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Molecular Characterization of Plasmacytoid Urothelial Carcinoma and the Impact on Treatment Implications - Beyond the Abstract

Plasmacytoid urothelial carcinoma (PUC) is an aggressive histologic subtype of urothelial carcinoma that demonstrates worse outcomes than conventional urothelial carcinoma (CUC).1,2

This differential response to treatment is likely due to differences in the underlying tumor biology and, therefore, understanding molecular alterations impacting the development and progression of PUC is critical to improving patient outcomes. To summarize what is known about molecular aberrations present in PUC, we reviewed the current literature and discussed how specific alterations could influence therapeutic efficacy.

As described in this comprehensive review, the most distinct alteration identified in PUC distinguishing it from CUC is loss of E-cadherin protein expression.3 This loss is frequently due to mutations in CDH1, the gene encoding E-cadherin. E-cadherin, a cell adhesion molecule, is part of the epithelial mesenchymal transition (EMT) pathway that can promote metastasis.4  In PUC, loss of E-cadherin likely explains the propensity of PUC to spread along pelvic fascial planes and the likelihood of peritoneal carcinomatosis, which is not as frequently seen in CUC.5 Other alterations identified more commonly in PUC compared to CUC include increased CD1386 and Her2 expression and a higher incidence of mutations in p53 and RB14.7 Additional alterations, such as those impacting the mTOR pathway8 and Nectin-4,9 among others, are seen in both PUC and CUC but could provide therapeutic targets.

While the reviewed studies demonstrate CDH1 mutation and E-cadherin loss in up to 100% of PUC3, the downstream effects of this loss in PUC have mostly been inferred from other tumor types or model systems. Therefore, the interplay between CDH1 loss and other mutations in urothelial carcinoma (such as p53 or RB1) or the bladder cancer microenvironment is not well understood. As immunotherapy is a mainstay of treatment for urothelial carcinoma, understanding how E-cadherin loss impacts the immune microenvironment and response to immune checkpoint inhibitors is critical to treatment selection for patients with PUC. Currently, there is conflicting data on how E-cadherin loss and the resulting downstream signaling pathways may impact immunotherapy response.10,11 Alternatively, targeted therapy counteracting E-cadherin loss or EMT pathway activation offers a promising opportunity to explore in future drug development and clinical trials.

Exciting advances in our understanding of PUC biology have started to provide insight into pathways promoting its aggressive behavior. Next steps involve further interrogating the interplay between E-cadherin loss, other aberrant pathways present in UC, and the bladder cancer microenvironment. Knowledge gained in these translational studies can inform future multi-site clinical trials evaluating the impact of immunotherapy or targeted therapy in PUC.

Written by: Kathryn H. Gessner, MD, PhD1 and Marc A. Bjurlin, DO, MSc1,2

  1. University of North Carolina Department of Urology, Chapel Hill, NC
  2. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, NC
References:

  1. Cockerill PA, Cheville JC, Boorjian SA, et al. Outcomes Following Radical Cystectomy for Plasmacytoid Urothelial Carcinoma: Defining the Need for Improved Local Cancer Control. Urology. 2017;102:143-147.
  2. Diamantopoulos LN, Khaki AR, Grivas P, et al. Plasmacytoid Urothelial Carcinoma: Response to Chemotherapy and Oncologic Outcomes. Bladder Cancer. 2020;6(1):71-81.
  3. Weiss K, Gessner KH, Demzik A, et al. Molecular characterization of plasmacytoid urothelial carcinoma and the impact on treatment implications. Cancer Treat Res Commun. 2023;37:100779.
  4. Teo MY, Al-Ahmadie H, Seier K, et al. Natural history, response to systemic therapy, and genomic landscape of plasmacytoid urothelial carcinoma. Brit J Cancer. 2021;124(7):1214-1221.
  5. Ricardo-Gonzalez RR, Nguyen M, Gokden N, Sangoi AR, Presti JC, McKenney JK. Plasmacytoid Carcinoma of the Bladder: A Urothelial Carcinoma Variant With a Predilection for Intraperitoneal Spread. J Urology. 2012;187(3):852-855.
  6. Shimada K, Nakamura M, Ishida E, Konishi N. Urothelial carcinoma with plasmacytoid variants producing both human chorionic gonadotropin and carbohydrate antigen 19-9. Urology. 2006;68(4):891.e7-891.e10.
  7. Kossaï M, Radulescu C, Adam J, et al. Plasmacytoid urothelial carcinoma (UC) are luminal tumors with similar CD8+ Tcell density and PD-L1 protein expression on immune cells as compared to conventional UC. Urologic Oncol Seminars Orig Investigations. 2022;40(1):12.e1-12.e11.
  8. Gonzalez-Roibon ND, Chaux A, Al-Hussain T, et al. Dysregulation of mammalian target of rapamycin pathway in plasmacytoid variant of urothelial carcinoma of the urinary bladder. Hum Pathol. 2013;44(4):612-622.
  9. Hoffman-Censits JH, Lombardo KA, Parimi V, et al. Expression of Nectin-4 in Bladder Urothelial Carcinoma, in Morphologic Variants, and Nonurothelial Histotypes. Appl Immunohistochem Mol Morphol. 2021;29(8):619-625.
  10. Romeo E, Caserta CA, Rumio C, Marcucci F. The Vicious Cross-Talk between Tumor Cells with an EMT Phenotype and Cells of the Immune System. Cells. 2019;8(5):460.
  11. Spranger S, Bao R, Gajewski TF. Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature. 2015;523(7559):231-235.
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