Female Urology Is There an Association Between Polypropylene Midurethral Slings and Malignancy? Ashley B. King, Anna Zampini, Sandip Vasavada, Courtenay Moore, Raymond R. Rackley, and Howard B. Goldman OBJECTIVE
MATERIALS AND METHODS RESULTS
CONCLUSION
To examine any association between polypropylene mesh used in midurethral slings and malignancy in humans. Macroporous, monofilament polypropylene midurethral slings have been established as a safe and effective treatment for stress urinary incontinence. However, despite long-term studies supporting the efficacy and safety of midurethral slings, there have been concerns regarding the general risks of using mesh in transvaginal surgery. In addition, concerns have recently been raised about synthetic midurethral slings and a possible link with malignancy. Therefore, the goal of this work was to further assess any association between polypropylene mesh slings and malignancy. All sling procedures performed at our institution from 2004 to 2013 were retrospectively reviewed. From within this group, the International Classification of Disease codes for urethral cancer, vaginal cancer, and bladder cancer were reviewed. From 2004-2013, 2545 procedures were performed. Of these, 2361 (96.3%) underwent polypropylene midurethral sling placement. Average follow-up after sling placement was 42.0 38.6 months, with follow-up extending up to 122.3 months. The rate of bladder cancer after the sling procedure was 1 of 2361 (0.0%), with the same rate of vaginal cancer. No sarcomas were noted. Overall, the rate of malignancy after polypropylene mesh midurethral sling placement in our series was 0.0% (2 of 2361). With a mean follow-up of almost 4 years and follow-up extending up to a maximum of 122.3 months, our series does not support any association between the polypropylene mesh used for midurethral slings and the development of malignancy in humans. UROLOGY 84: 789e792, 2014. 2014 Elsevier Inc.
S
tress urinary incontinence is a prevalent condition affecting up to 35% of women.1 Midurethral synthetic slings are a treatment for stress urinary incontinence, with an objective cure rates exceeding 90% in a recent study published with 17 years of follow-up.2 Despite long-term studies supporting the efficacy and safety of macroporous, monofilament polypropylene slings for the treatment of stress urinary incontinence, there have been concerns regarding the general risks of using mesh in transvaginal surgery. Although these concerns often relate to mesh used for prolapse repairs, some have voiced apprehension regarding mesh slings as well. However, the U.S. Food and Drug Administration reported in 2013 that, “the safety and effectiveness of multi-incision slings is well
Financial Disclosure: The authors declare that they have no relevant financial interests. From the Center for Female Pelvic Medicine and Reconstructive Surgery, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH Reprint requests: Ashley B. King, M.D., Center for Female Pelvic Medicine and Reconstructive Surgery, Glickman Urological and Kidney Institute, 9500 Euclid Avenue, Q10, Cleveland, OH 44195. E-mail: [email protected] Submitted: April 9, 2014, accepted (with revisions): July 3, 2014
ª 2014 Elsevier Inc. All Rights Reserved
established in clinical trials that followed patients for up to 1-year.”3 According to the recent American Urogynecologic Society and Society of Urodynamics, Female Pelvic Medicine and Urogenital Reconstruction position statement on midurethral slings, “The safety and effectiveness of multi-incision slings is well established.”4 Additional concerns have been raised recently about synthetic midurethral slings and a possible link with malignancy.5 These concerns are based on rodent models that demonstrated a high rate of sarcoma formation after subcutaneous implantation of polypropylene. However, further investigation suggests that the risk of malignancy may be related to the surface area and morphology of the implanted material more than to the composition of the material. Perforated materials have been shown to have a lower risk of malignancy.6 Because of these concerns regarding a possible link between polypropylene mesh and malignancy, further investigation is warranted. The objective of this study was to examine any association between polypropylene mesh used in midurethral slings and malignancy in humans. http://dx.doi.org/10.1016/j.urology.2014.07.011 0090-4295/14
789
MATERIALS AND METHODS A retrospective review was performed for all sling procedures performed within the urologic institution from 2004 to 2013, using the Current Procedural Terminology (CPT) code for “sling operation for stress incontinence,” or CPT number 57,288. Each operative report was reviewed to identify what type of sling was performed. Patients were excluded if the CPT code was incorrect or if there was inadequate information in the operative report to determine what type of sling was performed. Baseline demographics and information regarding follow-up was also obtained. Follow-up was defined as last office visit at our institution. Records were reviewed for local malignancy, specifically looking at the International Classification of Diseases codes for urethral cancer, vaginal cancer, and bladder cancer. Each case associated with malignancy was further examined. Data on sling placement, details regarding diagnosis and treatment of any malignancy, outcomes of treatment, any related pathologic findings, and other pertinent clinical data were obtained. Institutional Review Board approval was obtained for the study protocol (#14-150). Data points are presented as a percentage or as mean standard deviation.
