all patients for documentation of baseline penile sensation. Surgical Procedure All patients received preoperative antibiotics and general anesthesia. A circumcision incision was used with the skin and subcutaneous tissues sleeved to the base of the penis. The extent of curvature was documented by creating an artificial erection, which was performed by inserting a 19 gauge butterfly needle into the corpus cavernosum, with corpora restriction achieved by tightening a 12Fr red rubber catheter around the base of the penis. Sterile saline was then injected. Surgical loupe magnification was used to dissect the neurovascular bundle from the corpora cavernosa dorsally or the corpus spongiosum ventrally.

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The center of the curvature was identified and a relaxing incision was made into the plaque, extending the ends into an H shape when required. With the penis stretched using a 2-zero silk suture placed through the glans, a graft of Surgisis ES was rehydrated in sterile saline, sized approximately 30% larger than the defect and sutured with continuous 4-zero polyglycolic acid suture to cover the tunical defect. The graft size was determined by ruler measurement of the width and length of the defect with an additional 30% added to each measurement. A repeated artificial erection was performed to determine penile straightness.15 Subcutaneous tissues and skin were closed with 4-zero chromic interrupted sutures. A 12Fr Foley catheter was inserted and a loosely wrapped dressing was applied. Patients were discharged from the hospital the following day with instructions to keep the dressing in place for 72 hours, maintain the penis in a position 180 degrees opposite from the direction of the original curvature for at least the first 6 weeks and to abstain from sexual intercourse for 8 weeks. The first 25 patients were instructed to abort all conscious erections with amyl nitrate inhalers for the first 2 weeks to decrease the intracorporal pressure over the graft site, but the final 137 patients were not required to abort spontaneous erections. Patients were seen in the clinic 5 to 7 days after surgery for the evaluation of complications. Home photographic documentation was obtained 3 months postoperatively and all patients were examined 3 months postoperatively in the office. Additional assessment of penile length, straightness, sensation and rigidity was performed using a SHIM (Sexual Health Inventory for Men) questionnaire that included a specific question regarding penile straightness. This was completed by the patient at 3, 6 and 12 months, and the last 2 followups were by telephone. Additional followup was not routinely performed but most patients had additional followup in the office during their periodic benign prostatic hyperplasia/prostate examinations. RESULTS Dorsal curvature was documented in 111 patients (69%). A total of 27 (16%) patients had lateral curvature and 24 (15%) had ventral curvature. The degree of curvature ranged from 60 to 100 (median 70), with 20 patients having an indention at the plaque site. All patients had plaque palpable on physical examination of the penis before and after surgery. Penile curvature was corrected to less than 15 degrees in 148 patients, with curvature in 14 patients between 15 and 20 degrees after followup of 6 to 96 months (mean 38). Recurrent curvature developed in 14 (9%) patients, of which 5 required further surgical intervention. Severe indentation of the graft site developed in 5 patients and 3 required reoperation. The 8 patients requiring reoperation all complained of penile shortening, and underwent an additional plaque/graft incision and biomaterial grafting procedure. The overall reoperation rate for recurrent curvature was 5% (8 of 162 patients) in the entire series. Postoperative complications were minor. There were 27 patients with transient penile hypoesthesia (range 2 to 12 months, mean 3). Once penile hypoesthesia resolved, post-

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SUBMUCOSAL GRAFT FOR PEYRONIE’S DISEASE repopulation with connective tissue fibroblasts characteristic of penile connective tissue.

Postoperative results No. Pts (%) Penile straightness: Straight (less than 15 degrees) Recurrent curvature Penile indentation at graft site Penile length change: None Longer Shorter Penile sensation change: Yes (transient) No Immunogenic rejection reaction Unaided postop erectile function Aided postop erectile function: Oral therapy ICI/VED Penile implant

