Cancer Res Treat.  2024 Jan;56(1):280-293. 10.4143/crt.2023.577.

Clear Cell Adenocarcinoma of Urethra: Clinical and Pathologic Implications and Characterization of Molecular Aberrations

• Song B
• Lee SH
• Park JH
• Moon KC

• KMID: 2550343
• DOI: http://doi.org/10.4143/crt.2023.577

Abstract

Purpose
This study aimed to evaluate the molecular features of clear cell adenocarcinoma (CCA) of the urinary tract and investigate its pathogenic pathways and possible actionable targets.
Materials and Methods
We retrospectively collected the data of patients with CCA between January 1999 and December 2016; the data were independently reviewed by two pathologists. We selected five cases of urinary CCA, based on the clinicopathological features. We analyzed these five cases by whole exome sequencing (WES) and subsequent bioinformatics analyses to determine the mutational spectrum and possible pathogenic pathways.
Results
All patients were female with a median age of 62 years. All tumors were located in the urethra and showed aggressive behavior with disease progression. WES revealed several genetic alterations, including driver gene mutations (AMER1, ARID1A, CHD4, KMT2D, KRAS, PBRM1, and PIK3R1) and mutations in other important genes with tumor-suppressive and oncogenic roles (CSMD3, KEAP1, SMARCA4, and CACNA1D). We suggest putative pathogenic pathways (chromatin remodeling pathway, mitogen-activated protein kinase signaling pathway, phosphoinositide 3-kinase/AKT/mammalian target of rapamycin pathway, and Wnt/β-catenin pathway) as candidates for targeted therapies.
Conclusion
Our findings shed light on the molecular background of this extremely rare tumor with poor prognosis and can help improve treatment options.

Keyword

Clear cell adenocarcinoma of the urinary tract; Exome sequencing; Pathogenesis; Molecular targeted therapy

Figure

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  Fig. 1. Histopathology of the clear cell adenocarcinoma of the urinary tract. (A) The tumor within urethral diverticulum (×12.5). (B) Tubulopapillary architecture with fibrovascular cores (×40). (C) Urethral diverticulum showing atypical cell lining (×200). (D) Eosinophilic hobnail cells (×200). (E) Tubulocystic architecture (×100). (F) Clear cells with solid growth pattern (×400).

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  Fig. 2. Immunohistochemical features of the clear cell adenocarcinoma of the urinary tract. (A) CK7 positivity (membranous/cytoplasmic) (×200). (B) PAX8 positivity (nuclear) (×200). (C) AMACR (P504S) positivity (cytoplasmic granular) (×200). (D) GATA3 negativity (×200). (E) HNF1β positivity (nuclear) (×200). (F) Napsin A positivity (cytoplasmic) (×200).

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  Fig. 3. Comparison of the genetic alterations of clear cell adenocarcinoma of urinary tract with The Cancer Genome Atlas data sets of endometrial, ovarian, bladder, and clear cell kidney cancers. ccRCC, clear cell renal cell carcinoma; EC, endometrial carcinoma (uterus); SC, serous carcinoma (ovary); UC, urothelial carcinoma (bladder).

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  Fig. 4. Protein-protein interaction and network analysis.

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  Fig. 5. ARID1A protein expression and loss in clear cell adenocarcinoma (CCA) of the urinary tract. (A) ARID1A wild type with strong nuclear staining of ARID1A immunohistochemical staining (B) ARID1A protein loss in CCA with p.Trp1545*ARID1A mutation (case 5) (A and B, ×400).

Reference

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