RESULTS From 2004-2013, 2545 cases were found based on CPT coding; of these, 98 patients were excluded because the CPT code was in error or there was insufficient information to determine the type of sling placed. Of the remaining 2447 patients, a polypropylene mesh sling was placed in 2361 (96.3%). Nonpolypropylene mesh slings were placed in 2 patients (0.0%), comprising 1 polyester and 1 Vicryl (Ethicon, Somerville, NJ) mesh. The rest of the slings placed were biologic (1.6%) or autologous fascial slings (1.8%). The 86 patients who had a biologic, autologous, or nonpolypropylene mesh sling were excluded. Patients were a mean age of 59.3 13.0 years at the time of surgery. Average follow-up was 42.0 38.6 months, with follow-up extending up to a maximum of 122.3 months. The follow-up for the patients operated on from 2004-2006 was further delineated to assess the thoroughness of our long-term follow-up. From 20042006, 680 cases were performed. Of these patients, 508 (74.7%) had follow-up of 3 years or more, and 434 (63.8%) had follow-up of 6 years or more. Of the total cases, there were 12 cases of bladder cancer and 1 case of vaginal cancer. After reviewing the records further, 11 of the 12 cases of bladder cancer were diagnosed before the sling was placed; therefore, the rate of bladder cancer after the sling procedure was 1 of 2361 (0.0%), with the same rate of vaginal cancer. No sarcomas were noted. The patient diagnosed with bladder cancer after sling placement was diagnosed 4 years after placement of a transobturator polypropylene sling. She presented in acute renal failure with bilateral hydronephrosis secondary to high-grade, invasive urothelial carcinoma. Her disease was 790
aggressive, and she was transitioned to hospice care within 1 year from the diagnosis. The patient diagnosed with vaginal cancer had undergone a hysterectomy approximately 40 years earlier for unknown indications. Two years after placement of a tension-free vaginal tape obturator (TVT-O) sling (Ethicon), she was found to have a low-grade squamous intraepithelial lesion with the presence of human papilloma virus (HPV) on a surveillance Papanicolaou test of the vaginal cuff. A vaginal biopsy specimen showed carcinoma in situ (CIS). She underwent laser vaporization at the apex of the vagina and concomitant placement of a retropubic TVT sling for recurrent stress incontinence. The patient’s last follow-up was 4 years after placement of original sling, with no evidence of any recurrent issues.