148 (91) 14 (9) (reoperation in 5 pts) 5 (3) (reoperation in 3 pts) 75 (46) 79 (49) 8 (5) 27 (17) 135 (83) 0 (0) 130 (80) 32 (20) 17 (10) 8 (5) 7 (4)

operative biothesiometry showed no change from baseline examination. No patient had infection, permanent bulging at the graft site or local immunogenic rejection reaction (erythema or pain) to the Surgisis graft material. Hematoma developed in 3 patients, of which 1 required incision and drainage. All patients reported successful intercourse. A total of 130 patients (80%) were able to obtain full, unaided erections and 32 (20%) required assistance (17 oral therapy, 8 ICI/VED, 7 penile prostheses, see table). Histological Case Report One patient, 67 years old, returned to the clinic approximately 4 months after surgery complaining of residual curvature. After further evaluation he underwent additional surgical correction. During the reoperation a biopsy of the original graft site on his dorsal penis was obtained. The tissue was immediately fixed in formalin and processed for routine hematoxylin and eosin staining. Sections contained fragments of dense, relatively sparsely cellular fibrovascular tissue representing a pattern of mature fibrosis without an inflammatory component or ossification (part A of figure). Additional areas showed the presence of moderately dense fibrovascular connective tissue with a significant vascular component (part B of figure). In no portion of the biopsy could the acellular Surgisis material be identified, indicating its complete

DISCUSSION Patients with severe PD resulting in mechanical ED but with good erectile function are ideal candidates for penile straightening procedures, yet no single operation is ideal. Plaque incision rather than excision with grafting has been widely used. However, an ideal graft material for closure defects in the tunica albuginea has not been previously described.15 The shortcomings associated with autologous and synthetic materials include graft contracture, recurrent curvature, worsening erectile dysfunction and morbidity associated with autologous tissue harvesting. To our knowledge this report is the first to describe the long-term followup of a xenogenic, porcine small intestinal graft for coverage of cavernous defects after Peyronie’s plaque incision. This material may come close to the ideal material to effectively correct PD because it is not associated with the comorbidities common to other graft materials. The source of the Surgisis graft is the porcine small intestine. This naturally occurring, resorbable ECM consists of structural and functional proteins, including several collagens, fibronectin, glycosaminoglycans, proteoglycans and growth factors.10 –12 Studies have demonstrated that the graft has shown tissue repair and remodeling characteristics, and does not form a generalized fibrotic tissue when placed in vivo.13,16 The single biopsy specimen that we obtained shows the presence of moderately dense fibrovascular connective tissue with a significant vascular component consistent with complete replacement of the graft material with normal appearing fibrovascular tissue. In this series we found that the graft material was strong enough to prevent graft bulging at the graft site. No separation of the graft was identified on palpation, and only 3 patients had hematoma under the graft, with surgical drainage required in 1 patient. No patient had an infection after the procedure or demonstrated physical evidence of a local immunogenic rejection reaction, although no systemic immunological testing was performed. There was recurrence of curvature in 9%, with 5% requiring surgical correction. Postoperatively the first 25 patients were instructed as a precau-

Four months after implant, Surgisis ES graft area was populated with relatively sparsely cellular fibrovascular tissue representing pattern of mature fibrosis without inflammatory component or ossification (A). Additional areas of graft site were characterized by moderately dense fibrovascular connective tissue with significant vascular component (B). Reduced from ⫻200.

SUBMUCOSAL GRAFT FOR PEYRONIE’S DISEASE tion to abort all erections with amyl nitrate inhalers for the first 2 weeks, but we subsequently determined that this precaution was unwarranted and abandoned the recommendation. There have been no subsequent complications as a result. Our data are in agreement with the results reported by Pak17 and Eltahawy18 et al, both of whom reported minimal complications and 80% to 95% success using the Surgisis ES graft and other graft materials with plaque incision. However, all 3 of these reports disagree with a 4-patient case report published in 2006 by John et al19 and more recent data by Breyer et al,20 which suggested that Surgisis was associated with an overall complication rate in 37% of patients including recurvature in 37% and hematoma formation in 26%. There are several reasons that outcomes may vary when xenogenic graft materials are used to correct curvature in the penis, but the 3 most important predictors of outcome in our practice are material choice, graft size at surgery and adequate postoperative care. In our experience the 4-layer Surgisis ES graft material is superior for correcting PD compared to the 1-layer version of the graft. The added strength of the 4-layer material, combined with dressings held in place for 72 hours postoperatively have been adequate to eliminate hematoma formation and prevent bulging. Furthermore, over sizing the graft approximately 30% larger than the defect has been more effective in minimizing recurvature than when smaller grafts are placed. Finally, it is imperative to instruct the patient to place his penis 180 degrees opposite from the original curvature to keep the graft maximally stretched for tissue ingrowth and prevention of contraction. To maximize surgical outcome plaque stability and preoperative erectile function must be assessed thoroughly to minimize unrealistic expectations by patients. All 162 patients had good preoperative erectile function. However, postoperative ED developed in 32 patients (20%) within the first 6 months (range 2 to 6). A total of 17 patients responded to oral phosphodiesterase type 5 inhibitors. More distressing was that 8 patients required ICI/VED and 7 required placement of a 3-piece inflatable penile prosthesis. The exact mechanism of the development of postoperative ED is not entirely understood but in this series no single factor (ie plaque location, graft size) could be identified. Hourglass deformities were excluded from analysis in this series but have been successfully treated using Surgisis ES. Most patients with severe hourglass deformities have distal segmental flaccidity and are usually best treated with the insertion of a penile prosthesis. It is mandatory to ensure that plaque size and penile curvature are stable before considering an invasive surgical procedure. To avoid postoperative dissatisfaction because of unrealistic expectations, patients were informed that the surgery would correct the curvature but would not improve erectile ability or restore penile length to pre-Peyronie’s disease onset.

