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Protein Expression in Urethral Lichen Sclerosus: Potential for Biochemical Identification and Early Cancer Warning
Kristian D. Stensland, MD, Jennifer A. Bennett, MD, Brendan M. Browne, MD, Ariel K. Fredrick, MD, Jared P. Schober, MD, Travis B. Sullivan, MS, Kim M. Rieger-Christ, PhD, Alex J. Vanni, MD.
Lahey Hospital and Medical Center, Burlington, MA, USA.

BACKGROUND:
Lichen sclerosus (LS) is an inflammatory condition that, when expressed in the urethra, can lead to urethral stricture disease (USD). LS is a pathologic diagnosis, but the underlying pathophysiology leading to the disease is poorly understood. Prior biochemical research has focused on cutaneous and vulvar LS, but large-scale analysis of urethral LS has not been performed. Utilizing urethral samples with and without histologically confirmed LS, we sought to identify protein expression associated with LS USD.
METHODS:
Urethral tissue samples from patients undergoing urethroplasty for USD at a single institution were histologically evaluated for LS. Tissue from non-LS strictures, clinically suspected but not histologically confirmed LS strictures, and other control tissues (labia, foreskin, urethra) were also identified. A tissue microarray was created with cores from each sample and immunohistochemistry for p53, Ki-67, cyclin D1, and p16 was performed. p53 and Ki-67 were scored semiquantitatively and evaluated only in the basal and parabasal cells. Cyclin D1 was considered positive if >10% of cells were immunoreactive while p16 was positive if diffuse “block-like” nuclear staining was present in the basal cells. Data were compared by Kruskal-Wallis or Fisher’s exact test with significance of alpha=0.05, as appropriate.
RESULTS:
A total of 170 core samples, comprising 118 (69%) pathologic LS, 8 (4.7%) clinical LS, 18 (10.6%) non-LS strictures, and 26 (15.3%) control cores were assessed. p53 expression was significantly higher in pathologic LS compared to clinical LS and non-LS strictures (p=0.0018). Ki-67, cyclin D1, and p16 expression were not statistically significant (Table 1). The expression of p16, however, was only noted in pathologic LS samples.
CONCLUSION:
Urethral LS is more likely to express p53 compared to clinical LS and non-LS strictures. No difference in Ki-67 was observed among the three groups, which contrasts with increased expression previously reported in cutaneous and vulvar LS studies. Although p16 expression was not statistically significant, its expression was limited to pathological LS samples. Given that p16 is a surrogate marker for high-risk HPV infection, close clinical follow-up for patients with p16 positive LS USD is crucial to monitor for early squamous cell lesions. Molecular analysis of LS, and examination of early and late (or acute and chronic) phases of LS, will further elucidate potential mechanisms for pathologic transitions along the theoretical pathway from normal tissue to LS.
Table 1:
ImmunostainPathologic LSClinical LSNon-LS StrictureControlP value
P530.0018
Negative20 (16.9%)04 (22.2%)7 (26.9%)
<1%17 (14.4%)4 (50%)6 (33.3%)10 (38.5%)
<50%54 (46.8%)3 (37.5%)6 (33.3%)6 (23.1%)
>50%27 (22.9%)1 (12.5%)2 (11.1%)3 (11.5%)
Ki-670.2416
Negative10 (8.5%)2 (25%)03 (11.5%)
<1%8 (6.8%)02 (11.1%)2 (7.7%)
1-10%24 (20.3%)2 (25%)4 (22.2%)6 (23.1%)
10-25%46 (39.0%)3 (37.5%)11 (61.1%)12 (46.2%)
25-50%29 (24.6%)1 (12.5%)1 (5.6%)2 (7.7%)
>50%1 (0.8%)001 (3.8%)
Cyclin D10.919
Negative21 (17.8%)1 (12.5%)3 (16.7%)3 (11.5%)
Positive97 (82.2%)7 (87.5%)15 (83.3%)23 (88.5%)
P16
Negative110 (93.2%)8 (100%)18 (100%)26 (100%)0.5931
Positive8 (6.8%)000


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