COMMENT The risk of developing malignancy after implantation of a foreign material has been a long-standing concern and the subject of much research, especially in animal models. In particular, concerns regarding implantation of polypropylene mesh have been raised because of animal studies that showed a high rate of sarcoma formation when sheets of polypropylene were implanted into mice and rats. This has not been reproduced in other animal models.6 Much research has focused on the mechanism of tumor formation and has suggested that the composition of the material is not as important as the surface area and morphology of the implanted material in regards to tumor formation. This is known as the Oppenheimer effect.7 Others have also cautioned against extrapolating from animal studies because “such tests are rarely predictive of performance in humans. There are many examples in which animal studies are highly misleading with respect to clinical safety and efficacy in humans.”8 Concerns regarding malignancy apply not only to the use of mesh but also to orthopedic prostheses, cardiac pacemakers, and vascular grafts. Malignancy has been reported in patients with cardiac pacemakers, nonmetallic implants, and vascular grafts, but the incidence is low and no causality has been established.6 However, thus far in the literature, no malignancy associated with polypropylene mesh has been reported in humans. One case was reported of a benign inflammatory myofibroblastic tumor found in the bladder 10 weeks after placement of a TVT sling. The etiology of this benign tumor was not clear. No mesh perforation occurred, and the time course makes causality unlikely.9 Two cases were reported of cancer associated with polymeric mesh. The mesh in both patients was used to repair an abdominal wall defect. No polypropylene mesh was involved, and these cases were complicated by chronic infection at the site of the mesh.10 In our series, the rate of malignancy after polypropylene mesh midurethral sling placement was 0.0% (2 of 2361). This is consistent with the current literature.11-13 In addition, based on the location and cell type, the two cases of malignancy after sling placement in our study UROLOGY 84 (4), 2014
were very unlikely to be related to the sling itself. The most common type of bladder cancer associated with the presence of a foreign body is squamous cell carcinoma. This has been well established in the literature and is mostly seen after chronic exposure of the urothelium to an indwelling Foley catheter in the Western world.14 The patient in our series with bladder cancer had urothelial carcinoma. The incidence of bladder cancer in 2013 was 72,570 cases per year15; therefore, 1 case of bladder cancer diagnosed in our series after sling placement is not inconsistent with the overall incidence of bladder cancer. The disease in the patient with CIS at the vaginal apex was far from the site of the sling, and the more likely association was the presence of HPV and CIS. The connection between HPV and vaginal cancer is well established in the literature.16 No sarcomas were found in our study. Sarcoma formation has been the concern with implantation of polypropylene because of the studies performed in mice and rats. Again, these concerns are not based on implantation of polypropylene in the form of mesh. Nevertheless, these findings are not supported in our study and have not been substantiated in other human studies. Morgan et al17 reviewed 217 patients with sarcomas to see whether they had undergone any artificial implants in the past. No relationship was found between the development of sarcoma and artificial implants of any type. In addition, further animal studies using mesh forms of polypropylene have not shown development of sarcomas. Witherspoon et al18 implanted polypropylene mesh into rodents and monitored the animals for 2 years based on the previously established latency period for malignancy in rodents. No sarcoma developed. Our study does have several limitations. Because International Classification of Diseases codes were used, there is always a risk that the prevalence of malignancy could be underestimated. In addition, some patients were lost to follow-up and could have developed a malignancy. We reviewed our rates of follow-up from 2004 to 2006 to try to assess this, and most patients did have long-term follow-up. However, because the primary outcome assessed was malignancy, longer-term follow-up is likely required. We considered contacting the patients for complete follow-up; however, we did not believe it was appropriate ethically to raise a concern of malignancy with patients who were otherwise doing well. Another limitation in the study is lack of longer-term follow-up. However, a true latency period has not been established but has been extrapolated from animal data,18 other etiologies of malignancy, and the rare cases involving abdominal hernia mesh leading to malignancy in the face of significant infection.10 Of note, 1 of the 2 reported cases of malignancy that developed after placement of mesh for abdominal hernia repair presented 6 years after implantation. In our review, follow-up was 6 years or more for 63.8% (434 of 680) of our initial patients from 2004 to 2006. We agree that patients need continued follow-up but also see utility in reporting the UROLOGY 84 (4), 2014
malignancy rates at this point in follow-up as well. Our study does not support any link between midurethral slings and malignancy with a follow-up of up to 122.3 months. Midurethral slings have been well studied, with followup of 17 years.2 The literature suggests that these procedures are not only successful but also safe. No reports of malignancy have been reported, and our study supports this. The U.S. Food and Drug Administration, the Society of Urodynamics, Female Pelvic Medicine and Urogenital Reconstruction, and the American Urogynecologic Society have all reviewed the literature and agree that midurethral slings are safe and effective. Safety concerns are always at the forefront of any medical intervention. As physicians, we take the Hippocratic oath very seriously, and our primary objective is to “do no harm.” Ongoing research should always be done to continue to ensure that our treatments are not going to harm patients; however, this research should be done in a scientific fashion to ensure its validity.
