Author's Accepted Manuscript Lichen Sclerosus in Isolated Bulbar Urethral Stricture Disease Joceline S. Liu, Kelly Walker, Daniel Stein, Sanjiv Prabhu, Matthias D. Hofer, Justin Han, Ximing J. Yang, Chris M. Gonzalez

PII: DOI: Reference:

S0022-5347(14)03025-0 10.1016/j.juro.2014.03.090 JURO 11352

To appear in: The Journal of Urology Accepted Date: 13 March 2014 Please cite this article as: Liu JS, Walker K, Stein D, Prabhu S, Hofer MD, Han J, Yang XJ, Gonzalez CM, Lichen Sclerosus in Isolated Bulbar Urethral Stricture Disease, The Journal of Urology® (2014), doi: 10.1016/j.juro.2014.03.090. DISCLAIMER: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our subscribers we are providing this early version of the article. The paper will be copy edited and typeset, and proof will be reviewed before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to The Journal pertain. All press releases and the articles they feature are under strict embargo until uncorrected proof of the article becomes available online. We will provide journalists and editors with full-text copies of the articles in question prior to the embargo date so that stories can be adequately researched and written. The standard embargo time is 12:01 AM ET on that date.

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Lichen Sclerosus in Isolated Bulbar Urethral Stricture Disease

Joceline S. Liu MD1*, Kelly Walker BS1, Daniel Stein MD1, Sanjiv Prabhu MD2, Matthias D. Hofer MD1,

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Justin Han MD1, Ximing J. Yang MD, PhD2, Chris M. Gonzalez MD1

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Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL

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Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL

*Corresponding author 303 E Chicago Avenue, Tarry 16 Chicago, IL 60611

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Phone: +1312-695-8146 Fax: +1312-908-7275

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E-mail: [email protected]hwestern.edu

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Keywords: lichen sclerosus, urethral stricture, pathology

There are no conflicts of interest for the listed authors.

Abstract word count: 239 Text word count: 2156

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ABSTRACT

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Purpose: Lichen sclerosus (LS) is a chronic inflammatory genital skin condition that can cause

destructive urethral scarring. No prior studies have reported LS in isolated bulbar urethral stricture segments without the presence of progressive disease originating from the penile urethra.

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We report the incidence of LS in isolated bulbar urethral stricture segments.

Materials and Methods: We retrospectively reviewed 70 patients following urethroplasty for isolated

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bulbar stricture disease (2007-2013). Stricture specimens were re-reviewed by a single uropathologist. Cases were evaluated using common histologic features in LS including hyperkeratosis or epithelial atrophy, vacuolar degeneration of basal cells, lichenoid lymphocytic infiltrate, and presence of superepithelial sclerosis.

Results: Average patient age was 46.5 (19-77) years and stricture length was 3.5 (1-7) cm. Fifty-one

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patients (73.0%) underwent excision and primary anastomosis, and 19 (27.1%) onlay of buccal mucosal. Six patients (8.6%) developed recurrent stricture over a median follow-up of 22 (IQR 14, 44) months, of which 3 had LS. Initial pathology showed LS in 5 patients, (7.1%) (95% CI: 1.0-13.3%). On re-review of

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specimens using LS-specific pathologic criteria, 31 patients (44.3%) (95% CI: 32.4-56.2%), showed pathology highly suggestive (13) or diagnostic (18) for LS (p=0.0001). On pathologic re-review LS was

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associated with stricture recurrence.

Conclusions: On re-review of surgical specimens we report a significant incidence of LS in isolated bulbar strictures in men undergoing urethroplasty. The incidence of LS may be higher than reported in isolated bulbar urethral segments without evidence of distal to proximal progressive urethral disease.