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and placement, no associated comorbidities from harvesting techniques, and no adverse reactions make this material an anatomical and functional tunical substitute.

Abbreviations and Acronyms ECM ED ICI PD SIS VED

⫽ ⫽ ⫽ ⫽ ⫽ ⫽

extracellular matrix erectile dysfunction intracavernosal injection Peyronie’s disease small intestinal submucosa vacuum erection device

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CONCLUSIONS

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Surgisis grafts for the coverage of cavernous defects after Peyronie’s plaque incision allow for satisfactory clinical results in long-term followup. The ease of surgical handling

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Schwarzer U, Sommer F, Klotz T, Braun M, Reifenrath B and Engelmann U: The prevalence of Peyronie’s disease: results of a large survey. BJU Int 2001; 88: 727. Mulhall JP, Creech SD, Boorjian SA, Ghaly S, Kim ED, Moty A et al: Subjective and objective analysis of the prevalence of Peyronie’s disease in a population of men presenting for prostate cancer screening. J Urol 2004; 171: 2350. Usta MF, Bivalacqua TJ, Jabren GW, Myers L, Sanabria J, Sikka SC et al: Relationship between the severity of penile curvature and the presence of comorbidities in men with Peyronie’s disease. J Urol 2004; 171: 775. Kendirci M, Nowfar S, Gur S, Jabren GW, Sikka SC and Hellstrom WJ: The relationship between the type of penile abnormality and penile vascular status in patients with Peyronie’s disease. J Urol 2005; 174: 632. Chaudhary M, Sheikh N, Asterling S, Ahmad I and Greene D: Peyronie’s disease with erectile dysfunction: penile modeling over inflatable penile prostheses. Urology 2005; 65: 760. Yurkanin JP, Dean R and Wessells H: Effect of incision and saphenous vein grafting for Peyronie’s disease on penile length and sexual satisfaction. J Urol 2001; 166: 1769. Levine LA and Estrada CR: Human cadaveric pericardial graft for the surgical correction of Peyronie’s disease. J Urol 2003; 170: 2359. Hellstrom WJG: The use of prosthetic material in the surgical management of Peyronie’s disease. Int J Impot Res 1994; 6: D32. Knoll DL: Use of porcine small intestinal submucosal graft in the surgical management of Peyronie’s disease. Urology 2001; 57: 753. Hodde JP, Badylak SF, Brightman AO and Voytik-Harbin SL: Glycosaminoglycan content of small intestinal submucosa: a bioscaffold for tissue replacement. Tissue Eng 1996; 2: 209. McPherson TB and Badylak SF: Characterization of fibronectin derived from porcine small intestinal submucosa. Tissue Eng 1998; 4: 75. McDevitt CA, Wildey GM and Cutrone RM: Transforming growth factor-beta1 in a sterilized tissue derived from the pig small intestine submucosa. J Biomed Mater Res A 2003; 67: 637. Badylak SF: Small intestinal submucosa (SIS): a biomaterial conducive to smart tissue remodeling. In: Tissue Engineering: Current Perspectives. Edited by E Bell. Cambridge, Massachusetts: Burkhauser Publishers 1993; pp 179 –189. Rutner AB, Levine SR and Schmaelzle JF: Processed porcine small intestine submucosa as a graft material for pubovaginal slings: durability and results. Urology 2003; 62: 805. Knoll LD: Use of porcine small intestinal submucosal graft in the surgical management of Peyronie’s disease. In: Current