CONCLUSION With a mean follow-up of almost 4 years and follow-up extending up to a maximum of 122.3 months, our series does not support any association between polypropylene mesh used for midurethral slings and the development of malignancy in humans. References 1. Luber KM. The definition, prevalence, and risk factors for stress urinary incontinence. Rev Urol. 2004;6:S3-9. 2. Nilsson CG, Palva K, Aarnio R, et al. Seventeen years’ follow-up of the tension-free vaginal tape procedure for female stress urinary incontinence. Int Urogynecol J. 2013;24:1265-1269. 3. U.S. Food and Drug Administration. Considerations about surgical mesh for SUI. Available at: http://www.fda.gov/MedicalDevices/ ProductsandMedicalProcedures/ImplantsandProsthetics/UroGyn SurgicalMesh/ucm345219.htm. Accessed February 26, 2014. 4. American Urogynecologic Society (AUGS) and the Society of Urodynamics, Female Pelvic Medicine and Urogenital Reconstruction (SUFU). Position statement on mesh midurethral slings for stress urinary incontinence. Available at: http://www.augs.org/p/ cm/ld/fid¼202. Accessed March 27, 2014. 5. Ostergard DR, Azadi A. To mesh or not to mesh with polypropylene: does carcinogenesis in animals matter? Inturogynecol J. 2014;25:569-571. 6. McGregor DB, Baan RA, Partensky C, et al. Evaluation of the carcinogenic risks to humans associated with surgical implants and other foreign bodies - a report of an IARC Monographs Programme Meeting. International Agency for Research on Cancer. Eur J Cancer. 2000;36:307-313. 7. Oppenheimer BS, Oppenheimer ET, Stout AP, et al. The latent period in carcinogenesis by plastics in rats and its relation to the presarcomatous stage. Cancer. 1958;11:204-213. 8. Williams D. Carcinogenicity of implantable materials: experimental and epidemiological evidence. Int Urogynecol J. 2014;25:577-580. 9. Kwon S, Latchamsetty K, Benson J, Carreno M. Inflammatory myofibroblastic tumor of the urinary tract following a TVT. Female Pelvic Med Reconstr Surg. 2012;18:249-251. 10. Birolini C, Minossi J, Lima C, et al. Mesh cancer: long-term infection leading to squamous cell carcinoma of the abdominal wall [e-pub ahead of print]. Hernia; http://dx.doi.org/10.1007/s1002 9-013-1083-x, 2013. Accessed March 27, 2014.
791
11. American Urogynecologic Society (AUGS) and the Society of Urodynamics, Female Pelvic Medicine and Urogenital Reconstruction (SUFU). Frequently asked questions by providers: midurethral slings for stress urinary incontinence. Available at: http:// www.sufuorg.com/docs/news/Provider-FAQs.aspx. Accessed March 27, 2014. 12. Moalli P, Brown B, Nager CW. Polypropylene mesh: evidence for lack of carcinogenicity. Int Urogynecol J. 2014;25:573-576. 13. Dwyer P, Riss P. Carcinogenicity of implanted synthetic grafts and devices. Int Urogynecol J. 2014;25:567-568. 14. Locke JR, Hill DE, Walzer Y. Incidence of squamous cell carcinoma in patients with long-term catheter drainage. J Urol. 1985; 133:1034-1035.
792
15. American Cancer Society. Bladder cancer. What are the key statistics about bladder cancer? Available at: http://www.cancer.org/ cancer/bladdercancer/detailedguide/bladder-cancer-key-statistics. Accessed February 28, 2014. 16. Insinga RP, Liaw KL, Johnson LG, Madeleine MM. A systematic review of the prevalence and attribution of human papillomavirus types among cervical, vaginal, and vulvar precancers and cancers in the United States. Cancer Epidemiol Biomarkers Prev. 2008;17:1611-1622. 17. Morgan R, Elcock M. Artificial Implants and soft tissue sarcomas. J Clin Epidemiol. 1995;4:545-549. 18. Witherspoon P, Bryson G, Wright DM, et al. Carcinogenic potential of commonly used hernia repair prosthesis in an experimental model. Br J Surg. 2004;91:368-372.
