Comprehensive molecular, pathological, and clinical characterization of clear cell adenocarcinoma of the urinary tract Journal Article
| Authors: | Rammal, R.; Koll, F. J.; Chen, Z.; Tallman, J. E.; Alam, S. M.; Eichholz, J. E.; Chatila, W.; Agbamu, T.; Lenis, A. T.; Basar, M.; Yol, C.; Chen, J. F.; Sarungbam, J.; Chen, Y. B.; Gopalan, A.; Fine, S. W.; Tickoo, S. K.; Antonescu, C. R.; Weigelt, B.; Abu-Rustum, N. R.; Grisham, R. N.; Momeni-Boroujeni, A.; Pietzak, E. J.; Bochner, B. H.; Rosenberg, J. E.; Iyer, G.; Reuter, V. E.; Solit, D. B.; Al-Ahmadie, H. |
| Article Title: | Comprehensive molecular, pathological, and clinical characterization of clear cell adenocarcinoma of the urinary tract |
| Abstract: | 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 and whole exome and targeted sequencing were performed. The landscape of somatic alterations was compared with ovarian and uterine clear cell carcinoma, and urothelial carcinoma. Among 35 utCCA, most patients were female (86%), and the most common primary tumor site was the urethra (83%) in association with urethral diverticula (51%). Median disease-free and overall survival rates 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 the diverticular lining. Although this is the largest study of utCCA to date, the study is limited by its small sample size, retrospective design, and clinical heterogeneity of the cohort. Molecular analysis of utCCA, including multiregion 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 a progression from intestinal metaplasia or divergent differentiation of a precursor urothelial carcinoma. © 2025 United States & Canadian Academy of Pathology |
| Keywords: | clear cell carcinoma; clear cell adenocarcinoma; next-generation sequencing; müllerian; urethral cancer; urethral diverticulum |
| Journal Title: | Modern Pathology |
| Volume: | 38 |
| Issue: | 10 |
| ISSN: | 0893-3952 |
| Publisher: | Nature Research |
| Date Published: | 2025-10-01 |
| Start Page: | 100821 |
| Language: | English |
| DOI: | 10.1016/j.modpat.2025.100821 |
| PUBMED: | 40553939 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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