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INTRODUCTION

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Lichen sclerosus (LS) is a chronic inflammatory skin condition commonly involving the anogenital area.1 LS can cause destructive genitourinary scarring and confers an increased risk of penile squamous cell carcinoma although a causal relationship remains to be established.2 In men In

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with urethral stricture, the incidence of urethral LS is reported to be between 4.8-14%.3

comparison to urethral stricture of other etiologies, LS-related urethral strictures have a higher

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rate of treatment related morbidity and disease recurrence which necessitates accurate diagnosis and staging in order to plan the appropriate management.4 While treatment of LS limited to the glans and urethral meatus has acceptable outcomes with minimally invasive approaches such as circumcision and meatotomy, more extensive or pan-urethral disease warrants more invasive

genital skin or oral mucosa.5-7

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therapy including one-stage oral graft urethroplasty versus staged urethroplasty with non-

Urethral LS is thought to originate at the meatus and/or preputial skin, with potential

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progression of disease proximally along the urethra.7 The progressive, proximal spread of LS is believed to result from a combination of embryological factors with extension of disease through

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urethral glands or transformation of disease secondary to high pressure voiding and inflammation of the urethra.8, 9 No prior studies have reported LS in isolated bulbar urethral stricture segments, without the presence of progressive disease extending from the penile urethra or glans. We report the incidence of LS in isolated bulbar urethral stricture segments on re-review of bulbar urethroplasty specimens. We hypothesize that the incidence of LS involvement in isolated bulbar urethral stricture disease has been under-reported to date.

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MATERIALS AND METHODS

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We performed an institutional review board approved retrospective study of patients who underwent urethroplasty for isolated bulbar stricture disease at a single institution between 2007 and 2013. Isolated bulbar urethral stricture was defined based on intraoperative findings,

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with stricture disease limited to urethra proximal to penoscrotal junction and distal to the sphincter. Patients with less than 1 year of follow-up, history of LS involvement of the more

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distal penile urethra and meatus or a history of urethral trauma (i.e. straddle injury, urethral disruption or tear, pelvic fracture) were excluded from the analysis. The final study cohort included 70 patients. Patient data were retrospectively gathered from electronic medical records. Demographic information, etiology, comorbidities, smoking history, prior procedures, surgical

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intervention, outcomes and pathology were reviewed based on inpatient and outpatient history and physical, problem list, and progress notes. Initial surgical pathology results of excised stricture were reviewed from electronic medical records and categorized according to the original

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pathologic diagnosis.

At our institution, we routinely encounter and excise the stricture during end

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primary anastomosis (EPA), or a small sample of scar tissue at the cut edges of the urethrotomy during onlay urethroplasty, and send this for pathologic analysis. Stricture specimens at the time of urethroplasty were retrospectively reviewed by a single uropathologist (X.J.Y.), who was blinded to patient history and prior histopathologic diagnosis. Slides stained with hematoxylin and eosin were requested and obtained. Cases were evaluated using 5 common histologic features in LS: (1) hyperkeratosis, (2) thinning or thickening of the epidermis or squamous epithelium, (3) attenuation or vacuolar degeneration of the basal cell layer, (4)

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subepithelial hyalinization/dermal collagen homogenization, and (5) lichenoid lymphocytic or plasmacytic infiltrate. 10,11 While each individual finding is suggestive of LS, the combination of these pathologic features are the basis of pathologic diagnosis of LS12; there is no gold

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standard of objective criteria for the systematic evaluation of LS. Recently, new diagnostic pathologic criteria was developed for LS in which cases with 0 or 1 features were deemed

negative for LS, cases with 2 features, suggestive for LS and cases with 3 or more features,

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diagnostic for LS (The United States and Canadian Academy of Pathology 2014 Annual Meeting).

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The incidence of LS on original pathology (based on review of medical record pathology report) and on specimen re-review (categorized into those with pathology suggestive or diagnostic of LS based on the described scheme) were compared using student’s t-test. Patient characteristics were compared between those with and without LS on re-review of pathology

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slides using the Mann-Whitney U and Fisher’s exact tests. Recurrence was defined by patientreported urinary symptoms confirmed with the endoscopic diagnosis of recurrent urethral stricture < 16F in caliber. The rate of recurrence was compared between those patients with and

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without LS on re-review using the chi-squared test. For all statistical analyses, P < 0.05 was

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considered statistically significant. Analysis was performed using SPSS®, version 21.