UROLOGY 84 (4), 2014
MATERIALS AND METHODS RESULTS
CONCLUSION
To examine any association between polypropylene mesh used in midurethral slings and malignancy in humans. Macroporous, monofilament polypropylene midurethral slings have been established as a safe and effective treatment for stress urinary incontinence. However, despite long-term studies supporting the efficacy and safety of midurethral slings, there have been concerns regarding the general risks of using mesh in transvaginal surgery. In addition, concerns have recently been raised about synthetic midurethral slings and a possible link with malignancy. Therefore, the goal of this work was to further assess any association between polypropylene mesh slings and malignancy. All sling procedures performed at our institution from 2004 to 2013 were retrospectively reviewed. From within this group, the International Classification of Disease codes for urethral cancer, vaginal cancer, and bladder cancer were reviewed. From 2004-2013, 2545 procedures were performed. Of these, 2361 (96.3%) underwent polypropylene midurethral sling placement. Average follow-up after sling placement was 42.0 38.6 months, with follow-up extending up to 122.3 months. The rate of bladder cancer after the sling procedure was 1 of 2361 (0.0%), with the same rate of vaginal cancer. No sarcomas were noted. Overall, the rate of malignancy after polypropylene mesh midurethral sling placement in our series was 0.0% (2 of 2361). With a mean follow-up of almost 4 years and follow-up extending up to a maximum of 122.3 months, our series does not support any association between the polypropylene mesh used for midurethral slings and the development of malignancy in humans. UROLOGY 84: 789e792, 2014. 2014 Elsevier Inc.
S
tress urinary incontinence is a prevalent condition affecting up to 35% of women.1 Midurethral synthetic slings are a treatment for stress urinary incontinence, with an objective cure rates exceeding 90% in a recent study published with 17 years of follow-up.2 Despite long-term studies supporting the efficacy and safety of macroporous, monofilament polypropylene slings for the treatment of stress urinary incontinence, there have been concerns regarding the general risks of using mesh in transvaginal surgery. Although these concerns often relate to mesh used for prolapse repairs, some have voiced apprehension regarding mesh slings as well. However, the U.S. Food and Drug Administration reported in 2013 that, “the safety and effectiveness of multi-incision slings is well
Financial Disclosure: The authors declare that they have no relevant financial interests. From the Center for Female Pelvic Medicine and Reconstructive Surgery, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH Reprint requests: Ashley B. King, M.D., Center for Female Pelvic Medicine and Reconstructive Surgery, Glickman Urological and Kidney Institute, 9500 Euclid Avenue, Q10, Cleveland, OH 44195. E-mail: [email protected] Submitted: April 9, 2014, accepted (with revisions): July 3, 2014
ª 2014 Elsevier Inc. All Rights Reserved
established in clinical trials that followed patients for up to 1-year.”3 According to the recent American Urogynecologic Society and Society of Urodynamics, Female Pelvic Medicine and Urogenital Reconstruction position statement on midurethral slings, “The safety and effectiveness of multi-incision slings is well established.”4 Additional concerns have been raised recently about synthetic midurethral slings and a possible link with malignancy.5 These concerns are based on rodent models that demonstrated a high rate of sarcoma formation after subcutaneous implantation of polypropylene. However, further investigation suggests that the risk of malignancy may be related to the surface area and morphology of the implanted material more than to the composition of the material. Perforated materials have been shown to have a lower risk of malignancy.6 Because of these concerns regarding a possible link between polypropylene mesh and malignancy, further investigation is warranted. The objective of this study was to examine any association between polypropylene mesh used in midurethral slings and malignancy in humans. http://dx.doi.org/10.1016/j.urology.2014.07.011 0090-4295/14
789
MATERIALS AND METHODS A retrospective review was performed for all sling procedures performed within the urologic institution from 2004 to 2013, using the Current Procedural Terminology (CPT) code for “sling operation for stress incontinence,” or CPT number 57,288. Each operative report was reviewed to identify what type of sling was performed. Patients were excluded if the CPT code was incorrect or if there was inadequate information in the operative report to determine what type of sling was performed. Baseline demographics and information regarding follow-up was also obtained. Follow-up was defined as last office visit at our institution. Records were reviewed for local malignancy, specifically looking at the International Classification of Diseases codes for urethral cancer, vaginal cancer, and bladder cancer. Each case associated with malignancy was further examined. Data on sling placement, details regarding diagnosis and treatment of any malignancy, outcomes of treatment, any related pathologic findings, and other pertinent clinical data were obtained. Institutional Review Board approval was obtained for the study protocol (#14-150). Data points are presented as a percentage or as mean standard deviation.
