Ariel Fredrick

PURPOSE: We evaluated the pathophysiology of lichen sclerosus and nonlichen sclerosus urethral stricture disease by comparing protein expression related to inflammation, cell cycle disruption, oxidative stress, hormone receptor status and infection. MATERIALS AND METHODS: Tissue samples were collected from the urethral strictures of 81 patients undergoing urethroplasty. Clinical and demographic data were obtained by chart review. After identifying areas pathognomonic for lichen sclerosus a tissue microarray was created with cores from each sample and immunohistochemistry was performed. RESULTS: Patients had similar baseline demographics and comorbidities. Of the 81 strictures 58 were and 23 were not due to lichen sclerosus. Lichen sclerosus strictures were significantly longer and showed higher levels of inflammation. The proportion of T cells which stained positive for CD8 was significantly higher in strictures due to lichen sclerosus (50% vs 13%, p = 0.004). CCL-4 was expressed significantly more in strictures due to lichen sclerosus (76% vs 42%, p = 0.01). Several other inflammatory markers were only found in strictures due to lichen sclerosus. Block-like p16, a surrogate for high risk human papillomavirus infection, and varicella zoster virus were found only in lichen sclerosus urethral stricture disease samples, although both were rare. Epstein-Barr virus RNA was found in significantly more lichen sclerosus samples (37% vs 10%, p = 0.024). CONCLUSIONS: To our knowledge this is the first study to evaluate protein expression in lichen sclerosus urethral stricture disease. These strictures demonstrate increased inflammation compared to nonlichen sclerosus urethral strictures. Markers of oxidative stress, cell cycle dysregulation and the androgen receptor do not appear to be uniquely associated with lichen sclerosus urethral stricture disease. Positive staining for several viruses in samples of lichen sclerosus urethral stricture disease suggests a possible infectious etiology.

PURPOSE: Bulbar urethroplasty outcomes studies have shown low but significant rates of post-void dribbling and ejaculatory dysfunction. The bulbospongiosus muscle is involved with the expulsion of seminal fluid and urine from the bulbar urethra and, thus, we hypothesized that performing urethroplasty using a technique that does not split the muscle may result in better postoperative patient reported ejaculatory function and less post-void dribbling. MATERIALS AND METHODS: We performed a multi-institutional matched, case-control analysis comparing men treated with a bulbospongiosus sparing technique to men treated with the traditional nonbulbospongiosus sparing technique. Preoperative and postoperative (3 to 12 months) ejaculatory function was assessed using the 4 ejaculatory questions of the Male Sexual Health Questionnaire short form as well as a patient perception questionnaire. Post-void dribbling was assessed using a validated urethroplasty questionnaire. RESULTS: A total of 25 patients who underwent bulbospongiosus sparing urethroplasty and 25 who underwent nonbulbospongiosus sparing urethroplasty were matched by total preoperative Male Sexual Health Questionnaire score, age, and performance of excision and primary anastomosis. The bulbospongiosus sparing and nonbulbospongiosus sparing groups had similar postoperative total Male Sexual Health Questionnaire scores (15.24 vs 15.40, respectively, p=0.90) and there were no significant postoperative questionnaire score changes in either group (bulbospongiosus sparing 14.56 to 15.24, p=0.4; nonbulbospongiosus sparing 14.64 vs 15.40, p=0.44). Individual responses to the Male Sexual Health Questionnaire were analyzed and no statistically significant difference was found between the groups. Rates of postoperative post-void dribbling and perception of ejaculatory function were similar between the groups. CONCLUSIONS: Sparing the bulbospongiosus muscle during urethroplasty does not seem to have a significant impact on patient reported ejaculatory function or post-void dribbling compared with nonbulbospongiosus sparing urethroplasty at early followup.

PURPOSE: Urethroplasty of lichen sclerosus strictures has a significantly higher failure rate than strictures due to other causes. We sought to determine predictors of urethroplasty failure in men with lichen sclerosus urethral stricture disease by evaluating protein expression profiles. MATERIALS AND METHODS: Urethral tissue was excised from patients with lichen sclerosus who were undergoing urethroplasty of urethral stricture disease at a single institution. A tissue microarray was created with cores from each sample. Immunohistochemistry was performed to compare protein expression related to inflammation, cell cycle disruption, oxidative stress, hormone receptor status and infection. Stricture recurrence was defined by the need for a subsequent unanticipated procedure for urethral stricture disease. RESULTS: We evaluated 50 men with lichen sclerosus urethral stricture disease, including 31 with successful reconstruction and 19 with recurrent stricture. Recurrent strictures expressed lower levels of several inflammatory markers and had a lower Ki-67 mitotic index and significantly higher vascular endothelial growth factor levels than nonrecurrent strictures. CONCLUSIONS: To our knowledge this is the first study to use tissue protein expression to identify risk factors for urethroplasty failure among men with lichen sclerosus urethral stricture disease. Our findings suggest that recurrent lichen sclerosus strictures demonstrate a suppressed inflammatory response, a decreased cell turnover rate, and poor oxygenation and nutrient delivery. Prospective studies are needed to clarify the role of these pathways in the pathophysiology of lichen sclerosus urethral stricture disease, determine whether preoperative biopsy can predict urethroplasty success, help counsel patients and develop future treatments.