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Clinical Urology: Peyronie’s Disease: A Guide to Clinical Management. Edited by LA Levine. Totowa, New Jersey: Humana Press Inc 2006; pp 209 –216. Wiedemann A and Otto M: Small intestinal submucosa for pubourethral sling suspension for the treatment of stress incontinence: first histopathological results in humans. J Urol 2004; 172: 215. Pak RW, Waldorf JC and Broderick GA: Outcomes of autologous versus non-autologous grafts for Peyronie’s repair. J Sex Med 2007; 4: 76. Eltahawy EA, Virasoro R, McCammon KA, Schlossberg SM and Jordan GH: Management of Peyronie’s disease using dermal or porcine small intestinal submucosa (SIS) grafts. J Urol, suppl., 2006; 175: 321, abstract 996. John T, Bandi G and Santucci R: Porcine small intestinal submucosa is not an ideal graft material for Peyronie’s disease surgery. J Urol 2006; 176: 1025. Breyer BN, Brant WO, Garcia MM, Bella AJ and Lue TF: Complications of porcine small intestine submucosa graft for Peyronie’s disease. J Urol 2007; 177: 589.

EDITORIAL COMMENT Peyronie’s disease is a common urological condition affecting 3% to 9% of the adult male population. When men with PD cannot penetrate for satisfactory sexual intercourse and conservative or minimally invasive therapies have failed, surgery is offered. In men with PD with documented vascular insufficiency prosthetic options are used. When erectile function is maintained the surgeon can choose a plication procedure (with consequent loss of penile length) or plaque incision/excision with graft. The higher rate of fibrosis associated with synthetic grafts has led to their disfavor.1 Increased operative time and pain from the harvest site have contributed to the trend away from autologous materials, eg dermis, saphenous vein, etc. Current off-the-shelf allogenic/xenogenic graft choices include Alloderm®, pericardial Tutoplast® and porcine SIS. Knoll reports on 162 men with PD (penile curvature greater than 60 degrees) who underwent incision and grafting with Surgisis SIS. The author reports 91% of patients experiencing penile straightening, 9% with recurrent curva-

ture and 5% (8) requiring further surgical intervention. Postoperatively 79% of patients were potent while 21% required erectile assistance. These 1-year (range 6 to 96 months) followup results are credible and realistic. The ideal grafting material for PD surgery must be readily available, easy to use, inexpensive, and carry a low risk of infection and antigenicity. Attention to 2 recent publications comparing grafting materials used in men with PD is noted. In a smaller series Kovac and Brock revealed similar results using Tutoplast and SIS,2 while Kadioglu et al recommended either vein grafts or SIS.3 Perhaps more illuminating on the subject of grafts for PD are the 5-year results of men undergoing vein grafts for PD, in which 22% of patients reported a significant decrease in penile rigidity and only 60% were satisfied with surgical treatment.4 It is recognized that the majority of men with PD have vascular comorbidities that contribute over time to sexual dysfunction. Long-term followup with objective and validated subjective measures is needed in men with PD to better understand the natural history and consequences of these interventions. Wayne Hellstrom Department of Urology Tulane University New Orleans, Louisiana 1.

Leungwattanakij S, Bivalacqua TJ, Yang DY, Hyun JS and Hellstrom WJ: Comparison of cadaveric pericardial, dermal, vein, and synthetic grafts for tunica albuginea substitution using a rat model. BJU Int 2003; 92: 119. 2. Kovac JR and Brock GB: Surgical outcomes and patient satisfaction after dermal, pericardial, and small intestinal submucosal grafting for Peyronie’s disease. J Sex Med 2007; 4: 1500. 3. Kadioglu A, Sanli O, Akman T, Ersay A, Guven S and Mammadov F: Graft materials in Peyronie’s disease surgery: a comprehensive review. J Sex Med 2007; 4: 581. 4. Montorsi F, Salonia A, Briganti A, Deho F, Zanni G, Da Pozzo L et al: Five year followup of plaque incision and vein grafting for Peyronie’s disease. J Urol, suppl., 2004; 171: 331, abstract 1256.