RESULTS From 2004-2013, 2545 cases were found based on CPT coding; of these, 98 patients were excluded because the CPT code was in error or there was insufficient information to determine the type of sling placed. Of the remaining 2447 patients, a polypropylene mesh sling was placed in 2361 (96.3%). Nonpolypropylene mesh slings were placed in 2 patients (0.0%), comprising 1 polyester and 1 Vicryl (Ethicon, Somerville, NJ) mesh. The rest of the slings placed were biologic (1.6%) or autologous fascial slings (1.8%). The 86 patients who had a biologic, autologous, or nonpolypropylene mesh sling were excluded. Patients were a mean age of 59.3 13.0 years at the time of surgery. Average follow-up was 42.0 38.6 months, with follow-up extending up to a maximum of 122.3 months. The follow-up for the patients operated on from 2004-2006 was further delineated to assess the thoroughness of our long-term follow-up. From 20042006, 680 cases were performed. Of these patients, 508 (74.7%) had follow-up of 3 years or more, and 434 (63.8%) had follow-up of 6 years or more. Of the total cases, there were 12 cases of bladder cancer and 1 case of vaginal cancer. After reviewing the records further, 11 of the 12 cases of bladder cancer were diagnosed before the sling was placed; therefore, the rate of bladder cancer after the sling procedure was 1 of 2361 (0.0%), with the same rate of vaginal cancer. No sarcomas were noted. The patient diagnosed with bladder cancer after sling placement was diagnosed 4 years after placement of a transobturator polypropylene sling. She presented in acute renal failure with bilateral hydronephrosis secondary to high-grade, invasive urothelial carcinoma. Her disease was 790
aggressive, and she was transitioned to hospice care within 1 year from the diagnosis. The patient diagnosed with vaginal cancer had undergone a hysterectomy approximately 40 years earlier for unknown indications. Two years after placement of a tension-free vaginal tape obturator (TVT-O) sling (Ethicon), she was found to have a low-grade squamous intraepithelial lesion with the presence of human papilloma virus (HPV) on a surveillance Papanicolaou test of the vaginal cuff. A vaginal biopsy specimen showed carcinoma in situ (CIS). She underwent laser vaporization at the apex of the vagina and concomitant placement of a retropubic TVT sling for recurrent stress incontinence. The patient’s last follow-up was 4 years after placement of original sling, with no evidence of any recurrent issues.