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RESULTS

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A total of 70 men with an average age of 46.5 years (range 19-77) underwent bulbar urethroplasty for isolated bulbar stricture disease, with no preceding history of urethral trauma, and at least 1 year of follow-up. Average urethral stricture length was 3.5 cm (range 1 to 7). Ten

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patients (14.2%) had a smoking history, 43 (61.4%) had undergone prior intervention for

stricture, of which 3 (4.3%) had prior urethroplasty and 5 (7.1%) prior hypospadias repair related

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urethral complications. Fifty-one patients (73.0%) underwent EPA, and 18 (25.7%) and 1 (1.4%) underwent dorsal or ventral onlay of buccal mucosal graft, respectively. Initial surgical pathology reports mentioned LS involvement in 5 patients (7.1%) (95% CI: 1.0-13.3%) with findings suggestive of LS in one patient (1.4%) and diagnosis of LS in 4 patients (5.7%). On re-review of pathology slides in a blinded fashion by a single, specialized

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uropathologist, using the diagnostic criteria described previously, 31 patients (44.3%) (95% CI: 32.4-56.2%) fulfilled pathologic criteria for LS. Of these 31 patients, pathology was highly suggestive of LS in 13 patients (18.6%) and diagnostic for LS in 18 patients (25.7%) (Figure 1).

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Representative sections highlighting characteristic histopathologic findings in LS are shown in

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Figure 2. The incidence of LS on the initial pathology report as compared to re-review was significantly different (p=0.0001). No statistically significant difference existed between patients with and without LS on re-review, although patients with a history of prior failed intervention such as hypospadias repair or urethroplasty showed a trend towards pathologic findings of LS on re-review, p=0.08 (Table 1). Six patients (8.6%) developed stricture recurrence requiring intervention at a median follow-up of 22 months (IQR 14, 44). Average stricture length was 3.5 cm (95% CI: 3.1-3.8cm)

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in patients without recurrence versus 4.3 cm (95% CI: 2.7-5.8cm) in patients with recurrence; pre-operative stricture length was not statistically different in patients with and without recurrence (p=0.21). Five patients had buccal mucosal graft onlay, while one underwent

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EPA. Location of recurrence was distal relative to urethroplasty in 3 patients, proximal in 2 patients and unknown in one patient who underwent cystoscopy by an outside urologist. In patients without recurrence at last follow-up, the incidence of LS on re-review was 40.6%

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(95% CI: 28.3-52.3%), versus 83.3% (95% CI: 40.5-100%) in patients with recurrence.

Recurrence was significantly more common in patients with pathologic findings suggestive of or

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diagnostic for LS (p=0.04).

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DISCUSSION

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The true incidence of male urethral LS is unknown, but several retrospective studies have estimated the incidence of LS in males undergoing evaluation or repair of urethral strictures, ranges from 4.8-29%.3, 13 In a retrospective study of 1439 men with urethral stricture, Palminteri

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reported LS as the etiology of stricture in 13.5% of men overall, with specific involvement of the penile urethra in 24.4%, penile plus bulbar urethra in 23.9% and panurethral involvement in

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48.6%.3 Of note, no patients were identified with LS in an isolated bulbar stricture or posterior stenosis.3 Barbagli reviewed 106 patients undergoing urethroplasty for anterior urethral stricture, in which 29% had a pathologic diagnosis of LS.8 LS involved the meatus in 19%, fossa navicularis in 17%, penile urethra in 3% and the entire urethra in 52% of cases.8 Similar to Pamlinteri et al there was no report of an isolated bulbar stricture associated with LS. Numerous

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other reports on the etiopathogenesis of LS in urethral stricture corroborate these findings. 7,14,15 In our study 70 men underwent urethroplasty for isolated bulbar urethral stricture. Pathology at the time of surgery reported evidence of LS in 7.1% of these patients which is

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noteworthy. On histopathologic re-review by a blinded uropathologist using an expert consensus

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driven rubric of characteristic pathologic findings for LS, 44.3% of men had pathologic findings consistent with LS (18.6% suggestive, 25.7% diagnostic). The statistically significant increase in LS identified on re-review suggests that a combination of evaluation by a specialized uropathologist and reference to characteristic histopathologic findings in LS may allow for a higher detection rate. As a result of rigorous re-examination of isolated bulbar urethral stricture specimens within our institution, 26 cases of previously unrecognized LS were identified. This study comprises the only series where LS was identified pathologically following urethroplasty

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in isolated bulbar urethral strictures with no evidence of progressive disease extending to the bulbar urethra from more distal disease. Despite the study limitations these data call into question the previously accepted beliefs regarding the pathogenesis and pathophysiology of LS

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distal to proximal progression patterns within the male urethra. While the described incidence of LS may be higher than in the general population due to selection bias from a tertiary referral center, the identification of any LS in isolated bulbar urethral strictures is a novel finding and

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questions the existing understanding of the pathophysiology of disease progression.

