Clear cell adenocarcinoma of the urinary tract (utCCA) is a rare, Müllerian-type tumor typically arising in the urethra of female patients with poorly understood pathogenesis. Here, we report the clinical, pathologic, and molecular characterization of a cohort of utCCA treated at a tertiary referral center. Cases were centrally reviewed and immunohistochemistry was performed as needed. Whole exome and targeted sequencing were performed. The landscape of somatic alterations was compared to ovarian CCA, uterine CCA, and urothelial carcinoma (UC). Among 35 utCCA, most patients were female (86%), and most common primary tumor site was the urethra (83%) in association with urethral diverticula (51%). Median disease-free and overall survivals were 42 and 65 months, respectively. The most common mutations were in ARID1A and TP53. Mutations in TERT promoter and other chromatin modifying genes were rare. Phylogenic analysis suggested that utCCA arises from a dysplastic clear cell precursor developing within diverticular lining. While the largest study of utCCA to date, the study is limited by small sample size, retrospective design, and clinical heterogeneity of the cohort. Molecular analysis of utCCA, including multi-region sequencing of tumor and adjacent urethral and diverticular lining, supports a potential mechanism of disease pathogenesis in which most utCCA arise from regions of clear cell dysplasia, possibly resulting from chronic inflammation in the setting of urinary stasis, and not through progression from intestinal metaplasia or divergent differentiation of a precursor UC.
Keywords: Clear cell adenocarcinoma; Mullerian; next generation sequencing; urethral cancer; urethral diverticulum.
Copyright © 2025. Published by Elsevier Inc.