COMMENT The risk of developing malignancy after implantation of a foreign material has been a long-standing concern and the subject of much research, especially in animal models. In particular, concerns regarding implantation of polypropylene mesh have been raised because of animal studies that showed a high rate of sarcoma formation when sheets of polypropylene were implanted into mice and rats. This has not been reproduced in other animal models.6 Much research has focused on the mechanism of tumor formation and has suggested that the composition of the material is not as important as the surface area and morphology of the implanted material in regards to tumor formation. This is known as the Oppenheimer effect.7 Others have also cautioned against extrapolating from animal studies because “such tests are rarely predictive of performance in humans. There are many examples in which animal studies are highly misleading with respect to clinical safety and efficacy in humans.”8 Concerns regarding malignancy apply not only to the use of mesh but also to orthopedic prostheses, cardiac pacemakers, and vascular grafts. Malignancy has been reported in patients with cardiac pacemakers, nonmetallic implants, and vascular grafts, but the incidence is low and no causality has been established.6 However, thus far in the literature, no malignancy associated with polypropylene mesh has been reported in humans. One case was reported of a benign inflammatory myofibroblastic tumor found in the bladder 10 weeks after placement of a TVT sling. The etiology of this benign tumor was not clear. No mesh perforation occurred, and the time course makes causality unlikely.9 Two cases were reported of cancer associated with polymeric mesh. The mesh in both patients was used to repair an abdominal wall defect. No polypropylene mesh was involved, and these cases were complicated by chronic infection at the site of the mesh.10 In our series, the rate of malignancy after polypropylene mesh midurethral sling placement was 0.0% (2 of 2361). This is consistent with the current literature.11-13 In addition, based on the location and cell type, the two cases of malignancy after sling placement in our study UROLOGY 84 (4), 2014
were very unlikely to be related to the sling itself. The most common type of bladder cancer associated with the presence of a foreign body is squamous cell carcinoma. This has been well established in the literature and is mostly seen after chronic exposure of the urothelium to an indwelling Foley catheter in the Western world.14 The patient in our series with bladder cancer had urothelial carcinoma. The incidence of bladder cancer in 2013 was 72,570 cases per year15; therefore, 1 case of bladder cancer diagnosed in our series after sling placement is not inconsistent with the overall incidence of bladder cancer. The disease in the patient with CIS at the vaginal apex was far from the site of the sling, and the more likely association was the presence of HPV and CIS. The connection between HPV and vaginal cancer is well established in the literature.16 No sarcomas were found in our study. Sarcoma formation has been the concern with implantation of polypropylene because of the studies performed in mice and rats. Again, these concerns are not based on implantation of polypropylene in the form of mesh. Nevertheless, these findings are not supported in our study and have not been substantiated in other human studies. Morgan et al17 reviewed 217 patients with sarcomas to see whether they had undergone any artificial implants in the past. No relationship was found between the development of sarcoma and artificial implants of any type. In addition, further animal studies using mesh forms of polypropylene have not shown development of sarcomas. Witherspoon et al18 implanted polypropylene mesh into rodents and monitored the animals for 2 years based on the previously established latency period for malignancy in rodents. No sarcoma developed. Our study does have several limitations. Because International Classification of Diseases codes were used, there is always a risk that the prevalence of malignancy could be underestimated. In addition, some patients were lost to follow-up and could have developed a malignancy. We reviewed our rates of follow-up from 2004 to 2006 to try to assess this, and most patients did have long-term follow-up. However, because the primary outcome assessed was malignancy, longer-term follow-up is likely required. We considered contacting the patients for complete follow-up; however, we did not believe it was appropriate ethically to raise a concern of malignancy with patients who were otherwise doing well. Another limitation in the study is lack of longer-term follow-up. However, a true latency period has not been established but has been extrapolated from animal data,18 other etiologies of malignancy, and the rare cases involving abdominal hernia mesh leading to malignancy in the face of significant infection.10 Of note, 1 of the 2 reported cases of malignancy that developed after placement of mesh for abdominal hernia repair presented 6 years after implantation. In our review, follow-up was 6 years or more for 63.8% (434 of 680) of our initial patients from 2004 to 2006. We agree that patients need continued follow-up but also see utility in reporting the UROLOGY 84 (4), 2014
malignancy rates at this point in follow-up as well. Our study does not support any link between midurethral slings and malignancy with a follow-up of up to 122.3 months. Midurethral slings have been well studied, with followup of 17 years.2 The literature suggests that these procedures are not only successful but also safe. No reports of malignancy have been reported, and our study supports this. The U.S. Food and Drug Administration, the Society of Urodynamics, Female Pelvic Medicine and Urogenital Reconstruction, and the American Urogynecologic Society have all reviewed the literature and agree that midurethral slings are safe and effective. Safety concerns are always at the forefront of any medical intervention. As physicians, we take the Hippocratic oath very seriously, and our primary objective is to “do no harm.” Ongoing research should always be done to continue to ensure that our treatments are not going to harm patients; however, this research should be done in a scientific fashion to ensure its validity.
