Pathophysiology of Lichen Sclerosus Urethral Strictures: The Role of Inflammation and Viral Infection
Alison Levy, MD1; Kristian Stensland, MD1; Jennifer Bennett, MD1; Brendan Browne, MD1; Ariel Fredrick, MD1; Travis Sullivan, PhD1, Jason Badrinarain, MSc2, Jorge Yao, MD2; Kimberly Rieger-Christ, PhD1, Alex Vanni, MD1
1Lahey Hospital, Burlington, MA; 2Pathline Emerge, Ramsey, NJ
Background
Urethral stricture disease (USD) affects approximately 0.6-0.9% of susceptible populations. Lichen sclerosus (LS) is a chronic, inflammatory condition that is the presumed etiology in 14-29% of USD cases. Strictures due to LS are clinically distinct, behave more aggressively and are more likely to fail urethral reconstruction compared to non-LS strictures. The underlying pathophysiology of LS USD remains poorly understood, and to our knowledge no large-scale molecular studies have been performed on LS USD. To help elucidate the pathophysiology of LS USD we compared the protein expression of LS vs non-LS urethral strictures.
Methods
Tissue samples were collected from patients undergoing urethroplasty for USD and healthy controls. Clinical and demographic data was obtained from chart review. Paraffin slides were reviewed by in-house pathologists to identify areas of interest that appeared pathognomonic for LS. A tissue microarray (TMA) was created with cores from each sample and immunohistochemistry was performed for markers of inflammation, cell cycle disruption, oxidative stress, hormone receptor, and viral infection. Stains were evaluated semiquantitatively or qualitatively, as appropriate. Data were compared by Kruskal-Wallis or Fisher's exact test with significance of alpha=0.05.
Results
The cohort analyzed consisted of 58 men with LS USD, 23 men with non-LS USD, and 7 healthy controls. LS USD expressed significantly higher levers of CD8 and CCL4 than non-LS USD, both markers of inflammatory cell recruitment (p<0.01). TNF-alpha was only expressed in LS USD. Block-like p16 staining is associated with high-risk HPV infection and was only expressed in the LS USD tissues. LS USD was also significantly more likely to stain positively for latent Epstein-Barr Virus (p=0.02). There was no difference in markers of cell cycle disruption or oxidative stress and loss of androgen receptor expression was found in about half of all strictures.
Conclusion
To our knowledge, this is the first study to identify the molecular characteristics underlying the pathophysiology of LS USD. LS USD differs significantly from non-LS USD. Multiple markers indicate higher levels of inflammation in LS USD. The presence of EBV and block-like p16, which is associated with high-risk HPV infection, suggest there may be an infectious precursor to some LS urethral strictures. Expansion to a larger cohort of samples as well as analysis of biomarkers in different stages of LS (acute and chronic) are needed to help describe the molecular pathway of the disease.
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