We base our diagnosis of LS on re-review due to a newly developed histopathologic

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evaluation system based on five tissue features: hyperkeratosis, thinning or thickening of the epidermis or squamous epithelium, attenuation or vacuolar degeneration of the basal cell layer, subepithelial hyalinization/dermal collagen homogenization, and lichenoid lymphocytic or plasmacytic infiltrate. It is intriguing that nearly half of our patients with isolated bulbar

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strictures had at least two of these features. This could suggest that such features of mucosal atrophy are the result of an aberrant healing process and that LS may become fully apparent at the end of this process. LS could therefore be seen as a symptom of aberrant wound healing

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resulting in mucosal atrophy rather than a disease process itself. Further studies evaluating our histopathologic features in separate patient cohorts with isolated bulbar urethral stricture

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specimens would contribute to answering this question. LS has long been associated with chronicity of stricture disease, with subsequent increased risk of recurrence despite aggressive surgical management.8 Of the 70 patients studied in our series, six (8.6%) developed recurrence over the course of a median follow-up of 22 months. Of the six patients with recurrence, five (83.3%) had LS on pathologic re-review. Notably, mean stricture length in those with and without stricture recurrence (3.5 and 4.3 cm,

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respectively) were not statistically different. Pathologic evidence of LS on re-review was significantly associated with recurrence (p=0.04). These results support the existing body of literature on the increased risk of recurrence in patients with LS following definitive surgical

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management. 8 Stricture recurrence is likely multifactorial, involving patient comorbidities, surgical technique as well as surgical factors not captured in this study. LS may still exist in other areas of the urethra, not sampled during urethroplasty, despite focal bulbar stricture

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disease. Thus, our findings may result from a two-hit scenario, where LS and another insult in the bulbar urethra may translate to a clinically significant stricture. Nonetheless

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preoperative suspicion for LS involvement in isolated bulbar stricture segments may alter management strategy through the reconstructive approach offered, namely EPA versus substitution urethroplasty. The diagnosis of LS involvement in a short, isolated bulbar urethral stricture would also influence patient counseling regarding endoscopic approaches to establish

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urethral patency due to the aggressive pathophysiology of LS.

Although our study is limited in its retrospective nature of a limited sample size at a single institution, we feel the findings remain significant and warrant further investigation in

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regards to the pathophysiology of LS. Previously unrecognized LS was detected in a significant proportion of our study cohort of 70 patients within isolated bulbar stricture segments. We feel

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these results require elaboration and confirmation in large multi-institutional cohort with multiple pathologists. Our study is also limited by length of follow-up, which may prevent recognition of certain patient variables that are associated with recurrence after urethroplasty, that are not realized here. Controversy exists regarding the optimal management of urethral LS, with some studies proposing complete excision of the involved urethral mucosa and repair with single- or staged-urethroplasty using a non-genital skin graft 7, 16, 17, while others suggest

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consideration of perineal urethrostomy, particularly in the elderly population.18 Identification of LS prior to or at the time of surgery may not only afford an etiology for the stricture, but may

stricture recurrence and potential malignancy risk related to LS.

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CONCLUSIONS

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also provide guidance for surgical management as well as long-term follow-up strategy for

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We report a significant incidence of LS in isolated bulbar urethral stricture disease in men undergoing urethroplasty on re-review of surgical specimens, which has not been previously reported. The incidence of LS may be higher than previously believed in isolated bulbar urethral stricture segments. The early recognition of LS in an isolated bulbar urethral stricture may

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influence treatment planning and follow-up for the patient.