CONCLUSION With a mean follow-up of almost 4 years and follow-up extending up to a maximum of 122.3 months, our series does not support any association between polypropylene mesh used for midurethral slings and the development of malignancy in humans. References 1. Luber KM. The definition, prevalence, and risk factors for stress urinary incontinence. Rev Urol. 2004;6:S3-9. 2. Nilsson CG, Palva K, Aarnio R, et al. Seventeen years’ follow-up of the tension-free vaginal tape procedure for female stress urinary incontinence. Int Urogynecol J. 2013;24:1265-1269. 3. U.S. Food and Drug Administration. Considerations about surgical mesh for SUI. Available at: http://www.fda.gov/MedicalDevices/ ProductsandMedicalProcedures/ImplantsandProsthetics/UroGyn SurgicalMesh/ucm345219.htm. Accessed February 26, 2014. 4. American Urogynecologic Society (AUGS) and the Society of Urodynamics, Female Pelvic Medicine and Urogenital Reconstruction (SUFU). Position statement on mesh midurethral slings for stress urinary incontinence. Available at: http://www.augs.org/p/ cm/ld/fid¼202. Accessed March 27, 2014. 5. Ostergard DR, Azadi A. To mesh or not to mesh with polypropylene: does carcinogenesis in animals matter? Inturogynecol J. 2014;25:569-571. 6. McGregor DB, Baan RA, Partensky C, et al. Evaluation of the carcinogenic risks to humans associated with surgical implants and other foreign bodies - a report of an IARC Monographs Programme Meeting. International Agency for Research on Cancer. Eur J Cancer. 2000;36:307-313. 7. Oppenheimer BS, Oppenheimer ET, Stout AP, et al. The latent period in carcinogenesis by plastics in rats and its relation to the presarcomatous stage. Cancer. 1958;11:204-213. 8. Williams D. Carcinogenicity of implantable materials: experimental and epidemiological evidence. Int Urogynecol J. 2014;25:577-580. 9. Kwon S, Latchamsetty K, Benson J, Carreno M. Inflammatory myofibroblastic tumor of the urinary tract following a TVT. Female Pelvic Med Reconstr Surg. 2012;18:249-251. 10. Birolini C, Minossi J, Lima C, et al. Mesh cancer: long-term infection leading to squamous cell carcinoma of the abdominal wall [e-pub ahead of print]. Hernia; http://dx.doi.org/10.1007/s1002 9-013-1083-x, 2013. Accessed March 27, 2014.
791
11. American Urogynecologic Society (AUGS) and the Society of Urodynamics, Female Pelvic Medicine and Urogenital Reconstruction (SUFU). Frequently asked questions by providers: midurethral slings for stress urinary incontinence. Available at: http:// www.sufuorg.com/docs/news/Provider-FAQs.aspx. Accessed March 27, 2014. 12. Moalli P, Brown B, Nager CW. Polypropylene mesh: evidence for lack of carcinogenicity. Int Urogynecol J. 2014;25:573-576. 13. Dwyer P, Riss P. Carcinogenicity of implanted synthetic grafts and devices. Int Urogynecol J. 2014;25:567-568. 14. Locke JR, Hill DE, Walzer Y. Incidence of squamous cell carcinoma in patients with long-term catheter drainage. J Urol. 1985; 133:1034-1035.
792
15. American Cancer Society. Bladder cancer. What are the key statistics about bladder cancer? Available at: http://www.cancer.org/ cancer/bladdercancer/detailedguide/bladder-cancer-key-statistics. Accessed February 28, 2014. 16. Insinga RP, Liaw KL, Johnson LG, Madeleine MM. A systematic review of the prevalence and attribution of human papillomavirus types among cervical, vaginal, and vulvar precancers and cancers in the United States. Cancer Epidemiol Biomarkers Prev. 2008;17:1611-1622. 17. Morgan R, Elcock M. Artificial Implants and soft tissue sarcomas. J Clin Epidemiol. 1995;4:545-549. 18. Witherspoon P, Bryson G, Wright DM, et al. Carcinogenic potential of commonly used hernia repair prosthesis in an experimental model. Br J Surg. 2004;91:368-372.
UROLOGY 84 (4), 2014
