JU INSIGHT Deep Phenotyping the Anterior Urethral Stricture

By: Wade R. Gutierrez, MD, PhD, Carver College of Medicine, University of Iowa, Iowa City; Yi Luo, PhD, Carver College of Medicine, University of Iowa, Iowa City; Laila Dahmoush, MD, Carver College of Medicine, University of Iowa, Iowa City; Jacob J. Oleson, PhD, College of Public Health, University of Iowa, Iowa City; Charles H. Schlaepfer, MD, Carver College of Medicine, University of Iowa, Iowa City; Benjamin N. Breyer, MD, MAS, University of California, San Francisco; Sean P. Elliott, MD, MS, University of Minnesota, Minneapolis; Jeremy B. Myers, MD, University of Utah, Salt Lake City; Alex J. Vanni, MD, Lahey Hospital and Medical Center, Burlington, Massachusetts; Denise Juhr, BA, Carver College of Medicine, University of Iowa, Iowa City; Katherine N. Christel, MD, Carver College of Medicine, University of Iowa, Iowa City; Bradley A. Erickson, MD, MS, Carver College of Medicine, University of Iowa, Iowa City | Posted on: 17 Jul 2024

Gutierrez WR, Luo Y, Dahmoush L, et al. Deep phenotyping the anterior urethral stricture: characterizing the relationship between inflammation, fibrosis, patient history, and disease pathophysiology. J Urol. 2024;212(1):153-164. doi:10.1097/JU.0000000000003962

Study Need and Importance

The most common etiology of anterior urethral stricture disease (aUSD) is idiopathic. This gap in knowledge has been of little concern historically as surgical treatments for aUSD, especially in the bulbar urethra, rarely consider stricture cause. However, while urethroplasties have high anatomic surgical success rates, they are not benign procedures, with outcomes studies showing clinically significant rates of postoperative sexual dysfunction and persistent lower urinary tract symptoms that are of concern to our patients, both pre- and postoperatively. The recent addition of dilating balloons, capable of precisely delivering drugs to the urethra, to the treatment armamentarium has also generated a renewed interest in obtaining a better understanding of aUSD pathophysiology, as personalized, etiology-specific aUSD treatments appear to be getting closer to reality.

What We Found

Three aUSD cohorts were enrolled: traumatic (n = 33), idiopathic (n = 78), and lichen sclerosus (LS; n = 27). Deep phenotyping included patient-reported outcome measures, serum inflammatory/fibrosis markers, and histopathology. Our general hypothesis was that idiopathic and traumatic phenotypes would resemble each other given conventional wisdom that assumes idiopathic strictures are of subacute and/or forgotten urethral traumas. Instead, we found idiopathic strictures to more closely resemble LS strictures, with both having significantly higher rates of chronic inflammation in both the stricture (54% and 48% vs 27%) and in nonstrictured urethral tissue, vs traumatic strictures (Figure). All cohorts, regardless of etiology, had higher levels of circulating cytokines associated with inflammation (interleukin-9) and fibrosis (platelet-derived growth factor-BB and CCL5) vs controls, suggesting a possible shared aUSD predisposition.

Figure. A, Retrograde urethrogram and histopathologic specimen in a nonstrictured (proximal) urethra segment in a study participant with idiopathic urethral stricture etiology. B, Lymphocytic subepithelial infiltration. C, Normal urethral epithelium. D, Urethral squamous metaplasia.

Limitations

The antigen and/or organism responsible for the inflammation in idiopathic and LS strictures remains elusive, limiting our current ability to use histopathology to direct treatments.

Interpretation for Patient Care

Idiopathic strictures appear to be a unique subset of strictures with high rates of inflammation that extends beyond the visible stricture that is of unknown clinical significance. However, one might consider treating idiopathic strictures surgically and/or endoscopically beyond the visible stenosis if the entire field of pathology is to be managed. Urethral biopsy may eventually show pretreatment clinical utility.