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REFERENCES:

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1. Powell JJ, Wojnarowska F. Lichen sclerosus. Lancet 1999;353:1777. 2. Philippou P, Shabbir M, Ralph DJ, et al. Genital lichen sclerosus/balanitis xerotica obliterans in men with penile carcinoma: a critical analysis. BJU Int 2013;111:970. 3. Palminteri E, Berdondini E, Verze P, et al. Contemporary urethral stricture characteristics in the developed world. Urology 2013;81:191. 4. Dubey D, Sehgal A, Srivastava A, et al. Buccal mucosal urethroplasty for balanitis xerotica obliterans related urethral strictures: the outcome of 1 and 2-stage techniques. J Urol 2005;173:463. 5. Mangera A, Chapple C. Management of anterior urethral stricture: an evidence-based approach. Curr opin urol 2010;20:453. 6. Meeks JJ, Barbagli G, Mehdiratta N, et al. Distal urethroplasty for isolated fossa navicularis and meatal strictures. BJU Int 2012;109:616. 7. Kulkarni S, Barbagli G, Kirpekar D, et al. Lichen sclerosus of the male genitalia and urethra: surgical options and results in a multicenter international experience with 215 patients. Eur Urol 2009;55:945. 8. Barbagli G, Lazzeri M, Palminteri E, et al. Lichen sclerosis of male genitalia involving anterior urethra. Lancet 1999;354. 9. Barbagli G, Mirri F, Gallucci M, et al. Histological evidence of urethral involvement in male patients with genital lichen sclerosus: a preliminary report. J Urol 2011;185:2171. 10. Barbagli G, Palminteri E, Balo S, et al. Lichen sclerosus of the male genitalia and urethral stricture diseases. Urol Int 2004;73:1. 11. Clouston D, Hall A, Lawrentschuk N. Penile lichen sclerosus (balanitis xerotica obliterans). BJU Int 2011; 108: 14. 12. Murphy R. Lichen sclerosus. Dermatol clin 2010;28:707. 13. Stein DM, Thum DJ, Barbagli G, et al. A geographic analysis of male urethral stricture aetiology and location. BJU Int 2013;112:830. 14. Depasquale I, Park AJ, Bracka A. The treatment of balanitis xerotica obliterans. BJU Int 2000;86:459. 15. Lumen N, Hoebeke P, Willemsen P, et al. Etiology of urethral stricture disease in the 21st century. J Urol 2009;182:983. 16. Pugliese JM, Morey AF, Peterson AC. Lichen sclerosus: review of the literature and current recommendations for management. J Urol 2007;178:2268. 17. Levine LA, Strom KH, Lux MM. Buccal mucosa graft urethroplasty for anterior urethral stricture repair: evaluation of the impact of stricture location and lichen sclerosus on surgical outcome. J Urol 2007;178:2011. 18. Peterson AC, Palminteri E, Lazzeri M, et al. Heroic measures may not always be justified in extensive urethral stricture due to lichen sclerosus (balanitis xerotica obliterans). Urology 2004;64:565.

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LEGENDS: Figure 1: Incidence of lichen sclerosus (LS) on initial pathology and with re-review. Based on

categorized as having pathology suggestive or diagnostic of LS.

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number of characteristic histopathologic findings for LS identified, patients were further

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Figure 2: Two different cases considered diagnostic for lichen sclerosus (H&E, 10x original magnification). A. Prominent histopathologic features include basal layer degeneration (*) and

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chronic lichenoid inflammatory infiltrate (arrow). B. Hyperkeratosis ( ), attenuation of the epithelium (arrowhead), and subepithelial hyalinization (X) are present

Table 1: Patient characteristics with or without pathologic evidence of LS on re-review. Mann-

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Whitney U and Fischer’s exact test utilized to determine statistical significance. CI = 95% confidence intervals; LS = lichen sclerosus; EPA = excision and primary anastomosis;

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DM = diabetes mellitus.

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ABBREVIATIONS

LS = lichen sclerosus

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EPA = end primary anastomosis

Lichen sclerosus and isolated bulbar urethral stricture disease.

Lichen sclerosus is a chronic inflammatory genital skin condition that can cause destructive urethral scarring. To our knowledge no prior study has de...
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